Workplace interventions for treating work‐related rhinitis and rhinosinusitis

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effects of workplace interventions aimed at treating work‐related rhinitis and rhinosinusitis. We will combine findings of rhinitis and rhinosinusitis in this review due to their similarity in definition, presentation and reported effects but will separate the two entities if possible in our subgroup analysis.

Background

Description of the condition

Rhinitis and rhinosinusitis are part of a spectrum of inflammatory disorders of the respiratory tract. Rhinitis relates to the irritation or inflammation of the nasal mucous membrane, while sinusitis refers to inflammation of a sinus. The proximity between the sinus cavities and the nasal passages, as well as their common respiratory epithelia, lead to frequent simultaneous involvement of both structures. Rhinosinusitis refers to inflammation of the nasal cavities and sinuses (Desrosiers 2011) and is defined as an inflammatory condition of the nose and paranasal sinuses, characterised by nasal blockage, obstruction, congestion or discharge. It may be accompanied by facial discomfort or reduced sense of smell, supported by endoscopic signs of nasal polyps or mucopurulent discharge or mucosal oedema, primarily from the middle meatus. Mucosal changes within the osteomeatal complex and sinuses may also appear in a CT scan (Fokkens 2012). Rhinitis and rhinosinusitis can be allergic or non‐allergic(Quillen 2006). Allergic causes include immune‐mediated mechanism following exposure to various types of allergens such as dust mites, moulds or pollens, which may be seasonal or perennial. Non‐allergic causes include non‐immune‐mediated mechanisms such as exposure to an irritant that is capable of inducing an inflammatory reaction of the airways (Meggs 1996).

Occupational factors are important contributors to adult rhinitis and rhinosinusitis, and these conditions are two to four times more prevalent than occupational asthma, which is another well‐known illness in the same spectrum (Siracusa 2000). The workers at risk include laboratory workers, farmers, bakers, museum workers, textile workers, food‐processing workers, healthcare workers, farmers, electronic or electrical products assemblers, and boat builders (Brisman 1999; Heederik 1999; Hytonen 1997; Kaukiainen 2008; Moscato 2009; Wiszniewska 2009). Generally, rhinitis and sinusitis are two expressions of the same underlying inflammatory disease of the respiratory mucosa, affecting more than 20% of the population in the United States and European countries (Bauchau 2004; Nathan 2008). Rhinosinusitis is highly prevalent in the United States, affecting an estimated 16% of the adult population annually (Anand 2004). Medical treatment has been used for both of these conditions. The effect of work‐related rhinitis or rhinosinusitis in reducing workplace productivity are well documented (Crystal‐Peters 2002; Fireman 1997; Vandenplas 2010), as are their impact on health care costs (Weiss 2001).

Work‐related rhinitis (WRR) is an occupational disease defined by the European Academy of Allergy and Clinical Immunology (EAACI) as an inflammatory disease of the nose, which is characterised by intermittent or persistent symptoms (i.e. nasal congestion, sneezing, rhinorrhoea, itching), or variable nasal airflow limitation or hypersecretion due to causes and conditions attributable to a particular work environment and not to stimuli encountered outside the workplace (Moscato 2009; Önerci 2010). Work‐related rhinosinusitis (WRRS) includes symptoms such as nasal blockage, nasal secretion, itching and sneezing after exposure to allergens or irritants, as well as facial pressure, headache, loss of sense of smell, nasal crust formation, dryness of the nose and nosebleeds. The presence of these symptoms are sufficient evidence for reaching a diagnosis of occupational rhinosinusitis (Hellgren 2008). WRRS symptoms can be triggered by a wide variety of conditions at work, which are categorised into annoyance (e.g. perfumes or detergents), irritational (e.g. cigarette smoke or capsaicin), corrosive (e.g. formaldehyde or ammonia) and immunologic (caused by high‐molecular weight or low‐molecular weight allergens such as psyllium and guar gum) (Slavin 2010; Thilsing 2012). Both WRR and WRRS include allergic and non‐allergic components (Moscato 2011).

Common causes found at workplaces are irritants (e.g. chemicals, dusts, fumes), physical factors (e.g. temperature changes), socio‐environmental factors such as secondhand smoke, strong smells (e.g. perfumes) and allergens (e.g. psyllium and guar gum) (Zhao 2012). Exposure to multiple agents have also been documented among workers exposed to cleaning agents, pesticides, inhalant allergens, paints and microbiological contaminants, with the prevalence of rhinitis ranging from 31% to 61% (Chatzi 2007; De Fatima 2007; Kaukiainen 2008; Park 2008; Riu 2008). WRR can affect workers' quality of life, work productivity and absenteeism (Szeinbach 2007), and overall productivity losses may range from 1% to 4%, while on‐the‐job effectiveness can decline by approximately 11% to 40% (Vandenplas 2010).

Description of the intervention

Workplace interventions for treating WRR or WRRS, which take place irrespective of any medical care a person might be receiving, may be more effective in alleviating symptoms than medical treatment alone. As the underlying cause of WRR and WRRS are agents present at the workplace, it would seem reasonable wherever possible to address these through secondary prevention approaches. Occupational health and safety professionals commonly use a framework called the hierarchy of controls (HIRARC) to identify risks and devise appropriate control measures. In general, the hierarchical levels used, from top to bottom, are elimination, substitution, engineering controls, administrative controls, training and education and personal protective equipment (PPE). Complete elimination of the causal agents can be implemented at some workplaces, but this is usually associated with substantial socioeconomic consequences (Vandenplas 2003), so it may be more feasible to remove workers from the source of exposure (Vandenplas 2002) or substitute causal agents with safer ones, for example by replacing powdered latex gloves with non‐powdered ones (Filon 2006; Kelly 2011). Other exposure reduction measures that could be implemented at the workplace include engineering controls, administrative control and use of personal protective equipment. Engineering controls can be achieved by physical modification to a process or process equipment, or through the installation of further equipment (Ignacio 2006) to protect the workers from hazards, such as filters to capture and remove airborne emissions from exhaust ventilation. Limiting exposure by job rotation is one example of administrative controls; personal protective equipment such as ear plugs for noise reduction is considered the least effective measure. In one Cochrane review on workplace interventions, the authors conclude that complete removal from the exposure is more effective in improving asthma symptoms than reduction of the exposure (De Groene 2011). Any measures to treat WRR and WRRS are likely to be more effective in improving daily function and work productivity of the affected individuals if accompanied by a rehabilitation programme for patients who respond poorly to control measures.

How the intervention might work

The interventions might work differently depending on factors such as type or rhinitis (allergic or non‐allergic), type of workplace environment and type of exposure at the workplace.

While the allergic (IgE‐mediated) mechanism of WRR has been well‐described, the mechanism of non‐allergic WRR is still poorly understood (Schroer 2012). Obtaining detailed medical history, physical assesment and occupational records remain a key step in the investigation and diagnosis of WRR. Medical history is used to establish the timing of nasal symptoms, while the physical assessment gathers information on the nature, severity, and impact of WRR symptoms. Occupational history addresses duration of work (latency period), agents, tasks or processes associated with the onset or aggravation of symptoms, and it also notes improvements away from work (weekends or prolonged holidays) (Moscato 2009). This information helps in determining the causal agents and helps employers set up appropriate workplace intervention strategies.

Targeted interventions to treat symptoms of WRR or WRRS depend largely on the type of exposure. For example, for at‐risk individuals who are sensitised in their occupations, such as cleaners who are exposed to various cleaning agents (De Fatima 2007), laboratory workers to animal fur and danders (Ferraz 2013), farmers to pesticides (Chatzi 2007), greenhouse workers to pollens and pesticides (Riu 2008), construction painters to paints and solvents (Kaukiainen 2008) and automotive manufacturing workers to microbes, endotoxins and metals (Park 2008), complete avoidance of the causal agents are recommended as the most effective therapeutic option (Moscato 2009). Allergen avoidance has known beneficial effects on improving health‐related quality of life among workers exposed to bee pollen (Gerth 2011) and detergent enzymes (Adisesh 2011).

In certain high‐risk individuals, allergen avoidance might need to be augmented with engineering control measures. Improvement of ventilation following the installation of high‐efficiency air filters and electrostatic air cleaners that reduce the inhalable particles in the workplace decreases the likelihood of having work‐related respiratory symptoms (Graudenz 2004; Skulberg 2005).

Job rotation, personal hygiene and good housekeeping are some of the examples of administration controls (Harrison 2001). It has been shown, for example, that training and raising educational awarenessare beneficial in reducing symptoms among farmers with occupational asthma (Dressel 2007).

Providing workers with personal protective equipment (PPE) is also part of intervention programmes to treat WRR and WRRS. The application of PPE ensures minimal exposure to allergens via all possible routes; PPE may include safety goggles for protecting the eyes or the entire face; gloves, aprons and boots for dermal protection; and face masks or air respirators for respiratory protection against allergens (HSE 2013).

However, there are also drawbacks of to using PPE, such as sensitisation to latex gloves. Avoidance of latex gloves would be the most straightforward method among workers with sensitisation to latex (Filon 2006), but other methods may be more feasible depending on the route of exposure. For example, in individuals sensitive to latex‐aeroallergens, laminar flow helmet respirators are effective in reducing exposure to latex‐allergic individuals (Laoprasert 1998). Helmet respirators have also shown to be partially effective in reducing the consequences of exposure in workers with WRR and asthma due to laboratory animals (Slovak 1985).

Why it is important to do this review

Work‐related illnesses such as WRR and WRRS are problems of increasing magnitude (Moscato 2009). Several Cochrane reviews on pharmacological interventions for allergic rhinitis or related conditions have been published, including on the use of antibiotics (Arroll 2005), injection immunotherapy (Calderon 2007) and sublingual immunotherapy (Radulovic 2010). However, medical interventions targeting individuals have obvious limitations in reducing the incidence and severity of work‐related conditions, and workplace strategies need to be evaluated rigorously in a systematic review that synthesises the best available evidence on current practice for stakeholders and health care decision makers and informs future research. To date, there has been no systematic review that evaluates non‐pharmacological interventions instituted at the workplace with an aim to alleviate symptoms and shorten the recovery process from WRR or WRRS.

Objectives

To assess the effects of workplace interventions aimed at treating work‐related rhinitis and rhinosinusitis. We will combine findings of rhinitis and rhinosinusitis in this review due to their similarity in definition, presentation and reported effects but will separate the two entities if possible in our subgroup analysis.

Methods

Criteria for considering studies for this review

Types of studies

We will consider all randomised controlled trials, cluster‐randomised controlled trials and quasi‐randomised controlled trials that have assessed the effectiveness of interventions to treat work‐related rhinitis and rhinosinusitis in occupational settings for inclusion in this review. We define quasi‐randomised trials as studies which involve the use of quasi‐random methods of allocation, such as alternation by date of birth, medical registration number or the order in which participants are included in the study (Higgins 2011). Because a proper randomisation process is not always possible for studies conducted on a group level, we will also consider controlled before‐and‐after (CBA) studies, as long as they have at least two interventions and two control sites (EPOC 2013). We will include studies reported as full‐text, those published as abstract only and unpublished data.

Types of participants

We will include adult workers (aged 16 and over) of both sexes who are diagnosed with work‐related rhinitis or rhinosinusitis, characterised by the following symptoms: intermittent or persistent nasal congestion, sneezing, rhinorrhoea, itching, variable nasal airflow limitation or hypersecretion, facial discomfort, loss of smell, or a combination of these, attributable to causes and conditions in a particular work environment, such as exposure to allergens and irritants (not to stimuli encountered outside the workplace).

Types of interventions

We will include any type of workplace intervention aimed at treating workers with diagnosed with WRR or WRRS. The possible interventions will be classified as follows.

1. Removal from exposure.

   1. Elimination: removal of worker from the source of exposure at the workplace

   2. Substitution: replacement of an allergen or irritant with a non‐allergen or non‐irritant at workplace

2. Reduction of exposure.

   1. Engineering control: any physical modification of environment, equipment or work process to reduce the exposure of allergens or irritants at the workplace

   2. Administrative control: any workplace policies to reduce exposure to allergens or irritants

   3. Training and educational programme

   4. Use of personal protective equipment (PPE)

3. Rehabilitation of participants who fail to adequately respond to the above mode of interventions.

We will include studies that compare one or more of the above with no intervention or with other types of intervention.

Types of outcome measures

Primary outcomes

We will include trials that measure the effect of interventions on the severity of symptoms of rhinitis or rhinosinusitis. For these symptoms, we will consider the following options as equally valid outcome measurements.

• Rhinitis and rhinosinusitis symptoms.

• • The number of participants with total clearance of symptoms at specified time points, such as three, six and 12 months after the intervention

  • Reduction in severity of symptoms measured by a validated questionnaire using scoring systems such as the score for allergic rhinitis (Annesi‐Maesano 2002), validated symptoms diaries or a validated visual analogue scale (Bousquet 2007)

• Number of participants with a reduction in prescribed medication for rhinitis or rhinosinusitis.

Secondary outcomes

• Quality of life measured using validated scales such as the standardised version of the Rhinoconjunctivitis Quality of Life Questionnaire‐(RQLQ)

• Work performance measures such as work ability or absenteeism (work days lost per episode, work days lost per year)

Reporting one or more of the secondary outcomes listed here in the trial is not an inclusion criterion for the review.

Search methods for identification of studies

Electronic searches

We will conduct a systematic literature search to identify all published and unpublished trials that can be considered eligible for inclusion in this review. We will adapt the search strategy we developed for PubMed (see Appendix 1) for use in the other electronic databases. The literature search will identify potential studies in all languages. We will translate the non‐English language papers and fully assess them for potential inclusion in the review as necessary.

We will search different electronic databases to identify potential studies, including:

• Cochrane Central Register of Controlled Trials (CENTRAL) (Wiley Online Library);

• MEDLINE (PubMed) (Appendix 1);

• EMBASE ;

• PsycINFO (ProQuest);

• NIOSHTIC (OSH‐UPDATE);

• NIOSHTIC‐2 (OSH‐UPDATE);

• HSELINE (OSH‐UPDATE);

• CISDOC (OSH‐UPDATE).

We will also conduct a search of ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/). We will search all databases from their inception to the present, imposing no restriction on language of publication.

Searching other resources

We will handsearch reference lists of all primary studies and review articles for additional references. We will contact experts in the field to identify additional unpublished materials.

Data collection and analysis

Selection of studies

We plan to divide the team into five pairs of authors. Each pair will be partly responsible for the following tasks.

• Two pairs of review authors (NSIAT, NAM and LA, IH) will independently screen half of the titles and abstracts to examine all the potential studies we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'

• We will retrieve the full‐text study reports/publications, and two pairs of review authors (SKB, ZAM and MYA, MA) will independently screen the full text and identify studies for inclusion, also identifying and recording reasons for exclusion of the ineligible studies.

• We will resolve any disagreement through discussion or, if required, we will consult a third review author to make the final judgment (NM or SM).

We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Liberati 2009; Moher 2009) and construct a table describing the characteristics of the excluded studies.

Data extraction and management

We will use a data collection form for study characteristics and outcome data, which will have been piloted on at least one study in the review. One review author (NAM) will extract the following study characteristics from included studies.

1. Methods: study design, total duration of study, study location, study setting, withdrawals and study period.

2. Participants: N, mean age or age range, gender, severity of condition, diagnostic criteria if applicable, inclusion criteria and exclusion criteria.

3. Interventions: description of intervention, comparison, duration, intensity, content of both intervention and control condition, and cointerventions.

4. Outcomes: description of 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 (SKB, ZAM) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data was not reported in a usable way. We will resolve disagreements by consensus or by involving a third review author (LA). One review author (MA) will transfer data into the Review Manager (RevMan 2014) file. We will double‐check that data is entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (MYA) will spot‐check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two review authors (NAM, MFB) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another review author (SM). We will assess the risk of bias according to the following domains.

• Random sequence generation.

• Allocation concealment.

• Blinding of participants and personnel.

• Blinding of outcome assessment.

• Incomplete outcome data.

• Selective outcome reporting.

• Other bias.

We will grade each potential source of bias as high, low or unclear and provide a quotation from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trial ist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We will enter the outcome data for each study into the data tables in RevMan software (RevMan 2014) to calculate the treatment effects. We will use risk ratios for dichotomous outcomes, mean differences or standardised mean differences for continuous outcomes, or other types of data as reported by the authors of the studies. If only effect estimates and their 95% confidence intervals or standard errors are reported in studies, we will enter these data into RevMan using the generic inverse variance method. We will ensure that higher scores for continuous outcomes have the same meaning for the particular outcome, explain the direction to the reader and report where the directions were reversed if this is necessary. When the results cannot be entered as detailed here, we will describe them in the 'Characteristics of included studies' table or enter the data into additional tables.

Unit of analysis issues

For studies that employ a cluster‐randomised design and report sufficient data to be included in the meta‐analysis, but do not make an allowance for the design effect, we will calculate the design effect based on a fairly large assumed intracluster correlation of 0.10. We base this assumption of 0.10 being a realistic estimate by analogy on studies about implementation research (Campbell 2001). We will follow the methods stated in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) for the calculations.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.

If numerical outcome data are missing, such as standard deviations or correlation coefficients, and they cannot be obtained from the authors, we will calculate them from other available statistics such as P values according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Assessment of heterogeneity

We will assess the clinical homogeneity of the results of included studies based on similarity of population, intervention, outcome and follow‐up. We will consider populations as similar when they are exposed to similar potential aetiological factor(s) at the workplace, with outcomes measured in similar ways, as stated above in 'Types of outcome measures'. We will consider interventions as similar when they fall into the same category as mentioned in 'Types of interventions' above. We will consider the following outcomes to be similar: severity of rhinitis or rhinosinusitis after treatment at workplace measured with various scoring systems (e.g. severity scores for five individual symptoms [nasal congestion/stuffiness, sneezing, rhinorrhoea/nasal discharge, nasal pruritus and occular pruritus], validated visual analogue scale and validated symptoms diaries) and quality of life measured using validated scales (e.g. the standardised version of the Rhinoconjunctivitis Quality of Life Questionnaire). We will regard follow‐up times as: short term (seven days to six months) (Desrosiers 2011; Woodcock 2003), medium term (between six and 12 months) (Woodcock 2003) and long‐term (more than 12 months) (Quinlan 2009).

We will visually inspect the data to check for the presence and identify the sources of heterogeneity among the studies. We will then decide whether it is sensible to combine the studies in a single meta‐analysis. If we decide to combine the studies, we will use the Cochrane Q test to examine statistical heterogeneity between studies and the I² statistic to assess variability in estimates of effect due to heterogeneity. We will consider a value greater than 75% to represent significant heterogeneity.

Assessment of reporting biases

If we are able to pool more than five trials in any single meta‐analysis, we will create and examine a funnel plot to explore possible small study biases.

Data synthesis

We will pool data from studies judged to be clinically homogeneous using RevMan software (RevMan 2014). If more than one study provides usable data in any single comparison, we will perform a meta‐analysis. When studies are statistically heterogeneous, we will use a random‐effects model; otherwise we will use a fixed‐effect model. When using the random‐effects model, we will conduct a sensitivity check by using the fixed‐effect model to reveal differences in results. We will include a 95% confidence interval (CI) for all estimates.

We will describe skewed data reported as medians and interquartile ranges.

Where multiple trial arms are reported in a single trial, we will include only the relevant arms. If two comparisons are combined in the same meta‐analysis, we will halve the control group to avoid double‐counting.

Subgroup analysis and investigation of heterogeneity

We expect the following characteristics to introduce clinical heterogeneity. We plan to carry out the following subgroup analyses for the outcomes with a sufficient number of studies available.

1. Type of intervention.

2. Type of exposure.

3. Type of rhinitis (allergic or non‐allergic).

4. Type of workplace environment (indoor or outdoor).

5. Time point of measurement: 7 days to 6 months (short term), 7 to 12 months (medium term) and more than 12 months (long term).

We will use the test of subgroup differences to assess the effects of the intervention across different subgroups depending on the number of subgroups presented and subgroup interactions in RevMan (RevMan 2014).

Sensitivity analysis

We will perform sensitivity analyses for the primary outcomes and any secondary outcomes with sufficient number of studies included to assess the robustness of our findings by excluding studies with high risks in:

1. selection bias (in either one or both criteria of random sequence generation and allocation concealment, including non‐randomised studies such as CBA); and

2. attrition bias (incomplete outcome data).

Summary of findings table

We will create a 'Summary of findings' table using the following outcomes: severity of symptoms of rhinitis and/or rhinosinusitis, quality of life and work performance. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence as it relates to the studies which contribute data to the meta‐analyses for the prespecified outcomes. We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software (http://gdt.guidelinedevelopment.org). We will justify all decisions to downgrade or upgrade the quality of studies using footnotes, and we will make comments to aid readers' understanding of the review where necessary.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice because such recommendations would be based on more than just the evidence, such as values and available resources. Our implications for research will suggest priorities for future research and outline the remaining uncertainties in the area.

History

Protocol first published: Issue 7, 2015

Date	Event	Description
7 October 2021	New citation required and major changes	Withdrawn

Notes

This protocol for a Cochrane Review has been withdrawn from publication by the Editorial Team due to a lack of progress. The editorial group responsible for this previously published document have withdrawn it from publication.

Appendices

Appendix 1. MEDLINE Search Strategy (PubMed)

1	Search rhinitis[Title/Abstract]
2	Search rhinitis[MeSH Terms]
3	Search rhinosinusitis[Title/Abstract]
4	Search sinusitides[MeSH Terms]
5	Search (#1 OR #2 OR #3 OR #4)
6	Search work[Title/Abstract]
7	Search workplace[Title/Abstract]
8	Search work‐related[Title/Abstract]
9	Search workplace[MeSH Terms]
10	Search environment*[Title/Abstract]
11	Search environment[MeSH Terms]
12	Search employment[Title/Abstract]
13	Search employment[MeSH Terms]
14	Search occupation*[Title/Abstract]
15	Search air pollutants, occupational[MeSH Terms]
16	Search disease, occupational[MeSH Terms]
17	Search exposure, occupational[MeSH Terms]
18	Search (#6 OR #7 OR #8 OR #9 OR #10 Or #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17
19	Search (#5 AND #18)
20	Search randomized controlled trial [pt]
21	Search controlled clinical trial [pt]
22	Search randomized [tiab]
23	Search placebo [tiab]
24	Search clinical trials as topic [mesh: noexp]
25	Search randomly [tiab]
26	Search trial [ti]
27	Search (#20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26)
28	Search (animals [mh] NOT humans [mh])
29	Search (#27 NOT #28)
30	Search (#19 AND #29)

Contributions of authors

Conceiving the protocol: ZAM & SKB

Designing the protocol: NAM, MYA, MA, LA, IH & TJH

Coordinating the protocol: ZAM, SKB & NSIAT

Designing search strategies: ZAM, SKB, NSIAT, NM, NAM, MYA, MA & SM in collaboration with Cochrane Work Group Trials Search Co‐ordinator Kaisa Neuvonen

Writing the protocol: ZAM, SKB, NSIAT, NM, NAM, MYA, MA, LA, IH, MFB, SM & TJH

Providing general advice on the protocol: LA, IH, MFB, SM & TJH

Sources of support

Internal sources

• Institute for Medical Research, Ministry of Health, Malaysia

  Training for preparing Cochrane protocols and reviews for all authors in the Ministry of Health, Malaysia

External sources

• No sources of support provided

Declarations of interest

Zuraifah Asrah Mohamad: None known

Sophia K Bakon: None known

Masita Arip: None known

Nor Asiah Muhamad: None known

Nur Syimah Izzah Abdullah Thani: None known

Mohd Yusoff Adon: None known

Iskandar Hailani: None known

Liisa Airaksinen: None known

Shahnaz Murad: None known

Mohamed Faizal Bakhtiar: None known

Timo J Hannu: Dr Timo Hannu owns 150 shares (share class B) of Orion Corporation, a European pharmaceuticals and diagnostics company. In 2011, he received an honorarium of GBP 200 for writing a review entitled "Reactive arthritis", which was published in the journal Best Practice & Research Clinical Rheumatology.

Edited (no change to conclusions)