Zinc for prevention and treatment of the common cold

Abstract

Background

The common cold is an acute, self‐limiting viral respiratory illness. Symptoms include nasal congestion and mucus discharge, sneezing, sore throat, cough, and general malaise. Given the frequency of colds, they are a public health burden and a significant cause of lost work productivity and school absenteeism. There are no established interventions to prevent colds or shorten their duration. However, zinc supplements are commonly recommended and taken for this purpose.

Objectives

To assess the effectiveness and safety of zinc for the prevention and treatment of the common cold.

Search methods

We searched CENTRAL, MEDLINE, Embase, CINAHL, and LILACS to 22 May 2023, and searched Web of Science Core Collection and two trials registries to 14 June 2023. We also used reference checking, citation searching, and contact with study authors to identify additional studies.

Selection criteria

We included randomised controlled trials (RCTs) in children or adults that tested any form of zinc against placebo to prevent or treat the common cold or upper respiratory infection (URTI). We excluded zinc interventions in which zinc was combined with other minerals, vitamins, or herbs (e.g. a multivitamin, or mineral supplement containing zinc).

Data collection and analysis

We used the Cochrane risk of bias tool to assess risks of bias, and GRADE to assess the certainty of the evidence. We independently extracted data. When necessary, we contacted study authors for additional information. We assessed zinc (type and route) with placebo in the prevention and treatment of the common cold. Primary outcomes included the proportion of participants developing colds (for analyses of prevention trials only), duration of cold (measured in days from start to resolution of the cold), adverse events potentially due to zinc supplements (e.g. unpleasant taste, loss of smell, vomiting, stomach cramps, and diarrhoea), and adverse events considered to be potential complications of the common cold (e.g. respiratory bacterial infections).

Main results

We included 34 studies (15 prevention, 19 treatment) involving 8526 participants. Twenty‐two studies were conducted on adults and 12 studies were conducted on children. Most trials were conducted in the USA (n = 18), followed by India, Indonesia, Iran, and Turkey (two studies each), and Australia, Burkina Faso, Colombia, Denmark, Finland, Tanzania, Thailand, and the UK (one study each). The 15 prevention studies identified the condition as either common cold (n = 8) or URTI (n = 7). However, almost all therapeutic studies (17/19) focused on the common cold. Most studies (17/34) evaluated the effectiveness of zinc administered as lozenges (3 prevention; 14 treatment) in acetate, gluconate, and orotate forms; gluconate lozenges were the most common (9/17). Zinc gluconate was given at doses between 45 and 276 mg/day for between 4.5 and 21 days. Five (5/17) lozenge studies gave acetate lozenges and two (2/17) gave both acetate and gluconate lozenges. One (1/17) lozenge study administered intranasal (gluconate) and lozenge (orotate) zinc in tandem for cold treatment. Of the 17/34 studies that did not use lozenges, 1/17 gave capsules, 3/17 administered dissolved powders, 5/17 gave tablets, 4/17 used syrups, and 4/17 used intranasal administration. Most studies were at unclear or high risk of bias in at least one domain.

There may be little or no reduction in the risk of developing a cold with zinc compared to placebo (risk ratio (RR) 0.93, 95% CI 0.85 to 1.01; I² = 20%; 9 studies, 1449 participants; low‐certainty evidence). There may be little or no reduction in the mean number of colds that occur over five to 18 months of follow‐up (mean difference (MD) ‐0.90, 95% CI ‐1.93 to 0.12; I² = 96%; 2 studies, 1284 participants; low‐certainty evidence). When colds occur, there is probably little or no difference in the duration of colds in days (MD ‐0.63, 95% CI ‐1.29 to 0.04; I² = 77%; 3 studies, 740 participants; moderate‐certainty evidence), and there may be little or no difference in global symptom severity (standardised mean difference (SMD) 0.04, 95% CI ‐0.35 to 0.43; I² = 0%; 2 studies, 101 participants; low‐certainty evidence).

When zinc is used for cold treatment, there may be a reduction in the mean duration of the cold in days (MD ‐2.37, 95% CI ‐4.21 to ‐0.53; I² = 97%; 8 studies, 972 participants; low‐certainty evidence), although it is uncertain whether there is a reduction in the risk of having an ongoing cold at the end of follow‐up (RR 0.52, 95% CI 0.21 to 1.27; I² = 65%; 5 studies, 357 participants; very low‐certainty evidence), or global symptom severity (SMD ‐0.03, 95% CI ‐0.56 to 0.50; I² = 78%; 2 studies, 261 participants; very low‐certainty evidence), and there may be little or no difference in the risk of a change in global symptom severity (RR 1.02, 95% CI 0.85 to 1.23; 1 study, 114 participants; low‐certainty evidence).

Thirty‐one studies reported non‐serious adverse events (2422 participants). It is uncertain whether there is a difference in the risk of adverse events with zinc used for cold prevention (RR 1.11, 95% CI 0.84 to 1.47; I² = 0%; 7 studies, 1517 participants; very low‐certainty evidence) or an increase in the risk of serious adverse events (RR 1.67, 95% CI 0.78 to 3.57; I² = 0%; 3 studies, 1563 participants; low‐certainty evidence). There is probably an increase in the risk of non‐serious adverse events when zinc is used for cold treatment (RR 1.34, 95% CI 1.15 to 1.55; I² = 44%; 2084 participants, 16 studies; moderate‐certainty evidence); no treatment study provided information on serious adverse events. No study provided clear information about adverse events considered to be potential complications of the common cold.

Authors' conclusions

The findings suggest that zinc supplementation may have little or no effect on the prevention of colds but may reduce the duration of ongoing colds, with an increase in non‐serious adverse events. Overall, there was wide variation in interventions (including concomitant therapy) and outcomes across the studies, as well as incomplete reporting of several domains, which should be considered when making conclusions about the efficacy of zinc for the common cold.

Plain language summary

Zinc for the prevention and treatment of the common cold

Key messages
‐ There may be little or no reduction in the risk of developing a cold with zinc supplements compared to placebo.

‐ For people who already have a cold, there may be a reduction in how long the cold lasts with zinc supplements compared to placebo.

‐ There is probably an increase in the risk of non‐serious adverse events when zinc is used for cold treatment.

What is the common cold?
The common cold is primarily a viral infection of the upper respiratory tract. There is no specific combination of symptoms that defines a cold, but symptoms can include nasal congestion, sneezing, sore throat, cough, fatigue, and runny nose, with or without fever. Most people usually recover from this illness without medical treatment; however, there are no definitive treatments to prevent colds or shorten their duration. Given the frequency of colds in adults and children, they are a public health burden and a significant cause of lost work productivity and school absenteeism. Prevention and treatment for the common cold with zinc is an ongoing interest.

What did we want to find out? 
We wanted to find out if zinc was better than placebo at reducing the risk of developing a cold and shortening the duration of existing colds. A placebo is a substance similar in appearance to a treatment, but that has no known therapeutic effect. Placebos help assess the effects of the belief that a treatment has been received versus treatment actually being received.

We also wanted to find out if zinc was associated with any adverse effects (e.g. harms), especially harms considered to be potential complications of the common cold. Additionally, we looked at self‐reported overall cold severity, individual symptom severity, individual symptom duration, and days missed from work or school.

What did we do?
We searched six databases and two clinical trials registers for studies comparing zinc with placebo for the treatment or prevention of the common cold in adults and children. We compared and summarised the results of the studies, and we found and rated our confidence in the evidence based on specific factors such as risk of bias and study methods.

What did we find?
We found 34 studies of cold prevention or treatment. The studies were conducted in 13 countries, a majority taking place in the USA. Twelve studies were conducted on children (aged under 18 years) and 22 studies were conducted on adults. Most treatments ended with self‐reported resolution of symptoms, and the minimum treatment period was five days with a maximum period of 540 days. Most of the studies were funded by an organisation with ties to related commerce/industry or did not report their funding. The remainder were funded by private clinics, non‐government foundations, universities, or governmental entities.

We assessed the effects of:

‐ zinc as a preventative measure; and

‐ zinc as a treatment measure.

We obtained the following results:

Zinc for prevention

Compared with placebo, taking zinc may make little to no difference in preventing people from catching a cold (9 studies, 1449 people). Preventative zinc also probably makes little to no difference to the length of the cold if one has been caught (3 studies, 740 participants) and may make little to no difference to the severity of the symptoms experienced (2 studies, 101 people). Negative side effects were reported by people taking either zinc or placebo; irregularities in taste and stomach upset were the most common.

Zinc for treatment

Zinc taken for treatment of a cold may reduce the length of time that symptoms are present, by approximately two days, when compared with placebo (8 studies, 972 people). However, we have little confidence in the evidence supporting this conclusion. It is unclear whether zinc makes a difference to the severity of the cold symptoms experienced (2 studies, 261 people). Negative side effects were reported more frequently for those taking zinc as a cold treatment when compared to those taking placebo; irregularities in taste and stomach upset were the most common. Studies administering intranasal zinc did not report any cases of anosmia (loss of sense of smell) but information about specific side effects is uncertain.

What are the limitations of the evidence?
Our confidence in the evidence is mostly low to very low, and the results of further research could differ from the results of this review. Several factors reduced our confidence in the evidence. Firstly, some studies did not report adequately on how people in the studies were randomly placed into treatment groups, meaning that differences between the study groups could be due to differences between the participants and not the treatments. Secondly, some studies used widely different ways of delivering treatments. Finally, due to the large differences between studies in the approaches used to test the effectiveness of zinc, it is likely that additional studies are required before any firm conclusions can be drawn.

How up‐to‐date is this evidence?
The evidence is current to 22 May 2023.

Summary of findings

Summary of findings 1. Zinc compared to placebo for prevention of the common cold.

Patient or population: adults and children without colds Setting: community settings Intervention: zinc Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Effect (95% CI)	No. of participants (studies)	GRADE certainty of evidence	Comments
	Assumed risk	Corresponding risk
	Placebo	Zinc
Proportion of participants developing a cold Duration of follow‐up: 5 days to 7 months	635 per 1000	591 per 1000 (540 to 641)	RR 0.93 (0.85 to 1.01)	1449 (9 studies)	⊕⊕◯◯ Lowa	There may be little or no difference in the risk of developing a cold with zinc.
Mean number of colds developed Duration of follow‐up: 5 to 18 months	Mean number of colds developed in control groups ranged from 3.15 to 3.76	The mean number of colds developed in intervention groups was on average 0.90 lower (95% CI ‐1.93 to 0.12)	—	1284 (2 studies)	⊕⊕◯◯ Lowb	Zinc may lead to little or no reduction in the number of colds over 5 to 18 months of follow‐up.
Mean duration of colds in days Duration of follow‐up: 1 to 7 months	Mean duration of colds in control groups ranged from 2.1 to 4.5 days	The mean duration of colds in days in the intervention groups was on average ‐0.63 lower (95% CI ‐1.29 to 0.04)	—	740 (3 studies)	⊕⊕⊕◯ Moderatec	There is probably little or no difference in the mean duration of colds when they occur.
Standardised mean global symptom severity Duration of follow‐up: 5 days	—	The standardised mean global symptom severity score in the intervention groups was on average 0.04 lower (95% CI ‐0.35 to 0.43)	—	101 (2 studies)	⊕⊕◯◯ Lowd	There may be little or no difference in the global symptom severity of colds when they occur.
Risk of adverse events, including those that may be due to zinc supplements Duration of follow‐up: 5 days to 7 months	80 per 1000	89 per 1000 (68 to 118)	RR 1.11 (0.84 to 1.47)	1517 (7 studies)	⊕◯◯◯ Very lowe	It is uncertain whether there is a difference in the risk of non‐serious adverse events with zinc and placebo.
Risk of serious adverse events, including those that may be complications of the common cold Duration of follow‐up: 5 days to 18 months	13 per 1000	21 per 1000 (10 to 45)	RR 1.67 (0.78 to 3.57)	1563 (3 studies)	⊕⊕◯◯ Lowf	Only 3 studies reported serious adverse events and 2 studies reported that events had occurred. There may be no clear difference between zinc and placebo in the risk of having a serious adverse event.
*The basis for the assumed risk for ‘Study population’ was the average risk in the control groups (i.e. total number of participants with events divided by total number of participants included in the meta‐analysis). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; MD: mean difference; SMD: standardised mean difference
GRADE Working Group grades of evidence High‐certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate‐certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low‐certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low‐certainty: We are very uncertain about the estimate.

^aDowngraded two levels due to serious risk of bias.
^bDowngraded one level due to risk of bias and one level due to inconsistency (I² > 50%).
^cDowngraded one level due to inconsistency (I² > 50%).
^dDowngraded one level due to risk of bias and one level due to imprecision (total n < 400).
^eDowngraded one level due to risk of bias and two levels due to imprecision (total events < 300 and CI includes no effect and an important effect).
^fDowngraded two levels due to serious imprecision (total events < 300 and CI includes no effect and an important effect).

Summary of findings 2. Zinc compared to placebo for treatment of the common cold.

Patient or population: adults and children with colds and/or upper respiratory infections Setting: community, schools, outpatient and private health centre/clinics Intervention: zinc Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Effect (95% CI)	No. of participants (studies)	GRADE certainty of evidence	Comments
	Assumed risk	Corresponding risk
	Placebo	Zinc
Mean duration of colds in days Duration of follow‐up: 8 to 21 days	Mean duration of colds in control groups ranged from 5.1 to 9 days	The mean duration of colds in days in the intervention groups was on average 2.37 lower (95% CI ‐4.21 to ‐0.53)	—	972 (8 studies)	⊕⊕◯◯ Lowa	There may be a reduction in the duration of colds treated with zinc.
Risk of continuing colds at study end Duration of follow‐up: 5 to 18 days	229 per 1000	119 per 1000 (48 to 290)	RR 0.52 (0.21 to 1.27)	357 (5 studies)	⊕◯◯◯ Very lowb	It is uncertain whether there is a difference in the risk of having an ongoing cold at the end of study follow‐up.
Standardised mean global symptom severity Duration of follow‐up: 14 days	—	The standardised mean global symptom severity score in the intervention groups was on average ‐0.03 lower (95% CI ‐0.56 to 0.50)	—	261 (2 studies)	⊕◯◯◯ Very lowc	It is uncertain whether there is any difference in global symptom severity.
Proportion with improved global symptom severity Duration of follow‐up: 7 days	789 per 1000	805 per 1000 (671 to 971)	RR 1.02 (0.85 to 1.23)	114 (1 study)	⊕⊕◯◯ Lowd	There may be little or no difference in the risk of improved global symptom severity.
Risk of adverse events, including those that may be due to zinc supplements Duration of follow‐up: 5 to 21 days	360 per 1000	483 per 1000 (414 to 558)	RR 1.34 (1.15 to 1.55)	2084 (16 studies)	⊕⊕⊕◯ Moderatee	There is probably an increase in the risk of non‐serious adverse events.
Risk of serious adverse events, including those that may be complications of the common cold	—	—	—	—	—	No information in any study
*The basis for the assumed risk for ‘Study population’ was the average risk in the control groups (i.e. total number of participants with events divided by total number of participants included in the meta‐analysis). The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; MD: mean difference; SMD: standardised mean difference
GRADE Working Group grades of evidence High‐certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate‐certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low‐certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low‐certainty: We are very uncertain about the estimate.

^aDowngraded one level due to risk of bias and one level due to inconsistency (I² > 50%).
^bDowngraded one level due to risk of bias, one level due to inconsistency (I² > 50%), and one level due to imprecision (total events < 300).
^cDowngraded one level due to risk of bias, one level due to inconsistency (I² > 50%), and one level due to imprecision (n < 400).
^dDowngraded one level due to risk of bias and one level due to imprecision (total events < 300).
^eDowngraded one level due to risk of bias.

Background

Description of the condition

The common cold is an acute, self‐limiting respiratory illness characterised by several symptoms including nasal congestion, nasal mucus discharge, sneezing, sore throat, cough, and general malaise. The common cold is generally considered to be caused by viruses (e.g. some common rhinoviruses and coronaviruses). However, there is no minimum level or specific combination of symptoms that defines a cold, and viruses are often, but not always, detected in people exhibiting symptoms (Mäkelä 1998). The most bothersome symptoms of a cold may be sore throat on the first day, followed by nasal congestion and then cough on the following days (Witek 2015). These symptoms overlap with other conditions such as allergies, tonsillitis, and lower respiratory tract infection. Therefore, the diagnosis is partly one of exclusion and is generally based on a global clinical assessment by the patient or a healthcare provider. Whilst colds are generally limited in severity and duration, and do not lead to serious health outcomes such as hospitalisation, they do occur frequently at any time of year, and everyone is vulnerable to colds. It is estimated that children average between six and 10 colds per year, whilst adults average between two and four colds per year, thus the common cold is a public health burden (IQWiG 2020). Colds impact daily life and are a major cause of lost work productivity and school absenteeism (Dicpinigaitis 2015).

Description of the intervention

Zinc is an essential trace mineral for which the human body has no specialised storage mechanism (Rink 2000). Regular intake of small amounts is therefore necessary for the maintenance of health and optimal physiological functioning. Zinc is naturally present in some foods (e.g. red meat), is sometimes added to other foods (e.g. zinc‐fortified cereals), and may be taken as an over‐the‐counter dietary supplement. According to the US Institute of Medicine (IOM), the Recommended Dietary Allowance (RDA) for adults is 8 mg/day for women and 11 mg/day for men, whilst the Tolerable Upper Intake Level (UL) for adults is 40 mg/day (IOM 2001). The World Health Organization (WHO) estimates that 31% of the world's population is at risk for zinc deficiency, a percentage that ranges between 4% and 73% in different regions of the world and is higher in low‐income countries (Caulfield 2004). People who eat vegetarian or vegan diets, the elderly, and people who suffer from conditions causing poor zinc absorption or high zinc loss are also at risk (Maares 2020). The consequences of severe, moderate, and even marginal zinc deficiency are seen in multiple body systems, including immune function (Prasad 2020).

Zinc supplements exist in several forms, including zinc gluconate, zinc sulfate, zinc acetate, zinc carnosine, and zinc picolinate, which vary in percentage of elemental zinc. The bioavailability of zinc is affected by the form of zinc, whether zinc is included in a meal or alone as a supplement, and by zinc levels in the body (Maares 2020).

Whilst many people believe that zinc may be helpful in preventing or treating colds, there is currently no established intervention to prevent colds or to shorten their duration (IQWiG 2020). The risk of developing a cold can be reduced by avoiding contact with other people who have colds, and cold symptoms can be treated with over‐the‐counter medications such as non‐steroidal anti‐inflammatory drugs (NSAIDs), antihistamines, and decongestants, although these medications have potential side effects and contraindications (Harvard Health Letter 2014). The safety and efficacy of zinc for the prevention and treatment of colds is therefore of ongoing interest.

How the intervention might work

There are two main biologically plausible mechanisms for the potential effects of zinc on the common cold: 1) zinc may improve immune function (Maares 2016); and 2) zinc may interfere with the binding and replication of viruses involved in colds (Hulisz 2004; Read 2019). The mechanisms of zinc delivered by tablets, capsules, or syrups may differ from those of zinc delivered as lozenges (which are held and dissolved in the mouth, coating the tongue and throat) and those of zinc delivered as sprays or gels (which coat the nasal mucosa).

Why it is important to do this review

Given the frequency and impact of common colds (Dicpinigaitis 2015), reducing the incidence, duration, or severity of colds would benefit public health. Zinc is a popular supplement often recommended to reduce the duration of the common cold. However, uncertainty remains surrounding overall effectiveness, and the influence of different forms, dosages, and delivery methods on different populations. Meanwhile, there is concern about the potential for permanent anosmia from intranasal zinc (D'Cruze 2009). Several previous systematic reviews have investigated zinc for the treatment or prevention of the common cold (D'Cruze 2009; Hemilä 2011; Hemilä 2016; Hemilä 2017a; Hemilä 2017b; Jackson 1997; Moshtagh 2020; Science 2012; Wang 2020). However, Cochrane reviews on this topic are no longer current (Marshall 2007; Singh 2015). New randomised controlled trials (e.g. Hemilä 2020; Mandlik 2020) have been published since searching was conducted in the most recent systematic review (Wang 2020). It is important to incorporate the latest information about the potential benefits and harms of this popular intervention into a methodologically rigorous and up‐to‐date review of the evidence.

Objectives

To assess the effectiveness and safety of zinc for the prevention and treatment of the common cold.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) and excluded studies using quasi‐randomisation because they are susceptible to selection bias. We included studies in any language reported as full text, those published as abstracts only, and unpublished data.

Types of participants

We included studies on adults and children. To assess the prevention of the common cold, we included participants without a diagnosis of the common cold who are being followed to detect the development of the common cold and included both naturalistic studies and challenge studies of prevention. To assess the treatment of the common cold, we included participants with a clinical diagnosis of the common cold (i.e. acute viral rhinopharyngitis), either naturally or experimentally induced. We also included participants diagnosed with upper respiratory tract infections (URTIs) when we judged that such diagnoses could include the common cold. We excluded participants with diagnoses commonly resulting from other viruses (e.g. influenza) or commonly a result of bacterial infections (e.g. sinus infections). When studies contained only a subset of participants relevant to the review and that subset could be separated out, the data were included. In cases where the relevant subset's data were indiscernible, we described results narratively.

Types of interventions

We included trials comparing zinc interventions with placebo as well as zinc plus any other intervention versus placebo plus the same other intervention, so that the effect of zinc could be isolated. We included any form (e.g. zinc gluconate, zinc acetate, zinc citrate), delivery method (e.g. intranasal, tablet, lozenge), duration, and dose of zinc. We excluded zinc interventions in which zinc was combined with other minerals, vitamins, or herbs (e.g. a multivitamin, or mineral supplement containing zinc).

Types of outcome measures

We collected information on the outcomes listed below. We did not use the presence or absence of specific outcomes as eligibility criteria for the inclusion of studies.

Primary outcomes

1. Development of a cold (for analyses of prevention trials only), with colds as defined by each study. This outcome is measured in two ways:

   1. Proportion of participants developing colds/URTIs

   2. Mean number of colds/URTIs developed

2. Duration of cold (measured in days from start to resolution of the cold, as defined by each study).

   1. Mean duration of cold/URTI

   2. Proportion of participants with a cold/URTI at end of study

3. Adverse events, including those that may be due to zinc supplements (e.g. unpleasant taste).

4. Serious adverse events, including those that may be complications of the common cold (e.g. respiratory bacterial infections).

Secondary outcomes

1. Global severity of the cold using a global measure if available (e.g. visual analogue scale (VAS)), or by summing severity scores for individual symptoms.

2. Severity of individual cold symptoms (e.g. nasal congestion), measured on a scale.

3. Duration of individual cold symptoms (e.g. nasal congestion), measured in days from start to resolution of symptoms.

   1. Mean duration of individual cold/URTI symptoms

   2. Proportion of participants with a cold/URTI at end of study

4. Days missed from work or school.

   1. Proportion of participants missing from work or school

   2. Mean days missed from work or school

Search methods for identification of studies

Electronic searches

We searched the following databases on 22 May 2023:

1. The Cochrane Central Register of Controlled Trials (CENTRAL 2023, Issue 5), in the Cochrane Library.

2. MEDLINE (PubMed) (from 1946 to 22 May 2023).

3. Embase (Elsevier) (from 1947 to 22 May 2023).

4. CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCOhost) (from 1981 to 22 May 2023).

5. LILACS (Latin American and Caribbean Health Science Information database) (from 1985 to 22 May 2023).

We searched the Web of Science Core Collection (Clarivate Analytics) on 14 June 2023:

1. Science Citation Index Expanded (SCI‐EXPANDED) (from 1900 to 14 June 2023).

2. Social Sciences Citation Index (SSCI) (from 1900 to 14 June 2023).

3. Arts & Humanities Citation Index (AHCI) (from 1975 to 14 June 2023)

4. Conference Proceedings Citation Index ‐ Science (CPCI‐S) (from 1994 to 14 June 2023).

5. Conference Proceedings Citation Index ‐ Social Science & Humanities (CPCI‐SSH) (from 1994 to 14 June 2023).

6. Book Citation Index ‐ Science (BKCI‐S) (from 2005 to 14 June 2023)

7. Book Citation Index ‐ Social Sciences and Humanities (BKCI‐SSH) (from 2005 to 14 June 2023)

8. Emerging Sources Citation Index (ESCI) (from 2005 to 14 June 2023).

9. Current Chemical Reactions (CCR‐EXPANDED) (from 1985 to 14 June 2023).

10. Index Chemicus (IC) (from 1993 to 14 June 2023).

We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for randomised trials: sensitivity and precision‐maximising version (2008 revision) (Lefebvre 2023).

We also conducted a search of ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (apps.who.int/trialsearch/) on 14 June 2023. We did not impose any language or publication restrictions.

Searching other resources

We checked the reference lists of all relevant review articles identified through our electronic searches for additional studies and checked reference lists of all primary studies for additional references. We contacted experts in the field to identify any additional unpublished material.

Data collection and analysis

We used the Cochrane risk of bias tool to assess risks of bias, and GRADE to assess the certainty of the evidence. Review authors independently extracted data. We assessed zinc (type and route) compared with placebo in prevention and treatment of the common cold. Our primary outcomes were the proportion of participants developing colds (for analyses of prevention trials only), duration of cold, adverse effects potentially due to zinc supplements, and adverse events considered to be potential complications of the common cold. Secondary outcomes included global severity of the cold, severity of individual cold symptoms, duration of individual cold symptoms, and days missed from work or school.

Selection of studies

Two review authors (DN, DA, or LSW) independently screened the titles and abstracts of all studies identified as a result of the searches for inclusion in the review. We retrieved the full‐text study reports/publications for those studies deemed relevant based on the title and abstract, and two review authors (DN, DA, or LSW) independently and in duplicate screened the full texts and identified studies for inclusion based on the a priori defined eligibility criteria, and identified and recorded reasons for exclusion of the ineligible studies. We resolved any disagreements through discussion or by consulting a third review author (DN, DA, or LSW) if necessary. If information about relevant inclusion and exclusion criteria in the study report was unclear, we attempted to contact study authors for clarification. We identified and excluded duplicates, and collated multiple reports of the same study so that each study, rather than each report, was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram and Characteristics of excluded studies table (Moher 2009).

Data extraction and management

We used a data collection form for study characteristics and outcome data, which was piloted on at least one study in the review. One review author (DN, DA, SN, TM, or LSW) extracted study characteristics from the included studies. We extracted the following study characteristics.

1. Methods: study design, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals, and date of study.

2. Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria for the common cold, baseline zinc status and how this was measured, smoking history, and inclusion and exclusion criteria.

3. Interventions: intervention, comparison, concomitant medications, and excluded medications.

4. Outcomes: primary and secondary outcomes specified and collected, and time points reported.

5. Notes: funding for trial and notable conflicts of interest of trial authors.

Two review authors (DN, LSW or TM) independently and in duplicate extracted outcome data from the included studies. We noted in the 'Study characteristics' table (see Table 3) if outcome data were not reported in a useable way. We resolved any disagreements by consensus or by involving a third review author (SN, EP, or MK). One review author (DN) transferred data into the Review Manager Web file (RevMan Web 2020). We double‐checked that data were entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (SN or EP) spot‐checked study characteristics for accuracy against the trial report.

1. Study characteristics.

First author	Year	Trial type	Country	Setting	Age (mean (SD))	Gender (% female)	Total participants	Natural or challenge cold acquisition	Notes
Al‐Nakib	1987	Prevention	UK	Community	30.49	47.0%	57	Human rhinovirus‐2	Treatment portion was included in publication, but data were not appropriate for analysis. Prevention data included in quantitative analysis, treatment data reported narratively.
Belongia	2001	Treatment	USA	Clinic/medical centre	39 (11)	86.3%	160	Natural, for 24 hours or less	—
Caesar	2012	Treatment	Indonesia	Community	3 to 5 years (mean not reported)	55.0%	114	Natural, for 10 days or less	—
Douglas	1987	Treatment	Australia	Community	33.0 (NR) years	54.0%	58 users/63 courses	Natural, for 2 days or less	Narratively reported due to lack of adequate/appropriate data for outcomes.
Eby	1984	Treatment	USA	Community	36.6 (13.96)	46.0%	65	Natural, no limit on length Pre‐treatment duration shows up to 3 days	—
Eby	2006	Treatment	USA	Clinic/medical centre	38 (9 to 66)	33.0%	33	Natural, no limit on length Pretreatment duration shows up to 3 days	—
Farr (trial 1)	1987	Prevention	USA	Community	21.0 (2.2) years	56.0%	32	Rhinovirus type 39	—
Farr (trial 2)	1987	Prevention	USA	Community	21.1 (2.3)	46.0%	41	Rhinovirus type 13	Participants were challenged with virus, began prophylaxis 2 hours later, and were followed for development of a clinical cold.
Godfrey	1992	Treatment	USA	Clinic/medical centre	Range 18 to 40 years	40.0%	73	Natural, for 2 days or less	—
Hemilä	2020	Treatment	Finland	Community	47 (9.5)	90.0%	87	Natural, upon first symptom appearance	—
Hirt	2000	Treatment	USA	Community	Adults	NR	213	Natural, for 24 hours or less	Age distribution not given but appears to be adults.
Kartasurya	2012	Prevention	Indonesia	Clinic/medical centre	3.52	86.2%	826	Natural, presence of 2 symptoms	—
Kurugöl	2006	Prevention	Turkey	Community	5.6 (2.8) years	50.5%	200	Natural, presence of 2 symptoms	With temporarily increased zinc dosage in cases where colds developed.
Kurugöl	2007	Treatment	Turkey	Clinic/medical centre	Median 5.2 (IQR 1 to 10)	49.0%	120	Natural, for 48 hours or less	Narratively reported due to inconsistent outcome reporting.
Macknin	1998	Treatment	USA	Community	11.67 (7.5)	52.2%	249	Natural, for 24 hours or less	—
Malik	2014	Prevention	India	Community	8.77 (1.80)	50.4%	272	Natural, presence of cough/cold without fever	Narratively reported (other than serious side effects) due to instances of unclear denominators and because it would be inappropriate to combine adjusted incidence rate ratio data with results from studies assessing the risk of any cold.
Mandlik	2020	Prevention	India	Community	7.9 (1.1)	46.0%	243	Natural, as reported by survey	Some aspects of treatment present; narratively reported due to clustering not being accounted for in the analysis.
McDonald	2015	Prevention	Tanzania	Community	5.9 (0.4) weeks	50.9%	1200	Natural, pharyngitis or rhinitis	—
Mossad	1996	Treatment	USA	Clinic/medical centre	37.7 (8.4)	81.0%	99	Natural, for 24 hours or less	—
Mossad	2003	Treatment	USA	Community	29.5 (14)	62.8%	78	Natural, for 24 to 48 hours	—
Petrus	1998	Treatment	USA	Community	26.5 (1.3)	53.0%	102	Natural, presence of 2 symptoms	—
Pooya	2006	Prevention	Iran	Military	Adults	NR	59	Natural, as reported by surveillance	Age distribution not given but was conducted in soldiers. Treatment portion was included in publication, but data were not appropriate for analysis. Prevention data included in quantitative analysis, treatment data reported narratively.
Prasad	2000	Treatment	USA	Medical centre	37.1 (10.9)	62.5%	48	Natural, for 24 hours or less	—
Prasad	2007	Prevention	USA	Community	66 (8)	67.0%	50	Natural, following practice guidelines for evaluation of infections	—
Prasad	2008	Treatment	USA	Clinic/medical centre	35.2 (13.6)	68.0%	50	Natural, for 24 hours or less	—
Rerksuppaphol	2013	Prevention	Thailand	Community	10.7 (0.97)	44.0%	100	Natural, presence of any symptoms	—
Sánchez	2014	Prevention	Colombia	Community	3.31 (0.81)	47.9%	301	Natural, presence of 2 symptoms	Narratively reported due to clustering not being accounted for in the analysis.
Smith	1989	Treatment	USA	Outpatient/ community	> 18 years	NR	174	Natural, clinical diagnosis of URI at entry	Participants recruited from among college students and one family practice and there is no indication that children were included. Narratively reported due to inconsistent outcome reporting.
Somé	2015	Prevention	Burkina Faso	Community	9.4 months (range 8.7 to 10.7, SD = 0.4)	49.5%	2435	Natural, cough and nasal discharge	Narratively reported due to lack of adequate/appropriate data for outcomes.
Turner (challenge)	2000	Treatment	USA	Research centre	18 to 65 years	NR	272	Rhinovirus type 39	Participants were randomised to 5 mg zinc acetate, 11.5 mg zinc acetate, 4.9 mg zinc gluconate, or placebo. Data were presented in such a way that only adverse events could be extracted.
Turner (natural)	2000	Treatment	USA	Research centre	18 to 65 years	NR	279	Natural, for 36 hours or less	Participants were randomised to 5 mg zinc acetate, 11.5 mg zinc acetate, 4.9 mg zinc gluconate, or placebo.
Turner	2001	Prevention	USA	Community	> 18 years	NR	91	Rhinovirus type 23 and 39	5‐day window where treatment might also be considered.
Vakili	2009	Prevention	Iran	Community	78 to 120 months	50.0%	200	Natural, presence of 2 symptoms	—
Weismann	1990	Treatment	Denmark	Community	18 to 65 years	NR	145	Natural, upon first symptom appearance	Age distribution not given but no indication that any children were included. Narratively reported (other than side effects) due to lack of adequate/appropriate data for other outcomes.

IQR: interquartile range
NR: specifics not reported
SD: standard deviation
URI: upper respiratory infection

Assessment of risk of bias in included studies

Two review authors (DN, LSW) independently and in duplicate assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). We resolved any disagreements by discussion or by involving another review author (MK or SN). We assessed risk of bias according to the following domains.

1. Random sequence generation.

2. Allocation concealment.

3. Blinding of participants and personnel.

4. Blinding of outcome assessment.

5. Incomplete outcome data.

6. Selective outcome reporting.

7. Other bias.

We rated each potential source of bias as low, high, or unclear, and provided a quote from the study report together with a justification for our judgement in the risk of bias table. We summarised the risk of bias judgements across different studies for each of the domains listed. We considered blinding and incomplete outcome data separately for different key outcomes where necessary. Where information on risk of bias related to unpublished data or correspondence with a trialist, we noted this in the risk of bias table.

When considering treatment effects, we took into account the risk of bias for the studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to our published protocol (Wieland 2021) and reported any deviations from it in the Differences between protocol and review section of this review.

Measures of treatment effect

We entered the outcome data for each study into the data tables in Review Manager Web to calculate the treatment effects (RevMan Web 2020). We used risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes on the same scale. For continuous outcomes where different scales measure the same underlying construct (e.g. severity of a symptom), we used standardised mean differences (SMD). A conventional interpretation of the SMD is that 0.2 corresponds to a small effect, 0.5 to a moderate effect, and 0.8 to a large effect (Cohen 1988). We reported 95% confidence intervals (CI) for all effects.

We undertook meta‐analyses only where meaningful, that is, if the treatments, participants, and the underlying clinical question(s) were similar enough for pooling to make sense. Because the likely mechanisms and potential adverse effects of oral and intranasal zinc differ, we analysed trials of oral zinc (including tablets, capsules, syrups, or lozenges) separately from trials of intranasal zinc (including sprays or gels). If statistical pooling was not appropriate, we produced a narrative summary.

Unit of analysis issues

We did not find relevant cross‐over studies, but we did find one study with a parallel, randomised, single‐case experimental design (Douglas 1987) and three cluster‐randomised trials (Mandlik 2020; Sánchez 2014; Somé 2015). We followed the guidance in Chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019) and the instructions of our statistician co‐author (MK) and chose to discuss each of these studies narratively instead of extracting data for analysis. For multi‐arm studies that required division into arms for subgroup analysis, the total size of the placebo group was also divided to avoid double counting (Turner 2000 challenge; Turner 2000 natural).

Dealing with missing data

We contacted investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome data where possible (e.g. when a study was identified as abstract only). We noted all attempts to contact trialists, and the results of these attempts, in the Characteristics of included studies table for that study. If numerical outcome data were missing, such as standard deviations (SD) or correlation coefficients, and we were unable to obtain these from the trial authors, we calculated them from other available statistics, such as P values, according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). If these values could not be estimated, we discussed the impact of the missing data in the Discussion section.

For each outcome, we conducted our analyses to the greatest degree possible using the intention‐to‐treat (ITT) principle. We defined the denominator as the number randomised minus any participants whose outcome was known to be missing. We identified the levels of attrition, and explored the impact of excluding studies with attrition of 20% or greater on the overall assessment of results by a sensitivity analysis.

Assessment of heterogeneity

We assessed and measured the presence and extent of between‐study variation (heterogeneity) in each meta‐analysis (Higgins 2019). We used the Chi² test to assess whether the observed variation between effect estimates was compatible with chance alone (P < 0.10), and the I² statistic to describe the percentage of the variability in effect estimates due to heterogeneity rather than chance. We considered an I² statistic of 50% or higher as indicative of substantial heterogeneity. We recognise that the I² measurement must be interpreted in the context of the size and direction of effect estimates and the evidence of the existence of heterogeneity, and that there is uncertainty in the I² measurement when there are few studies in a meta‐analysis (Higgins 2019). We report any substantial heterogeneity and explore possible causes for it by prespecified subgroup analysis.

Assessment of reporting biases

We created and examined a funnel plot to explore possible small‐study and publication biases when analyses contained a minimum of 10 studies. We investigated discrepancies between reporting in studies and their corresponding protocols as a source of publication bias.

Data synthesis

We pooled data from studies that we judged to be clinically homogeneous using Review Manager Web software (RevMan Web 2020). We performed a meta‐analysis if more than one study provided useable data for any single comparison. For analyses in which a single time point was present, we used the random‐effects model to carry out meta‐analyses due to expected variation in participants, settings, interventions, and measurement of outcomes, such that a fixed‐effect model would not be appropriate.

Subgroup analysis and investigation of heterogeneity

We considered the following factors to be potential causes of heterogeneity in the effects of the intervention: formulation, form, and dose of the zinc intervention; the presence of intervention components that may reduce the bioavailability of zinc; the presence of zinc deficiency amongst participants; and the age (children, adults, elderly) of participants. We planned to carry out the following subgroup analyses for the primary outcomes in the case of sufficient data:

1. different oral formulations of product (i.e. syrup versus capsules or tablets versus lozenges);

2. different administration/absorption routes (e.g. mucosal versus systemic);

3. different forms of zinc (e.g. zinc gluconate, zinc acetate, zinc citrate);

4. different doses of zinc (e.g. < 75 mg versus 75 mg or higher);

5. zinc interventions with and without components that are thought to potentially reduce bioavailability of zinc (e.g. mannitol or sorbitol, citric acid);

6. different participant age groups (e.g. age < 18, adults 18 to 65, age > 65); and

7. participants with and without zinc deficiency at baseline.

We presented a forest plot and used the Chi² test to test for subgroup interactions in Review Manager Web when there were at least 10 trials overall and at least two trials in each subgroup (Deeks 2023). In addition, we tested for subgroup interactions where the primary analysis had high heterogeneity (I² ≥ 50%) and there were at least eight trials overall with at least two trials in each subgroup.

Sensitivity analysis

We explored the robustness of effect estimates by carrying out the following sensitivity analyses, if sufficient data were available.

1. Excluding trials with high or unclear risk of selection bias (i.e. random sequence generation or allocation concealment, or both).

2. Excluding trials with 20% or greater attrition.

3. Using endpoint outcome data versus change outcome data.

4. Using adjusted outcome data versus unadjusted outcome data.

5. Excluding trials identifying outcome as upper respiratory tract infections versus common cold.

Summary of findings and assessment of the certainty of the evidence

We created a summary of findings table for cold prevention using the following outcomes.

• Proportion of participants developing a cold.

• Mean number of colds developed.

• Mean duration of colds.

• Mean severity of global symptoms.

• Number of adverse events, including those that may be due to zinc supplements.

• Number of serious adverse events, including those that may be complications of the common cold.

We created a separate summary of findings table for cold treatment using the following outcomes.

• Mean duration of colds.

• Number of colds by study end.

• Mean severity of global symptoms.

• Proportion of participants with improved symptoms.

• Number of adverse events, including those that may be due to zinc supplements.

• Number of serious adverse events, including those that may be complications of the common cold.

We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of a body of evidence as it relates to the studies that contributed data to the meta‐analyses for the prespecified outcomes (Atkins 2004). We assessed the certainty of evidence only for the primary analyses. Two authors (DA, LSW) used the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019), and reached consensus on the certainty of the evidence through discussion. We justified all decisions to down‐ or upgrade the certainty of evidence of studies using footnotes, and made comments to aid the reader's understanding of the review where necessary.

We described the overall strength of the evidence, implications for further research, clinical importance of the results, impact of contextual factors, and considerations of equity in summarising and discussing the results of the review.

Results

Description of studies

Results of the search

The searches of the databases and trials registers retrieved 1360 records (see Electronic searches). Reference screening included 818 records and expert recommendation suggested another 13 records. After deduplication, we screened a total of 1108 records.

We excluded 1034 records based on titles and abstracts. We obtained the full text of the remaining 74 records. We excluded 37 studies reported in 38 articles (see Characteristics of excluded studies table) and added four articles to awaiting classification (see Characteristics of studies awaiting classification table).

We included 34 studies reported in 32 articles (see Included studies). Though Al‐Nakib 1987 reported both a prevention and a treatment trial, it did not contain any data that could be used under treatment, and is therefore considered as a prevention trial for the purposes of this review. One article reported two treatment trials using zinc gluconate (Farr Trial 1 1987; Farr Trial 2 1987). A second article reported one treatment trial based on colds resulting from a rhinovirus challenge (Turner 2000 challenge), and one treatment trial based on naturally acquired colds (Turner 2000 natural); each of these trials compared zinc acetate and zinc gluconate to placebo. For further description of our screening process, see Figure 1 for the study flow diagram.

1.

Included studies

We included 34 studies with 6107 participants in 15 prevention studies and 2419 participants in 19 treatment studies. The 15 prevention‐focused studies identified the condition as the common cold (n = 8) or an upper respiratory tract infection (URTI) (n = 7), while almost all treatment studies (17/19) identified the condition as a common cold.

Participants

Twenty‐two studies included adult participants (≥ 18 years), with 16/22 of these being treatment studies (Belongia 2001; Douglas 1987; Eby 1984; Eby 2006; Godfrey 1992; Hemilä 2020; Hirt 2000; Mossad 1996; Mossad 2003; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Turner 2000 challenge; Turner 2000 natural; Weismann 1990). One prevention study focused on elderly participants (Prasad 2007). Of the studies including participants who were minors (n = 12), 9/12 were prevention focused (Kartasurya 2012; Kurugöl 2006; Malik 2014; Mandlik 2020; McDonald 2015; Rerksuppaphol 2013; Sánchez 2014; Somé 2015; Vakili 2009). On average, 56% of participants included identified as female, ranging from 33% to 90%. Of the 10 studies that reported on zinc deficiency/sufficiency in participants, three studies indicated participants were deficient (Kartasurya 2012; Mandlik 2020; Somé 2015), one study reported that approximately 35% of participants were deficient (Prasad 2007), and six studies contained participants that were zinc sufficient (Al‐Nakib 1987; Farr Trial 1 1987; Farr Trial 2 1987; Kurugöl 2006; Kurugöl 2007; Macknin 1998). Demographics for each study are summarised in Table 3.

Settings

The majority of studies took place in the United States with 18 studies and a total of 2109 participants. India, Indonesia, Iran, and Turkey had two studies each with a total of 2363 participants. There was one study from Australia with 58 participants, Burkina Faso with 2435 participants, Colombia with 301 participants, Denmark with 145 participants, Finland with 87 participants, Tanzania with 1200 participants, Thailand with 100 participants, and the UK with 57 participants. Studies conducted in Africa and Australia took place entirely in community settings. European and South American studies incorporated community and clinic/medical centre settings. Finally, Asian and North American studies varied from community and clinic/medical centres to research centres/outpatient and military settings. Settings for each study are summarised in Table 3.

Interventions

Fifteen studies evaluated the effectiveness of the interventions for prevention and 19 for treatment. Nineteen of the studies in total assessed adherence to the intervention. Interventions are briefly described here and are summarised in Table 4 and Table 5.

2. Characteristics of interventions.

Study identifier	Zinc form(s)	Administration	Zinc per administration	Doses per day	Approximate zinc dose per day*	Duration of intervention	Concomitant treatments explicitly allowed	Ability to distinguish between zinc and control assessed?	Adherence assessment
Treatment trials
Belongia 2001	Sulfate	Intranasal	0.00275 mg/spray (0.011 mg/dose)	2 x sprays per nostril 4 x per day (8 total doses per day)	0.044 mg/d	Resolution of symptoms OR up to 14 days	Fever‐reducer allowed; all others forbidden	Yes	Assessed
Caesar 2012	NR	Powder	20 mg/powder dose	1 x powder dose per day	20 mg/d	7 days	Fever‐reducer	NR	Assessed
Douglas 1987	Acetate	Lozenge	10 mg/lozenge	1 x lozenge every 2 hours; 6 to 8 per day total	60 to 80 mg/d	Minimum of 3 days and up to 6 days if symptoms continued	NR	Yes	Assessed
Eby 1984	Gluconate	Lozenge	23 mg/tablet	Adults: 12 tablets per day (1 x every 2 hours); youths: 9 tablets per day (1 x every 2 hours); children: 6 tablets per day (0.5 x every 2 hours)	Adults: 12/day x 23 mg = 276 mg; youths: 9/day x 23 mg = 207 mg; children: 6/day x 23 mg = 138 mg	Resolution of symptoms OR up to 7 days	Forbidden	NR	Not assessed/unknown
Eby 2006	Orotate Gluconate	Lozenge Intranasal	37 mg/lozenge 10 mmol concentration/spray	1 x lozenge every 2 to 3 hours awake 2 to 3 x sprays per nostril (4 to 6 sprays total) every 15 to 30 mins awake	Lozenge 296 mg/d Intranasal ~2 to 3 mg/d	Resolution of symptoms OR up to 7 days	NR	Yes	Assessed
Godfrey 1992	Gluconate	Lozenge	23.7 mg/lozenge	1 x lozenge every 2 hours; 8 per day max	189.6 mg/d	Minimum of 2 days and up to 8 days if symptoms continued	Fever‐reducer allowed; all others forbidden	Yes	Assessed
Hemilä 2020	Acetate	Lozenge	13 mg/lozenge	6 x lozenges per day	78 mg/d	5 days	No limitations	Yes	Assessed
Hirt 2000	Gluconate	Intranasal	33 mmol concentration/spray	1 x spray per nostril 4 x per day (8 total doses per day)	2.1 mg/d	Resolution of symptoms OR up to 16 days	Forbidden	NR	Not assessed/unknown
Kurugöl 2007	Sulfate	Syrup	15 mg/5 mL syrup dose	2 x 5 mL per day	30 mg/d	10 days	Fever‐reducer allowed; all others forbidden	Yes	Not assessed/unknown
Macknin 1998	Gluconate	Lozenge	10 mg/lozenge	3 x lozenges during school day; 2 x school night and 5 x lozenges per day on weekends (grades 1 to 6) OR 3 x school night and 6 x lozenges per day on weekends (grades 7 to 12)	50 to 60 mg/d	Resolution of symptoms OR up to 21 days	Forbidden	Yes	Assessed
Mossad 1996	Gluconate	Lozenge	13.3 mg/lozenge	1 x lozenge every 2 hours awake	106.4 mg/d	Resolution of symptoms OR up to 18 days	Fever‐reducer	Yes	Assessed
Mossad 2003	Gluconate	Intranasal	33 mmol concentration/spray	1 x spray per nostril 4 x per day (8 total doses per day)	2.1 mg/d	Resolution of symptoms OR up to 10 days	Fever‐reducer	Yes	Assessed
Petrus 1998	Acetate	Lozenge	9 mg/lozenge	1 x lozenge every 1.5 hours awake (day 0); 1 x lozenge every 2 hours awake thereafter	90 mg/d	Resolution of symptoms OR up to 14 days	Forbidden	Yes	Not assessed/unknown
Prasad 2000	Acetate	Lozenge	12.8 mg/lozenge	1 x lozenge every 2 to 3 hours awake	102.4 mg/d	Resolution of symptoms OR up to 12 days	Forbidden	Yes	Assessed
Prasad 2008	Acetate	Lozenge	13.3 mg/lozenge	1 x lozenge every 2 to 3 hours awake	106.4 mg/d	Resolution of symptoms OR up to 10 days	Forbidden	Yes	Assessed
Smith 1989	Gluconate	Lozenge	11.5 mg/lozenge	4 x lozenges first dose; 2 x lozenges every 2 hours awake thereafter	184 mg/d	Resolution of symptoms OR up to 7 days	Forbidden	Yes	Not assessed/unknown
Turner (challenge) 2000	Gluconate Acetate Acetate	Lozenge Lozenge Lozenge	13.3 mg/lozenge 11.5 mg/lozenge 5 mg/lozenge	1 x lozenge every 2 to 3 hours awake (6 x lozenges per day)	79.8 mg/d 69 mg/d 30 mg/d	Resolution of symptoms OR up to 14 days	NR	Yes	Not assessed/unknown
Turner (natural) 2000	Gluconate Acetate Acetate	Lozenges	13.3 mg/lozenge 11.5 mg/lozenge 5 mg/lozenge	1 x lozenge every 2 to 3 hours awake (6 x lozenges per day)	79.8 mg/d 69 mg/d 30 mg/d	Resolution of symptoms OR up to 14 days	NR	Yes	Not assessed/unknown
Weismann 1990	Gluconate	Lozenge	4.5 mg/lozenge	1 x lozenge every 1 to 1.5 hours awake (10 x lozenges per day)	45 mg/d	Resolution of symptoms OR up to 10 days	Forbidden	Unclear	Assessed
Prevention trials
Al‐Nakib 1987	Gluconate	Lozenge	23 mg/lozenge	1 x lozenge every 2 hours; up to 12 per day	276 mg/d	Prevention = 4.5 days; treatment = 6 days	NR	Yes	Not assessed/unknown
Farr (trial 1) 1987	Gluconate	Lozenge	23 mg/lozenge	2 x lozenges, first dose; 1 x lozenge after, every 2 hours awake; 8 lozenges per day	207 mg/d, day 1 and 184 mg/d thereafter	5 days	NR	Yes	Not assessed/unknown
Farr (trial 2) 1987	Gluconate	Lozenge	23 mg/lozenge	1 x lozenge, every 2 hours awake; 8 lozenges per day	184 mg/d	7 days	NR	Yes	Not assessed/unknown
Kartasurya 2012	NR	Syrup	10 mg/syrup dose	1 x dose per day	10 mg/d	60 days with zinc alone; vitamin A added for additional 60 days	NR	NR	Assessed
Kurugöl 2006	Sulfate	Syrup	15 mg/5 mL syrup dose	1 x 5 mL per day when well and 2 x 5 mL per day (30 mg) during colds	15 to 30 mg/d	210 days (7 months) and until resolution of symptoms and/or up to 10 days (when increased to 30 mg/day due to cold)	Fever‐reducer allowed; all others forbidden	NR	Not assessed/unknown
Malik 2014	Sulfate	Syrup	20 mg/5 mL syrup dose	1 x 5 mL per day	20 mg/d	14 days	Forbidden	NR	Assessed
Mandlik 2020	Sulfate	Tablet	10 mg/tablet	1 x tablet per day	10 mg/d	180 days (6 months)	NR	NR	Assessed
McDonald 2015	NR	Capsule powder mixed with water	5 mg/capsule in 5 mL water	1 x capsule in 5 mL water (0 to 6 months) and 2 x capsules in 5 mL water at 7 months on	5 to 10 mg/d	540 days (18 months)	Vitamin A supplementation given	Yes	Not assessed/unknown
Pooya 2006	Sulfate	Tablet	NR/tablet	2 x tablet per day	NR mg/d	21 days	NR	NR	Assessed
Prasad 2007	Gluconate	Capsule	15 mg/capsule	3 x capsule per day	45 mg/d	12 months	NR	NR	NR
Rerksuppaphol 2013	Chelate	Tablet	15 mg/tablet	1 x tablet per day	15 mg/d	90 days	Vitamins, zinc, or other minerals forbidden	NR	Assessed
Sánchez 2014	Chelate Sulfate Chelate + Sulfate	Powder dissolved in milk	7 mg or 9.45 mg/milk dose	2 x milk dissolution per day	14 to 18.9 mg/d	Monday to Friday for 120 days (4 months)	NR	Yes	Assessed
Somé 2015	Sulfate	Tablet	5 to 10 mg/tablet	1 x tablet per day	5 to 10 mg/d	270 days (9 months)	Liquid nutrient supplement also given	NR	Assessed
Turner 2001	Gluconate	Intranasal	33 mmol concentration/spray	1 x spray per nostril 5 x per day (10 total doses per day)	2.6 mg/d	5 days	NR	Yes	Not assessed/unknown
Vakili 2009	Sulfate	Tablet	10 mg/tablet	1 x tablet per day	10 mg/d	6 days a week for 150 days (5 months)	NR	NR	Not assessed/unknown

d: day
IU: international units
mg: milligrams
mg/d: milligrams per day
ml: millilitres 
mmol: millimole
NR: specifics not reported
Zn: zinc
*Approximate Zn estimates are based on either maximum dose per day (if provided) or an assumption of a 16‐hour waking day (when taken at a given interval of hours, i.e. every 2 hours).

3. Summary of interventions.

Study type	Zinc form	Administration	Minimum dose (mg/d)	Maximum dose (mg/d)	Minimum intervention duration (days)	Maximum intervention duration (days)	# Studies
Prevention	Zinc chelate	Powder	14	18.9	112.0	112.0	1
	Zinc chelate	Tablet	15.0	15.0	90.0	90.0	1
	Zinc gluconate	Capsule	45.0	45.0	365.0	365.0	1
	Zinc gluconate	Intranasal	2.6	2.6	8.0	8.0	1
	Zinc gluconate	Lozenge	184.0	276.0	4.5	7.0	3
	Zinc sulfate	Powder	14	18.9	112.0	112.0	1
	Zinc sulfate	Syrup	15.0	30.0	14.0	210.0	2
	Zinc sulfate	Tablet	5.0	10.0	21.0	180.0	4
	NR	Powder	5.0	10.0	540.0	540.0	1
	NR	Syrup	10.0	10.0	120.0	120.0	1
Treatment	Zinc acetate	Lozenge	30.0	106.4	5.0	14.0	7
	Zinc gluconate	Intranasal	2.1	2.1	10.0	16.0	2
	Zinc gluconate	Lozenge	45.0	276.0	7.0	21.0	8
	Zinc gluconate + orotate	Intranasal + lozenge	300.0	300.0	7.0	7.0	1
	Zinc sulfate	Intranasal	0.044	0.044	14.0	14.0	1
	Zinc sulfate	Syrup	30.0	30.0	10.0	10.0	1
	NR	Powder	20.0	20.0	7.0	7.0	1

d: day
NR: specifics not reported

Note: three studies had more than one zinc arm, therefore the total number of studies in the table is greater than the number of included studies.

Most studies (17/34 studies) evaluated the effectiveness of zinc administered as lozenges (3 prevention; 14 treatment) in acetate, gluconate, and orotate forms. Amongst these studies, gluconate lozenges were the most common (9/17). Gluconate lozenges were given at doses between 45 and 276 mg/day (for durations ranging from 4.5 to 21 days). Five (5/17) studies gave acetate lozenges at doses between 60 and 106.4 mg/day (for durations ranging from 3 to 14 days). Two studies tested gluconate lozenges at a dose of 79.8 mg/day and acetate lozenges at 30 mg/day and 69 mg/day. One treatment study administered both intranasal zinc (zinc gluconate) and lozenges (zinc orotate) in tandem (~ 299 mg/day combined for a duration of up to seven days).

Tablet administration was the next most commonly used route (5/34 studies). Tablets were used in prevention studies as zinc sulfate (4/5 studies) and zinc chelate (1/5 studies) forms in doses ranging from 10 to 15 mg/day (for durations ranging from 21 to 270 days). One study administering zinc sulfate in tablet form did not report the dose given. Not including the previously mentioned treatment study that administered intranasal zinc together with lozenges, intranasal zinc was the next most commonly used method of administration (4/34 studies). Intranasal zinc was used primarily for treatment studies via zinc gluconate (2/4 studies) and sulfate (1/4 studies) and was administered in doses ranging from 0.044 to 2.6 mg/day (for durations ranging from 7 to 16 days).

Four studies administered zinc as a syrup, usually as zinc sulfate (3/4 studies), in doses ranging from 10 to 30 mg/day (for durations ranging from 10 to 210 days). Three of the included studies administered zinc as a powder, dissolved into liquid, and dosed between 5 and 20 mg/day over a range of 7 to 540 days. Only one of the powder administration studies reported the form of zinc, where it was as zinc chelate and sulfate forms (14 to 18.9 mg/day). One study administered zinc gluconate in capsule form (45 mg/day for 12 months). There were three studies that did not report the form of zinc used. These were studies administering zinc via powder (2/3 studies) or syrup (1/3 studies).

Excluded studies

We excluded 37 studies at the full‐text screening phase due to mismatches with inclusion/exclusion criteria. See Characteristics of excluded studies for reasons.

Risk of bias in included studies

Almost all studies were at unclear or high risk of bias in at least one domain. Detailed information about the risk of bias in the included studies is presented in the table for each study and overviews are provided in Figure 2 and Figure 3.

2.

3.

Random sequence generation (selection bias)

We rated random sequence generation low risk of bias in 15 studies (Belongia 2001; Douglas 1987; Farr Trial 1 1987; Godfrey 1992; Hemilä 2020; Kartasurya 2012; Kurugöl 2006; Kurugöl 2007; Macknin 1998; Malik 2014; McDonald 2015; Mossad 1996; Mossad 2003; Rerksuppaphol 2013; Somé 2015). We rated it high risk of bias in one study (Weismann 1990), and it was not clearly described enough for judgement in 18 studies (Al‐Nakib 1987; Caesar 2012; Eby 1984; Eby 2006; Farr Trial 2 1987; Hirt 2000; Mandlik 2020; Petrus 1998; Pooya 2006; Prasad 2000; Prasad 2007; Prasad 2008; Sánchez 2014; Smith 1989; Turner 2000 challenge; Turner 2000 natural; Turner 2001; Vakili 2009).

Allocation

We rated allocation concealment low risk of bias in 16 studies (Belongia 2001; Douglas 1987; Godfrey 1992; Hemilä 2020; Kurugöl 2006; Kurugöl 2007; Macknin 1998; Malik 2014; Mandlik 2020; McDonald 2015; Mossad 1996; Prasad 2000; Prasad 2007; Prasad 2008; Rerksuppaphol 2013; Somé 2015). We rated it high risk of bias in one study (Pooya 2006), and it was not clearly described enough for judgement in 17 studies (Al‐Nakib 1987; Caesar 2012; Eby 1984; Eby 2006; Farr Trial 1 1987; Farr Trial 2 1987; Hirt 2000; Kartasurya 2012; Mossad 2003; Petrus 1998; Sánchez 2014; Smith 1989; Turner 2000 challenge; Turner 2000 natural; Turner 2001; Vakili 2009; Weismann 1990).

Blinding

Blinding of participants, personnel, and outcome assessment/outcome assessors was either adequate or unclear for all the included studies.

Performance bias

In nine studies, blinding of participants and personnel was not clear enough to judge (Al‐Nakib 1987; Eby 1984; Hirt 2000; Macknin 1998; Pooya 2006; Sánchez 2014; Turner 2001; Vakili 2009; Weismann 1990). For the remaining studies, we rated participant and personnel blinding at low risk of bias.

Detection bias

Ten studies did not clearly describe outcome assessment blinding clearly enough for judgement to be made (Al‐Nakib 1987; Eby 1984; Farr Trial 1 1987; Farr Trial 2 1987; Hirt 2000; Macknin 1998; Pooya 2006; Turner 2001; Vakili 2009; Weismann 1990). The remaining studies demonstrated a low risk of bias in blinding procedures for outcome assessment.

Incomplete outcome data

Data were fully detailed in 22 studies demonstrating a reasonable (or reasonably explained, low risk) level of attrition (Belongia 2001; Caesar 2012; Farr Trial 1 1987; Farr Trial 2 1987; Hemilä 2020; Kartasurya 2012; Kurugöl 2006; Kurugöl 2007; Macknin 1998; Malik 2014; McDonald 2015; Mossad 1996; Mossad 2003; Petrus 1998; Prasad 2000; Prasad 2007; Prasad 2008; Rerksuppaphol 2013; Somé 2015; Turner 2000 natural; Turner 2001; Vakili 2009). The details in the remaining 12 studies were either too unclear for evaluation (Al‐Nakib 1987; Douglas 1987; Godfrey 1992; Hirt 2000; Mandlik 2020; Sánchez 2014; Turner 2000 challenge; Weismann 1990) or contained substantial concerns (high risk) about how missing data might impact findings (Eby 1984; Eby 2006; Pooya 2006; Smith 1989).

Selective reporting

Selective reporting was questionable (high risk of bias) in seven studies (Eby 1984; Eby 2006; Farr Trial 1 1987; Farr Trial 2 1987; Hirt 2000; Kurugöl 2007; Somé 2015; Turner 2001). One study (low risk of bias) clearly avoided selective reporting (Hemilä 2020). In the remaining studies, selective reporting could not be adequately assessed (largely due to a lack of preregistered protocols being available for comparison).

Other potential sources of bias

While none of the studies contained any overt biases that have not otherwise been covered above, 17 studies were funded by an organisation with ties to related commerce or industry or did not report their funding (Al‐Nakib 1987; Belongia 2001; Douglas 1987; Eby 1984; Farr Trial 1 1987; Farr Trial 2 1987; Godfrey 1992; Kurugöl 2006; Kurugöl 2007; Macknin 1998; Mossad 2003; Petrus 1998; Smith 1989; Turner 2000 challenge; Turner 2000 natural; Turner 2001; Weismann 1990), and one was funded by a private clinic (Eby 2006). Five studies were provided funding by a non‐governmental foundation in some capacity (Kartasurya 2012; Mossad 1996; Prasad 2000; Prasad 2008; Somé 2015), one study reported both government funding and support from a private company (extent unclear; Prasad 2007), and the remaining 10 studies were funded either by a university or a governmental entity.

Effects of interventions

See: Table 1; Table 2

Comparison 1: zinc for prevention of the common cold

Fifteen studies tested zinc for prevention of the common cold or upper respiratory tract infection (Al‐Nakib 1987; Farr Trial 1 1987; Farr Trial 2 1987; Kartasurya 2012; Kurugöl 2006; Malik 2014; Mandlik 2020; McDonald 2015; Pooya 2006; Prasad 2007; Rerksuppaphol 2013; Sánchez 2014; Somé 2015; Turner 2001; Vakili 2009). Four studies, whose data were not included in the quantitative results for reasons outlined in the Characteristics of included studies table, are reported narratively (Malik 2014; Mandlik 2020; Sánchez 2014; Somé 2015).

Primary outcomes

1. Development of a cold/upper respiratory tract infection (URTI), with colds as defined by each study

1.1 Proportion of participants developing colds/URTI

We pooled nine prevention studies reporting the risk of developing colds (Al‐Nakib 1987; Farr Trial 1 1987; Farr Trial 2 1987; Kartasurya 2012; Kurugöl 2006; Pooya 2006; Prasad 2007; Rerksuppaphol 2013; Turner 2001). There may be little or no difference in the risk for development of common cold for those taking zinc compared with those taking placebo (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.85 to 1.01; I² = 20%; 9 studies, 1449 participants, 882 events; low‐certainty evidence; Analysis 1.1).

1.1. Analysis.

Comparison 1: Proportion of participants developing colds (for analyses of prevention trials only), with colds as defined by each study ‐ prevention, Outcome 1: Proportion of participants developing colds/URTI: primary analysis

Subgroup analyses

We did not have sufficient studies to test for differences between subgroups by administration types or routes, forms or doses of zinc, bioavailability of zinc, participant age groups, or zinc sufficiency status.

Sensitivity analyses

Table 6 provides all the relevant figures for each sensitivity analysis that could be performed. Excluding trials with high or unclear risk of selection bias (i.e. high risk from random sequence generation or allocation concealment, or both) yielded two studies with 294 participants (Kurugöl 2006; Rerksuppaphol 2013). The overall effect estimate was similar to that in the main analyses, but the CI widened slightly (RR 0.94, 95% CI 0.84 to 1.07; I² = 18%; 2 studies, 294 participants; 241 events). With the removal of Pooya 2006 for high risk of attrition bias (attrition > 20%), the overall effect estimate was similar to that of the main analysis, although heterogeneity decreased (RR 0.95, 95% CI 0.88 to 1.02; I² = 0%; 8 studies, 1390 participants, 838 events). Removal of the two studies that identified the outcome as URTI instead of common cold (Kartasurya 2012; Pooya 2006) also resulted in little change from the primary analysis (RR 0.95, 95% CI 0.86 to 1.05; I² = 6%; 7 studies, 564 participants; 392 events). We incorporated and reanalysed studies with available change data or unadjusted estimates. There were no differences in the overall effect or heterogeneity estimates found, so only results presenting the endpoint data and adjusted analyses are reported.

4. Sensitivity analysis summary table.

	Prevention or treatment?	Estimate	Heterogeneity (I2)	Studies	Participants
Proportion of participants developing colds (for analyses of prevention trials only), with colds as defined by each study	Prevention	RR 0.93, 95% CI 0.85 to 1.01	20%	9	1449
Low risk of selection bias		RR 0.94, 95% CI 0.84 to 1.07	18%	2	294
Low risk of attrition bias		RR 0.95, 95% CI 0.88 to 1.02	0%	8	1390
Common cold specific (not URTI)		RR 0.95, 95% CI 0.86 to 1.05	6%	7	564
Mean duration of colds (measured in days from start to resolution of the cold, as defined by each study)	Prevention	MD ‐0.63, 95% CI ‐1.29 to 0.04	77%	3	740
Low risk of selection bias		MD ‐1.07, 95% CI ‐2.21 to 0.08	76%	2	294
Adverse events	Prevention	RR 1.11, 95% CI 0.84 to 1.47	0%	7	1517
Low risk of selection bias		RR 0.92, 95% CI 0.38 to 2.28	14%	2	300
Common cold specific (not URTI)		RR 1.11, 95% CI 0.84 to 1.47	0%	6	691
Mean duration of colds (measured in days from start to resolution of the cold, as defined by each study)	Treatment	MD ‐2.37, 95% CI ‐4.21 to ‐0.53	97%	8	972
Low risk of selection bias		MD ‐0.57, 95% CI ‐1.30 to 0.16	0%	3	482
Common cold specific (not URTI)		MD ‐2.67, 95% CI ‐4.57 to ‐0.77	97%	7	812
Risk of cold/URTIs at end of study (measured in days from start to resolution of the cold, as defined by each study)	Treatment	RR 0.52, 95% CI 0.21 to 1.27	65%	5	357
Low risk of selection bias		RR 0.45, 95% CI 0.08 to 2.61	63%	3	259
Low risk of attrition bias		RR 0.95, 95% CI 0.21 to 4.33	32%	2	186
Adverse events	Treatment	RR 1.34, 95% CI 1.15 to 1.55	44%	16	2084
Low risk of selection bias		RR 1.28, 95% CI 1.05 to 1.56	61%	5	669
Common cold specific (not URTI)		RR 1.39, 95% CI 1.18 to 1.62	45%	15	1924

MD: mean difference
RR: risk ratio
URTI: upper respiratory tract infection
95% CI: 95% confidence interval

1.2 Mean number of colds/URTIs developed

Two prevention studies did not report the risk of developing any cold over a short period of follow‐up, but instead reported the mean number of colds observed in children during 5 to 18 months receipt of zinc or placebo (McDonald 2015; Vakili 2009). There may be little to no difference in the number of colds for those taking zinc compared with those taking placebo (mean difference (MD) ‐0.90, 95% CI ‐1.93 to 0.12; I² = 96%; 2 studies, 1284 participants; low‐certainty evidence; Analysis 2.1). No further subgroup or sensitivity analyses were performed due to insufficient data (too few studies) on this outcome.

2.1. Analysis.

Comparison 2: Mean number of colds/URTIs developed (for analyses of prevention trials only), with colds as defined by each study ‐ prevention, Outcome 1: Mean number of colds/URTIs developed: primary analysis

Qualitative narrative

Four prevention studies were not included in the quantitative analysis for various reasons outlined in the Characteristics of included studies table (Malik 2014; Mandlik 2020; Sánchez 2014; Somé 2015). Mandlik 2020 found that the zinc‐treated group (n = 119) experienced an average of 1 (standard deviation (SD) = 1) URTI episodes when compared to the placebo group (n = 124) experiencing an average of 1 (standard deviation (SD) = 0) episodes. Somé 2015 reported their longitudinal prevalence for URTI at 7.3 (6.2 to 8.4) and 8.1 (6.9 to 9.3) for the 5 mg and 10 mg zinc groups, respectively, compared with the group who received a placebo tablet’s longitudinal prevalence of 7.5 (6.3 to 8.7). Sánchez 2014 found incidence rates of acute respiratory infections (ARI) for those receiving chelated zinc (1.42 per 1000 child‐days), zinc sulfate (1.57 per 1000 child‐days), and placebo (3.3 per 1000 child‐days). Conversely, Malik 2014 found a 1% increase in the number of URTIs (incidence rate ratio (IRR) 1.01, 95% CI 0.89 to 1.14) when the zinc group was compared to control.

2. Duration of cold (measured in days from start to resolution of the cold, as defined by each study)

2.1 Mean duration of cold/URTI ‐ prevention

We pooled three prevention studies representing 740 participants (Kartasurya 2012; Kurugöl 2006; Rerksuppaphol 2013). There is probably little or no difference in the mean duration of colds for those taking zinc prophylactically compared with those taking placebo (MD ‐0.63, 95% CI ‐1.29 to 0.04; I² = 77%; 3 studies, 740 participants; moderate‐certainty evidence; Analysis 3.1).

3.1. Analysis.

Comparison 3: Mean duration of colds (measured in days from start to resolution of the cold, as defined by each study) ‐ prevention, Outcome 1: Mean duration of colds/URTIs (prevention): primary analysis

Subgroup analyses

For prevention studies, when grouped by all administration routes, forms of zinc, and zinc sufficiency status, each subgroup held too few studies to test for subgroup differences. All studies used the same administration status (oral‐systemic), dose range of zinc (< 85 mg/day), bioavailability impact factors (no clear interfering factors), and participant age group (under 18 years), and no subgroups could be examined for these factors.

Sensitivity analyses

Table 6 provides all of the relevant figures for each sensitivity analysis that could be performed. When the one study with a high or unclear risk of selection bias (i.e. high risk from random sequence generation or allocation concealment, or both) and identifying the outcome as URTI was removed (Kartasurya 2012), two studies representing 293 participants remained (Kurugöl 2006; Rerksuppaphol 2013). The effect estimate increased from 0.63 to 1.07 days reduction in cold duration, but the confidence interval widened and heterogeneity remained high (MD ‐1.07, 95% CI ‐2.21 to 0.08; I² = 76%; 2 studies, 294 participants). No studies in this set met the criteria for removal due to attrition rates or re‐analysis due to alternative (change estimate) reporting formats. We incorporated and reanalysed studies with available unadjusted estimates. There were no differences in the overall effect or heterogeneity estimates found, so only results presenting the adjusted analyses are reported.

2.2 Proportion of participants with a cold/URTI at end of study ‐ prevention

None of the included prevention studies used this method to assess the duration of a cold.

Qualitative narrative

In prevention studies, Somé 2015 reported the mean (SD) number of days with an acute upper respiratory infection (AURI) at 18.6 (30.3) and 20.3 (32.0) for the 5 mg and 10 mg zinc groups, respectively, compared with the group who received a placebo tablet’s average of 19.1 (32.6). For those participants in Mandlik 2020, the zinc‐treated group (n = 119) experienced an average duration of 3 (4) days for upper respiratory episodes, compared to the placebo group (n = 124) experiencing upper respiratory infections durations of 2 (3) days. Malik 2014 reported that, on average, their zinc group experienced 11.4 (6.6) days with ARI compared with the placebo group’s average of 14.7 (8.0) days. However, this study does not differentiate duration between upper respiratory and lower respiratory infections.

Farr Trial 1 1987 and Farr Trial 2 1987 gave information about cold duration, but it was not assessed in a way that could be combined with the rest of the data. Farr Trial 1 1987 provided a median duration of days when participants were still shedding the virus coming in at seven days (both for zinc and placebo), and Farr Trial 2 1987 provided a median duration of eight days (both for zinc and placebo).

3. Adverse events, including those potentially due to zinc supplements

Studies reporting adverse events were inconsistent in differentiation between events likely due to the zinc supplementation and events that may have occurred as a result of having a cold (e.g. headache). For this reason, we did not attempt to separate out zinc‐related and cold‐related adverse events. General reporting of adverse events is included in the quantitative pooling and all studies are included in the qualitative narrative.

We pooled seven prevention studies (Al‐Nakib 1987; Farr Trial 2 1987; Kartasurya 2012; Kurugöl 2006; Rerksuppaphol 2013; Turner 2001; Vakili 2009). There may be little or no difference in the risk for adverse events for those taking zinc compared with those taking placebo, but the estimate is uncertain due to risk of bias and very serious imprecision (RR 1.11, 95% CI 0.84 to 1.47; I² = 0%; 7 studies, 1517 participants; very low‐certainty evidence; Analysis 4.1).

4.1. Analysis.

Comparison 4: Adverse events ‐ prevention, Outcome 1: Adverse events (prevention): primary analysis

Subgroup analyses

There were too few studies to test for subgroup differences by administration routes, type of zinc product (with no omissions and with omission of intranasal), forms of zinc, doses of zinc, factors impacting bioavailability, participant age, and zinc status at baseline. Although there were insufficient data for testing these observations through subgroups, the highest number of adverse events (when compared with placebo counts) occurred for those studies using tablet or powder administration, zinc sulfate form, and including factors that would likely interfere with zinc bioavailability. Lower counts of adverse events for zinc compared to placebo were seen in studies using the bis‐glycinate form of zinc. Other subgroupings held relatively equal counts for adverse events between zinc and placebo.

Sensitivity analyses

Table 6 provides all the relevant figures for each sensitivity analysis that could be performed. When studies with a high or unclear risk of selection bias were removed, two studies representing 300 participants remained (Kurugöl 2006; Rerksuppaphol 2013). The effect estimate remained close to the null, the CI widened, and heterogeneity remained low (RR 0.92, 95% CI 0.38 to 2.28; I² = 14%; 2 studies, 300 participants). Removal of the study that identified the outcome as URTI instead of common cold (Kartasurya 2012) had no effect on the analysis because the study reported no adverse events. Studies with available change data or unadjusted estimates were incorporated and reanalysed. There were no differences in the overall effect or heterogeneity estimates found, so only results presenting the endpoint data and adjusted analyses are reported.

Qualitative narrative

As Table 7 presents, the most commonly recorded adverse events reported in trials of zinc for prevention were unspecified adverse events with 110 reports in four studies (Kartasurya 2012; Kurugöl 2006; Rerksuppaphol 2013; Turner 2001), followed by some form of taste aberration with 34 reports in five studies (Al‐Nakib 1987; Farr Trial 1 1987; Kurugöl 2006; Rerksuppaphol 2013; Turner 2001).

5. Adverse events summary.

	Number of studies	Total participants (n)	Zinc participants (n)	Placebo participants (n)
Prevention or combo studies
All publications	15	4891	2492	2399
AE reporting publications	12	4539	43	43
Serious complications/death (SAEs)	4	48	29	19
Non‐specific AEs	4	110	56	54
Taste aberrations	5	34	17	17
Mouth pain, irritation, or sensitivity	3	33	17	16
Headache	2	33	17	16
Vomiting	3	30	20	10
Gastrointestinal discomfort	5	29	18	11
Diarrhoea	3	29	16	13
Oro‐/nasopharyngeal dryness	2	11	5	6
Constipation	2	5	3	2
Nasal pain, irritation, or sensitivity	1	4	4	0
Dizziness	1	3	2	1
Itching	1	3	1	2
Biomarkers	2	2	1	1
Oral ulcerations/bleeding	1	2	1	1
Nosebleed	1	2	1	1
Fever	1	2	2	0
Sleepiness	1	1	0	1
Rash/skin discolouration or irritation	1	1	0	1
Treatment studies
	Number of studies	Total participants (n)	Zinc participants (n)	Placebo participants (n)
All publications	19	2417	1348	1069
AE reporting publications	19	2417	103	103
Serious complications/death (SAEs)	0	0	0	0
Non‐specific AEs	7	509	354	155
Taste aberrations	15	362	236	126
Gastrointestinal discomfort	14	193	122	71
Oro‐/nasopharyngeal dryness	8	182	105	77
Mouth pain, irritation, or sensitivity	10	149	91	58
Nasal pain, irritation, or sensitivity	4	129	71	58
Headache	7	118	59	59
Dizziness	6	39	21	18
Diarrhoea	7	34	23	11
Vomiting	8	30	23	7
Constipation	6	25	17	8
Nosebleed	2	20	11	9
Sleepiness	5	5	1	4
Oral ulcerations/bleeding	2	4	3	1
Rash/skin discolouration or irritation	1	1	0	1
Throat irritation	1	1	1	0
Itching	0	0	0	0
Biomarkers	0	0	0	0
Fever	0	0	0	0

AEs: adverse events
n: number
SAEs: serious adverse events

Pain, irritation, or sensitivity of mouth was reported 33 times in three studies (Farr Trial 1 1987; Kurugöl 2006; Turner 2001), or nose (four reports in one intranasal administration study (Turner 2001)) and headache (33 reports in two studies) also occurred with some frequency (Kurugöl 2006; Turner 2001). Vomiting (30 reports over Kurugöl 2006; Malik 2014; Sánchez 2014), gastrointestinal discomfort (29 reports over Farr Trial 1 1987; Farr Trial 2 1987; Kurugöl 2006; Sánchez 2014; Vakili 2009), and diarrhoea (29 reports over Kurugöl 2006; Malik 2014; Sánchez 2014), and oro‐nasopharyngeal dryness (11 reports in Kurugöl 2006; Turner 2001) were also recorded.

The remaining adverse events (constipation, nasal sensitivity, dizziness, itching, biomarkers, oral ulcerations or bleeding, nose bleeding, fever, sleepiness, rash or skin irritation, and throat irritation) were reported fewer than 10 times in total across multiple studies (Al‐Nakib 1987; Farr Trial 1 1987; Farr Trial 2 1987; Kurugöl 2006; Kurugöl 2007; Malik 2014; Rerksuppaphol 2013; Turner 2001). Ten of the 14 included treatment trials did not report on significant differences between groups regarding adverse events, though they did report raw counts. Six of the 14 included trials with a prevention element did not report on significant differences between groups regarding adverse events, though they did report raw counts. Of those reporting on whether significant differences existed between zinc and placebo, five reported that no significant differences existed between groups (Farr Trial 1 1987; Malik 2014; McDonald 2015; Sánchez 2014; Somé 2015). Two studies did not report on adverse events at all (Mandlik 2020; Pooya 2006).

4. Serious adverse events, including those that may be complications of the common cold

We pooled three prevention studies reporting on the occurrence of serious adverse events (Malik 2014; McDonald 2015; Turner 2001). There may be little or no increase in the risk of experiencing a serious adverse event for those taking zinc compared with those taking placebo (RR 1.67, 95% CI 0.78 to 3.57; I² = 0%; 3 studies, 1563 participants; low‐certainty evidence; Analysis 4.2). No further subgroup or sensitivity testing was performed due to insufficient data (too few studies) on this outcome.

4.2. Analysis.

Comparison 4: Adverse events ‐ prevention, Outcome 2: Serious adverse events (prevention): primary analysis

Qualitative narrative

Four studies referenced serious adverse events (all‐cause mortality, hospitalisation or death due to gastrointestinal disease, malaria, or respiratory infections), but no difference between zinc (29/2467) and placebo (19/2374) groups was reported (Malik 2014; McDonald 2015; Somé 2015; Turner 2001). Somé 2015 is the only one of this set that was not included in the quantitative analyses, where 70 severe adverse events occurred in total (nine in the non‐zinc group and two (5 mg), 10 (10 mg), and 12 (5 mg) in the groups who did take some form of zinc). There was no significant difference in these events amongst the intervention groupings.

Secondary outcomes

1. Global severity of the cold

We pooled two prevention studies of 101 participants (Farr Trial 1 1987; Turner 2001). There may be little or no difference in the standardised mean global severity of cold symptoms for those taking zinc compared with those taking placebo (standardised mean difference (SMD) 0.04, 95% CI ‐0.35 to 0.43; I² = 0%; 2 studies, 101 participants; low‐certainty evidence; Analysis 5.1).

5.1. Analysis.

Comparison 5: Global severity of the cold (using a global measure, or by summing severity scores for individual symptoms) ‐ prevention, Outcome 1: Standardised mean global symptom severity (prevention)

Qualitative narrative

One study that reported on global severity of cold symptoms was not included in the quantitative analysis (Mandlik 2020). At the start of Mandlik 2020, 61% of the zinc group (n = 73/119) and 67% of the placebo (n = 83/124) groups began with a URTI severity rating of moderate to severe. By the end of the study, 44% of the zinc group (overall mean severity score (SD) = 15 (18)), and 41% of the placebo group (overall mean severity score (SD) = 12 (15)) had URTI ratings of moderate to severe.

2. Severity of individual cold symptoms

Two studies reported on individual symptom severity scores (Farr Trial 1 1987; Turner 2001). It is uncertain whether there is a difference between zinc and placebo recipients for severity of nasal congestion (SMD ‐0.08, 95% CI ‐0.55 to 0.40; 1 study, 69 participants; very low‐certainty evidence; Analysis 6.1), severity of nasal drainage (SMD ‐0.28, 95% CI ‐0.75 to 0.20; 1 study, 69 participants; very low‐certainty evidence; Analysis 6.2), or severity of general nasal symptoms (SMD ‐0.05, 95% CI ‐0.74 to 0.64; 1 study, 32 participants; very low‐certainty evidence; Analysis 6.3).

6.1. Analysis.

Comparison 6: Severity of individual cold symptoms (measured on a scale) ‐ prevention, Outcome 1: Severity of nasal congestion (prevention)

6.2. Analysis.

Comparison 6: Severity of individual cold symptoms (measured on a scale) ‐ prevention, Outcome 2: Severity of nasal drainage (prevention)

6.3. Analysis.

Comparison 6: Severity of individual cold symptoms (measured on a scale) ‐ prevention, Outcome 3: Severity of nasal symptoms (prevention)

3. Duration of individual cold symptoms, measured in days from start to resolution of symptoms

Two studies reported duration of individual symptoms of cough, nasal drainage, fever, headache, hoarseness, nasal congestion, sneezing, or sore throat (Kurugöl 2006; Rerksuppaphol 2013). Duration of the individual symptoms was recorded by the number of participants who initially reported the symptoms through symptomatic resolution or end of study.

3.1 Mean duration of individual cold/URTI symptoms

Data from both studies could be pooled for the average duration of cough, nasal drainage, and fever (Kurugöl 2006; Rerksuppaphol 2013). It is uncertain whether there is a reduction in the duration of cough (MD ‐1.84, 95% CI ‐5.41 to 1.74; I² = 82%; 2 studies, 294 participants; very low‐certainty evidence; Analysis 7.1), or nasal drainage (MD ‐1.90, 95% CI ‐5.86 to 2.06; I² = 82%; 2 studies, 294 participants; very low‐certainty evidence; Analysis 7.2) with zinc. There may be little or no reduction in the duration of fever with zinc (MD ‐0.09, 95% CI ‐0.43 to 0.25; I² = 0%; 2 studies, 294 participants; low‐certainty evidence; Analysis 7.3).

7.1. Analysis.

Comparison 7: Mean duration of individual cold symptoms ‐ prevention, Outcome 1: Cough (continuous) (prevention)

7.2. Analysis.

Comparison 7: Mean duration of individual cold symptoms ‐ prevention, Outcome 2: Nasal drainage (continuous) (prevention)

7.3. Analysis.

Comparison 7: Mean duration of individual cold symptoms ‐ prevention, Outcome 3: Fever (continuous) (prevention)

Kurugöl 2006 provided additional information on the duration of several additional symptoms. There may be little or no difference in duration of headache (MD 0.00, 95% CI ‐0.16 to 0.16; 1 study, 194 participants; low‐certainty evidence; Analysis 7.4), hoarseness (MD ‐0.02, 95% CI ‐0.18 to 0.14; 1 study, 194 participants; Analysis 7.5), muscle aches (MD ‐0.10, 95% CI ‐0.25 to 0.05; 1 study, 194 participants; low‐certainty evidence; Analysis 7.6), nasal congestion (MD ‐0.20, 95% CI ‐0.45 to 0.05; 1 study, 194 participants; low‐certainty evidence; Analysis 7.7), or sneezing (MD ‐0.20, 95% CI ‐0.36 to ‐0.04; 1 study, 194 participants; low‐certainty evidence; Analysis 7.8). There may be a slight reduction in the duration of sore throat (MD ‐0.60, 95% CI ‐1.05 to ‐0.15; 1 study, 194 participants; low‐certainty evidence; Analysis 7.9).

7.4. Analysis.

Comparison 7: Mean duration of individual cold symptoms ‐ prevention, Outcome 4: Headache (continuous) (prevention)

7.5. Analysis.

Comparison 7: Mean duration of individual cold symptoms ‐ prevention, Outcome 5: Hoarseness (continuous) (prevention)

7.6. Analysis.

Comparison 7: Mean duration of individual cold symptoms ‐ prevention, Outcome 6: Muscle aches (continuous) (prevention)

7.7. Analysis.

Comparison 7: Mean duration of individual cold symptoms ‐ prevention, Outcome 7: Nasal congestion (continuous) (prevention)

7.8. Analysis.

Comparison 7: Mean duration of individual cold symptoms ‐ prevention, Outcome 8: Sneezing (continuous) (prevention)

7.9. Analysis.

Comparison 7: Mean duration of individual cold symptoms ‐ prevention, Outcome 9: Sore throat (continuous) (prevention)

3.2 Proportion of participants with cold symptoms at end of study

No prevention studies reported the proportion of participants with symptoms at the end of the study.

4. Days missed from work or school

Three studies reported on absenteeism of the participants due to cold and were included in the quantitative analyses (Kurugöl 2006; Rerksuppaphol 2013; Vakili 2009).

4.1 Proportion missing days from work or school

Rerksuppaphol 2013 did not report the total number of days of school absence, but did report the number of participants who had any cold‐related school absence. There may be little or no difference in the risk of having a school absence in children taking zinc compared to placebo (RR 0.93, 95% CI 0.49 to 1.77; 1 study, 100 participants; 27 participants with absences; low‐certainty evidence; Analysis 8.1).

8.1. Analysis.

Comparison 8: Days missed from work or school ‐ prevention, Outcome 1: Proportion of participants missing days from work or school (prevention)

4.2 Mean days missed from work or school

Two studies reported the average days missed from work or school (Kurugöl 2006; Vakili 2009). There may be a slight reduction in the average days absent for children in the zinc group compared with children in the placebo group (MD ‐0.65, 95% CI ‐1.03 to ‐0.27; I² = 21%; 2 studies, 394 participants; low‐certainty evidence; Analysis 8.2).

8.2. Analysis.

Comparison 8: Days missed from work or school ‐ prevention, Outcome 2: Mean days missed from work or school (prevention)

Publication bias

No prevention analyses contained at least 10 trials, and so we did not construct any funnel plots.

Comparison 2: zinc for treatment of the common cold

Nineteen studies tested zinc for treatment of the common cold or upper respiratory tract infection (Belongia 2001; Caesar 2012; Douglas 1987; Eby 1984; Eby 2006; Godfrey 1992; Hemilä 2020; Hirt 2000; Kurugöl 2007; Macknin 1998; Mossad 1996; Mossad 2003; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Turner 2000 challenge; Turner 2000 natural; Weismann 1990). Four studies are reported narratively and do not have data included in the quantitative results for reasons outlined in Table 3 (Douglas 1987; Kurugöl 2007; Smith 1989; Weismann 1990).

Primary outcomes

1. Duration of cold (measured in days from start to resolution of the cold, as defined by each study)

1.1 Mean duration of cold/URTI ‐ treatment

Eight treatment studies representing 972 participants were pooled (Belongia 2001; Godfrey 1992; Hirt 2000; Macknin 1998; Mossad 2003; Petrus 1998; Prasad 2000; Prasad 2008). Colds may be shortened for those taking zinc compared with those taking placebo (MD ‐2.37, 95% CI ‐4.21 to ‐0.53; I² = 97%; 8 studies, 972 participants; low‐certainty evidence, Analysis 9.1).

9.1. Analysis.

Comparison 9: Mean duration of colds (measured in days from start to resolution of the cold, as defined by each study) ‐ treatment, Outcome 1: Mean duration of colds/URTIs (treatment): primary analysis

Subgroup analyses

When three studies utilising intranasal zinc (Belongia 2001; Hirt 2000; Mossad 2003) were compared with five studies utilising zinc lozenges (Godfrey 1992; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008), there was no apparent difference between subgroups (I² = 0%; Analysis 9.2). When four studies using > 85 mg/day of zinc (Godfrey 1992; Petrus 1998; Prasad 2000; Prasad 2008) were compared with four studies using < 85 mg/day of zinc (Belongia 2001; Hirt 2000; Macknin 1998; Mossad 2003) there was no apparent difference between subgroups (I² = 0%; Analysis 9.3).

9.2. Analysis.

Comparison 9: Mean duration of colds (measured in days from start to resolution of the cold, as defined by each study) ‐ treatment, Outcome 2: Subgroup analysis (treatment): all administration routes

9.3. Analysis.

Comparison 9: Mean duration of colds (measured in days from start to resolution of the cold, as defined by each study) ‐ treatment, Outcome 3: Subgroup analysis (treatment): daily dose of zinc

When studies were grouped by forms of zinc, factors affecting bioavailability, age groupings, and zinc sufficiency status, each subgroup had too few studies to perform a subgroup analysis. Although we could not formally test for differences, we observed that while acetate and gluconate forms seemed to lower the mean duration of colds by just over two days for those taking zinc compared to placebo, zinc sulfate did not show reductions beyond a half day by comparison. Neither subgrouping for bioavailability appears to reduce cold duration by a full day. The studies reporting on adults, which also did not report on zinc sufficiency at baseline, seem to suggest that zinc might reduce duration of cold symptoms by two to three days, while there was no difference in cold duration between zinc and placebo for the study reporting on minors who were zinc sufficient at baseline.

All studies used the same administration route (lozenges) and administration status (mucosal), and no subgroups could be examined.

Sensitivity analyses

Table 6 provides all of the relevant figures for each sensitivity analysis that could be performed. When we removed studies with a high or unclear risk of selection bias, three studies remained (Belongia 2001; Godfrey 1992; Macknin 1998). Both the effect estimate and the I² value were markedly reduced (MD ‐0.57, 95% CI ‐1.30 to 0.16; I² = 0%; 3 studies, 482 participants). Removal of the one study that identified the outcome as URTI instead of common cold produced little change in the analysis (MD ‐2.67, 95% CI ‐4.57 to ‐0.77; I² = 97%; 7 studies, 812 participants) (Belongia 2001). Studies with available change data or unadjusted estimates were incorporated and reanalysed. There were no differences in the overall effect or heterogeneity estimates found, so only results presenting the endpoint data and adjusted analyses are reported.

1.2 Proportion of participants with a cold/URTI at end of study

Not all treatment studies reported the duration of colds, as some studies ended the follow‐up before all colds had resolved. Five treatment studies reported the number of colds or URTIs still present at the end of follow‐up (Eby 1984; Eby 2006; Godfrey 1992; Hemilä 2020; Mossad 1996). There may be little or no difference in the risk of having a continuing cold at the end of follow‐up for those taking zinc compared with those taking placebo, but the evidence is uncertain due to risk of bias, heterogeneity, and imprecision (RR 0.52, 95% CI 0.21 to 1.27; I² = 65%; 5 studies, 357 participants; 64 events; very low‐certainty evidence; Analysis 10.1).

10.1. Analysis.

Comparison 10: Risk of cold/URTIs at end of study (measured in days from start to resolution of the cold, as defined by each study) ‐ treatment, Outcome 1: Risk of ongoing cold/URTIs at end of study (treatment): primary analysis

Subgroup analyses

When studies were grouped by all administration routes (with no omissions or recategorisation), forms of zinc, and factors impacting bioavailability, each subgroup held too few studies to test for subgroup differences. Generally, there were fewer participants taking zinc who still had a cold at the end of the study, compared to the numbers in placebo groups, except for those taking zinc acetate at doses lower than 86 mg/day with potential (but unlikely) factors that might impact bioavailability of zinc in the study.

There was only one subgroup for the groupings of administration omitting intranasal (lozenge), administration route categories (mucosal), age groupings (over 18 years), and zinc status (status not reported at baseline), leaving their estimates the same as the primary analysis results.

Sensitivity analyses

Table 6 provides all of the relevant figures for each sensitivity analysis that could be performed. When studies with a high or unclear risk of selection bias were removed (Eby 1984; Eby 2006), three studies representing 259 participants remained (Godfrey 1992; Hemilä 2020; Mossad 1996). The summary effect estimate was similar to that in the primary analysis, but the confidence interval increased in width and covered less benefit from zinc (RR 0.45, 95% CI 0.08 to 2.61; I² = 63%; 3 studies, 259 participants; 31 events). Only two studies had a low risk of attrition bias (Hemilä 2020; Mossad 1996). The summary effect estimate limited to those studies was close to the null with a broad confidence interval (RR 0.95, 95% CI 0.21 to 4.33; I² = 32%; 2 studies, 186 participants; 22 events). All the studies included in the primary analysis referred to the outcome as a common cold, so no further sensitivity analyses were applied. We incorporated and re‐analysed studies with available change data or unadjusted estimates. There were no differences in the overall effect or heterogeneity estimates found, so only results presenting the endpoint data and adjusted analyses are reported.

Qualitative narrative

In treatment studies, Kurugöl 2007 reported a median resolution time of six days for both the placebo (95% CI 6 to 7 days) and zinc groups (95% CI 5 to 6 days). Douglas 1987, Smith 1989, and Weismann 1990 all reported similar response times, with divergence between their zinc and placebo groupings occurring at around Day 6 of treatment. While the Smith 1989 and Douglas 1987 studies suggested the five to seven days of treatment divergence then favouring the zinc intervention, Weismann 1990 had the opposite occur, wherein placebo began to perform better in terms of cold durations.

Finally, several studies provided information about duration, but it was not assessed in a way that could be combined with the rest of the data. Pooya 2006 reported a MD of common cold being significantly different between the zinc and placebo groups, but no further discussion of superiority was provided. For viral challenge acquired colds, Turner 2000 challenge reported that when colds were induced, a significant difference was observed in median duration of cold for the zinc gluconate only (2.5 days) versus placebo (3.5 days) group; zinc acetate (at both dosages) did not demonstrate an effect on duration, however (3.25 to 3.5 days). For naturally acquired colds, Turner 2000 natural reported that when colds were naturally acquired, no significant differences were observed in median duration of cold for any of the zinc groups (placebo = 5.5 days; gluconate and 5 mg acetate = 6 days; 11.5 mg acetate = 5.5 days).

2. Adverse events, including those potentially due to zinc supplements

Studies reporting adverse events were inconsistent in differentiation between events likely due to the zinc supplementation and events that may have occurred as a result of having a cold (e.g. headache). For this reason, we did not attempt to separate out zinc‐related and cold‐related adverse events. General reporting of adverse events is included in the quantitative pooling and all studies are included in the qualitative narrative.

We pooled 16 treatment studies (Belongia 2001; Caesar 2012; Eby 1984; Eby 2006; Godfrey 1992; Hemilä 2020; Hirt 2000; Macknin 1998; Mossad 1996; Mossad 2003; Petrus 1998; Prasad 2000; Prasad 2008; Turner 2000 challenge; Turner 2000 natural; Weismann 1990). There is probably an increase in the risk of experiencing non‐serious adverse events for those taking zinc compared with those taking placebo (RR 1.34, 95% CI 1.15 to 1.55; I² = 44%; 16 studies, 2084 participants; moderate‐certainty evidence; Analysis 11.1).

11.1. Analysis.

Comparison 11: Adverse events ‐ treatment, Outcome 1: Adverse events (treatment): primary analysis

Subgroup analyses

In a subgroup analysis by daily dose of zinc, we observed that the risk for adverse events was increased with doses < 85 mg/day (RR 1.20, 95% CI 1.03 to 1.40; I² = 25%), but the risk for adverse events was higher with doses > 85 mg/day (RR 1.54, 95% CI 1.19 to 1.99; I² = 43%); the test for heterogeneity across subgroup results was not significant, however the I² value indicates moderate to high heterogeneity between groups (Chi² = 2.61, df = 1 (P = 0.11), I² = 61.7%) (Analysis 11.4).

11.4. Analysis.

Comparison 11: Adverse events ‐ treatment, Outcome 4: Subgroup analysis (treatment): daily dose of zinc

In a subgroup analysis by age groupings, we pooled two studies for the < 18 years old subgroup (Caesar 2012; Macknin 1998) and compared them to the remaining studies, which were carried out in adults. The risk of adverse events was not significantly higher with zinc in studies of children (RR 1.11, 95% CI 0.99 to 1.24; I² = 0%) but the risk was increased with zinc in studies of adults (RR 1.40, 95% CI 1.17 to 1.68; I² = 44%); the test for heterogeneity across subgroup results was significant (Chi² = 4.53, df = 1 (P = 0.03), I² = 77.9%) (Analysis 11.5).

11.5. Analysis.

Comparison 11: Adverse events ‐ treatment, Outcome 5: Subgroup analysis (treatment): age groupings

When studies were grouped by intranasal versus lozenge administration routes, we observed that the risk of adverse events was not significantly higher with zinc in studies using intranasal zinc (RR 1.12, 95% CI 0.85 to 1.47; I² = 25%) but the risk was increased with zinc in studies using lozenges (RR 1.44, 95% CI 1.19 to 1.75; I² = 57%); the test for heterogeneity across subgroup results was not significant, however the I² value indicates moderate to high heterogeneity between groups (Chi² = 2.20, df = 1 (P = 0.14), I² = 54.6%) (Analysis 11.2).

11.2. Analysis.

Comparison 11: Adverse events ‐ treatment, Outcome 2: Subgroup analysis (treatment): intranasal vs lozenge

When studies were grouped by zinc acetate versus zinc gluconate, there was no apparent difference between subgroups (I² = 0%; Analysis 11.3).

11.3. Analysis.

Comparison 11: Adverse events ‐ treatment, Outcome 3: Subgroup analysis (treatment): zinc acetate vs zinc gluconate

When we conducted subgroup analyses for other administration routes (with no omissions, with omission of intranasal, and when grouped by oral‐systemic/mucosal administration), factors impacting bioavailability, and zinc status at baseline, each subgroup held too few studies to perform a subgroup analysis. Although we could not formally test for differences, we observed that the highest number of adverse events (when compared with placebo counts) occurred for those studies using intranasal + lozenge administration, zinc orotate + gluconate, and included factors that were likely to interfere with zinc bioavailability. The remaining subgroupings had relatively equal counts for adverse events between zinc and placebo.

Sensitivity analyses

Table 6 provides all the relevant figures for each sensitivity analysis that could be performed. When studies with a high or unclear risk of selection bias were removed, five studies remained and the result was similar to that in the primary analysis, although heterogeneity increased slightly (RR 1.28, 95% CI 1.05 to 1.56; I² = 61%; 5 studies, 669 participants) (Belongia 2001; Godfrey 1992; Hemilä 2020; Macknin 1998; Mossad 1996). When we removed the study that identified the outcome as URTI instead of common cold (Belongia 2001), results were similar to the primary analysis (RR 1.39, 95% CI 1.18 to 1.62; I² = 45%; 15 studies, 1924 participants). Studies with available change data or unadjusted estimates were incorporated and reanalysed. There were no differences in the overall effect or heterogeneity estimates found, so only results presenting the endpoint data and adjusted analyses are reported.

Qualitative narrative

As Table 7 presents, the most commonly recorded adverse events reported in trials of zinc for treatment were unspecified adverse events, with 509 reports in seven studies (Belongia 2001; Hemilä 2020; Macknin 1998; Mossad 1996; Turner 2000 challenge; Turner 2000 natural; Weismann 1990), aberrations of taste in 362 reports in 15 studies (Belongia 2001; Douglas 1987; Eby 1984; Eby 2006; Godfrey 1992; Hemilä 2020; Hirt 2000; Kurugöl 2007; Macknin 1998; Mossad 1996; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990), and some form of gastrointestinal discomfort, with 193 reports in 14 studies (Belongia 2001; Douglas 1987; Eby 1984; Eby 2006; Godfrey 1992; Hemilä 2020; Hirt 2000; Kurugöl 2007; Macknin 1998; Mossad 1996; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989). Oropharyngeal or nasopharyngeal dryness was reported 182 times in eight studies (Belongia 2001; Kurugöl 2007; Macknin 1998; Mossad 1996; Mossad 2003; Prasad 2000; Prasad 2008; Smith 1989). Pain, irritation, or sensitivity of mouth was reported 149 times in 10 studies (Belongia 2001; Douglas 1987; Eby 1984; Eby 2006; Godfrey 1992; Kurugöl 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008), or nose (129 reports in four intranasal administration studies (Belongia 2001; Eby 2006; Hirt 2000; Mossad 2003)) and headache (118 reports in seven studies) also occurred with some frequency (Belongia 2001; Godfrey 1992; Macknin 1998; Mossad 1996; Mossad 2003; Smith 1989; Weismann 1990).

Less commonly reported adverse events included: 39 reports of dizziness (Belongia 2001; Godfrey 1992; Hirt 2000; Macknin 1998; Mossad 1996; Smith 1989), 34 reports of diarrhoea (Eby 1984; Eby 2006; Kurugöl 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008), 30 reports of vomiting (Belongia 2001; Caesar 2012; Eby 1984; Eby 2006; Kurugöl 2007; Macknin 1998; Mossad 1996; Prasad 2000), 25 reports of constipation (Kurugöl 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008; Smith 1989), and 20 reports of nosebleeds (Belongia 2001; Mossad 2003). The remaining adverse events (sleepiness, mouth ulcers/bleeding, itching, biomarker changes, fever, skin irritation/discolouration, and throat irritation) were reported fewer than 10 times across multiple studies (Caesar 2012; Eby 1984; Eby 2006; Godfrey 1992; Hirt 2000; Kurugöl 2007; Mossad 2003). Ten of the 19 included treatment trials did not report on significant differences between groups regarding adverse events, though they did report raw counts. Of those reporting on whether significant differences existed between zinc and placebo, six reported that no significant differences existed between groups (Belongia 2001; Caesar 2012; Kurugöl 2007; Mossad 2003; Prasad 2008; Weismann 1990), while four studies reported significant differences in adverse effects between groups. When significant differences were reported, zinc groups experienced more mouth dryness, constipation, nausea, taste aberrations, oral irritation, diarrhoea, and “other” (not specified) in comparison to the placebo groups; see Table 7 for additional details (Hemilä 2020; Macknin 1998; Mossad 1996; Prasad 2000).

3. Serious adverse events, including those that may be complications of the common cold

No treatment studies reported the assessment or occurrence of serious adverse events.

Secondary outcomes

1. Global severity of the cold

1.1 Severity of global cold symptoms

We pooled two treatment studies reporting on cold severity (Belongia 2001; Petrus 1998). The severity of global cold symptoms was not lower for those taking zinc compared with those taking placebo (SMD ‐0.03, 95% CI ‐0.56 to 0.50; I² = 78%; 2 studies, 261 participants; very low‐certainty evidence; Analysis 12.1).

12.1. Analysis.

Comparison 12: Global severity of the cold (using a global measure, or by summing severity scores for individual symptoms) ‐ treatment, Outcome 1: Standardised mean global symptom severity (treatment)

Qualitative narrative

Two studies that reported on global severity of cold symptoms were not included in the quantitative analysis (Kurugöl 2007; Weismann 1990). Kurugöl 2007 reported a significantly lower total symptom severity score for the zinc group (n = 60), when compared to placebo (n = 60), starting on Day 2 (symptom score mean standard deviation (SD) 3.6 (1.7) versus 4.9 (1.7); P < 0.001) and through to Day 5 (symptom score mean SD 0.3 (0.6) versus 0.7 (0.9); P = 0.05) of treatment. At the start of this study, the mean SD severity score for the zinc group was 6.8 (1.8) and 6.7 (1.9) for the placebo group, totalling an average severity score decrease of 6.5 points for zinc and 6 points for placebo. However, Weismann 1990 did not report similar significant reductions. Weismann 1990 noted that Day 6 of the study was the largest difference observed between zinc and placebo with regard to severity score. This difference was still not statistically significant. Even when Weismann 1990 queried participants in the groups whether they felt the cold experienced was different from prior colds, there was no difference in reports between zinc and placebo.

1.2 Proportion with improvement in global symptom severity

One treatment study reported the proportion of participants whose global symptom severity improved from baseline (Caesar 2012). There may be little or no difference in the risk of improved global symptom severity with zinc versus placebo (RR 1.02, 95% CI 0.85 to 1.23; 1 study, 114 participants; low‐certainty evidence; Analysis 12.2).

12.2. Analysis.

Comparison 12: Global severity of the cold (using a global measure, or by summing severity scores for individual symptoms) ‐ treatment, Outcome 2: Proportion with changes in global symptom severity (treatment)

2. Severity of individual cold symptoms

One study reported on the severity of cough, headache, hoarseness, malaise, muscle ache, nasal congestion, nasal drainage, scratchy throat, sneezing, and sore throat (Petrus 1998). There may be a reduction in the severity of cough with zinc (SMD ‐0.40, 95% CI ‐0.80 to ‐0.01; 1 study, 101 participants; low‐certainty evidence; Analysis 13.1), but it is uncertain whether there is a difference between zinc and placebo for severity of headache (SMD ‐0.15, 95% CI ‐0.54 to 0.24; 1 study, 101 participants; very low‐certainty evidence; Analysis 13.2), hoarseness (SMD ‐0.09, 95% CI ‐0.48 to 0.30; 1 study, 101 participants; very low‐certainty evidence; Analysis 13.3), malaise (SMD 0.00, 95% CI ‐0.39 to 0.39; 1 study, 101 participants; very low‐certainty evidence; Analysis 13.4), muscle aches (SMD ‐0.15, 95% CI ‐0.54 to 0.24; 1 study, 101 participants; very low‐certainty evidence; Analysis 13.5), nasal congestion (SMD 0.23, 95% CI ‐0.16 to 0.62; 1 study, 101 participants; very low‐certainty evidence; Analysis 13.6), nasal drainage (SMD ‐0.32, 95% CI ‐0.71 to 0.07; 1 study, 101 participants; very low‐certainty evidence; Analysis 13.7), scratchy throat (SMD ‐0.23, 95% CI ‐0.62 to 0.16; 1 study, 101 participants; very low‐certainty evidence; Analysis 13.8), sneezing (SMD ‐0.15, 95% CI ‐0.54 to 0.24; 1 study, 101 participants; very low‐certainty evidence; Analysis 13.9), or sore throat (SMD ‐0.13, 95% CI ‐0.52 to 0.26; 1 study, 101 participants; very low‐certainty evidence; Analysis 13.10). Petrus 1998 also reported on the severity of fever, but the difference between zinc and placebo was not estimable (Analysis 13.11).

13.1. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 1: Severity of cough (treatment)

13.2. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 2: Severity of headache (treatment)

13.3. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 3: Severity of hoarseness (treatment)

13.4. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 4: Severity of malaise (treatment)

13.5. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 5: Severity of muscle aches (treatment)

13.6. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 6: Severity of nasal congestion (treatment)

13.7. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 7: Severity of nasal drainage (treatment)

13.8. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 8: Severity of scratchy throat (treatment)

13.9. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 9: Severity of sneezing (treatment)

13.10. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 10: Severity of sore throat (treatment)

13.11. Analysis.

Comparison 13: Severity of individual cold symptoms (measured on a scale) ‐ treatment, Outcome 11: Severity of fever (treatment)

Qualitative narrative

Four studies that reported severity of individual symptoms were not included in the quantitative analysis (Douglas 1987; Eby 1984; Godfrey 1992; Kurugöl 2007). Douglas 1987 reported no consistent or significant differences between zinc and placebo symptomology involving nasal, throat, cough, or systemic symptoms. Kurugöl 2007 reported that the mean score for cough was lower in the zinc group on Day 2 (1 ± 0.5 versus 1.3 ± 0.7; P = 0.023). However, this was not consistent for the other reported days. It was also reported that a fever (≥ 38.5 °C) was present in two zinc recipients and three placebo (P = 0.94). Scores for nasal symptoms were significantly lower in the zinc group from Day 2 (1.3 ± 0.9 versus 2.4 ± 1.0; P = 0.000) through Day 5 of the study (0.1 ± 0.3 versus 0.3 ± 0.5; P = 0.041). There were no significant differences in mean scores for headache, muscle ache or throat symptoms. Finally, two studies provided some information about individual symptom severity, but this was not assessed in a way that could be combined with the rest of the data (Eby 1984; Godfrey 1992). Eby 1984 and Godfrey 1992, reported individual symptom severity results as number of participants with symptoms remaining/number of participants with symptoms originally. Godfrey 1992 also reported on Day 7 that 14.3% (5/35) zinc recipients had a total of 15 reported symptoms, and 44.7% (17/38) placebo recipients had a total of 45 reported symptoms.

3. Duration of individual cold symptoms, measured in days from start to resolution of symptoms

Eight studies reported duration of individual symptoms of cough, fever, headache, hoarseness, malaise, scratchy throat, nasal drainage, nasal congestion, muscle aches, sneezing, sore throat, and/or an amalgamation of nasal/throat symptoms (Eby 1984; Godfrey 1992; Macknin 1998; Mossad 1996; Mossad 2003; Petrus 1998; Prasad 2000; Prasad 2008). Duration of the individual symptoms was recorded by the number of participants who initially reported the symptoms through symptomatic resolution or end of study.

3.1 Mean duration of individual cold/URTI symptoms

The mean duration of cough in days may be shorter with zinc (MD ‐1.67, 95% CI ‐2.97 to ‐0.37; I² = 69%; 6 studies, 537 participants; low‐certainty evidence; Analysis 14.1) but there may be little or no difference in the duration of fever (MD ‐0.29, 95% CI ‐0.80 to 0.21; I² = 46%; 5 studies, 376 participants; low‐certainty evidence; Analysis 14.2). There appears to be a reduction in the duration of headache, although it may be very small (MD ‐0.49, 95% CI ‐0.97 to ‐0.02; I² = 0%; 6 studies, 488 participants; moderate‐certainty evidence; Analysis 14.3). It is uncertain whether there is a difference in the duration of hoarseness (MD ‐0.94, 95% CI ‐1.89 to 0.00; I² = 51%; 6 studies, 493 participants; very low‐certainty evidence; Analysis 14.4), or malaise (MD 0.70, 95% CI ‐1.53 to 2.93; 1 study, 101 participants; very low‐certainty evidence; Analysis 14.5). There is probably some reduction in the duration of muscle aches (MD ‐0.66, 95% CI ‐1.17 to ‐0.16; I² = 11%; 6 studies, 441 participants; moderate‐certainty evidence; Analysis 14.6), and nasal congestion (MD ‐1.41, 95% CI ‐2.20 to ‐0.62; I² = 31%; 6 studies, 588 participants; moderate‐certainty evidence; Analysis 14.7), and there may be a reduction in the duration of nasal drainage (MD ‐1.75, 95% CI ‐2.73 to ‐0.77; I² = 62%; 6 studies, 582 participants; low‐certainty evidence; Analysis 14.8). It is uncertain whether there is a difference in the duration of scratchy throat (MD ‐0.15, 95% CI ‐0.40 to 0.10; 1 study, 101 participants; very low‐certainty evidence; Analysis 14.9). There is probably a reduction with zinc in the duration of sneezing (MD ‐0.77, 95% CI ‐1.31 to ‐0.23; I² = 0%; 6 studies, 543 participants; moderate‐certainty evidence; Analysis 14.10), and there may be a reduction in the duration of sore throat (MD ‐0.88, 95% CI ‐1.60 to ‐0.16; I² = 60%; 6 studies, 514 participants; low‐certainty evidence; Analysis 14.11).

14.1. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 1: Cough (continuous) (treatment)

14.2. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 2: Fever (continuous) (treatment)

14.3. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 3: Headache (continuous) (treatment)

14.4. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 4: Hoarseness (continuous) (treatment)

14.5. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 5: Malaise (continuous) (treatment)

14.6. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 6: Muscle aches (continuous) (treatment)

14.7. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 7: Nasal congestion (continuous) (treatment)

14.8. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 8: Nasal drainage (continuous) (treatment)

14.9. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 9: Scratchy throat (continuous) (treatment)

14.10. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 10: Sneezing (continuous) (treatment)

14.11. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 11: Sore throat (continuous) (treatment)

Mossad 1996 reported on the duration of overall nasal symptoms and overall throat symptoms. There may be a reduced duration of both nasal symptoms (MD ‐3.70, 95% CI ‐5.72 to ‐1.68; 1 study, 99 participants; moderate‐certainty evidence; Analysis 14.12), and throat symptoms (MD ‐2.30, 95% CI ‐3.84 to ‐0.76; 1 study, 99 participants; moderate‐certainty evidence; Analysis 14.13).

14.12. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 12: Nasal symptoms (continuous) (treatment)

14.13. Analysis.

Comparison 14: Mean duration of individual cold symptoms ‐ treatment, Outcome 13: Throat symptoms (continuous) (treatment)

3.2 Proportion of participants with cold symptoms at end of study

Two studies of 138 participants reported on the number of individual symptoms (existing at baseline) that continued to the end of the study (Eby 1984; Godfrey 1992). We pooled study data to estimate the risk of individual symptoms persisting at the end of study follow‐up in participants treated with zinc versus placebo. Due to risk of bias and imprecision, it is uncertain whether zinc reduces the risk of persistent cough (RR 0.42, 95% CI 0.19 to 0.94; I² = 0%; 2 studies, 106 participants; very low‐certainty evidence; Analysis 15.1), fever (RR 0.10, 95% CI 0.01 to 1.76; 1 study, 22 participants; very low‐certainty evidence; Analysis 15.2), headache (RR 0.50, 95% CI 0.10 to 2.57; I² = 26%; 2 studies, 111 participants; very low‐certainty evidence; Analysis 15.3), hoarseness (RR 0.23, 95% CI 0.05 to 1.02; I² = 0%; 2 studies, 115 participants; very low‐certainty evidence; Analysis 15.4), muscle aches (RR 0.33, 95% CI 0.05 to 2.11; I² = 18%; 2 studies, 104 participants; very low‐certainty evidence; Analysis 15.5), nasal congestion (RR 0.38, 95% CI 0.17 to 0.82; I² = 0%; 2 studies, 119 participants; very low‐certainty evidence; Analysis 15.6), nasal drainage (RR 0.36, 95% CI 0.19 to 0.71; I² = 0%; 2 studies, 124 participants; very low‐certainty evidence; Analysis 15.7), scratchy throat (RR 0.18, 95% CI 0.03 to 0.94; I² = 0%; 2 studies, 116 participants; very low‐certainty evidence; Analysis 15.8), sneezing (RR 0.40, 95% CI 0.12 to 1.40; I² = 0%; 2 studies, 110 participants; very low‐certainty evidence; Analysis 15.9) or sore throat (RR 0.25, 95% CI 0.03 to 1.97; I² = 43%; 2 studies, 114 participants; very low‐certainty evidence; Analysis 15.10).

15.1. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 1: Cough (dichotomous) (treatment)

15.2. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 2: Fever (dichotomous) (treatment)

15.3. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 3: Headache (dichotomous) (treatment)

15.4. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 4: Hoarseness (dichotomous) (treatment)

15.5. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 5: Muscle aches (dichotomous) (treatment)

15.6. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 6: Nasal congestion (dichotomous) (treatment)

15.7. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 7: Nasal drainage (dichotomous) (treatment)

15.8. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 8: Scratchy throat (dichotomous) (treatment)

15.9. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 9: Sneezing (dichotomous) (treatment)

15.10. Analysis.

Comparison 15: Number of individual cold symptoms by end of study ‐ treatment, Outcome 10: Sore throat (dichotomous) (treatment)

Qualitative narrative

Two studies that reported duration of individual symptoms were not included in the quantitative analysis (Douglas 1987; Kurugöl 2007). Kurugöl 2007 reported that the median time to resolution of nasal symptoms was 5 days (95% CI 4 to 6 days) in the placebo group and 5 days (95% CI 4 to 5 days) in the zinc group; duration of sore throat was shorter in the placebo group. However, the difference between the placebo and zinc groups was not statistically significant. Duration of cough, headache, muscle aches, and fever were similar in both groups. Douglas 1987 reported no consistent or significant differences in individual symptom duration.

4. Days missed from work or school

One treatment study reported the number of participants who had school absences and also the number of days of school missed over the entire follow‐up period (Macknin 1998).

4.1 Proportion missing days from work or school

It is uncertain whether there is a difference in the risk of having a school absence in children taking zinc compared to placebo (RR 0.89, 95% CI 0.54 to 1.47; 1 study, 249 participants, 49 participants with absences; very low‐certainty evidence; Analysis 16.1).

16.1. Analysis.

Comparison 16: Days missed from work or school ‐ treatment, Outcome 1: Proportion of participants missing days from work or school (treatment)

There may be little difference in the proportion of days of follow‐up missed with zinc versus placebo (RR 0.64, 95% CI 0.41 to 0.98; 1 study, 249 participants, 2454 days of follow‐up, 85 absences; very low‐certainty evidence; Analysis 16.2).

16.2. Analysis.

Comparison 16: Days missed from work or school ‐ treatment, Outcome 2: Proportion of days absent from work or school (treatment)

4.2 Mean days missed from work or school

No treatment study reported the mean days missed from work or school.

Publication bias

Only the analysis of adverse events during treatment met the criteria of having 10 or more studies required for publication bias assessment through construction of a funnel plot (Figure 4). We did not observe a strong suggestion of publication bias in the figure.

4.

Discussion

This review included 32 articles that reported on 34 unique studies, with two publications reporting multiple studies and arms within the publication (Farr Trial 1 1987; Farr Trial 2 1987; Turner 2000 challenge; Turner 2000 natural). Although the searches for this review were run on 22 May 2023 or later, the latest study included was published in 2020. This may be due to the pivoting of research to COVID‐19 in general, and for zinc as well. For example, a meta‐analysis published in 2022 on the use of zinc in COVID‐19 identified five studies, three of which were randomised controlled trials (RCTs), evaluating zinc and mortality in COVID‐19 (Tabatabaeizadeh 2022).

Summary of main results

The trials included in this review evaluated the effectiveness of zinc for the prevention, treatment, or combined prevention and treatment of the common cold. We included 15 prevention studies and 19 treatment studies.

Proportion of people developing a cold/upper respiratory tract infection (URTI)

When nine prevention studies were combined, we observed that zinc may lead to little or no difference in the proportion of those developing a cold over five days to seven months. We had insufficient studies to conduct pre‐planned subgroup analyses, but heterogeneity in the overall analysis was low (I² = 20%).

Mean number of colds/URTI developed

Two prevention studies reported the mean number of colds developed. When combined, we found that zinc may lead to little or no reduction in the number of colds over 5 to 18 months follow‐up time.

Mean duration of a cold/URTI

Eleven studies were meta‐analysed (three prevention, eight treatment). For prevention studies, there is likely little or no difference in the mean duration of colds when they do occur. When treatment studies were meta‐analysed, those taking zinc had a shorter duration of illness by about 2.4 days, but heterogeneity was high (I² = 97%). When intranasal versus lozenge administration routes and higher versus lower doses were compared, we observed no differences between subgroups (I² = 0%).

Proportion of participants with a cold/URTI at end of study

It is not certain whether there is a difference in the risk of having an ongoing cold at the end of the study follow‐up in those taking zinc compared to placebo (five treatment studies).

Adverse events, including those potentially due to zinc supplements

The majority of studies reported adverse events that were not considered serious, but could have possibly been due to zinc supplements. There was a very low certainty of evidence to determine whether there was a difference in the risk of adverse events for seven zinc prevention studies. There is probably an increase, however, in the risk of adverse events amongst 16 treatment studies. This effect appeared to be higher in studies of adults versus children (I² = 77.9%), for those taking higher doses of zinc (I² = 61.7%), and for lozenges versus intranasal zinc (I² = 54.6%), but there was no difference between zinc acetate and zinc gluconate (I² = 0%). The most common side effects were aberrations of taste, gastrointestinal discomfort, oropharyngeal or nasopharyngeal dryness, pain, irritation or sensitivity of the mouth or nose, and headache.

Serious adverse events, including those that may be complications of the common cold

Serious adverse events were only reported in three prevention studies included in the quantitative analysis; there was no significant difference between zinc and placebo. There was also no difference in the studies that were reported narratively in this review.

Variation in included studies

Overall, there was wide variation in interventions (including concomitant therapy) and outcomes across the studies, which needs to be considered when drawing conclusions on the efficacy of zinc for the common cold.

Zinc route of administration and formulation

In the included studies, zinc was most commonly taken as a lozenge, but it was also in several other forms, including intranasal spray, powder, gel, syrup, and tablet. Additionally, there are various formulations of zinc, which vary across methods of administration or within a method of administration. For example, in the included studies, lozenges contained zinc in the form of acetate, gluconate, and orotate. Intranasal administration had sulfate and gluconate, syrups had sulfate, and tablets had sulfate and chelate.

Dose

The dose of zinc also differed between administration types, zinc form, as well as within administration types. For example, amongst the studies reporting daily doses of gluconate lozenges in adults, daily doses were 106.4 mg (Mossad 1996), 184 mg (Smith 1989), 189.6 mg (Godfrey 1992), and 276 mg/day (Eby 1984).

Duration of treatment

Amongst treatment studies, most had treatment timing ending with the resolution of symptoms (14/19 studies) up to a maximum number of days, ranging from 7 to 21 days. However, zinc could have been taken for as little as two days up to 21 days. Duration of zinc use in prevention studies ranged even more, with the minimum treatment period of 4.5 days to a maximum period of 540 days (18 months).

Outcome reporting

There is variation in how outcomes are reported in the included studies. For example, one of the primary outcomes in the current review is the proportion of participants developing colds (in prevention trials). This was reported in the primary studies as:

1. the proportion of participants developing colds/URTI (Al‐Nakib 1987; Farr Trial 1 1987; Farr Trial 2 1987; Kartasurya 2012; Kurugöl 2006; Pooya 2006; Prasad 2007; Rerksuppaphol 2013; Turner 2001); and

2. the mean number of colds/URTI developed (McDonald 2015; Vakili 2009).

Although there are 11 studies reporting information on prevention, there were insufficient studies for either outcome to conduct exploratory subgroup analyses (e.g. method of administration, formulation of zinc, daily dose, factors impacting bioavailability, age groupings, zinc sufficiency/deficiency). A search of the Core Outcome Measures in Effectiveness Trials (COMET Initiative) (https://www.comet-initiative.org/) resulted in no results for outcomes for the common cold. A consistent set of outcomes for primary study authors to report on could strengthen the evidence and potentially increase the certainty of the evidence by allowing for additional studies to be included in a meta‐analysis, may have resulted in less downgrading for imprecision, and would have allowed for an assessment of publication bias (i.e. ≥ 10 studies) in this review.

Concomitant therapy

The use of concomitant therapy varied across the studies. Amongst the 19 treatment studies, six allowed the use of fever‐reducers, eight forbade any concomitant therapies, one study had no limitations, and three studies did not report this detail. Amongst the prevention studies, one study allowed fever‐reducers, two studies forbade any concomitant therapies, one study also gave vitamin A, one study provided a liquid nutrient supplement, and seven did not report on this. As some medications and other supplements may interact with zinc and make it less effective, it is unclear if this was the case in the studies that did not report on concomitant therapies.

Overall completeness and applicability of evidence

The majority of the trials were conducted in adults (22/34). This may impact generalisability in all populations. The number of participants in the trials was small (12 of 34 studies included ≥ 200 participants), which may limit precision, even when meta‐analysed. The majority of the trials were conducted in countries identified as high (5/34) and very high (23/34) human development using the United Nations Development Programme Human Development Index categorisation (https://hdr.undp.org/data-center/human-development-index#/indicies/HDI. Note: Turkey was not in the list, therefore two studies did not have a category assigned).

Certainty of the evidence

We conducted GRADE assessments to determine the certainty of the evidence. For our primary outcomes, the certainty of the evidence was moderate for two analyses, low for six analyses, and very low for three analyses (i.e. risk of adverse events with prophylactic zinc, risk of continuing colds at study’s end, standardised mean global symptom severity) (Table 1; Table 2). Amongst the 11 analyses, the domain‐specific information is as follows:

1. nine analyses were rated down by one or two levels due to risk of bias (further described below), with only duration of colds in prevention studies and number of serious adverse events in treatment studies outcomes not rated down;

2. five analyses were rated down due to inconsistency (i.e. heterogeneity (I² ≥ 50%));

3. zero analyses were rated down due to indirectness, as all studies matched the population of interest for this review;

4. six analyses were rated down for imprecision (four by one level and two by two levels); and

5. zero analyses were rated down for other reasons (e.g. publication bias), although only one of the analyses had ≥ 10 studies that would allow for publication bias assessment (Egger 1997).

The certainty of the evidence for these analyses suggests that use of zinc may result in little or no reduction in the risk of developing a cold, but when used as a treatment may result in some reduction in cold duration.

Risk of bias

Using the Cochrane risk of bias tool (Higgins 2011), incomplete reporting of several domains did not allow for assessment, which resulted in an 'unclear' judgement. Specifically, amongst the 34 trials, 19 trials reported an inadequate or unclearly reported method of randomisation, 18 trials reported an inadequate or unclear method for how allocation concealment was done, nine trials did not report if the participants and personnel were blind to treatment group, 10 trials did not report if outcome assessors were blind to treatment group, 12 trials did not report adequately enough to determine if there was incomplete outcome data (or there were concerns as to how missing data might impact findings), and only one trial clearly avoided selective outcome reporting (e.g. provided a trial registry number or a protocol that could be checked).

Overall, one trial was determined to be low risk of bias across all domains, 23 trials had at least one unclear judgement (but no high risk judgements), seven trials had one high‐risk judgement, and three trials had two high‐risk judgements.

Potential biases in the review process

We searched multiple electronic databases, performed supplemental searching, contacted an expert in the field, and two review authors independently screened records for inclusion, and we are confident that we have identified all, or nearly all, relevant studies. However, we did not search Asian databases (e.g. the China Knowledge Resource Integrated Database (CNKI)) and cannot be certain that we did not miss relevant studies from these sources. Furthermore, as we judged most trials as having unclear risk of selective reporting bias and seven trials as high risk for selective reporting, it is possible that not all relevant outcomes were captured in the published trials that we identified.

We also included participants diagnosed with upper respiratory tract infections (URTIs) when we judged that such diagnoses could include the common cold. This decision was made to ensure that we included the most accurate evidence possible, but it may also have incurred bias depending on how the original authors defined such terms. To mitigate this potential for bias, we performed an additional sensitivity analysis, removing studies that used the URTI terminology instead of 'common cold' as we originally intended.

Agreements and disagreements with other studies or reviews

Several meta‐analyses and reviews have been conducted in this area. The reviews were withdrawn (Singh 2015), included only adults (Wang 2020), and/or were specific to zinc formulations and administration (e.g. orally administered, zinc acetate) (Hemilä 2015; Science 2012; Wang 2020), or were not systematic reviews (i.e. did not assess risk of bias of included studies) (Hulisz 2004). This current review expands on these existing reviews by including all methods of administration and formulations of zinc for prevention or treatment of colds in adults and children.

Results tend to be similar across meta‐analyses regardless of studies included. For example, the mean difference in those taking zinc (any method of administration and formulation) compared to placebo in the duration of the common cold in the current review was ‐2.37 days (95% CI ‐4.21 to ‐0.53; P = 0.01, I² = 97%; 8 studies, 972 participants; low‐certainty evidence; Analysis 9.1). We discuss the other reviews here and compare this outcome, as an illustration. Briefly, across the current review and the other systematic reviews that performed a meta‐analysis, the mean duration of the cold symptoms was reduced (i.e. statistically significant), but there were high levels of heterogeneity.

The 2004 overview by Hulisz 2004 investigating the efficacy of zinc for the common cold included 16 RCTs, all of which were included in this review. Hulisz 2004 concluded that “Clinical trial data support the value of zinc in reducing the duration and severity of symptoms of the common cold when administered within 24 hours of the onset of common cold symptoms.” However, the overview did not evaluate the risk of bias of the included studies, meta‐analyse the data, or assess the certainty of the evidence, which may have affected their overall conclusions.

The 2012 systematic review and meta‐analysis by Science 2012 included 15 publications with 17 trials evaluating oral zinc formulations for treatment of the common cold. All publications and their studies are included in the current review. The authors reported that oral zinc formulations may shorten the duration of symptoms of the common cold (MD ‐1.65, ‐2.50 to ‐0.81; I² = 93.6%; 8 studies).

The 2015 Cochrane review by Singh 2015, which has since been withdrawn, included 15 unique publications and 18 studies. All 15 publications and their studies are included in the current review. However, Singh 2015 did not include studies that evaluated intranasal zinc administration and the latest study was published in 2009. The authors concluded that zinc administered within 24 hours of symptom onset reduced the duration of the cold in healthy people (MD ‐1.03 days, ‐1.72 to ‐0.34; I² = 89%; 14 studies), but due to the heterogeneity of the data, caution is needed.

The 2015 meta‐analysis by Hemilä 2015 investigated whether high‐dose zinc acetate lozenges have different effects on the duration of various common cold symptoms originating from different anatomical regions. Zinc reduced the symptoms of many common cold symptoms (e.g. nasal discharge, nasal congestion, scratchy throat, cough, muscle ache) but not all (headache and fever) and the authors reported that there “is no indication that the effect of zinc lozenges on nasal symptoms is less than the effect on the symptoms of the pharyngeal region, which is more exposed to released zinc ions.” The three studies in the meta‐analysis (Petrus 1998; Prasad 2000; Prasad 2008) were captured in the current review and the findings are consistent with those of our meta‐analyses.

Three additional meta‐analyses primarily focused on zinc acetate (Hemilä 2016; Hemilä 2017a; Hemilä 2017b) found that treatment with zinc acetate reduced the duration of the common cold by approximately three days (Hemilä 2016), that people treated with zinc recovered faster by a rate ratio of 3.1 (Hemilä 2017b), and that the effect of zinc acetate appeared similar to that of zinc gluconate and did not appear to be modified by high versus low dose (Hemilä 2017a). Although the analyses in the current review were different from those of these reviews (Hemilä 2016 and Hemilä 2017b were individual patient data meta‐analyses, Hemilä 2017a used different dose ranges in the subgroup analyses by dose, and Hemilä 2017b used survival analysis), we included the same studies and our findings were broadly consistent.

The 2020 systematic review by Wang 2020 evaluated the use of several different micronutrient supplements, and included 10 studies of oral administration of zinc given to adults. The authors concluded that micronutrient supplementation may not prevent cold incidence or reduce symptom severity amongst healthy adults, which is consistent with our findings on zinc to prevent the common cold. For cold treatment with zinc, the authors found no evidence of a reduction of global symptom severity but reported that zinc supplementation reduced cold duration by 2.25 days, 95% CI ‐3.39 to ‐1.12; I² = 83%; 6 studies; both observations are consistent with our findings.

A rapid review published during the conduct of this review examined zinc for the prevention and treatment of viral respiratory illnesses in adults (Hunter 2021). Hunter 2021 concluded that oral or intranasal zinc has no effect on preventing a clinical cold after human rhinovirus inoculation but prevents five community‐acquired respiratory tract infections per 100 person‐months, which is not consistent with our finding of little or no reduction in overall risk of the common cold/URTI with zinc. This discrepancy may be explained by a different classification of viral illness, a different study population, and the inclusion of different studies. Hunter 2021 separately analysed cold infections acquired in the community and those resulting from viral challenge, while we did not differentiate between these and also included participants diagnosed with URTIs when we judged that such diagnoses likely represented the common cold. While Hunter 2021 includes only studies in adults, the current review includes studies in both children and adults, and our primary analysis of risk of developing a common cold/URTI includes four studies of community‐acquired infections in children. While our analysis did not have the 10 studies necessary to conduct a subgroup analysis by age, the overall heterogeneity was low (I² = 20%). In addition, Hunter 2021 includes two trials testing nasal spray for prevention of community‐acquired infection that are available only in Chinese and were not found in our searches, and one trial that we excluded as a quasi‐randomised study (Veverka 2009), while we included one study of community‐acquired common colds in adults (Pooya 2006) not included in Hunter 2021. Since our rating of certainty of the evidence for this outcome was 'low', it is possible that further study identification and analysis may identify specific populations, interventions, or outcomes where zinc has some preventative activity. In regard to treatment, Hunter 2021 estimates that zinc treatment may reduce the duration of symptoms of viral illness by two days (95% CI 0.59 to 3.50; I² = 97%), which is broadly consistent with the findings of this review. Hunter 2021 is also in agreement with this review that when zinc is compared with placebo to prevent the common cold there may be no difference in the risk of adverse events, but when zinc is compared with placebo for the treatment of the common cold there is probably an increase in the risk of non‐serious adverse events.

Authors' conclusions

Implications for practice.

This Cochrane review found varied evidence to support the effectiveness of zinc in the prevention or treatment of the common cold. Zinc supplementation may provide some limited benefits for people with the common cold. On the basis of this review, the current evidence is insufficient to provide firm conclusions or recommend zinc supplementation for the prevention or treatment of the common cold.

Implications for research.

Zinc supplementation for the prevention of the common cold or as an effective treatment has been widely studied. However, the certainty of evidence was mostly low to very low, and was insufficient to draw firm conclusions. Future researchers should note the need for standardised methods when providing zinc supplementation for the prevention or treatment of the common cold. More research is needed to determine the exact zinc type, dose, and duration of supplementation appropriate for the prevention or treatment of the common cold. Future directions for research might be to consider exploring the subjective experience or quality of life of participants while taking zinc, increasing the diversity of characteristics in the participants recruited (varied race/ethnicity, age, gender, health status), and further examining factors that may interfere with the bioavailability of zinc.

History

Protocol first published: Issue 9, 2021

Appendices

Appendix 1. Search strategies

PubMed (1809 to present)

#1 (zinc[tiab] OR zn[tiab] OR zinc[mesh] OR “zinc compounds”[mesh] OR “zinc acetate”[mesh])
#2 (common cold*[tiab] OR rhinovirus*[tiab] OR rhinitis[tiab] OR coryza[tiab] OR catarrh[tiab] OR
upper respiratory infection*[tiab] OR upper respiratory tract infection*[tiab] OR uri[tiab] OR urti[tiab]
OR upper airway infection*[tiab] OR cold virus*[tiab] OR colds[tiab] OR “common cold”[mesh] OR
“rhinovirus”[mesh] OR “rhinitis”[mesh] OR “respiratory tract infections”[mesh])
#3 #1 AND #2
#4 randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR
placebo[tiab] OR clinical trials as topic[mesh:noexp] OR randomly[tiab] OR trial[ti]
#5 Animals[mh] NOT humans[mh]
#6 #4 NOT #5
#7 #3 AND #6

Embase (embase.com, 1947 to present)

#1 (zinc:ab,ti OR zn:ab,ti OR zinc/de OR ‘zinc derivative’/de OR ‘zinc acetate’/de OR ‘zinc sulfate’/de
OR ‘gluconate zinc’/de)
#2 (‘common cold*’:ab,ti OR rhinovirus*:ab,ti OR rhinitis:ab,ti OR coryza:ab,ti OR catarrh:ab,ti OR
‘upper respiratory infection*’:ab,ti OR ‘upper respiratory tract infection*’:ab,ti OR uri:ab,ti OR urti:ab,ti
OR ‘upper airway infection*’:ab,ti OR ‘cold virus*’:ab,ti OR colds:ab,ti OR ‘common cold’/de OR
‘rhinovirus infection’/exp OR rhinitis/de OR ‘upper respiratory tract infection’/exp)
#3 #1 AND #2
#4 ‘randomized controlled trial’/exp OR ‘controlled clinical trial’/exp OR randomized:ab,ti OR
placebo:ab,ti OR ‘clinical trial (topic)’/exp OR randomly:ab,ti OR trial:ti
#5 [animals]/lim NOT [humans]/lim
#6 #4 not #5
#7 #3 and #6

Cochrane CENTRAL (Wiley, 1996 to present)

#1 (zinc or zn):ti,ab,kw
#2 MeSH descriptor: [Zinc] explode all trees
#3 MeSH descriptor: [Zinc Compounds] explode all trees
#4 MeSH descriptor: [Zinc Acetate] explode all trees
#5 #1 or #2 or #3 or #4
#6 (“common cold*” or rhinovirus* or rhinitis or coryza or catarrh or “upper respiratory infection*”
or “upper respiratory tract infection*” or uri or urti or “upper airway infection*” or “cold virus*” or
colds):ti,ab,kw
#7 MeSH descriptor: [Common Cold] explode all trees
#8 MeSH descriptor: [Rhinovirus] explode all trees
#9 MeSH descriptor: [Respiratory Tract Infections] explode all trees
#10 #6 or #7 or #8 or #9
#11 #5 and #10

CINAHL (EBSCOhost, 1981 to present)

S1 zinc or zn S2 "common cold*" or rhinovirus* or rhinitis or coryza or catarrh or "upper respiratory infection*"or "upper respiratory tract infection*" or uri or urti or "upper airway infection*" or "cold virus*" or coldsS3 S1 AND S2S4 TI double‐blind OR AB double‐blind OR TI random* assigned OR AB random* assigned OR TIcontrol OR AB controlS5 S3 and S4LILACS (https://lilacs.bvsalud.org/en/, 1985‐present) 11 results on 8/4/2021; 12 results on 5/22/2023(zinc or zn [Words])AND("common cold$" or rhinovirus$ or rhinitis or coryza or catarrh or "upper respiratory infection$" or"upper respiratory tract infection$" or uri or urti or "upper airway infection$" or "cold virus$" or colds[Words])Web of Science Core Collection (Clarivate Analytics, 1900‐present) 254 results on 6/14/2023#1 (TI=(zinc or zn)) OR AB=(zinc or zn)#2 TS=(zinc or “zinc compounds” or “zinc acetate”)#3 #1 or #2#4 (TI=("common cold" or "common colds" or rhinovirus* or rhinitis or coryza or catarrh or "upperrespiratory infection" or "upper respiratory infections" or "upper respiratory tract infection" or "upperrespiratory tract infections" or uri or urti or "upper airway infection" or "upper airway infections" or"cold virus" or "cold viruses" or colds)) OR AB=("common cold" or "common colds" or rhinovirus* orrhinitis or coryza or catarrh or "upper respiratory infection" or "upper respiratory infections" or "upper respiratory tract infection" or "upper respiratory tract infections" or uri or urti or "upper airway
infection" or "upper airway infections" or "cold virus" or "cold viruses" or colds)
#5 TS=("common cold" or rhinovirus or rhinitis or "respiratory tract infections")
#6 #4 or #5
#7 #3 and #6
#8 (TI=(randomized or placebo or randomly or trial)) OR AB=(randomized or placebo or randomly)
#9 TS=("randomized controlled trial" or "controlled clinical trial" or "clinical trials as topic")
#10 #8 or #9
#11 #7 and #10

ClinicalTrials.gov

Other terms: ("common cold" OR rhinovirus OR rhinitis) AND (zinc)

WHO ICTRP

Title: (“common cold” OR rhinovirus OR rhinitis) AND zinc

Data and analyses

Comparison 1. Proportion of participants developing colds (for analyses of prevention trials only), with colds as defined by each study ‐ prevention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Proportion of participants developing colds/URTI: primary analysis	9	1449	Risk Ratio (IV, Random, 95% CI)	0.93 [0.85, 1.01]

Comparison 2. Mean number of colds/URTIs developed (for analyses of prevention trials only), with colds as defined by each study ‐ prevention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Mean number of colds/URTIs developed: primary analysis	2	1284	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.93, 0.12]

Comparison 3. Mean duration of colds (measured in days from start to resolution of the cold, as defined by each study) ‐ prevention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Mean duration of colds/URTIs (prevention): primary analysis	3	740	Mean Difference (IV, Random, 95% CI)	‐0.63 [‐1.29, 0.04]

Comparison 4. Adverse events ‐ prevention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Adverse events (prevention): primary analysis	7	1517	Risk Ratio (IV, Random, 95% CI)	1.11 [0.84, 1.47]
4.2 Serious adverse events (prevention): primary analysis	3	1563	Risk Ratio (IV, Random, 95% CI)	1.67 [0.78, 3.57]

Comparison 5. Global severity of the cold (using a global measure, or by summing severity scores for individual symptoms) ‐ prevention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Standardised mean global symptom severity (prevention)	2	101	Std. Mean Difference (IV, Random, 95% CI)	0.04 [‐0.35, 0.43]

Comparison 6. Severity of individual cold symptoms (measured on a scale) ‐ prevention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Severity of nasal congestion (prevention)	1	69	Std. Mean Difference (IV, Random, 95% CI)	‐0.08 [‐0.55, 0.40]
6.2 Severity of nasal drainage (prevention)	1	69	Std. Mean Difference (IV, Random, 95% CI)	‐0.28 [‐0.75, 0.20]
6.3 Severity of nasal symptoms (prevention)	1	32	Std. Mean Difference (IV, Random, 95% CI)	‐0.05 [‐0.74, 0.64]

Comparison 7. Mean duration of individual cold symptoms ‐ prevention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Cough (continuous) (prevention)	2	294	Mean Difference (IV, Random, 95% CI)	‐1.84 [‐5.41, 1.74]
7.2 Nasal drainage (continuous) (prevention)	2	294	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐5.86, 2.06]
7.3 Fever (continuous) (prevention)	2	294	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.43, 0.25]
7.4 Headache (continuous) (prevention)	1	194	Mean Difference (IV, Random, 95% CI)	0.00 [‐0.16, 0.16]
7.5 Hoarseness (continuous) (prevention)	1	194	Mean Difference (IV, Random, 95% CI)	‐0.02 [‐0.18, 0.14]
7.6 Muscle aches (continuous) (prevention)	1	194	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.25, 0.05]
7.7 Nasal congestion (continuous) (prevention)	1	194	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.45, 0.05]
7.8 Sneezing (continuous) (prevention)	1	194	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.36, ‐0.04]
7.9 Sore throat (continuous) (prevention)	1	194	Mean Difference (IV, Random, 95% CI)	‐0.60 [‐1.05, ‐0.15]

Comparison 8. Days missed from work or school ‐ prevention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Proportion of participants missing days from work or school (prevention)	1	100	Risk Ratio (IV, Random, 95% CI)	0.93 [0.49, 1.77]
8.2 Mean days missed from work or school (prevention)	2	394	Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.03, ‐0.27]

Comparison 9. Mean duration of colds (measured in days from start to resolution of the cold, as defined by each study) ‐ treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Mean duration of colds/URTIs (treatment): primary analysis	8	972	Mean Difference (IV, Random, 95% CI)	‐2.37 [‐4.21, ‐0.53]
9.2 Subgroup analysis (treatment): all administration routes	8	972	Mean Difference (IV, Random, 95% CI)	‐2.37 [‐4.21, ‐0.53]
9.2.1 Intranasal	3	451	Mean Difference (IV, Random, 95% CI)	‐3.15 [‐7.36, 1.05]
9.2.2 Lozenge	5	521	Mean Difference (IV, Random, 95% CI)	‐1.96 [‐3.14, ‐0.77]
9.3 Subgroup analysis (treatment): daily dose of zinc	8	972	Mean Difference (IV, Random, 95% CI)	‐2.37 [‐4.21, ‐0.53]
9.3.1 > 85 mg/d	4	272	Mean Difference (IV, Random, 95% CI)	‐2.36 [‐3.51, ‐1.22]
9.3.2 < 85 mg/d	4	700	Mean Difference (IV, Random, 95% CI)	‐2.38 [‐6.10, 1.34]

Comparison 10. Risk of cold/URTIs at end of study (measured in days from start to resolution of the cold, as defined by each study) ‐ treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Risk of ongoing cold/URTIs at end of study (treatment): primary analysis	5	357	Risk Ratio (IV, Random, 95% CI)	0.52 [0.21, 1.27]

Comparison 11. Adverse events ‐ treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Adverse events (treatment): primary analysis	16	2084	Risk Ratio (IV, Random, 95% CI)	1.34 [1.15, 1.55]
11.2 Subgroup analysis (treatment): intranasal vs lozenge	14	1923	Risk Ratio (IV, Random, 95% CI)	1.35 [1.16, 1.58]
11.2.1 Intranasal	3	451	Risk Ratio (IV, Random, 95% CI)	1.12 [0.85, 1.47]
11.2.2 Lozenge	11	1472	Risk Ratio (IV, Random, 95% CI)	1.44 [1.19, 1.75]
11.3 Subgroup analysis (treatment): zinc acetate vs zinc gluconate	12	1633	Risk Ratio (IV, Random, 95% CI)	1.39 [1.17, 1.64]
11.3.1 Zinc acetate	6	655	Risk Ratio (IV, Random, 95% CI)	1.53 [1.06, 2.20]
11.3.2 Zinc gluconate	8	978	Risk Ratio (IV, Random, 95% CI)	1.33 [1.10, 1.62]
11.4 Subgroup analysis (treatment): daily dose of zinc	16	2084	Risk Ratio (IV, Random, 95% CI)	1.34 [1.15, 1.55]
11.4.1 < 85 mg/d	9	1584	Risk Ratio (IV, Random, 95% CI)	1.20 [1.03, 1.40]
11.4.2 > 85 mg/d	7	500	Risk Ratio (IV, Random, 95% CI)	1.54 [1.19, 1.99]
11.5 Subgroup analysis (treatment): age groupings	15	1954	Risk Ratio (IV, Random, 95% CI)	1.33 [1.14, 1.54]
11.5.1 < 18 yo	2	363	Risk Ratio (IV, Random, 95% CI)	1.11 [0.99, 1.24]
11.5.2 > 18 yo	13	1591	Risk Ratio (IV, Random, 95% CI)	1.40 [1.17, 1.68]

Comparison 12. Global severity of the cold (using a global measure, or by summing severity scores for individual symptoms) ‐ treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Standardised mean global symptom severity (treatment)	2	261	Std. Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.56, 0.50]
12.2 Proportion with changes in global symptom severity (treatment)	1	114	Risk Ratio (IV, Random, 95% CI)	1.02 [0.85, 1.23]

Comparison 13. Severity of individual cold symptoms (measured on a scale) ‐ treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Severity of cough (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	‐0.40 [‐0.80, ‐0.01]
13.2 Severity of headache (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.54, 0.24]
13.3 Severity of hoarseness (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.48, 0.30]
13.4 Severity of malaise (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	0.00 [‐0.39, 0.39]
13.5 Severity of muscle aches (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.54, 0.24]
13.6 Severity of nasal congestion (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	0.23 [‐0.16, 0.62]
13.7 Severity of nasal drainage (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	‐0.32 [‐0.71, 0.07]
13.8 Severity of scratchy throat (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	‐0.23 [‐0.62, 0.16]
13.9 Severity of sneezing (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.54, 0.24]
13.10 Severity of sore throat (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.52, 0.26]
13.11 Severity of fever (treatment)	1	101	Std. Mean Difference (IV, Random, 95% CI)	Not estimable

Comparison 14. Mean duration of individual cold symptoms ‐ treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
14.1 Cough (continuous) (treatment)	6	537	Mean Difference (IV, Random, 95% CI)	‐1.67 [‐2.97, ‐0.37]
14.2 Fever (continuous) (treatment)	5	376	Mean Difference (IV, Random, 95% CI)	‐0.29 [‐0.80, 0.21]
14.3 Headache (continuous) (treatment)	6	488	Mean Difference (IV, Random, 95% CI)	‐0.49 [‐0.97, ‐0.02]
14.4 Hoarseness (continuous) (treatment)	6	493	Mean Difference (IV, Random, 95% CI)	‐0.94 [‐1.89, 0.00]
14.5 Malaise (continuous) (treatment)	1	101	Mean Difference (IV, Random, 95% CI)	0.70 [‐1.53, 2.93]
14.6 Muscle aches (continuous) (treatment)	6	441	Mean Difference (IV, Random, 95% CI)	‐0.66 [‐1.17, ‐0.16]
14.7 Nasal congestion (continuous) (treatment)	6	588	Mean Difference (IV, Random, 95% CI)	‐1.41 [‐2.20, ‐0.62]
14.8 Nasal drainage (continuous) (treatment)	6	582	Mean Difference (IV, Random, 95% CI)	‐1.75 [‐2.73, ‐0.77]
14.9 Scratchy throat (continuous) (treatment)	1	101	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.40, 0.10]
14.10 Sneezing (continuous) (treatment)	6	543	Mean Difference (IV, Random, 95% CI)	‐0.77 [‐1.31, ‐0.23]
14.11 Sore throat (continuous) (treatment)	6	514	Mean Difference (IV, Random, 95% CI)	‐0.88 [‐1.60, ‐0.16]
14.12 Nasal symptoms (continuous) (treatment)	1	99	Mean Difference (IV, Random, 95% CI)	‐3.70 [‐5.72, ‐1.68]
14.13 Throat symptoms (continuous) (treatment)	1	99	Mean Difference (IV, Random, 95% CI)	‐2.30 [‐3.84, ‐0.76]

Comparison 15. Number of individual cold symptoms by end of study ‐ treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
15.1 Cough (dichotomous) (treatment)	2	106	Risk Ratio (IV, Random, 95% CI)	0.42 [0.19, 0.94]
15.2 Fever (dichotomous) (treatment)	1	22	Risk Ratio (IV, Random, 95% CI)	0.10 [0.01, 1.76]
15.3 Headache (dichotomous) (treatment)	2	111	Risk Ratio (IV, Random, 95% CI)	0.50 [0.10, 2.57]
15.4 Hoarseness (dichotomous) (treatment)	2	115	Risk Ratio (IV, Random, 95% CI)	0.23 [0.05, 1.02]
15.5 Muscle aches (dichotomous) (treatment)	2	104	Risk Ratio (IV, Random, 95% CI)	0.33 [0.05, 2.11]
15.6 Nasal congestion (dichotomous) (treatment)	2	119	Risk Ratio (IV, Random, 95% CI)	0.38 [0.17, 0.82]
15.7 Nasal drainage (dichotomous) (treatment)	2	124	Risk Ratio (IV, Random, 95% CI)	0.36 [0.19, 0.71]
15.8 Scratchy throat (dichotomous) (treatment)	2	116	Risk Ratio (IV, Random, 95% CI)	0.18 [0.03, 0.94]
15.9 Sneezing (dichotomous) (treatment)	2	110	Risk Ratio (IV, Random, 95% CI)	0.40 [0.12, 1.40]
15.10 Sore throat (dichotomous) (treatment)	2	114	Risk Ratio (IV, Random, 95% CI)	0.25 [0.03, 1.97]

Comparison 16. Days missed from work or school ‐ treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
16.1 Proportion of participants missing days from work or school (treatment)	1	249	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.54, 1.47]
16.2 Proportion of days absent from work or school (treatment)	1	2454	Risk Ratio (IV, Random, 95% CI)	0.64 [0.41, 0.98]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Al‐Nakib 1987.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: there were 3 separate trials: a tolerance study, a prophylaxis study, and a therapeutic study. Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: generally, the lozenges were well tolerated despite the relatively large number taken. Some volunteers complained that the taste of food was affected by the lozenges, but there were no serious objections to either zinc or placebo lozenges. A similar finding was obtained with the other 8 volunteers, of whom 3 received zinc and 5 placebo and who were challenged with saline. These results supported those of preliminary tests, which indicated that the placebo and medicated lozenges were indistinguishable by appearance and taste. Duration of follow‐up: it is not explicitly stated, but it appears from Figures 1 and 2 that participants in both the prophylaxis and therapeutic studies were followed for 6 days. Duration of intervention: for prophylaxis trial, intervention began 24 hours before viral challenge and ended 3.5 days after the challenge. For treatment, intervention began after development of colds and lasted 6 days. Duration of run‐in or washout period: all participants were kept in quarantine for 48 hours before beginning the trial, to ensure they were free of cold symptoms. Viral challenge (prevention): "The morning of the second day of medication volunteers were challenged with either 102 tissue culture infecting dose (TCID50) of human rhinovirus2 (HRV‐2) or saline administered in a volume of 1 ml as nose drops (0‐5 ml per nostril). A bacteria free pool of nasal washings was prepared from volunteers inoculated with HRV‐2, and the washings then diluted in Hanks' saline with 0‐2% bovine plasma albumin (BPA). Volunteers received 102 TCID50 of virus in 1 ml (0‐5 per nostril)." How participants were identified as having colds/URTI at baseline (treatment trial): participants had developed colds, which was defined as "the use of four or more tissues over the baseline number for that volunteer with at least one other symptom of a cold, e.g. sore throat, nasal stuffiness, sneezing." Outcomes measured: prophylaxis study: 1) development of a clinical cold (y/n); 2) mean daily clinical score (details not provided); 3) mean nasal secretion weight; 4) excretion of virus. Therapeutic study: 1) mean daily clinical score (details not provided); 2) mean daily nasal secretion weights; 3) mean number of tissues used; excretion of virus
Participants	Setting: community participants, housed in the Common Cold Unit for the duration of the study Country: UK Zinc gluconate 276 mg/d lozenge Number: 29 Percentage female: 48% Age (mean (SD)): 31.55 Placebo lozenge Number: 28 Percentage female: 46% Age (mean (SD)): 29.39 Overall Number: 57 Percentage female: 47% Age (mean (SD)): 30.49 Inclusion criteria: participants were healthy volunteers of either sex aged 19 to 50 years. However, it is unclear whether the age range reflects specific inclusion criteria. Exclusion criteria: no specific exclusion criteria Group differences: similar in pre‐trial rhinovirus antibody titres, sex distribution, and mean age (described for the prophylaxis trial only). Table 1 shows volunteers were also well‐balanced for psychological scores. Condition studied: common cold Description of recruitment: NR Diagnostic criteria for condition: for prophylaxis study, virus isolation (from nasal washing) and/or 4‐fold or greater rises in antibody titre were considered to indicate infection. "Volunteers were examined daily and their symptoms and signs recorded and scored. Colds were graded as doubtful, mild, moderate or severe." In the therapeutic study, development of a cold was defined as "the use of four or more tissues over the baseline number or that volunteer with at least one other symptom of a cold, e.g. sore throat, nasal stuffiness, sneezing." Number of study centres: 1 Number of withdrawals: NR Total number screened/eligible/randomised: NR/NR/57 (prophylaxis study) 69/12/12 (treatment study) NR/NR/69 (all trials combined)
Interventions	Zinc gluconate 276 mg/d lozenge Study description of intervention and administration: "Zinc gluconate lozenges (23 mg) and identical placebo lozenges containing no zinc gluconate were supplied by RBS Pharma, Milan, Italy. They were formulated with sugar and flavoured." "Volunteers were asked to suck slowly and dissolve in the mouth one zinc gluconate lozenge containing 23 mg of elemental zinc or placebo every 2 h while they were awake, to a maximum of 12 lozenges a day." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): zinc gluconate Frequency of dose: every 2 hours while awake Dose per day (elemental zinc in mg): NR max allowable 276 mg Duration of treatment: 4.5 days for prophylaxis; 6 days for treatment Placebo lozenge Study description of intervention and administration: "Zinc gluconate lozenges (23 mg) and identical placebo lozenges containing no zinc gluconate were supplied by RBS Pharma, Milan, Italy. They were formulated with sugar and flavoured." "Volunteers were asked to suck slowly and dissolve in the mouth one zinc gluconate lozenge containing 23 mg of elemental zinc or placebo every 2 h while they were awake, to a maximum of 12 lozenges a day." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: every 2 hours while awake Duration of treatment: 4.5 days for prophylaxis; 6 days for treatment
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Direction: lower is better Data value: endpoint
Identification	Author's name: W. Al‐Nakib Institution: MRC Common Cold Unit, Harvard Hospital Email: none Address: Coombe Road, Salisbury, Wiltshire SP2 8BW, UK Trial registration identifier: none Year study recruitment began: NR prior to 1987
Notes	Declaration of interest: zinc gluconate and placebo lozenges were donated by RBS Pharma, Milan Funding source: NR Contact with study authors: none Other: the article reports 3 trials: a tolerance study (not relevant to this review), a prophylaxis study (only data on development of a clinical cold could be extracted), and a therapeutic study (data for relevant outcomes cannot be extracted).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "In the tolerance and prophylactic trials, they were divided into groups balanced for age and sex and members of each group were randomly allocated to receive zinc gluconate lozenges or placebo." Judgement comment: says they were randomly allocated, not how.
Allocation concealment (selection bias)	Unclear risk	Judgement comment: no information about processes for allocation
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Some volunteers complained that the taste of food was affected by the lozenges but there were no serious objections to either zinc or placebo lozenges. A similar finding was obtained with the other eight volunteers, of whom three received zinc and five placebo and who were challenged with saline. These results supported those of preliminary tests which indicated that the placebo and medicated lozenges were indistinguishable by appearance and taste." Judgement comment: trial was designed to blind participants by using placebo however the participants in the prophylaxis and treatment trials were not asked whether they could distinguish between zinc and placebo. No information about blinding of personnel.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Judgement comment: no information about blinding of outcome assessors.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Judgement comment: although the study report did not explicitly state that there were no withdrawals, the short duration of the studies and the lack of mention of withdrawals makes it very possible that there were no withdrawals.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: there was no mention of a protocol or pre‐planned outcome assessment and analysis.
Other bias	Low risk	Judgement comment: no other apparent sources of risk of bias.

Belongia 2001.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments are explicitly allowed or forbidden: "In addition, patients who received antibiotics while participating in the study were excluded from analyses." "They were asked to refrain from using cough and cold medications (other than acetaminophen), and multivitamins containing zinc." Investigation of ability to distinguish between zinc and placebo: "During the exit interview, 22 (27%) participants in the zinc group and 18(23%) in the placebo group guessed that they received the zinc preparation (P=0.59)." Duration of follow‐up: "Participants were asked to return for an exit interview after symptoms had resolved for at least 24 hours or upon completion of 14 days of treatment, whichever came first." Duration of intervention: up to 14 days Duration of run‐in or washout period: NR How participants were identified as having colds/URTI at baseline (treatment trial): "...two or more of the following symptoms for less than 24 hours at the time of enrolment: cough, stuffy nose, runny nose, hoarseness, sore/itchy throat, headache, sneezing, or muscle ache." "During the initial intake, a nasopharyngeal swab was collected for virus detection, a urine pregnancy test was per‐formed (if appropriate), and a throat swab was collected for Group A Streptococcus rapid antigen detection and culture. A structured interview was conducted to assess eligibility criteria and symptom status." "Nasopharyngeal swabs were tested for respiratory syncytial virus antigen, and cell culture was performed to detect influenza A and B, parainfluenza, and rhinovirus." Outcomes measured: duration of cold; global severity of the cold; duration of individual cold symptoms; severity of individual cold symptoms; adverse events
Participants	Setting: clinic Country: US Zinc sulfate 0.044 mg/d nasal spray Number: 81 Percentage female: 86.4% Age (mean (SD)): 40 (11) Placebo nasal spray Number: 79 Percentage female: 86.1% Age (mean (SD)): 38 (11) Overall Number: 160 Percentage female: 86.3% Age (mean (SD)): 39(11) Inclusion criteria: "Eligibility criteria included having two or more of the following symptoms for less than 24 hours at the time of enrolment: cough, stuffy nose, runny nose, hoarseness, sore/itchy throat, headache, sneezing, or muscle ache." Exclusion criteria: "Patients were excluded if they were pregnant, smoked tobacco products during the past 12 months, or had any of the following: immunodeficiency, recent sinus infection(diagnosed by a physician in the past 30 days), chronic lung disease, zinc allergy, or allergic rhinitis (diagnosed or treated by a physician in the past 12 months). Patients with symptoms for longer than 24 hours or with a positive culture or rapid antigen test for Group A Streptococcus were also excluded. In addition, patients who received antibiotics while participating in the study were excluded from analyses" Group differences: "The symptom scores at the time of enrolment were similar (P=0.10) in the two groups with the exception of headache. The mean baseline headache score was 0.76(0.8) in the zinc group and 0.96(0.9) in the placebo group (P=0.07). There was a modest difference in the total symptom score between the two groups at the time of enrolment" Condition studied: AURI Description of recruitment: "Participants were recruited by advertising in a weekly newsletter for Marshfield Clinic employees and through limited newspaper advertising. Potential participants were encouraged to contact the study coordinator within 24 hours after onset of cold symptoms. Callers were initially screened for eligibility by phone." Diagnostic criteria for condition: "Eligible recruits were asked to visit the clinic to complete enrolment procedures before the end of the 24‐hour period. During the initial intake, a nasopharyngeal swab was collected for virus detection [INCLUSION], a urine pregnancy test was performed (if appropriate), and a throat swab was collected for Group A Streptococcus rapid antigen detection [EXCLUSION] and culture. A structured interview was conducted to assess eligibility criteria and symptom status. Eligibility criteria included having two or more of the following symptoms for less than 24 hours at the time of enrolment: cough, stuffy nose, runny nose, hoarseness, sore/itchy throat, headache, sneezing, or muscle ache." Number of study centres: 1 Number of withdrawals: none reported but not explicit. Imputation and last observation carried forward were used for missing observations. Total number screened/eligible/randomised: 185/160/160
Interventions	Zinc sulfate 0.044 mg/d nasal spray Study description of intervention and administration: "The participants received the spray bottle at the intake visit (day 0) and were instructed to administer two inhalations into each nostril four times daily until symptoms resolved, up to a maximum of 14 days."; "The active medication was an isotonic preparation containing 0.12% zinc (as zinc sulfate heptahydrate), benzalkonium chloride, benzyl alcohol, sodium chloride, and water." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): intranasal spray Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): sulfate Frequency of dose: 4x/d Dose per day (elemental zinc in mg): 0.044 mg Duration of treatment: resolution of symptoms, up to 14 days Placebo nasal spray Study description of intervention and administration: "The participants received the spray bottle at the intake visit (day 0) and were instructed to administer two inhalations into each nostril four times daily until symptoms resolved, up to a maximum of 14 days."; "The placebo spray was an isotonic preparation containing all the same components except zinc. Each inhalation delivered 0.1 mL spray," Form of product (tablet, lozenge, syrup, intranasal, other (specify)): intranasal spray Frequency of dose: 4 x/d Duration of treatment: resolution of symptoms, up to 14 days
Outcomes	Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Global severity of cold symptoms (0 to 3 rating) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Notes: Figure 1 indicates that 100% were still sick up until Day 3. Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N)
Identification	Author's name: Edward A. Belongia Institution: e Marshfield Medical Research Foundation and Marshfield Clinic, Marshfield, Wisconsin Email: NA Address: Epidemiology Research Center, Marshfield Medical Research Foundation (ML‐2), 1000 N. Oak Avenue, Marshfield, Wisconsin 54449 Trial registration identifier: none Year study recruitment began: 1999
Notes	Declaration of interest: NR Funding source: supported by CNS Inc., Minneapolis, Minnesota Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The active and placebo nasal spray bottles were randomly placed in blocks of four by the manufacturer (CNS Inc., Minneapolis, Minnesota). The spray dispensers were identical in appearance except for an identifying code number. All study personnel were blinded to the group assignments. The manufacturer held the randomization key until all participants had completed the protocol and the data were entered." Judgement comment: generation method was centralised, but not explained entirely clearly.
Allocation concealment (selection bias)	Low risk	Quote: "The spray dispensers were identical in appearance except for an identifying code number." Judgement comment: identical appearance and coded by a separate entity from the study team.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "All study personnel were blinded to the group assignments. The manufacturer held the randomization key until all participants had completed the protocol and the data were entered." Judgement comment: blinded to assignment, however could they have detected differences in the zinc and placebo spray? No discussion. Low or unclear.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Participants were asked to complete a symptom diary twice a day while on the protocol. Eight symptoms were evaluated based on a modification of criteria developed and validated by Jackson et al. (14). The symptoms were cough, stuffy nose, runny nose, hoarseness, sore/itchy throat, headache, sneezing, and muscle ache. Each symp‐ tom was rated on the following severity scale: none (0), mild (1), moderate (2), or severe (3). The daily symptom diary included documentation of each nasal spray dose, oral temperature (twice daily), use of over‐the‐counter cough or cold medications, and adverse effects." Judgement comment: participants were blinded and were responsible for assessing and reporting outcomes. Low or unclear (if any suspicion about blinding).
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Of the remaining 160 patients, 81 (51%) received zinc and 79 (49%) received placebo." Judgement comment: all participants were followed for outcomes.
Selective reporting (reporting bias)	Unclear risk	Quote: "The primary efficacy variable was the duration of symp‐ toms, defined as the number of days from the date of randomization (day 0) to the first day of resolution. “Asymptomatic” was defined as a total symptom score of 0 or 1 (no more than one mild symptom)." Judgement comment: no apparent problems with selection and analysis of outcomes, however there is no protocol or registration to check against.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Caesar 2012.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "Any subject with fever received paracetamol." Investigation of ability to distinguish between zinc and placebo: NR Duration of follow‐up: 7 days Duration of intervention: 7 days Duration of run‐in or washout period: none How participants were identified as having colds/URTI at baseline (treatment trial): "Diagnosis of common cold were based on cough and runny nose with clear or mucopurulent secretions of less than 10 days, with or without mild fever of <39 degrees, good general condition and no thoracic abnormalities on physical examination." Outcomes measured: decreased cold severity, side effects
Participants	Setting: outpatient Country: Indonesia Zinc NR 20 mg/d powder Number: 57 Percentage female: 54% Age, (n (%)): 3 to 5 years (mean not given) Placebo powder Number: 57 Percentage female: 56% Age, (n (%)): 3 to 5 years (mean not given) Overall Number: 114 Percentage female: 55% Age, (n (%)): 3 to 5 years (mean not given) Inclusion criteria: "We included subjects aged 3–5 years who lived in Yogyakarta, suffered from the common cold for less than 2 days, had good general appearance, had parents willing to participate by signing the proxy consent and had an active phone number to maintain contact." Exclusion criteria: "Those suffering from a common cold with complications such as pneumonia, acute otitis media, sinusitis, exacerbation of asthma, as well as immunocompromised status such as HIV infection, malignancy or on steroid therapy for more than 4 weeks were excluded." Group differences: no apparent difference in baseline characteristics (Table 1) Condition studied: common cold Description of recruitment: participants were recruited by consecutive sampling from primary health care centres in Gedongtengen, Umbulharjo I and Kotagede II, Yogyakarta. Diagnostic criteria for condition: diagnosis of common cold was based on cough and runny nose with clear or mucopurulent secretions of less than 10 days with or without fever < 39 °C, good general condition, and no thoracic abnormalities on physical examination. Number of study centres: 1 Number of withdrawals: none Total number screened/eligible/randomised: 120/114/114
Interventions	Zinc NR 20 mg/d powder Study description of intervention and administration: "The treatment group received zinc powder (1x20mg) for seven days, while control group received placebo powder." "Any subject with fever received paracetamol." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): powder Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): NR Frequency of dose: 1x day Dose per day (elemental zinc in mg): 20 mg Duration of treatment: 7 days Placebo powder Study description of intervention and administration: "The treatment group received zinc powder (1x20mg) for seven days, while control group received placebo powder." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): powder Frequency of dose: 1 x day Duration of treatment: 7 days
Outcomes	Global severity of cold symptoms (0 to 3 rating) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: only given in terms of the number whose cold severity decreased (see Tables 1 and 2) Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N)
Identification	Author's name: Cahalafa Shinta Caesar Institution: Department of Child Health, Gadjah Mada University Medical School Email: cahalafa@gmail.com Address: Department of Child Health, School, Gadjah Mada University Medical School, Jalan Kesehatan No 1 Sekip, Yogyakarta 55284, Indonesia Trial registration identifier: NR Year study recruitment began: 2009
Notes	Declaration of interest: "The authors declare that they have no conflict of interest in this research." Funding source: NR Contact with study authors for additional information: none Other: study does not have any outcomes that correspond to the predetermined outcomes for this review. Closest outcome is proportion of participants with decreased cold severity. Primary healthcare centres in Gedongtengen, Umbulharjo I and Kotagede II, Yogyakarta.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Judgement comment: Stated to be randomised. "Subjects were collected by consecutive sampling." No other details.
Allocation concealment (selection bias)	Unclear risk	Judgement comment: no details about allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "A pharmacist from an outside primary health care center held the key, so subjects and researchers were blinded until the end of the study." Judgement comment: stated to be double‐blind and although there are no descriptions of the constitution of the placebo powder it is likely that participants and personnel were blinded. We assume that researchers were also personnel, but not clear.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement comment: it is not explicitly stated that the nurses assessing the cold symptoms were blinded to treatment group, however the key was held by a pharmacist from an outside primary healthcare centre.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Judgement comment: no participants were lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no protocol or trial registration available.
Other bias	Low risk	Judgement comment: no other apparent source of bias.

Douglas 1987.

Study characteristics
Methods	Study design: parallel, randomised, single‐case, experimental design Further information on study design: study participants were re‐randomised to zinc or placebo treatment each time they developed a cold over the follow‐up period. Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: "As a test of the adequacy of the placebo, 20 specially recruited volunteers were invited to identify each of a randomly assigned block of four tablets two zinc and two placebo‐and to record their findings after allowing each of the tablets to effervesce in their mouths for 2 min. The tests were done 1 h apart, and each tablet remnant was retained for further checking if desired." "In the evaluation of distinguishability between placebo and zinc lozenges, 9 of 20 volunteers correctly identified differences in the two pairs of lozenges, but only 5 of the 9 correctly identified zinc from placebo; the remaining 4 said the zinc was placebo and vice versa. We estimate that the probability that 5 or more of 20 volunteers would correctly assign the four tablets on chance alone is 0.10." Note that the test was 2 minutes, but the actual treatment was to let the lozenge dissolve for 10 minutes. Duration of follow‐up: 2 weeks after commencement of therapy Duration of intervention: 3 to 6 days, dependent on symptom continuations Duration of run‐in or washout period: NA How participants were identified as having colds/URTI at baseline (treatment trial): "The protocol required that when a participating individual developed two respiratory symptoms for 1 day or one respiratory symptom for 2 days, he or she reported at once to the nurse at the office of his or her general practitioner, nasal and pharyngeal swabs were collected for viral study, and medication from the bottle assigned to that individual was commenced immediately." Outcomes measured: 1) severity of symptoms (mild (1 point), moderate (2 points), or severe (3 points)) summed as total nasal, throat, and cough scores, and 2) days of symptoms defined as onset of nasal, throat, or cough symptoms to the last consecutive day of symptoms
Participants	Setting: community/outpatient Country: Australia Zinc acetate 80 mg/d lozenge Number: 30 users/33 courses Percentage female: 58% Age (mean (SD)): 30.7 (NR) years Placebo lozenge Number: 28 users/30 courses Percentage female: 50% Age (mean (SD)): 35.6 (NR) years Overall Number: 58 users/63 courses Percentage female: 54% Age (mean (SD)): 33.0 (NR) years Inclusion criteria: unclear, seems like prior study would have more information: "All of the participants in the main trial were healthy adults who had in the previous year participated in a study of intranasal interferon prophylaxis against rhinovirus infections (3). In that study, they maintained throughout the winter diary records of respiratory symptomatology and cooperated in a complex study protocol which called for initiation of prophylaxis when another member of the family developed a cold. For the present study, the manufacturers provided 150 sequentially numbered bottles, each of which contained 48 effervescent tablets of either zinc acetate or placebo randomly allocated to the sequence." The previous study recruited families from family practices. The families had to comprise at least 4 members, of whom 2 were aged 18 to 75 and 2 were aged 2 to 17. Exclusion criteria: NR Group differences: "Those who used zinc were slightly more likely to be female, to smoke, and to have histories of hay fever. The zinc users also had slightly more severe experiences of respiratory infections during the 6 months of the previous interferon study in 1984 (Table 1)." Condition studied: common cold Description of recruitment: recruited from participants in a previous cluster‐randomised study testing intranasal alpha2‐interferon as prophylaxis against respiratory infections. Diagnostic criteria for condition: "The protocol required that when a participating individual developed two respiratory symptoms for 1 day or one respiratory symptom for 2 days, he or she reported at once to the nurse at the office of his or her general practitioner, nasal and pharyngeal swabs were collected for viral study, and medication from the bottle assigned to that individual was commenced immediately." Number of study centres: not explicit but appears to be one Number of withdrawals: no withdrawals from follow‐up, however some courses were excluded from analysis: "We excluded from the analysis treatment courses in which the residual tablet counts indicated that the individual had not used the tablets at least for 3 days and at the rate of 4 or more per day. Using these criteria, seven courses were excluded as unevaluable (two zinc and five placebo recipients)." Total number screened/eligible/randomised: NR/99 participants/70 courses in 55 participants
Interventions	Zinc acetate 80 mg/d lozenge Study description of intervention and administration: "For the present study, the manufacturers provided 150 sequentially numbered bottles, each of which contained 48 effervescent tablets of either zinc acetate or placebo randomly allocated to the sequence."; "For each family, one individual was appointed to supervise the maintenance of symptom diaries and to maintain regular weekly contact with the study supervisor. The protocol required that when a participating individual developed two respiratory symptoms for 1 day or one respiratory symptom for 2 days, he or she reported at once to the nurse at the office of his or her general practitioner, nasal and pharyngeal swabs were collected for viral study, and medication from the bottle assigned to that individual was commenced immediately. The lozenge was to be slowly dissolved in the mouth, a process which took about 10 min. The study office was notified, and the instructions required that each treated individual use from six to eight lozenges at about 2‐h intervals each day for a minimum of 3 days and for up to 6 days if symptoms continued. At 2 weeks after therapy commenced, a home visit was made, at whicH time all leftover tablets were collected and a new bottle of medication was left in the event of further cold symptoms developing."; "Fauldings Ltd. prepared effervescent lozenges of zinc acetate, each containing 10 mg of elemental zinc, and a placebo which contained sodium acetate." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): acetate Frequency of dose: 6 to 8 times/day Dose per day (elemental zinc in mg): 6 to 8 lozenges @ 10 mg = 60 to 80 mg Zn/d Duration of treatment: 3 to 6 days Placebo lozenge Study description of intervention and administration: "For the present study, the manufacturers provided 150 sequentially numbered bottles, each of which contained 48 effervescent tablets of either zinc acetate or placebo randomly allocated to the sequence."; "For each family, one individual was appointed to supervise the maintenance of symptom diaries and to maintain regular weekly contact with the study supervisor. The protocol required that when a participating individual developed two respiratory symptoms for 1 day or one respiratory symptom for 2 days, he or she reported at once to the nurse at the office of his or her general practitioner, nasal and pharyngeal swabs were collected for viral study, and medication from the bottle assigned to that individual was commenced immediately. The lozenge was to be slowly dissolved in the mouth, a process which took about 10 min. The study office was notified, and the instructions required that each treated individual use from six to eight lozenges at about 2‐h intervals each day for a minimum of 3 days and for up to 6 days if symptoms continued. At 2 weeks after therapy commenced, a home visit was made, at whicH time all leftover tablets were collected and a new bottle of medication was left in the event of further cold symptoms developing." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: 6 to 8 times/day Duration of treatment: 3 to 6 days
Outcomes	Placebo adequacy, impact of illness (duration and severity), tablet acceptability
Identification	Author's name: Robert M. Douglas Institution: Department of Community Medicine, University of Adelaide Email: NR Address: Department of Community Medicine, University of Adelaide, Adelaide 5001, South Australia, Australia Trial registration identifier: none Year study recruitment began: 1985
Notes	Declaration of interest: NR Funding source: "We thank Fauldings Ltd., who provided the zinc and placebo formulations" Contact with study authors for additional information: none Other: data were presented by treatment course rather than by individual, and the unit of reporting in Table 2 is not the number of patients but rather the number of courses. Our statistician (MK) advised that the outcomes should not be extracted due to this approach.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "the family developed a cold. For the present study, the manufacturers provided 150 sequentially numbered bottles, each of which contained 48 effervescent tablets of either zinc acetate or placebo randomly allocated to the sequence." Judgement comment: central randomisation almost certainly used/adequate for sequence generation.
Allocation concealment (selection bias)	Low risk	Quote: "the family developed a cold. For the present study, the manufacturers provided 150 sequentially numbered bottles, each of which contained 48 effervescent tablets of either zinc acetate or placebo randomly allocated to the sequence." Judgement comment: central randomisation and appears no chance that allocation sequence was disclosed.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "In the evaluation of distinguishability between placebo and zinc lozenges, 9 of 20 volunteers correctly identified differences in the two pairs of lozenges, but only 5 of the 9 correctly identified zinc from placebo; the remaining 4 said the zinc was placebo and vice versa. We estimate that the probability that 5 or more of 20 volunteers would correctly assign the four tablets on chance alone is 0.10." Quote: "It was a double‐blind study and all observers remained blind to the identity of the treatment courses until all data were collected. For the first 30 cases, the code was broken in July, and for the entire study, it was broken in November." Judgement comment: low‐unclear. While they say it was blinded, it is not clear how. Although it does seem likely that the participants were blinded and this was demonstrated through the placebo adequacy portion of the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "It was a double‐blind study and all observers remained blind to the identity of the treatment courses until all data were collected." Judgement comment: not entirely clear who were the outcome assessors that were completing the questionnaire, but it is assumed that both were blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "Datum analysis was by treatment course. The study design meant that an individual could use more than one treatment course and that the identity of the treatment course he used could be different from one course to the next." Judgement comment: 58/70 treatment courses were deemed evaluable. The 7 treatment courses (2 zinc and 5 placebo) in which the individuals did not use the tablets for at least 3 days at the rate of at least 4 tablets/day were excluded from analysis.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no obvious issues with selective outcome reporting, however there is no prospective trial registration or protocol to check against. No protocol. Methods section is unclear about what they were measuring there, so no comparison can be made between that and the results either.
Other bias	Low risk	Judgement comment: "No other apparent risks of bias."

Eby 1984.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "Other common cold treatments were not permitted." Investigation of ability to distinguish between zinc and placebo: "It may be possible to find zinc compounds and formulations which are more palatable and more effective than the unflavoured zinc gluconate tablets we used. In limited trials zinc ascorbate and zinc aspartate seemed similar to zinc gluconate in their effects. However, in a companion study we found that zinc orotate was substantially less effective, perhaps because it is only very slightly soluble. Zinc sulfate and zinc chloride were not tested due to reports of very painful and caustic effects on mucous membranes." Duration of follow‐up: NA Duration of intervention: participants were instructed to treat their cold until all symptoms had been absent for 6 h and then to stop all treatment (7 d max) Duration of run‐in or washout period: NA How participants were identified as having colds/URTI at baseline (treatment trial): "All were accepted who were diagnosed by the physician (W.W.H.) to have signs and symptoms of the common cold."; "Subjects recorded the presence and severity of 10 common cold symptoms on a report form. Headache, fever, muscle pain, sneezing, nasal drainage, nasal obstruction, sore throat, scratchy throat, cough, and hoarseness were scored at specific times during the first day and at the same time of day as the initial treatment during the following 6 days. Symptoms were scored as being severe (3 points), moderate (2 points), minor (1 point), or absent (no points). Subjects also recorded side effects or complaints and any deviation from the protocol. Reports were returned by mail or in person to the physician." Outcomes measured: duration of cold, severity of symptoms
Participants	Setting: outpatient Country: US Zinc gluconate 207 mg/d lozenge Number: 37 Percentage female: 43% Age (mean (SD)): 35.6 (13.4) Placebo lozenge Number: 28 Percentage female: 50% Age (mean (SD)): 38 (14.8) Overall Number: 65 Percentage female: 46% Age (mean (SD)): 36.6 (13.96) Inclusion criteria: "All were accepted who were diagnosed by the physician (W.W.H.) to have signs and symptoms of the common cold. No limitation on the length of illness was imposed to encourage accurate reporting of length of illness. Informed consent was obtained in writing after explanation of the study and possible side effects." Exclusion criteria: not explicitly clear; sounds like as long as they were diagnosed by the physician, they were included. Group differences: "The placebo‐treated group initially had significantly more severe colds than the zinc‐treated group, but several careful analyses of correlations and variance showed that initial severity (and initial number of symptoms) had virtually no effect on the duration of colds studied here." Zinc group had more men, and were on average ~3 years younger than placebo group Condition studied: common cold Description of recruitment: "During the fall of 1981, the local media were used to invite persons with colds to volunteer for this experiment. All were accepted who were diagnosed by the physician (W.W.H.) to have signs and symptoms of the common cold. No limitation on the length of illness was imposed to encourage accurate reporting of length of illness. Informed consent was obtained in writing after explanation of the study and possible side effects." Diagnostic criteria for condition: "All were accepted who were diagnosed by the physician (W.W.H.) to have signs and symptoms of the common cold."; "Subjects recorded the presence and severity of 10 common cold symptoms on a report form. Headache, fever, muscle pain, sneezing, nasal drainage, nasal obstruction, sore throat, scratchy throat, cough, and hoarseness were scored at specific times during the first day and at the same time of day as the initial treatment during the following 6 days. Symptoms were scored as being severe (3 points), moderate (2 points), minor (1 point), or absent (no points). Subjects also recorded side effects or complaints and any deviation from the protocol. Reports were returned by mail or in person to the physician." Number of study centres: 1 Number of withdrawals: unclear "Of 146 (83 zinc, 63 placebo) original volunteers, 120 subjects returned reports. Initially, to use as much of the data as possible, we analysed the 80 complete reports from 108 subjects who had been ill for 10 days or less at the start of treatment."; "Consequently, this report is restricted to those 65 subjects who reported being ill for 3 days or less before starting the experiment. The results are similar, but (as expected) the statistical significance is reduced in this smaller group." Total number screened/eligible/randomised: NR/NR/146
Interventions	Zinc gluconate 207 mg/d lozenge Study description of intervention and administration: "We used unflavored zinc gluconate tablets commonly available over‐the‐counter as nutritional supplements, with matching placebos. Tablets contained 23 mg of zinc or 50 mg of calcium lactate. Both tablets were manufactured by Truett Laboratories of Dallas, Tex., and were otherwise identical, including excipients of dicalcium phosphate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, and FD&C yellow no. 5 and blue no. 1 (aluminum lake). A 7‐day supply of tablets (active or placebo) was given to each subject, using a double‐blind, random method."; "The initial (loading) dose for all subjects was two tablets, one followed by the other, dissolved in the mouth as lozenges (about 10 to 20 min each). Thereafter, adults and youths dissolved one tablet every 2 wakeful h, not exceeding 12 and 9 tablets per day, respectively. Children under 60 pounds (27 kg) received one‐half tablet every 2 wakeful h, not exceeding six tablets per day. Subjects were instructed to treat their cold until all symptoms had been absent for 6 h and then to stop all treatment. They were instructed to treat the cold during the night only if they were already awake. Other common cold treatments were not permitted. Emphasis was placed on the necessity of dissolving the tablets in the mouth as lozenges." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate Frequency of dose: 1 tablet every 2 wakeful h, not exceeding 12 and 9 tablets per day Dose per day (elemental zinc in mg): adults: 12/day x 23 mg = 276 mg; youths: 9/day x 23mg = 207 mg; children: 6/day x 23 mg = 138 mg Duration of treatment: until all symptoms had been absent for 6 h (or 7 d max) Placebo lozenge Study description of intervention and administration: "Tablets contained 23 mg of zinc or 50 mg of calcium lactate. Both tablets were manufactured by Truett Laboratories of Dallas, Tex., and were otherwise identical, including excipients of dicalcium phosphate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, and FD&C yellow no. 5 and blue no. 1 (aluminum lake). A 7‐day supply of tablets (active or placebo) was given to each subject, using a double‐blind, random method."; "The initial (loading) dose for all subjects was two tablets, one followed by the other, dissolved in the mouth as lozenges (about 10 to 20 min each). Thereafter, adults and youths dissolved one tablet every 2 wakeful h, not exceeding 12 and 9 tablets per day, respectively. Children under 60 pounds (27 kg) received one‐half tablet every 2 wakeful h, not exceeding six tablets per day. Subjects were instructed to treat their cold until all symptoms had been absent for 6 h and then to stop all treatment. They were instructed to treat the cold during the night only if they were already awake. Other common cold treatments were not permitted. Emphasis was placed on the necessity of dissolving the tablets in the mouth as lozenges." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: one tablet every 2 wakeful h, not exceeding 12 and 9 tablets per day Duration of treatment: until all symptoms had been absent for 6 h (or 7 d max)
Outcomes	Duration of cold symptoms (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of headache (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of fever (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of muscle aches (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of sneezing (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of nasal drainage (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of nasal congestion (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of sore throat (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of scratchy throat (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of cough (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of hoarseness (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N)
Identification	Author's name: George A. Eby Institution: George Eby Research, Austin, Texas 787041; Clayton Foundation Biochemical Institute, University of Texas at Austin, Austin, Texas 787122; and 8311 Shoal Creek Boulevard, Austin, Texas 787563 Email: none Address: University of Texas at Austin, Austin, Texas 787122; and 8311 Shoal Creek Boulevard, Austin, Texas 787563 Trial registration identifier: NR Year study recruitment began: 1981
Notes	Declaration of interest: NR Funding source: "We thank Karen Lynn Eby for inspiration and Truett Laboratories for supplying the tablets used." Clayton Foundation Biochemical Institute Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "A 7‐day supply of tablets (active or placebo) was given to each subject, using a double‐blind, random method." Judgement comment: sequence generation not described.
Allocation concealment (selection bias)	Unclear risk	Quote: "study and possible side effects. We used unflavored zinc gluconate tablets commonly available over‐the‐counter as nutritional supplements, with matching placebos. Tablets contained 23 mg of zinc or 50 mg of calcium lactate. Both tablets were manufactured by Truett Laboratories of Dallas, Tex., and were otherwise identical, including excipients of dicalcium phosphate". Judgement comment: allocation process not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "... and FD&C yellow no. 5 and blue no. 1 (aluminum lake). A 7‐ day supply of tablets (active or placebo) was given to each subject, using a double‐blind, random method." Judgement comment: tablets identical except with regard to the zinc or calcium lactate, however no description of whether they were made similar in taste, or to what extent they might be distinguished. Unclear or low.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Subjects recorded the presence and severity of 10 common cold symptoms on a report form. Headache, fever, muscle pain, sneezing, nasal drainage, nasal obstruction, sore throat, scratchy throat, cough, and hoarseness were scored at specific times during the first day and at the same time of day as the initial treatment during the following 6 days. Symptoms were scored as being severe (3 points), moderate (2 points), minor (1 point), or absent (no points). Subjects also recorded side effects or complaints and any deviation from the protocol. Reports were returned by mail or in person to the physician." Judgement comment: unclear that participants were adequately blinded, and no discussion of this issue in the report.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "Of 146 (83 zinc, 63 placebo) original volunteers, 120 subjects returned reports. Initially, to use as much of the data as possible, we analyzed the 80 complete reports from 108 subjects who had been ill for 10 days or less at the start of treatment. After the 7‐day experiment, 90% of these zinc‐treated subjects reported no symptoms, compared with only 49% of the placebo subjects (P < 0.0001). However, this choice of subjects raised concerns about superimposed allergies or bacterial infections and about a disproportionate number of dropouts from the zinc group; also, it did not fully reflect our goal of a treatment for early colds." Judgement comment: substantial opportunity for bias from missing data. Of 146 participants, 120 returned outcome data, 80 returned complete reports and, of these, 65 were ill for 3 days or less. Although the authors performed a sensitivity analysis showing that the effect of zinc upon response at 7 days remained statistically significant under the assumption that people who dropped out or were lost to follow‐up had the same response as the placebo group, this does not fully address the issue of the effect of missing data on the outcomes.
Selective reporting (reporting bias)	High risk	Judgement comment: choice of analysis (analysis participants who had symptoms < 4 days versus analysis of participant who had symptoms < 11 days) appears to have been made on the basis of the results.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Eby 2006.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: NA Investigation of ability to distinguish between zinc and placebo: "The double‐blinding was preserved throughout the study, as there was no bitterness or astringent mouth‐feel from the zinc orotate lozenges and there were no other noticeable differences between the lozenges or sprays. Compliance with the protocol was reported as being good in patients who completed the study." Duration of follow‐up: NR Duration of intervention: 7 d (or until cessation of symptoms for at least 6 h) Duration of run‐in or washout period: NR How participants were identified as having colds/URTI at baseline (treatment trial): "The study was conducted in a private physician’s clinic in Austin, Tex. Only patients diagnosed by the physician—William W. Halcomb, DO—an allergist and general practitioner—as having 2 or more signs and symptoms of common colds (with at least 1 nasal symptom) were accepted into the study. A differential diagnosis was performed to exclude those with allergic reactions or bacterial infections." Outcomes measured: "Each day, patients recorded at the same time of day as the initial exam the presence and severity of each of 10 common cold symptoms—headache, fever, muscle pain, sneezing, nasal drainage, nasal obstruction, sore throat, scratchy throat, cough, and hoarseness—in a diary. Symptoms were scored as being severe (3 points), moderate (2 points), minor (1 point), or absent (0 points). The patients returned their diaries to the physician on day 7 at their exit exams."
Participants	Setting: private physician’s clinic in Austin, Texas Country: US Zinc orotate 296 mg/d lozenge + gluconate ??mg/d nasal gel Number: 16 Percentage female: 37.5% Age (mean (SD)): 38.8 (14 to 66) Placebo lozenge + nasal gel Number: 17 Percentage female: 29.4% Age (mean (SD)): 37.4 (9 to 65) Overall Number: 33 Percentage female: 33% Age (mean (SD)): 38 (9 to 66) Inclusion criteria: "Only patients diagnosed by the physician—William W. Halcomb, DO—an allergist and general practitioner—as having 2 or more signs and symptoms of common colds (with at least 1 nasal symptom) were accepted into the study." Exclusion criteria: "A differential diagnosis was performed to exclude those with allergic reactions or bacterial infections." Group differences: "The characteristics of the study group members and their colds are shown in Table 1. No unusual characteristics or significant deviations between groups were evident." Condition studied: common cold Description of recruitment: "The study was conducted in a private physician’s clinic in Austin, Tex. Only patients diagnosed by the physician—William W. Halcomb, DO—an allergist and general practitioner—as having 2 or more signs and symptoms of common colds (with at least 1 nasal symptom) were accepted into the study. A differential diagnosis was performed to exclude those with allergic reactions or bacterial infections. Informed consent was obtained in writing after explanation of the study and possible side effects. Potential side effects included possible oral and nasal irritation and nasal pain. The Austin area institutional review board reviewed and approved the study." Diagnostic criteria for condition: "The study was conducted in a private physician’s clinic in Austin, Tex. Only patients diagnosed by the physician—William W. Halcomb, DO—an allergist and general practitioner—as having 2 or more signs and symptoms of common colds (with at least 1 nasal symptom) were accepted into the study. A differential diagnosis was performed to exclude those with allergic reactions or bacterial infections. " Number of study centres: 1 Number of withdrawals: 14 Total number screened/eligible/randomised: NR/NR/77
Interventions	Zinc orotate 296 mg/d lozenge + gluconate ??mg/d nasal gel Study description of intervention and administration: "Zinc gluconate was added to 45 cc isotonic aqueous solution in spray bottles (Ocean Nasal Spray, Fenton, Mo) to produce a 10‐mmol concentration of zinc gluconate. The solution also contained benzyl alcohol as a preservative."; "The nasal spray was to be used aggressively, in both nostrils 2 or 3 times every 15 to 30 minutes while awake with the intent of keeping the nasal tissues wet. Treatment was to be continued until symptoms had been absent for 6 hours, at which time all treatment was to be stopped. Patients were also asked to treat at bedtime and during the night if awake. One lozenge was dissolved in the mouth every 2 to 3 wakeful hours" Form of product (tablet, lozenge, syrup, intranasal, other (specify)): intranasal spray + lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate (spray) orotate (lozenge) Frequency of dose: spray: "in both nostrils 2 or 3 times every 15 to 30 minutes while awake with the intent of keeping the nasal tissues wet"; lozenge: "One lozenge was dissolved in the mouth every 2 to 3 wakeful hours" Dose per day (elemental zinc in mg): spray: 10 mmol ‐ uncertain if this is the total in the spray or the dosage??; lozenge: 37 mg x 8 = 296 mg/d Duration of treatment: 7 d Placebo lozenge + nasal gel Study description of intervention and administration: "The placebo was free of zinc but otherwise identical. We also used slightly sweet and bland (non‐astringent) zinc orotate throat lozenges containing either 37 mg zinc, or, as placebo, 50 mg calcium (from calcium lactate). A 7‐day supply of nasal spray and lozenges was given to each patient using a random, double‐blind method wherein it was impossible for patients to receive zinc lozenges with placebo nasal spray and vice versa." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): intranasal spray + lozenge Frequency of dose: spray: "in both nostrils 2 or 3 times every 15 to 30 minutes while awake with the intent of keeping the nasal tissues wet"; lozenge: "One lozenge was dissolved in the mouth every 2 to 3 wakeful hours" Duration of treatment: 7 d
Outcomes	Duration of cold symptoms (n) Outcome type: dichotomous outcome Reported as: percentage of participants with event (%, N) Notes: days 3 and 5 are estimates from Figure 1 Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: looks like this table mixes up their N. In Fig 1 it shows Zn = 16, P = 17, but in this table it is the opposite.
Identification	Author's name: George A. Eby Institution: George Eby Research; Eby Pharma, LLC; William W. Halcomb Clinic Email: NA Address: George Eby Research, in Austin, Texas Trial registration identifier: NR Year study recruitment began: NR
Notes	Declaration of interest: "There are no conflicts of interest, although there is 1 year remaining on patent rights of George A. Eby, and Eby Pharma, LLC, sells zinc acetate lozenges." Funding source: "George A. Eby, MS, is owner of George Eby Research, in Austin, Tex. William W. Halcomb, DO, is owner of the William W. Halcomb Clinic in Mesa, Ariz. This work was privately supported and was conducted at the William W. Halcomb Clinic in Austin, Tex. No outside financial support was provided."; "We thank The Makers of Kal Inc, Canoga Park, Calif, for the lozenges; Truett Laboratories, Inc, Fort Worth, Tex, for the granular zinc gluconate; and Fleming & Company Pharmaceuticals, Fenton, Mo, for the zinc gluconate‐treated Ocean Nasal Spray and placebo." Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "A 7‐day supply of nasal spray and lozenges was given to each patient using a random, double‐blind method wherein it was impossible for patients to receive zinc lozenges with placebo nasal spray and vice versa." Judgement comment: method of sequence generation not described.
Allocation concealment (selection bias)	Unclear risk	Quote: "Zinc gluconate was added to 45 cc isotonic aqueous solution in spray bottles (Ocean Nasal Spray, Fenton. Mo) to produce a 10‐mmol concentration of zinc gluconate, The solution also contained benzyl alcohol as a preservative. The placebo was free of zinc but otherwise identical." Judgement comment: allocation processes not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The double‐blinding was preserved throughout the study, as there was no bitterness or astringent mouth‐feel from the zinc orotate lozenges and there were no other noticeable differences between the lozenges or sprays." Judgement comment: blinding not explicitly assessed; attention was paid to taste and mouthfeel.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Each day, patients recorded at the same time of day as the initial exam the presence and severity of each of 10 common cold symptoms—headache, fever, muscle pain, sneezing, nasal drainage, nasal obstruction, sore throat, scratchy throat, cough, and hoarseness—in a diary. Symptoms were scored as being severe (3 points), moderate (2 points), minor (1 point), or absent (0 points). The patients returned their diaries to the physician on day 7 at their exit exams." Judgement comment: patients were outcome assessors and they were blinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "... considered statistically significant. RESULTS There were 77 volunteers (39 zinc. 38 placebo), of whom 28 zinc‐treated patients and 27 placebo‐treated patients returned report forms. Twenty‐four of the 28 zinc‐treated patients and 23 of the 27 placebo‐treated patients had colds for 3 days or less before starting treatment, with a mean duration of 1.5 days and a median duration of 1 day for each group. Of those patients, 8 zinc‐treated and 6 placebo‐treated patients dropped out of the study. Consequently, the study groups consisted of 16 zinc‐treated and 17 placebo‐treated patients—those who had colds for 3 days or less and had not dropped out. The characteristics of the study group". Judgement comment: substantial opportunity for bias from missing outcome data. Only 55/77 (71%) participants returned report forms and, of these, 47 had colds for 3 days or less and 33/47 (70%) of these did not drop out and provided outcome data. No reasons for missing data given. Fairly equal amounts between groups at least.
Selective reporting (reporting bias)	High risk	Quote: "The duration of colds in patients who were treated with zinc was comparable to that of colds in patients treated with placebo (Figure 1). Two zinc‐treated patients reported being asymptomatic in 24 hours. Although none of the placebo‐treated patients were asymptomatic in the same period, there was no statistical significance in the difference between the groups (P = .23. exact binomial) for that day. After the first day, there was no difference in the rate of recovery between the 2 groups throughout the remainder of the study, and the lines representing rate of recovery had essentially the same slope and were parallel. Consequently, there was no evidence of reduction in cold duration after zinc treatment. There was no statistical difference between the 2 groups at any time during the study. By the end of the 7‐day study, the statistical significance of the difference (P = .57, by chi square) was even less than at day 1 (P= .23, exact binomial)." Judgement comment: no protocol present ‐ also looks like they did not report anything to do with the severity of the colds (as measured in methods), just duration, compliance, and adverse events.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Farr Trial 1 1987.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: "We have developed a taste‐matched placebo containing denatonium benzoate (a bitter substance used to discourage thumb sucking in children) and have demonstrated in previous studies that our zinc and placebo lozenges are comparable both in palatability and in the proportion of subjects who believe they are receiving active medication (B. M. Farr and J. M. Gwaltney, Jr., J. Chronic Dis., in press)."; "On the final day of the study, each subject completed a questionnaire regarding taste, aftertaste, and any adverse effects of the medication, in addition to whether he believed he was given active medication and not placebo."; "Perceptions were not significantly different regarding predominant lozenge taste and palatability or whether medication was active (Table 3)." Duration of follow‐up: 21 days Duration of intervention: 5 days Duration of run‐in or washout period: treatment began 36 hours after viral inoculation If prevention, describe challenge if any: "Rhinovirus type 39 was administered by intranasal drops (0.25 ml per nostril) on two occasions 30 min apart just after admission to the motel in trial 1. The viral inoculum pool had a titer of 103 550% tissue culture infective doses per ml. A 1:10 (vol/vol) dilution of this pool was used for inoculation." If treatment, describe how participants were identified as having colds/URTI: NA Outcomes measured: 1) self‐report of 8 common cold symptoms (sneezing, nasal discharge, nasal congestion, malaise, headache, chilliness, sore throat, and cough), each rated for severity from 0 (none) to 3 (severe); 2) development of a cold, defined as a total symptom score of 0.5 plus either nasal discharge for 3 days or the belief of the participant that a cold had occurred; 3) nasal mucus weight collected from tissues each morning on days 1 to 7; 4) clinical laboratory tests (e.g. levels of zinc in serum) on day 7
Participants	Setting: community Country: USA Zinc gluconate 184 mg/d lozenge Number: 16 Percentage female: 50% Age (mean (SD)): 21.4 (2.4) years Placebo lozenge Number: 16 Percentage female: 69% Age (mean (SD)): 20.6 (2.0) years Overall Number: 32 Percentage female: 56% Age (mean (SD)): 21.0 (2.2) years Inclusion criteria: NR ‐ participants described as 'healthy adult volunteers'. "Healthy adult volunteers (n = 32) with titers of serum neutralizing antibody to rhinovirus type 39 of <1:2 were assigned by prior computer randomization to receive either zinc gluconate or placebo lozenge therapy in trial 1," Exclusion criteria: "Exclusion criteria included symptoms of any respiratory illness in the week before the study, a history of hayfever, any familiarity with the taste of either denatonium benzoate or zinc, a history of any chronic disease, pregnancy, lactation or an unacceptable contraceptive method in women of childbearing potential, and known abuse of habit‐forming drugs." Group differences: differences are small and appear consistent with chance and small sample size. "In trial 1, 19 (56%) of the subjects (8 zinc, 11 placebo) were women. Of the 32 volunteers, 27 were students (14 zinc, 13 placebo). Only four of the subjects were smokers (2 zinc, 2 placebo). The mean age was 21.4 (+ 0.6, standard error of the mean [SEM]) years in the zinc group and 20.6 (± 0.5, SEM) years in the placebo group." Condition studied: common cold Description of recruitment: NR Diagnostic criteria for condition: "Trial 1 subjects were interviewed in the afternoon before viral challenge (study day 0) and then each morning on study days 1 through 7 regarding eight common cold symptoms, including sneezing, nasal discharge, nasal congestion, malaise, headache, chilliness, sore throat, and cough. Subjects were interviewed each morning and afternoon in trial 2. Symptoms were rated for severity according to the following scale: 0, none; 1, mild; 2, moderate; and 3, severe. Criteria for a cold were based on a modification (6) of the criteria proposed by Jackson et al. (8) and required a total symptom score of.5 plus either nasal discharge for 3 days or the belief of the subject that a cold had occurred."; "Infection rates were determined by viral isolation in both trials and /or by documentation of a fourfold or greater rise in serum‐neutralizing‐antibody titre in paired specimens obtained on the day of viral challenge and 21 days later in trial 1." Number of study centres: 1 Number of withdrawals: 0 Total number screened/eligible/randomised: NR/NR/32
Interventions	Zinc gluconate 184 mg/d lozenge Study description of intervention and administration: "The lozenges were identical in size, shape, and appearance and were similar in taste, as documented in our previous studies. Both lozenges contained 2% citric acid and a lemon flavoring. The zinc gluconate lozenge (RF 2546; Bristol Myers Products, Hillside, N.J.) contained 23 mg of elemental zinc." "Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the number of the subject, the treatment day, and dosing instructions." "The first dose consisted of two lozenges, one followed by the other. Subsequent doses consisted of a single lozenge, and the dosage interval was 2 h. A total of eight doses was administered each day for 5 days in trial 1" "The total daily dosages of zinc were 207 mg on day 1 of treatment and 184 mg on each subsequent study day in trial 1" Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate Frequency of dose: every 2 h/8 doses Dose per day (elemental zinc in mg): 204 mg day 1 and 184 mg on days 2 to 5 Duration of treatment: 5 days Placebo lozenge Study description of intervention and administration: "The lozenges were identical in size, shape, and appearance and were similar in taste, as documented in our previous studies. Both lozenges contained 2% citric acid and a lemon flavoring." "The placebo lozenge for trial 1 (RF 2547; Bristol Myers Products) contained 0.00125 mg of denatonium benzoate" "Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the number of the subject, the treatment day, and dosing instructions." "The first dose consisted of two lozenges, one followed by the other. Subsequent doses consisted of a single lozenge, and the dosage interval was 2 h. A total of eight doses was administered each day for 5 days in trial 1" "The total daily dosages of zinc were 207 mg on day 1 of treatment and 184 mg on each subsequent study day in trial 1" Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: every 2 h/8 doses Duration of treatment: 5 days
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Global severity of cold symptoms (0 to 3 rating) Outcome type: dichotomous outcome Reported as: standard error (mean, SE, N) Notes: measured as "total symptom score" Severity of nasal symptoms (0 to 3 rating) Outcome type: dichotomous outcome Reported as: standard error (mean, SE, N) Notes: sum symptom scores
Identification	Author's name: Barry M. Farr Institution: University of Virginia School of Medicine Email: none Address: Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 229081 Trial registration identifier: none Year study recruitment began: NR (1987 or earlier)
Notes	Declaration of interest: NR Funding source: "This work was supported in part by Bristol Myers Products, Hillside, N.J. B.M.F. is the recipient of a Milbank Scholar Award in Clinical Epidemiology from the Milbank Memorial Fund, New York, N.Y. We acknowledge with gratitude the assistance of Katherine F. Adams, Kathleen M. Kiehl, and Pat P. Beasley in conducting the volunteer study, Deborah F. Thacker and Kate K. Engleby for technical assistance, and Madeleine Ward and Marjorie Jensen for assistance in the preparation of the manuscript. We also gratefully acknowledge the help of Joseph Armellino, Joseph Migliardi, George Blewitt, Niroo Gupta, and their colleagues at Bristol Myers Products and Denis Schisano at Pragma Biotech, Inc., Bloomfield, N.J." Contact with study authors for additional information: none Other: might be a possible source of bias: "We have developed a taste‐matched placebo containing denatonium benzoate (a bitter substance used to discourage thumb sucking in children) and have demonstrated in previous studies that our zinc and placebo lozenges are comparable both in palatability and in the proportion of subjects who believe they are receiving active medication (B. M. Farr and J. M. Gwaltney, Jr., J. Chronic Dis., in press)."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Healthy adult volunteers (n = 32) with titers of serum neutralizing antibody to rhinovirus type 39 of <1:2 were assigned by prior computer randomization to receive either zinc gluconate or placebo lozenge therapy in trial 1" Judgement comment: computer‐generated randomisation sequence.
Allocation concealment (selection bias)	Unclear risk	Quote: "Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the nuniber of the subject, the treatment day, and dosing instructions." Judgement comment: allocation processes not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The lozenges were identical in size, shape, and appearance and were similar in taste, as documented in our previous studies." Judgement comment: likely that participants were blinded although not explicit that personnel were also blinded.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Trial 1 subjects were interviewed in the afternoon before viral challenge (study day 0) and then each morning on study days 1 through 7 regarding eight common cold symptoms, including sneezing, nasal discharge, nasal congestion, malaise, headache, chilliness, sore throat, and cough." Judgement comment: insufficient information on outcome assessment to be certain that outcome assessment was blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The zinc gluconate and placebo groups demonstrated equivalent infection rates of 100 and 94%, respectively (Table 1). All of the infected subjects except for one placebo recipient, who only seroconverted, shed rhinovirus type 39. Only one individual, also in the placebo group, lacked any evidence of infection by viral isolation or seroconversion. The proportions of subjects who seroconverted were similar in the two treatment groups." Judgement comment: incomplete data due to lack of infection, which was measured. Appears that data were collected for all participants (32/32).
Selective reporting (reporting bias)	Unclear risk	Judgement comment: insufficient information to permit judgement of ‘low risk’ or ‘high risk’. Severity of symptoms could have been reported a bit more transparently.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Farr Trial 2 1987.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention ‐ participants were challenged with virus, began prophylaxis 2 hours later, and were followed for development of a clinical cold Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: not investigated for Trial 2, but investigators assessed this in Trial 1 and stated that participants were not able to distinguish between zinc and placebo. "Perceptions were not significantly different regarding predominant lozenge taste and palatability or whether medication was active (Table 3)." Duration of follow‐up: 21 days? Duration of intervention: 7 days Duration of run‐in or washout period: 7 days (same as intervention time) Challenge (prevention trial): "Volunteers were admitted to a motel where they were housed in separate rooms from the time of viral challenge until 7 days afterward. ... Rhinovirus type 13 was similarly administered by intranasal drops (0.25 ml per nostril) from a 1:5,000 (vol/vol) dilution of an inoculum pool with a concentration of 105 8 50% tissue culture infective doses per ml in trial 2." Outcomes measured: "eight common cold symptoms, including sneezing, nasal discharge, nasal congestion, malaise, headache, chilliness, sore throat, and cough. Subjects were interviewed each morning and afternoon in trial 2. Symptoms were rated for severity according to the following scale: 0, none; 1, mild; 2, moderate; and 3, severe. Criteria for a cold were based on a modification (6) of the criteria proposed by Jackson et al. (8) and required a total symptom score of.5 plus either nasal discharge for 3 days or the belief of the subject that a cold had occurred. After discharge from the motel, subjects kept a daily record of the same cold symptoms for 7 days." "After the study participants blew their noses, their paper tissues were collected and stored in airtight containers. These tissues were collected daily, counted, and weighed to determine nasal mucus weights. Clinical laboratory tests, including a complete blood count, a differential leukocyte count, a metabolic profile, hepatic enzymes, a urinalysis, and levels of copper and zinc in serum, were obtained on admission to the motel and again on discharge from the motel on study day 7." Viral cultures Measurement of side effects
Participants	Setting: community Country: USA Zinc gluconate 184 mg/d lozenge Number: 21 Percentage female: 38% Age (mean (SD)): 21.1 (2.7) Placebo lozenge Number: 20 Percentage female: 55% Age (mean (SD)): 21.1 (1.8) Overall Number: 41 Percentage female: 46% Age (mean (SD)): 21.1 (2.3) Inclusion criteria: "...and 45 healthy adult volunteers with titers of antibody to rhinovirus type 13 of <1:2 were enroled in trial 2." Exclusion criteria: "Exclusion criteria included symptoms of any respiratory illness in the week before the study, a history of hayfever, any familiarity with the taste of either denatonium benzoate or zinc, a history of any chronic disease, pregnancy, lactation or an unacceptable contraceptive method in women of childbearing potential, and known abuse of habit‐forming drugs." Group differences: of the 41 participants who completed the trial, there were imbalances between groups in gender and smoking but not in age. "Of the subjects, 41 completed the trial and were available for analysis. There were 13 men in the zinc group (62%) and 9 men in the placebo group (45%). Eight zinc recipients were smokers (38%), compared with six placebo recipients (30%). The mean age was 21.1 (± 0.6, SEM) years in the zinc group and 21.1 (± 0.4, SEM) years in the placebo group." Condition studied: rhinovirus type 13 (common cold) Description of recruitment: NR Diagnostic criteria for condition: "Criteria for a cold were based on a modification (6) of the criteria proposed by Jackson et al. (8) and required a total symptom score of.5 plus either nasal discharge for 3 days or the belief of the subject that a cold had occurred." Number of study centres: 1 Number of withdrawals: 2 exclusions after randomisation and 2 withdrawals after randomisation Total number screened/eligible/randomised: NR/NR/45
Interventions	Zinc gluconate 184 mg/d lozenge Study description of intervention and administration: "In trial 2, treatment was begun 2 h after viral inoculation, which occurred at 7 a.m. on study day 1. The first dose consisted of two lozenges, one followed by the other. Subsequent doses consisted of a single lozenge, and the dosage interval was 2 h. A total of eight doses was administered each day for ... 7 days in trial 2. The total daily dosages of zinc were ... 184 mg each day in trial 2." "Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the number of the subject, the treatment day, and dosing instructions." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate Frequency of dose: every 2 h/8 doses Dose per day (elemental zinc in mg): 184 mg Duration of treatment: 7 days Placebo lozenge Study description of intervention and administration: "The placebo lozenge for trial 2 (RF 2548; Bristol Myers Products) contained 0.0025 mg of [denatonium benzoate].. Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the number of the subject, the treatment day, and dosing instructions." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: every 2 h/8 doses Duration of treatment: 7 days
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: development of a cold (number of participants shedding virus (n) as a proportion of total (N))
Identification	Author's name: Barry M. Farr Institution: University of Virginia School of Medicine Email: NR Address: Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 229081 Trial registration identifier: NR Year study recruitment began: NR
Notes	Declaration of interest: NR Funding source: "This work was supported in part by Bristol Myers Products, Hillside, N.J. B.M.F. is the recipient of a Milbank Scholar Award in Clinical Epidemiology from the Milbank Memorial Fund, New York, N.Y. We acknowledge with gratitude the assistance of Katherine F. Adams, Kathleen M. Kiehl, and Pat P. Beasley in conducting the volunteer study, Deborah F. Thacker and Kate K. Engleby for technical assistance, and Madeleine Ward and Marjorie Jensen for assistance in the preparation of the manuscript. We also gratefully acknowledge the help of Joseph Armellino, Joseph Migliardi, George Blewitt, Niroo Gupta, and their colleagues at Bristol Myers Products and Denis Schisano at Pragma Biotech, Inc., Bloomfield, N.J." Contact with study authors for additional information: none Other: might be a possible source of bias: "We have developed a taste‐matched placebo containing denatonium benzoate (a bitter substance used to discourage thumb sucking in children) and have demonstrated in previous studies that our zinc and placebo lozenges are comparable both in palatability and in the proportion of subjects who believe they are receiving active medication (B. M. Farr and J. M. Gwaltney, Jr., J. Chronic Dis., in press)."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "In trial 2, 23 subjects were randomly chosen to receive zinc and 22 were randomly chosen to receive placebo" Judgement comment: method of sequence generation not described.
Allocation concealment (selection bias)	Unclear risk	Quote: "Each lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the nuniber of the subject, the treatment day, and dosing instructions." Judgement comment: allocation process not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Our formulations of zinc gluconate and the matching placebo lozenges had been previously studied to assure comparability and effective blinding (Farr and Gwaltney, in press)." Quote: "The lozenges were identical in size, shape, and appearance and were similar in taste, as documented in our previous studies." Judgement comment: comparison was zinc versus placebo and it is likely that the participants were adequately blinded although it is not explicit that the study personnel were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Subjects were interviewed each morning and afternoon in trial 2. Symptoms were rated for severity according to the following scale: 0, none; 1, mild; 2, moderate; and 3, severe. Criteria for a cold were based on a modification (6) of the criteria proposed by Jackson et al. (8) and required a total symptom score of.5 plus either nasal discharge for 3 days or the belief of the subject that a cold had occurred. After discharge from the motel, subjects kept a daily record of the same cold symptoms for 7 days. Each subject was contacted twice by telephone during this period to assure compliance in keeping the diary." Judgement comment: comparison was zinc versus placebo but blinding of outcome assessors is not explicitly described.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "In trial 2, 23 subjects were randomly chosen to receive zinc and 22 were randomly chosen to receive placebo, but one subject in the placebo group was shedding virus on admission to the study and was thus excluded. Another subject was excluded because of a neuromuscular disorder noted after randomization to the placebo group but before viral inoculation. Two more subjects dropped out of the zinc group because of fever and nausea, respectively, on study days 0 and 2. Of the subjects, 41 completed the trial and were available for analysis. There were 13 men in the zinc group (62%) and 9 men in the placebo group (45%)." Judgement comment: 41/45 (91%) of participants provided outcome data and the reasons for exclusion or loss to follow‐up are described.
Selective reporting (reporting bias)	High risk	Quote: "13 in the zinc group. There were no significant differences between the two groups in the frequency, severity, or duration of any individual cold symptoms. There were also no differences in the rate or type of adverse reactions between the two groups. DISCUSSION Zinc gluconate lozenge therapy" Judgement comment: results of the severity assessments are only reported as a brief 'non‐significant' summary with no numerical data. No protocol available to verify planned choice of outcomes and analyses.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Godfrey 1992.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment: "The present study was carried out to test the hypothesis that pleasant‐tasting ZGG lozenges that release 93% of the ionic zinc into saliva may produce similar efficacy to that originally reported by Eby et al." Concomitant treatments explicitly allowed or forbidden: paracetamol allowed and others forbidden. "Patients were also provided with paracetamol and instructed not to exceed the dosage stated on the label, nor to use any other form of medication." Investigation of ability to distinguish between zinc and placebo: "At their final visits, the patients were asked by the nurse which treatment they thought they had received. A total of 19 patients in each group guessed correctly; 12 of those who had received ZGG and 15 of those who received the placebo guessed incorrectly. In each treatment group there were four who did not know, and these eight patients were divided evenly among the four cells for the test of independence. The resulting x"‐value of 0.8975 was not significant; thus, the patients did not know which treatment they had received." There was also some initial taste‐testing to get the placebo‐zinc to be as close to one another as possible in taste. Duration of follow‐up: 7 days Duration of intervention: 7 days Duration of run‐in or washout period: none Describe how participants were identified as having colds/URTI at baseline (treatment trial): nurse or physician confirmed diagnosis on the basis of between 2 and 4 symptoms (cough; fever; headache; hoarseness; muscle ache; nasal drainage; nasal congestion; scratchy throat; sore throat; and/or sneezing) consistent with the common cold. Outcomes measured: participants kept diaries to record the severity of 10 cold symptoms on a 0 to 3 scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) at 6 and 12 h after the first dose of the study medication, and at 20.00 h on each subsequent day. They were also asked to record any side effects. "In the present study, the strict criterion of complete disappearance of all symptoms was used as the definition of the cold being over."
Participants	Setting: Dartmouth College Medical School cold clinic, outpatient Country: United States Zinc gluconate 190 mg/d lozenge Number: 35 Percentage female: 34% Age (median, range): median 21.2 years, range 18 to 40 years Placebo lozenge Number: 38 Percentage female: 45% Age (median, range): median 20.1 years, range 18 to 24 years Overall Number: 73 Percentage female: 40% Age (median, range): range 18 to 40 years Inclusion criteria: "All patients were examined and diagnosed by a physician or nurse clinician as having shown, for no more than 2 days, between two and nine symptoms consistent with a common cold. These symptoms included any of the following: cough; fever; headache; hoarseness; muscle ache; nasal drainage; nasal congestion; scratchy throat; sore throat; and/or sneezing." Exclusion criteria: "Participants were excluded if they had a positive bacteriological throat culture, were pregnant, or had symptoms consistent with influenza or any other illness" Group differences: groups appeared similar with the exception of some older participants in the active group: the age range for the ZGG treatment group (18 to 40 years) was greater than that of participants in the placebo group (18 to 24 years); however, the mean duration of colds for those patients in the ZGG treatment group who were older than 24 years was the same as for those who were under 25 years of age. The mean number of days that the patients had experienced symptoms prior to entering the programme was 1.34 days, the same mean for both groups. There was no significant (P < 0.05) difference between the ZGG and placebo treatment groups as to the distribution of female and male participants...; Condition studied: common cold Description of recruitment: "A total of 87 patients were recruited from among Dartmouth College students and staff who spontaneously presented to the cold clinic at the Dartmouth College Health Service over a 28‐day period." Diagnostic criteria for condition: "All patients were examined and diagnosed by a physician or nurse clinician as having shown, for no more than 2 days, between two and nine symptoms consistent with a common cold." Symptoms are the same as those that were assessed throughout the study. Number of study centres: 1 Number of withdrawals: 14 Total number screened/eligible/randomised: NR/NR/87
Interventions	Zinc gluconate 190 mg/d lozenge Study description of intervention and administration: “The ZGG lozenges, which were prepared in the same boiled candy base as the placebo contained glycine and zinc gluconate trihydrate, and the zinc content was 5.26 ± 0.20 mg/g, or 23.7 mg zinc in each 4.5 g lozenge. Placebo and ZGG lozenges were bacteriologically sterile.” “[Participants] were instructed (both verbally and in writing) to suck, not chew, the lozenges as required but at not less than 2‐h intervals taking up to a maximum of eight lozenges per day.” Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): zinc gluconate trihydrate Frequency of dose: as needed with at least 2‐hour intervals between doses. Dose per day (elemental zinc in mg): 23.7 mg/lozenge x 8/day = 189.6 mg zinc Duration of treatment: 2 days unless symptoms persisted, then they were given another 8‐day supply of lozenges Placebo lozenge Study description of intervention and administration: “The placebo that subjects considered most like ZGG in astringency and pleasantness was selected; it contained US Pharmacopoeia tannic acid, glycine and calcium saccharinate in an orange‐flavoured, boiled candy base, weighed 4.5 g and was identical to the ZGG lozenges in all characteristics.” “Placebo and ZGG lozenges were bacteriologically sterile.““[Participants] were instructed (both verbally and in writing) to suck, not chew, the lozenges as required but at not less than 2‐h intervals taking up to a maximum of eight lozenges per day.” Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: as needed with at least 2‐hour intervals between doses Duration of treatment: 2 days unless symptoms persisted, then they were given another 8‐day supply of lozenges.
Outcomes	Duration of cold symptoms (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of cold symptoms (days) Outcome type: dichotomous outcome Reported as: standard deviation (mean, SD, N) Duration of cough (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of nasal drainage (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of nasal congestion (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of hoarseness (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of sore throat (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of scratchy throat (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of sneezing (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of headache (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of muscle aches (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Adverse events Outcome type: dichotomous outcome Reported as: percentage of participants with event (%, N)
Identification	Author's name: Dr J C Godfrey Institution: Godfrey Science & Design, Inc. Email: NR Address: 1649 Old Welsh Road, Huntingdon Valley, Pennsylvania, PA 19006, USA Trial registration identifier: NR Year study recruitment began: NR ‐ 1992 or earlier
Notes	Declaration of interest: NR Funding source: "This study was sponsored by Godfrey Science & Design, Inc., Huntingdon Valley, Pennsylvania, USA and by a grant from the Rorer Pharmaceutical Corp., FortWashington, Pennsylvania, USA" Contact with study authors for additional information: none Other: narrative description: authors undertook a pre‐specified comparison of the effects of ZN at day 2 versus < 2 days of infection. "When the duration of the cold prior to beginning treatment was allowed for, the significance of the differences between the day 1 and the day 2 ZGG treatment groups was increased to P<0.001 (t = ‐3.737)"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization by a third party was used to assign the 87 participants to treatment groups. A pharmacist, using a randomization table provided by the study statistician, packaged containers for individual subjects with lozenges according to the production run number and subject identification number."
Allocation concealment (selection bias)	Low risk	Judgement comment: investigators were blinded as to treatment group during assignment as a third party used a randomisation table to assign treatment and package containers.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Judgement comment: extensive efforts were made to select a placebo lozenge that was similar to the active lozenge, and blinding appears to be confirmed by questioning of participants.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All patients kept diaries recording the severity of their symptoms upon enrollment, at 6 and 12 h after the first dose of the study medication, and at 20.00 h on each subsequent day. They were instructed to rate the severity of 10 cold symptoms on a scale of a ‐ 3 (0, none; 1, mild; 2, moderate; and 3, severe) and, in addition, were asked to record any side‐effects." Judgement comment: if blinding of participants was adequate, then it seems likely this would be as well, since they reported their own change in outcome. It does also state that "complete disappearance of all symptoms was used as the definition for the cold being over." Being a binary that was based on the participant's self‐report it seems to indicate that if they were blinded, the outcome was too?
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "total of eight ZGG‐ and six placebo‐treated patients withdrew from the trial leaving 35 and 38 evaluable patients, respectively. Illnesses that resulted in patients withdrawing from the study were as follows: two patients had bronchitis and one had viral gastroenteritis in the placebo treatment group; and there was one patient with influenza and one with a bacterial infection in the ZGG treatment group. Other reasons for withdrawing were: failure to appear at follow‐up (three ZGG‐ and one placebo‐treated patient); efficacy doubted by the patient (one ZGG‐ and one placebo‐treated patient); nausea (one ZGG‐ and one placebo‐treated patient); and sports injury (one ZGG‐treated patient)." Judgement comment: numbers and reasons for attrition were given and the numbers were balanced, however the loss to follow‐up is a relatively large proportion of those randomised (14/87; 16%) and the effects of this loss are uncertain.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: although expected outcomes are reported, there is no protocol or registration and the methods section is somewhat unclear regarding details such as the definition of when a cold is over.
Other bias	Low risk	Judgement comment: the study appears to be free of other sources of bias.

Hemilä 2020.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "Participation in the trial did not limit the use of usual healthcare services or over‐the‐counter medicines during the study." Describe any investigation of ability to distinguish between zinc and placebo: "On the first follow‐up day, the participants were asked to guess whether they received zinc or placebo lozenges (table2). Sixty‐five percent of participants did not guess the kind of lozenge that they were taking. Of those who responded either zinc or placebo, about half responded incorrectly, consistent with guessing" Duration of follow‐up: until the participant recovered or until the 10th follow‐up day when the follow‐up recording was terminated Duration of intervention: 5 days after first symptoms Duration of run‐in or washout period: NA Describe how participants were identified as having colds/URTI at baseline (treatment trial): their personal consideration that they have the common cold Outcomes measured: the primary outcome was the self‐reported recovery from the common cold, based on the patient’s own interpretation of when he or she recovered. Outcomes were duration of cold, global severity of the cold (noted as collected but not clearly reported), severity of individual cold symptoms (noted as collected but not clearly reported), and adverse events.
Participants	Setting: working population in Finland, community Country: Finland Zinc acetate 78 mg/d lozenge Number: 45 Percentage female: 87% Age (mean (SD)): 46 (10) Placebo lozenge Number: 42 Percentage female: 93 Age (mean (SD)): 48 (9) Overall Number: 87 Percentage female: 90% Age (mean (SD)): 47 (9.5) Inclusion criteria: "Participants were recruited from the employees of City of Helsinki, Finland in collaboration with occupational health unit. We included male and female employees, age ≥18 years and with a self‐report that they usually have had ≥1 colds per winter" Exclusion criteria: "Exclusion criteria were pregnancy, lactation, chronic runny nose or chronic cough." Group differences: "Differences in the baseline characteristics were small between the treatment groups except for the occurrence of sinusitis, which was twice as common in the placebo group as in the zinc lozenge group." Condition studied: common cold Description of recruitment: "The randomised controlled trial was conducted from 1 December 2017 to 30 April 2018. Participants were recruited from the employees of City of Helsinki, Finland in collaboration with occupational health unit." "Initial invitation to the study was sent by email to approximately 6000 employees (figure 1). Of them, 253 met the inclusion and exclusion criteria, were willing to participate, gave signed informed consent and were randomised..." Diagnostic criteria for condition: "The participants were instructed to start taking lozenges as soon as they started to suffer from the first symptoms of the common cold, defined as their personal consideration that they have the common cold..." Number of study centres: web‐based (1) Number of withdrawals: 1 Total number screened/eligible/randomised: 6000/253/87
Interventions	Zinc acetate 78 mg/d lozenge Study description of intervention and administration: "The zinc lozenge was a commercially available zinc acetate lozenge with 13mg elemental zinc per lozenge (University Pharmacy, Helsinki, Finland). The lozenge weighed 0.9g and had a diameter of 13mm. The lozenges contained isomaltulose, sorbitol, magnesium stearate, orange and peppermint flavours and sucralose. The instruction of the commercial package for patients with common cold is to dissolve slowly six lozenges per day in the mouth, which totals to 78mg/day of elemental zinc, at most for 5 days. The same instruction was used in this trial. Each package contained 30 lozenges." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): acetate Frequency of dose: 6/d Dose per day (elemental zinc in mg): 78 mg/d Duration of treatment: 5 days Placebo lozenge Study description of intervention and administration: "The placebo lozenges, formulated by University Phar‐macy, contained 0.13mg sucrose octa‐acetate, which has previously been used in the construction of slightly bitter placebo lozenges to imitate zinc acetate lozenges. The placebo lozenges were closely similar with the zinc lozenges in visual appearance and in taste.When allowing the zinc and placebo lozenges to slowly dissolve in the mouth, they dissolved in about 8min." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: 6/d Duration of treatment: 5 days
Outcomes	Duration of cold symptoms (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: "The median duration of colds was 5 days in the placebo group and 7 days in the zinc lozenge group." Supplementary tables included data, which were used to calculate the mean and SD for duration. Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N)
Identification	Author's name: Dr Harri Hemilä Institution: Department of Public Health, University of Helsinki, Helsinki, Finland Email: harri.hemila@helsinki.fi Address: University of Helsinki Trial registration identifier: NCT03309995 Year study recruitment began: 2017
Notes	Declaration of interest: "Competing interests: None declared." Funding source: "This study was investigator‐initiated trial, which was supported by NordForsk (75021) and Academy of Finland (311492). Zinc and placebo lozenges were donated by the University Pharmacy, Helsinki, Finland." Contact with study authors for additional information: none Other: supplementary tables include raw data, much of it is in Finnish. Link to data: https://bmjopen.bmj.com/content/bmjopen/10/1/e031662/DC3/embed/inline-supplementary-material-3.xlsx?download=true
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The randomisation code was generated at the University Pharmacy and the code was maintained by them until the end of the trial period." Judgement comment: central randomisation done by a pharmacy and although the source of the sequence was not specified, it was almost certainly a random number table or computer program. No possibility of quasi‐randomisation.
Allocation concealment (selection bias)	Low risk	Quote: "The lozenge packages were numbered with 3‐ digit codes that were used in the identification of the packages (zinc vs placebo). The packages were distributed to participants without the participants and the researchers knowing the contents of the packages. Thus, both participants and researchers were blinded of the type of lozenge during the trial." Judgement comment: pharmacy‐controlled randomisation with 3‐digit code identifiers.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "After the trial was concluded, we asked for the group data as coded to A and B after cleaning the data and the actual group identification (zinc or placebo) after carrying out the primary analyses of the primary outcome." Judgement comment: attention was paid to making the zinc lozenge imitate the taste of the zinc lozenge and when blinding was tested it was found to be successful.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The primary outcome was the self‐reported recovery from the common cold, based on the patient’s own interpretation when he or she recovered." Judgement comment: participants assessed their own recovery and they were blinded to treatment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "In our primary analysis, we included 87 participants who contracted the common cold during the follow‐up (figure 1)." Judgement comment: primary outcome reported for 87/88 (99%) participants after 1 participant withdrew due to an adverse event.
Selective reporting (reporting bias)	Low risk	Judgement comment: trial registration number NCT03309995 and it was registered prior to study start date. Outcomes and analysis correspond to study report. Aligns with NCT report for outcome measures. https://clinicaltrials.gov/ct2/show/NCT03309995.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Hirt 2000.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "Participants were instructed not to take any other cold remedies or any drugs that might affect symptom scores." Investigation of ability to distinguish between zinc and placebo: NR Duration of follow‐up: "Subjects were asked to return to their study site within 24 hours of symptom resolution for verification and followup." 24 h? Duration of intervention: "The primary endpoint was the complete resolution of symptoms, which was determined when the total symptom score fell to zero. Subjects were instructed to spray one dose into each nostril every 4 hours (9 a.m. , I p.m. , 5 p.m. , and 9 p.m .) for as long as they experienced symptoms." Max appears to be ~16 days. Duration of run‐in or washout period: NR Describe how participants were identified as having colds/URTI at baseline (treatment trial): "Only subjects whose cold symptoms had been manifest for 24 hours or less were enroled in the study. Subjects were required to have had at least three of the following symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, or sneezing." Outcomes measured: duration of cold, global severity of cold (NR in results), severity of individual cold symptoms (NR in results), adverse events
Participants	Setting: participants were recruited at 4 sites in the Los Angeles area (not described in further detail). Country: US Zinc gluconate 960 mg/d nasal gel Number: 108 Percentage female: NR Age (mean (SD)): NR Placebo nasal gel Number: 105 Percentage female: NR Age (mean (SD)): NR Overall Number: 213 Percentage female: NR Age (mean (SD)): NR Inclusion criteria: "Only subjects whose cold symptoms had been manifest for 24 hours or less were enroled in the study. Subjects were required to have had at least three of the following symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, or sneezing." Exclusion criteria: "Exclusion criteria were pregnancy, an immunocompromised state, a duration of common cold symptoms beyond 24 hours, and the use of certain medications." Group differences: NR Condition studied: common cold Description of recruitment: "Our methodology was similar to that used by Mossad et al. in their clinical evaluation of zinc lozenges in 1996. Subjects were recruited at four sites in the Los Angeles area.The study population consisted of 213 subjects; they were randomly assigned to receive either zine nasal gel (n = 108) or placebo (n = 105)." Diagnostic criteria for condition: "Only subjects whose cold symptoms had been manifest for 24 hours or less were enroled in the study. Subjects were required to have had at least three of the following symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, or sneezing." Number of study centres: 4 Number of withdrawals: NR Total number screened/eligible/randomised: NR/NR/213
Interventions	Zinc gluconate 960 mg/d nasal gel Study description of intervention and administration: "The zinc nasal gel consisted of zinc gluconate in an emulsion of benzalkonium chloride, glycerin, hydroxyethylcellulose, sodium chloride, and sodium hydroxide; its pH level was 7.2." "Both gels were dispensed in a double‐blind fashion in metered doses of 120 microliters in applicators supplied by Botanical Laboratories (Ferndale, Wash.). Subjects were instructed to spray one dose into each nostril every 4 hours (9 a.m. , 1 p.m. , 5 p.m. , and 9 p.m .) for as long as they experienced symptoms." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): spray Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate Frequency of dose: 4 x/d Dose per day (elemental zinc in mg): unclear Duration of treatment: 0 to 16 days Placebo nasal gel Study description of intervention and administration: "The composition of the placebo gel was identical except that it did not contain zinc." "Both gels were dispensed in a double‐blind fashion in metered doses of 120 microliters in applicators supplied by Botanical Laboratories (Ferndale, Wash.). Subjects were instructed to spray one dose into each nostril every 4 hours (9 a.m. , 1 p.m. , 5 p.m. , and 9 p.m .) for as long as they experienced symptoms." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): spray Frequency of dose: 4 x/d Duration of treatment: 0 to 16 days
Outcomes	Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: "Subjects had also been provided a list of five potential side effects (nausea, bad taste reactions, odor, dizziness, and drowsiness) and asked during the study and again at the end of the study whether they had experienced these or any others. While none of the subjects reported any of these five side effects, 45 zinc patients (42%) and 39 controls (37%) did report that they had experienced a slight tingling or burning sensation." Duration of cold symptoms Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N)
Identification	Author's name: Michael Hirt, MD Institution: Center of Integrative Medicine, Tarzana, Calif. Email: NA Address: Michael Hirt, MD, Center of Integrative Medicine, 5525 Etiwanda Ave., Suite222, Tarzana, CA 9 1356. Phone: (818)344‐0200; fax: (818) 758‐3464 Trial registration identifier: NR Year study recruitment began: NR ‐ after 1999 at least. "Recently, a new approach to zinc therapy‐an over the‐counter nasal gel formulation (Zicam)‐was the subject of a preliminary study (C.B. Hensley, PhD, and R. Davidson, PhD, unpublished data, 1999)."
Notes	Declaration of interest: NR Funding source: NR ‐ reproduction of an earlier brand name (Zicam) study Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The study population consisted of 213 subjects; they were randomly assigned to receive either zinc nasal gel (n = 108) or placebo (n = 105)." Judgement comment: no description of method of sequence generation.
Allocation concealment (selection bias)	Unclear risk	Quote: "... its pH level was 7.2. The composition of the placebo gel was identical except that it did not contain zinc. Both gels were dispensed in a double‐blind fashion in metered doses of 120 III in applicators supplied by Botanical Laboratories (Ferndale, Wash.). Subjects were instructed to spray one" Judgement comment: not described clearly aside from them being identical.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "the use of certain medications. The zinc nasal gel consisted of zinc gluconate in an emulsion of benzalkonium chloride, glycerin, hydroxyethylcellulose, sodium chloride, and sodium hydroxide; its pH level was 7.2. The composition of the placebo gel was identical except that it did not contain zinc. Both gels were dispensed in a double‐blind fashion in metered doses of 120 III in applicators supplied by Botanical Laboratories (Ferndale, Wash.). Subjects were instructed to spray one" Judgement comment: "The study was placebo controlled and it is almost certain that the participants and personnel were blinded. Low or Unclear."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Patients were provided with a diary to document the severity of their symptoms. Twice eac h day (at 9 a.m. and 9 p.m.), patients graded each of nine symptoms on a scale of 0 (absent) to 3 (severe)." Judgement comment: low‐unclear. Only low if the blinding was actually maintained.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Judgement comment: it is possible that all participants were followed and provided outcome data, but the number of people who dropped out (if any) and the number of people who provided follow‐up data were not specified.
Selective reporting (reporting bias)	High risk	Judgement comment: protocol not found for comparison but it is mentioned that they collected symptom severity, yet only duration and presence of symptoms appear in the results.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Kartasurya 2012.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: both Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: NR Duration of follow‐up: 2 mos (still taking Zn but also with vitamin A and they were followed) Duration of intervention: 2 mos zn only (4 mos total, but vitamin A was added at 2 mos in) Duration of run‐in or washout period: NR Describe how participants were identified as having colds/URTI (treatment trial): "An URTI episode was defined as the presence of at least two of the following clinical symptoms experienced for at least 1 d: runny nose (ongoing discharge from the nose), cough, sore throat and raised body temperature, or one of the symptoms for at least 2 d, without the signs of difficult or rapid breathing. A total of three aspects of URTI morbidity, namely the number of episodes, percentage of days with URTI and duration per episode, were used as dependent variables in the present study. A period of three illness‐free days between the episodes was required for a new episode to be defined. This definition of URTI episode is adapted from definitions used in previous randomised controlled Zn supplementation studies( Reference Ruel, Rivera and Santizo16 – Reference Osendarp, Van Raaij and Darmstadt19 ) modified to specifically measure URTI (instead of respiratory infections more generally, or irritation problem) in preschool‐age children." Outcomes measured: proportion developing colds, duration of cold, adverse events
Participants	Setting: 36 posyandu (health centres) in Semarang, Indonesia Country: Indonesia Zinc NR 10 mg/d syrup Number: 415 Percentage female: 92.3% Age (mean (SD)): 3.56 years Placebo syrup Number: 411 Percentage female: 50% Age (mean (SD)): 3.48 years Overall Number: 826 Percentage female: 86.2% Age (mean (SD)): NR Inclusion criteria: "The age group was selected due to their relatively high risk of both malnutrition – including vitamin A deficiency – and URTI, and the feasibility of selecting a community‐based sample of this age through the posyandu. Apparently healthy children aged 2–5 years were included." Exclusion criteria: "Moderately and severely malnourished children, defined by a weight‐for‐height ≤ − 2 SD of the WHO/National Center for Health Statistics reference( 14 ) were excluded, as malnutrition may modify a treatment effect from supplementation." Group differences: "There were no differences in age, anthropometric status and socio‐economic conditions between the subjects who received Zn v. placebo." Condition studied: URTI Description of recruitment: "Mothers of all children aged 2–5 years attending thirty‐six posyandu (health centres) in Semarang, Indonesia were invited to join the study." "Children were recruited during June 2003 and given a Zn supplement or placebo daily for 4 months." Diagnostic criteria for condition: "An URTI episode was defined as the presence of at least two of the following clinical symptoms experienced for at least 1 d: runny nose (ongoing discharge from the nose), cough, sore throat and raised body temperature, or one of the symptoms for at least 2 d, without the signs of difficult or rapid breathing. A total of three aspects of URTI morbidity, namely the number of episodes, percentage of days with URTI and duration per episode, were used as dependent variables in the present study. A period of three illness‐free days between the episodes was required for a new episode to be defined. This definition of URTI episode is adapted from definitions used in previous randomised controlled Zn supplementation studies( Reference Ruel, Rivera and Santizo16 – Reference Osendarp, Van Raaij and Darmstadt19 ) modified to specifically measure URTI (instead of respiratory infections more generally, or irritation problem) in preschool‐age children." Number of study centres: 36 Number of withdrawals: by end of 4 mos (399 + 399) = 798; 826 ‐ 798 = 28 total 411 ‐ 399 = 12 placebo 415 ‐ 399 = 16 zn By end of 2 mos (zn only) (409 + 413) = 822; 826 ‐ 822 = 4 total 411 ‐ 409 = 2 placebo 415 ‐ 413 = 2 zn Total number screened/eligible/randomised: 1047/826/826
Interventions	Zinc NR 10 mg/d syrup Study description of intervention and administration: "In each posyandu, one of the physicians (not investigators) used random numbers to allocate each child to receive daily either Zn (10 mg elemental Zn) or a placebo syrup for the 4 months. Supplements were prepared and labelled with alphabetic codes by the Pharmacy Department of Diponegoro University. There was no difference between the syrups in taste or appearance. Trained health workers were recruited from the thirty‐six posyandu and made home visits to each subject every third day. During these visits they supervised consumption of syrup, recorded compliance data and observed the amount of syrup left in the bottles. They supplied new bottles of syrup to mothers each fortnight, rotating strawberry and lemon flavours to maximise compliance. Both health workers and mothers were blinded to the syrup content. Non‐compliance was defined as syrup consumption on less than 75 % of the total supplement days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): syrup Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): NR Frequency of dose: daily Dose per day (elemental zinc in mg): 10 mg Duration of treatment: 2 mos Zn alone; 4 mos + vitamin A Placebo syrup Study description of intervention and administration: "In each posyandu, one of the physicians (not investigators) used random numbers to allocate each child to receive daily either Zn (10 mg elemental Zn) or a placebo syrup for the 4 months. Supplements were prepared and labelled with alphabetic codes by the Pharmacy Department of Diponegoro University. There was no difference between the syrups in taste or appearance. Trained health workers were recruited from the thirty‐six posyandu and made home visits to each subject every third day. During these visits they supervised consumption of syrup, recorded compliance data and observed the amount of syrup left in the bottles. They supplied new bottles of syrup to mothers each fortnight, rotating strawberry and lemon flavours to maximise compliance. Both health workers and mothers were blinded to the syrup content. Non‐compliance was defined as syrup consumption on less than 75 % of the total supplement days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): syrup Frequency of dose: daily Duration of treatment: 2 mos placebo alone; 4 mos placebo + vitamin A
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: measured in episodes per child Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Notes: measured in days
Identification	Author's name: Martha I. Kartasurya Institution: Public Health Faculty, Diponegoro University, Semarang, Indonesia Email: m_kartasurya@yahoo.com Address: Public Health Faculty, Diponegoro University, Semarang, Indonesia Trial registration identifier: ACTRN12611000659909 Year study recruitment began: 2003
Notes	Declaration of interest: "There are no conflicts of interest in the conduct or reporting of the present study." Funding source: "The research was conducted with funding support from a Nestle ´Foundation Research Grant." Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "In each posyandu, one of the physicians (not investigators) used random numbers to allocate each child to receive daily either Zn (10 mg elemental Zn) or a placebo syrup for the 4 months." Judgement comment: random numbers were used, but how those were derived randomly is unclear.
Allocation concealment (selection bias)	Unclear risk	Quote: "In each posyandu, one of the physicians (not investigators) used random numbers to allocate each child to receive daily either Zn (10 mg elemental Zn) or a placebo syrup for the 4 months." Judgement comment: no description of allocation process.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Supplements were prepared and labelled with alphabetic codes by the Pharmacy Department of Diponegoro University. There was no difference between the syrups in taste or appearance." Judgement comment: personnel (investigators) presumably did not know of the allocations, but clinicians may have, which might lead them to treat participants differently (performance bias).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The results of the observation and interview were recorded on structured questionnaires and reported to supervising physicians fortnightly. The latter diagnosed URTI based on symptoms reported, and randomly checked children’s health status and visited the subjects if necessary." Judgement comment: health workers collected outcomes by observation and interviewing mothers. Both health workers and mothers were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The analysis was initially conducted on an intention‐ to‐treat basis, with the code of Zn or placebo syrup broken only after the initial analyses were completed." Judgement comment: 822/826 (99.5%) participants were followed at the 2‐month endpoint. Reasons for discontinuation are also noted and also roughly equivalent between groups.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: methods and results correspond with each other and with the trial registration but the trial was retrospectively registered (ACTRN12611000659909).
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Kurugöl 2006.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention, with temporarily increased zinc dosage in cases where colds developed Concomitant treatments explicitly allowed or forbidden: "Parents were asked to give no cough and cold preparations, antibiotics, zinc‐containing multivitamins or mineral supplements, or other zinc products during the course of the study. However, the children were allowed to use acetaminophen to control fever." Investigation of ability to distinguish between zinc and placebo: NR Duration of follow‐up: 7 months (from 4 October 2004 through to 3 May 2005) for all children, and until symptoms resolved up to a maximum of 10 days for each treated cold episode during this time. Duration of intervention: 7 months (from 4 October 2004 through to 3 May 2005) for all children, and until symptoms resolved up to a maximum of 10 days for each treated cold episode during this time. Duration of run‐in or washout period: NR Describe how participants were identified as having colds/URTI at baseline (treatment trial): the treatment component of the trial began when children developed symptoms of a cold, defined as "two of the following 10 symptoms consistent with the common cold: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, itchy throat, sneezing, sore throat and fever (axillar temperature /378C)." Outcomes measured: 1) occurrences of the common cold, 2) severity of the common cold, 3) duration of cold symptoms, 4) severity of cold symptoms, 5) cold‐related school absences, 6) usage of cold medications, 7) concomitant antibiotic therapy, 8) adverse effects
Participants	Zinc sulfate 15 to 30 mg/d syrup Number: 100 Percentage female: 52% Age (mean (SD)): 5.7 (2.8) years Placebo syrup Number: 100 Percentage female: 49% Age (mean (SD)): 5.5 (2.7) years Overall Number: 200 Percentage female: 50.5% Age (mean (SD)): 5.6 (2.8) years Inclusion criteria: "The children were required to be in overall good health and to be 2 to 10 y of age." Exclusion criteria: "Children who had a known chronic disease, immunodeficiency disorder or asthma were excluded. Children were also excluded if they had a history of sensitivity to or an idiosyncratic experience with zinc, or whose parents were unwilling or unable to comply with clinical study procedures." Group differences: "baseline characteristics of the children, including age, distribution of sex, proportion whose parents smoked, prevalence of allergies, number of colds and the number of prescriptions for antibiotics in the previous year were similar between the two groups" Condition studied: common cold Description of recruitment: "This randomized, double‐blind, placebo‐controlled, prospective study was conducted at Ege University Nursery and Primary School between October 2004 and May 2005. The study was approved by the local Ethical Committee of the Ege University Medical Faculty. Before enrollment, all parents and guardians of children were informed by the school doctor and the principal investigator about the nature of the study. Parents gave informed consent for their children to participate in the study." Diagnostic criteria for condition: "two of the following 10 symptoms consistent with the common cold: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, itchy throat, sneezing, sore throat and fever (axillar temperature >37 C)" Number of study centres: 1 Number of withdrawals: "A total of 200 healthy children were enrolled in the study. The children received either oral zinc sulphate (zinc group, n/100) or an identically packaged placebo (placebo group, n/100). Overall, 97% (n/ 194) of the children (97 in the zinc group and 97 in the placebo group) completed the 7‐mo study period; six (3%) discontinued, four for non‐compliance and two for adverse effects due to medication." Total number screened/eligible/randomised: NR/NR/200
Interventions	Setting: community (school) Country: Turkey Zinc sulfate 15 to 30 mg/d syrup Study description of intervention and administration: "The licensed zinc syrup consisted of 1.32 g zinc sulphate in 100 cm3 (15 mg of zinc in a 5‐cm3 spoonful), and glycerin, glucose, sunset yellow, orange essence and nipajin as preservative. " "Eligible children received zinc sulphate (15 mg of zinc) or placebo syrup once daily during the cold season, from 4 October 2004 through to 3 May 2005. The dose was increased to two times per day (30 mg of zinc or placebo) in children who exhibited at least two of the following 10 symptoms consistent with the common cold: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, itchy throat, sneezing, sore throat and fever (axillar temperature /378C). Children received medication two times per day until cold symptoms resolved, up to a maximum of 10 d." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): syrup Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): sulfate Frequency of dose: "Eligible children received zinc sulphate (15 mg of zinc) or placebo syrup once daily during the cold season, from 4 October 2004 through to 3 May 2005. The dose was increased to two times per day (30 mg of zinc or placebo) in children who exhibited at least two of the following 10 symptoms consistent with the common cold: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, itchy throat, sneezing, sore throat and fever (axillar temperature /37C). Children received medication two times per day until cold symptoms resolved, up to a maximum of 10 d." Dose per day (elemental zinc in mg): 15 mg when well and 30 mg during colds Duration of treatment: 7 months Placebo syrup Study description of intervention and administration: "The licensed zinc syrup consisted of 1.32 g zinc sulphate in 100 cm3 (15 mg of zinc in a 5‐cm3 spoonful), and glycerin, glucose, sunset yellow, orange essence and nipajin as preservative. ""Placebo and active syrups were identical in appearance, texture and flavouring content, except that the placebo lacked the zinc component." "Eligible children received zinc sulphate (15 mg of zinc) or placebo syrup once daily during the cold season, from 4 October 2004 through to 3 May 2005. The dose was increased to two times per day (30 mg of zinc or placebo) in children who exhibited at least two of the following 10 symptoms consistent with the common cold: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, itchy throat, sneezing, sore throat and fever (axillar temperature /378C). Children received medication two times per day until cold symptoms resolved, up to a maximum of 10 d." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): syrup Frequency of dose: "Eligible children received zinc sulphate (15 mg of zinc) or placebo syrup once daily during the cold season, from 4 October 2004 through to 3 May 2005. The dose was increased to two times per day (30 mg of zinc or placebo) in children who exhibited at least two of the following 10 symptoms consistent with the common cold: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, itchy throat, sneezing, sore throat and fever (axillar temperature /37C). Children received medication two times per day until cold symptoms resolved, up to a maximum of 10 d." Duration of treatment: 7 months
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: participants were on 15 mg of zinc/d during prevention and then increased to 30 mg if cold developed. Cold: Day 0*** indicates the time point where the dosage was increased. Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Notes: could have happened at any point in the course of the study. Dose was increased to 30 mg at onset. "The duration of common cold was calculated as the number of days starting from the onset of symptoms until resolution of cold, as defined by two consecutive symptom scores of 1 or more." Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Global severity of cold symptoms (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Notes: "A total of 200 healthy children were enrolled in the study." Duration of cough (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal drainage (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal congestion (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of headache (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of hoarseness (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of muscle aches (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of scratchy throat (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sore throat (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sneezing (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of fever (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Severity of nasal symptoms (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Days missed from work or school (per child) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N)
Identification	Author's name: Zafer Kurugöl Institution: Department of Paediatrics, Faculty of Medicine, Ege University, Izmir, Turkey Email: kurugol@med.ege.edu.tr Address: Department of Paediatrics, Faculty of Medicine, Ege University, 35100 Bornova, Izmir, Turkey. 69 90. E‐mail: Trial registration identifier: NR Year study recruitment began: 2004
Notes	Declaration of interest: NR Funding source: "We also thank Berko Ilac Company, Turkey, for supplying the active and placebo medications, and for supplying the digital thermometers. The company did not participate in designing the study, collecting and analysing the data, or in writing the report." Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A statistical consultant programmed a computer‐generated randomization code and prepared the packages of medication. The packages were randomly distributed to the study personnel, all of whom were blind to the group assignments." Judgement comment: the investigators describe a random component in the sequence generation process such as using a computer random number generator.
Allocation concealment (selection bias)	Low risk	Quote: "The packages were randomly distributed to the study personnel, all of whom were blind to the group assignments." Judgement comment: centralised randomisation with packages of medication distributed to study personnel who were blind to group assignments ‐ appears that there was no opportunity to reveal allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Placebo and active syrups were identical in appearance, texture and flavouring content, except that the placebo lacked the zinc component." Judgement comment: placebo‐controlled and study personnel and parents were described as blind to group assignments.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Throughout the study period, all children were followed up daily by a paediatrician, and the occurrence of common cold and adverse effects from medications were recorded daily on school days. On non‐school days and missed school days, parents were asked to complete a daily symptom chart including documentation of symptoms, the usage of cold medications and adverse effects. The paediatrician also called parents to discuss and to review the symptom charts." Judgement comment: study personnel described as blinded, and while the paediatrician is not explicitly a member of the blinded study staff, if the children, parents, and study personnel were all blinded it appears that outcome assessment was blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "... group, n 0 / 100). Overall, 97% (n 0 / 194) of the children (97 in the zinc group and 97 in the placebo group) completed the 7‐mo study period; six (3%) discontinued, four for non‐compliance and two for adverse effects due to medication. Enrolment characteristics of the children". Judgement comment: the groups of the non‐compliant participants and the participants with adverse events are not described, however the overall numbers and percentage of losses to follow‐up are small. Potential for bias in ascertaining adverse events, however it appears that adverse event information was collected on all participants, presumably including those who dropped out due to adverse events.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no protocol and it seems like this study had some overlap with the other Kurugol study, but this one has different presentation of outcome measures.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Kurugöl 2007.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "Parents were instructed not to give children cough and cold preparations, antibiotics, zinc‐containing multivitamins or mineral supplements, or other zinc products during the course of the study. However, the children were allowed to use acetaminophen for fever control only." Investigation of ability to distinguish between zinc and placebo: "The parents were asked to guess whether their children were using active or placebo drug on the first day of medication and at the end of treatment as well, to assess the adequacy of blinding." "On the first day of medication, 53% of parents in the zinc group and 48% of the parents in the placebo group believed that their children were using an active medication. At the end of the study, 70% and 63% of the parents, respectively, believed that their children had received an active medication." Duration of follow‐up: 10 d Duration of intervention: 7 d Duration of run‐in or washout period: NA Describe how participants were identified as having colds/URTI at baseline (treatment trial): "Children were recruited among those who had had two or more of the following 10 symptoms: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, scratchy throat, sneezing, sore throat, and fever (axillary temperature >37°C), as in previous studies." "The children were asked to return to the clinic for the final visit when cold symptoms had resolved. On the final visit they were also examined by the same pediatrician to confirm that cold symptoms had resolved and that the daily symptom dairies were completed." Outcomes measured: duration of cold, global severity of cold, duration of individual cold symptoms, severity of individual cold symptoms, adverse events due to zinc
Participants	Zinc sulfate 30 mg/d syrup Number: 60 Percentage female: 47% Age (mean (SD)): median 5.1 (IQR 1, 10) Placebo syrup Number: 60 Percentage female: 52% Age (mean (SD)): median 5.3 (IQR 1, 10) Overall Number: 120 Percentage female: 49% Age (mean (SD)): median 5.2 (IQR 1, 10) Inclusion criteria: "Children were recruited among those who had had two or more of the following 10 symptoms: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, scratchy throat, sneezing, sore throat, and fever (axillary temperature >37°C), as in previous studies." Exclusion criteria: "Patients with common cold symptoms for >48 h were excluded. Patients were also excluded if they had any of the following: immunodeficiency disorder, chronic disease, recent acute respiratory disease (diagnosed by a physician in the previous 2 weeks), zinc allergy, allergic disease or non‐allergic rhinitis. In addition, patients with a positive culture for group A Streptococcus and a positive cell culture for influenza A or B viruses were excluded." Group differences: "Of 120 children, 61 were female and 59 were male; the median age was 5.2 years (5.1 years, zinc group; 5.3 years, placebo group). There were no significant differences between the zinc and placebo groups in age, sex, proportion who lived in homes with smokers, frequency of infection, duration of the symptoms before admission, or serum zinc level ( Table 1 ). All children in both groups had normal serum zinc levels. The proportions of children with each initial symptom were similar in the two groups. No children in both groups had influenza virus cultured. " Condition studied: common cold Description of recruitment: "This prospective, randomized, double‐blind, placebo‐controlled study was performed at the outpatient clinic of Ege University Medical Faculty, during the cold season, from December 2004 through March 2005. The children who developed symptoms of common cold within the first 24 – 48 h were registered in the study." Diagnostic criteria for condition: "Children were recruited among those who had had two or more of the following 10 symptoms: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, scratchy throat, sneezing, sore throat, and fever (axillary temperature >37°C), as in previous studies." "The children were asked to return to the clinic for the final visit when cold symptoms had resolved. On the final visit they were also examined by the same pediatrician to confirm that cold symptoms had resolved..." Number of study centres: 1 Number of withdrawals: "Nine children (three in the zinc group and six in the placebo group) dropped out during the study period because of using antibiotics, decongestants, or cough medicine." Total number screened/eligible/randomised: NR/150/129
Interventions	Setting: outpatient Country: Turkey Zinc sulfate 30 mg/d syrup Study description of intervention and administration: "Two preparations were used in the present study: zinc sulfate syrup and placebo syrup. The licensed zinc syrup consisted of 1.32 g zinc sulfate in 100 mL (15 mg of zinc in 5 mL spoonful) and glycerin, glucose, sunset yellow, orange essence and nipajin as preservative. Placebo and active syrups were identical in appearance, texture and flavoring content, except that the placebo lacked the zinc component. Both zinc sulfate and placebo syrups were supplied by Berko Ilaç, Istanbul, Turkey. " "The packages were randomly distributed by the study nurse. Each parent was given a bottle of zinc sulfate or placebo syrup (totally 100 mL ). All study personnel and parents were blinded to the distribution of the study medications. Parents were asked to give one spoonful syrup twice a day to their children for 10 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): syrup Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): zinc sulfate Frequency of dose: 2 x/d Dose per day (elemental zinc in mg): 30 mg Duration of treatment: 10 days Placebo syrup Study description of intervention and administration: "Two preparations were used in the present study: zinc sulfate syrup and placebo syrup. The licensed zinc syrup consisted of 1.32 g zinc sulfate in 100 mL (15 mg of zinc in 5 mL spoonful) and glycerin, glucose, sunset yellow, orange essence and nipajin as preservative. Placebo and active syrups were identical in appearance, texture and flavoring content, except that the placebo lacked the zinc component. Both zinc sulfate and placebo syrups were supplied by Berko Ilaç, Istanbul, Turkey. " "The packages were randomly distributed by the study nurse. Each parent was given a bottle of zinc sulfate or placebo syrup (totally 100 mL ). All study personnel and parents were blinded to the distribution of the study medications. Parents were asked to give one spoonful syrup twice a day to their children for 10 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): syrup Frequency of dose: 2 x/d Duration of treatment: 10 days
Outcomes	Global severity of cold symptoms (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Notes: converted from medians/CI or median/IQR using the formula provided Adverse events Outcome type: dichotomous outcome Reported as: percentage of participants with event (%, N) Duration of nasal drainage Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sore throat Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal congestion Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sneezing Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of cough Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of scratchy throat Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of hoarseness Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of muscle aches Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of fever Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of headache Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Severity of nasal symptoms (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of cough (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N)
Identification	Author's name: Zafer Kurugöl, MD Institution: Department of Pediatrics, Ege University Email: zafer.kurugol@ege.edu.tr Address: Zafer Kurugöl, MD, Department of Pediatrics, Ege University, Faculty of Medicine, 35100 Bornova, Izmir, Turkey Trial registration identifier: NR Year study recruitment began: 2004
Notes	Declaration of interest: NR Funding source: "The authors thank Berko Ilaç, Turkey, for supplying the active and placebo medication, and for supplying the digital thermometers. The company did not participate in designing the study, collecting and analyzing the data, or in writing the report" Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A statistical consultant programmed a computer‐generated randomization code and prepared the packages of medication." Judgement comment: a statistical consultant programmed a computer‐generated randomisation code and prepared the packages of medication. The packages were identical in appearance except for the randomisation numbers. The packages were randomly distributed by the study nurse. The investigators describe a random component in the sequence generation process such as using a computer random number generator.
Allocation concealment (selection bias)	Low risk	Quote: "The packages were identical in appearance except for the randomization numbers. The packages were randomly distributed by the study nurse." Judgement comment: a statistical consultant programmed a computer‐generated randomisation code and prepared the packages of medication. The packages were identical in appearance except for the randomisation numbers. The packages were randomly distributed by the study nurse.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Judgement comment: the parents were asked to guess whether their children were using active or placebo drug on the first day of medication and at the end of treatment as well, to assess the adequacy of blinding. On the first day of medication, 53% of parents in the zinc group and 48% of the parents in the placebo group believed that their children were using an active medication. At the end of the study, 70% and 63% of the parents, respectively, believed that their children had received an active medication. Assessment of assignment on the last day of the study may be biased by effects of the treatment. Based on the assessment of assignment on the first day of the study, it appears that blinding was successful.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement comment: the children and their parents were the outcome assessors and it appears that their blinding was successful.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Nine children (three in the zinc group and six in the placebo group) dropped out during the study period because of using antibiotics, decongestants, or cough medicine." Judgement comment: missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; 120/129 (93%) were included in the final analysis. Exclusions (3 in the zinc group and 6 in the placebo group) were due to use of antibiotics, decongestants, or cough medicine, which could be a source of bias, however the numbers of such exclusions were small.
Selective reporting (reporting bias)	High risk	Judgement comment: no available trial registration or protocol. Insufficient information to permit judgement of ‘low risk’ or ‘high risk’. Outcome data are reported inconsistently, increasing the risk of bias in this domain.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Macknin 1998.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "They were asked to take no other cold preparations, if possible, during the study."; "At enrollment, all students were asked to discontinue taking any zinc‐containing vitamins or mineral supplements during the course of the study." Describe any investigation of ability to distinguish between zinc and placebo: "Students were asked to indicate whether they thought they were taking the active drug, the placebo, or whether they didn't know on day 2 and at the conclusion of the study. Defining the guesses on day 2 and at the end of the study as either correct or incorrect (which included the response of "don't know"), 35% (85/242) of the patients guessed correctly on day 2. A significantly higher proportion of students receiving zinc (46% [55/119]) guessed correctly than did controls (24% [30/123]); P = .001) on day 2. At the end of the study the results were similar, with 56% (67/119) of students receiving zinc guessing correctly vs 42% (51/123) of controls (P=.02). Six patients who had previously taken Cold‐Eeze were inadvertently enrolled in the study. Of these 6, 1 of 3 taking placebo and 1 of 3 taking zinc correctly identified their study medication. When we performed the analysis excluding students with the "don't know" responses (n=103 students on days 2 and 41 at the end of the study), the results similarly showed that students who received zinc were more likely to guess their group assignment than those receiving placebo." Duration of follow‐up: "Students were given exactly enough lozenges for 3 weeks of treatment, 126 and 105 lozenges for secondary and elementary students, respectively. However, students were followed up until their cold symptoms resolved, even if their symptoms persisted beyond 21 days." Duration of intervention: "Patients were asked to take study lozenges until their cold symptoms had been completely resolved for 6 hours." Duration of run‐in or washout period: none Describe how participants were identified as having colds/URTI at baseline (treatment trial): students were required to report having at least 2 of the following 9 symptoms: cough, headache, hoarseness, muscle ache, nasal congestion, nasal drainage, scratchy throat, sore throat, or sneezing. All students had a brief examination at the time of enrolment by trained study personnel, who confirmed the presence of at least 1 sign of a cold (cough, hoarseness, nasal drainage, nasal congestion, throat redness and exudate, enlarged tonsils, and sneezing). Outcomes measured: duration of cold; adverse events; global severity of the cold; duration of individual cold symptoms; days missed from work or school
Participants	Setting: outpatient Country: US Zinc gluconate 55 mg/d lozenge Number: 124 Percentage female: 52.4% Age (mean (SD)): 11.67 (7.5) Placebo lozenge Number: 125 Percentage female: 52.0% Age (mean (SD)): 11.67 (7.5) Overall Number: 249 Percentage female: 52.2% Age (mean (SD)): 11.67 (7.5) Inclusion criteria: "Students were required to report having at least 2 of the following 9 symptoms: cough, headache, hoarseness, muscle ache, nasal congestion, nasal drainage, scratchy throat, sore throat, or sneezing." Exclusion criteria: "Students were excluded if they had an oral temperature greater than 37.7°C, had previously taken the zinc preparation (Cold‐Eeze, Quigley Corporation, Doylestown, Pa), were pregnant, had a known adverse reaction to zinc, or had a known immune deficiency. Other reasons for exclusion were an acute illness other than the common cold (eg, pneumonia, gastroenteritis) or cold symptoms lasting more than 24 hours." Group differences: "Baseline characteristic were similar between the 2 groups (Table 1). Distributions of race and sex within the students on the study (overall, 92.4% white, 4.0% black, and 3.6% other, and 52.2% female) were similar to those of the entire school population (88.0% white, 7.3% black, and 4.7% other, and 48.4% female). Baseline characteristics of the students, including prevalence of allergies, proportion who smoked, frequency of colds and other infections, and temperatures between 37.1°C and 37.7°C were similar between the groups (Table 1). The only characteristic for which there was an imbalance was asthma. Seventeen (14%) of 120 patients in the placebo group and 9 (7.5%) of 120 in the zinc group reported a history of asthma (P=.10). (Cox regression analysis revealed that this imbalance had no significant effect on time to cold resolution.) Medications used by the groups at enrollment were similar. However, 31 subjects (25.0%) in the zinc group and 20 subjects (16.0%) in the placebo group were taking vitamins or mineral supplements (P=.08)." Condition studied: common cold Description of recruitment: "The study was approved by the Cleveland Clinic institutional review board. Presentations were made to school administrators and school boards in the communities, and their permission to conduct the study in the school systems was obtained.Students were recruited from the Beachwood and Mayfield school districts in the eastern suburbs of Cleveland, Ohio, during the winter cold season, from October 7, 1996, through March 13, 1997. Before enrollment began, students willing to participate in the study were identified by responses to a consent form and cover letter from school administrators and the principal investigator, which were mailed to all parents and guardians of children in the study schools. The principal investigator and study personnel attempted to contact the family of every potential enrollee by telephone to answer any questions about the study. The principal investigator spoke about scientific research in general and the study in particular to most science classes in the participating high schools and middle schools. School‐based study personnel collected consent forms. As an incentive, all students who returned signed consent forms were entered into a raffle with a grand prize of a trip for 4 to a popular theme park or the cash equivalent. Students did not have to become ill and be enrolled in the study to be eligible to win the raffle. Only students with informed consent forms on file at school and signed by their parents or guardians (for students younger than 18 years) were eligible for enrollment in the study. Study personnel enrolled patients before school, at lunchtime, and at the end of the school day, or in the patients' homes if they were contacted on nonschool days, during the first 24 hours of the student's cold symptoms." Diagnostic criteria for condition: "All students had a brief examination at the time of enrollment by trained study personnel, who confirmed the presence of at least 1 sign of a cold (cough, hoarseness, nasal drainage, nasal congestion, throat redness and exudate, enlarged tonsils, and sneezing)" Number of study centres: 2 Number of withdrawals: placebo = 2, zinc = 6, total = 8 Total number screened/eligible/randomised: 580/249/249
Interventions	Zinc gluconate 55 mg/d lozenge Study description of intervention and administration: "The ZGG and placebo lozenges were supplied by the Quigley Corporation. The zinc lozenges consisted of a hard‐candy base prepared with approximately equal proportions of sucrose and corn syrup, zinc gluconate trichydrate (AKZO Chemie, Amersfoort, the Netherlands), a molar proportion of glycine (aminoacetic acid), and cherry flavoring oils. The mixture was formed into lozenges that weighed 3.75 g and contained 10 mg of zinc."; "Students had 2 packages of identical medication, 1 for home and 1 for school. Home medication was delivered by study personnel to the students' homes, while a parent or guardian was present, on the day that the student was enrolled in the study. All students were asked to take 3 lozenges per day in the school study personnel offices: before school, at lunchtime, and before school was dismissed. If the students did not come to the office to receive their medication, the study personnel went to their classes to distribute it. If students missed school, they were instructed to take their regularly scheduled medications from their home medication package. Students in grades 1 through 6 were instructed to take 2 lozenges at home on school nights and 5 lozenges per day at home on weekends. Students in grades 7 through 12 were instructed to take 3 lozenges at home on school nights and 6 per day at home on weekends. Students were instructed to let the lozenges dissolve in their mouths and not to chew them. Patients were asked to take study lozenges until their cold symptoms had been completely resolved for 6 hours." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate Frequency of dose: 5 lozenges/day for Grades 1 to 6; 6 lozenges/day for Grades 7 to 12 Dose per day (elemental zinc in mg): 50 mg for Grades 1 to 6; 60 mg for Grades 7 to 12 Duration of treatment: up to 21 days (or until cold symptoms completely resolved for 6 hours) Placebo lozenge Study description of intervention and administration: "Placebo lozenges were prepared from the same flavored hard‐candy base and contained calcium lactate pentahydrate instead of zinc. Placebo and active lozenges were as identical as possible in appearance, flavoring content, and texture."; "Students had 2 packages of identical medication, 1 for home and 1 for school. Home medication was delivered by study personnel to the students' homes, while a parent or guardian was present, on the day that the student was enrolled in the study. All students were asked to take 3 lozenges per day in the school study personnel offices: before school, at lunchtime, and before school was dismissed. If the students did not come to the office to receive their medication, the study personnel went to their classes to distribute it. If students missed school, they were instructed to take their regularly scheduled medications from their home medication package. Students in grades 1 through 6 were instructed to take 2 lozenges at home on school nights and 5 lozenges per day at home on weekends. Students in grades 7 through 12 were instructed to take 3 lozenges at home on school nights and 6 per day at home on weekends. Students were instructed to let the lozenges dissolve in their mouths and not to chew them. Patients were asked to take study lozenges until their cold symptoms had been completely resolved for 6 hours." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: 5 to 6 lozenges/day; 5 lozenges/day for Grades 1 to 6; 6 lozenges/day for Grades 7 to 12 Duration of treatment: up to 21 days (or until cold symptoms completely resolved for 6 hours)
Outcomes	Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Notes: duration was only reported as median time + CI, so while CI could be converted to SD, the median could not. "The median time to resolution of all cold symptoms was 9.0 days (95% CI, 8‐9 days) in the placebo group and 9.0 days (95% CI, 7‐10 days) in the zinc group (P=.71; Figure 2)." They also reported the number whose symptoms resolved over the course of the 21 days vs those who did not. That is reported here. Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Global severity of cold symptoms (0 to 3 rating) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Notes: "The median score for overall severity of initial symptoms, computed as the sum of the initial scores for each symptom, was10 (range, 3‐22; mean ± SD, 10.1 ± 3.9) for the placebo group, vs 9 (range, 2‐22;mean ± SD, 9.2 ± 3.9) for the zinc group." Days missed from work or school Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of cough (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of headache (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of hoarseness (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal congestion (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal drainage (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of muscle aches (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of scratchy throat (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sore throat (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sneezing (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N)
Identification	Author's name: Michael L. Macknin, MD Institution: Cleveland Clinic Foundation Email: none Address: Michael L. Macknin, MD, Department of Pediatrics and Adolescent Medicine, A120, Cleveland Clinic Foundation, Cleveland, OH 44195 Trial registration identifier: none Year study recruitment began: 1996
Notes	Declaration of interest: "Dr Macknin owns 20,000 shares that he acquired in December 1996 in a private placement upon the exercise of stock options granted by the Quigley Corporation." Funding source: "This study was supported by a grant from the Quigley Corporation, Doylestown, Pa." Contact with study authors for additional information: none Other: for editorial comment see p 1999
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "... computer‐generated randomization code was provided to the pharmacist, who held the code and prepared the packages of medication."
Allocation concealment (selection bias)	Low risk	Quote: "The packages were identical in appearance, except for the identifying code number, and were distributed to the study personnel, all of whom were masked to the group assignments."
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "students who received zinc were more likely to guess their group assignment than those receiving placebo." Judgement comment: although study personnel were blinded and the zinc and placebo tablets were made as identical as possible, it appears that many of the zinc recipients were able to guess that they were on zinc.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "... they called students at home. Students graded each symptom on a numerical scale of 0 to 3 each day, but parents occasionally questioned the symptom rating assigned by students. In cases of dispute, the parent’s evaluation was used instead of the child’s." Judgement comment: outcomes were reported by participants, and the adequacy of their blinding is unclear.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Judgement comment: low‐unclear: no losses to follow‐up from study. Not all participants had zero symptom scores at the end of the study, and they were considered lost to follow‐up, however "statistical methods for incomplete data were used" and the number with unresolved symptoms is a small proportion of the total (8/249; 3%).
Selective reporting (reporting bias)	Unclear risk	Judgement comment: outcomes were the severity of 9 symptoms on a 0 to 3 scale, the total severity of symptoms, and median time to resolution of all symptoms. Adverse events were identified with open‐ended questions and a list of potential adverse effects. The outcomes are adequately reported and correspond with the methods section, however there is no trial preregistration or protocol to confirm that all analyses were preplanned.
Other bias	Low risk	Judgement comment: it is clearly reported in the study, but it should be noted that this was not only grant‐funded by the corporation who produced the lozenges, but also that the first author held shares in the company.

Malik 2014.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention mainly, but it might be considered treatment as well, since they were looking at duration Concomitant treatments explicitly allowed or forbidden: "To ensure that the child did not receive additional doses of zinc, we provided mothers with identity cards indicating the study title and that the infant was participating in the study. These cards were to be produced whenever the child was taken to any medical practitioner." Describe any investigation of ability to distinguish between zinc and placebo: NR Duration of follow‐up: 5 months Duration of intervention: 14 days Duration of run‐in or washout period: NA Describe challenge if any (for prevention trials): none Outcomes measured: "The primary outcome was the incidence of ARIs per child‐year. Secondary outcomes included incidence of Acute Upper Respiratory Infections (AURI) and ALRI per child‐year, duration of ARIs, and side effects."
Participants	Setting: community based Country: India Zinc sulfate 20 mg/d syrup Number: 141 Percentage female: 52.5% Age (mean (SD)): 8.77 (1.73) Placebo syrup Number: 131 Percentage female: 48.1% Age (mean (SD)): 8.76 (1.86) Overall Number: 272 Percentage female: 50.4% Age (mean (SD)): 8.77 (1.80) Inclusion criteria: "We included all infants 6‐11 months of age residing in Gokulpuri, an urban resettlement colony in North East District of Delhi, India, who were likely to stay till the completion of the study." Exclusion criteria: "We excluded children receiving zinc supplement in the past 3 months, those who were severely malnourished, known immuno‐deficient or on steroid therapy, severely ill children requiring hospitalization, and children of families likely to migrate from the study area." Group differences: "Infants in both the groups shared similar baseline characteristics (Table1). Seven families which migrated during the study period also shared similar baseline characteristics" Condition studied: AURI Description of recruitment: "Gokulpuri has a predominantly migrant population of about 23000, the majority belonging to the middle and lower socioeconomic strata. To achieve the final sample size, additional children were recruited from adjacent area of Gangavihar which has a similar population." "A house‐to‐house survey was done at the beginning of the study to identify and recruit the eligible infants. The study purpose was explained and an informed consent was obtained from parents of all infants before they were recruited. The recruitment was done during first two weeks of January and July followed by subsequent five months of follow‐up." Diagnostic criteria for condition: "AURI was diagnosed if the child had cough or cold with or without fever." Number of study centres: 1? Number of withdrawals: 6 Total number screened/eligible/randomised: 272/272/272
Interventions	Zinc sulfate 20 mg/d syrup Study description of intervention and administration: "The liquid preparations were prepared by Abyss Pharma, Delhi. Each 5 mL of the preparation contained placebo (syrup base) or zinc (20 mg elemental zinc as zinc sulfate). The syrups were of similar color(orange), taste (orange flavored), and consistency, and were packaged in similar bottles." "The field investigator administered the first dose of the intervention at the time of recruitment and advised the mother to give 5 mL of syrup (using standard 5 mL plastic spoon) daily to the infant for the remaining 13 days. Subsequently visits were made on the 7th and the 14th day to ensure compliance. Incase the syrup had not been given regularly, a maximum of one week was given to complete the dosages." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): syrup Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): sulfate Frequency of dose: 1x/d Dose per day (elemental zinc in mg): 20 mg Duration of treatment: 14 days Placebo syrup Study description of intervention and administration: "The liquid preparations were prepared byAbyss Pharma, Delhi. Each 5 mL of the preparation contained placebo (syrup base) or zinc (20 mg elemental zinc as zinc sulfate). The syrups were of similar color(orange), taste (orange flavored), and consistency, and were packaged in similar bottles." "The field investigator administered the first dose of the intervention at the time of recruitment and advised the mother to give 5 mL of syrup (using standard 5 mL plastic spoon) daily to the infant for the remaining 13 days. Subsequently visits were made on the 7th and the 14th day to ensure compliance. Incase the syrup had not been given regularly, a maximum of one week was given to complete the dosages." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): syrup Frequency of dose: 1 x/d Duration of treatment: 14 days
Outcomes	Incidence of acute respiratory infections (ARI) per child‐year, incidence of acute upper respiratory infections (AURI) per child‐year, incidence of acute lower respiratory infections (ALRI) per child‐year, duration of ARIs, and side effects
Identification	Author's name: Dr Akash Malik Institution: National RMNCH+A Unit, Room No. 107 D, Ministry of Health and Family Welfare, Government of India Email: drakashmalik28@gmail.com Address: National RMNCH+A Unit, Room No. 107 D, Ministry of Health and Family Welfare, Government of India Nirman Bhawan, New Delhi 110 001, India Trial registration identifier: Trial Registration No. CTRI/2010/091/001417 Year study recruitment began: 2011
Notes	Declaration of interest: "Competing interests: None stated." Funding source: "Indian Council of Medical Research, Department of Health Research (Ministry of Health and Family Welfare), the Government of India. Ref No. 3/2/2011/PG‐thesis‐MPD‐10." Contact with study authors for additional information: none Other: study data were reported narratively
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "We randomized the treatment allocation by simple randomization using computer generated random numbers (Excel 2010)." Judgement comment: computer‐generated randomisation.
Allocation concealment (selection bias)	Low risk	Quote: "The bottles were labeled with serial numbers after randomization in the Department of Community Medicine, MAMC, without the knowledge of the field investigator. The field investigator and parents were blinded to the treatment allocation till the end of follow‐up period. The mothers received the bottles with labeled serial numbers and names." Judgement comment: it does say the bottles were 'similar' (not identical), but otherwise all other signs point to sequentially numbered containers and this was done separately from the field investigators.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The liquid preparations were prepared by Abyss Pharma, Delhi. Each 5 mL of the preparation contained placebo (syrup base) or zinc (20 mg elemental zinc as zinc sulfate). The syrups were of similar color (orange), taste (orange flavored), and consistency, and were packaged in similar bottles." Judgement comment: the field investigator and parents were blinded to the treatment allocation until the end of follow‐up period.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All the outcomes were assessed by a trained field investigator based on history by caregiver." Judgement comment: it was stated that both caregivers and field investigators were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "by intention to treat analysis. The exchangeable working correlation matrix was selected for all the outcomes. We included all children who had taken at least two doses of the intervention for the analyses. The follow‐up visits for which the infant outcomes were not available were imputed using the worst case (2 episodes of ARI) and best case scenarios (no episodes). As it did not change the study results, the missing data were excluded from the final analysis." Judgement comment: missing data were imputed, but this was found to not have an effect on the study results. This raises the question of why they excluded the data. 258/272 (95%) of participants completed the study. Reasons for loss are described and are similar between groups.
Selective reporting (reporting bias)	Unclear risk	Quote: "The primary outcome was the incidence of ARIs per child‐year." Judgement comment: based upon CTRI/2010/091/001417 there was no selective outcome reporting for ARI. The diarrhoea and height and weight outcomes are not included in this paper, but this is not relevant to the outcomes that were reported. However, see https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-016-1551-6/tables/1.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Mandlik 2020.

Study characteristics
Methods	Study design: cluster‐randomised controlled trial Analysis details of cluster‐randomised trial: "The cluster randomization method was used to randomly allocate the 435 participants to the three trial arms: vitamin D, zinc and placebo. Each class or grade in the school had 3 divisions, A, B and C, which were categorized as the designated clusters. Children in the A divisions of all 4 classes were administered supplement from the bottles labelled A, those in B divisions were administered supplement from the bottles labelled B, and those in C divisions were administered supplement from the bottles labelled C." No mention of an ICC or an analysis incorporating clustering. Prevention or treatment trial: prevention, but some aspects of treatment present Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: NR Duration of follow‐up: NR Duration of intervention: 6 mos Duration of run‐in or washout period: NR Outcomes measured: compliance, living conditions, personal hygiene, dietary history, anthropometrics, biochemical markers, infection incidence and severity
Participants	Setting: Public Elementary School (Grade 1 to 4) located in a rural region 65 km east from Pune city (18°N), Western India Country: India Zinc sulfate 13 mg/d tablet Number: 119 Percentage female: 44% Age (mean (SD)): 7.9 (1.2) Placebo tablet Number: 124 Percentage female: 48% Age (mean (SD)): 7.9 (1.1) Overall Number: 243 Percentage female: 46% Age (mean (SD)): 7.9 (1.1) Inclusion criteria: "Inclusion criteria of this study were children between the ages of 6‐12 years who were not consuming any supplements or preparations containing vitamin D or calcium or zinc."Exclusion criteria: "Our exclusion criteria were children with congenital abnormalities, chronic medical conditions, and conditions which could affect the vitamin D and calcium metabolism." Group differences: "No significant differences were observed in gender, height and weight z‐scores, socio‐economic status, infection scores and nutrient intakes, when comparing participants who completed the trial and those who did not. However, the ages of participants included in the final analysis were significantly lower than those who did not complete the trial (8.0 ± 1.2 vs. 8.5 ± 1.3 years; P < 0.001)." Condition studied: URTI Description of recruitment: "This randomized, double‐blind, placebo‐controlled trial was conducted in a Public Elementary School (Grade 1 to 4) located in a rural region 65 kms east from Pune city (18°N), Western India. Selection of the school was after surveying rural areas around Pune city to assess site accessibility, subject availability and cooperation of school authorities. We connected with the local governing authority to obtain a list of schools in the area, and 10 schools satisfying the inclusion criteria were short‐listed and approached for consent. The final school was randomly selected from the 8 schools which consented for the trial to be executed on their premises." Diagnostic criteria for condition: "To collect information on infection‐related symptoms of the participant, a validated questionnaire was administered by trained social workers to the primary caregiver [38]. Information on common infections (URTI, gastrointestinal and others, i.e. eye, skin, urinary tract infections) were collected by recording details on the duration, frequency and severity of infection‐related symptoms." Number of study centres: 1 Number of withdrawals: 45 Total number screened/eligible/randomised: NR/544/435
Interventions	Zinc sulfate 13 mg/d tablet Study description of intervention and administration: "A supplement containing zinc sulfate providing 10 mg of zinc was administered to participants in the zinc arm. The RDA of zinc for Indian children aged 6‐12 years is 7‐9 mg of zinc per day. Since additional recommendations regarding dose, duration and frequency of supplementation are not available, we decided to provide a supplement meeting the RDA requirement for zinc."; "The supplementation process was rigorously monitored. Trained social workers administered the supplement/placebo to the participants in the classrooms during the first period, daily for 6 months. Records of supplement intake were maintained in a register, immediately after consumption. Every Saturday, a supplement packet was handed over to the child, with instructions to consume the same on Sunday. Caregivers were also reminded during each home‐visit to ensure their child consumed the supplement. Furthermore, on the Monday that followed, it was enquired if the Sunday supplement had been consumed, and this was duly noted in the register." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): tablet Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): sulfate Frequency of dose: 1x/d? Dose per day (elemental zinc in mg): "(including zinc supplement) was 13 ± 0.6 mg/day during the supplementation period" Duration of treatment: 6 mos Placebo tablet Study description of intervention and administration: "Placebo: The children in the placebo group were administered a tablet containing 10 mg fructose." "The zinc and placebo tablets were manufactured by SDS Nutraceuticals, Karad, India, to appear identical to the vitamin D‐calcium tablet. The supplements and placebo were thus, similar looking white, oval‐shaped tablets, and each weighing 1500 mg. These were packed in high‐density polyethylene plastic jars and labelled A, B and C. Coding of the supplements was performed by the supplier, and the codes were revealed only after completion of the trial." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): tablet Frequency of dose: 1x/d? Dose per day (elemental zinc in mg): "participants in the placebo and vitamin D group, whose diets supplied 3 ± 1 mg zinc per day" Duration of treatment: 6 mos
Outcomes	Compliance, living conditions, personal hygiene, dietary history, anthropometrics, biochemical markers, infection incidence and severity
Identification	Author's name: Anuradha Khadilkar, Tel. 91‐20‐26141340, Fax. 91‐20‐26141340 Institution: Interdisciplinary School of Health Sciences, Savitribai Phule Pune University, Ganeshkind Road, Pune ‐ 411007, Maharashtra, India Email: Email. anuradhavkhadilkar@gmail.com Address: Hirabai Cowasji Jehangir Medical Research Institute, Lower ground floor, Jehangir Hospital, 32, Sassoon Road, Pune, Pune, MAHARASHTRA, 411001, India Trial registration identifier: CTRI/2014/08/004854 Year study recruitment began: 2014
Notes	Declaration of interest: "The authors declare no potential conflicts of interest." Funding source: "Rubina Mandlik was funded by a Fellowship Grant from the University Grants Commission, Government of India. Eris Lifesciences Ltd. Ahmedabad supplied the vitamin D‐calcium supplements." Contact with study authors for additional information: LSW e‐mailed Dr. Khadilkar on 22 December 2022 to obtain additional data on the episodes, duration, and URTI score for zinc versus placebo and was sent these data by Dr. Mandlik on 18 January 2023. Additional information on whether clustering was accounted for in the analysis was not obtained. Other: the study data were used narratively due to uncertainty regarding whether clustering was accounted for in the analysis.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The cluster randomization method was used to randomly allocate the 435 participants to the three trial arms: vitamin D, zinc and placebo." Judgement comment: unclear whether the method was truly random.
Allocation concealment (selection bias)	Low risk	Quote: "The vitamin D‐calcium supplement was supplied by Eris Lifesciences Ltd., Ahmedabad, India. The zinc and placebo tablets were manufactured by SDS Nutraceuticals, Karad, India, to appear identical to the vitamin D‐calcium tablet. The supplements and placebo were thus, similar looking white, oval‐shaped tablets, and each weighing 1,500 mg. These were packed in high‐density polyethylene plastic jars and labelled A, B and C. Coding of the supplements was performed by the supplier, and the codes were revealed only after completion of the trial." Judgement comment: as per the Cochrane Handbook: "Cluster‐randomized trials often randomize all clusters at once, so lack of concealment of an allocation sequence should not usually be an issue."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Coding of the supplements was performed by the supplier, and the codes were revealed only after completion of the trial. The trial staff as well as the participants were unaware of the intervention being administered, thereby achieving double blinding." Quote: "The zinc and placebo tablets were manufactured by SDS Nutraceuticals, Karad, India, to appear identical to the vitamin D‐calcium tablet. The supplements and placebo were thus, similar looking white, oval‐shaped tablets, and each weighing 1,500 mg." Judgement comment: low‐unclear ‐ the groups were clustered, but there would have been ABC groups in each class ‐ could they have compared?
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "To collect information on infection‐related symptoms of the participant, a validated questionnaire was administered by trained social workers to the primary caregiver [38]." Judgement comment: just states that they were unaware of the intervention, but how blinding was ensured is not clear. Participants and trial staff were unaware of the intervention.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Judgement comment: 363/435 (83%) participants were analysed. Reasons are given and numbers did not differ markedly between the zinc and placebo groups, but there were high numbers excluded on the basis of 'missing data' in both groups. No evidence that this did not bias the outcome estimates. Unclear or high.
Selective reporting (reporting bias)	Unclear risk	Quote: "The trial was registered with the Clinical Trials Registry‐India (CTRI/2014/08/004854)." Judgement comment: methods and results correspond with each other and with the trial registration, but the trial was retrospectively registered.
Other bias	Low risk	Judgement comment: no recruitment bias or baseline imbalances in participants. Unclear whether the analysis took clustering into account, in which case the estimate would be too precise. This is technically not a bias in the estimate of effect, but would cause the study to be weighted too heavily in the meta‐analysis.

McDonald 2015.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention Concomitant treatments explicitly allowed or forbidden: "During this follow‐up period, mothers and children were asked to return to the study clinic every 4 wk for data collection and standard clinical care, including growth monitoring, immunizations, routine medical treatment for illnesses, and periodic vitamin A supplementation (100,000 IU at 9 mo and 200,000 IU at 15 mo)." Describe any investigation of ability to distinguish between zinc and placebo: "The supplement used was an orange‐flavored powder encapsulated in an opaque gelatinous capsule and was manufactured by Nutriset. All 4 regimens were field tested and the taste, smell, and appearance were found to be indistinguishable between groups." Duration of follow‐up: "Mothers and children were followed from the time of randomization for 18 mo, until the child’s death, or until loss to follow‐up." Duration of intervention: 18 mos Duration of run‐in or washout period: none If prevention, describe challenge if any: none Outcomes measured: incidence of diarrhoea; number of respiratory infections; growth (weight and length/height) 6 weeks to 18 months
Participants	Setting: community Country: Tanzania Zinc NR 5 mg/d capsule Number: 596 Percentage female: 50.3% Age (mean (SD)): 5.9 (0.4) weeks Placebo capsule Number: 604 Percentage female: 51.5% Age (mean (SD)): 5.9 (0.4) weeks Overall Number: 1200 Percentage female: 50.9% Age (mean (SD)): 5.9 (0.4) weeks Inclusion criteria: "Inclusion Criteria: Singleton, live born infants born to HIV‐ negative women Mothers will need to have registered for pre‐natal care before 34 weeks gestation intend to stay in Dar es Salaam for until delivery and 18 months thereafter." Exclusion criteria: "Infants of multiple births and infants with congenital anomalies or other conditions that would interfere with the study procedures were excluded." Group differences: "With the exception of length‐for‐age z score, there were no significant differences in any maternal, socioeconomic, or child characteristics between the 4 groups at baseline (Table 1)." Condition studied: cold/acute upper respiratory infection Description of recruitment: "Mothers of potentially eligible infants were recruited into the study in 1 of 2 ways: 1) pregnant women ≤34 wk gestation presenting at 1 of 3 prenatal clinics in Dar es Salaam were informed about the study and consented prenatally or 2) women were recruited from the labor ward of Muhimbili National Hospital within 12 h of delivering a healthy singleton baby. In both cases, written informed consent was obtained and mothers were asked to present at a study clinic within 1–2 wk of delivery for HIV testing." Diagnostic criteria for condition: "Acute upper respiratory infection was defined as pharyngitis or rhinitis (both without fast breathing or chest indrawing)." Number of study centres: 4 Number of withdrawals: 26 died (from zn and placebo groups only) Total number screened/eligible/randomised: 14901 (pregnant women)/4650 women met eligibility/2400 infants randomised
Interventions	Zinc NR 5 mg/d capsule Study description of intervention and administration: "Capsules were packaged in a blister pack of 15 each and numbered boxes containing 6 blister packs were prepared containing the corresponding treatments. Each eligible infant was assigned the next numbered box of capsules at his/her respective site. The supplement used was an orange‐flavored powder encapsulated in an opaque gelatinous capsule and was manufactured by Nutriset. All 4 regimens were field tested and the taste, smell, and appearance were found to be indistinguishable between groups."; "From the time of randomization to 6 mo of age, infants received 1 capsule/d, and from 7 mo of age to the end of follow‐up, 2 capsules were provided daily. For infants in the zinc group, the capsule contained 5 mg of zinc. For infants in the MV group, the capsule contained 60 mg of vitamin C, 8 mg of vitamin E, 0.5 mg of thiamine, 0.6 mg of riboflavin, 4 mg of niacin, 0.6 mg of vitamin B‐6, 130 mg of folate, and 1 mg of vitamin B‐12. Infants in the MV + zinc group received 1 capsule containing the micronutrients listed in both the MV and the zinc groups. For children 0–6 mo of age, these doses represented between 150% and 600% of the RDA or Adequate Intake, and for children 7–12 mo of age, the doses were equivalent to 200–400% of the RDA or Adequate Intake. Mothers were shown how to push the capsule through the back of the blister pack, open the capsule, decant the powder into a small plastic cup, mix the powder with 5 mL of sterile water, and administer the solution to the child orally." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): capsule powder mixed with water Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): NR Frequency of dose: "From the time of randomization to 6 mo of age, infants received 1 capsule/d, and from 7 mo of age to the end of follow‐up, 2 capsules were provided daily." Dose per day (elemental zinc in mg): NA Duration of treatment: 18 mos Placebo capsule Study description of intervention and administration: "Capsules were packaged in a blister pack of 15 each and numbered boxes containing 6 blister packs were prepared containing the corresponding treatments. Each eligible infant was assigned the next numbered box of capsules at his/her respective site. The supplement used was an orange‐flavored powder encapsulated in an opaque gelatinous capsule and was manufactured by Nutriset. All 4 regimens were field tested and the taste, smell, and appearance were found to be indistinguishable between groups."; "From the time of randomization to 6 mo of age, infants received 1 capsule/d, and from 7 mo of age to the end of follow‐up, 2 capsules were provided daily. For infants in the zinc group, the capsule contained 5 mg of zinc. For infants in the MV group, the capsule contained 60 mg of vitamin C, 8 mg of vitamin E, 0.5 mg of thiamine, 0.6 mg of riboflavin, 4 mg of niacin, 0.6 mg of vitamin B‐6, 130 mg of folate, and 1 mg of vitamin B‐12. Infants in the MV + zinc group received 1 capsule containing the micronutrients listed in both the MV and the zinc groups. For children 0–6 mo of age, these doses represented between 150% and 600% of the RDA or Adequate Intake, and for children 7–12 mo of age, the doses were equivalent to 200–400% of the RDA or Adequate Intake. Mothers were shown how to push the capsule through the back of the blister pack, open the capsule, decant the powder into a small plastic cup, mix the powder with 5 mL of sterile water, and administer the solution to the child orally." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): capsule powder mixed with water Frequency of dose: "From the time of randomization to 6 mo of age, infants received 1 capsule/d, and from 7 mo of age to the end of follow‐up, 2 capsules were provided daily." Duration of treatment: 18 mos
Outcomes	Development of common cold/URTI Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Notes: obtained from the authors on 3 June 2023
Identification	Author's name: Christopher P Duggan, MD, MPH Institution: Harvard School of Public Health (HSPH) Email: christopher.duggan@childrens.harvard.edu Address: Harvard T.H. Chan School of Public Health, Boston, MA Trial registration identifier: NCT00421668 Year study recruitment began: 2007
Notes	Declaration of interest: authors report no conflicts of interest Funding source: "Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD R01 HD048969‐01 and K24HD058795)." Contact with study authors for additional information: DN emailed Dr. Duggan on 7 November 2022 to obtain additional data on the prevalence of common cold for zinc versus placebo and was sent these data by Dr. Duggan on 6 March 2023. Other: 2 x 2 factorial assignment ‐ MV/MV + Zn does not fit our inclusion criteria so only Zn + placebo groups are being reported. Physician diagnosed AURI.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The biostatistician in Boston prepared a randomization list from 1 to 2400 that used blocks of 20 and was stratified by study clinic." Judgement comment: central randomisation by a biostatistician was presumably authentically random.
Allocation concealment (selection bias)	Low risk	Judgement comment: central randomisation and sequentially numbered boxes of identical appearance.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Judgement comment: all study personnel and participants were blinded to treatment assignment for the duration of the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "At baseline, every 3 mo, and/or when acute illnesses were noted by the study nurse a study physician conducted a physical examination, diagnosed illnesses, and provided necessary medical treatment. Physicians underwent regular training so that they used standardized diagnostic criteria and treatment guidelines consistent with the WHO and Tanzanian Ministry of Health and Social Welfare policies. For the purposes of the analysis of physician diagnosis, ‘‘any form of diarrhea’’ included persistent diarrhea, acute diarrhea, dysentery, and/or intestinal parasites. Acute upper respiratory infection was defined as pharyngitis or rhinitis (both without fast breathing or chest indrawing)." Judgement comment: all study personnel and participants were blinded to treatment assignment for the duration of the study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Of the 40 children who were lost to follow‐up, 8 received the placebo, 11 received zinc only, 15 received MVs only, and 6 received zinc and MVs. We observed a nonsignificant increase in all‐cause mortality among children who received zinc compared with children who did not receive zinc (HR: 1.80; 95% CI: 0.98, 3.31; P = 0.06). MVs did not significantly alter the risk of all‐ cause mortality (HR: 0.73; 95% CI: 0.40, 1.32; P = 0.30). Information on the cause of death was available for 39 study participants. Respiratory illness (n = 13), diarrheal disease (n = 5), malaria (n = 7), other infectious diseases (n = 8), and neonatal conditions (n = 2) were the primary causes of deaths. There were no significant differences in cause‐specific mortality between treatment groups (all, P > 0.05)." Judgement comment: few lost proportionally 40/2400 (with reason provided) and non‐significant differences between groups.
Selective reporting (reporting bias)	Unclear risk	Quote: "The primary outcomes of the study were the incidence of clinical symptoms of diarrhea and lower respiratory infection." Judgement comment: clinical trial registry states: "Primary Outcome Measures: Incidence of diarrhea [ Time Frame: from ages 6 weeks to 18 months ] respiratory tract infections [ Time Frame: from ages 6 weeks to 18 months ] Secondary Outcome Measures: Weight gain [ Time Frame: from age 6 weeks to 18 months ] Length/height gain [ Time Frame: from age 6 weeks to 18 months ]" No mention in the trial registration of colds or acute upper respiratory illnesses (only respiratory illnesses generally). Potential for selective reporting.
Other bias	Low risk	Judgement comment: no other apparent risk of bias.

Mossad 1996.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "Participants were asked to take no other cold preparations during the study period. Acetaminophen samples and oral digital thermometers were given to the patients at the time of enrollment." Investigation of ability to distinguish between zinc and placebo: "All patients were called on the second day of medication use to make sure that they were not developing a more serious illness and to assess the adequacy of the masking through responses to a questionnaire. By assessing the adequacy of the placebo on the second day of treatment rather than only at the end of treatment, we hoped to decrease the likelihood that a rapid cure would help patients in the zinc group correctly determine that they were receiving the active medication. This questionnaire was also administered at the end of treatment with the addition of questions about the occurrence of specific, previously described side effects of zinc therapy." Duration of follow‐up: "Patients were asked to complete a daily log documenting the severity of symptoms and the medications taken throughout the duration of their cold for as long as 18 days." Duration of intervention: presumably up to 18 days. "Patients were given 120 lozenges and were asked to dissolve 1 lozenge in their mouths every 2 hours while awake for as long as they had cold symptoms." How long this supply would last and how or whether participants could request additional lozenges is unclear. Duration of run‐in or washout period: "The study nurse administered the first lozenge to assess initial tolerability." Describe how participants were identified as having colds/URTI at baseline (treatment trial): "Patients who volunteered for the study were enrolled only if they had had cold symptoms for 24 hours or less. Patients must have had at least two of the following 10 symptoms: cough, headache, hoarsenes muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, or an oral temperature greater than 37.7 [degrees]c." Outcomes measured: daily severity of each of 10 symptoms (scale 0 to 3); total symptom score (sum of severity for the 10 symptoms); number of days each symptom present; days to cold resolution (defined as symptom score of 0 or 1); side effects (both an open‐ended question asked daily and an assessment of presence of a predetermined list of side effects asked at the end of the study)
Participants	Setting: outpatient Country: United States Zinc gluconate 159.6 mg/d lozenge Number: 49 Percentage female: 84% Age (mean (SD)): 37.5 (7.5) Placebo lozenge Number: 50 Percentage female: 78% Age (mean (SD)): 37.9 (9.2) Overall Number: 99 Percentage female: 81% Age (mean (SD)): 37.7 (8.4) Inclusion criteria: "Patients who volunteered for the study were enrolled only if they had had cold symptoms for 24 hours or less. Patients must have had at least two of the following 10 symptoms: cough, headache, hoarsenes muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, or an oral temperature greater than 37.7" Exclusion criteria: "Patients were excluded if they were pregnant, had a known immune deficiency, or had had symptoms of the common cold for more than 24 hours." Group differences: demographically there is not anything obvious; these are not mentioned in reporting aside from reference to Table 1. "incidence of individual symptoms at baseline was similar in the two groups for all but two symptoms: sneezing (31 of 50 placebo recipients [62%] and 38 of 49 zinc recipients [775%); p = 0.09) and sore throat (39 of 50 placebo recipients [78%] and 25 of 49 zinc recipients 151%]; P = 0.005). No patients had fever at baseline." Condition studied: common cold Description of recruitment: "Patients were recruited from among the Cleveland Clinic staff through announcements in internal Clinic publications and by word of mouth. One hundred volunteers were enrolled between 3 October and 4 November 1994. All patients who completed the study as specified by the protocol were enrolled in a raffle for one of two prizes: dinner for two or a trip for two to the Bahamas." Diagnostic criteria for condition: "Patients who volunteered for the study were enrolled only if they had had cold symptoms for 24 hours or less. Patients must have had at least two of the following 10 symptoms: cough, headache, hoarseness muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, or an oral temperature greater than 37.7" Number of study centres: 1 Number of withdrawals: 1 (zinc group) withdrew due to tolerance, 6 (2 zinc, 4 placebo) dropped out between days 7 to 16, and 17 (10 zinc, 7 placebo) were considered non‐adherent Total number screened/eligible/randomised: NR/NR/100
Interventions	Zinc gluconate 159.6 mg/d lozenge Study description of intervention and administration: "The zinc lozenges consisted of a boiled hard‐candy base prepared with approximately equal proportions of sucrose and corn syrup, zinc gluconate trihydrate (AKZO Chemie, Amersfoort, the Netherlands), a molar proportion of glycine (aminoacetic acid), and lemon and lime flavoring oils. The mixture was formed into lozenges that weighed 4.4 g and contained 13.3 mg of zinc." "Patients were given 120 lozenges and were asked to dissolve 1 lozenge in their mouths every 2 hours while awake for as long as they had cold symptoms. Study nurse administered the first lozenge to assess initial tolerability." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate‐glycine Frequency of dose: 1 lozenge every 2 hours while awake Dose per day (elemental zinc in mg): 13.3 mg* (max) 12 oz/day = 159.6 mg/d Duration of treatment: up to 18 days or resolution of symptoms Placebo lozenge Study description of intervention and administration: "Placebo lozenges, also weighing 4.4 g, were prepared from the same flavored hard‐candy base and contained 5.0% calcium lactate pentahydrate. Placebo and active lozenges were identical in weight, appearance, flavoring content, and texture. The zinc lozenges, however, were more astringent than the placebo lozenges."; "Patients were given 120 lozenges and were asked to dissolve 1 lozenge in their mouths every 2 hours while awake for as long as they had cold symptoms. Study nurse administered the first lozenge to assess initial tolerability." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: 1 lozenge every 2 hours while awake Duration of treatment: up to 18 days or resolution of symptoms
Outcomes	Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of cold symptoms (n) Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: these may not be using the total numbers (n = 50, n = 49) but it is not entirely clear from the Kaplan‐Meier plot so we went with the overall totals. Duration of nasal symptoms Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of throat symptoms Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of cough Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of headache Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of hoarseness Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal congestion Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal drainage Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sore throat Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of muscle aches Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of scratchy throat Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sneezing Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of fever Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N)
Identification	Author's name: Michael L Macknin Institution: Department of Pediatrics and Medicine, A 120, Cleveland Clinic Foundation Email: NR Address: Drs. Mossad and MS. Medendorp and MS. Mason: The Cleveland Clinic Foundation, Euclid Avenue, Cleveland, OH 44195 Trial registration identifier: none Year study recruitment began: 1994
Notes	Declaration of interest: NR Funding source: grant support: by the General Pediatrics Research Fund and the Departments of Infectious Diseases and General Pediatrics of the Cleveland Clinic Foundation Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A statistical consultant prepared a computer‐generated randomization code and the packages of medication." Judgement comment: the investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random number generator.
Allocation concealment (selection bias)	Low risk	Quote: "The packages were identical in appearance except for the randomization numbers. The study medication was distributed by the study nurse, who was masked to treatment assignments." Judgement comment: a statistical consultant prepared a computer‐generated randomisation code and the packages of medication. The packages were identical in appearance except for the randomisation numbers.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The placebo lozenge contained 5% calcium lactate so that it had a medicinal taste similar to that of the zinc gluconate lozenge." "All patients were called on the second day of medication use to make sure that they were not developing a more serious illness and to assess the adequacy of the masking through responses to a questionnaire. By assessing the adequacy of the placebo on the second day of treatment rather than only at the end of treatment, we hoped to decrease the likelihood that a rapid cure would help patients in the zinc group correctly determine that they were receiving the active medication." "On the initial questionnaire, 50% of the placebo recipients (25 of 50) and 55.2% of the zinc recipients (27 of 49) correctly guessed their study assignment."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement comment: patients were asked to complete a daily log documenting the severity of symptoms and the medications taken throughout the duration of their cold for as long as 18 days. Patients were the outcome assessors and they were adequately blinded to treatment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "One patient in the zinc group withdrew from the study on the first day because she could not tolerate the lozenges; she did not complete the symptom diary." "Eight patients (six in the placebo group and two in the zinc group) had colds that did not resolve while they remained in the study. Two of these patients (both were placebo recipients) completed the 18 days of the study, and the remaining six (four were placebo recipients and two were zinc recipients) dropped out after 7 to 16 days." Judgement comment: appears that 4 placebo recipients and 3 zinc recipients dropped after randomisation, and outcome data were obtained for 93/100 participants. Adherence varied, however "These analyses were done using an intention‐to‐treat framework, regardless of patient adherence (20‐22)."
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no protocol or trial registration.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Mossad 2003.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "Patients were instructed not to use cold remedies during the study period, including aspirin, decongestants, antihistamines, and other zinc products. They were, however, allowed to take acetaminophen (paracetamol) 500 mg every 6 h for temperature control only." Investigation of ability to distinguish between zinc and placebo: "Asking patients on their first day of pump use whether they thought they were receiving an active agent or placebo assessed adequacy of the blinding procedure. This was done early in the process of the study rather than at the end, in order to decrease the possibility that a rapid improvement in symptoms would help patients in the zinc group correctly infer that they were receiving the active drug." Duration of follow‐up: NR Duration of intervention: until resolution or 10 days at most Duration of run‐in or washout period: NR Describe how participants were identified as having colds/URTI at baseline (treatment trial): "During the initial visit, patients completed a screening health questionnaire, were interviewed and examined by the same physician to confirm the presence of rhinitis (as noted by erythema of the nasal mucosa and excessive mucopurulent dis‐charge) and to exclude other clinically obvious illnesses. Although there is a large variance in the signs associated with rhinitis, documenting their presence supported the diagnosis of common cold." "Upon enrollment, all patients underwent testing to identify the viruses, if any, causing their illness.Nasal lavage samples were collected by instillation of 3 ml 0.9%saline into each nostril. The samples were divided into three aliquots; two were frozen at708C, and one was used for viral isolation attempts. Tubes containing human fetal diploid lung cells and primary monkey kidney cells were inoculated, and cultures were rotated in a roller drum and incubated at 338C. Viral isolation and identification were performed by standard methods. Rhinovirus growth was recognized by the characteristic cytopathic effects and confirmed by the acid lability assay. Polymerase chain reaction (PCR) for detection of rhinovirus was performed by standard methods 27 by Tsunami Biotechnology" Outcomes measured: "The primary outcome measure was the time to cold resolution, calculated as the number of days starting from the onset of symptoms till their complete resolution. The secondary outcome measures were the total daily symptom scores and the presence of adverse effects."
Participants	Setting: Los Angeles, California, community Country: United States Zinc gluconium 2.1 mg/d nasal gel Number: 40 Percentage female: 60% Age (mean (SD)): 30 (13) Placebo nasal gel Number: 38 Percentage female: 66% Age (mean (SD)): 29 (15) Overall Number: 78 Percentage female: 62.8% Age (mean (SD)): 29.5 (14) Inclusion criteria: "When patients who thought they had the common cold called the study coordinator to inquire about the study, a telephone pre‐screen was performed to assess eligibility.A patient was deemed eligible if he or she was 18–55 years of age and had had symptoms of the common cold for 24–48 h.Common cold symptoms were designated as either major or minor. Major symptoms were nasal drainage and sore throat, and minor symptoms were nasal congestion, sneezing, scratchy throat, hoarseness, cough, headache, muscle aches and fever (oral temperature)98.68F). Presence of two major and at least one minor symptom, or one major and three minor symptoms were required for enrollment." Exclusion criteria: "Women also received a urine pregnancy test, which had to be negative for them to be included in the study. Patients were excluded if they had common cold symptoms for)48 h. Other exclusion criteria included: known immune system disorder (such as systemic lupus erythematosis or acquired immuno‐deficiency syndrome), diabetes mellitus, known uncorrected deviated nasal septum, or a history of recurrent sinusitis (more than two per year), bronchitis (more than six per year), or otitis. Patients who were receiving treatment for asthma or allergic rhinitis, those who were currently using decongestants, antihistamines, antibiotics, aspirin, or zinc products, and anyone who had ever used Zicam were also excluded. Lastly, all habitual smokers and women who were pregnant, lactating, planned to become pregnant within 30 days of enrollment or unwilling to use birth control measures were likewise excluded." Group differences: "Of the 78 patients (40 in the zinc group, and 38 in the placebo group) who were included in the final analysis, 49 were women and29 were men; the median age was 26 years. There were no statistically significant differences between the zinc and placebo groups in age, sex, total symptoms scores, or prevalence of individual symptoms of the common cold at the time of enrolment in the study (Table 1). Nine of the 78 patients(12%)—4 in the zinc group (10%), and 5 in the placebo group (13%)—had rhinovirus isolated on viral cultures. Eighteen of the 78 patients (23%)—7in the zinc group (18%) and 11 in the placebo group (29%)—had rhinovirus identified by PCR(p=0.29" Condition studied: common cold Description of recruitment: "Global Clinicals recruited patients at a single private practice clinic in Los Angeles, CA. The study was approved by the Institutional ReviewBoard at Century City Hospital in Los Angeles, CA. Advertisements for the study appeared in the LATimes, college papers of the University of SouthernCalifornia and the University of California in LosAngeles, and in physicians’ private practice offices in the surrounding area. Patients were enrolled during the fall and winter seasons between August2000 and March 2001. They were informed of the double‐blind, placebo‐controlled nature of the study, and gave their written informed consent to participate after reviewing the consent form alone, and with the study coordinator. They were also informed of the potential to publish the results of the study in a scientific journal. They were compensated with a $100 check, mailed to them 2–4 weeks after they completed the study." Diagnostic criteria for condition: "During the initial visit, patients completed a screening health questionnaire, were interviewed and examined by the same physician to confirm the presence of rhinitis (as noted by erythema of the nasal mucosa and excessive mucopurulent dis‐charge) and to exclude other clinically obvious illnesses. Although there is a large variance in the signs associated with rhinitis, documenting their presence supported the diagnosis of common cold." Number of study centres: 1 Number of withdrawals: 6 Total number screened/eligible/randomised: 1087/80/80
Interventions	Zinc gluconium 2.1 mg/d nasal gel Study description of intervention and administration: "The zinc nasal gel consisted of 33 mmol/l of zincum gluconicum (Zenullose) in an emulsification of benzalkonium chloride, glycerin, hydroxyethylcellulose, sodium chloride, and sodium hydroxide (pH 7.2)."; "Metered dose applicators delivered individual doses of120ml. All patients were instructed in scoring their cold symptoms and trained to use the hand‐held nasal pump properly. The first dose was applied in each nostril at 9:00 pm on the day of enrollment. Patients were told to continue using the study drug four times per day (9:00 am, 1:00 pm, 5:00 pm, and 9:00 pm) thereafter until all their symptoms resolved (see Outcome measures) or for 10 days, whichever came first. Because one dose constituted two sprays, the total daily volume used was 960ml, giving a total daily dose of elemental zinc of about 2.1 mg." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): intranasal Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconium Frequency of dose: 4 x/d Dose per day (elemental zinc in mg): 2.1 mg Duration of treatment: "until all their symptoms resolved (see Outcome measures) or for 10 days, whichever came first." Placebo nasal gel Study description of intervention and administration: "Placebo was identical in appearance and content, except that it lacked the zinc component. Gel Tech LLC supplied both. Metered dose applicators delivered individual doses of 20ml. All patients were instructed in scoring their cold symptoms and trained to use the hand‐held nasal pump properly. The first dose was applied in each nostril at 9:00 pm on the day of enrollment. Patients were told to continue using the study drug four times per day (9:00 am, 1:00 pm, 5:00 pm, and 9:00 pm) thereafter until all their symptoms resolved (see Outcome measures) or for 10 days, whichever came first. Because one dose constituted two sprays, the total daily volume used was 960ml, giving a total daily dose of elemental zinc of about 2.1 mg." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): intranasal Frequency of dose: 4 x/d Duration of treatment: "until all their symptoms resolved (see Outcome measures) or for 10 days, whichever came first."
Outcomes	Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Notes: mean SD estimated from median/IQR Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of cough (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Data value: endpoint Duration of hoarseness (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of scratchy throat (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sore throat (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal drainage (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal congestion (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sneezing (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of headache (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of muscle aches (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of fever (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N)
Identification	Author's name: S.B. Mossad Institution: Department of Infectious Diseases, Cleveland Clinic Foundation, Cleveland, USA Email: mossads@ccf.org Address: address correspondence to Dr S.B. Mossad, Department of Infections Diseases, S‐32, Cleveland Clinic Foundation,9500 Euclid Avenue, Cleveland, OH 44195, USA Trial registration identifier: none Year study recruitment began: 2000
Notes	Declaration of interest: "The author has no conflicts of interest related to the study." Funding source: "Gel Tech LLC, Woodland Hills, CA, provided funding support for the study. The company did not participate in designing the study, collecting, analysing, or interpreting the data, or in writing the report. It approved submission of the paper for publication." Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "An independent company, Botanicals International, prepared a computer‐generated randomization code for the hand‐held nasal pumps that remained concealed until the treatment assignment." Judgement comment: independent company randomisation that was computer‐generated.
Allocation concealment (selection bias)	Unclear risk	Quote: "This company was the only party that knew of the actual treatment assignment before enrolment. Randomization was performed in blocks of 10 (5 zinc and 5 placebo). The study coordinator enrolled the eligible patients and assigned them to their respective groups." Judgement comment: the text implies that at enrolment the treatment assignment was known. It is possible that the study co‐ordinator could have known or predicted the next treatment assignment. This possibility is insufficiently clarified.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "To ensure blinding of patients to treatment assignment, all pumps were identical in appearance except for the randomization numbers. The physician who examined the patients at enrolment and the clinical research coordinator that distributed the pumps were blinded to the treatment assignment." Quote: "However, a similar proportion of patients in both groups correctly identified their group assignment on the first day of taking the study drug; 48% in the zinc group and 58% in the placebo group (p = 0.66)."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The investigator who assessed the outcomes was blinded to the treatment assignment until all patients were enrolled and returned their symptoms score charts." Judgement comment: participants assessed and recorded their symptoms and they, as well as the investigator who assessed outcomes, were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "An intention‐to‐treat analysis of the primary outcome measure, the time to cold resolution, was performed for all enrolled patients, except two from the placebo group who were lost to follow‐up and did not return their symptoms scores charts. Data for four patients who were diagnosed clinically by a physician as having an illness other than the common cold and one patient who was not compliant with the study drug were included in the intention‐to‐treat analysis of the primary outcome measure." Judgement comment: 78/80 (97.5%) randomised participants were included in the analyses.
Selective reporting (reporting bias)	Unclear risk	Quote: "The primary outcome measure was the time to cold resolution, calculated as the number of days starting from the onset of symptoms till their complete resolution. The secondary outcome measures were the total daily symptom scores and the presence of adverse effects." Judgement comment: results are consistent with methods, however there is no preregistration or protocol to check for plans for selection and analysis of outcomes.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Petrus 1998.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "Subjects were instructed not to use antihistamines, decongestants, aspirin, or vitamin supplements." Investigation of ability to distinguish between zinc and placebo: no explicit description of whether participants could distinguish the two. "To achieve masking, sucrose octaacetate (0.169 mg) was used in the placebo, and both the placebo and zinc lozenges were peppermint flavored. A review of participants’ diary entries revealed that 4 participants noted a chalky taste, 4 experienced a metallic aftertaste, and 3 complained of an upset stomach; none of the subjects noted a bitter taste. Most subjects liked the peppermint flavor." Duration of follow‐up: "Subjects recorded their symptoms every day until their symptoms ceased; this was considered the day their involvement in the study ended." Duration of intervention: "14 days or until symptoms ended" Duration of run‐in or washout period: none Describe how participants were identified as having colds/URTI at baseline (treatment trial): "two or more common cold symptoms (nasal drainage, nasal congestion, cough, fever, myalgia, headache, sore throat, scratchy throat, hoarseness, sneezing, or malaise)" Outcomes measured: outcomes were based on participants rating each symptom (nasal drainage, nasal congestion, cough, fever, myalgia, headache, sore throat, scratchy throat, hoarseness, sneezing, or malaise) on a 0 to 3 scale where 0 = absent; 1 = mild (symptom is present but not particularly a discomfort); 2 = moderate (symptom is clearly evident and a discomfort); or 3 = severe (symptom is a serious problem and clearly evident and a discomfort). This was summarised as 1) mean duration of all symptoms (duration of each symptom + number of symptoms), 2) mean duration of the longest‐lasting symptom (symptom with the longest duration), and 3) mean severity rating (a mean score for all symptoms)
Participants	Setting: community/university Country: United States Zinc acetate 90 mg/d lozenge Number: 52 Percentage female: 52% Age (mean (SD)): 26.7 (1.3) Placebo lozenge Number: 49 Percentage female: 55% Age (mean (SD)): 26.3 (1.2) Overall Number: 102 Percentage female: 53% Age (mean (SD)): 26.5 (1.3) Inclusion criteria: "Subjects were 18 to 54 years of age (mean age, 26.5 years; median age, 22 years) and were healthy except for common cold symptoms. All subjects signed an informed consent form approved by an institutional review board."; "To be eligible for this study, subjects had to have two or more common cold symptoms (nasal drainage, nasal congestion, cough, fever, myalgia, headache, sore throat, scratchy throat, hoarseness, sneezing, or malaise) and had to be willing to use lozenges for 14 days or until symptoms stopped." Exclusion criteria: "Subjects with serious illnesses, organ transplants, or disability (including human immunodeficiency virus infection) were excluded from the study. Subjects were instructed not to use antihistamines, decongestants, aspirin, or vitamin supplements. None of the subjects had a history of alcohol or drug abuse, and none had participated in an investigational drug study within the preceding 30 days. Physical examinations were within acceptable limits, and all women had a negative result on a urine pregnancy test. " Group differences: "The study group was predominantly white (72%) with relatively even distributions by sex and allergy test status. Chi‐square tests showed no significant associations between treatment group membership and sex, race/ethnicity, and allergy test status. An independent groups t test showed no significant difference in mean age between the zinc group (26.7 f 1.3 years) and the placebo group (26.3 f 1.2 years) (t = 0.197, df = 99, P = 0.844). " Condition studied: common cold Description of recruitment: "102 volunteers recruited from the campus of the University of Texas at Austin through posted announcements" Diagnostic criteria for condition: "two or more common cold symptoms (nasal drainage, nasal congestion, cough, fever, myalgia, headache, sore throat, scratchy throat, hoarseness, sneezing, or malaise)" Number of study centres: 1 Number of withdrawals: 1 Total number screened/eligible/randomised: NR/NR/102
Interventions	Zinc acetate 90 mg/d lozenge Study description of intervention and administration: "Each subject was given a bottle of 180 lozenges. The lozenges with zinc contained 9 mg of zinc in a 2.7‐g dextrose base"; "Subjects were instructed to use a lozenge every 1.5 hours while awake during day 0, then one lozenge every 2 hours while awake on following days while symptoms were present. They stopped taking lozenges 6 hours after the symptoms stopped." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): acetate Frequency of dose: "Subjects were instructed to use a lozenge every 1.5 hours while awake during day 0, then one lozenge every 2 hours while awake on following days while symptoms were present." Dose per day (elemental zinc in mg): 10/d (estimate) x 9 mg = 90 mg/day ...."A mean total of 60.4 lozenges were taken by each subject for the study, which averaged 9.9 lozenges per subject per day as long as symptoms persisted." Duration of treatment: day 0 to 6 h after resolution or 14 days Placebo lozenge Study description of intervention and administration: "Each subject was given a bottle of 180 lozenges." "sucrose octaacetate (0.169 mg) was used in the placebo, and both the placebo and zinc lozenges were peppermint flavored." "Subjects were instructed to use a lozenge every 1.5 hours while awake during day 0, then one lozenge every 2 hours while awake on following days while symptoms were present. They stopped taking lozenges 6 hours after the symptoms stopped.." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: "Subjects were instructed to use a lozenge every 1.5 hours while awake during day 0, then one lozenge every 2 hours while awake on following days while symptoms were present." Duration of treatment: day 0 to 6 h after resolution or 14 days
Outcomes	Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Notes: (duration of each symptom/number of symptoms) Global severity of cold symptoms (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Notes: symptom severity rating scale: 0 = absent; 1 = mild; 2 = moderate; and 3 = severe. Duration of headache (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of fever (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of muscle aches (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of sneezing (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of nasal drainage (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of nasal congestion (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of sore throat (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of scratchy throat (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of cough (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of hoarseness (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Duration of malaise (days) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of headache (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Data value: endpoint Severity of fever (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of muscle aches (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of sneezing (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of nasal drainage (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of nasal congestion (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of sore throat (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of scratchy throat (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of cough (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of hoarseness (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of malaise (0 to 3 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N)
Identification	Author's name: Edward J. Petrus, MD Institution: Applied Medical Research Email: ejpetrus@pol.net Address: 3413 Spanish Oak Drive, Austin, TX 78731 Trial registration identifier: none Year study recruitment began: 1997
Notes	Declaration of interest: NR Funding source: "Special thanks to James Hine and the staff at Weider Nutrition International, Salt Lake City, Utah, for their financial support for this study and for providing the placebo and zinc lozenges." Contact with study authors for additional information: none Other: third author (Bucci) works for the company that provided the financial support and lozenges.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "The subjects of this randomized, double‐masked, placebo‐controlled study" Judgement comment: no description of sequence generation.
Allocation concealment (selection bias)	Unclear risk	Quote: "The zinc treatment group consisted of 52 subjects (51.5%), and the placebo group consisted of 49 subjects (48.5%). Each subject was given a bottle of 180 lozenges. The lozenges with zinc contained 9 mg of zinc in a 2.7‐g dextrose base." Judgement comment: no description of allocation procedures.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "To achieve masking, sucrose octaacetate (0.169 mg) was used in the placebo, and both the placebo and zinc lozenges were peppermint flavored. A review of subjects’ diary entries revealed that 4 subjects noted a chalky taste, 4 experienced a metallic aftertaste, and 3 complained of an upset stomach; none of the subjects noted a bitter taste. Most subjects liked the peppermint flavor." Judgement comment: success of blinding not thoroughly assessed, but it was noted that they were 'double‐masked'.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Because this was a randomized, double‐masked study, subjects were informed that some individuals would receive zinc lozenges and some would receive placebo. Subjects were also informed that they were required to rate and record their symptoms in a diary at the same time each day." Judgement comment: participants recorded their outcomes and they were blinded to treatment. Same as noted in blinding of participants and personnel, it is not entirely clear, but we are erring on the side of 'low' risk based on what is present.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Only 1 subject was lost to follow‐up, and none of the remaining 101 subjects discontinued because of side effects from the lozenges." Judgement comment: only one participant lost to follow‐up although reason not given.
Selective reporting (reporting bias)	Unclear risk	Quote: "Symptoms were graded as follows: 0 = absent; 1 = mild (symptom is present but not particularly a discomfort); 2 = moderate (symptom is clearly evident and a discomfort); or 3 = severe (symptom is a serious problem and clearly evident and a discomfort). Subjects were instructed to use a lozenge every 1.5 hours while awake during day 0, then one lozenge every 2 hours while awake on following days while symptoms were present. They stopped taking lozenges 6 hours after the symptoms stopped. Subjects recorded their symptoms every day until their symptoms ceased; this was considered the day their involvement in the study ended." Judgement comment: no indication of problems, however there is no protocol or prospective registration available to check the planned outcomes and analyses.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Pooya 2006.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: both Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: NR Duration of follow‐up: 3 weeks Duration of intervention: 3 weeks Duration of run‐in or washout period: NR Describe challenge if any (prevention trial): NR Describe how participants were identified as having colds/URTI: unclear: "...surveillance for common cold was started by the garrison practitioners and continued for six weeks. After a six‐week surveillance, soldiers regarding practiced health behavior and drug usage answered a questionnaire." Outcomes measured: proportion developing colds, duration of cold (?)
Participants	Setting: "group of soldiers in a garrison in Isfahan" Country: Iran Zinc sulfate NR mg/d tablet Number: 32 Percentage female: NR Age (mean (SD)): NR Placebo tablet Number: 27 Percentage female: NR Age (mean (SD)): NR Overall Number: 59 Percentage female: NR Age (mean (SD)): NR Inclusion criteria: "Inclusion criterion was acceptance of the studied individual for Zinc‐ sulfate usage." Exclusion criteria: "Exclusion criteria were no tendency for remaining in the study and intolerable gastrointestinal complications." Group differences: NR Condition studied: "viral upper respiratory tract infections " Description of recruitment: "a group of soldiers in a garrison in Isfahan were enrolled by census in 2005 spring." Diagnostic criteria for condition: NR Number of study centres: 2 Number of withdrawals: NR Total number screened/eligible/randomised: NR/225/225 ‐ says all were enroled, but it is not clear what happened to create the difference between 225 and the 178 reported in tables.
Interventions	Zinc sulfate NR mg/d tablet Study description of intervention and administration: "Only Zinc sulfate prescription two times a day for three weeks." "All groups were informed about the usage of Zinc sulfate tablets and received drug packages." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): tablet Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): sulfate Frequency of dose: 2 x/d Dose per day (elemental zinc in mg): unknown Duration of treatment: 3 weeks Placebo tablet Study description of intervention and administration: "Only placebo prescription two times a day for three weeks. " "All groups were informed about the usage of Zinc sulfate tablets and received drug packages." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): tablet Frequency of dose: 2 x/d Duration of treatment: 3 weeks
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: + education
Identification	Author's name: Arash Pooya Institution: Department of Community Medicine, School of Medicine, Hamedan University of Medical Sciences Email: NR Address: Department of Community Medicine, School of Medicine, Hamedan University of Medical Sciences, Shahid Fahmideh Boulevard, Hamedan, Iran, Tel: +988114230934, +989133008663 Trial registration identifier: none Year study recruitment began: 2005
Notes	Declaration of interest: "Also special thanks to Dr. M.Dehghannejhad and Vatanpour garrison commanders and soldiers who really helped us during execution. In addition we appreciate Dr. R.Rouzbehani for his helpful comments during proposal writing and execution and Dr.Varshosaz for preparing zinc sulfate and placebo tablets." Funding source: "We would like to thank medical university of Isfahan for supporting the study" Contact with study authors for additional information: none Other: duration was reported as, "Mean duration of common cold was significantly different between zinc group and placebo group: (P value=0.007) as it was between group of education and group of no education (P value=0.008)."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Options 1 and 2 were allocated randomly to one sanatorium and options 3and 4 to the other one." Quote: "Practitioners and commanders of the garrison were informed about the project including allocation of interventions and data gathering, in different sessions. All soldiers (225 individuals) were enrolled as sample. These soldiers lived in two independent 24‐hour sanatoriums. Residents of each sanatorium were randomly divided into two groups. Each soldier performed this randomization through picking up an even or odd number. This way we had four groups to which options mentioned below were allocated:" Quote: "Each soldier performed this randomization through picking up an even or odd number. This way we had four groups" Quote: "Residents of each sanatorium were randomly divided into two groups. Each soldier performed this randomization through picking up an even or odd number. This way we had four groups" Judgement comment: true random sequence generation is questionable.
Allocation concealment (selection bias)	High risk	Quote: "Options 1 and 2 were allocated randomly to one sanatorium and options 3and 4 to the other one. As we could not educate just half of a group, association of options 1 and 2 and therefore 3 and 4 were inevitable." Judgement comment: selection of even and odd numbers appears susceptible to lack of allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Judgement comment: the study is described as double‐blinded with regard to zinc and placebo tablets, but there is no description of the constituents, taste, or appearance of the two tablets.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Two days after performing the education and distribution of tablets, surveillance for common cold was started by the garrison practitioners and continued for six weeks." Judgement comment: no statement that the garrison practitioners were blinded, and lack of clarity regarding blinding of the participants who might have reported cold symptoms.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "In addition, best case‐worst case analysis was carried out to solve the problem of missing data. By this analysis, results were the same as what is mentioned above." Judgement comment: data reported for 178 participants, however it states that 225 were enrolled.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: insufficient information to permit judgement of ‘low risk’ or ‘high risk’. It is likely that the majority of studies will fall into this category.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Prasad 2000.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "They were instructed to take no other cold preparations during the study period." Describe any investigation of ability to distinguish between zinc and placebo: "Comparability in taste between zinc and placebo was tested in healthy volunteers. Ten participants were given a zinc lozenge and 10 received a placebo lozenge. One week later, the participants who received zinc were given placebo and those who received placebo were given zinc. At each visit, the participants filled out a questionnaire in which they were asked to guess whether they received a zinc or placebo lozenge. They had seven choices: certainly placebo, certainly zinc, do not know, possibly placebo, possibly zinc, probably placebo, and probably zinc. Volunteers who selected “certainly,” “probably,” or “possibly” and were correct about the type of lozenge they received were considered correct. We therefore categorized participants as “correct,” “incorrect,” or “do not know.” We assessed the adequacy of blinding among study participants by administering the questionnaire used to assess comparability of taste in healthy volunteers. Participants filled out the questionnaire at the beginning and at the end of the trial." Duration of follow‐up: appears to be 12 days Duration of intervention: "Participants were given 50 lozenges and were asked to dissolve one lozenge in their mouths every 2 to 3 hours while awake for as long as they had cold symptoms." Duration of run‐in or washout period: NA If treatment, describe how participants were identified as having colds/URTI: "Volunteers were recruited if they had had cold symptoms for 24 hours or less and had at least 2 of the following 10 symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever." Outcomes measured: "Our primary end point was the average duration of cold symptoms. Secondary end points were plasma levels of zinc and proinflammatory cytokines." Outcomes reported were duration of cold, global severity of the cold, duration of individual cold symptoms, and adverse events.
Participants	Setting: medical centre Country: USA Zinc acetate 102.4 mg/d lozenge Number: 25 Percentage female: 72% Age (mean (SD)): 36.4 (11.1) Placebo lozenge Number: 23 Percentage female: 52% Age (mean (SD)): 37.8 (10.9) Overall Number: 48 Percentage female: 62.5% Age (mean (SD)): 37.1 (10.9) Inclusion criteria: "Volunteers were recruited if they had had cold symptoms for 24 hours or less and had at least 2 of the following 10 symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever." Exclusion criteria: "We excluded persons who were pregnant, had a known immunodeficiency disorder, had a chronic illness, had had symptoms of the common cold for more than 24 hours, or had previously used zinc lozenges to treat the common cold." Group differences: not reported clearly in text. Placebo group was slightly older (37.8 years versus 36.4 years avg). There were more females in the Zinc group (18 versus 12), more males in the placebo (7 versus 11). More of the placebo group reported being ethnically black (11 versus 5). Roughly similar proportions for smokers and history of allergy in each group. Slightly more smokers in Zinc (20 v. 15) and slightly more allergy sufferers in zinc as well (23 versus 19). Condition studied: common cold Description of recruitment: "We recruited 50 volunteers from Detroit Medical Center, Detroit, Michigan, to participate in a randomized, placebo‐controlled trial of the efficacy of zinc acetate lozenges in treating the common cold. Two participants in the placebo group dropped out on day 2. We therefore had complete data on 48 participants. Participants were medical students, graduate and undergraduate students, staff, and employees at Wayne State University who were older than 18 years of age. Recruitment took place throughout 1998. Each volunteer was paid $10 for participation and transportation costs." Diagnostic criteria for condition: "Volunteers were recruited if they had had cold symptoms for 24 hours or less and had at least 2 of the following 10 symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever."; "Participants were asked to complete a daily log documenting the severity of symptoms and the medications taken throughout the duration of the cold. Every day, the participants graded each symptom as 0 for none, 1 for mild, 2 for moderate, and 3 for severe. Total symptom scores were calculated by summing the scores of the 10 symptoms for each day. Resolution of cold symptoms was defined as resolution of all symptoms (a total symptom score of 0) or resolution of all but one mild symptom (a total symptom score of 1)." Number of study centres: 1 Number of withdrawals: 2 Total number screened/eligible/randomised: NR/NR/50
Interventions	Zinc acetate 102.4 mg/d lozenge Study description of intervention and administration: "Each zinc lozenge consisted of 42.96 mg of zinc acetate dihydrate (USP) (Heico Chemicals, Delaware Water Gap, Pennsylvania), 6.0 mg of peppermint oil (National Formulary) (Bell Flavors, North Brook, Illinois), 16.0 mg of silica gel (National Formulary) (Siloid 244 FP, Davidson Chemical, Baltimore, Maryland), 4.0 mg of stevia extract powder (90% pure steviodside), 3835.04 mg of directly compressible dextrose (USP) (Unidex 2034), and 100 mg of glycerol monostearate (Myvaplex TM 600 P, Eastman Chemical, Kingsport, Tennessee). Each lozenge contained 12.8 mg of zinc"; "A research assistant who was blinded to treatment assignments distributed the study medication. Participants were given 50 lozenges and were asked to dissolve one lozenge in their mouths every 2 to 3 hours while awake for as long as they had cold symptoms. They were instructed to take no other cold preparations during the study period." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): acetate Frequency of dose: every 2 to 3 h Dose per day (elemental zinc in mg): 12.8 mg x 8 = 102.4 mg (estimated number of lozenges per day) Duration of treatment: duration of cold symptoms Placebo lozenge Study description of intervention and administration: "Each placebo lozenge contained 0.25 mg of sucrose octa acetate, 6.0 mg of peppermint oil, 16.0 mg of silica gel, 3877.75 mg of dextrose DC, and 100 mg of glycerol monostearate. The placebo and zinc lozenges were identical in weight (4000 mg), appearance, flavor, and texture."; "A research assistant who was blinded to treatment assignments distributed the study medication. Participants were given 50 lozenges and were asked to dissolve one lozenge in their mouths every 2 to 3 hours while awake for as long as they had cold symptoms. They were instructed to take no other cold preparations during the study period." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): NA Frequency of dose: every 2 to 3 h Dose per day (elemental zinc in mg): NA Duration of treatment: duration of cold symptoms
Outcomes	Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: reported as overall number of events not number of individuals. "The zinc group and placebo group did not differ significantly in incidence of nausea (0 vs. 1 [0% vs. 4%]; P . 0.2), vomiting (0 vs. 0), abdominal pain (0 vs. 2 [0% vs. 9%]; P . 0.2), diarrhea (2 vs. 1 [8% vs. 4%]; P. 0.2), bad taste (13 vs. 6 [52% vs. 26%]; P 5 0.08), or mouth irritation (10 vs. 4 [40% vs. 17%]; P 5 0.12). Compared with placebo recipients, zinc recipients reported more mouth dryness (18 vs. 6 [72% vs. 26%]; P 5 0.003) and constipation (6 vs. 0 [24% vs. 0%]; P 5 0.02)." Global severity of cold symptoms (0 to 3 rating) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Notes: spread not reported Duration of sore throat (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N) Duration of nasal drainage (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N) Duration of nasal congestion (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N) Duration of sneezing (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N) Duration of cough (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N) Duration of scratchy throat (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N) Duration of hoarseness (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N) Duration of muscle aches (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N) Duration of fever (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N) Duration of headache (days) Outcome type: continuous outcome Reported as: confidence intervals (mean, CI, N)
Identification	Comments: "See editorial comment on pp 302‐303" Author's name: Ananda S. Prasad, MD, PhD, Institution: Department of Medicine, Division of Hematology‐Oncology, Wayne State University Email: NR Address: Ananda S. Prasad, MD, PhD, Department of Medicine, Division of Hematology‐Oncology, Wayne State University, University Health Center 5‐C, 4201 St. Antoine, Detroit, MI 48201 Trial registration identifier: NR Year study recruitment began: 1998
Notes	Declaration of interest: "In part by an unrestricted fund from the George and Patsy Eby Research Foundation"; "The George and Patsy Eby Research Foundation, Austin, Texas, donated unrestricted research funds to Wayne State University for partial support of this study. The research foundation had no role in the collection, analysis, or interpretation of the data or in the decision to publish the study. George Eby holds U.S. patent rights for zinc lozenges and donated funds earned from his patent rights to the research foundation. George Eby supplied zinc and placebo lozenges for this study." Funding source: "The authors have neither industry connections nor personal financial conflicts of interest related to the study" Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "A research consultant prepared the randomization code and the packages of medication (18)." Judgement comment: unclear how the code was generated. Source of randomisation code not specified, however most likely a number table or computer. Source of randomisation numbers could not have been a quasi‐random source such as medical record number, alternation, day of presentation, etc.
Allocation concealment (selection bias)	Low risk	Quote: "The packages were identical in appearance except for the randomization numbers. A research assistant who was blinded to treatment assignments distributed the study medication." Judgement comment: identical appearance with only the randomisation numbers on them. Allocation performed by a research assistant blinded to assignment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Of 20 participants who received zinc, 5% correctly guessed that they were receiving active therapy. Of 20 participants who received placebo, 10% correctly guessed that they were receiving placebo. Therefore, participants did not correctly guess which type of lozenge they were receiving much better than by chance." Judgement comment: participant blinding appears to be adequate, but this is all that is noted regarding the personnel blinding. Study personnel blinded. More placebo participants than zinc participants made correct guesses about their treatment status, however this was not statistically significant.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Participants were asked to complete a daily log documenting the severity of symptoms and the medications taken throughout the duration of the cold. Every day, the participants graded each symptom as 0 for none, 1 for mild, 2 for moderate, and 3 for severe." Judgement comment: participants were assessing their own symptoms. Other outcome measures appear to be biomarkers so unlikely to have been influenced.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Twenty‐five volunteers were initially recruited in each group. Two persons in the placebo group dropped out on day 2 and were lost to follow‐up. One of the two persons had a sore mouth, and the other developed an ear infection for which care was transferred to a physician outside of Detroit Medical Center." Judgement comment: 50 participants randomised (25 to each group) and 2 participants dropped out of the placebo group on the second day ("One of the two persons had a sore mouth, and the other developed an ear infection for which care was transferred to a physician outside of Detroit Medical Center."). While all attrition was from the placebo group, it is not likely that the large difference in the severity score and duration of illness would have been affected by this attrition. Missing data are explained.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no apparent selection of outcomes or analyses used in this review, however there is no protocol or preregistration to check this.
Other bias	Low risk	Judgement comment: nothing noted; they were also quite transparent about their funding source and its connection to the study.

Prasad 2007.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: NR Duration of follow‐up: 12 months Duration of intervention: 12 months Duration of run‐in or washout period: none Describe how participants were identified as having colds/URTI at baseline (treatment trial): NR Outcomes measured: 1) development of the common cold, 2) other outcomes not relevant to this review included other types of infections, laboratory values including plasma zinc, percentages of cells producing cytokines, and generation of cytokines and plasma oxidative stress markers
Participants	Zinc gluconate 24 mg/d capsule Number: 50 Percentage female: 67% Age (mean (SD)): 65 (9) years Placebo capsule Number: 25 Percentage female: 68% Age (mean (SD)): 67 (6) years Overall Number: 49 Percentage female: 67% Age (mean (SD)): 66 (8) years Inclusion criteria: "healthy elderly adults of both sexes (aged 55– 87 y) and all ethnic groups" Exclusion criteria: "life expectancy (estimated by the physician) of 8 mo; progressive neoplastic disease; severe cardiac dysfunction (New York Heart Association Class IV); significant kidney disease (blood urea nitrogen 40 mg/dL or creatinine 2.0 mg/dL); significant liver disease (known active hepatitis or cirrhosis) or transferrin concentrations 25% above the upper normal laboratory values; or serum alkaline phosphatase concentrations 200 IU." "We excluded those persons who were self‐supplementing with zinc, who were not mentally competent, or who did not understand the study information and could not provide informed consent." Group differences: "The demographic characteristics of the elderly participants in the zinc‐supplemented and placebo‐supplemented groups are shown in Table 1. Neither the ages of the 2 groups or the number of men and women participating in each group differed significantly. An equal number of African Americans and whites participated in the 2 groups. No other variables differed significantly between the groups." Condition studied: common cold Description of recruitment: NR Diagnostic criteria for condition: not defined. "[P]ractice guidelines for evaluation of fever and infections in long‐term care facilities was used as our basis." Number of study centres: 1 Number of withdrawals: 1 Total number screened/eligible/randomised: NR/NR/50
Interventions	Setting: outpatient Country: USA Zinc gluconate 35 mg/d capsule Study description of intervention and administration: "zinc gluconate (15 mg elemental zinc) orally 1 h before breakfast and 2 capsules before going to bed (2 h after dinner or last meal)" Form of product (tablet, lozenge, syrup, intranasal, other (specify)): capsule Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): zinc gluconate Frequency of dose: 2 x/d Dose per day (elemental zinc in mg): 45 mg Duration of treatment: 12 months Placebo capsule Study description of intervention and administration: "Subjects in the placebo group received placebo capsules in the same manner." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): capsule Frequency of dose: 2 x/d Duration of treatment: 12 months
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Notes: reported in text as percentage developing colds
Identification	Author's name: Ananda S Prasad Institution: Wayne State University School of Medicine Email: prasada@karmanos.org Address: Wayne State University School of Medicine 1122 Elliman Building, 421 East Canfield, Detroit, MI 48201 Trial registration identifier: NR Year study recruitment began: NR
Notes	Declaration of interest: "None of the authors had any personal or financial conflict of interest." Funding source: "Supported by NIH grant no. 5 RO1 A150698‐04 and Labcatal Laboratories (Paris, France)" Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Elderly subjects were randomly assigned in pairs to the zinc supplemented or the placebo group with the use of envelopes that each contained 2 smaller envelopes (1 assigning a subject to zinc treatment and 1 assigning a subject to placebo)." Judgement comment: randomisation method not described.
Allocation concealment (selection bias)	Low risk	Quote: "envelopes that each contained 2 smaller envelopes (1 assigning a subject to zinc treatment and 1 assigning a subject to placebo)." Judgement comment: envelopes used and although it is not explicit that they concealed the allocation, it is likely.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The persons caring for the patient, involved in drawing blood, or running laboratory analyses were blinded to the assignment." Judgement comment: placebo‐controlled trial using capsules, therefore participants likely unaware of assignment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement comment: statement that people caring for the subjects were blinded to treatment. Participants were blinded for purposes of self‐report of symptoms and there was no apparent opportunity for nurses obtaining health outcome measurements to become unblinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Judgement comment: only 1 participant of 25 in the zinc group dropped out and there was no loss to follow‐up from the placebo group.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no protocol or trial registration.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Prasad 2008.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "They were instructed to take no other cold preparations during the study period." Investigation of ability to distinguish between zinc and placebo: "Comparability in taste between zinc and placebo was tested in the participants at the beginning and the end of the trial. The participants filled out a questionnaire in which they were asked to guess whether they had received zinc or placebo lozenges. They had 5 choices: certainly placebo, certainly zinc, do not know, probably placebo, and probably zinc. Subjects who selected certainly or probably and were correct about the type of lozenges they received were considered to be correct. We therefore categorized participants as correct, incorrect, or do not know." Duration of follow‐up: NR Duration of intervention: end of cold Duration of run‐in or washout period: NA Describe how participants were identified as having colds/URTI at baseline (treatment trial): "Volunteers were recruited if they had had cold symptoms for 24 h or less and had at least 2 of the following 10 symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever."; "Resolution of cold symptoms was defined as resolution of all symptoms (a total symptom score of 0) or resolution of all but 1 mild symptom (a total symptom score of 1)." Outcomes measured: "Our primary end point was the average duration of cold symptoms. Secondary end points were plasma levels of (1) zinc; (2) soluble interleukin (IL)–1 receptor antagonist (sIL‐1ra) and soluble tumor necrosis factor (TNF) receptor (sTNF‐R) 1; and (3) the plasma adhesion molecules, soluble vascular endothelial cell adhesion molecule (sVCAM)–1 and soluble ICAM (sICAM)–1."
Participants	Setting: Detroit Medical Center (Detroit, Michigan) Country: United States Zinc acetate 106.4 mg/d lozenge Number: 25 Percentage female: 72% Age (mean (SD)): 34.52 (14.06) Placebo lozenge Number: 25 Percentage female: 64% Age (mean (SD)): 35.88 (13.40) Overall Number: 50 Percentage female: 68% Age (mean (SD)): 35.2 (13.6) Inclusion criteria: "Volunteers were recruited if they had had cold symptoms for 24 h or less and had at least 2 of the following 10 symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever." Exclusion criteria: "We excluded persons who were pregnant, had any known immune deficiency disorder or chronic illness, had had symptoms of the common cold for 24 h, or had previously used zinc lozenges to treat the common cold, to assure blinding." Group differences: not clearly reported. Condition studied: common cold Description of recruitment: "We recruited 50 volunteers from the Detroit Medical Center (Detroit, Michigan) to participate in a randomized, placebo‐controlled trial of the efficacy of zinc acetate lozenges in treating the common cold. Recruitment was started in January 1999 and ended in January 2003. Participants were medical students, house staff, and employees at Wayne State University who were 18 years of age. Participants were informed of the placebo‐controlled, double‐blind nature of the study, and the study protocol was approved by the Human Investigation Committee of Wayne State University. Each subject was paid $10 for participation and transportation costs. We recruited healthy volunteers who were free of any illness for various laboratory tests as control subjects." Diagnostic criteria for condition: "Volunteers were recruited if they had had cold symptoms for 24 h or less and had at least 2 of the following 10 symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever." Number of study centres: 1 Number of withdrawals: none reported Total number screened/eligible/randomised: NR/NR/50
Interventions	Zinc acetate 106.4 mg/d lozenge Study description of intervention and administration: "The lozenges were cherry oil–flavored Fast Dry [18] zinc acetate lozenges, manufactured byF&F Foods (Chicago, IL). The active lozenges contained 13.3 mg of zinc as zinc acetate in a hard candy that contained 3.8 g of sucrose and corn syrup and that was prepared using the open‐pot batch method, with the active ingredient added last. One hundred percent of the zinc was available at physiologic pH 7.4 in positively charged, ionic form."; "Participants were given 50 lozenges and were asked to dissolve 1 lozenge in their mouth every 2–3 h while awake for as long as they had cold symptoms." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): acetate Frequency of dose: every 2 to 3 h while awake Dose per day (elemental zinc in mg): 13.3 mg*8 = 106.4 mg/d Duration of treatment: for as long as they had cold symptoms. Placebo lozenge Study description of intervention and administration: "The placebo lozenges were of identical composition, except that they contained 0.25 mg of sucrose octaacetate rather than the active ingredient, zinc. There were no fats, metal chelators, or other zinc ion– binding agents in either the active or placebo lozenges. The placebo and zinc lozenges were identical in weight, appearance, flavor, and texture and were supplied by George Eby." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: every 2 to 3 h while awake Duration of treatment: for as long as they had cold symptoms.
Outcomes	Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Global Severity of Cold Symptoms (0 to 3 rating) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sore throat (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal drainage (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of nasal congestion (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of sneezing (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of cough (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of scratchy throat (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of hoarseness (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of muscle aches (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of fever (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Duration of headache (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N)
Identification	Author's name: Dr. Ananda Prasad Institution: Dept. of Internal Medicine, Wayne State University School of Medicine Email: prasada@karmanos.org Address: Wayne State University School of Medicine, 1122 Elliman Bldg., 421 E. Canfield, Detroit, MI 48201 Trial registration identifier: none Year study recruitment began: 1999
Notes	Declaration of interest: "Potential conflicts of interest: none reported" Funding source: "Financial support: National Institutes of Health (grant 5 R01 A150698 – 04); George and Patsy Eby Foundation, Austin, Texas (unrestricted research funds to Wayne State University for partial support of this study)" Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "A research consultant prepared the randomization code and the packages of medication." Judgement comment: randomisation code prepared prior to allocation and although the source of the code was not described it was likely a random number table or computer. Randomisation could not have been based on quasi‐random methods such as alternation, days of the week, or medical record number.
Allocation concealment (selection bias)	Low risk	Quote: "The packages were identical in appearance except for the randomization numbers. A research assistant who was blinded to treatment assignments distributed the study medication."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "research assistant who was blinded to treatment assignments distributed the study medication." Judgement comment: little description of staff blinding, however it is very likely as the packages did not reveal treatment assignment and the study was primarily conducted by the participants themselves. Extensive description of blinding and blinding assessment shows that participants were likely blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "5.61, respectively. Adequacy of blinding. In the zinc group at the beginning of the study, only 1 subject identified the lozenges as certainly zinc, and 2 subjects identified them as probably zinc. Thus, 3 (12%) of 25 subjects in this group were correct. At the end of the study, 2 (8%) were correct; 1 subject identified the lozenges as certainly zinc, and another subject identified them as probably zinc. In the placebo group at the beginning of the study, 1 subject said that the lozenges were certainly placebo, and another subject identified them as probably placebo. Thus, 2 subjects (8%) in this group were correct. At the end of the study, none of the subjects identified the placebo lozenge correctly. Contingency analysis of correctness by group at the beginning of the study yielded P 1.0, by the 2 test (Fisher’s exact test). At the end of the study, the same test yielded P.489. Thus, there was no significant difference between the 2 groups. From these data, we concluded" Judgement comment: participants were the outcome assessors for the outcomes in this review and they were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Because the data on duration of symptoms were normally distributed according to the Shapiro‐Wilk test, a t test was used to analyze the differences between the groups. b Blinded subjects: we excluded 3 in the zinc group and 2 in the placebo group who correctly identified their lozenges as zinc or placebo at the beginning of the study." Judgement comment: it appears that there was no loss to follow‐up. Explained and analysis done with both all and removal of those who may not have been blinded.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no apparent selection of outcomes or analyses for the information included in this review, however there is no protocol or preregistration to check against.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Rerksuppaphol 2013.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention Concomitant treatments explicitly allowed or forbidden: "Parents were instructed not to give any vitamin, zinc or mineral supplements during the study period." Describe any investigation of ability to distinguish between zinc and placebo: placebo tablets were prepared by the same company and were of identical colour, size, and taste ‐ no specific investigation into blinding of participants Duration of follow‐up: 3 months Duration of intervention: 3 months Duration of run‐in or washout period: none Describe challenge if any (prevention trial): none Outcomes measured: "The primary outcome was the occurrence of any symptom of cold (fever, cough, rhinorrhoea) at anytime during the 3‐month study period. Fever was defined as oral temperature.37.7uC as measured by digital thermometer (model CT‐513W, CitizenSystems Japan Co. Ltd, Tokyo, Japan). Secondary outcomes were the occurrence of vomiting, diarrhoea, use of antibiotics, school absence for any reason, school absence owing to a cold and duration of all symptoms during the 3‐month study period."
Participants	Setting: community (school) Country: Thailand Zinc bis‐glycinate 15 mg/d tablet Number: 50 Percentage female: 40% Age (mean (SD)): 10 (0.5) Body mass index, kg/m2, mean (SD): 16.9 (3.8) Placebo tablet Number: 50 Percentage female: 48% Age (mean (SD)): 11.4 (0.8) Body mass index, kg/m2, mean (SD): 17.8 (4.4) Overall Number: 100 Percentage female: 44% Age (mean (SD)): 10.7 (0.97) Body mass index, kg/m2, mean (SD): 17.4 (4.1) Inclusion criteria: "Healthy children aged 8–13 years who were in grades 3–6 were eligible for inclusion." Exclusion criteria: participation in a concurrent trial of probiotics for the prevention of upper respiratory infections Children with a history of chronic illness such as chronic cough or chronic respiratory disease, asthma, chronic gastrointestinal conditions, behavioural or psychiatric problems or other neurological conditions, immune deficiency, diabetes mellitus, malignancy, chronic renal diseases, congenital heart diseases, or chronic liver disease. Children who were taking vitamin or mineral supplements or had a history of any drug allergy. Group differences: "Children in the zinc group were younger, lighter and shorter than those in the placebo group, [p<0.05] but the gender distribution and body mass index were similar. The incidences of fever, cough, rhinorrhoea, vomiting, diarrhoea, antibiotic usage and school absence were comparable between the two groups(Table 2)." Condition studied: common cold Description of recruitment: "This was a double‐blind randomized controlled trial, conducted in a public school in Ongkharuck district, Nakorn Nayok, Thailand in the winter season from November 2010 to January 2011....The trial was concurrent with another trial of probiotics for the prevention of upper respiratory infections in the same population. Parents and children were informed about the two trials and had the choice of enter one or the other." Diagnostic criteria for condition: "The primary outcome was the occurrence of any symptom of cold (fever, cough, rhinorrhoea) at anytime during the 3‐month study period. Fever was defined as oral temperature.37.7uC as measured by digital thermometer (model CT‐513W, CitizenSystems Japan Co. Ltd, Tokyo, Japan)." Number of study centres: 1 Number of withdrawals: 5 Total number screened/eligible/randomised: 220/100/100
Interventions	Zinc bis‐glycinate 15 mg/d tablet Study description of intervention and administration: "Children in the treatment group were given chelated zinc in the form of a zinc bis‐glycinate (QualimedH, Thailand) tablet, 15 mg once a day for 3 months."; "Trained staff distributed the medication to teachers and parents for administration to the children. The teachers and parents were trained to give the assigned tablet on week days and during weekends, holidays and absence days. Parents were instructed not to give any vitamin, zinc or mineral supplements during the study period." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): tablet Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): zinc bis‐glycinate Frequency of dose: 1 x/d Dose per day (elemental zinc in mg): 15 mg Duration of treatment: 3 months Placebo tablet Study description of intervention and administration: "Placebo tablets were prepared by the same company and were of identical colour, size and taste. Trained staff distributed the medication to teachers and parents for administration to the children. The teachers and parents were trained to give the assigned tablet on week days and during weekends, holidays and absence days. Parents were instructed not to give any vitamin, zinc or mineral supplements during the study period." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): tablet Frequency of dose: 1 x/d Duration of treatment: 3 months
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Outcome group: all outcomes Notes: duration of at least 2 cold symptoms Duration of cough (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Outcome group: all outcomes Duration of fever (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Outcome group: all outcomes Duration of nasal drainage (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Outcome group: all outcomes Days missed from work or school Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Direction: lower is better Data value: endpoint Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Direction: lower is better Data value: endpoint
Identification	Author's name: Sanguansak Rerksuppaphol Institution: Departments of Paediatrics, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand Email: sanguansak_r@hotmail.com Address: Department of Paediatrics, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand Trial registration identifier: none Year study recruitment began: 2010
Notes	Declaration of interest: none Funding source: the study was supported by grants from the Faculty of Medicine, Srinakharinwirot University, Thailand Contact with study authors for additional information: none Other: 2 outcomes; common cold and symptom duration
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "The code to the randomization sequence was opened only after the study was complete." Quote: "Using a computerized programme (GraphPad QuickCals), the enrolled children were randomized to the zinc or placebo group using blocks of two".
Allocation concealment (selection bias)	Low risk	Quote: "Placebo tablets were prepared by the same company and were of identical colour, size and taste." Quote: "Using a computerized programme (GraphPad QuickCals), the enrolled children were randomized to the zinc or placebo group using blocks of two by a statistical consultant who was not involved in the implementation phase of the study." Judgement comment: identical preparations and randomisation to groups was not opened until after the study was completed.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The investigators, teachers, children and parents were masked to the intervention. The code to the randomization sequence was opened only after the study was complete." Judgement comment: blinding unlikely to have been broken.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "During the course of the study, symptoms of a cold (fever, cough and rhinorrhoea), other symptoms (vomiting, diarrhoea), antibiotics used during sickness, school absence and school absence related to cold symptoms were recorded every day by trained teachers. During weekends, holidays and school absence, symptoms were recorded by parents and reported on the next working day. Open‐ended questions assessed side‐effects in both groups. Before the study commenced, teachers and parents were trained in data‐collection methods." Judgement comment: as long as blinding was maintained, outcome assessors would have remained blinded. They were also trained in data collection.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Of the 100 children, 47 in the zinc group and 48 in the placebo group completed the study (Fig. 1). The parents of three children in the zinc group withdrew their consent in the first week of the study owing to concern about potential adverse effects of the medication. Two children in the placebo group were withdrawn, one on day 31 owing to moving to a different school and another on day 2 because of having a rash. Up to the withdrawal date, none of the withdrawn children had any cold symptoms." Judgement comment: "Few withdrawals and reasons were explained."
Selective reporting (reporting bias)	Unclear risk	Quote: "The primary outcome was the occurrence of any symptom of cold (fever, cough, rhinorrhoea) at any time during the 3‐month study period. Fever was defined as oral temperature >37.7°C as measured by digital thermometer (model CT‐513W, Citizen Systems Japan Co. Ltd, Tokyo, Japan). Secondary outcomes were the occurrence of vomiting, diarrhoea, use of antibiotics, school absence for any reason, school absence owing to a cold and duration of all symptoms during the 3‐month study period." Judgement comment: no protocol for comparison, but these do align with what was in the methods.
Other bias	Low risk	Judgement comment: none noted.

Smith 1989.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "Subjects were not allowed to use additional cold or analgesic preparations." Describe any investigation of ability to distinguish between zinc and placebo: "In order to assess the efficacy of blinding, a subsample of 40 subjects were asked at the conclusion of the trial to indicate whether they had been taking zinc or placebo. Their responses were compared with their actual assignments by a chi‐square test of significance." Duration of follow‐up: 7 days or 24 h after the disappearance of the last symptom Duration of intervention: 7 days or 24 h after the disappearance of the last symptom Duration of run‐in or washout period: none Describe how participants were identified as having colds/URTI at baseline (treatment trial): "All eligible subjects had a clinical diagnosis of acute URI. No viral cultures were taken." Outcomes measured: severity of 11 symptoms (sneezing, runny nose, stopped‐up nose, sore or scratchy throat, hoarseness, postnasal drip, cough, watery eyes, headache, chilliness, and muscle aches) and the overall severity of their URI on a scale of 0 to 3 (absent to severe)
Participants	Setting: outpatient and community (students from 3 colleges and 1 family health practice) Country: United States Zinc gluconate 230 mg/d lozenge Number: 86 Percentage female: NR Age (mean (SD)): NR Placebo lozenge Number: 88 Percentage female: NR Age (mean (SD)): NR Overall Number: 174 Percentage female: NR Age (mean (SD)): NR Inclusion criteria: "All eligible subjects had a clinical diagnosis of acute URI. ...All those enrolled were over 18 years old and gave written informed consent." Exclusion criteria: "Potential subjects were excluded from the study if they had serious acute or chronic medical conditions, seasonal allergies, productive cough, or indication for antibiotic therapy or had taken treatment for symptoms within 8 h of the baseline evaluation." Group differences: "The remaining groups of 53 subjects taking placebo and 57 taking zinc did not differ with respect to age, sex, initial severity score, number of symptoms, or duration of symptoms." Condition studied: acute upper respiratory tract infection (URI) Description of recruitment: "Subjects were recruited from among the students of three colleges and from one family practice during January to May 1986. All eligible subjects had a clinical diagnosis of acute URI. No viral cultures were taken." "Subjects were informed of the positive outcome of the initial study and were told that the purpose of the present study was to confirm this result." Diagnostic criteria for condition: "Upon enrollment and at the end of each study day, subjects rated the severity of 11 symptoms and the overall severity of their URI on a scale of 0 to 3 (absent to severe). The individual symptoms assessed were sneezing, runny nose, stopped‐up nose, sore or scratchy throat, hoarseness, postnasal drip, cough, watery eyes, headache, chilliness, and muscle aches." Number of study centres: 1 Number of withdrawals: 35/88 placebo participants and 29/86 zinc participants were excluded from analysis for reasons of insufficient dose (less than 10 lozenges on any day) or duration of therapy or loss to follow‐up. 2 participants in each group were lost to follow‐up. Total number screened/eligible/randomised: NR/174/174
Interventions	Zinc gluconate 230 mg/d lozenge Study description of intervention and administration: "Identical‐appearing lozenges containing either 11.5 mg of elemental zinc or sucrose octaacetate were used. The latter was chosen because its taste empirically approximated that of zinc gluconate. Upon enrollment, subjects were randomly assigned to receive either zinc gluconate or placebo. Both subjects and investigators were blinded to treatment. An initial dose of four lozenges was used, followed by two lozenges dissolved in the mouth every 2 h while awake. This course was continued for 7 days or 24 h after the disappearance of the last symptom. Subjects were not allowed to use additional cold or analgesic preparations." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate Frequency of dose: every 2 h while awake Dose per day (elemental zinc in mg): 2 x 11.5 = 23 mg/dose x 10/day = 230 mg Duration of treatment: 7 days or 24 h after disappearance of last symptom Placebo lozenge Study description of intervention and administration: "Identical‐appearing lozenges containing either 11.5 mg of elemental zinc or sucrose octaacetate were used. The latter was chosen because its taste empirically approximated that of zinc gluconate. Upon enrollment, subjects were randomly assigned to receive either zinc gluconate or placebo. Both subjects and investigators were blinded to treatment. An initial dose of four lozenges was used, followed by two lozenges dissolved in the mouth every 2 h while awake. This course was continued for 7 days or 24 h after the disappearance of the last symptom. Subjects were not allowed to use additional cold or analgesic preparations." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: every 2 h while awake Duration of treatment: 7 days or 24 h after disappearance of last symptom
Outcomes	Severity of 11 symptoms (sneezing, runny nose, stopped‐up nose, sore or scratchy throat, hoarseness, postnasal drip, cough, watery eyes, headache, chilliness, and muscle aches) and the overall severity of their URI on a scale of 0 to 3 (absent to severe)
Identification	Author's name: David S. Smith Institution: University of Pennsylvania School of Medicine Email: david.smith2@pennmedicine.upenn.edu Address: General Internal Medicine, Dartmouth‐Hitchcock Medical Center, Hanover, NH 03756 Trial registration identifier: NR Year study recruitment began: 1986
Notes	Declaration of interest: NR Funding source: "This study was supported by a grant from McNeil Consumer Products Company." Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Upon enrollment, subjects were randomly assigned to receive either zinc gluconate or placebo." Judgement comment: not clear how this was done.
Allocation concealment (selection bias)	Unclear risk	Quote: "Identical‐appearing lozenges containing either 11.5 mg of elemental zinc or sucrose octaacetate were used." Judgement comment: no description of allocation processes.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Both subjects and investigators were blinded to treatment." Quote: "In a comparison of which compound the subjects guessed they had received with the actual assignment, 19 subjects (47%) correctly identified whether they were on zinc gluconate or placebo, while the other 53% were either incorrect or uncertain. Of those given zinc gluconate, 57% identified it correctly, while 32% of subjects given placebo incorrectly thought it was zinc. The ability to discriminate between zinc gluconate and sucrose octaacetate was not significant (P = 0.24)."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement comment: participant blinding was used ‐ they were the ones making the outcome judgements in the ratings of symptoms.
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "Of 174 eligible subjects with a clinical diagnosis of acute URI, 88 were assigned to receive placebo and 86 were assigned to receive zinc gluconate. Thirty‐five subjects in the placebo group and 29 taking zinc were excluded from analysis for reasons of insufficient dose or duration of therapy. Only two in each group were lost to follow‐up. The remaining groups of 53 subjects taking pla‐ cebo and 57 taking zinc did not differ with respect to age, sex, initial severity score, number of symptoms, or duration of symptoms." Judgement comment: > 30% were lost in each group: 35/88 placebo and 29/86 zinc. While these are not incredibly different between groups (40% and 34%), it really is curious why so many did not continue the therapy. Large exclusions from analysis due to insufficient dose or duration of therapy; intention‐to‐treat analysis not done but rather an as‐treated analysis.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no apparent problems with selection, analysis and reporting of outcomes, however no protocol or trial preregistration is available to check against.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Somé 2015.

Study characteristics
Methods	Study design: cluster‐randomised controlled trial Analysis details of cluster‐randomised trial: "A total of 34 villages were selected for inclusion in the study based on their accessibility during the rainy season. Target villages were stratified by health clinic affiliation, average population size, and distance from the paved road and Bobo‐Dioulasso, and assigned to the intervention cohort or the non‐intervention cohort. Because morbidity was not assessed in the non‐intervention cohort, this paper will focus just on the intervention cohort, which consisted of 25 villages. A statistician from the University of California Davis, who was blinded to the intervention groups, generated a random allocation sequence at the level of the concession (extended family compound) using SAS V.9.3 (SAS Institute Inc, Cary, North Carolina, USA) to assign eligible children in the intervention cohort to one of four intervention groups. Every concession had a 1/8 chance of receiving one of the eight colour codes (two colours for each group to reinforce the blinding). During the trial, all participants, field staff, study statistician and investigators were blinded to the intervention groups." Prevention or treatment trial: prevention Concomitant treatments explicitly allowed or forbidden: during enrolment, participants were screened for malaria, fever, reported diarrhoea, and low haemoglobin, and treatments were provided. No other mention of allowed or forbidden treatments during the trial. Investigation of ability to distinguish between zinc and placebo: none reported Duration of follow‐up: 9 months for URTI Duration of intervention: 9 months Duration of run‐in or washout period: none reported Describe challenge if any (prevention trial): none Outcomes measured: diarrhoea, fever, malaria, acute upper respiratory infections (AURI), and acute lower respiratory infections (ALRI); 9 to 18 months of age
Participants	Setting: community Country: Burkina Faso Zinc sulfate 5 mg/d tablet Number: 602 Percentage female: 49.3% Age (mean (SD)): 9.4 (0.3) months Placebo tablet Number: 617 Percentage female: 50.7% Age (mean (SD)): 9.4 (0.4) months Overall Number: 2435 Percentage female: 49.5% Age (mean (SD)): 9.4 months (range 8.7 to 10.7, SD = 0.4) Inclusion criteria: "Children were eligible if they were 8.80–9.99 months old, a permanent resident of Dandé health district, and their caregivers planned to be available during the study period and accepted home visits for data collection." Exclusion criteria: "Children were excluded when they had haemoglobin (Hb) concentration <50 g/L, weight‐for‐length <70% of the National Center of Health Statistics (NCHS) reference median,22 bipedal oedema, other severe illness requiring hospital referral, a congenital abnormality or chronic medical condition, allergy towards peanuts or history of anaphylaxis or serious allergic reactions to any substance requiring emergency medical care, or were concurrently participating in any other clinical trial." Group differences: not discussed in text but participant characteristics appear similar in Table 1. Condition studied: URTI Description of recruitment: "Potentially eligible children were identified by two censuses in a 1‐year interval (November–December 2009 and 2010) in participating communities." No further description of recruitment to participate. Diagnostic criteria for condition: "Acute upper respiratory illness (AURI) was defined as any episode in which the caregiver reported cough and a purulent nasal discharge. An episode of AURI ended on the last day the child had AURI that was followed by at least 7 days free of purulent nasal discharge." Number of study centres: unclear, appears to be one co‐ordinating centre and study conducted in 25 different villages. Number of withdrawals: it appears that there were no withdrawals, however "71 children ... were excluded from the final analyses because they provided less than 30 days of morbidity observations". Total number screened/eligible/randomised: 3402/3220/2435
Interventions	Zinc sulfate 5 mg/d tablet Study description of intervention and administration: 1 sachet of 20 g SQ‐LNS providing 118 kcal, 6 mg of iron and 19 other micronutrients. Placebo dispersible tablet identical in appearance and flavour to zinc tablet. Caregivers were also instructed to administer 20 g SQ‐LNS per day in 2 separate servings, preferably mixed in a small portion of the child’s meal, and to give the dispersible tablet once a day at least 30 min away from meals and SQ‐LNS. Form of product (tablet, lozenge, syrup, intranasal, other (specify)): small‐quantity lipid‐based nutrient supplement (SQ‐LNS) and tablet, neither of which contain zinc Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): unclear Frequency of dose: daily Dose per day (elemental zinc in mg): 0 mg Duration of treatment: 9 months Placebo tablet Study description of intervention and administration: "SQ‐LNS, zinc and placebo tablets were produced by Nutriset SAS (Malaunay, France). All SQ‐LNS products had the same appearance, aroma and flavour, and the zinc and placebo dispersible tablets were identical in appearance and flavour." Frequency of dose: daily Duration of treatment: 9 months
Outcomes	Diarrhoea, fever, malaria, acute upper respiratory infections (AURI), and acute lower respiratory infections (ALRI)
Identification	Author's name: Dr Sonja Y Hess Institution: Program in International and Community Nutrition, Department of Nutrition, University of California, Davis, California, USA Email: syhess@ucdavis.edu Address: Program in International and Community Nutrition, Department of Nutrition, University of California, Davis, California, USA Trial registration identifier: NCT00944281 Year study recruitment began: 2010
Notes	Declaration of interest: "Competing interests: None declared." Funding source: "This article is based on research funded by a grant to the University of California, Davis from the Bill and Melinda Gates Foundation." Contact with study authors for additional information: none Other: 4‐armed trial of which 2 arms are reported: SQ‐LNS without zinc and a placebo tablet (arm named LNS‐Zn0) and LSQ‐LNS without zinc and a 5 mg zinc tablet (named LNS‐TabZn5). Study is reported narratively here due to no intraclass correlation coefficient (ICC) reported, and no information available to calculate the ICC.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A statistician from the University of California Davis, who was blinded to the intervention groups, generated a random allocation sequence at the level of the concession (extended family compound) using SAS V.9.3 (SAS Institute Inc, Cary, North Carolina, USA) to assign eligible children in the intervention cohort to one of four intervention groups. Every concession had a 1/8 chance of receiving one of the eight colour codes (two colours for each group to reinforce the blinding)." Judgement comment: computer‐generated randomisation.
Allocation concealment (selection bias)	Low risk	Quote: "SQ‐LNS, zinc and placebo tablets were produced by Nutriset SAS (Malaunay, France). All SQ‐LNS products had the same appearance, aroma and flavour, and the zinc and placebo dispersible tablets were identical in appearance and flavour." Judgement comment: central randomisation and very unlikely that allocation was unconcealed. Field staff were blinded to interventions.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "During the trial, all participants, field staff, study statistician and investigators were blinded to the intervention groups." Judgement comment: the trial was partially masked, as all participants, field staff and researchers remained blinded to the 4 intervention groups until data analyses were completed, but were aware which communities were assigned to the intervention cohort and non‐intervention cohort.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "tablets and empty packages. 23 Field data collectors used a structured questionnaire to collect a weekly morbidity history, including the child’s general state, appetite, number of semiliquid/ liquid stools, presence of blood or mucus in stools, vomiting, fever, signs of respiratory tract infections, and any treatment received by the child either from study staff members or outside the study. If the child had a reported fever during the previous 24 h, auricular temperature was measured, and an RDT and blood smear slide were performed. As a quality control measure, auricular temperature was also measured once per month for all children independent of the caregiver’s report. In the case of reported". Judgement comment: outcomes reported and recorded by parents and field staff, who were blinded to treatment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The 2435 children in the intervention cohort were randomly assigned to one of the four intervention groups and were followed weekly for morbidity assessment (figure 1). Caregivers of 97% of the participating children provided information on at least 30 days of morbidity surveillance, and 78% of the caregivers provided information for at least 35 weeks. The 71 children who were excluded from the final analyses because they provided less than 30 days of morbidity observations did not differ at baseline from those included in the analysis (data not shown). There were no differences in participation or reporting rates among the four intervention groups." Judgement comment: exclusion from analysis is explained and no differences between groups were found.
Selective reporting (reporting bias)	High risk	Quote: "Trial registration number: NCT00944281." Judgement comment: prospective trial registration does not include acute upper respiratory illness as a primary or secondary outcome. Possible that this was selected and reported only after results were known.
Other bias	Low risk	Judgement comment: no other apparent sources of bias

Sánchez 2014.

Study characteristics
Methods	Study design: cluster‐randomised controlled trial Analysis details of cluster‐randomised trial: there is a mention of intraclass correlation but no detail about what this was or how or whether it was used in the analysis. Prevention or treatment trial: prevention Concomitant treatments explicitly allowed or forbidden: none reported Investigation of ability to distinguish between zinc and placebo: investigators did a pilot test (with 25 participants) and assessed whether it was possible to distinguish between fortified and unfortified milk preparations, reporting it wasn't possible to distinguish between them: "Se hizo una prueba piloto con 25 padres para la valoración de los instrumentos de consentimiento informado y el formulario de reclutamiento; además, en 25 niños se realizaron pruebas de aceptación del producto lácteo con zinc o sin él y del enmascaramiento de las leches fortificadas, de forma que se parecieran lo más posible en sabor y presentación" Duration of follow‐up: 4 months Duration of intervention: 4 months Duration of run‐in or washout period: NR Describe challenge if any (prevention trial): no challenge Outcomes measured: incidence of ARI, incidence of acute diarrhoeal disease, adverse events (abdominal pain, vomiting, and unpleasant taste). Additional data measured included weight and height.
Participants	Setting: community (6 daycare centres) in Medellin Country: Colombia Zinc amino acid chelate Number: 93 Percentage female: 41.9% Age (mean (SD)): 3.28 (0.73) Zinc sulfate Number: 112 Percentage female: 53.6% Age (mean (SD)): 3.45 (0.78) Zinc Number: 205 Percentage female: 48.3% Age (mean (SD)): 3.37 (0.76) Placebo Number: 96 Percentage female: 45.9% Age (mean (SD)): 3.19 (0.92) Overall Number: 301 Percentage female: 47.9% Age (mean (SD)): 3.31 (0.81) Inclusion criteria: children 2 to 5 yo at the start of the study that attended 8 hours daily of daycare, ate 80% or more of their daily intake in the daycare, and liked milk Exclusion criteria: children with a medical diagnosis of recurrent pneumonia, fibrosis, digestive malformations, persistent diarrhoea of any cause, inflammatory bowel disease or lactose intolerance, and children who at the time of intervention had a respiratory infection or acute diarrhoea diagnosed by a physician as well as children who received zinc supplement in the 2 months previous to the start of the study Group differences: no statistical differences were found between the groups with respect to age (Kruskal Wallis test, P = 0.057) or sex (Chi² test of independence, P = 0.245). The groups were comparable with respect to the socio‐demographic variables, with the exception of socioeconomic status stratum, family typology, and type of homeownership (Chi² test of independence, P < 0.05) (Tables 1 and 2). Condition studied: acute respiratory infection (ARI) Description of recruitment: non‐probabilistic sampling, selected 6 daycares from the FAN foundation in Medellin and assigned 1 intervention to 2 clusters (daycares). All children in the daycare were invited to participate in the study. Diagnostic criteria for condition: acute respiratory infection: the presence of 2 or more symptoms, cough, rhinorrhoea, difficulty breathing, and pharyngitis for 2 or more days. An incident case was considered as the development of 2 episodes of 5 or more days without 2 or more symptoms previously described. Number of study centres: trial was run out of a single centre, and included 6 children's centres, 2 of them assigned to each of the 3 arms of the study Number of withdrawals: 17 withdrew before beginning the intervention, and of the 357 who began the intervention, 17 (4.76%) were lost to follow‐up and 39 were excluded from the analysis due to insufficient adherence. Total number screened/eligible/randomised: 441/357/357
Interventions	Zinc amino acid chelate Study description of intervention and administration: the zinc dose was 7 mg in children aged 2 to 3 years and 9.45 mg in children 4 to 5 years (doses recommended by the IZINCG). The vehicle used was fortified milk with the respective zinc compound; the 3 dairy supplements were similar in colour, smell, and taste. The laboratory NUTREO (Rionegro, Colombia) was in charge of supplying them. The school restaurant staff provided the milk (supplemented or not, depending on the case) to preschoolers after receiving instructions and training from researchers. The daily dose was given in 2 doses, 1 in the breakfast and another in the snack, from Monday to Friday for 16 weeks. Form of product (tablet, lozenge, syrup, intranasal, other (specify)): dissolved in milk Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): chelated zinc Frequency of dose: 2 x/day Monday to Friday Dose per day (elemental zinc in mg): 7 mg to 9.45 mg Duration of treatment: 16 weeks Zinc sulfate Study description of intervention and administration: the zinc dose was 7 mg in children aged 2 to 3 years and 9.45 mg in children 4 to 5 years (doses recommended by the IZINCG). The vehicle used was fortified milk with the respective zinc compound; the 3 dairy supplements were similar in colour, smell, and taste. The laboratory NUTREO (Rionegro, Colombia) was in charge of supplying them. The school restaurant staff provided the milk (supplemented or not, depending on the case) to preschoolers after receiving instructions and training from researchers. The daily dose was given in 2 doses, 1 in the breakfast and another in the snack, from Monday to Friday for 16 weeks. Form of product (tablet, lozenge, syrup, intranasal, other (specify)): dissolved in milk Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): zinc sulfate Frequency of dose: 2 x/day Monday to Friday Dose per day (elemental zinc in mg): 7 mg to 9.45 mg Duration of treatment: 16 weeks Combined zinc groups Study description of intervention and administration: the zinc dose was 7 mg in children aged 2 to 3 years and 9.45 mg in children 4 to 5 years (doses recommended by the IZINCG). The vehicle used was fortified milk with the respective zinc compound; the 3 dairy supplements were similar in colour, smell, and taste. The laboratory NUTREO (Rionegro, Colombia) was in charge of supplying them. The school restaurant staff provided the milk (supplemented or not, depending on the case) to preschoolers after receiving instructions and training from researchers. The daily dose was given in 2 doses, 1 in the breakfast and another in the snack, from Monday to Friday for 16 weeks. Form of product (tablet, lozenge, syrup, intranasal, other (specify)): dissolved in milk Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): chelated zinc and zinc sulfate Frequency of dose: 2 x/day Monday to Friday Dose per day (elemental zinc in mg): 7 mg to 9.45 mg Duration of treatment: 16 weeks Placebo Study description of intervention and administration: no specific description of placebo composition other than it was similar to zinc in colour, smell, and taste. The vehicle used was fortified milk with the respective zinc compound (or placebo); the 3 dairy supplements were similar in colour, smell, and taste. The laboratory NUTREO (Rionegro, Colombia) was in charge of supplying them. The school restaurant staff provided the milk (supplemented or not, depending on the case) to preschoolers after receiving instructions and training from researchers. The daily dose was given in 2 doses, 1 in the breakfast and another in the snack, from Monday to Friday for 16 weeks. Form of product (tablet, lozenge, syrup, intranasal, other (specify)): dissolved in milk Frequency of dose: 2 x/day Monday to Friday Duration of treatment: 16 weeks
Outcomes	Development of at least 1 ARI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Incidence rate of ARIs Outcome type: continuous outcome Reported as: custom (incidence rate) Direction: lower is better Notes: incidence rate is the rate of colds per child‐days of observation Calculated incidence rate in combined zinc group from Table 4 as follows: total number of children is 9 + 12 = 21 Total number of child‐days of observation is 6.305 + 7.629 = 13.934 Incidence rate is 21/13,934 x 1.51 Children experiencing any side effect Outcome type: dichotomous outcome Reported as: percentage of participants with event (%, N) Direction: lower is better Data value: endpoint Notes: percentage for combined zinc group was calculated from number in chelated zinc = 6 + number in zinc sulfate = 16 then 22/205 x 100 Children with at least 1 episode of vomiting Outcome type: dichotomous outcome Reported as: percentage of participants with event (%, N) Direction: lower is better Data value: endpoint Children with at least 1 episode of abdominal pain Outcome type: dichotomous outcome Reported as: percentage of participants with event (%, N) Direction: lower is better
Identification	Author's name: Juliana Sánchez Institution: NR Email: july912@yahoo.com.ar Address: Carrera 81 B N° 7A‐40, interior 120, Medellín, Colombia Trial registration identifier: NCT01791608 Year study recruitment began: 2012
Notes	Declaration of interest: 1 researcher is employed by one of the sponsor institutions. Funding source: Universidad CES y Nutreo, S.A.S., Rionegro, Antioquia Country: Colombia Contact with study authors for additional information: none Other: study is reported narratively here due to no intraclass correlation coefficient (ICC) reported, and no information available to calculate the ICC.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Se asignaron en forma aleatoria, por medio de balota, los seis conglomerados de manera que dos centros infantiles quedaron en cada uno de los tres grupos de estudio. Un grupo recibió sulfato de zinc, otro grupo recibió zinc aminoquelado y el último grupo recibió placebo." Judgement comment: there is no clear description about the ballot procedures undertaken, and the mechanisms to ensure that the cluster assignment to groups was bias‐free.
Allocation concealment (selection bias)	Unclear risk	Judgement comment: not described. Although allocation was all done at once, and there may be low risk of anticipating the allocation sequence, this is unclear.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "El vehículo utilizado fue leche fortificada con el respectivo compuesto de zinc; los tres suplementos lácteos fueron similares en color, olor y sabor. El laboratorio NUTREO (Rionegro, Colombia) se encargó de suministrarlos. El estudio fue triple ciego durante toda la intervención y análisis de la información." Quote: "El laboratorio produjo las leches fortificadas cada mes y se encargó de entregarlas al centro infantil correspondiente también mensualmente manteniendo el enmascaramiento." Quote: "en 25 niños se realizaron pruebas de aceptación del producto lácteo con zinc o sin él y del enmascaramiento de las leches fortificadas, de forma que se parecieran lo más posible en sabor y presentación." Quote: "El estudio fue triple ciego durante toda la intervención y análisis de la información." Judgement comment: the study was triple‐blind for both the intervention and analysis of the information. Although there was no discussion about whether participants could distinguish between zinc and placebo, there is no indication that blinding was inadequate. However, it is unclear what kind of procedures were used to ensure unmasking the intervention by the NUTREO Lab staff handling the fortified milk and its distribution. It is unclear what kind of procedures were used to ensure unmasking of the intervention by the NUTREO Lab staff handling the fortified milk and its distribution.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Judgement comment: assessors were teachers, with no direct contact with lab personnel. Anthropometric measures were made by independent assessors.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "Quedaron, entonces, 357 menores que recibieron los complementos con zinc o sin él durante 16 semanas (entre el 4 de junio y el 22 de septiembre del 2012); de estos, 17 (4,76 %) se perdieron durante el seguimiento de la intervención y 39 fueron excluidos del análisis final por haber ingerido la leche durante menos de 75 % del tiempo de observación definido por el protocolo. Así, el análisis se hizo con 301 infantes: 93 de ellos tomaron leche fortificada con zinc aminoquelado, 112, leche fortificada con sulfato de zinc y 96 recibieron placebo (figura 1)." Judgement comment: low loss to follow‐up, however over 10% of participants were excluded from analysis due to low adherence. Attrition and exclusions from the analysis are reported for each intervention group (compared with total randomised participants). Only one reason for attrition was provided (relocation due to security problems) and it is unclear how the researchers gather this information. Only one reason for exclusion was reported (drinking milk for less than 75% of the observation period). Although an intention‐to‐treat analysis might have been indicated here, there do not seem to be differences in attrition across groups.
Selective reporting (reporting bias)	Unclear risk	Quote: "NCT01791608" Judgement comment: the study report corresponds to the study registration, however registration was done after collection of all study data.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Turner 2000 challenge.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: "After receiving the first dose of study medication, 60% of placebo recipients, 53% of zinc gluconate recipients, 64% of 5‐mg zinc acetate recipients, and 66% of 11.5‐mg zinc acetate recipients believed they were taking an active medication. At the end of the study, 72%, 64%, 77%, and 79%, respectively, believed they had received an active medication." Duration of follow‐up: 14 days Duration of intervention: 5 days Duration of run‐in or washout period: none described Describe challenge if any (prevention trial): "The challenge virus used for this study was rhinovirus type 39. This challenge pool has been safety‐tested according to consensus guidelines [11]. All subjects were inoculated with ∼100 TCID50. The virus was administered as drops in 2 inocula of 250 mL per nostril given ∼15 min apart while the subjects were supine…" If treatment, describe how participants were identified as having colds/URTI: "Subjects who presented to the study sites with a common‐cold illness of 2 different symptoms, and had a total symptom score of >2 were randomized..." "Subjects were asked to judge the maximum severity of 7 symptoms—sneezing, rhinorrhea, nasal obstruction, sore throat, cough, headache, and hoarseness—occurring in the interval since the last symptom evaluation." Outcomes measured: duration of cold, global severity of cold, adverse events
Participants	Setting: 2 different study sites: participants were recruited for these studies at MUSC and at Research Testing Laboratories in Hackensack, New Jersey. Country: United States Zinc acetate 30 mg/d lozenge Number: 67 Percentage female: NR Age (mean (SD)): NR Zinc acetate 69 mg/d lozenge Number: 69 Percentage female: NR Age (mean (SD)): NR Zinc gluconate 79.8 mg/d lozenge Number: 66 Percentage female: NR Age (mean (SD)): NR Placebo lozenge Number: 70 Percentage female: NR Age (mean (SD)): NR Overall Number: 272 Percentage female: NR Age (mean (SD)): NR Inclusion criteria: "Subjects were required to be in good health and 18–65 years old. In addition, subjects were required to be susceptible to the study virus, as evidenced by a serum neutralizing antibody titer of <1:4." Exclusion criteria: "Subjects who had a history of allergic disease or nonallergic rhinitis, had abnormal nasal anatomy or mucosa, had had a respiratory tract infection in the previous 2 weeks, were pregnant or lactating, or were not taking medically approved birth control were excluded. Subjects were compensated for their participation." Group differences: "There were no significant differences in the age, sex, race, or height of subjects randomized to the 4 treatment groups. Subjects randomized to the 5‐mg zinc acetate group had a significantly lower mean weight (72.3 kg) than the subjects in the other 3 groups (77.7–81.4 kg). The mean total symptom scores (5 SEM) at the start of study‐medication administration were 5.7 (.41) in the placebo, 4.9 (.31) in the zinc gluconate group, 5.1 (.32) in the 5‐mg zinc acetate group, and 5.7 (.38) in the 11.5‐mg zinc acetate group ( p = .263)." Condition studied: rhinovirus/common‐cold Description of recruitment: "Subjects were recruited for these studies at MUSC and at Research Testing Laboratories, in Hackensack, NJ. Subjects were required to be in good health and 18–65 years old" Diagnostic criteria for condition: "Illness severity was assessed by subjective symptom scores. Subjects were asked to judge the maximum severity of 7 symptoms—sneezing, rhinorrhea, nasal obstruction, sore throat, cough, headache, and hoarseness—occurring in the interval since the last symptom evaluation. Each symptom was assigned a severity score of 0–4, corresponding to the reported severity (absent, mild, moderate, severe, or very severe). Before each patient was randomized to treatment, the symptom scores were recorded in an interactive interview with the study staff once each day, and symptom scores for the 7 individual symptoms were summed to yield the total daily symptom score." Number of study centres: 2 Number of withdrawals: not reported Total number screened/eligible/randomised: NR/413/273
Interventions	Zinc acetate 30 mg/d lozenge Study description of intervention and administration: "Three different preparations were used in these studies: zinc acetate lozenges (5 mg or 11.5 mg; WarnerLambert, Morris Plains, NJ), zinc gluconate lozenges (13.3 mg; Cold‐Eeze, Quigley Corp., Doylestown, PA), and placebo lozenges. The zinc acetate lozenges contained zinc acetate, sugar, glucose syrup, artificial flavoring (citrus), soy lecithin, and artificial coloring." "The study medications were dissolved in the mouth and taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): acetate Frequency of dose: "taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Dose per day (elemental zinc in mg): acetate 5 mg = 30 mg Duration of treatment: up to 14 days Zinc acetate 69 mg/d lozenge Study description of intervention and administration: "Three different preparations were used in these studies: zinc acetate lozenges (5 mg or 11.5 mg; WarnerLambert, Morris Plains, NJ), zinc gluconate lozenges (13.3 mg; Cold‐Eeze, Quigley Corp., Doylestown, PA), and placebo lozenges. The zinc acetate lozenges contained zinc acetate, sugar, glucose syrup, artificial flavoring (citrus), soy lecithin, and artificial coloring." "The study medications were dissolved in the mouth and taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): acetate Frequency of dose: "taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Dose per day (elemental zinc in mg): acetate 11.5 mg = 69 mg Duration of treatment: up to 14 days Zinc gluconate 79.8 mg/d lozenge Study description of intervention and administration: "Three different preparations were used in these studies: zinc acetate lozenges (5 mg or 11.5 mg; WarnerLambert, Morris Plains, NJ), zinc gluconate lozenges (13.3 mg; Cold‐Eeze, Quigley Corp., Doylestown, PA), and placebo lozenges. The zinc acetate lozenges contained zinc acetate, sugar, glucose syrup, artificial flavoring (citrus), soy lecithin, and artificial coloring." "The study medications were dissolved in the mouth and taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate Frequency of dose: "taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Dose per day (elemental zinc in mg): gluconate 13.3 mg = 79.8 mg Duration of treatment: up to 14 days Placebo lozenge Study description of intervention and administration: "The placebo lozenges contained tannic acid, sucrose octaacetate, sugar, glucose syrup, quinine hydrochloride, artificial flavoring, and artificial coloring." "The study medications were dissolved in the mouth and taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: "taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Duration of treatment: up to 14 days
Outcomes	Global severity of cold symptoms (0 to 4 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Adverse events Outcome type: dichotomous outcome Reported as: percentage of participants with event (%, N) Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N)
Identification	Author's name: Dr. Ronald B. Turner, Institution: Dept. of Pediatrics, Medical University of South Carolina, Email: turnerr@musc.edu Address: 171 Ashley Ave., Charleston, SC 29425 Trial registration identifier: none Year study recruitment began: NR
Notes	Declaration of interest: NR Funding source: "These studies were funded by Warner Lambert Consumer Healthcare, Morris Plains, New Jersey." Contact with study authors for additional information: DN emailed Dr. Turner on 3 October 2022 to obtain additional data on the prevalence of common cold and symptom severity for zinc versus placebo. Dr. Turner responded on 4 October 2022 to let us know that: "All of the volunteers treated with zinc or placebo in our study had a common cold illness at the time of treatment. We did evaluate severity of illness but these data were only collected for the day of randomization and the subsequent three days. These data are presented in the manuscript." Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Subjects who met the criteria for randomization to treatment were randomly assigned to 1 of the 4 treatments in accordance with the drug‐randomization code." Judgement comment: no details about who carried out randomisation and what methods were used to generate the randomisation sequence.
Allocation concealment (selection bias)	Unclear risk	Judgement comment: no information about allocation procedures.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "After receiving the first dose of study medication, 60% of placebo recipients, 53% of zinc gluconate recipients, 64% of 5‐mg zinc acetate recipients, and 66% of 11.5‐mg zinc acetate recipients believed they were taking an active medication. At the end of the study, 72%, 64%, 77%, and 79%, respectively, believed they had received an active medication. Analysis of taste‐acceptability in the subset of subjects enrolled at MUSC suggested that unblinding did not occur because of taste." Judgement comment: multiple methods were used to check that participants were blinded to treatment assignment and it appears that blinding was likely successful.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "After randomization to treatment, the symptom scores were recorded by the subject at ∼12‐h intervals, just prior to the first and the last daily doses of study medication." Judgement comment: participants recorded outcomes and they were *likely* blinded to treatment.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Judgement comment: no protocol to compare with and no explicit mention of withdrawal. The numbers of participants randomised was never explicit although Figure 1B presents numbers for each randomised group.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: outcomes reported are consistent with methods, and an additional exploration of rhinovirus infection is clearly identified as a post hoc analysis. However, there is no trial preregistration or protocol to check for selective outcome choice or analysis. Many of the outcomes are not reported in a way that allows them to be extracted for use in this review.
Other bias	Low risk	Judgement comment: no other apparent sources of risk of bias.

Turner 2000 natural.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: "After receiving the first dose of study medication, 75% of placebo recipients, 70% of zinc gluconate recipients, 58% of 5‐mg zinc acetate recipients, and 81% of 11.5‐mg zinc acetate recipients believed they were taking an active medication. At the end of the study, 65% of placebo recipients, 60% of zinc gluconate recipients, 44% of 5‐mg zinc acetate recipients, and 78% of 11.5‐mg zinc acetate recipients believed they had received an active medication." Duration of follow‐up: 14 d Duration of intervention: 3 d Duration of run‐in or washout period: NA Describe how participants were identified as having colds/URTI at baseline (treatment trial): "Illness severity was assessed by subjective symptom scores, as described for the challenge studies. Before randomization, symptom scores were recorded in an interactive interview with the study staff. After randomization, the symptom scores were recorded by the subject at ∼12‐h intervals..." "Subjects who presented to the study sites with a common‐cold illness of 2 different symptoms, and had a total symptom score of >2 were randomized..." "Subjects were asked to judge the maximum severity of 7 symptoms—sneezing, rhinorrhea, nasal obstruction, sore throat, cough, headache, and hoarseness—occurring in the interval since the last symptom evaluation." Outcomes measured: duration of cold, global severity of the cold, adverse events
Participants	Setting: 4 different study sites: IMTCI (Lenexa, KS), GFI Pharmaceutical Services (Evansville, IN), TKL Research (Paramus, NJ), and Research Across America (RAA; Dallas) Country: US Zinc acetate 30 mg/d lozenge Number: 72 Percentage female: NR Age (mean (SD)): NR Zinc acetate 69 mg/d lozenge Number: 68 Percentage female: NR Age (mean (SD)): NR Zinc gluconate 79.8 mg/d lozenge Number: 68 Percentage female: NR Age (mean (SD)): NR Placebo lozenge Number: 71 Percentage female: NR Age (mean (SD)): NR Overall Number: 279 Percentage female: NR Age (mean (SD)): NR Inclusion criteria: "Subjects were required to be in good health and 18–65 years old. In addition, subjects were required to be susceptible to the study virus, as evidenced by a serum neutralizing antibody titer of <1:4." Exclusion criteria: "Subjects who had a history of allergic disease or nonallergic rhinitis, had abnormal nasal anatomy or mucosa, had had a respiratory tract infection in the previous 2 weeks, were pregnant or lactating, or were not taking medically approved birth control were excluded. Subjects were compensated for their participation." Group differences: "No differences were noted in the demographic characteristics of the subjects randomized to the different treatment groups. The mean total symptom scores (5 SEM) at the start of study‐medication administration were 6.34 (.39) in the placebo group, 6.7 (.44) in the zinc gluconate group, 6.3 (.40) in the 5‐mg zinc acetate group, and 6.9 (.38) in the 11.5‐mg zinc acetate group (P = .448)." Condition studied: rhinovirus/common‐cold Description of recruitment: "Natural Colds Subjects. Volunteers aged 18–65 years with a common‐cold illness of recent onset were recruited at 4 different study sites: IMTCI (Lenexa, KS), GFI Pharmaceutical Services (Evansville, IN), TKL Research (Paramus, NJ), and Research Across America (RAA; Dallas)." Diagnostic criteria for condition: "Illness severity was assessed by subjective symptom scores. Subjects were asked to judge the maximum severity of 7 symptoms—sneezing, rhinorrhea, nasal obstruction, sore throat, cough, headache, and hoarseness—occurring in the interval since the last symptom evaluation. Each symptom was assigned a severity score of 0–4, corresponding to the reported severity (absent, mild, moderate, severe, or very severe). Before each patient was randomized to treatment, the symptom scores were recorded in an interactive interview with the study staff once each day, and symptom scores for the 7 individual symptoms were summed to yield the total daily symptom score." Number of study centres: 4 Number of withdrawals: NR Total number screened/eligible/randomised: NR/NR/281
Interventions	Zinc acetate 30 mg/d lozenge Study description of intervention and administration: "Three different preparations were used in these studies: zinc acetate lozenges (5 mg or 11.5 mg; WarnerLambert, Morris Plains, NJ), zinc gluconate lozenges (13.3 mg; Cold‐Eeze, Quigley Corp., Doylestown, PA), and placebo lozenges. The zinc acetate lozenges contained zinc acetate, sugar, glucose syrup, artificial flavoring (citrus), soy lecithin, and artificial coloring." "The study medications were dissolved in the mouth and taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): acetate Frequency of dose: "taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Dose per day (elemental zinc in mg): acetate 5 mg = 30 mg Duration of treatment: up to 14 days Zinc acetate 69 mg/d lozenge Study description of intervention and administration: "Three different preparations were used in these studies: zinc acetate lozenges (5 mg or 11.5 mg; WarnerLambert, Morris Plains, NJ), zinc gluconate lozenges (13.3 mg; Cold‐Eeze, Quigley Corp., Doylestown, PA), and placebo lozenges. The zinc acetate lozenges contained zinc acetate, sugar, glucose syrup, artificial flavoring (citrus), soy lecithin, and artificial coloring." "The study medications were dissolved in the mouth and taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): acetate Frequency of dose: "taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Dose per day (elemental zinc in mg): acetate 11.5 mg = 69 mg Duration of treatment: up to 14 days Zinc gluconate 79.8 mg/d lozenge Study description of intervention and administration: "Three different preparations were used in these studies: zinc acetate lozenges (5 mg or 11.5 mg; WarnerLambert, Morris Plains, NJ), zinc gluconate lozenges (13.3 mg; Cold‐Eeze, Quigley Corp., Doylestown, PA), and placebo lozenges. The zinc acetate lozenges contained zinc acetate, sugar, glucose syrup, artificial flavoring (citrus), soy lecithin, and artificial coloring." "The study medications were dissolved in the mouth and taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): gluconate Frequency of dose: "taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Dose per day (elemental zinc in mg): gluconate 13.3 mg = 79.8 mg Duration of treatment: up to 14 days Placebo lozenge Study description of intervention and administration: "The placebo lozenges contained tannic acid, sucrose octaacetate, sugar, glucose syrup, quinine hydrochloride, artificial flavoring, and artificial coloring." "The study medications were dissolved in the mouth and taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: "taken every 2–3 waking hours (total of 6 lozenges per day) for up to 14 days." Duration of treatment: up to 14 days
Outcomes	Global severity of cold symptoms (0 to 4 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Notes: results are presented in figures that are not extractable Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Duration of cold symptoms (days) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N)
Identification	Author's name: Dr. Ronald B. Turner Institution: Dept. of Pediatrics, Medical University of South Carolina Email: turnerr@musc.edu Address: 171 Ashley Ave., Charleston, SC 29425 Trial registration identifier: none Year study recruitment began: NR
Notes	Declaration of interest: NR Funding source: "These studies were funded by Warner Lambert Consumer Healthcare, Morris Plains, New Jersey." Contact with study authors for additional information: DN emailed Dr. Turner on 3 October 2022 to obtain additional data on the prevalence of common cold and symptom severity for zinc versus placebo. Dr. Turner responded on 4 October 2022 to let us know that: "All of the volunteers treated with zinc or placebo in our study had a common cold illness at the time of treatment. We did evaluate severity of illness but these data were only collected for the day of randomization and the subsequent three days. These data are presented in the manuscript." Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Judgement comment: sequence generation not described.
Allocation concealment (selection bias)	Unclear risk	Judgement comment: allocation procedures not described.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The adequacy of subject blinding was assessed by asking subjects in the challenge study to report whether they were taking active or placebo medication after the first dose of medication and at the end of treatment." Judgement comment: placebo‐controlled trial and it does appear that placebo participants were more likely than some zinc recipients to believe they were receiving zinc. Blinding of study personnel not explicitly described, but likely they were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "After randomization, the symptom scores were recorded by the subject at ∼12‐h intervals, just before the first and last daily administration of study medication." Judgement comment: participants were outcome assessors and they were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Judgement comment: no protocol to compare with and no explicit mention of withdrawal led initially to an unclear rating. After realising that the summed n in the results = 279, as data for 279 participants were presented in figure 1B, it appears that loss to follow‐up was minimal.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no apparent issues with selective reporting, however no protocol or trial preregistration is available to check against.
Other bias	Low risk	Judgement comment: no other apparent sources of bias.

Turner 2001.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: "The effectiveness of the placebo blinding was assessed by asking the volunteers to indicate whether they believed they were using the active or placebo preparation just prior to virus challenge." Duration of follow‐up: ~2 weeks (3 weeks minus the 5 days of treatment/run‐in) Duration of intervention: 5 days Duration of run‐in or washout period: 3 days run‐in Describe challenge if any (prevention trial): "The challenge viruses used for this study were rhinovirus type 23 (RV23) and type 39 (RV39). These challenge pools have been safety tested according to consensus guidelines [20]. All subjects were inoculated with a total of 100–300 TCID50. The virus was administered as drops in 2 inocula of 250 mL per nostril given ∼15 min apart while the subjects were supine." Describe how participants were identified as having colds/URTI (treatment trial): viral shedding, serological study of antibody to the challenge virus, and illness severity scoring. "Subjects with a positive viral culture on any of the post challenge study days were considered to be infected." "Subjects with at least a 4‐fold rise in antibody titer to the challenge virus when the convalescent serum was compared with the acute serum were considered to be infected." "Subjects who had a total symptom score of at least 6 and either at least 3 days of rhinorrhea or the subjective impression that they had a cold were defined as having a clinical cold." Outcomes measured: proportion developing colds, global severity of the cold, severity of individual cold symptoms, adverse events
Participants	Setting: "University community of the Medical University of South Carolina in Charleston" Country: United States Zinc gluconate 1200 mg/day nasal gel Number: 41 Percentage female: NR Age (mean (SD)): NR Placebo nasal gel Number: 50 Percentage female: NR Age (mean (SD)): NR Overall Number: 91 Percentage female: NR Age (mean (SD)): NR Inclusion criteria: "Subjects were required to be in good health and at least 18 years old. In addition, subjects were required to have a serum neutralizing antibody titer 1:4 to the study virus." Exclusion criteria: "Subjects with a history of allergic disease or nonallergic rhinitis, abnormal nasal anatomy or mucosa, a respiratory tract infection during the previous 2 weeks, pregnant or lactating women, or women not on medically approved birth control were excluded." Group differences: NR Condition studied: rhinovirus Description of recruitment: "Subjects were recruited for these studies from the university community of the Medical University of South Carolina in Charleston. [Inclusion/exclusion] ..Subjects were compensated for participation." Diagnostic criteria for condition: "Subjects who had a total symptom score of at least 6 and either at least 3 days of rhinorrhea or the subjective impression that they had a cold were defined as having a clinical cold." "At each evaluation, subjects were asked to judge the maximum severity of 8 symptoms—sneezing, rhinorrhea, nasal obstruction, sore throat, cough, headache, malaise, and chilliness—in the interval since the last symptom evaluation. Each symptom was assigned a severity score of 0–4, which corresponded to a report of symptom severity of “absent,” “mild,” “moderate,” “severe,” or “very severe.” The daily symptom scores for the 8 individual symptoms were summed to yield the total daily symptom score. The total daily symptom scores for the first 5 days after virus challenge (study days 1–5) were summed to yield the total symptom score. Subjects who had a total symptom score of at least 6 and either at least 3 days of rhinorrhea or the subjective impression that they had a cold were defined as having a clinical cold." Number of study centres: 1? Number of withdrawals: 13 (prior to virus challenge) Total number screened/eligible/randomised: 386/NR/105
Interventions	Zinc gluconate 1200 mg/day nasal gel Study description of intervention and administration: "The active preparation (Zicam) consisted of 33 mM zinc gluconate in an emulsification of benzalkonium chloride, glycerine, hydroxymethylcellulose, sodium chloride, and sodium hydroxide (pH 7.2)." "Study medications were administered as a single nasal spray of 120 mL per nostril, at ∼4‐h intervals, 5 times each day. On study days 1–5, the first dose of medication was given after the morning nasal lavage." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): intranasal spray Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): zinc gluconate Frequency of dose: 4‐h intervals, 5 times each day Dose per day (elemental zinc in mg): "The active preparation (Zicam) consisted of 33 mM zinc gluconate in an emulsification..." "120uL per nostril, at∼4‐h intervals, 5 times each d". 120 uL * 2 = 240 uL *5 = 1200 uL/mg. Duration of treatment: 8 days total Placebo nasal gel Study description of intervention and administration: "The placebo was an identical preparation, with the exception of the omission of the zinc gluconate."; "Study medications were administered as a single nasal spray of 120 mL per nostril, at ∼4‐h intervals, 5 times each day. On study days 1–5, the first dose of medication was given after the morning nasal lavage." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): intranasal spray Frequency of dose: 4 h intervals, 5 times each day Duration of treatment: 8 days total
Outcomes	Development of common cold/URTI Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N) Global severity of cold symptoms (0 to 4 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Notes: given in total symptom scores. "Each symptom was assigned a severity score of 0–4, which corresponded to a report of symptom severity of “absent,” “mild,” “moderate,” “severe,” or “very severe.” The daily symptom scores for the 8 individual symptoms were summed to yield the total daily symptom score. The total daily symptom scores for the first 5 days after virus challenge (study days 1–5) were summed to yield the total symptom score" Severity of nasal drainage (0 to 4 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N) Severity of nasal congestion (0 to 4 rating) Outcome type: continuous outcome Reported as: standard error (mean, SE, N)
Identification	Author's name: Dr. Ronald B. Turner Institution: University of Virginia Health System Email: rbt2n@virginia.edu Address: Dr. Ronald B. Turner, Dept. of Pediatrics, P.O. Box 800386, University of Virginia Health System, Charlottesville, VA 22908‐0386 Trial registration identifier: none Year study recruitment began: NR
Notes	Declaration of interest: NR Funding source: "Financial support: Funding for this study was provided by Gel Tech, LLC, Woodland Hills, California" Contact with study authors for additional information: none Other: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Volunteers were randomly assigned to receive either the active preparation or placebo." Judgement comment: sequence generation not described.
Allocation concealment (selection bias)	Unclear risk	Quote: "The effectiveness of the placebo blinding was assessed by asking the volunteers to indicate whether they believed they were using the active or placebo preparation just prior to virus challenge." Judgement comment: allocation processes not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Assessment of study blinding. Taste acceptability was assessed after 3 days of treatment and before virus challenge. Six (12%) of the placebo‐treated subjects reported that they could taste the study medication, compared with 18 (44%) of the subjects who received active medication ... Taste acceptability was assessed in those subjects who reported that they could taste the study medication by use of a 10‐cm visual analog scale with 0, “taste good” and 10, “taste bad.” The mean ( SE) taste visual analog score was in the 6 placebo 5.3 0.77 subjects and in the 18 subjects on active medication. 5.5 0.54. After 3 days of treatment and prior to virus challenge, 20 (39%) of 51 of the placebo recipients and 21 (51%) of 41 active drug recipients believed they were receiving the active treatment". Judgement comment: placebo‐controlled study. However, a higher proportion of zinc participants, versus placebo participants, reported tasting the medication (P < 0.001), and believed they were receiving active treatment (P = 0.29).
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "for the next 5 days. At each evaluation, subjects were asked to judge the maximum severity of 8 symptoms—sneezing, rhinorrhea, nasal obstruction, sore throat" Judgement comment: the participants (who were blinded, although the success of blinding is not entirely clear) likely participated in reporting of symptoms, but it is unclear how the information was obtained and recorded. Nasal lavage and viral culture were done to establish infection and, while this is an objective outcome, the procedures surrounding the collection and assessment of the data are not described at all.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "105 volunteers were enrolled in the study and randomized to study medication. Thirteen subjects either withdrew or were removed from the study prior to the virus challenge (table 1). One subject received placebo medication for part of the study and active zinc medication for the remainder—this subject was considered not evaluable for the endpoints of the study. Ninety‐one subjects, 41 randomized to active medication and 50 randomized to placebo, were challenged with virus and completed the study as planned." Judgement comment: attrition was present, but explained.
Selective reporting (reporting bias)	High risk	Quote: "Subjects with a positive viral culture on any of the postchallenge study days were considered to be infected." Quote: "Subjects with at least a 4‐fold rise in antibody titer to the challenge virus when the convalescent serum was compared with the acute serum were considered to be infected." Quote: "The daily symptom scores for the 8 individual symptoms were summed to yield the total daily symptom score. The total daily symptom scores for then first 5 days after virus challenge (study days 1–5) were summed to yield the total symptom score. Subjects who had a total symptom score of at least 6 and either at least 3 days of rhinorrhea or the subjective impression that they had a cold were defined as having a clinical cold." Judgement comment: all of the symptoms were given a severity score, but not all were reported. Only a few and the total. Multiple definitions of infection (4‐fold rise in antibody titre, positive viral culture) are given. Multiple symptom scores contributed to the total symptom score, but only the rhinorrhoea symptom score, the nasal obstruction score, and the total symptom score were discussed. No protocol or preregistration is available to establish whether this was planned.
Other bias	Low risk	Judgement comment: no other apparent risks of bias.

Vakili 2009.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: prevention Concomitant treatments explicitly allowed or forbidden: NR Investigation of ability to distinguish between zinc and placebo: NR Duration of follow‐up: 5 mos Duration of intervention: 5 mos Duration of run‐in or washout period: none Describe challenge if any (prevention trial): none Outcomes measured: number of common colds (defined as the presence of at least 2 of the following symptoms: cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever); number of days missing from school
Participants	Setting: community Country: Iran Zinc sulfate 10 mg/d tablet Number: 100 Percentage female: 50% Age (mean (SD)): 93.7 (7.38) months Placebo tablet Number: 100 Percentage female: 50% Age (mean (SD)): 93.1 (7.35) months Overall Number: 200 Percentage female: 50% Age (mean (SD)): 78 to 120 months Inclusion criteria: NR Exclusion criteria: not explicitly exclusion criteria, however statement that: "The subjects were free of chronic diseases, such as sickle cell disease, or protein‐energy malnutrition." Group differences: groups appear similar (Table 1) Condition studied: common cold Description of recruitment: NR Diagnostic criteria for condition: NA Number of study centres: NR Number of withdrawals: NR Total number screened/eligible/randomised: NR/NR/200
Interventions	Zinc sulfate 10 mg/d tablet Study description of intervention and administration: "A total of 200 children (aged 78 to 120 months) were randomly assigned to daily (6 days in week) supplementation with 10 mg elemental zinc as a tablet (n=100, 50 males, and 50 females), or placebo (n=100, 50 males, and 50 females)." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): tablet Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): sulfate Frequency of dose: daily, 6 days/week Dose per day (elemental zinc in mg): 10 mg Duration of treatment: 5 months Placebo tablet Study description of intervention and administration: "A total of 200 children (aged 78 to 120 months) were randomly assigned to daily (6 days in week) supplementation with 10 mg elemental zinc as a tablet (n=100, 50 males, and 50 females), or placebo (n=100, 50 males, and 50 females). " Form of product (tablet, lozenge, syrup, intranasal, other (specify)): tablet Frequency of dose: daily, 6 days/week Duration of treatment: 5 months
Outcomes	Development of common cold/URTI Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Days missed from work or school (per child) Outcome type: continuous outcome Reported as: standard deviation (mean, SD, N) Adverse events Outcome type: dichotomous outcome Reported as: number of participants with event (n, N)
Identification	Author's name: Mohammad Vahedian Institution: Department of Public Health faculty Mashhad University of Medical sciences, Mashhad, IR Iran Email: vahedianm@mums.ac.ir Address: Department of Public Health faculty Mashhad University of Medical sciences, Mashhad, IR Iran Trial registration identifier: none Year study recruitment began: 2004
Notes	Declaration of interest: NR Funding source: "This study was supported by grant No. 83047 of vice president for research, Mashhad University of Medical Sciences." Contact with study authors for additional information: none Other: there is a mention of adverse events (mild gastrointestinal discomfort, which was resolved within a few days) in 3 participants in the zinc‐supplemented group but no systematic assessment of adverse events overall is mentioned.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Judgement comment: no description of method of sequence generation.
Allocation concealment (selection bias)	Unclear risk	Judgement comment: no description of allocation procedures.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "These workers were also responsible for proper administration of the zinc or placebo tablets. Regular field visits (once a week) for additional data collection and supervision of the health workers were made by our physician." Judgement comment: no discussion of characteristics of placebo that would make it difficult to distinguish from zinc. No mention of asking participants to guess allocation. No mention of blinding of study personnel.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "All participants were observed on a daily basis for any medical sign and symptom especially cold symptoms. This daily surveillance for the detection of any sign and symptom of common cold and other possible diseases was conducted by trained health workers." Judgement comment: no mention of blinding of outcome assessors (trained health workers).
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "In the zinc‐supplemented group, three participants complained from mild gastrointestinal discomfort which was resolved within few days and there was no need for their exclusion from the study." Judgement comment: appears that data were collected from all participants.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: protocol or trial registration not available.
Other bias	Low risk	Judgement comment: no other apparent risks of bias.

Weismann 1990.

Study characteristics
Methods	Study design: parallel randomised controlled trial Prevention or treatment trial: treatment Concomitant treatments explicitly allowed or forbidden: "No other drugs for common cold were allowed during the study." Investigation of ability to distinguish between zinc and placebo: considered, but not investigated fully it seems, "Preliminary studies had shown us that treatment with lozenges with a 3.5 mg zinc content resulted in saliva zinc levels ranging from about 60 to 250 mol/l. With a 7.5 zinc content per lozenge, the saliva concentration ranged from about 1,400 to 4,400 mol/l, well above the intended level of 0.1 mM/l, but produced an unbearable metallic taste in the volunteers. Therefore, we decided on a zinc dose of 4.5 mg per lozenge which was generally well tolerated. The medication did not produce significant changes in the serum zinc levels when given 12 times daily for seven days to nine patients." Duration of follow up: up to 10 days Duration of intervention: until cold was over, up to 10 days Duration of run‐in or washout period: none Describe how participants were identified as having colds/URTI at baseline (treatment trial): participants diagnosed themselves as having cold symptoms Outcomes measured: participants' diaries capturing many, some, or no symptoms each day; participant assessment of overall condition on 11 cm VAS each day; participant assessment of side effects
Participants	Setting: community/outpatient Country: Denmark Zinc gluconate 45 mg/d lozenge Number: 68 Percentage female: NR Age (mean (SD)): NR Placebo lozenge Number: 77 Percentage female: NR Age (mean (SD)): NR Overall Number: 145 Percentage female: NR Age (mean (SD)): NR Inclusion criteria: "Patients 18‐65 years old who were known to suffer from common cold during the cold season were invited to participate in the study." Exclusion criteria: "Pregnant, lactating women and patients with diabetes mellitus were not included." Group differences: "No statistically significant difference at 5% level between the two groups with regard to sex, age, smoking or severity of symptoms at the start of the study was present. There was no statistically significant difference between treatment groups with respect to the frequency of patients who did not experience a cold and hence did not participate in the study (cf. Table 1)." Condition studied: common cold Description of recruitment: NR Diagnostic criteria for condition: participants diagnosed themselves with symptoms of the common cold Number of study centres: "Six general practitioners residing in the suburban area of Copenhagen conducted the study..." Sounds like it may be just one, but it's not entirely clear. Number of withdrawals: 15/145 Total number screened/eligible/randomised: NR/463/145
Interventions	Zinc gluconate 45 mg/d lozenge Study description of intervention and administration: "After giving their informed consent, the patients received written information about the study, instructing them to start therapy immediately after the first symptoms of common cold appeared. The lozenges were to be taken every 1 to 1 1/2 waking hours, in all 10 lozenges daily for a maximum of 10 days. A diary was to be kept daily stating the approximate hour when each lozenge was taken.""The zinc and placebo lozenges consisted of maltitol syrup with natural flavours. The active lozenges contained 31.3 mg zinc gluconate (=4.5 mg zinc). The daily medication was 10 lozenges, corresponding to 45 mg elemental zinc." Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Type of zinc (zinc sulfate, zinc gluconate, zinc acetate, other (specify)): zinc gluconate Frequency of dose: every 1 to 1 1/2 hours while awake Dose per day (elemental zinc in mg): up to 45 mg Duration of treatment: up to 10 days Placebo lozenge Study description of intervention and administration: "The zinc and placebo lozenges consisted of maltitol syrup with natural flavours." "After giving their informed consent, the patients received written information about the study, instructing them to start therapy immediately after the first symptoms of common cold appeared. The lozenges were to be taken every 1 to 1½ waking hours, in all 10 lozenges daily for a maximum of 10 days. " Form of product (tablet, lozenge, syrup, intranasal, other (specify)): lozenge Frequency of dose: every 1 to 1 1/2 hours while awake Duration of treatment: up to 10 days
Outcomes	Participant diaries capturing many, some, or no symptoms each day; patient assessment of overall condition on 11 cm VAS each day; participant assessment of side effects
Identification	Author's name: Kaare Weismann Institution: Bispebjerg Hospital Email: none Address: Bispebjerg Hospital, DK‐2400 København NV Trial registration identifier: none Year study recruitment began: 1987
Notes	Declaration of interest: NR Funding source: "This study was conducted in cooperation with Kirsten B. Stæhr, A/S Alfred Benzon, Helseholmen 1, DK‐2650 Hvidovre. The zinc gluconate and placebo lozenges were manufactured and supplied by the firm. We gratefully acknowledge their support." Contact with study authors for additional information: none Other: 3 people in the zinc lozenge group complained of bad taste, while no people in the placebo group did. Study is narratively reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Judgement comment: study does not explicitly state that participants were randomised, or describe allocation sequence generation.
Allocation concealment (selection bias)	Unclear risk	Judgement comment: no information on allocation procedures.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Judgement comment: trial used placebo lozenges, but there may be differences in taste that led to unblinding (e.g. 3 people in the zinc group complained of bad taste, while none in the placebo group did so). No discussion of placebo lozenge composition or taste in the study report.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Judgement comment: unclear whether participants, who assessed outcomes, were blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "A total of 463 patients were primarily enrolled in the study which ran over two periods (1 February 1987‐15 April 1987 and 1 September 1987‐1 Februar 1988), during which a common cold was experienced by a total of 145 patients, of whom 130 completed the trial. Sixty‐nine patients received placebo and 61 received zinc (Table 1)." Judgement comment: of 145 people entering the trial, 14 were excluded because of lack of records and 1 was excluded because of too low an age. Relatively high rate of attrition and the effect on outcomes is not clear.
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no protocol.
Other bias	Low risk	Judgement comment: no apparent other sources of bias noted.

ARI: acute respiratory infection
AURI: acute upper respiratory infection
d: day
g: grams
ICC: intraclass correlation coefficient
IQR: interquartile range
mM/l: millimoles per litre
mol/l: moles per litre
mos: months
n: number of participants with event
N: number of total participants
NA: not applicable 
NR: not reported
SD: standard deviation
SE: standard error
URI: upper respiratory infection
URTI: upper respiratory tract infection
VAS: visual analogue scale
yo: years old
ZGG: zinc gluconate group
Zn: zinc

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Abdulhamid 2008	Wrong condition of interest
Australian Journal of Pharmacy 2011	Wrong study design
Bansal 2011	Wrong condition of interest
Barffour 2020	Wrong intervention
Bates 1993	Wrong condition of interest
Brown 2007	Wrong intervention
Chandyo 2010	Wrong condition of interest
Girard 1991	Wrong condition of interest
Habibian 2013	Wrong patient population ‐ participants are children with the common cold, viral pneumonia, or bacterial pneumonia, and there is no information on the subgroup of children with the common cold
Khera 2020	Wrong study design
Kujinga 2018	No placebo
Lira 1998	Wrong condition of interest
Long 2006	Wrong condition of interest
Luabeya 2007	No placebo
Maggini 2012	Wrong intervention
Makonnen 2003	Wrong condition of interest
Martinez‐Estevez 2016	No placebo
Masoodpoor 2008	Wrong condition of interest
McElroy 2003	Wrong study design
Meeks Gardner1998	Wrong condition of interest
NCT01092039	Wrong intervention
NCT04672850	Wrong intervention
Ninh 1996	Wrong condition of interest
Penny 2004	Wrong condition of interest
Rahman 2001	Wrong condition of interest
Richard 2006	Wrong condition of interest
Roy 1999	No placebo
Ruel 1997	Wrong condition of interest
Sampaio 2013	Wrong condition of interest
Sempértegui 1996	Wrong condition of interest
Shaker 2018	Wrong patient population ‐ children had conditions such as the common cold, pharyngitis, tonsillitis, laryngitis, otitis media, sinusitis, or epiglottitis
Silk 2005	Wrong condition of interest
Smith 1991	Wrong study design (summary of Al‐Nakib 1987)
Taneja 2006	Wrong condition of interest
Veverka 2009	Wrong study design (quasi‐randomised)
Walker 2007	Wrong condition of interest
Yousefichaijan 2017	No placebo

Characteristics of studies awaiting classification [ordered by study ID]

Bobat 2005.

Methods	Randomised, double‐blind, placebo‐controlled trial
Participants	Children with HIV‐1 infection
Interventions	10 mg of elemental zinc as sulphate or placebo daily for 6 months
Outcomes	Concentrations of HIV‐1 RNA in plasma and CD4 T lymphocyte cell counts were measured 1 month before randomisation, at the time of randomisation, and at 3, 6, and 9 months after the start of supplementation. Upper respiratory tract infections and otitis media were diagnosed by history and examination, including otoscopy.
Notes	—

NCT05002101.

Methods	Parallel randomised controlled trial
Participants	Children aged 6 months to 5 years
Interventions	Zinc sulphate syrup (3 mg/day to children whose weight is less than 10 kg and 7 mg/day to children whose weight is 10 kg or more) versus non‐nutritious and vitamin‐free placebo syrup
Outcomes	Change in the baseline cumulative incidence rate of acute respiratory infections at 4 months; change in the baseline cumulative incidence rate of diarrhoea at 4 months
Notes	Study title is 'The Effect of Daily Zinc Supplementation on Prevention of Diarrhea and Acute Respiratory Infections Among Children Less Than Five Years: A Randomized Controlled Trial'. Study results for diarrhoea have been published and we are seeking results for acute respiratory infections. LSW emailed Yosra S. Abd El‐Ghaffar on 6 June 2023 to obtain information on acute respiratory infections but did not receive a reply.

Osendarp 2001.

Methods	Randomised, placebo‐controlled trial
Participants	Bangladeshi infants and mothers
Interventions	Mothers took 30 mg daily elemental zinc or placebo, respectively, from 12 to 16 weeks’ gestation until delivery
Outcomes	Morbidity every week by mothers’ recall. Infants’ anthropometric measurements were done every month, and their serum zinc was assessed at 1 and 6 months of age
Notes	—

Wuehler 2008.

Methods	Randomised, double‐masked, community‐based intervention trial
Participants	Ecuadorian children who were 12 to 30 months old at baseline and who had initial length‐for‐age z scores < ‐ 1.3
Interventions	Children received 1 of 5 daily supplements for 6 mo: 3, 7, or 10 mg Zn as zinc sulfate, 10 mg Zn 0.5 mg Cu as copper sulfate, or placebo.
Outcomes	Plasma zinc concentration, morbidity, and growth of young children; to detect any adverse effects of 10 mg supplemental Zn on markers of copper or iron status; and to determine whether any adverse effects are alleviated by providing copper with zinc
Notes	—

Cu: copper
HIV: human immunodeficiency virus
mo: months
RNA: ribonucleic acid
Zn/d: zinc per day

Differences between protocol and review

We added upper respiratory tract infections (URTI) to the outcomes and types of participants, because URTIs could be common colds. We did not consider respiratory tract infections in general to be colds. When study reports made it clear that URTIs were definitely not colds, we did not include the studies or extract URTI information.

We originally planned to search the Cochrane Acute Respiratory Infections Specialised Register, but this has been incorporated into the Cochrane Central Register of Controlled Trials (CENTRAL) and was not searched separately. We had originally planned to peer review the search strategy for searching MEDLINE but failed to complete the peer review due to job transitions.

The threshold for higher versus lower zinc dosage was changed to 85 mg (rather than 75 mg/day as stated in the protocol) because 85 mg/day was the average of all doses included, and we found no clinical reason for using 75 mg/day.

Several outcome measures from the protocol had to be sub‐categorised to accurately describe the data that were available. We made the following changes due to having both dichotomous and continuous data available:

1. Development of a cold (for analyses of prevention trials only), with colds as defined by each study; this outcome is measured in two ways:

   1. Proportion of participants developing colds/URTIs (dichotomous)

   2. Mean number of colds/URTIs developed (continuous)

2. Duration of cold (measured in days from start to resolution of the cold, as defined by each study)

   1. Mean duration of cold/URTI (continuous)

   2. Proportion of participants with a cold/URTI at end of study (dichotomous)

3. Duration of individual cold symptoms (e.g. nasal congestion) (measured in days from start to resolution of symptoms)

   1. Mean duration of individual cold/URTI symptoms (continuous)

   2. Proportion of participants with a cold/URTI at end of study (dichotomous)

4. Days missed from work or school

   1. Proportion of participants missing from work or school (dichotomous)

   2. Mean days missed from work or school (continuous)

The protocol did not specify that we would analyse prevention and treatment trials separately. Since these are different study questions, we analysed prevention and treatment studies separately.

In the protocol, we included two types of adverse events: adverse events potentially due to zinc supplements (e.g. unpleasant taste) and adverse events considered to be potential complications of the common cold (e.g. respiratory bacterial infections). Studies reporting adverse events in any capacity were inconsistent in differentiation between events due to the zinc supplementation or those that simply may have occurred as a result of having a cold (e.g. headache). We therefore reported adverse events as a whole and changed the outcome name to "Adverse events, including those that may be due to zinc supplements". There was also a lack of clear information from the included studies on adverse events potentially due to exacerbation of colds. When serious adverse events were reported, they did not provide specific information on the numbers that may have been due to exacerbation of colds (e.g. total deaths due to diarrhoea or respiratory infection were reported together). Since studies gave information on serious adverse events overall, we included serious adverse events as a primary outcome and adjusted the name of the original outcome to "Serious adverse events, including those that may be complications of the common cold".

In the protocol we stated that we would present forest plots for subgroups regardless of whether there were sufficient studies to test for subgroup differences. Upon editorial advice, we only presented forest plots for subgroup analyses where we could test for subgroup differences.

In the protocol we stated that we would test for subgroup differences if there were at least 10 studies overall and at least two studies in each subgroup. In the review, we decided that it was particularly important to carry out subgroup analyses when heterogeneity was high in the main analysis. We therefore added tests for subgroup differences when heterogeneity was high (≥ 50%) if there were at least eight studies overall and there were at least two studies in each subgroup.

Contributions of authors

Daryl Nault (DN) screened studies, extracted data, contributed to analysis of data and interpretation of results, and contributed to writing the review and creating tables.

Taryn Machingo (TM) screened studies, extracted data, contributed to analysis of data and interpretation of results, and contributed to writing the review and creating tables.

Andrea Shipper (AS) developed the search strategies, carried out the searches, uploaded references to Covidence and RevMan, and completed the first draft of Figure 1.

Daniel A Antiporta (DA) screened studies, extracted data, and contributed to the writing and review of the manuscript.

Candyce Hamel (CH) developed the protocol and aided in the discussion and results of the manuscript.

Sahar Nourouzpour (SN) developed the protocol and extracted data from studies.

Menelaos Konstantinidis (MK) developed the protocol and oversaw the statistical analysis and results.

Erica Phillips (EP) extracted data from papers and contributed to writing the review.

Elizabeth A Lipski (EL) developed the protocol and served as the subject expert.

L Susan Wieland (LSW) screened studies, selected studies, wrote to authors for additional information, extracted data, assessed risk of bias, contributed to analysis of data and interpretation of results, and co‐ordinated the review.

Sources of support

Internal sources

• No internal sources of support., Other

  No internal sources of support to report

External sources

• National Institutes of Health, USA

  Research reported in this publication was supported by the National Center for Complementary and Integrative Health of the National Institutes of Health under award number R24 AT001293. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declarations of interest

Daryl Nault: declares no conflict of interest.

Taryn Machingo: declares no conflict of interest.

Andrea G Shipper: declares no conflict of interest.

Daniel A Antiporta: declares no conflict of interest.

Candyce Hamel: declares no conflict of interest.

Sahar Nourouzpour: declares no conflict of interest.

Menelaos Konstantinidis: reports being a Statistical Editor for Cochrane Acute Respiratory Infections, but had no role in the editorial process of this review.

Erica Phillips: declares no conflict of interest.

Elizabeth Lipski: declares no conflict of interest.

L Susan Wieland: reports funding for Cochrane Complementary Medicine from the US National Institutes of Health, National Center for Complementary and Alternative Medicine, R24 AT001293; paid to institution.

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