Colchicine for the treatment of COVID‐19

Agata Mikolajewska; Anna-Lena Fischer; Vanessa Piechotta; Anika Mueller; Maria-Inti Metzendorf; Marie Becker; Elena Dorando; Rafael L Pacheco; Ana Luiza C Martimbianco; Rachel Riera; Nicole Skoetz; Miriam Stegemann

doi:10.1002/14651858.CD015045

. 2021 Oct 18;2021(10):CD015045. doi: 10.1002/14651858.CD015045

Colchicine for the treatment of COVID‐19

Agata Mikolajewska ¹, Anna-Lena Fischer ², Vanessa Piechotta ³, Anika Mueller ⁴, Maria-Inti Metzendorf ⁵, Marie Becker ⁶, Elena Dorando ³, Rafael L Pacheco ^7,^8,⁹, Ana Luiza C Martimbianco ^7,^9,^10,¹¹, Rachel Riera ^9,^11,¹², Nicole Skoetz ^13,^✉, Miriam Stegemann ¹

Editor: Cochrane Haematology Group

¹Department of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

²Department of Anaesthesia and Intensive care, Universitätsklinikum Leipzig, 04103 Leipzig, Germany

³Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

⁴Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

⁵Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany

⁶Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

⁷Center of Health Technology Assessment, Hospital Sírio-Libanês, São Paulo, Brazil

⁸Núcleo de Ensino e Pesquisa em Saúde Baseada em Evidências e Avaliação Tecnológica em Saúde (NEP-Sbeats), Universidade Federal de São Paulo, São Paulo, Brazil

⁹Cochrane Affiliate Rio de Janeiro, Cochrane, Petrópolis, Brazil

¹⁰Postgraduate Program in Health and Environment, Universidade Metropolitana de Santos (UNIMES), Santos, Brazil

¹¹Núcleo de Ensino e Pesquisa em Saúde Baseada em Evidências e Avaliação de Tecnologias em Saúde (NEP-Sbeats), Universidade Federal de São Paulo, São Paulo, Brazil

¹²Centre of Health Technology Assessment, Hospital Sírio-Libanês, São Paulo, Brazil

¹³Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany

^✉

Corresponding author.

PMCID: PMC8521385 PMID: 34658014

Abstract

Background

The development of severe coronavirus disease 2019 (COVID‐19) and poor clinical outcomes are associated with hyperinflammation and a complex dysregulation of the immune response. Colchicine is an anti‐inflammatory medicine and is thought to improve disease outcomes in COVID‐19 through a wide range of anti‐inflammatory mechanisms. Patients and healthcare systems need more and better treatment options for COVID‐19 and a thorough understanding of the current body of evidence.

Objectives

To assess the effectiveness and safety of Colchicine as a treatment option for COVID‐19 in comparison to an active comparator, placebo, or standard care alone in any setting, and to maintain the currency of the evidence, using a living systematic review approach.

Search methods

We searched the Cochrane COVID‐19 Study Register (comprising CENTRAL, MEDLINE (PubMed), Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv), Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index), and WHO COVID‐19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 21 May 2021.

Selection criteria

We included randomised controlled trials evaluating colchicine for the treatment of people with COVID‐19, irrespective of disease severity, age, sex, or ethnicity.

We excluded studies investigating the prophylactic effects of colchicine for people without severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection but at high risk of SARS‐CoV‐2 exposure.

Data collection and analysis

We followed standard Cochrane methodology. We used the Cochrane risk of bias tool (ROB 2) to assess bias in included studies and GRADE to rate the certainty of evidence for the following prioritised outcome categories considering people with moderate or severe COVID‐19: all‐cause mortality, worsening and improvement of clinical status, quality of life, adverse events, and serious adverse events and for people with asymptomatic infection or mild disease: all‐cause mortality, admission to hospital or death, symptom resolution, duration to symptom resolution, quality of life, adverse events, serious adverse events.

Main results

We included three RCTs with 11,525 hospitalised participants (8002 male) and one RCT with 4488 (2067 male) non‐hospitalised participants. Mean age of people treated in hospital was about 64 years, and was 55 years in the study with non‐hospitalised participants. Further, we identified 17 ongoing studies and 11 studies completed or terminated, but without published results.

Colchicine plus standard care versus standard care (plus/minus placebo)

Treatment of hospitalised people with moderate to severe COVID‐19

All‐cause mortality: colchicine plus standard care probably results in little to no difference in all‐cause mortality up to 28 days compared to standard care alone (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.93 to 1.08; 2 RCTs, 11,445 participants; moderate‐certainty evidence).

Worsening of clinical status: colchicine plus standard care probably results in little to no difference in worsening of clinical status assessed as new need for invasive mechanical ventilation or death compared to standard care alone (RR 1.02, 95% CI 0.96 to 1.09; 2 RCTs, 10,916 participants; moderate‐certainty evidence).

Improvement of clinical status: colchicine plus standard care probably results in little to no difference in improvement of clinical status, assessed as number of participants discharged alive up to day 28 without clinical deterioration or death compared to standard care alone (RR 0.99, 95% CI 0.96 to 1.01; 1 RCT, 11,340 participants; moderate‐certainty evidence).

Quality of life, including fatigue and neurological status: we identified no studies reporting this outcome.

Adverse events: the evidence is very uncertain about the effect of colchicine on adverse events compared to placebo (RR 1.00, 95% CI 0.56 to 1.78; 1 RCT, 72 participants; very low‐certainty evidence).

Serious adverse events: the evidence is very uncertain about the effect of colchicine plus standard care on serious adverse events compared to standard care alone (0 events observed in 1 RCT of 105 participants; very low‐certainty evidence).

Treatment of non‐hospitalised people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19

All‐cause mortality: the evidence is uncertain about the effect of colchicine on all‐cause mortality at 28 days (Peto odds ratio (OR) 0.57, 95% CI 0.20 to 1.62; 1 RCT, 4488 participants; low‐certainty evidence).

Admission to hospital or death within 28 days: colchicine probably slightly reduces the need for hospitalisation or death within 28 days compared to placebo (RR 0.80, 95% CI 0.62 to 1.03; 1 RCT, 4488 participants; moderate‐certainty evidence).

Symptom resolution: we identified no studies reporting this outcome.

Quality of life, including fatigue and neurological status: we identified no studies reporting this outcome.

Adverse events: the evidence is uncertain about the effect of colchicine on adverse events compared to placebo . Results are from one RCT reporting treatment‐related events only in 4412 participants (low‐certainty evidence).

Serious adverse events: colchicine probably slightly reduces serious adverse events (RR 0.78, 95% CI 0.61 to 1.00; 1 RCT, 4412 participants; moderate‐certainty evidence).

Colchicine versus another active treatment (e.g. corticosteroids, anti‐viral drugs, monoclonal antibodies)

No studies evaluated this comparison.

Different formulations, doses, or schedules of colchicine

No studies assessed this.

Authors' conclusions

Based on the current evidence, in people hospitalised with moderate to severe COVID‐19 the use of colchicine probably has little to no influence on mortality or clinical progression in comparison to placebo or standard care alone. We do not know whether colchicine increases the risk of (serious) adverse events.

We are uncertain about the evidence of the effect of colchicine on all‐cause mortality for people with asymptomatic infection or mild disease. However, colchicine probably results in a slight reduction of hospital admissions or deaths within 28 days, and the rate of serious adverse events compared with placebo.

None of the studies reported data on quality of life or compared the benefits and harms of colchicine versus other drugs, or different dosages of colchicine.

We identified 17 ongoing and 11 completed but not published RCTs, which we expect to incorporate in future versions of this review as their results become available.

Editorial note: due to the living approach of this work, we monitor newly published results of RCTs on colchicine on a weekly basis and will update the review when the evidence or our certainty in the evidence changes.

Plain language summary

Is colchicine an effective treatment for people with COVID‐19?

Key messages

○ In hospitalised people with moderate to severe COVID‐19, colchicine probably has little to no benefit; we are uncertain about its side effects.

○In non‐hospitalised people with no symptoms or mild COVID‐19, we are uncertain whether colchicine prevents deaths or side effects, however it probably reduces the need for hospitalisation or death and serious side effects slightly.

○ Future studies should assess quality of life in people with no symptoms or mild COVID‐19 and non‐serious side effects and compare colchicine to other medicines for COVID‐19, such as corticosteroids.

What is colchicine?

Colchicine is a medicine used to reduce swelling and inflammation and may consequently relieve pain. It is often used to treat gout, a condition where people’s joints become swollen and painful. On the other hand, colchicine can be harmful to people with some health conditions, such as kidney or liver problems, or if you take too much of it.

How might colchicine treat COVID‐19?

Since colchicine is an anti‐inflammatory drug; researchers are interested in whether it might help with reducing inflammation caused by COVID‐19.

What did we want to find out?

We wanted to know whether colchicine is an effective treatment for people with COVID‐19 compared to placebo (a treatment that looks and tastes the same as colchicine but with no active ingredient) or usual care alone. We looked at people with moderate or severe disease being treated in hospital or with mild disease being treated in the community. We were particularly interested in the effects of colchicine on:

○ number of deaths;

○ whether people’s condition worsened or improved;

○ quality of life;

○ serious and non‐serious side effects

What did we do?

We searched for studies that compared colchicine together with usual care to usual care (plus/minus placebo). Studies could take place anywhere in the world and include people with mild or no symptoms, moderate or severe COVID‐19, of any age, sex, or ethnicity.

We compared and summarised the results of the studies and rated our certainty in the evidence, based on factors such as study methods and sizes.

What did we find?

We identified four eligible randomised trials. Three included 11,525 hospitalised people and one included 4488 non‐hospitalised people. For hospitalised people, the average age was 64 years, and for non‐hospitalised people, the average age was 55 years. Two studies compared colchicine and usual care with usual care alone and 2 studies compared colchicine with usual care and placebo. None of the studies reported quality of life. We also found 17 ongoing studies and 11 completed but unpublished studies.

Main results

Hospitalised people with moderate to severe COVID‐19 (3 studies, 11,525 people)

○Colchicine probably does not reduce deaths in the 28 days after treatment (2 studies, 11,445 people).

○Colchicine probably does not prevent the worsening of patients’ condition (2 studies, 10,916 people) and probably does not improve it (1 study, 11,340 people).

○We are very uncertain about the effect of colchicine on side effects and serious side effects (2 studies, 177 people).

Non‐hospitalised people with no symptoms or mild COVID‐19 (1 study, 4488 people)

○We are uncertain whether colchicine prevents deaths up to 28 days after treatment.

○Colchicine probably slightly reduces the risk of hospitalisation or death.

○We are uncertain about the effect of colchicine on side effects, but it probably slightly reduces serious side effects.

What are the limitations of the evidence?

Our certainty in the evidence is limited. Two studies did not use a placebo, so everybody knew who was treated with colchicine, which could influence the results. There were too few events for non‐hospitalised people, such as admissions to hospital and deaths, to be certain about the evidence. Studies used different ways to assess and report unwanted effects, so we could not combine studies into a single result to make a judgement.

How up to date is this evidence?

The evidence is up to date to 21 May 2021.

Editorial note: this is a living systematic review. We search for new evidence every week and update the review when we identify relevant new evidence. Refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Summary of findings

Summary of findings 1. Colchicine plus standard care compared to standard care (plus/minus placebo) for hospitalised patients with COVID‐19 and moderate to severe disease.

Colchicine plus standard care compared to standard care (plus/minus placebo) for hospitalised patients with COVID‐19 and moderate to severe disease
Patient or population: people with COVID‐19 and moderate to severe disease Settings: hospitalised Intervention: colchicine plus standard care Comparator: standard care (plus/minus placebo)
Outcomes	*Absolute effects from study(ies) (95% CI)**			No of participants (studies)	Certainty of the evidence (GRADE)	Plain language summary	Comments
Outcomes	Risk with placebo or standard care alone	Risk with colchicine	Relative risk [risk difference; 95% CI]	No of participants (studies)	Certainty of the evidence (GRADE)	Plain language summary	Comments
All‐cause mortality assessed up to day 28	207 per 1000	207 per 1000 (193 to 224)	RR 1.00 (95% CI 0.93 to 1.08)^a [0 more per 1000; 14 fewer to 17 more]	11,445 (2 studies)	⊕⊕⊕⊖ Moderate^b	Colchicine probably results in little to no difference in all‐cause mortality up to 28 days.	Additionally, one study reported all‐cause mortality at hospital discharge for 75 participants (Lopes 2021). One study analysed also reported all‐cause mortality over time (time‐to‐event) for 11,340 participants (Horby 2021), which similarly showed little to no effect on mortality (HR 1.01, 95% CI 0.93 to 1.10).
Worsening of clinical status: participants with clinical deterioration, defined as new need for invasive mechanical ventilation or death up to day 28	244 per 1000	249 per 1000 (234 to 266)	RR 1.02 (95% CI 0.96 to 1.09)^c [4 more per 1000, 95% CI 10 fewer to 22 more]	10916 (2 studies)	⊕⊕⊕⊖ Moderate^b	Colchicine probably has little to no impact on new need for invasive mechanical ventilation or death.	—
Improvement of clinical status: participants discharged alive up to day 28 without clinical deterioration or death	704 of 1000	697 of 1000 (676 to 711)	RR 0.99 (95% CI 0.96 to 1.01) [7 fewer per 1000, 95% CI 28 fewer to 7 more]	11,340 (1 study)	⊕⊕⊕⊖ Moderate^b	Colchicine probably results in little to no difference in improvement of clinical status, if this is measured with the number of participants discharged alive up to day 28 without clinical deterioration or death.	One study reported participants discharged alive at the longest follow‐up and followed all participants until discharge (Lopes 2021) which similarly showed that colchicine may result in little to no difference in the improvement of clinical status assessed as participants discharged alive (RR 1.09, 95% CI 0.98 to 1.21)
Quality of life, including fatigue and neurological status at longest follow‐up available	We identified no studies reporting quality of life.			—	—	We do not know whether colchicine has any impact on quality of life.	—
Adverse events (follow‐up: until discharge)	389 per 1000	389 per 1000 (218 to 692)	RR 1.00 (95% CI 0.56 to 1.78) [0 fewer per 1000, 95% CI 171 fewer to 303 more]	72 (1 study)	⊕⊖⊖⊖ Very low^d,e,f	The evidence is very uncertain about the effect of colchicine on adverse events	—
Serious adverse events (follow‐up: until hospital discharge or a maximum of 21 days)	0 events observed	0 events observed	Not estimable	105 (1 study)	⊕⊖⊖⊖ Very low^e,g,h	The evidence is very uncertain about the effect of colchicine on adverse events	—
The basis for the control group absolute risks* from the study(ies) is mean risk across study(ies) unless otherwise stated in comments. The intervention absolute risk and difference is based on the risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; COVID‐19: coronavirus disease 2019; HR: hazard ratio; RR: risk ratio. GRADE Working User Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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 quality: we are very uncertain about the estimate.

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^aSensitivity analysis results presented using a fixed‐effect model. This was because the random‐effects model meta‐analysis resulted in very wide confidence intervals (RR 0.72, 95% CI 0.21 to 2.44), due to more weight being given to one small study with few events (Deftereos 2020), and contributing only 105/11,445 participants included in the mortality analysis. ^bDowngraded one level for serious study limitations due to the unblinded study design. ^cSensitivity analysis results presented using a fixed‐effect model. This was because the random‐effects model meta‐analysis resulted in very wide confidence intervals (RR 0.53, 95% CI 0.09 to 3.15), due to more weight being given to one small study with few events (Deftereos 2020), and contributing only 105/10,916 participants included in the analysis of the worsening of clinical status. ^dDowngraded two levels for very serious imprecision due to only one study with very small number of participants and events. ^eDowngraded one level for other considerations due to selective reporting of adverse events across studies (e.g. severe treatment‐associated events only). ^fDowngraded one level for serious study limitations due to the high risk of bias because of the competing event 'death.' ^gDowngraded one level for serious study limitations due to the unblinded study design, and high risk of bias because of the competing event 'death.' ^hDowngraded two levels for very serious imprecision due to only one study and no events were observed.

Summary of findings 2. Colchicine compared to placebo or standard care alone for non‐hospitalised patients with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19.

Colchicine compared to placebo or standard care alone for non‐hospitalised patients with SARS‐CoV‐2 infection and asymptomatic or mild disease
Patient or population: people with SARS‐CoV‐2 infection and asymptomatic or mild disease Settings:non‐hospitalised Intervention: colchicine Comparator: placebo or standard care alone
Outcomes	*Absolute effects from study(ies) (95% CI)**			No of participants (studies)	Certainty of the evidence (GRADE)	Plain language summary
Outcomes	Risk with placebo or standard care alone	Risk with colchicine	Relative risk [risk difference; 95% CI]	No of participants (studies)	Certainty of the evidence (GRADE)	Plain language summary
All‐cause mortality up to day 28	4 per 1000	2 per 1000 (0 to 6)	Peto OR 0.57 (95% CI 0.20 to 1.62) [2 fewer per 1000, 95% CI 4 fewer to 2 more]	4488 (1 study)	⊕ ⊕ ⊖ ⊖ Low^a	The evidence is uncertain about the effect of colchicine on all‐cause mortality at 28 days.
Admission to hospital or death within 28 days	58 per 1000	46 per 1000 (36 to 60)	RR 0.80 (95% CI 0.62 to 1.03) [12 fewer per 1000, 95% CI 22 fewer to 2 more]	4488 (1 study)	⊕ ⊕ ⊕ ⊖ Moderate^b	Colchicine probably results in a slight reduction in the risk of admission to hospital or death within 28 days.
Symptom resolution	We identified no studies reporting symptom resolution, defined as all initial symptoms resolved (asymptomatic) at day 14, day 28, or up to longest follow‐up.			—	—	We do not know whether colchicine has any impact on symptom resolution.
Duration to symptom resolution	We identified no studies reporting symptom resolution, defined as all initial symptoms resolved (asymptomatic) at day 14, day 28, or up to longest follow‐up.			—	—	We do not know whether colchicine has any impact on symptom resolution.
Quality of life	We identified no studied reporting quality of life.			—	—	We do not know whether colchicine has any impact on quality of life.
Adverse events within 28 days	We identified no study reporting any adverse events. 1 study (4412 participants) reported treatment‐related adverse events for 532/2195 (24.2%) participants in the colchicine group and 344/2217 (15.5%) participants in the control group.			4412 (1 study)	⊕⊕ ⊖ ⊖ Low^c	The evidence is uncertain about the effect of colchicine on the risk of adverse events.
Serious adverse events within 28 days	63 per 1000	49 per 1000 (38 to 63)	RR 0.78 (95% CI 0.61 to 1.00) [14 fewer per 1000, 95% CI 25 fewer to 0 more]	4412 (1 study)	⊕ ⊕ ⊕ ⊖ Moderate^b	Colchicine probably results in a slight reduction of serious adverse events.
The basis for the control group absolute risks* from the study(ies) is mean risk across study(ies) unless otherwise stated in comments. The intervention absolute risk and difference is based on the risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; COVID‐19: coronavirus disease 2019; OR: odds ratio; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2.
GRADE Working User Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: 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 quality: we are very uncertain about the estimate.

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^aDowngraded two levels for very serious imprecision, because of very few events, and wide confidence intervals. ^bDowngraded one level for imprecision due to data from only one study. ^cDowngraded two levels for serious indirectness, because definition of outcome differed substantially from definition used in our review (treatment‐related adverse events instead of any adverse events).

Background

This work is part of a series of Cochrane Reviews investigating treatments and therapies for coronavirus disease 2019 (COVID‐19). Reviews in this series share information in the background section and methodology based on the first published reviews about monoclonal antibodies (Kreuzberger 2021) and convalescent plasma (Piechotta 2021).

Description of the condition

COVID‐19 is a rapidly spreading infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2; WHO 2020a). Declared a pandemic on 11 March 2020 by the World Health Organization (WHO), the COVID‐19 outbreak is unprecedented in comparison to previous coronavirus outbreaks, such as severe acute respiratory syndrome (SARS) with 813 deaths and Middle East respiratory syndrome (MERS) with 858 deaths (WHO 2007; WHO 2019). Despite intensive international efforts to contain its spread, COVID‐19 has resulted in more than 184 million confirmed cases and almost four million deaths worldwide as of July 2021 (WHO 2021a). At the same time, the emergence of variants of SARS‐CoV‐2, with potential for altered transmission or disease characteristics and vaccine and therapeutics effectiveness could impact established and proven disease control methods and the epidemiological situation.

Vaccination is highly effective at reducing severe illness and death from COVID‐19 (WHO 2021a). However, most vaccines have been administered in a few high‐income countries. The majority of the world's population still remains susceptible to SARS‐CoV‐2 infection and at risk of developing COVID‐19. Besides unequal access to vaccines, it is still not well‐defined how long the effect of protection against an infection or transmission (or both) will last, or how well vaccinated people will be protected (WHO 2021b).

Specific risk factors for severe disease, hospitalisation, and mortality have been identified: older age, certain underlying medical conditions, and pregnancy can increase the risk for severe disease (Huang 2020; Liang 2020; WHO 2020a; Williamson 2020).

The median incubation time is estimated to be between five and six days, and 97.5% of symptomatic cases develop symptoms within 11.5 days of exposure (Lauer 2020). Sore throat, cough, fever, headache, fatigue, and myalgia or arthralgia are the most commonly reported symptoms (Struyf 2020). Other symptoms include shortness of breath, chills, nausea or vomiting, diarrhoea, nasal congestion, haemoptysis, and conjunctival congestion (WHO 2020a). Most infected people remain completely asymptomatic or develop mild symptoms, and do not require admission to hospital (approximately 80% to 90%, Chen 2020; Funk 2021; Wu 2020). However, the reported frequency of asymptomatic infections varies greatly, depending on the time of the investigation, the cohort investigated, and the virus variant, and ranges between 6% and even up to 96% (Buitrago‐Garcia 2020; Funk 2021;Oran 2020).

A smaller proportion of people is affected by severe (approximately 11% to 20%) or critical (approximately 1% to 5%) disease with hospitalisation and intensive care unit (ICU) admission due to respiratory failure, septic shock, or multiple organ dysfunction syndrome (Funk 2021; Wu 2020). In one case series from 12 New York hospitals, 14% of patients hospitalised due to COVID‐19 were treated in the ICU (Richardson 2020). In one observational study of 10,021 hospitalised adults with a confirmed COVID‐19 diagnosis in Germany, 17% received mechanical ventilation. Mortality in patients without mechanical ventilation was 16% and up to 53% in ventilated patients. Mortality in patients who received mechanical ventilation and dialysis was 73% (Karagiannidis 2020). In one systematic review and meta‐analysis of international studies, the proportion of patients who died among those treated in ICU was estimated to be 34% and for those who received invasive mechanical ventilation it was 83% (Potere 2020). There may have been different thresholds for admission to hospital or ICU during the course of the pandemic. Depending on the local pressure on ICU resources, some normal wards will have learned to provide continuous positive airway pressure (CPAP) therapy equivalent to ICU support in other healthcare systems. It is unclear whether triage criteria in some healthcare systems may have influenced admission to hospital or ICU (or both).

Due to the extent of the COVID‐19 pandemic with its pressure on health systems, especially in the face of evolving virus variants with potential increased transmissibility and altered disease characteristics, the ongoing scarcity of effective treatments, and the low global vaccination coverage, there is an urgent need for effective and safe therapies to save lives and to reduce the burden on healthcare systems.

Description of the intervention

Colchicine is a lipid‐soluble alkaloid, earlier identified in Colchicum autumnale and originally used as anti‐cancer drug and a treatment for gout. By inhibiting microtubule polymerisation, it impairs cell division and migration, and interferes with cellular trafficking (Angelidis 2018). However, aside from interfering with cytoskeleton‐dependent cellular functions, colchicine also interferes with other molecular pathways related to inflammation (Martínez 2018).

The drug has been used for treating inflammatory diseases such as gout (van Echteld 2014), idiopathic recurrent pericarditis (Alabed 2014), coronary disease, and familial Mediterranean fever as it suppresses neutrophil activity, including endothelium adhesion, the release of chemotaxis factors, the neutrophil‐platelet interaction, and aggregation, which compounds the anti‐inflammatory properties of colchicine (Leung 2015; Nuki 2008).

Colchicine is deemed a safe drug in therapeutic doses (Imazio 2007), but has a restricted dosage range of 4 mg to 7 mg per 24 hours (Finkelstein 2010). Overdose is associated with an increased risk of gastrointestinal, renal, neuromuscular, hepatic, and cerebral toxicity, and bone marrow damage (Finkelstein 2010; Nuki 2008). A single dose of 15 mg to 20 mg can be fatal. Therefore, this drug should be used with caution.

It is worth mentioning that colchicine is a generic medication that is widely available at relatively low costs, also in low‐resource settings.

How the intervention might work

Some researchers have suggested that colchicine could be effective against COVID‐19 by mitigating or preventing inflammation‐associated manifestations of the disease. Severe acute respiratory syndrome coronavirus 1 (SARS‐CoV‐1), which is closely related to SARS‐CoV‐2, has been shown to activate the NLRP3 inflammasome (Nieto‐Torres 2015).

Several anti‐inflammatory therapies have been proposed to target inflammasome activity and reduce the risk of complications. In one experimental model of acute respiratory distress syndrome, colchicine reduced inflammatory lung injury and respiratory failure by interfering with leukocyte activation and recruitment (Dupuis 2020).

Due to its broad spectrum of anti‐inflammatory activities, colchicine may have the capability to modify the pathogenic mechanisms implicated in COVID‐19 by:

interfering with the chemotaxis of neutrophils and monocytes, inflammatory cells that have been observed in the lungs of people with severe COVID‐19 (Reyes 2021);
disrupting NLRP3 inflammasome activation (Misawa 2013) – a process trigged by viroporin E, a SARS‐CoV‐2 component (Castaño‐Rodriguez 2018);
by suppressing the release of interleukin (IL)‐1β and IL‐18 (Martínez 2018; Toldo 2018), cytokines associated with COVID‐19 severity (Conti 2020).

Treating people with COVID‐19 early in the course of the disease and preventing or reducing systemic inflammation is crucial to avoid tissue damage caused by a dysregulated immune response and high levels of inflammatory cytokines (Della‐Torre 2020). Therefore, the anti‐inflammatory mechanisms of colchicine offer a plausible mechanism of action to reduce inflammation and associated immunopathologies observed in people with COVID‐19.

Why it is important to do this review

The continuously increasing numbers of COVID‐19 cases and associated deaths worldwide and the enduring scarcity of effective treatment options has a substantial impact on healthcare systems. Vaccination is beginning to have a substantial impact on case numbers and mortality in different countries, but most of the global population remains vulnerable to infection and there is an urgent need for effective treatments for COVID‐19. Numerous ongoing trials are investigating pharmacological treatment options, but up to May 2021, only a few options have reliably demonstrated clinical effectiveness for COVID‐19 or a benefit for individual patients or healthcare systems. Completed primary studies of colchicine for hospitalised and non‐hospitalised participants with COVID‐19 suggest that it may be a useful therapeutic for improving clinical symptoms without increasing the risk of adverse events at specific doses when compared to supportive care (Deftereos 2020; Della‐Torre 2020; McCullough 2021).

Objectives

To assess whether colchicine is an effective and safe treatment option for COVID‐19 in comparison to an active comparator, placebo, or standard care alone in any setting, and to maintain the currency of the evidence, using a living systematic review approach.

Methods

Criteria for considering studies for this review

Types of studies

The main description of methods is based on the standard template of the Cochrane Haematology review group and is in line with a series of Cochrane Reviews investigating treatments and therapies for COVID‐19. Specific adaptions related to the research question were made if necessary. The protocol for this review was registered with PROSPERO on 19 February 2021 (Mikolajewska 2021a).

To assess the effectiveness and safety of colchicine for the treatment of COVID‐19, we included randomised controlled trials (RCTs), as this study design, if performed appropriately, provides the best evidence for experimental therapies in highly controlled therapeutic settings. We used the methods recommended in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2021a). We had planned to also accept cross‐over RCT designs, but we would have only considered results from the first period before cross‐over because COVID‐19 is not a chronic condition and its exact course and long‐term effects are yet to be defined (Higgins 2021b). We excluded cluster‐randomised trials.

We excluded controlled non‐randomised studies of intervention and observational studies. We also excluded animal studies, pharmacokinetic studies, and in vitro studies.

We included the following formats, if there was sufficient information available on study design, characteristics of participants, interventions, and outcomes.

Full‐text publications.
Preprint versions.
Abstract publications.
Results published in trials registries.

We included preprints and conference abstracts to have a complete overview of the ongoing research activity, especially for tracking newly emerging studies about colchicine in the treatment of COVID‐19. We applied no limitations with respect to the length of follow‐up.

Types of participants

We included adults with a confirmed or suspected diagnosis of COVID‐19 (as described in the study) and we did not exclude any studies based on sex, ethnicity, disease severity, or setting.

We excluded studies that evaluated colchicine for the treatment of other coronavirus diseases such as SARS or MERS, or other viral diseases, such as influenza. If studies enrolled populations with or exposed to mixed viral diseases, we had planned to only include these if trial authors provided subgroup data for SARS‐CoV‐2 infection. We excluded studies investigating the prophylactic effects of colchicine for people who did not have SARS‐CoV‐2 but were at high risk of developing the infection (e.g. high‐risk exposure) or at high risk of fatal disease (e.g. high‐risk populations).

Types of interventions

We included the following comparison:

colchicine plus standard care versus standard care (plus/minus placebo).

In addition, we had planned to include the following comparisons, but identified no studies:

colchicine versus another active treatment (e.g. corticosteroids, anti‐viral drugs, monoclonal antibodies);
different formulations, doses, or schedules of colchicine.

We considered any co‐intervention, including supportive care, anticoagulants, anti‐viral drugs, and corticosteroids, for example, but co‐interventions should have been comparable between intervention groups.

We excluded the following comparison:

colchicine in combination with another active treatment (e.g. corticosteroids) versus other active treatments (e.g. monoclonal antibodies).

Types of outcome measures

We evaluated core outcomes based on the Core Outcome Measures in Effectiveness Trials (COMET) Initiative for people with COVID‐19 (COMET 2021), and additional outcomes that have been prioritised by consumer representatives and the German guideline panel for hospitalised and non‐hospitalised therapy of people with COVID‐19.

We defined outcome sets for two populations: hospitalised people with a confirmed diagnosis of COVID‐19 and moderate to severe disease, and non‐hospitalised managed people with a confirmed diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease, according to WHO clinical progression scale (WHO 2020b). We separated outcomes into primary outcomes, the ones included in the summary of findings tables, and deemed most relevant for patients, and additional (i.e. secondary) outcomes.

Timing of outcome measurement

In case of time‐to‐event analysis (e.g. for all‐cause mortality, time to discharge from hospital), we included the outcome measure based on the longest follow‐up time. We also collected information on outcomes from all other time points reported in the publications.

We included adverse events occurring during active treatment and included long‐term adverse events. If sufficient data were available, we grouped the measurement time points of eligible outcomes, for example, adverse events and serious adverse events, into those measured directly after treatment (up to seven days after treatment), medium‐term outcomes (up to 15 days after treatment), and longer‐term outcomes (more than 30 days after treatment).

Hospitalised people with moderate to severe COVID‐19

All‐cause mortality up to day 28, day 60, time‐to‐event, and at hospital discharge.
Clinical status up to day 28, day 60, and up to the longest follow‐up, including:
- worsening of clinical status (i.e. participants with clinical deterioration), defined as new need for invasive mechanical ventilation or death;
- improvement of clinical status (i.e. participants discharged alive). Participants should have been discharged without clinical deterioration or death.
Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) up to seven days; up to 28 days, and longest follow‐up available.
Adverse events (any grade) during the study period, defined as number of participants with any event.
Serious adverse events during the study period, defined as number of participants with any event.

Non‐hospitalised people with SARS‐CoV‐2 infection and asymptomatic or mild disease

All‐cause mortality up to day 28, day 60, time‐to‐event, and up to the longest follow‐up.
Admission to hospital or death within 28 days.
Symptom resolution (i.e. all initial symptoms resolved (asymptomatic)) at day 14, day 28, and up to the longest follow‐up.
Duration to symptom resolution.
Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) up to seven days, up to 28 days, and longest follow‐up available.
Adverse events (any grade) during the study period, defined as number of participants with any event.
Serious adverse events during the study period, defined as number of participants with any event.

Hospitalised people with moderate to severe COVID‐19

Clinical status up to day 28, day 60, and up to the longest follow‐up, including:
- worsening of clinical status:
  - new need for invasive mechanical ventilation;
  - new need for non‐invasive mechanical ventilation or high flow;
  - new need for oxygen by mask or nasal prongs;
- improvement of clinical status:
  - weaned or liberated from invasive mechanical ventilation, and surviving, in subgroup of participants requiring invasive mechanical ventilation at baseline;
  - ventilator‐free days;
  - duration to liberation from invasive mechanical ventilation;
  - liberation from supplemental oxygen in surviving patients, including the liberation from invasive mechanical ventilation;
  - duration to liberation from supplemental oxygen.
Need for new dialysis up to 28 days.
Admission to ICU up to day 28.
Duration of hospitalisation.
Viral clearance, assessed with reverse transcription‐polymerase chain reaction (RT‐PCR) test for SARS‐CoV‐2 at baseline, up to three, seven, and 14 days.
Incidence of abdominal pain during the study period, defined as number of participants with any event.
Incidence of diarrhoea during the study period, defined as number of participants with any event.
Incidence of nausea and vomiting during the study period, defined as number of participants with any event.

Non‐hospitalised people with SARS‐CoV‐2 infection and asymptomatic or mild disease

Clinical status up to day 28 and up to the longest follow‐up;
- worsening of clinical status (moderate to severe COVID‐19 symptoms):
  - need for invasive mechanical ventilation;
  - need for non‐invasive mechanical ventilation or high flow;
  - need for hospitalisation with need for oxygen by mask or nasal prongs;
  - need for hospitalisation without oxygen therapy.
Viral clearance, assessed with RT‐PCR for SARS‐CoV‐2 at baseline, up to three, seven, and 14 days.
Incidence of abdominal pain during the study period, defined as number of participants with any event.
Incidence of diarrhoea during the study period, defined as number of participants with any event.
Incidence of nausea and vomiting during the study period, defined as number of participants with any event.

Search methods for identification of studies

Electronic searches

Our Information Specialist (MIM) conducted systematic searches of the following sources from the inception of each database to 21 May 2021 (date of last search for all databases) placing no restrictions on the language of publication.

Cochrane COVID‐19 Study Register (CCSR) (www.covid‐19.cochrane.org), comprising:
- Cochrane Central Register of Controlled Trials (CENTRAL), monthly updates;
- MEDLINE (PubMed), daily updates;
- Embase, weekly updates;
- ClinicalTrials.gov (www.clinicaltrials.gov), daily updates;
- WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/trialsearch), weekly updates;
- medRxiv (www.medrxiv.org), weekly updates.
Web of Science Core Collection.
- Science Citation Index Expanded (from 1945);
- Emerging Sources Citation Index (from 2015).
WHO COVID‐19 Global literature on coronavirus disease (search.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/).

For detailed search strategies, see Appendix 1.

We did not conduct separate searches of the databases required by the MECIR standards (Higgins 2021c), since these databases are already regularly searched for the production of the CCSR.

We additionally searched the CCSR for platform trials to identify prospectively registered platform trials that may add a colchicine arm during the course of the study (Appendix 2). We listed them in the section 'studies awaiting classification' and regularly checked whether they had added additional treatment arms that included relevant data.

Living systematic review considerations

We will use the CCSR to monitor newly published results of RCTs on colchicine on a weekly basis.

Searching other resources

We identified other potentially eligible studies or ancillary publications by searching the reference lists of included studies, relevant systematic reviews, and meta‐analyses. In addition, we cross‐checked the National Institute for Health and Care Excellence (NICE) guidelines for included studies (NICE 2021).

Once we established our set of included studies, we searched for preprints via Europe PMC (europepmc.org/), to check if any preprints for ongoing studies were published since our database search. We also compared our identified studies with results from projects that aimed to track COVID‐19 intervention research (i.e.www.covid-trials.organd covid-nma.com/dataviz).

Living systematic review considerations

The signal for updating this review will stem from the weekly monitoring of the published relevant RCTs via the CCSR, as described under Electronic searches. Once the decision to update the review has been made, the methods mentioned in this section will be incorporated in the review update.

Data collection and analysis

Selection of studies

Two review authors (NS, VP) independently screened the results of the search strategies for eligibility for this review by reading the abstracts using EndNote software (EndNote X9). We coded the abstracts as either 'include' or 'exclude.' In the case of disagreement or if it was unclear whether we should retrieve the abstract or not, we obtained the full‐text publication for further discussion. Two review authors (NS, VP) assessed the full‐text articles of selected studies. If the two review authors were unable to reach a consensus, they consulted a third review author (AM, ALF, or MS) to reach a final decision.

We documented the study selection process in a flow chart, as recommended in the PRISMA statement (Moher 2009), and showed the total numbers of retrieved references and the numbers of included and excluded studies. We listed all studies that we excluded after full‐text assessment and the reasons for their exclusion in the Characteristics of excluded studies table.

Living systematic review considerations

Two review authors will screen records derived from CCSR weekly to identify new studies.

Data extraction and management

We conducted data extraction according to the guidelines proposed by Cochrane (Li 2021). Two out of three review authors (AM, ALF, VP) extracted data of eligible studies independently and in duplicate, using a customised data extraction form developed in Microsoft Excel (Microsoft 2018). We resolved disagreements by discussion. If there was no agreement, a third review author resolved the disagreement.

If study results were uploaded into trials registries and not yet been published elsewhere, we integrated these data for the current review and will add or replace data in future updates of this review in case of publication.

We extracted the following information if reported.

General information: author, title, source, publication date, country, language, duplicate publications.
Study characteristics: trial design, setting and dates, source of participants, inclusion/exclusion criteria, comparability of groups, treatment cross‐overs, compliance with assigned treatment, length of follow‐up.
Participant characteristics: age, sex, ethnicity, number of participants recruited/allocated/evaluated, additional diagnoses, severity of disease, previous treatments, concurrent treatments and standard care, complementary medicine (e.g. quercetin, elderberry, zinc).
Interventions: dose, frequency, timing, duration and route of administration, setting (e.g. hospitalised, non‐hospitalised), duration of follow‐up.
Control intervention: placebo, no treatment; dose, frequency, timing, duration and route of administration, setting, duration of follow‐up.
Outcomes: as specified under Types of outcome measures.

Living systematic review considerations

Two review authors will extract, evaluate, and integrate studies identified through the weekly searches following the guidance for Cochrane living systematic reviews (Cochrane LSR).

Assessment of risk of bias in included studies

We used Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021d), and the Risk of Bias 2.0 (RoB 2) tool to analyse the risk of bias of study results (Sterne 2019). Of interest for this review is the effect of the assignment to the intervention (the intention‐to‐treat (ITT) effect), thus, we performed all assessments with RoB 2 on this effect. The outcomes that we assessed are those specified for inclusion in the summary of findings tables.

Two of four review authors (AM, ALF, VP, ED) independently assessed the risk of bias for each outcome. In case of discrepancies among their judgements and inability to reach consensus, we consulted another review author (NS) to reach a final decision. We assessed the following types of bias as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021d).

Bias arising from the randomisation process.
Bias due to deviations from the intended interventions.
Bias due to missing outcome data.
Bias in measurement of the outcome.
Bias in selection of the reported result.

To address these types of bias, we used the signalling questions recommended in RoB 2 and made a judgement using the following options.

'Yes': if there is firm evidence that the question was fulfilled in the study (i.e. the study was at low or high risk of bias for the given the direction of the question).
'Probably yes': a judgement was made that the question was fulfilled in the study (i.e. the study was at low or high risk of bias given the direction of the question).
'No': if there was firm evidence that the question was unfilled in the study (i.e. the study was at low or high risk of bias for the given the direction of the question).
'Probably no': a judgement was made that the question was unfilled in the study (i.e. the study was at low or high risk of bias given the direction of the question).
'No information': if the study report provided insufficient information to allow any judgement.

We used the algorithms proposed by RoB 2 to assign each domain one of the following levels of bias.

Low risk of bias.
Some concerns.
High risk of bias.

Subsequently, we derived an overall risk of bias rating for each prespecified outcome in each study in accordance with the following suggestions.

'Low risk of bias': we judged the trial at low risk of bias for all domains for this result.
'Some concerns': we judged the trial to raise some concerns in at least one domain for this result, but not at high risk of bias for any domain.
'High risk of bias': we judged the trial at high risk of bias in at least one domain for the result, or we judged the trial to have some concerns for multiple domains in a way that substantially lowered confidence in the results.

We used the RoB 2 Excel tool to implement RoB 2 (available from riskofbias.info), and stored and presented our detailed RoB 2 assessments as supplementary online material (Mikolajewska 2021b).

Measures of treatment effect

For continuous outcomes, we recorded the mean, standard deviation (SD), and total number of participants in both treatment and control groups. Where continuous outcomes used the same scale, we performed analyses using the mean difference (MD) with 95% confidence intervals (CIs). For continuous outcomes measured with different scales, we had planned to perform analyses using the standardised mean difference (SMD). For interpreting SMDs, we would have re‐expressed SMDs in the original units of a particular scale with the most clinical relevance and impact (e.g. clinical symptoms with the WHO Clinical Progression Scale (WHO 2020b)).

For dichotomous outcomes, we recorded the number of events and total number of participants in both treatment and control groups. We reported the pooled risk ratio (RR) with a 95% CI and risk difference (RD) with its associated 95% CI (Deeks 2021). If the number of observed events was small (less than 5% of sample per group), and if studies had a balanced number of participants in all treatment groups, we reported the Peto odds ratio (OR) with 95% CI (Deeks 2021).

If available, we extracted and reported hazard ratios (HRs) for time‐to‐event outcomes (e.g. time to death). If HRs were not available, we made every effort to estimate the HR as accurately as possible from available data using the methods proposed by Parmar and Tierney (Parmar 1998; Tierney 2007). If sufficient studies provided HRs, we used HRs rather than RRs or MDs in a meta‐analysis, as they provide more information.

Unit of analysis issues

The aim of this review was to summarise trials that analysed data at the level of the individual. We would also have accepted cluster‐randomised trials for inclusion, in case we had found any. We collated multiple reports of one study so that the study, and not the report, was the unit of analysis.

Studies with multiple treatment groups

As recommended in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021e), for studies with multiple treatment groups of the same intervention (i.e. dose, route of administration), we planned to evaluate if study arms were sufficiently homogeneous to be combined. If arms could not be pooled, we planned to compare each arm with the common comparator separately. For pair‐wise meta‐analysis, we had planned to split the 'shared' group into two or more groups with smaller sample size, and include two or more (reasonably independent) comparisons. For this purpose, for dichotomous outcomes, both the number of events and the total number of participants would have been divided, and for continuous outcomes, the total number of participants would have been divided with unchanged means and SDs.

Dealing with missing data

First, when data were missing at outcomes and study level, we contacted principal investigators and requested these data. If, after this, data were still missing, we assumed data to be missing at random if missing outcomes were balanced across study arms and the method of detecting outcomes was comparable across study arms. In that case, we made no assumptions about the missing outcome data and did not test the robustness of the results. When we assumed that data were not missing at random and we identified no supporting evidence that the result were not biased by missing outcome data, we planned to exclude these data from meta‐analysis and discuss the potential impact of its absence on the results. In case we were concerned about missing data from all studies, we decided not to perform a meta‐analysis and to provide subtotals per study only.

Assessment of heterogeneity

We assessed heterogeneity of treatment effects between trials using the I² statistic (Higgins 2003) and visual examination, to assess possible heterogeneity (I² statistic > 30% to signify moderate heterogeneity, I² statistic > 75% to signify considerable heterogeneity; Deeks 2021). If heterogeneity was above 80%, we had planned to explore potential causes through sensitivity and subgroup analyses. If we could not find a reason for heterogeneity, we did not perform a meta‐analysis, but had planned to comment on results from all studies and present these in tables.

Assessment of reporting biases

We searched trials registries to identify completed trials that had not been published elsewhere, to minimise or determine publication bias. We contacted investigators of the studies listed as 'awaiting classification' to follow up whether study data might be available but not published.

We intended to explore potential publication bias by generating a funnel plot and statistically testing this by conducting a linear regression test for meta‐analyses involving at least 10 trials (Page 2021); however, we included four studies only. We considered P < 0.1 as significant for this test.

Data synthesis

If the clinical and methodological characteristics of individual studies were sufficiently homogeneous, we pooled the data in meta‐analyses. We performed analyses according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2021). We analysed trials including different severities of disease separately, grouping them into asymptomatic and mild, and moderate to severely ill, as these are different populations in different settings, resulting in differing outcomes (see Types of outcome measures). We treated placebo and no treatment as the same intervention, as well as standard care at different institutions and time points.

We used Review Manager Web (RevMan Web) software for analyses (RevMan Web 2019). One review author (VP) entered the data into the software, and a second review author (AM or ALF) checked the data for accuracy. We prioritised the random‐effects model for analyses as we anticipated that true effects are related, but are not the same for included studies. In case single studies with few participants contribute too much weight to the analysis due to very wide CIs, we preferred the fixed‐effect model for analysis.

If meta‐analysis was possible, we assessed the effects of potential biases in sensitivity analyses (see Sensitivity analysis). For binary outcomes, we based the estimation of the between‐study variance using the Mantel‐Haenszel method. We used the inverse variance method for continuous outcomes, outcomes that included data from cluster‐RCTs, or outcomes where HRs were available. We explored heterogeneity above 80% with subgroup analyses. If we could not find a cause for the heterogeneity, we performed no meta‐analysis. If we deemed meta‐analysis inappropriate for a certain outcome because of heterogeneity or because of serious study limitations leading to considerably high risk of bias (e.g. competing risk of death not taken into account in outcome measurement), we presented descriptive statistics only.

Living systematic review consideration

Whenever new evidence (studies, data, or information) that meets the review inclusion criteria is identified, we will immediately assess risk of bias and extract the data and incorporate it in the synthesis, as appropriate. We will not adjust the meta‐analyses to account for multiple testing given the methods related to frequent updating of meta‐analyses are under development (Simmonds 2017).

Subgroup analysis and investigation of heterogeneity

To explore heterogeneity, we had planned to perform subgroup analyses of the following characteristics, if sufficient data had been available:

age of participants (divided into applicable age groups, e.g. children; aged 18 to 65 years, aged 65 years and older);
pre‐existing conditions (diabetes, respiratory disease, hypertension, immunosuppression).

Sensitivity analysis

We performed sensitivity analysis of the following characteristics for the primary outcome, all‐cause mortality up to day 28.

Comparison between random‐effects and fixed‐effect models meta‐analysis. If the results were inconsistent between models, we presented both results.
Risk of bias assessment components (studies with a low risk of bias or some concerns versus studies with a high risk of bias).
Comparison of preprints of COVID‐19 interventions versus peer‐reviewed articles.
Comparison of premature termination of studies with completed studies.
Comparison of confirmed and suspected cases.

Summary of findings and assessment of the certainty of the evidence

Summary of findings

We used MAGICapp software to create 'Summary of findings' tables (MAGICapp). For time‐to‐event outcomes, we calculated absolute effects at specific time points, as recommended in the GRADE guidance 27 (Skoetz 2020).

According to Chapter 14 of the updated Cochrane Handbook for Systematic Reviews of Interventions, the "most critical and/or important health outcomes, both desirable and undesirable, limited to seven or fewer outcomes" should be included in the summary of findings tables (Schünemann 2021). We included outcomes prioritised according to the Core Outcome Set for intervention studies (COMET 2021) and patient‐relevance. Those were: hospitalised people with a confirmed or suspected diagnosis of COVID‐19 and moderate to severe disease and non‐hospitalised people with a confirmed or suspected diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease.

Hospitalised people with a confirmed or suspected diagnosis of COVID‐19 and moderate to severe disease

All‐cause mortality up to day 28, day 60, time‐to‐event, and at hospital discharge.
Clinical status up to day 28, day 60, and up to the longest follow‐up, including:
- worsening of clinical status (i.e. participants with clinical deterioration), defined as new need for invasive mechanical ventilation or death;
- improvement of clinical status (i.e. participants discharged alive). Participants should be discharged without clinical deterioration or death.
Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) up to seven days; up to 28 days, and longest follow‐up available.
Serious adverse events during the study period, defined as number of participants with any event.
Adverse events (any grade) during the study period, defined as number of participants with any event.

Non‐hospitalised managed individuals with a confirmed or suspected diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease

All‐cause mortality up to day 28, day 60, time‐to‐event, and up to the longest follow‐up.
Admission to hospital or death within 28 days.
Symptom resolution (i.e. all initial symptoms resolved (asymptomatic)) at day 14, day 28, and up to the longest follow‐up.
Duration to symptom resolution.
Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) up to seven days, up to 28 days, and longest follow‐up available.
Serious adverse events during the study period, defined as number of participants with any event.
Adverse events (any grade) during the study period, defined as number of participants with any event.

Assessment of the certainty in the evidence

We used the GRADE approach to assess the certainty in the evidence for the outcomes listed in the previous section.

The GRADE approach uses five domains (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty in the body of evidence for each prioritised outcome.

We downgraded our certainty of evidence for:

serious (–1) or very serious (–2) risk of bias;
serious (–1) or very serious (–2) inconsistency;
serious (–1) or very serious (–2) uncertainty about directness;
serious (–1) or very serious (–2) imprecise or sparse data;
serious (–1) or very serious (–2) probability of reporting bias.

The GRADE system used the following criteria for assigning grade of evidence.

High: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.
Low: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

We followed the current GRADE guidance for these assessments in their entirety as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 14; Schünemann 2021).

We used the overall risk of bias judgment, derived from the RoB 2 Excel tool, to inform our decision on downgrading for risk of bias. We phrased the findings and certainty in the evidence as suggested in the informative statement guidance (Santesso 2020).

Methods for future updates – living systematic review considerations

We will use the CCSR to monitor newly published results of RCTs on colchicine on a weekly basis. Two review authors will screen, extract, evaluate, and integrate following the guidance for Cochrane living systematic reviews (Cochrane LSR).

We will manually check platform trials that were previously identified and listed as 'studies awaiting classification' for additional treatment arms.

We will wait until the accumulating evidence changes one or more of the following components of the review before republishing the review.

The findings of one or more prioritised outcomes.
The credibility (e.g. GRADE rating) of one or more prioritised outcomes.
New settings, populations, interventions, comparisons, or outcomes studied.

When review methods will be reviewed

We will check the review scope and methods approximately monthly, or more frequently if appropriate, in light of potential changes in COVID‐19 research (e.g. when additional comparisons, interventions, subgroups, or outcomes, or new review methods become available).

Conditions under which the review will no longer be maintained as a living systematic review

In our regular review of the scope, we will decide whether to continue or stop updating the review. Decisions to stop may be that the conclusions for our main outcomes and populations of interest are unlikely to change with future studies included in the review, no new evidence is expected, or the review question is no longer a priority for policy and practice.

Results

Description of studies

Results of the search

Our database search resulted in 316 references. We excluded 88 duplicates and 186 records after title and abstract screening that did not meet the inclusion criteria. Of the remaining 42 records, we excluded eight references after full‐text screening. We included 34 references in the review:

four RCTs (six records) for inclusion in this review;
17 RCTs (17 records) are currently ongoing;
11 RCTs (11 records) are awaiting classification:
- 10 as they are reported as being completed, but results not published yet;
- one unclear reporting.

The study flow diagram in Figure 1 illustrates the study selection process according to PRISMA guidelines (Moher 2009).

Obtaining additional data

As described in the Dealing with missing data, we contacted investigators of completed or ongoing studies to obtain any missing data.

We received responses from six investigators of studies that exceeded the prospective completion dates provided in the trials' registry (IRCT20190804044429N5; IRCT20190810044500N5; IRCT20200408046990N2; NCT04322565; NCT04355143; NCT04527562). At the time the review was written, there were no data from the studies and they could not be incorporated into the current analyses.

To obtain data missing at the outcome level, we contacted principal investigators from all four included studies (Deftereos 2020; Horby 2021; Lopes 2021; Tardif 2021). Lopes 2021 provided us with additional data on adverse events (any grade), severity of condition at baseline in each study group, and mean duration of respiratory support. We also received information on which days the two participants died in the placebo group, information on the further clinical course of the five participants (four in placebo group, one in colchicine group) who had not yet been discharged on day 15 as well as the further clinical course of the participant from the colchicine group who was excluded before the start of intervention. We did not receive any other requested data from any trial.

Study design

We included four RCTs describing 16,013 enrolled adults (Deftereos 2020; Horby 2021; Lopes 2021; Tardif 2021). Three studies were peer‐reviewed journal publications (Deftereos 2020; Lopes 2021; Tardif 2021), while Horby 2021 was a preprint at the time we prepared the current version of this review (May 2021). Two studies were double‐blind and placebo‐controlled (Lopes 2021; Tardif 2021). Both studies prescribed placebo at the same frequency as colchicine intake. In Tardif 2021, the same manufacturer provided placebo as the colchicine tablets. Lopes 2021 informed us on request that placebo tablets were made from corn starch and were the same size and colour as colchicine tablets. Other two studies had an open‐label design (Deftereos 2020; Horby 2021). Deftereos 2020; Horby 2021; and Tardif 2021 were performed as multicentre studies: Deftereos 2020 in 16 centres in one country (Greece), while Horby 2021 and Tardif 2021 had an international character. Lopes 2021 was performed in one centre in Brazil.

Setting

Three of the four studies were conducted with hospitalised participants with COVID‐19 (Deftereos 2020; Horby 2021; Lopes 2021). Tardif 2021 was performed in a non‐hospitalised setting.

Participants

Diagnosis of COVID‐19

In Deftereos 2020 and Lopes 2021, the SARS‐CoV‐2‐PCR‐positivity was one of the inclusion criteria. However, the studies do not report whether all the recruited participants actually met this criterion and whether there were protocol violations. Horby 2021 and Tardif 2021 included participants according to PCR‐positivity or clinical criteria of SARS‐CoV‐2 infection. However, most participants in both studies had a PCR‐confirmed diagnosis of COVID‐19 (in Horby 2021 in 97% of participants in both study arms, in Tardif 2021 in 92.8% in intervention arm and in 92.5% in control arm).

Disease severity

Deftereos 2020, Horby 2021, and Lopes 2021 investigated hospitalised patients with moderate to severe disease according to the study definition, which corresponded to WHO 10‐points severity score (WHO 2020b) of 4 to 6 in Deftereos 2020 and Lopes 2021, and 4 to 7 in Horby 2021. Most participants in the three studies received supplemental low flow oxygen support. In Deftereos 2020, only three (6%) participants in the control group and none in the intervention group were receiving non‐invasive ventilation at baseline. In Horby 2021, only 5% of participants in both study arms needed invasive mechanical ventilation at baseline. In Tardif 2021 the participants presented with symptoms of a mild disease, which corresponds to WHO 10‐points severity score of one to three.

Age

In Deftereos 2020 and Horby 2021, the age of the participants was a median of 65 or 63 years (in colchicine versus control group, Deftereos 2020) or a mean of 63 years (in both groups, Horby 2021). In Lopes 2021 and Tardif 2021 the age of the participants in both study arms was a median of about 10 years less than in the other two studies.

Risk factors

The most common risk factor in Deftereos 2020 was arterial hypertension, which was present in 50% of participants in the colchicine group and 40% of participants in the control group. In Lopes 2021, over 40% of participants in both study arms had a cardiovascular disease that was not otherwise specified (NOS). In Tardif 2021 hypertension was reported in 34.9% of participants in the colchicine group and in 37.6% of participants in the control group. Horby 2021 reported heart disease (NOS) in 21% of participants in both study arms.

Diabetes mellitus was a frequently occurring risk factor in Lopes 2021 and it was present in 36% (colchicine group) and 42% (control group) of participants. Deftereos 2020 reported the lowest frequency of diabetes mellitus with 16.4% of participants in the intervention group and 24.0% of participants in the control group.

The frequency of chronic respiratory disease was also various; however, there was no consistency of definition across the studies. Horby 2021, Lopes 2021, and Tardif 2021 report the frequency of chronic lung disease (Horby 2021) or respiratory disease ( Lopes 2021; Tardif 2021), which was present in about 22% and 21% (Horby 2021), in about 11% and 14% (Lopes 2021) or in 26.1% and 26.9% (Tardif 2021) of study participants (each for colchicine versus control group). Deftereos 2020 reported the frequency of chronic obstructive pulmonary disease, which was present in 5.5% and 4% of participants (colchicine versus control group).

Sex

In Lopes 2021, 43% of the participants were men (53% in the intervention group and 39% in the placebo group), Deftereos 2020 reported 58% of the participants to be men (56% in the intervention group and 60% in the standard care group), and Horby 2021reported 70% men (69% in the intervention group and 70% in the standard care group). Tardif 2021 reported 45% men in the intervention group and 48% in the placebo group (overall 46% participants were men).

Interventions and comparators

The participants in the intervention arm all received oral colchicine. However, the dosage and duration of intake differed between studies. In Deftereos 2020, the participants in the intervention arm received a single loading dose of 1 mg (in case of azithromycin co‐administration or 1.5 mg) followed by 0.5 mg 60 minutes later. The loading dose was followed by 0.5 mg twice daily until discharge or day 21, whichever occurred earlier. In Horby 2021 the loading dose was 1.5 mg on day one. The loading dose was followed by 0.5 mg twice daily for 10 days or until discharge, whichever occurred earlier (with halved dosage frequencies for people with renal impairment, a bodyweight below 70 kg, or a medication with a moderate CYP3A4 inhibitor). In Lopes 2021, participants received colchicine 0.5 mg three times a day for five days and then reduced to twice a day. Tardif 2021 administered the increased dosage of 0.5 mg twice daily for three days and then reduced to 0.5 mg once daily. Most of the studies made dosage adjustments regarding participant's comorbidities. The entire duration of the therapy differed also among the included studies from 10 days in total (Horby 2021; Lopes 2021) to 30 days (Tardif 2021).

Participants in control arms in Lopes 2021 and Tardif 2021 received placebo in addition to standard care, while in Deftereos 2020 and Horby 2021 they received standard care alone. In Lopes 2021, all participants received a concomitant therapy consisting of azithromycin, hydroxychloroquine, and unfractionated heparin, as well as methylprednisolone if the participants needed higher oxygen amounts from the amount of 6 L. In Deftereos 2020, participants received various concomitant therapy regimens in different frequencies (chloroquine or hydroxychloroquine, azithromycin, lopinavir and ritonavir, tocilizumab and concomitant anticoagulation medication). In Horby 2021 as a platform trial, participants could be simultaneously randomised to other treatment groups: convalescent plasma versus monoclonal antibody (REGN‐129 CoV2) versus usual care, aspirin versus usual care, and baricitinib versus usual care. The trial also allowed a subsequent randomisation for people with progressive COVID‐19 (evidence of hypoxia and a hyperinflammatory state) to tocilizumab versus usual care. At randomisation, 94% of participants in this study were receiving corticosteroids. Tardif 2021 reported the use of hydroxychloroquine in 0.5% of participants in both study arms, 10% of participants received aspirin and the proportion of participants taking other platelet agents and oral anticoagulants was less than 3% in both study arms.

Outcome measures

Primary outcomes were different in all four studies, including 28‐day mortality (Horby 2021); a composite of death or hospitalisation due to COVID‐19 in the 30 days after randomisation (Tardif 2021); the time from baseline to clinical deterioration, defined as a 2‐grade increase on a 7‐point ordinal clinical scale (Deftereos 2020), as well as time of need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in ICU, death rate and causes of mortality (Lopes 2021). In addition to the clinical outcomes, Deftereos 2020 reported biochemical endpoints such as difference in maximal high‐sensitivity cardiac troponin levels between the two study arms and time for C‐reactive protein to reach levels greater than three times the upper reference limit.

All four studies reported secondary outcomes such as percentage of participants requiring mechanical ventilation; all‐cause mortality at the end of follow‐up; and the number, type, severity, and seriousness of total adverse events and treatment‐related adverse events (Deftereos 2020); time to discharge from hospital, and, among participants not on invasive mechanical ventilation at randomisation, a new invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death (Horby 2021); serum C‐reactive protein level, serum lactate dehydrogenase level and ratio of neutrophil to lymphocyte of peripheral blood samples from day zero to day seven, the number, type and severity of adverse events; frequency of interruption of the study protocol due to adverse events, and frequency of QT interval above 450 mseconds (Lopes 2021); and death, hospitalisation due to COVID‐19, and the need for mechanical ventilation in the 30 days following randomisation (Tardif 2021).

Excluded studies

Our comprehensive search strategy found eight registered studies that we excluded for different reasons.

Mostly, colchicine was given with other medications (three trials) or phytotherapeutic agents (two trials) that were not applied in the control group and, therefore, lacked balanced co‐intervention.
One trial was registered as an RCT but did not fulfil the criteria of an RCT (only 5/21 participants of the control group were truly randomised, the remaining 17 were retrospectively matched).
One study was withdrawn due to lack of funding.
One study was planned to prevent COVID‐19 (postexposure prophylaxis).

Studies awaiting classification

Eleven studies are currently awaiting classification (see Table 3). One preprint publication was not included due to some inconsistency on the reported outcomes that still have to be resolved (Salehdazeh 2020). This was an RCT with 100 participants comparing colchicine to standard care in hospitalised participants. We observed some discrepancies in the tables containing baseline data and results (time from suffering to enrolment was exactly the same as the outcome duration of hospitalisation). We recognised that this might be a typing error and attempted to contact the authors via email. However, we have not received a response to date, so we elected to not use the data. We will wait until final publication of this study before considering it further.

1. Summary of ongoing studies and studies awaiting classification.

Study registration number	Study acronym	Intervention	Comparator	Planned number of participants	Setting	Planned/actual completion date	Results available
EUCTR2020‐001511‐25	—	Colchicine	Standard care alone	102	Hospitalised	October 2020	No
EUCTR2020‐001841‐38	—	Colchicine	Standard care alone	240	Hospitalised	September 2020	No
IRCT20190804044429N5	—	Colchicine	Placebo	110	Hospitalised	NR	No
IRCT20190810044500N5	—	Colchicine	Placebo	152	Hospitalised	14 January 2021	No
IRCT20200408046990N2	—	Colchicine	Placebo	40	Hospitalised	NR	No
Salehdazeh 2020	—	Colchicine and chloroquine	Chloroquine	50	Hospitalised	21 September 2020	Yes (preprint)
ISRCTN86534580	PRINCIPLE	Colchicine	Standard care alone	NR	Non‐hospitalised	NR	No
jRCT2071200078	DRC‐06C	Colchicine	Placebo	100	Hospitalised	NR	No
NCT04322565	ColCOVID‐19	Colchicine	Standard care alone	310	Hospitalised	20 December 2020	No
NCT04324463	ACTCOVID19	Colchicine	Standard care alone	4000	Hospitalisedand non‐hospitalised	30 April 2022	No
NCT04328480	COLCOVID	Colchicine	Standard care alone	1279	Hospitalised	26 April 2021	No
NCT04350320	COL‐COVID	Colchicine	Standard care alone	120	Hospitalised	30 December 2020	No
NCT04355143	COLHEART‐19	Colchicine	Standard care alone	150	Hospitalised	8 September 2021	No
NCT04360980	—	Colchicine	Standard care alone	80	Hospitalised	30 November 2021	No
NCT04363437	COMBATCOVID19	Colchicine	Standard care alone	70	Hospitalised	14 July 2020	No
NCT04367168	ColchiVID	Colchicine	Placebo	174	Hospitalised	27 April 2021	No
NCT04375202	COLVID‐19	Colchicine	Standard care alone	308	Hospitalised	31 October 2021	No
NCT04416334	COLCHI‐COVID	Colchicine	Standard care alone	954	Non‐hospitalised	31 December 2021	No
NCT04510038	COLHEART‐19	Colchicine	Standard care alone	75	Hospitalised	Suspended 12 March 2021	No
NCT04516941	CONVINCE	Colchicine and endoxaban	Endoxaban	420	Non‐hospitalised	31 December 2021	No
NCT04527562	COLCOVIDBD	Colchicine	Placebo	299	Hospitalised	10 December 2020	No
NCT04539873	COLCOVID19	Colchicine	Standard care alone	128	Hospitalised	15 December 2021	No
NCT04667780	—	Colchicine	Standard care alone	102	Hospitalised	9 July 2021	No
NCT04724629	STRUCK	Colchicine	Standard care alone or ixekizumab or aldesleukin	60	Hospitalised	30 July 2021	No
NCT04756128	COLTREXONE	Colchicine and naltrexone	Naltrexone	164	Hospitalised	31 December 2021	No
NCT04762771	COLHEART‐19	Colchicine	Standard care alone	75	Hospitalised	Suspended 12 March 2021	No
NCT04818489	—	Colchicine	Standard care alone	250	NR	10 July 2021	No
NCT04867226	—	Colchicine	Standard care alone	100	Hospitalisedand non‐hospitalised	30 June 2021	No

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NR: not reported.

Further systematic research retrieved 10 studies that had already completed recruitment according to their registration updates or to personal email request. Four had registered a comparison of colchicine plus standard care to standard care treatment alone, another six planned to compare colchicine plus standard care to placebo plus standard care.

One trial, "Trial to study the benefit of colchicine in patients with COVID‐19 (COL‐COVID)" with 120 participants (NCT04350320) seems to be part of the separately announced multicentre 'ECLA PHRI COLCOVID trial' (NCT04328480), that announced a complete recruitment with 1279 participants. Another completed study without publication 'Colchicine in moderate symptomatic COVID‐19 patients (COLCOVIDBD)' announced inclusion of 299 participants in Bangladesh and is currently preparing the final analysis (NCT04527562). The Italian ColCOVID‐19 study terminated enrolment after the interim analysis, and is in the process of completing participant follow‐up according to personal communication from the author (NCT04322565). There are three studies from Iran registered as completed: IRCT20200408046990N2 (40 participants) planned to investigate the influence of colchicine admission on clinical parameters and is still awaiting the last data. Author requests via email provided that the authors of IRCT20190810044500N5 (152 participants) have prepared a manuscript that is currently under review and authors of IRCT20190804044429N5 (110 participants) are waiting for the final analysis of the results and the final format of the manuscript. The authors of the COLHEART‐19 study included 150 participants and are still waiting on their final 90‐day outcomes (NCT04355143). There were two more trial registrations for COLHEART‐19 (NCT04510038) and (NCT04762771) as the authors joined the multicentre study, but received their own funding. Those two are registered as suspended, as the results of the RECOVERY trial "showed no convincing evidence that further recruitment would provide conclusive proof of worthwhile benefit for the evaluation of colchicine in patients with COVID‐19."

Ongoing studies

We identified 17 ongoing studies that were registered as RCTs, comparing colchicine treatment to either placebo (two studies), standard care (nine studies), non‐specified comparator (five studies), or, in one case with three groups colchicine and naltrexone versus naltrexone only versus standard care (see Table 3). Another study was registered to compare colchicine treatment with ixekizumab, aldesleukin, or standard care alone. Furthermore, there was one study registered to compare colchicine treatment alone versus edoxaban tablets, no intervention, and the combination of edoxaban plus colchicine.

According to registered study protocols, two were registered in 2020 and should have lasted only a few months. Those trials already have completed, but there are no published results available at the time we prepared this review. Our requests via email provided no further information.

Risk of bias in included studies

We assessed risk of bias for four RCTs (Deftereos 2020; Horby 2021; Lopes 2021; Tardif 2021), using the RoB 2 tool recommended in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021d). The completed RoB 2 tool with responses to all assessed signalling questions is available online at zenodo.org/record/5377507 (Mikolajewska 2021b).

Overall judgements for studies including people with moderate to severe COVID‐19

Three studies assessed people with moderate to severe COVID‐19 (Deftereos 2020; Horby 2021; Lopes 2021).

All‐cause mortality

We had some concerns regarding risk of bias for one of the three studies that reported a mortality outcome (Lopes 2021), and detected high risk of bias for the other two studies (Deftereos 2020; Horby 2021). We assessed this outcome on a study level up to day 28, time‐to‐event, and at hospital discharge. For Deftereos 2020, there was high risk of bias arising from deviations of the intended intervention, because 5% of participants withdrew consent before study start. This was probably due to the unblinded study design. Also Horby 2021 reported deviations from the intended intervention, as 7% of participants in the colchicine arm did not receive the intervention and the study was unblinded (see Table 36; Table 37). We had some concerns in the randomisation method of Lopes 2021, as insufficient information on whether and how the randomisation sequence was concealed were provided. However, baseline differences between study arms did not suggest a problem with the randomisation process in general. Furthermore, we expected low risk arising from deviations of intended interventions because the trial was blinded and unblinding was considered unlikely as the placebo tablets were made from corn starch and had the same size and colour of colchicine ones (see Table 38).

Risk of bias for analysis 1.1 All‐cause mortality at up to day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Deftereos 2020

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

High risk of bias

Four participants in the intervention arm and one in control arm did not receive the allocated intervention and this is probably a deviation from the intended intervention that arose because of the trial context. The analysis was appropriate.

Low risk of bias

Data was available for 105 of 110 randomised participants.

Low risk of bias

Mortality was only reported as part of a composite outcome, but we do not expect differences between groups in measurement of the outcome and the outcome assessment is unlikely to being influenced by the knowledge of the intervention.

Low risk of bias

The data that produced this result was analysed in accordance with the study protocol.

High risk of bias

For the outcome "mortality" in this study, there is a low risk of bias from the randomization process, missing outcome data, measurement of the outcome and in selection of the reported result. However, we expect high risk of bias for deviations from intended interventions due to the unblinded study design.

Horby 2021

Low risk of bias

Randomisation and allocation concealment were performed with a web‐system. Baseline characteristics were well‐balanced between groups, and no problems with randomisation process was identified.

High risk of bias

The study was not blinded, and 7% of participants in the intervention group did not receive the allocated interventions. Protocol deviations may have arisen due to the unblinded study design.

Low risk of bias

The outcome was reported for all randomised participants.

Low risk of bias

The outcome was assessed as defined in the protocol and for both groups at the same timepoint. Outcome assessors were aware of the intervention, however occurence and detection of the event cannot be influenced through the awareness.

Low risk of bias

The outcome is reprted as defined in the statistical analysis plan.

High risk of bias

For the outcome "mortality" in this study, there is a high risk of bias due to protocol deviations that are probably caused by the unblinded study design. There was low risk of bias for the randomisation process, missing outcomes, measurement of the outcome, and selection of reported results.

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Risk of bias for analysis 1.2 All‐cause mortality (time‐to‐event).

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Horby 2021

Low risk of bias

Randomisation and allocation concealment were performed with a web‐system. Baseline characteristics were well‐balanced between groups, and no problems with randomisation process was identified.

High risk of bias

The study was not blinded, and 7% of participants in the intervention group did not receive the allocated interventions. Protocol deviations may have arisen due to the unblinded study design.

Low risk of bias

The outcome was reported for all randomised participants.

Low risk of bias

The outcome is reprted as defined in the statistical analysis plan.

High risk of bias

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Risk of bias for analysis 1.3 All‐cause mortality at hospital discharge.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopes 2021

Some concerns

The allocation sequence was random but it was unclear whether it was concealed. Differences between intervention groups were unlikely to be a result of problems with randomisation.

Low risk of bias

Data for this outcome was available for 73 out of 75 participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Some concerns

For the outcome "mortality" in this study, there is a low risk of bias from deviations from intended interventions, missing outcome data, measurement of the outcome and in selection of the reported result. However, there are some concerns for bias arising from the randomisation process.

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Clinical status

Worsening of clinical status

For the combined outcome need for new invasive mechanical ventilation or death, we expected high risk of bias for both studies that reported this outcome, because participants and outcome assessors were not blinded (Deftereos 2020; Horby 2021). It is possible that the lack of blinding caused deviations from the intended intervention due to the study context. Furthermore, we had some concerns for risk of bias regarding the outcome determination, which could have been influenced by knowledge of the intervention (see Table 39).

Risk of bias for analysis 1.4 Worsening of clinical status: participants with clinical deterioration, defined as new need for invasive mechanical ventilation or death up to day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Deftereos 2020

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

High risk of bias

Low risk of bias

Data were available for 105 of 110 randomised participants. The missing participants withdrew consent before the start of the study.

Some concerns

Need for invasive ventilation was only reported as part of a composite outcome, but we do not expect differences between groups in measurement of the outcome. Nonetheless, it is possible that the outcome assessment is being influenced by the knowledge of the intervention, therefor we have some concerns regarding bias in measurement of the outcome.

Low risk of bias

The data that produced this result was analysed in accordance with the study protocol.

High risk of bias

For the outcome "need for invasive ventilation" in this study, there is a low risk of bias arising from the randomization process and in selection of the reported result. However, there are some concerns for measurement of the outcome and we expect high risk of bias for deviations from intended interventions due to the unblinded study design.

Horby 2021

Low risk of bias

Randomisation and allocation concealment were performed with a web‐system. Baseline characteristics were well‐balanced between groups, and no problems with randomisation process was identified.

High risk of bias

The study was not blinded, and 7% of participants in the intervention group did not receive the allocated interventions. Protocol deviations may have arisen due to the unblinded study design.

Low risk of bias

Outcome reported for all randomised participants who were not ventilated at baseline (10811 participants).

Some concerns

The outcome was assessed as defined in the protocol and for both groups at the same timepoint. Outcome assessors were aware of the intervention, and occurence and detection of the event can be influenced through the awareness (e.g. counting or not counting patients that were ventilated as part of resuscitation procedures), however differences in assessment are unlikely.

Low risk of bias

The outcome was reported as defined in statistical analysis plan

High risk of bias

For the outcome "need for invasive mechanical intervention" in this study, there is a high risk of bias due to protocol deviations that are probably caused by the unblinded study design. Furthermore we had some concerns for meausurement of the outcome, but expected low risk of bias arising from the randomisation process, missing outcomes and selection of reported results.

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For the outcome new need for invasive ventilation without consideration of death as competing event, we rated high risk of bias because the study was unblinded and the effect estimate for clinical worsening s likely to be underestimated when participants die before a non‐terminal event, such as need for invasive mechanical ventilation, occurs (Horby 2021; Table 44).

Risk of bias for analysis 1.9 Worsening of clinical status: new need for invasive mechanical ventilation.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Deftereos 2020

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

High risk of bias

Given that one participant in the control group died due to sudden cardiorespiratory arrest the competing event “death” seems to have an impact on the outcome, although the effect direction remains the same.

Some concerns

Need for invasive ventilation was only reported as part of a composite outcome, but we do not expect differences between groups in measurement of the outcome. Nonetheless, it is possible that the outcome assessment is being influenced by the knowledge of the intervention, therefore we have some concerns regarding bias in measurement of the outcome.

Low risk of bias

The data that produced this result was analysed in accordance with the study protocol.

High risk of bias

For the outcome "need for invasive ventilation" in this study, there is a low risk of bias from the randomization process and in selection of the reported result. However, there are some concerns for bias due to measurement of the outcome. And given that one participant in the control group died due to sudden cardiorespiratory arrest, we expect high risk of bias arising from competing events in the missing outcomes domain. Furthermore, we expect high risk of bias for deviations from intended interventions due to the unblinded study design.

Horby 2021

Low risk of bias

Randomisation and allocation concealment were performed with a web‐system. Baseline characteristics were well‐balanced between groups, and no problems with randomisation process was identified.

High risk of bias

The study was not blinded, and 7% of participants in the intervention group did not receive the allocated interventions. Protocol deviations may have arisen due to the unblinded study design.

High risk of bias

2123 out of 10811 participants of this subgroup died during the measurement period, but only 1191 were intubated. Therefore, there is a high risk of bias due to the competing event death.

Some concerns

The outcome was assessed as defined in the protocol and for both groups at the same time point. Outcome assessors were aware of the intervention, and occurrence and detection of the event can be influenced through the awareness, however differences in assessment are unlikely.

Low risk of bias

The outcome was reported as defined in statistical analysis plan.

High risk of bias

For the outcome “need for invasive mechanical ventilation” in this study, there is a high risk of bias because of protocol deviations due to protocol deviations that are probably caused by the unblinded study design and missing outcome data due to the competing event "death". Furthermore, we had some concerns for bias regarding the measurement of the outcome. We expect low risk of bias for the randomisation process and selection of reported results.

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Improvement of clinical status

For the improvement of clinical status outcomes reported by Lopes 2021, we had some concerns for risk of bias, due to uncertainties regarding concealment of the allocation sequence. Furthermore, we expected low risk arising from deviations of intended interventions because the trial was blinded and unblinding was considered unlikely as the placebo tablets were made from corn starch and had the same size and colour of colchicine ones. Both improvement of clinical status outcomes reported by Horby 2021 were at high risk of bias because there were deviations from the intended intervention that probably arose because the trial was unblinded. Additionally, we expected a high risk of bias arising from selection of reported results, since study authors planned to calculate rate ratios and time‐to‐event estimates but did not report results for time‐to‐event estimates (see Table 41; Table 40; Table 45; Table 46).

Risk of bias for analysis 1.6 Improvement of clinical status: participants discharged alive at longest follow‐up.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopes 2021

Some concerns

The allocation sequence was random but it was unclear whether it was concealed. Differences between intervention groups were unlikely to be a result of problems with randomisation.

Low risk of bias

Data for this outcome was available for all randomised participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Some concerns

For the outcome "hospital discharge alive" in this study, there is a low risk of bias from deviations from intended interventions, missing outcome data, measurement of the outcome and in selection of the reported result. However, there are some concerns for bias arising from the randomisation process.

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Risk of bias for analysis 1.5 Improvement of clinical status: participants discharged alive up to day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Horby 2021

Low risk of bias

Randomisation and allocation concealment were performed with a web‐system. Baseline characteristics were well‐balanced between groups, and no problems with randomisation process was identified.

High risk of bias

The study was not blinded, and 7% of participants in the intervention group did not receive the allocated interventions. Protocol deviations may arose due to the design of the study, allowing simultaneous randomisation to mutliple treatments, and it is unclear whether deviations affected the outcome. An ITT analysis was used to estimate the treatment effect.

Low risk of bias

Outcome reported for all randomised participants; Colchicine (n=5610), Usual care (n=5730)

Low risk of bias

High risk of bias

The outcome was defined as time to hospital discharge in the statistical analysis plan, but number of participants discharged at day 28 reported.

High risk of bias

For the outcome "hospital discharge" in this study, there are serious concerns because of protocol deviations (7% of participants in the intervention group did not receive the intervention) and selective outcome reporting that may have biased the outcome. There was low risk of bias arising from the ramdomisation process, missingoutcomes, and measurement of the outcome.

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Risk of bias for analysis 1.10 Improvement of clinical status: weaned or liberated from invasive mechanical ventilation, and surviving (in subgroup of participants requiring invasive mechanical ventilation at baseline).

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Horby 2021

Low risk of bias

Randomisation and allocation concealment were performed with a web‐system. Baseline characteristics were well‐balanced between groups, and no problems with randomisation process was identified.

High risk of bias

The study was not blinded, and 7% of participants in the intervention group did not receive the allocated interventions. Protocol deviations may have arisen due to the unblinded study design.

Low risk of bias

The outcome was reported for all participants that were ventilated at baseline.

Some concerns

High risk of bias

Rate ratio and time to event estimates were planned in statistical analysis plan, but only rate ratio was reported.

High risk of bias

For the outcome "liberation from invasive mechanical ventilation" in this study, there is a high risk of bias due to protocol deviations that are probably caused by the unblinded study design and selective reporting of estimated effects that may have biased the outcome. We had some concerns for measurement of the outcome and expect low risk of bias for the randomisation process and missing outcomes.

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Risk of bias for analysis 1.11 Improvement of clinical status: duration to liberation from supplemental oxygen.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopes 2021

Some concerns

The allocation sequence was random but it was unclear whether it was concealed. Differences between intervention groups were unlikely to be a result of problems with randomisation.

Low risk of bias

Data for this outcome was available for all randomised participants.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration or compatible with usual clinical practice.

Some concerns

For the outcome "duration to liberation from respiratory support" in this study, there is a low risk of bias arising from deviations from the intended intervention, missing outcomes, measurement of the outcome, and selection of the reported result. However, there are some concerns for bias arising from the allocation concealment.

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Quality of life

None of the included studies reported quality of life.

Any grade adverse events

Lopes 2021 reported any grade adverse events as the number of participants with at least one adverse event and was at high risk of bias arising from missing outcome data due to the competing event death, in addition to some concerns for bias arising from the randomisation process (see Table 42).

Risk of bias for analysis 1.7 Adverse events (any grade) until discharge.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopes 2021

Some concerns

The allocation sequence was random but it was unclear whether it was concealed. Differences between intervention groups were unlikely to be a result of problems with randomisation.

Low risk of bias

High risk of bias

We rate high risk of bias due to the competing event "death".

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

High risk of bias

For the outcome "any adverse events" in this study, there is a low risk of bias from deviations from intended interventions, measurement of the outcome and in selection of the reported result. However, there are some concerns for bias arising from the randomisation process. We expect high risk of bias from missing outcome data due to competing events.

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Serious adverse events

Deftereos 2020 reported serious adverse events as the number of participants with at least one serious adverse event and was at high risk of bias arising from deviations from intended interventions due to the unblinded study and the competing event death (see Table 43).

Risk of bias for analysis 1.8 Serious adverse events until hospital discharge or a maximum of 21 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Deftereos 2020

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

High risk of bias

4/55 participants of the control arm were not assessed even though they received the intervention. There is no evidence the result was not biased by missing data or the competing event "death".

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups or that assessment of the outcome have been influenced by knowledge of the intervention.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the study protocol.

High risk of bias

For the outcome "serious adverse events" in this study, there is a low risk of bias from the randomization process, measurement of the outcome and in selection of the reported result. However, there are serious concerns for bias arising from deviations from intended interventions due to the unblinded study design and missing outcome data due to the competing event "death" in five participants which occurred more often than severe adverse events.

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Need for new dialysis

We expected the outcome need for new dialysis to be at high risk of bias because of protocol deviations that were probably caused by the unblinded study design (Horby 2021). For this outcome, deviations from intended interventions were of special importance since the intervention was nephrotoxic. Furthermore, it is likely that a substantial share of participants of this subgroup died during the measurement period, causing a high risk of bias due to competing events (Table 47).

Risk of bias for analysis 1.12 Need for new dialysis.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Horby 2021

Low risk of bias

Randomisation and allocation concealment were performed with a web‐system. Baseline characteristics were well‐balanced between groups, and no problems with randomisation process was identified.

High risk of bias

In the intervention group, 7% of participants did not take the potentially nephrotoxic intervention medication. It is likely that this could have an impact on the measured effect.

High risk of bias

It is likely that a substantial share of participants of this subgroup died during the measurement period. Therefore there is a high risk of bias due to competing events.

Some concerns

There was no information on how the outcome was determined. Outcome assessors were aware of the intervention, and it is possible that invetigators anticipates that participants in the intervention group would rather dialysis due to nephrotoxic intervention.

Low risk of bias

The result was reported as defined in statistical analysis plan.

High risk of bias

For the outcome "dialysis among those without dialysis at baseline" in this study, there is a high risk of bias due to protocol deviations that are probably caused by the unblinded study design. and the competing event "death" due to missing outcome data. We had some concerns reagrding the measurement of the outcome and we rated a low risk of bias concerning the randomisation process and the selection of the reported results.

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Admission to intensive care unit

For the outcome admission to ICU reported by Lopes 2021, we had some concerns due to uncertainties regarding the concealment of the allocation sequence. Here, we expected no risk of bias due to competing events because the information was provided that the two participants who died were admitted to ICU before. Furthermore, we expected low risk arising from deviations of intended interventions because the trial was blinded and unblinding was considered unlikely as the placebo tablets were made from corn starch and had the same size and colour of colchicine tablets (see Table 48).

Risk of bias for analysis 1.13 Admission to intensive care unit.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopes 2021

Some concerns

The allocation sequence was random but it was unclear whether it was concealed. Differences between intervention groups were unlikely to be a result of problems with randomisation.

Low risk of bias

Participants and carers were blinded and the risk for unblinding was considered low as the placebo tablets were made from corn starch with the same size and colour of colchicine ones.One participant was initially not included in the mITT, because he evolved to mechanical ventilation before intervention, but additional information received from the authors allowed to include all randomised participants in analysis.

Low risk of bias

For this outcome, death as competing event did not occur. We obtained data from every included patient.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration or compatible with usual clinical practice.

Some concerns

For the outcome "admission to ICU" in this study, there is a low risk of bias arising from measurement of the outcome, in selection of the reported result and missing outcome data. However, there are some concerns for bias arising from the allocation concealment.

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Duration of hospitalisation

For the outcome duration of hospitalisation, we detected a high risk of bias due to the competing event death (Lopes 2021; Table 49).

Risk of bias for analysis 1.14 Duration of hospitalisation.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopes 2021

Some concerns

The allocation sequence was random but it was unclear whether it was concealed. Differences between intervention groups were unlikely to be a result of problems with randomisation.

Low risk of bias

High risk of bias

We rated high risk of bias due to the competing event "death" and the exclusion of one participant after his intubation.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration or compatible with usual clinical practice.

High risk of bias

For the outcome "duration of hospitalisation" in this study, there is a low risk of bias arising from deviations from intended interventions, measurement of the outcome, and selection of the reported result. However, there are some concerns for bias arising from the allocation concealment. We expect high risk of bias from missing outcome data due to competing events.

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Viral clearance

None of the included studies reported viral clearance.

Incidence of abdominal pain

We expected the two studies that reported incidence of abdominal pain to be at high risk of bias. Lopes 2021 did not account for the competing event death, since 3% of participants died at least during hospitalisation. Deftereos 2020 did not follow up on four participants of the control group, who withdrew from the study after receiving the allocated intervention. It is possible that the withdrawals were connected to experiencing the examined outcome or the unblinded study design. Furthermore, the outcome determination method was prone to bias, since assessment of abdominal pain is subjective, the study was unblinded, and there was no information on how the outcome was determined (see Table 50).

Risk of bias for analysis 1.15 Incidence of abdominal pain during the study period, defined as number of participants with any event.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Deftereos 2020

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

High risk of bias

Some concerns

4/55 participants of the control arm were not assessed even though they received the intervention. There is no evidence the result was not biased.

High risk of bias

The measurement of the outcome was not described and could have differed between groups because of the open‐label study design.

Some concerns

Specific adverse evebts not included in study protocol.

High risk of bias

For the outcome "abdominal pain" in this study, there is a low risk of bias from the randomization process. There are some concerns for missing outcomes and selection of reported results, and high risk of bias from deviations from the intended intervention, and measurement of the outcome.

Lopes 2021

Some concerns

The allocation sequence was random but it was unclear whether it was concealed. Differences between intervention groups were unlikely to be a result of problems with randomisation.

Low risk of bias

High risk of bias

We rate high risk of bias due to the competing event "death" and the exclusion of one participant after his intubation.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups.

Some concerns

Study protocol not available, and specific adverse events not included in trial registry

High risk of bias

For the outcome "abdominal pain" in this study, there is a low risk of bias from deviations from intended interventions, and measurement of the outcome. However, there are some concerns for bias arising from the randomisation process and selection of reported results. We expect high risk of bias from missing outcome data due to competing events.

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Incidence of diarrhoea

We judged the two studies which reported this outcome to be at high risk of bias. Lopes 2021 did not account for the competing event death and 0.3% of participants died at least during hospitalisation. Deftereos 2020 had a high risk of bias due to deviations from intended intervention and determination method of the outcome, as described above for incidence of abdominal pain (see Table 51).

Risk of bias for analysis 1.16 Incidence of diarrhoea during the study period, defined as number of participants with any event.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Deftereos 2020

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

High risk of bias

Some concerns

4/55 participants of the control arm were not assessed even though they received the intervention. There is no evidence the result was not biased.

High risk of bias

The measurement of the outcome was not described and could have differed between groups because of the open‐label study design.

Some concerns

Specific adverse events were not included in study protocol.

High risk of bias

For the outcome "diarrhea" in this study, there is a low risk of bias from the randomization process. However, there are some concerns for selection of reported results and missing outcomes, and high risk of bias from deviations from the intended interventio and measurement of the outcome.

Lopes 2021

Some concerns

The allocation sequence was random but it was unclear whether it was concealed. Differences between intervention groups were unlikely to be a result of problems with randomisation.

Low risk of bias

High risk of bias

We rate high risk of bias due to the competing event "death" and the exclusion of one participant after his intubation.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups.

Some concerns

Study protocol not available and specific adverse events were not included in trial registry.

High risk of bias

For the outcome "diarrhea" in this study, there is a low risk of bias from deviations from intended interventions and from measurement of the outcome. However, there are some concerns for bias arising from the randomisation process and selection of reported results. We expect high risk of bias from missing outcome data due to competing events.

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Incidence of nausea and vomiting

For the outcome nausea and vomiting reported by Lopes 2021, we expected a high risk of bias due to the competing event death and 0.3% of participants died at least during hospitalisation (see Table 52).

Risk of bias for analysis 1.17 Incidence of nausea and vomiting during the study period, defined as number of participants with any event.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Lopes 2021

Some concerns

The allocation sequence was random but it was unclear whether it was concealed. Differences between intervention groups were unlikely to be a result of problems with randomisation.

Low risk of bias

High risk of bias

We rated high risk of bias due to the competing event "death" and the exclusion of one participant after his intubation.

Low risk of bias

The measurement of the outcome was appropriate and it is unlikely that it differed between intervention groups.

Some concerns

Study protocol not available, and specific adverse events not included in trial registry

High risk of bias

For the outcome "Nausea&Vomiting" in this study, there is a low risk of bias from deviations from intended interventions, and measurement of the outcome. However, there are some concerns for bias arising from the randomisation process and selection of reported results. We expect high risk of bias from missing outcome data due to competing events.

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Overall judgements for studies including people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19

One study assessed treatment for people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19 (Tardif 2021).

All‐cause mortality

Tardif 2021 examined participants with asymptomatic or mild disease and was at low risk for bias for all‐cause mortality (see Table 53).

Risk of bias for analysis 2.1 All‐cause mortality at day 28.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Tardif 2021

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

Low risk of bias

Participants and carers were blinded and unblinding was considered very unlikely because placebo tablets were produced by the same manufacturer as colchicine tablets. An appropriate analysis was performed to estimate the effect of assignment to intervention.

Low risk of bias

Data for this outcome was available for 4488 of 4506 randomised participants.

Low risk of bias

The measurement of the outcome was probably appropriate and it is unlikely that it differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Low risk of bias

For the outcome "mortality" in this study, there is a low risk of bias from the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of reported results.

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Clinical status

Worsening of clinical status

For the combined outcome admission to hospital or death within 28 days, we expected low risk of bias in all domains. Additionally, we expected low risk arising from deviations of intended interventions because the trial was blinded and unblinding was considered unlikely as the placebo tablets were produced by the same manufacturer as the colchicine tablets (Tardif 2021; Table 54).

Risk of bias for analysis 2.2 Admission to hospital or death within 28 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Tardif 2021

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

Low risk of bias

Data were available for all randomised participants

Low risk of bias

The measurement of the outcome was probably appropriate and it is unlikely that it differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

Low risk of bias

For the outcome "need for hospitalisation" in this study, there is a low risk of bias from the randomization process, deviations from intended interventions, measurement of the outcome, and selection of reported results.

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For the outcome need for invasive mechanical ventilation, we expected high risk of bias due to the competing event death and its potential impact on results due to a low overall event rate (Tardif 2021; Table 56).

Risk of bias for analysis 2.4 Worsening of clinical status: need for invasive mechanical ventilation.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Tardif 2021

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

Low risk of bias

High risk of bias

With a very low event rate, we have to consider the competing event of death that could have an impact to fog the real effect.

Low risk of bias

The measurement of the outcome was probably appropriate and it is unlikely that it differed between intervention groups.

Low risk of bias

The data that produced this result was analysed in accordance with the predefined outcomes stated in the trial registration.

High risk of bias

For the outcome "need for invasive ventilation" in this study, there is a low risk of bias from the randomization process, deviations from intended interventions, measurement of the outcome, and selection ofreported results. Concerning the domain missing outcome data we suspect death to be a competing event that could have produced "missings" skewing the effect.

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Improvement of clinical status

We could not assess risk of bias for symptom resolution or duration to symptom resolution because the included study did not report improvement of clinical status.

Quality of life

The included study did not report quality of life.

Any grade adverse events

Tardif 2021 reported treatment‐related adverse events. We had some concerns for selective reporting because the outcome was not prespecified in the trial registry and for bias due to missing information regarding the analysis method. The missing information refers to three participants in the colchicine group who were probably included in the analysis despite not receiving the treatment, and one participant in the control group, who was probably not included in the analysis despite receiving the treatment. We consider that the competing risk of death had no or minimal impact on the results, as the overall event rate of death in comparison to overall event rate of treatment‐related adverse events was low. Additionally, we expected low risk arising from deviations of intended interventions because the trial was blinded and unblinding was considered unlikely as the placebo tablets were produced by the same manufacturer as the colchicine tablets. As there is no analysis for this outcome included in our review, judgements could not be included in a risk of bias table, and are provided in the supplementary online appendix instead (Mikolajewska 2021b ).

Serious adverse events

For serious adverse events, we had some concerns for bias due to missing information regarding the analysis method as described for any grade adverse events. Additionally, we expected low risk arising from deviations of intended interventions because the trial was blinded and unblinding was considered unlikely as the placebo tablets were produced by the same manufacturer as the colchicine tablets. Furthermore, there were some concerns for selected reporting because this outcome was not prespecified in the study protocol. We consider that the competing risk of death had no or minimal impact on the results, as the overall event rate of death in comparison to overall event rate of serious adverse events was low (Tardif 2021; Table 55).

Risk of bias for analysis 2.3 Serious adverse events within 28 days.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Tardif 2021

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

Some concerns

Participants and carers were blinded and unblinding was considered very unlikely because placebo tablets were produced by the same manufacturer as colchicine tablets. There was insufficient information to decide whether the analysis was appropriate, as according to the study flow diagram the safety set in the colchicine group should be 2192, but SAEs were reported for 2195 participants (in the placebo group, safety set should be 2218 participants, but SAEs reported for 2217).

Low risk of bias

Data available for most participants (missing for approximately 0.1%).

Low risk of bias

Outcome was assessed by telephone evaluations. We do not expect any differences in measurement between intervention groups, because of the double‐blinded design.

Some concerns

The outcome was not defined in the study registry.

Some concerns

For the outcome "serious adverse events" in this study, there is a low risk of bias from the randomization process, missing outcome data, and measurement of the outcome. However, there are some concerns for bias due to deviations from intended interventions, and selection of the reported result.

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Viral clearance

The included study did not report viral clearance.

Incidence of abdominal pain

The included study did not report incidence of abdominal pain.

Incidence of diarrhoea

We assessed the outcome incidence of diarrhoea to be at some concerns for bias, because it was unclear who was included in the analysis, analysis was appropriate, and whether this outcome was biased by selected reporting since it was not prespecified in the trial registry (Tardif 2021; Table 57). We consider that the competing risk of death had no or minimal impact on the results, as overall event rate of death in comparison to overall event rate of diarrhoea was low. Additionally, we expected low risk arising from deviations of intended interventions because the trial was blinded and unblinding was considered unlikely as the placebo tablets were produced by the same manufacturer as the colchicine tablets.

Risk of bias for analysis 2.5 Incidence of diarrhoea during the study period, defined as number of participants with any event.

Study

Bias

Randomisation process

Deviations from intended interventions

Missing outcome data

Measurement of the outcome

Selection of the reported results

Overall

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Authors' judgement

Support for judgement

Tardif 2021

Low risk of bias

The allocation sequence was probably random and concealed and there were no differences between intervention groups suggesting a problem with the randomization process.

Some concerns

Participants and carers were blinded, but there was insufficient information to decide whether the analysis was appropriate, as according to the study flow diagram the safety set in the colchicine group should be 2192, but SAEs were reported for 2195 participants (in the placebo group, safety set should be 2218 participants, but SAEs reported for 2217).

Some concerns

It was unclear how many participants were analysed for this outcome. The outcome could have been influenced by the inadequate knowledge of the relatives who responded the outcome assessment via telephone.

Low risk of bias

Outcome measurement is insufficiently described, however we do not expect any differences in measurement between intervention groups, because of the double‐blinded design

Some concerns

The outcome was not prespecified in the trial registry.

Some concerns

For the outcome "diarrhea" in this study, there is a low risk of bias from the randomization process and measurement of the outcome. However, there are some concerns for bias due to selection of the reported result, deviations from intended interventions and missing outcome data.

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Incidence of nausea and vomiting

The included study did not report incidence of nausea and vomiting.

Effects of interventions

See: Table 1; Table 2

Colchicine plus standard care versus standard care (plus/minus placebo)

Hospitalised people with COVID‐19 and moderate to severe disease

Three studies compared colchicine plus standard care versus standard care (plus/minus placebo) for treatment of hospitalised people with a confirmed or suspected diagnosis of COVID‐19 and moderate to severe disease (Deftereos 2020; Horby 2021; Lopes 2021).

Primary outcomes

See Table 1.

All‐cause mortality up to day 28, day 60, time‐to‐event, and at hospital discharge

Three trials reported all‐cause mortality (Deftereos 2020; Horby 2021; Lopes 2021), with one study reporting it at hospital discharge for 75 participants (Lopes 2021).

We found that colchicine plus standard care probably results in little to no difference in all‐cause mortality up to day 28 compared to standard care alone (RR 1.00, 95% CI 0.93 to 1.08; RD 0 fewer per 1000, 95% CI 14 fewer to 17 more; 2 studies, 11,445 participants; I² = 45%; moderate‐certainty evidence; Analysis 1.1).

1.1 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 1: All‐cause mortality at up to day 28

Mortality over time up to day 28 was reported in one study (Horby 2021). If measured over time (time to event), we found that colchicine compared to standard care probably has little to no effect on mortality up to day 28 (HR 1.01, 95% CI 0.93 to 1.10; 1 study, 11,340 participants; moderate‐certainty evidence; Analysis 1.2). We downgraded the certainty of evidence for these outcomes one level due to serious study limitations due to the unblinded study design. On day 28, 1044 (9.2%) participants of this study (Horby 2021) were neither discharged (7933 participants) nor dead (2363 participants). Horby 2021 also reported the effect of allocation to colchicine on 28‐day mortality stratified by subgroups (age, sex, ethnicity, days since symptom onset, respiratory support at randomisation, and use of corticosteroids) and found no differences between groups.

1.2 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 2: All‐cause mortality (time‐to‐event)

Lopes 2021 reported all‐cause mortality at hospital discharge for 75 participants. Nobody died in the intervention group (0%) of 38 participants, while 3/37 (8.1%) participants died in the placebo group. We are uncertain about the effect of colchicine on all‐cause mortality at hospital discharge compared to placebo (RR 0.14, 95% CI 0.01 to 2.60; RD 70 fewer per 1000, 95% CI 80 fewer to 130 more; 1 study, 75 participants; low‐certainty evidence; Analysis 1.3). We downgraded the certainty of evidence two levels for very serious imprecision due to few events and few participants.

1.3 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 3: All‐cause mortality at hospital discharge

Deftereos 2020 reported mortality until discharge or a maximum of 21 days, with 1/55 (1.8%) deceased participants in the colchicine group and 4/50 (8%) deceased participants in the standard care group.

There was no study reporting all‐cause mortality at day 60.

Sensitivity analyses

We conducted sensitivity analyses for all‐cause mortality up to day 28 comparing fixed‐effect and random‐effects meta‐analyses, excluding studies at high risk of bias, publication status excluding preprints, study termination excluding prematurely ended studies, and confirmed cases only (excluding those studies that included confirmed and suspected cases) (see Table 4).

2. Sensitivity analysis for the primary outcome all‐cause mortality at up to day 28 for people with a diagnosis of COVID‐19 and moderate to severe disease.

Outcome	Main analysis using random‐effects model	Main analysis using fixed‐ effects model	Risk of bias (excluding studies^a at high risk of bias)	Publication status (excluding preprints^b)	Study termination (excluding premature termination studies^c)	Confirmed cases only (excluding studies including confirmed and suspected cases)^d
All‐cause mortality at up to day 28	RR 0.72, 95% CI 0.21 to 2.44; 2 RCTs, 11,445 participants	RR 1.00, 95% CI 0.93 to 1.08; 2 RCTs, 11,445 participants	No effect estimate available^a	RR 0.23, 95% CI 0.03 to 1.97; 1 RCT, 105 participants^b	RR 1.00, 95% CI 0.93 to 1.08; 2 RCTs, 11,445 participants; fixed‐effect model	RR 0.23, 95% CI 0.03 to 1.97; 1 RCT, 105 participants^d

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CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio.

^aExcluded studies with high risk of bias: Deftereos 2020; Horby 2021. ^bExcluded preprints: Horby 2021. ^cExcluded studies with premature termination: none. ^dExcluded studies including confirmed and suspected cases: Horby 2021.

Comparison of random‐ to fixed‐effect model meta‐analysis indicated high inconsistency between the two included RCTs, due to very wide CIs in the random‐effects model giving too much weight to one small study contributing only 105/11,445 participants included in the analysis (Deftereos 2020). Therefore, we decided to report the results of the fixed‐effect model in the main text, anticipating that true effects are comparable across studies.

Sensitivity analyses excluding preprint articles, and studies also including suspected cases led to the exclusion of the largest study (Horby 2021). Effect estimates of the remaining study varied from the overall analysis, but differences are likely related to the small sample size and event rate, and probably do not show true differences between the analyses (Deftereos 2020).

Clinical status up to day 28, day 60, and up to the longest follow‐up

Worsening of clinical status

Two studies reported participants with clinical deterioration (new need for invasive mechanical ventilation or death) (Deftereos 2020; Horby 2021). Colchicine probably has little to no impact on new need for invasive mechanical ventilation or death up to day 28 compared to standard care alone (RR 1.02, 95% CI 0.96 to 1.09; RD 4 more per 1000, 95% CI 10 fewer to 22 more; 2 studies, 10,916 participants; moderate‐certainty evidence; Analysis 1.4). We downgraded the evidence because of serious study limitations due to deviations from intended interventions.

1.4 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 4: Worsening of clinical status: participants with clinical deterioration, defined as new need for invasive mechanical ventilation or death up to day 28

Improvement of clinical status: participants discharged alive up to day 28

Horby 2021 reported the number of participants discharged alive up to day 28, with 3901/5610 (69.5%) participants in the colchicine group and 4032/5730 (70.4%) participants in the standard care group. Colchicine plus standard care probably results in little to no difference in the number of participants discharged alive up to day 28 without clinical deterioration or death compared to standard care alone (RR 0.99, 95% CI 0.96 to 1.01; RD 7 fewer per 1000, 95% CI 28 fewer to 7 more; 1 study, 11,340 participants; moderate‐certainty evidence; Analysis 1.5). We downgraded one level due to serious study limitations due to deviations from intended interventions.

1.5 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 5: Improvement of clinical status: participants discharged alive up to day 28

Improvement of clinical status: participants discharged alive at longest follow‐up

One study reported participants discharged alive at the longest follow‐up and followed all participants until discharge (Lopes 2021). All 38 participants in the colchicine group survived and were discharged, while in the placebo group 34/37 (91.9%) participants survived and were discharged. Colchicine may result in little to no difference in the improvement of clinical status assessed as participants discharged alive compared to placebo (RR 1.09, 95% CI 0.98 to 1.21; RD 83 more per 1000, 95% CI 18 fewer to 193 more; 1 study, 72 participants; low‐certainty evidence; Analysis 1.6). Our main reasons for downgrading the certainty of the evidence by two levels were serious imprecision due to few events, few participants, and wide CIs.

1.6 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 6: Improvement of clinical status: participants discharged alive at longest follow‐up

Quality of life, including fatigue and neurological status

No studies reported quality of life in people with COVID‐19 treated with colchicine.

Adverse events (any grade) during the study period, defined as number of participants with any event

We found a wide variety of adverse events in the studies. One study reported any grade adverse events occurring in 28/72 participants until hospital discharge (Lopes 2021). The evidence is very uncertain about the effect of colchicine on adverse events compared to placebo (RR 1.00, 95% CI 0.56 to 1.78; RD 0 fewer per 1000, 95% CI 171 fewer to 303 more; 1 study, 72 participants; very low‐certainty evidence; Analysis 1.7). We downgraded two levels for very serious imprecision due to only one study and wide CIs, one level for publication bias because several completed studies without results (three) were identified, and other published studies selectively reported adverse events, and one level for serious study limitations due to the high risk of bias due to the competing event 'death.' The other two studies did not report adverse events, defined as number of participants with any event (Deftereos 2020; Horby 2021). Horby 2021 provided data about selected and not intervention‐specific adverse events in the supplementary appendix; without further information how many participants experienced at least one adverse event. Table 5 provides an overview of reported adverse events per study.

1.7 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 7: Adverse events (any grade) until discharge

3. Adverse events in the hospitalised setting.

Number of participants with ≥ 1 event	Deftereos 2020		Lopes 2021		Horby 2021(preprint)
Number of participants with ≥ 1 event	Colchicine n = 55 (n)	Standard care n = 50 (n)	Colchicine n = 36 (n)	Placebo n = 36 (n)	Colchicine n = 2195 (n)	Standard care n = 2217 (n)
Serious adverse events	0	0	N/A	N/A	N/A^a	N/A^a
Adverse events	N/A^b	N/A^b	14	14	N/A^c	N/A^c
Abdominal pain	5 (9%)	0 (0%)	4 (11%)	4 (11%)	N/A^c	N/A^c
Diarrhoea	25 (46%)	9 (18%)	6 (17%)	2 (6%)	N/A^c	N/A^c
Nausea and vomiting	3 (5%)	2 (4%)	4 (11%)	2 (6%)	N/A^c	N/A^c

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n: number of participants; N/A: not available.

^aHorby reported two "serious adverse reaction believed related to colchicine" but not the number of participants with at least one severe adverse event. ^bDeftereos reported the number of adverse events, but not the number of participants with at least one adverse event. ^cHorby reported diverse adverse events, and partly the number of participants with at least one of those adverse events, but not the adverse events that are most common with colchicine treatment or adverse events in general.

Serious adverse events during the study period, defined as number of participants with any event

One study reported no serious adverse events for 105 participants until hospital discharge or a maximum of 21 days (Deftereos 2020). The evidence is very uncertain about the effect of colchicine plus standard care on serious adverse events compared to standard care alone (0 events observed in 1 RCT of 105 participant s; very low‐certainty evidence). Horby 2021 mentioned two reports of a serious adverse reaction believed related to colchicine: “one case of severe acute kidney injury and one case of rhabdomyolysis” but did not report the number of participants with at least one serious adverse event. A request to the study investigators provided no answer. Table 5 provides an overview of reported serious adverse events per study. The evidence is very uncertain about the effect of colchicine on serious adverse events (see Analysis 1.8). We downgraded one level for publication bias because several completed studies without results (three) were identified, and other published studies selectively reported adverse events (e.g. severe treatment‐associated events only). Another reason for downgrading one level was due to the high risk of bias due to the competing event 'death' and two more levels for very serious imprecision due to only one study and no events observed.

1.8 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 8: Serious adverse events until hospital discharge or a maximum of 21 days

Secondary outcomes

Clinical status up to day 28, day 60, and up to the longest follow‐up

Worsening of clinical status: new need for invasive mechanical ventilation

Two studies reported the new need for invasive mechanical ventilation (i.e. WHO 7–9; for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6). Deftereos 2020 reported new need for invasive mechanical ventilation for 6/105 participants (RR 0.18, 95% CI 0.02 to 1.50; RD 82 fewer per 1000, 95% CI 98 fewer to 50 more; Analysis 1.9), while Horby 2021 reported 1191/10,811 participants meeting the endpoint (RR 1.04, 95% CI 0.93 to 1.16; RD 4 more per 1000, 95% CI 98 fewer to 50 more; Analysis 1.9). We perform no meta‐analysis due to the competing risk of death.

1.9 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 9: Worsening of clinical status: new need for invasive mechanical ventilation

Worsening of clinical status: new need for non‐invasive mechanical ventilation or high flow

No studies reported the need for new non‐invasive mechanical ventilation or high flow.

Worsening of clinical status: new need for oxygen by mask or nasal prongs

No studies reported the new need for oxygen by mask or nasal prongs.

Improvement of clinical status: weaned or liberated from invasive mechanical ventilation, and surviving, in subgroup of participants requiring invasive mechanical ventilation at baseline

Horby 2021 reported the liberation from invasive mechanical ventilation at 28 days for 169/529 participants who had been invasively ventilated at baseline. The results showed no effect of colchicine on weaning from invasive mechanical ventilation (RR 1.06, 95% CI 0.82 to 1.36, RD 19 more per 1000, 95% CI 56 fewer to 112 more; Analysis 1.10).

1.10 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 10: Improvement of clinical status: weaned or liberated from invasive mechanical ventilation, and surviving (in subgroup of participants requiring invasive mechanical ventilation at baseline)

Improvement of clinical status: ventilator‐free days

No studies reported clinical improvement assessed with ventilator‐free days.

Improvement of clinical status: duration to liberation from invasive mechanical ventilation

No studies reported duration to liberation from invasive mechanical ventilation.

Improvement of clinical status: liberation from supplemental oxygen in surviving participants

No studies reported liberation from supplemental oxygen in surviving participants.

Improvement of clinical status: duration to liberation from supplemental oxygen

In personal communication with the authors of Lopes 2021, we requested additional information and learned the mean time to liberation from supplemental oxygen was 3.8 (SD 2.5) days for colchicine and 6.3 (SD 2.7) days for placebo. This results in an MD of −2.5 days (95% CI −3.7 to −1.3; Analysis 1.11).

1.11 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 11: Improvement of clinical status: duration to liberation from supplemental oxygen

Need for new dialysis up to 28 days

Horby 2021 reported the new need of dialysis in 415/11,253 participants who had not been on dialysis at baseline. The resulting OR slightly favoured the treatment without colchicine (OR 1.07, 95% CI 0.88 to 1.30; RD 2 more per 1000, 95% CI 4 fewer to 10 more; Analysis 1.12).

1.12 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 12: Need for new dialysis

Admission to intensive care unit up to day 28

One study reported the need of admission to ICU (Lopes 2021). Upon personal requests, the authors provided information including the entire ITT population. A total of 7/75 participants needed admission to ICU (RR 0.73, 95% CI 0.18 to 3.04; RD 29 fewer per 1000, 95% CI 89 fewer to 221 more; Analysis 1.13).

1.13 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 13: Admission to intensive care unit

Duration of hospitalisation

Lopes 2021 reported the duration of hospitalisation in means; with 6.6 days for the colchicine arm and 8.6 days for the placebo arm (MD −2.0 days, 95% CI −3.32 to −0.68; Analysis 1.14). In Horby 2021, the median time to being discharged alive was 10 days in both groups with concurring interquartile ranges (IQR) from 5 to more than 28 days.

1.14 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 14: Duration of hospitalisation

Viral clearance

We found no studies reporting viral clearance.

Incidence of abdominal pain during the study period, defined as number of participants with any event

Deftereos 2020 reported abdominal pain in 5/55 (9%) participants with colchicine treatment and 0/50 participants with standard care (hypothetic RR 10.02, 95% CI 0.57 to 176.70; Analysis 1.15). Lopes 2021 reported abdominal pain for 4/36 (11%) participants for colchicine and 4/36 (11%) participants with placebo treatment (RR 1.00, 95% CI 0.27 to 3.69; RD 0 more per 1000, 95% CI 81 fewer to 299 more; Analysis 1.15). We performed no meta‐analysis due to the competing risk of death.

1.15 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 15: Incidence of abdominal pain during the study period, defined as number of participants with any event

Incidence of diarrhoea during the study period, defined as number of participants with any event

Deftereos 2020 reported diarrhoea in 25/55 (46%) participants with colchicine treatment and 9/50 (18%) participants with standard care (RR 2.53, 95% CI 1.31 to 4.88; RD 255 more per 1000, 95% CI 56 more to 698 more). Lopes 2021 reported diarrhoea in 6/36 (17%) participants for colchicine and 2/36 (6%) participants with placebo (RR 3.00, 95% CI 0.65 to 13.88; RD 111 more per 1000, 95% CI 20 fewer to 715 more; Analysis 1.16). We performed no meta‐analysis due to the competing risk of death.

1.16 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 16: Incidence of diarrhoea during the study period, defined as number of participants with any event

Incidence of nausea and vomiting during the study period, defined as number of participants with any event

Deftereos 2020 reported nausea and vomiting only separately, without information whether there were participants experiencing both. Lopes 2021 reported nausea and vomiting in 4/36 (11%) participants for colchicine and 2/36 (6%) participants with placebo (RR 2.00, 95% CI 0.39 to 10.24; RD 55 more per 1000, 95% CI 34 fewer to 513 more; Analysis 1.17).

1.17 — Comparison 1: People with a diagnosis of COVID‐19 and moderate to severe disease, Outcome 17: Incidence of nausea and vomiting during the study period, defined as number of participants with any event

Non‐hospitalised people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19

One study compared colchicine versus placebo for treatment of non‐hospitalised people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19 (Tardif 2021)).

Primary outcomes

See Table 2.

All‐cause mortality up to day 28, day 60, time‐to‐event, and up to the longest follow‐up

The evidence is uncertain about the effect of colchicine on all‐cause mortality at day 28 compared to placebo (Peto OR 0.57, 95% CI 0.20 to 1.62; RD 2 fewer per 1000, 95% CI 4 fewer to 2 more; 1 study, 4488 participants; low‐certainty evidence; Analysis 2.1) (Tardif 2021). The main reason for downgrading the certainty of the evidence was very serious imprecision due to few events, wide CIs, and data from only one study.

2.1 — Comparison 2: People with a diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease, Outcome 1: All‐cause mortality at day 28

Admission to hospital or death within 28 days

Tardif 2021 reported the need for hospitalisation or death within 28 days for 104/2235 (4.7%) participants in the colchicine group and 131/2253 (5.8%) participants in the control group. Colchicine probably results in a slight reduction in the risk of admission to hospital or death within 28 days compared to placebo (RR 0.80, 95% CI 0.62 to 1.03; RD 12 fewer per 1000, 95% CI 22 fewer to 2 more; moderate‐certainty evidence; Analysis 2.2). The main reason for downgrading the certainty of the evidence was serious imprecision due to data from only one study that was stopped preliminary after enrolment of 75% of the planned sample size due to resource problems.

2.2 — Comparison 2: People with a diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease, Outcome 2: Admission to hospital or death within 28 days

Tardif 2021 reported admission to hospital or death within 28 days stratified by baseline characteristics (PCR‐confirmed COVID‐19, history of diabetes, history of hypertension, smoking, age, sex, race, body‐mass index, respiratory disease, cardiovascular disease, and use of angiotensin‐converting enzyme inhibitor or angiotensin‐receptor blocker) with no differences between groups, except from PCR‐confirmed COVID‐19 (OR 0.75, 95% CI 0.57 to 0.99) and men (OR 0.67, 95% CI 0.48 to 0.95).

Symptom resolution: all initial symptoms resolved (asymptomatic) at day 14, day 28, and up to the longest follow‐up and duration to symptom resolution

The study did not report symptom resolution.

Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) up to seven days, up to 28 days, and longest follow‐up available

The study did not report quality of life.

Adverse events (any grade) during the study period, defined as number of participants with any event

Tardif 2021 did not report adverse events defined as number of participants with an event. Table 6 provides an overview of reported adverse events. Tardif 2021 reported the number of participants with at least one treatment‐related adverse event for 532 (24.2%) participants in the colchicine group versus 344 (15.5%) participants in the placebo group. The evidence is uncertain about the effect of colchicine on adverse events compared to placebo (low‐certainty evidence). Our certainty in the evidence was downgraded to low due to very serious indirectness because the definition of outcome differs from the definition used in our review.

4. Adverse events in the non‐hospitalised setting.

Number of participants with ≥ 1 event	Tardif 2021
Number of participants with ≥ 1 event	Colchicine n = 2195 (n)	Standard care n = 2217 (n)
Serious adverse event	108 (5%)	139 (6%)
Adverse event	N/A^a	N/A^a
Abdominal pain	N/A	N/A
Diarrhoea	300 (14%)	161 (7%)
Nausea and vomiting	43 (2%)	47 (2%)

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n: number of participants; N/A: not available

^aTardif reported "any related adverse event" (532 versus 344 for colchicine versus standard care), but not number of participants with at least one adverse event.

Serious adverse events during the study period, defined as number of participants with any event

Tardif 2021 reported serious adverse events defined as number of participants with at least one event for 4412 participants. Considering the reported event rates across the study, we estimated that 49/1000 participants experienced serious adverse events when treated with colchicine and 63/1000 participants when treated with placebo. We found that colchicine probably results in a slight reduction in the occurrence of serious adverse events within 28 days compared to placebo (RR 0.78, 95% CI 0.61 to 1.00; RD 14 fewer per 1000, 95% CI 25 fewer to 0 more; moderate‐certainty evidence; Analysis 2.3; Table 6). The main reason for downgrading the certainty of the evidence was serious imprecision due to data from only one study that was stopped preliminary after enrolment of 75% of the planned sample size due to resource problems.

2.3 — Comparison 2: People with a diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease, Outcome 3: Serious adverse events within 28 days

Secondary outcomes

Clinical status up to day 28 and up to the longest follow‐up

Worsening of clinical status: need for invasive mechanical ventilation

Tardif 2021 reported the need for invasive mechanical ventilation for 11/2235 (0.5%) participants treated with colchicine and 21/2253 (0.9%) participants treated with placebo. We found that colchicine may reduce the need for invasive mechanical ventilation within 28 days compared to placebo (OR 0.54, 95% CI 0.27 to 1.08; RD 4 fewer per 1000, 95% CI 6 fewer to 1 more; Analysis 2.4). We suspect a high risk of bias for this outcome due to the competing event of death that could have skewed the effect.

2.4 — Comparison 2: People with a diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease, Outcome 4: Worsening of clinical status: need for invasive mechanical ventilation

Worsening of clinical status: need for non‐invasive mechanical ventilation or high flow

The study did not report the need for non‐invasive mechanical ventilation or high flow.

Worsening of clinical status: need for hospitalisation with need for oxygen by mask or nasal prongs

The study did not report the need for hospitalisation with need for oxygen by mask or nasal prongs.

Worsening of clinical status: need for hospitalisation without oxygen therapy

The study did not report the need for hospitalisation without oxygen therapy.

Viral clearance, assessed with RT‐PCR for SARS‐CoV‐2 at baseline, up to three, seven, and 14 days

The study did not report viral clearance.

Incidence of abdominal pain during the study period, defined as number of participants with any event

The study did not report incidence of abdominal pain.

Incidence of diarrhoea during the study period, defined as number of participants with any event

Tardif 2021 reported diarrhoea in 300/2195 (14%) participants with colchicine treatment and in 161/2217 (7%) participants with standard care treatment. We found that colchicine increases the occurrence of diarrhoea within 28 days compared to placebo (RR 1.88, 95% CI 1.57 to 2.26; RD 64 more per 1000, 95% CI 41 more to 91 more; Analysis 2.5; Table 6). We had some concerns for risk of bias due to the selection of the reported result, deviations from intended interventions, and missing outcome data.

2.5 — Comparison 2: People with a diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease, Outcome 5: Incidence of diarrhoea during the study period, defined as number of participants with any event

Incidence of nausea and vomiting during the study period, defined as number of participants with any event

Incidence of nausea and vomiting during the study period was not reported as defined. Tardif 2021 reported incidence of nausea in 43/2195 (2%) participants with colchicine treatment and 47/2217 (2%) participants with standard care.

Colchicine versus another active treatment (e.g. corticosteroids, anti‐viral drugs, monoclonal antibodies)

No studies compared colchicine versus another active treatment.

Different formulations, doses, or schedules of colchicine

No studies evaluated different formulations, doses, or schedules of colchicine.

Discussion

Summary of main results

The aim of this review was to investigate the effectiveness and safety of colchicine in people with moderate to severe COVID‐19, or people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19. We included three RCTs with 11,525 hospitalised patients (Deftereos 2020; Horby 2021; Lopes 2021), and one RCT with 4488 non‐hospitalised patients comparing colchicine versus placebo or standard care alone (Tardif 2021).

Colchicine plus standard care versus standard care (plus/minus placebo)

Treatment of hospitalised people with moderate to severe COVID‐19

Colchicine probably results in little to no difference in all‐cause mortality up to 28 days (RR 1.00, 95% CI 0.93 to 1.08; 2 RCTs, 11,445 participants; moderate‐certainty evidence), and may result in little to no difference on clinical worsening defined as the new need for invasive mechanical ventilation or death (RR 1.02, 95% CI 0.96 to 1.09; 2 RCTs, 10,916 participants; moderate‐certainty evidence). Colchicine probably results in little to no difference in the improvement in clinical status defined as the number of participants discharged alive up to day 28 without clinical deterioration or death (RR 0.99, 95% CI 0.96 to 1.01; 1 RCT, 11,340 participants; moderate‐certainty evidence). We identified no studies reporting quality of life. We do not know whether colchicine has any impact on adverse events or serious adverse events (very low‐certainty evidence for both outcomes).

Treatment of non‐hospitalised people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19

We are uncertain about the effect of colchicine on all‐cause mortality at 28 days (OR 0.57, 95% CI 0.20 to 1.62; 1 RCT, 4488 participants; low‐certainty evidence). Colchicine probably results in slight reduction of the risk of admission to hospital or death within 28 days (RR 0.80, 95% CI 0.62 to 1.03; 1 RCT, 4488 participants; moderate‐certainty evidence). We identified no studies reporting symptom resolution or quality of life. We are uncertain about the effect of colchicine on the risk of adverse events (low‐certainty evidence). The risk of serious adverse events was slightly lower with colchicine (moderate‐certainty evidence).

Colchicine versus another active treatment (e.g. corticosteroids, antiviral drugs, monoclonal antibodies)

We identified no studies comparing colchicine versus another active treatment.

Different formulations, doses, or schedules of colchicine

We identified no studies assessing different formulations, doses, or schedules of colchicine.

Overall completeness

Overall, this review identified a lack of evidence about the effect of colchicine for:

people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19 (with different levels of exposition for SARS‐Cov‐2);
quality of life among people with any severity of the disease;
adverse events and serious adverse events related to colchicine (especially for people in the community setting who might be at risk of accidental overdosing given the relatively narrow margin for error for this intervention);
compared to other active treatments or of different oral formulations (e.g. tablets versus capsules), doses, or schedules of colchicine.

No study reported results for colchicine versus another active treatment (e.g. corticosteroids, antiviral drugs, monoclonal antibodies) or of different formulations, doses, or schedules of colchicine.

For specific adverse events, we decided to report on the most common and clinically relevant adverse effects of colchicine. The large study RECOVERY reported adverse events as the number of events rather than the number of participants with adverse events (which we were interested in) (Horby 2021). For this reason, this study could not be included in the analysis of adverse events outcomes.

We identified 17 ongoing RCTs and 11 completed, but not published trials comparing colchicine to placebo, standard care alone, or other treatments that we aim to include in updates of this review.

Treatment of people with moderate to severe COVID‐19

Three RCTs addressed five of our six primary outcomes (all‐cause mortality, improvement and worsening of clinical status, any and severe adverse events) (Deftereos 2020; Horby 2021; Lopes 2021). The studies did not report quality of life.

Studies reported the time point for mortality data inconsistently. One study with 75 participants reported mortality at hospital discharge (Lopes 2021), Deftereos 2020 reported mortality at hospital discharge or up to day 21, if discharge did not occur earlier. One study with 11,340 participants reported all‐cause mortality at day 28 (Horby 2021). We decided to pool the data of Deftereos 2020 and Horby 2021 in 'all‐cause mortality up to day 28', as in Deftereos 2020, at the end of observation, 14 participants were still hospitalised and in Horby 2021, 1044 (9.2%) participants were neither discharged nor dead.

All three studies reported some information on clinical worsening or improvement, even though the results could not be pooled due to heterogeneous outcome definitions (i.e. Lopes 2021 provided information about the need for admission to ICU, while Deftereos 2020 and Horby 2021 reported the composite outcome of invasive mechanical ventilation or death).

Considering the rate of any or severe adverse events, there was no report of the number of participants with at least one event. Regarding the report of any adverse events, although some included studies had described the occurrence of multiple events (including abdominal pain, diarrhoea, nausea, and vomiting), the number of participants with at least one of these events was also unclear. Furthermore, there was insufficient data to presume whether colchicine treatment has any impact on these individual events.

Treatment of people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19

Tardif 2021 assessed the effects of colchicine 0.5 mg once to twice daily for 30 days for non‐hospitalised patients aged 40 years or older, with mild disease and at least one high‐risk criterion for poor prognosis. Thus, the applicability of our findings for other subgroups (i.e. asymptomatic or younger people) or different treatment schemes must be applied with caution. A proportion of participants have no PCR‐confirmed COVID‐19 and despite the low frequency (92.8% in the intervention arm and 92.5% in the control arm), we are uncertain about its impact on the effect size estimates.

The RCT addressed four of our seven prioritised outcomes: all‐cause mortality, admission to hospital or death, any and serious adverse events. The study did not report quality of life, symptom resolution, or duration to symptom resolution.

Applicability of evidence

Critical appraisal of selected outcomes considering death as competing event

As with other reviews in this series (e.g. Wagner 2021), we have considered whether treatment effects are likely to be underestimated when participants die before a non‐terminal event. We identified that for instance with outcome parameters such as 'progression to invasive mechanical ventilation,' a simple RR cannot take into account the risk of dying before being a candidate for 'invasive mechanical ventilation.' This led us to the conclusion that pooling outcome data of non‐terminal events regardless of the scale level might be misleading.

We decided to address this in our bias assessments and rated, in case outcome parameters with the competing risk of death could have occurred, as a specific example of missing data. We assumed that the non‐availability of an outcome measurement due to the competing event death is related to the true value that would have occurred.

We did not perform a meta‐analysis for outcomes at high risk of bias arising from the competing risk of death. For example, we identified in Deftereos 2020 and Horby 2021 that participants died without previous intubation. In particular, Horby 2021 reported need for invasive mechanical ventilation, all‐cause mortality, and the composite outcome of both for all randomised participants who were not ventilated at baseline (10,811 participants). The available data suggest that among the participants not intubated at baseline, at least 291 participants in the intervention group and at least 273 participants in the control group died without previous intubation, underlining this problem. This is why we argue that the competing event death might have a high impact on the true value, and thus revised our core outcome set to take this issue into account and increase the applicability of our summarised evidence (see also Potential biases in the review process; Differences between protocol and review).

Quality of the evidence

Colchicine plus standard care versus standard care (plus/minus placebo) for the treatment of people with moderate to severe COVID‐19

We have moderate certainty in the identified evidence for effectiveness outcomes (all‐cause mortality, and worsening or improvement of clinical status), and very low certainty in the identified evidence for safety outcomes (any grade and serious adverse events). Our main concerns for effectiveness outcomes were serious study limitations due to deviations from intended interventions, especially in unblinded studies. In addition to this, another concern related to safety outcomes was very serious imprecision, as the largest included study did not report safety data for all participants.

Colchicine plus standard care versus standard care (plus/minus placebo) for the treatment of people with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19

We have low to moderate certainty in the identified evidence for the effectiveness outcomes (all‐cause mortality and admission to hospital or death), due to very serious or serious imprecision, as not many events (deaths/hospital admissions) occurred. The evidence is low to moderate for safety outcomes. For adverse events, we identified very serious indirectness, as only treatment‐related adverse events were reported (low‐certainty evidence). We downgraded one level for imprecision for serious adverse events as the number of events was small (moderate‐certainty evidence).

Potential biases in the review process

To avoid potential bias in the review process, we were committed at all times to follow the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021a).

An experienced medical information specialist of the CEOsys consortium developed an all‐encompassing search strategy, which was peer‐reviewed by another information specialist. We included all identified published studies, but also kept track of studies that were either still ongoing or labelled as completed in the study registry, to avoid overseeing any upcoming evidence. The sensitive search included relevant electronic databases as well as clinical trial registries. We contacted principal investigators and requested additional information of our interest. In addition to peer‐reviewed full‐text articles, we also included preprints. We interpreted results of preprint publications carefully as there might be changes once the peer‐reviewed journal publications are available. We are confident that we identified all relevant studies to date and will monitor ongoing studies as well as full publication of preprints closely after the publication of this first review version.

We performed sensitivity analyses with fixed‐effect models and decided to report the estimate of the fixed‐effect instead of random‐effects model for the outcomes 'all‐cause mortality up to day 28' and 'worsening of clinical status: participants with clinical deterioration, defined as new need for invasive mechanical ventilation or death,' due to very wide CIs in the random‐effects model giving too much weight to one small study contributing only 105/11,445 participants included in the mortality analysis, and 105/10,916 participants included in the analysis of the worsening of clinical status (Deftereos 2020).

We performed any step from study selection to GRADE assessment in duplicate, and consulted with at least one other review author, in case of any discrepancies. Since the publication of the review protocol, we have considered competing events carefully. As a consequence, we revised our outcomes to take this issue into account and included outcomes adjusted to the competing risk of death instead (see Differences between protocol and review). We described each included study in full detail and made explicit judgements on individual risk of bias.

Agreements and disagreements with other studies or reviews

There are several meta‐analyses on colchicine (Hariyanto 2021; Nawangsih 2021; Siemieniuk 2020). However, most of the meta‐analyses published did not perform essential steps in a systematic research synthesis such as a comprehensive literature search, risk of bias assessment, and evidence certainty grading, or pooled non‐randomised and randomised studies in the same analysis. For this reason, we compared our results only with one published systematic review with similar methodology as ours (Siemieniuk 2020).

One previous systematic review assessed the role of colchicine in the treatment of COVID‐19 (Siemieniuk 2020). This review is being used as a main evidence source for the living WHO guideline (Lamontagne 2021), and their last search update was 12 February 2021.

The review considered the results of three prospective RCTs that were also included in our review (Deftereos 2020; Lopes 2021; Tardif 2021). We also included the RECOVERY trial results by Horby 2021, which considerably improved the precision for primary outcomes.

The results of their meta‐analyses based on indirect comparisons found low‐certainty evidence on mortality reduction and shortened duration of hospitalisation with the use of colchicine (Siemieniuk 2020). These estimates are conflicting with our estimates. One key analytical difference is that they combined studies regarding setting (hospitalised and non‐hospitalised patients) and did not include the large RECOVERY study by Horby 2021. The inclusion of this study changed the estimates for these outcomes considerably. Therefore, our review included higher certainty evidence for the outcomes addressed by Horby 2021, especially mortality.

Authors' conclusions

Implications for practice.

Based on the current evidence, in people with moderate to severe coronavirus disease 2019 (COVID‐19) the use of colchicine plus standard care in comparison to standard care (plus/minus placebo) probably results in little to no difference on mortality or clinical progression. We do not know whether colchicine has any impact on (serious) adverse events, as these results were reported too heterogeneously. No studies assessed quality of life.

We are uncertain about the evidence of the effect of colchicine on all‐cause mortality for people with asymptomatic infection or mild disease. However, colchicine probably results in a slight reduction of admissions to hospital or death within 28 days and serious adverse events. No studies assessed quality of life.

Implications for research.

As none of the studies evaluated the effect of colchicine on quality of life, there is a need to assess this patient‐relevant outcome in ongoing studies that are being conducted to assess the effects of colchicine for people with asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection or symptomatic COVID‐19. In addition, adverse events and serious adverse events should be evaluated more consistently and according to good clinical practice guidance, to provide a more comprehensive picture of potential benefits and harms.

As none of the studies reported the benefits and harms of colchicine versus other drugs, this should be evaluated in the future, especially for non‐hospitalised patients as we have identified moderate‐certainty evidence of reduced hospital admission with colchicine. Studies used different dosages, but there was no evidence that different doses could change the effect estimates relevantly. Additionally, different dosages of colchicine could be evaluated in direct comparisons.

We identified 17 ongoing and 11 completed but not published RCTs, which we expected to incorporate in updates of this review as their results become available.

Notes

Reviews of this series share information in the background section and methodology based on the first published reviews about monoclonal antibodies (Kreuzberger 2021) and convalescent plasma (Piechotta 2021).

Risk of bias

Acknowledgements

This work is part of a series of reviews investigating treatments and therapies for COVID‐19 as part of the project CEOsys. Text passages in the background section (e.g. 'description of the condition' and 'why it is important to do this review"') are shared between reviews of this series (Kreuzberger 2021; Piechotta 2021). We thank the authors of the first published reviews of this series for providing and sharing this information. Moreover, we thank the Cochrane Haematology working group for using the template for the description of methods. Furthermore, we thank our colleagues for their work at the hospitals (Charité – Universitätsmedizin Berlin, Universitätsklinikum Leipzig, University of Cologne) that made it possible for us to take the time for this review.

This review was published in collaboration with the Cochrane Editorial and Methods Department. We particularly thank our managing editor Lara Kahale, and our peer reviewers Sarah Hodgkinson, Theresa Moore, Ruth Foxlee, Mouhand FH Mohamed, Alexandros A Drosos, and Stella O'Brien for their helpful suggestions.

The research was part of a project supported by the German Federal Ministry of Education and Research (NaFoUniMedCovid19, funding number: 01KX2021; part of the project "CEOsys"). The contents of this document reflect only the authors' views and the German Ministry is not responsible for any use that may be made of the information it contains.

Appendices

Appendix 1. Search strategies

Cochrane COVID‐19 Study Register

colchicin* OR colchicum OR colchisol OR colchysat OR colcin OR colcrys OR colsaloid OR condylon OR goutnil OR kolkicin OR mitigare OR demecolcin* OR lumicolchicin* = 90 studies (106 references)

Web of Science Core Collection (Advanced search)

1. TI=(colchicin* OR colchicum OR colchisol OR colchysat OR colcin OR colcrys OR colsaloid OR condylon OR goutnil OR kolkicin OR mitigare OR demecolcin* OR lumicolchicin*) OR AB=( colchicin* OR colchicum OR colchisol OR colchysat OR colcin OR colcrys OR colsaloid OR condylon OR goutnil OR kolkicin OR mitigare OR demecolcin* OR lumicolchicin*)

2. TI=(COVID OR COVID19 OR "SARS‐CoV‐2" OR "SARS‐CoV2" OR SARSCoV2 OR "SARSCoV‐2" OR "SARS coronavirus 2" OR "2019 nCoV" OR "2019nCoV" OR "2019‐novel CoV" OR "nCov 2019" OR "nCov 19" OR "severe acute respiratory syndrome coronavirus 2" OR "novel coronavirus disease" OR "novel corona virus disease" OR "corona virus disease 2019" OR "coronavirus disease 2019" OR "novel coronavirus pneumonia" OR "novel corona virus pneumonia" OR "severe acute respiratory syndrome coronavirus 2") OR AB=(COVID OR COVID19 OR "SARS‐CoV‐2" OR "SARS‐CoV2" OR SARSCoV2 OR "SARSCoV‐2" OR "SARS coronavirus 2" OR "2019 nCoV" OR "2019nCoV" OR "2019‐novel CoV" OR "nCov 2019" OR "nCov 19" OR "severe acute respiratory syndrome coronavirus 2" OR "novel coronavirus disease" OR "novel corona virus disease" OR "corona virus disease 2019" OR "coronavirus disease 2019" OR "novel coronavirus pneumonia" OR "novel corona virus pneumonia" OR "severe acute respiratory syndrome coronavirus 2")

3. #1 AND #2

= 90 references

WHO COVID‐19 Global literature on coronavirus disease

"Title, abstract, subject": (colchicin* OR colchicum OR colchisol OR colchysat OR colcin OR colcrys OR colsaloid OR condylon OR goutnil OR kolkicin OR mitigare OR demecolcin* OR lumicolchicin*) AND (random* OR placebo OR trial OR groups OR "phase 3" or "phase3" or p3 or "pIII")

= 120 references

Appendix 2. Search strategy: Cochrane COVID‐19 Study Register for platform trials

platform OR "adaptive*" OR "multiple studies" OR "multiarm" OR "multi‐arm"

INTERVENTION ASSIGNMENT: randomised

Appendix 3. Summary of ongoing platform trials

Study acronym	Study ID	Title	Link	Setting	Planned number of participants	Planned completion date	Other study interventions	Other study ID
COLHEART‐19	NCT04355143	Colchicine to reduce cardiac injury in COVID‐19	clinicaltrials.gov/show/NCT04355143	Hospitalised	150	25 April 2021	None	NCT04510038
PRINCIPLE	ISRCTN86534580	A trial evaluating treatments for suspected coronavirus infection in people aged 50 years and above with pre‐existing conditions and those aged 65 years and above	www.isrctn.com/ISRCTN86534580	NR	NR	NR	Inhaled budesonide (completed) Azithromycin (completed) Doxycycline (completed) Favipiravir (ongoing)	—
RECOVERY	NCT04381936	Randomised evaluation of COVID‐19 therapy (RECOVERY)	clinicaltrials.gov/ct2/show/NCT04381936	Hospitalised	40,000	December 2021	Azithromycin (completed) Convalescent plasma (completed) Dexamethasone (completed) Hydroxychloroquine (completed) Lopinavir‐ritonavir (completed) Tocilizumab (completed) Immunoglobulin (ongoing) Synthetic neutralising antibodies (ongoing) Aspirin (ongoing) Baricitinib (ongoing) Anakinra (ongoing) Dimethyl fumarate (ongoing) Corticisteroid (ongoing)	ISRCTN50189673, EudraCT 2020‐001113‐21

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Data and analyses

Comparison 1. People with a diagnosis of COVID‐19 and moderate to severe disease.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality at up to day 28	2	11445	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.93, 1.08]
1.2 All‐cause mortality (time‐to‐event)	1	11340	Hazard Ratio (IV, Random, 95% CI)	1.01 [0.93, 1.10]
1.3 All‐cause mortality at hospital discharge	1	75	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.60]
1.4 Worsening of clinical status: participants with clinical deterioration, defined as new need for invasive mechanical ventilation or death up to day 28	2	10916	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.96, 1.09]
1.5 Improvement of clinical status: participants discharged alive up to day 28	1	11340	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.96, 1.01]
1.6 Improvement of clinical status: participants discharged alive at longest follow‐up	1	75	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.98, 1.21]
1.7 Adverse events (any grade) until discharge	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.8 Serious adverse events until hospital discharge or a maximum of 21 days	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.9 Worsening of clinical status: new need for invasive mechanical ventilation	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.10 Improvement of clinical status: weaned or liberated from invasive mechanical ventilation, and surviving (in subgroup of participants requiring invasive mechanical ventilation at baseline)	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.11 Improvement of clinical status: duration to liberation from supplemental oxygen	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.12 Need for new dialysis	1		Odds Ratio (M‐H, Random, 95% CI)	Subtotals only
1.13 Admission to intensive care unit	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.14 Duration of hospitalisation	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
1.15 Incidence of abdominal pain during the study period, defined as number of participants with any event	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.16 Incidence of diarrhoea during the study period, defined as number of participants with any event	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.17 Incidence of nausea and vomiting during the study period, defined as number of participants with any event	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

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Comparison 2. People with a diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All‐cause mortality at day 28	1	4488	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.57 [0.20, 1.62]
2.2 Admission to hospital or death within 28 days	1	4488	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.62, 1.03]
2.3 Serious adverse events within 28 days	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.4 Worsening of clinical status: need for invasive mechanical ventilation	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
2.5 Incidence of diarrhoea during the study period, defined as number of participants with any event	1	4412	Risk Ratio (M‐H, Random, 95% CI)	1.88 [1.57, 2.26]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Deftereos 2020.

*Study characteristics*
Methods	Trial design: prospective, open‐label, randomised controlled trial Type of publication: journal publication Setting: hospitalised Recruitment dates: started 3 April 2020, terminated 27 April 2020 Country: Greece Language: English Number of centres: 16 tertiary care hospitals in Greece Trial registration number: NCT04326790 Date of trial registration: 30 March 2020
Participants	Age (median): colchicine group: 63 (range 55–70) years; control group: 65 (range 54–80) years Sex (n male): colchicine group: 31 (56.4%); control group: 30 (60.0%) Ethnicity: NR n recruited/allocated/evaluated: 184/110/105 Participants with positive SARS‐CoV‐2 RT‐PCR test result (n (%)): NR (RT‐PCR positivity belongs to inclusion criteria) Severity of condition according to study definition: moderate to severe Severity of condition according to WHO score (n) (WHO 2020b): WHO 4: colchicine group: 19 (34.5%); control group: 17 (34.0%) WHO 5: colchicine group: 36 (65.5%); control group: 30 (60%) WHO 6: colchicine group: 0 (0%); control group: 3 (6%) Comorbidities (colchicine group vs control group, n): arterial hypertension 22 (40.0%) vs 25 (50.0%); diabetes 9 (16.4%) vs 12 (24.0%); dyslipidaemia 17 (30.9%) vs 16 (32.0%); coronary artery disease 9 (16.4%) vs 5 (10.0%); valvulopathy 4 (7.3%) vs 1 (2.0%); atrial fibrillation 6 (10.9%) vs 5 (10.0%); chronic obstructive pulmonary disease 3 (5.5%) vs 2 (4.0%); known immunosuppression 3 (5.5%) vs 1 (2.0%) Inclusion criteria Age > 18 years Laboratory confirmed SARS‐CoV‐2 (by RT‐PCR) Clinical symptoms body temperature > 37.5 °C and ≥ 2 of: persistent cough; persistent throat pain; anosmia, ageusia; asthenia; PaO₂ < 95 mmHg Exclusion criteria Pregnancy, breastfeeding, or unwillingness to use effective contraceptive measures during the clinical trial in people of childbearing potential Known hypersensitivity to colchicine or to any of the excipients of the product (lactose, gum arabic, sucrose, magnesium stearate, microcrystalline cellulose, polyvinylpyrrolidone, methylene casein, erythrosine lacquer) Severe hepatic impairment eGFR < 20 mL/min/1.73 m² Corrected QT interval ≥ 450 msecond (according to the Bazett formula) on a 12‐lead surface ECG Clinical assessment indicating that ventilatory support would be inevitable in the following 24 hours because of rapidly declining respiratory status Any condition or circumstances which, at the discretion of the treating physician, would prevent the indicated follow‐up of the participant Participation in a clinical trial with an investigational product (drug or medical device) or intervention Receiving colchicine for other indications. Unable to comply with the requirements of the clinical trial or his/her participation in it may put him/her at unacceptable risks for his/her health Undergoing haemodialysis Severe gastrointestinal failure, severe gastrointestinal disorders, or stomach ulcer Haematological disorders, such as blood diseases Under treatment or had received within the past 14 days drugs belonging to the classes of P‐glycoprotein inhibitors or CYP3A4 enzyme inhibitors. Previous treatments: NR
Interventions	Intervention group Colchicine: loading dose day 1 colchicine 1.5 mg, followed by another 0.5 mg after 60 min if no gastrointestinal complications, reduced to 1.0 mg in case of azithromycin coadministration then twice daily 0.5 mg until discharge or day 21 Comparator group Standard care: treatment details: NR Concomitant therapy (e.g. description of standard care) Colchicine group vs control group (n): chloroquine or hydroxychloroquine 55 (100%) vs 48 (96.0%); azithromycin 51 (92.7%) vs 46 (92.0%); lopinavir or ritonavir 14 (25.5%) vs 19 (38.0%); tocilizumab 2 (3.6%) vs 2 (4.0%); concomitant anticoagulation medication 31 (56.3%) vs 26 (52.0%) Duration of follow‐up: until hospital discharge or a maximum of 21 days; hospitalisation duration (median): colchicine group: 12 (IQR 9‐22) days; control group: 13 (IQR 9‐18) days Treatment cross‐overs: none Compliance with assigned treatment: 5 participants withdrew consents before study
Outcomes	Primary study outcome Time from baseline to clinical deterioration, defined as a 2‐grade increase on an ordinal clinical scale, based on the WHO R&D Blueprint Ordinal Clinical Scale (up to 21 days or hospital discharge) Difference in maximal hscTn levels between the 2 groups Time for C‐reactive protein (CRP) to reach levels > 3 times the upper reference limit Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: reported (up to day 20) Clinical status up to day 28, day 60, and up to longest follow‐up Worsening of clinical status; i.e. participants with clinical deterioration, defined as new need for invasive mechanical ventilation or death: reported Improvement of clinical status; i.e. participants discharged alive: NR Quality of life: NR Serious adverse events, defined as number of participants with event: NR, but data received on request Adverse events (any grade, grade 1–2, grade 3–4): NR Clinical status up to day 28, day 60, and up to longest follow‐up Worsening of clinical status New need for invasive mechanical ventilation: reported New need for non‐invasive mechanical ventilation or high flow: NR New need for oxygen by mask or nasal prongs: NR Improvement of clinical status Weaned or liberated from invasive mechanical ventilation, and surviving, in subgroup of participants requiring invasive mechanical ventilation at baseline: NR Ventilator‐free days: NR Duration to liberation from invasive mechanical ventilation: NR Liberation from supplemental oxygen in surviving participants, including the liberation from invasive mechanical ventilation: NR Duration to liberation from supplemental oxygen: NR Need for new dialysis up to 28 days: NR Admission to ICU up to day 28: NR Duration of hospitalisation: NR Viral clearance: NR Incidence of abdominal pain during study: reported Incidence of diarrhoea during study: reported Incidence of nausea and vomiting during study NR Additional study outcomes Number of treatment‐related adverse events (adverse effects)
Notes	Date of publication: 24 June 2020 Sponsor/funding: ELPEN Pharmaceuticals, Acarpia Pharmaceuticals, and Karian Pharmaceuticals.

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Horby 2021.

*Study characteristics*
Methods	Trial design: open‐label, randomised controlled platform trial Type of publication: preprint in medRxiv Setting: hospitalised Recruitment dates: 19 March 2020 (according to registration form at ClinicalTrials.gov) to 5 March 2021 Country: UK, Indonesia, Nepal Language: English Number of centres: 177 hospitals in the UK (supported by the National Institute for Health Research Clinical Research Network), 2 hospitals in Indonesia, and 2 hospitals in Nepal Trial registration number: NCT04381936, ISRCTN (50189673) Date of trial registration: 11 May 2020
Participants	Age: overall 63.4 (SD 13.8) years; colchicine group: 63.3 (SD 13.8) years; control group: 63.5 (SD 13.7) years Sex (n male): colchicine group: 3896 (69%); control group: 4012 (70%) Ethnicity (colchicine group vs control group, n (%)): white 4344 (77) vs 4383 (76); black, Asian, and minority ethnic 758 (14) vs 813 (14); unknown 508 (9) vs 534 (9) n recruited/allocated/evaluated: 19,423/11,340 (colchicine group: 5610; control group: 5730)/11,340 (colchicine group: 5610; control group: 5730) Participants with positive SARS‐CoV‐2 RT‐PCR test result (n): colchicine group: 5456 (97%); control group: 5553 (97%) Severity of condition according to study definition: moderate to severe Severity of condition according to WHO score (n) (WHO 2020b): WHO 4 and 5: colchicine group: 3815 (68%); control group: 3962 (69%) WHO 6: colchicine group: 1527 (27%); control group: 1507 (26%) WHO 7: colchicine group: 268 (5%); control group: 261 (5%) Co‐morbidities (colchicine group vs control group, n): diabetes 1426 (25%) vs 1470 (26%); heart disease 1189 (21%) vs 1231 (21%); chronic lung disease 1208 (22%) vs 1206 (21%), tuberculosis 16 (< 1%) vs 13 (< 1%); HIV 11 (< 1%) vs 20 (< 1%); severe liver disease 0 (0%) vs 0 (0%); severe kidney impairment 170 (3%) vs 166 (3%), any of the above 2880 (51%) vs 2963 (52%) Inclusion criteria Hospitalised patients with clinically suspected or laboratory‐confirmed SARS‐CoV‐2 infection No medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial Colchicine available in the hospital at the time No known indication for or contraindication to colchicine Written informed consent by participant or a legal representative Exclusion criteria Pregnancy Children Severe liver impairment Significant cytopenia Concomitant use of strong CYP3A4 or P‐glycoprotein inhibitors Hypersensitivity to lactose Previous treatments: NR
Interventions	Intervention group Colchicine: 1 mg after randomisation followed by 0.5 mg 12 hours later and then 0.5 mg twice daily for 10 days in total or until discharge, whichever occurred earlier dose frequency halved for participants receiving a moderate CYP3A4 inhibitor or who had renal impairment (eGFR < 30 mL/min/1.73 m²) or estimated bodyweight < 70 kg) administration route: oral or via nasogastric tube Comparator group Usual care Concomitant therapy (colchicine group vs control group, n) Lopinavir‐ritonavir 0 (0%) vs 4 (< 1%); corticosteroid 4780 (87%) vs 4895 (87%); hydroxychloroquine 11 (< 1%) vs 14 (< 1%); azithromycin or other macrolide 637 (12%) vs 755 (13%); tocilizumab or sarilumab 710 (13%) vs 775 (14%); remdesivir 1259 (23%) vs 1283 (23%); convalescent plasma 594 (11%) vs 606 (11%); REGN‐COV2 913 (17%) vs 1010 (18%); aspirin 2131 (39%) vs 2263 (40%) At randomisation, 10,603 (94%) of participants were receiving corticosteroids Duration of follow‐up: 28 days Treatment cross‐overs: 20 participants (< 1%) in the usual care group received colchicine Compliance with assigned treatment: among participants with a completed follow‐up form, 5122 (93%) allocated to colchicine received ≥ 1 dose
Outcomes	Primary study outcome All‐cause mortality at day 28 Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: reported (up to day 28) Clinical status up to day 28, day 60, and up to longest follow‐up Worsening of clinical status; i.e. participants with clinical deterioration, defined as new need for invasive mechanical ventilation or death: reported Improvement of clinical status; i.e. participants discharged alive: NR Quality of life: NR Serious adverse events: NR Adverse events (any grade, grade 1–2, grade 3–4): NR Clinical status up to day 28, day 60, and up to longest follow‐up Worsening of clinical status New need for invasive mechanical ventilation: reported New need for non‐invasive mechanical ventilation or high flow: NR New need for oxygen by mask or nasal prongs: NR Improvement of clinical status Weaned or liberated from invasive mechanical ventilation, and surviving, in subgroup of participants requiring invasive mechanical ventilation at baseline: reported Ventilator‐free days: NR Duration to liberation from invasive mechanical ventilation: NR Liberation from supplemental oxygen in surviving participants, including the liberation from invasive mechanical ventilation: NR Duration to liberation from supplemental oxygen: NR Need for new dialysis up to 28 days: reported Admission to ICU up to day 28: NR Duration of hospitalisation: reported Viral clearance: NR Incidence of abdominal pain during study: NR Incidence of diarrhoea during study: NR Incidence of nausea and vomiting during study: NR Additional study outcomes: none
Notes	Date of publication: 18 May 2021 Sponsor/funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056). Wellcome Trust (Grant Ref: 53 222406/Z/20/Z) through the COVID‐19 Therapeutics Accelerator.

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Lopes 2021.

*Study characteristics*
Methods	Trial design: randomised, double‐blind, placebo‐controlled trial Type of publication: journal article Setting: hospitalised Recruitment dates: started 11 April 2020, terminated 31 August 2020 Country: Brazil Language: English Number of centres: 1 Trial registration number: RBR‐8jyhxh Date of trial registration: 30 July 2020
Participants	Age (median): colchicine group: 54.5 (IQR 42.5–64.5) years; control group: 55.0 (IQR 42.0–67.0) years Sex (n male): colchicine group: 19 (53%); control group: 14 (39%) Ethnicity: NR n recruited/allocated/evaluated: 131/75/72 Participants with positive SARS‐CoV‐2 RT‐PCR test result: NR (RT‐PCR positivity required in inclusion criteria) Severity of condition according to study definition: moderate to severe Severity of condition according to WHO score (n) (WHO 2020b): WHO 4: colchicine group: 1 (3%); control group: 4 (11%) WHO 5: colchicine group: 28 (78%); control group: 24 (67%) WHO 6: colchicine group: 7 (19%); control group: 8 (22%) Co‐morbidities (colchicine group vs control group, n): respiratory diseases 4 (11%) vs 5(14%); cardiovascular diseases 17 (47%) vs 16 (44%); diabetes mellitus 13 (36%) vs 15 (42%); dyslipidaemia 10 (28%) vs 12 (33%); smoking currently or formerly 7 (19%) vs 9 (25%); BMI (median): 33.5 (IQR 28.6–37.8) kg/m² vs 29.7 (IQR 26.3–36.0) kg/m² Inclusion criteria Moderate to severe COVID‐19 Diagnosed by RT‐PCR in nasopharyngeal swab specimens and lung CT scan involvement compatible with COVID‐19 pneumonia Age > 18 years Bodyweight > 50 kg Normal levels of serum calcium and kalium QT interval < 450 mseconds at 12 derivations ECG (according to the Bazett formula) Negative serum or urinary β‐hCG if woman aged < 50 years Exclusion criteria Mild COVID‐19 Need for ICU admission Diarrhoea resulting in dehydration Known allergy to colchicine Diagnosis of porphyria, myasthenia gravis, or uncontrolled arrhythmia at enrolment Pregnancy or lactation Metastatic cancer or immunosuppressive chemotherapy Regular use of digoxin, amiodarone, verapamil, or protease inhibitors Chronic liver disease with hepatic failure Inability to understand the consent form
Interventions	Intervention group Colchicine: standard: 0.5 mg 3 times daily for 5 days, then 0.5 mg twice daily for 5 days if bodyweight ≥ 80 kg: first dose was 1.0 mg if participant with CKD: 0.25 mg 3 times daily for 5 days, then 0.25 mg twice daily for 5 days (independent of bodyweight) route of administration: oral Comparator group Placebo (corn starch), tablets with the same size and colour of colchicine Route of administration: oral Concomitant therapy (e.g. description of standard care) Azithromycin 500 mg once daily for up to 7 days, hydroxychloroquine 400 mg twice daily for 2 days, then 400 mg once daily for up to 8 days and unfractionated heparin 5000 IU 3 times daily until the end of hospitalisation Methylprednisolone 0.5 mg/kg/day for 5 days was added to the institutional protocol, for use if the patient's need for supplemental oxygen ≥ 6 L/min Duration of follow‐up: up to hospital discharge Treatment cross‐overs: none Compliance with assigned treatment: 1 participant in each group stopped drug/placebo intake due to ICU admission
Outcomes	Primary study outcomes Time of need for supplemental oxygen Time of hospitalisation Need for admission and length of stay in ICU Death rate and causes of mortality Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: reported (at hospital discharge) Clinical status up to day 28, day 60, and up to longest follow‐up Worsening of clinical status; i.e. participants with clinical deterioration, defined as new need for invasive mechanical ventilation or death: NR Improvement of clinical status; i.e. participants discharged alive: NR Quality of life: NR Serious adverse events, defined as number of participants with event: NR Adverse events (any grade, grade 1–2, grade 3–4): reported Clinical status up to day 28, day 60, and up to longest follow‐up Worsening of clinical status New need for invasive mechanical ventilation: reported New need for non‐invasive mechanical ventilation or high flow: NR New need for oxygen by mask or nasal prongs: NR Improvement of clinical status Weaned or liberated from invasive mechanical ventilation, and surviving, in subgroup of participants requiring invasive mechanical ventilation at baseline: NR Ventilator‐free days: NR Duration to liberation from invasive mechanical ventilation: NR Liberation from supplemental oxygen in surviving participants, including the liberation from invasive mechanical ventilation: reported (day 12) Duration to liberation from supplemental oxygen: NR Need for new dialysis up to 28 days: NR Admission to ICU: reported (up to day 15) Duration of hospitalisation: reported Viral clearance: NR Incidence of abdominal pain during study: reported Incidence of diarrhoea during study: reported Incidence of nausea and vomiting during study: reported Additional study outcomes Measures of serum CRP, serum lactate dehydrogenase and ratio neutrophil to lymphocyte of peripheral blood samples from day 0 to day 7 Number, type, and severity of adverse events; frequency of interruption of the study protocol due to adverse events Frequency of QT interval > 450 ms
Notes	Date of publication: 4 February 2021 Sponsor/funding: FAPESP grants (2013/08216‐2, 2020/05601‐6, 2020/04964‐8,2020/05288‐6), CNPq (425075/2016–8) and CAPES grants

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Tardif 2021.

*Study characteristics*
Methods	Trial design: randomised, double‐blind, placebo‐controlled trial Type of publication: journal article Setting: Non‐hospitalised Recruitment dates: 23 March 2020 to 11 December 2020 Country: 6 countries Language: English Number of centres: 22 Trial registration number: NCT04322682 Date of trial registration: 26 March 2020
Participants	Age (mean): colchicine group: 54.4 (SD 9.7) years; control group: 54.9 (SD 9.9) years Sex (n male): colchicine group: 997 (44.6%); control group: 1070 (47.5%) Ethnicity: (colchicine group vs control group, n): white 2086 (93.3%) vs 2096 (93.2%); black 114 (5.1%) vs 119 (5.3%) n recruited/allocated/evaluated: 4506/4488/4488 n with positive SARS‐CoV‐2 RT‐PCR test result: colchicine group: 2075 (92.8%); control group: 2084 (92.5%) Severity of condition according to study definition: non‐hospitalisedmild disease Severity of condition according to WHO score (WHO 2020b): WHO 1–3 (proportion of participants in each group NR) Co‐morbidities (colchicine group vs control group, n): hypertension 781 (34.9%) vs 848 (37.6%); diabetes 444 (19.9%) vs 450 (20.0%); respiratory disease 583 (26.1%) vs 605 (26.9%); prior myocardial infarction 65 (2.9%) vs 72 (3.2%); prior heart failure 24 (1.1%) vs 18 (0.8%) Inclusion criteria Diagnosis of COVID‐19 within 24 hours of enrolment (by PCR testing or clinical criteria) Aged ≥ 40 years Not currently hospitalised and not under immediate consideration for hospitalisation ≥ 1 of the following high‐risk criteria: aged ≥ 70 years; obesity (BMI ≥ 30 kg/m²); diabetes; uncontrolled hypertension (systolic blood pressure ≥ 150 mmHg); respiratory disease; heart failure; coronary disease; fever ≥ 38.4 °C within the last 48 hours; dyspnoea at time of presentation; bicytopenia, pancytopenia, or the combination of high neutrophil and low lymphocyte counts People who were either not of childbearing potential or were practicing adequate contraception Exclusion criteria Inflammatory bowel disease, chronic diarrhoea, or malabsorption Pre‐existent progressive neuromuscular disease eGFR < 30 mL/minute/1.73 m² Severe liver disease Current treatment with colchicine Current chemotherapy for cancer History of significant sensitivity to colchicine Previous treatments: NR
Interventions	Intervention group Colchicine: 0.5 mg twice daily for the first 3 days and then once daily for 27 days thereafter route of administration: oral Comparator group 0.5 mg twice daily for the first 3 days and then once daily for the last 27 days Route of administration: oral Concomitant therapy Colchicine group vs control group, n: hydroxychloroquine 12 (0.5%) vs 11 (0.5%); oral anticoagulant 48 (2.1%) vs 65 (2.9%); aspirin 195 (8.7%) vs 235 (10.4%); other platelet agent 32 (1.4%) vs 43 (1.9%) Duration of follow‐up: 30 days Treatment cross‐overs: NR Compliance with assigned treatment Vital and primary endpoint event status were available for all except for 93 participants (97.9%) Drop‐outs (n): withdrew consent: colchicine group: 33; control group: 45 Lost to follow‐up (n): colchicine group: 4; control group: 8
Outcomes	Primary study outcome Composite outcome of death or hospitalisation due to COVID‐19 infection (day 30), components of the outcome also reported separately Review outcomes All‐cause mortality at up to day 28, day 60, time‐to‐event, and up to longest follow‐up: reported (day 28 and longest follow‐up) Admission to hospital or death within 28 days: reported Symptom resolution at day 14, day 28, and up to longest follow‐up: NR Duration to symptom resolution: NR Quality of life: NR Serious adverse events: reported (day 30) Adverse events (any grade): reported (day 30) Clinical status at up to day 28 and up to the longest follow‐up Worsening of clinical status (moderate to severe COVID‐19 symptoms) Need for invasive mechanical ventilation: reported (day 30) Need for non‐invasive mechanical ventilation or high flow: NR Need for hospitalisation with need for oxygen by mask or nasal prongs: NR Need for hospitalisation without oxygen therapy: NR Viral clearance: NR Incidence of abdominal pain during study: NR Incidence of diarrhoea during study: reported Incidence of nausea and vomiting during study: NR Additional study outcomes: none
Notes	Date of publication: 27 May 2021 Sponsor/funding: Government of Quebec, the Bill and Melinda Gates Foundation, the National Institutes of Health and philanthropist Sophie Desmarais

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BMI: body‐mass index; COVID‐19: coronavirus disease 2019; CRP: C‐reactive protein; ECG: electrocardiogram; eGFR: estimated glomerular filtration rate; hscTn: high‐sensitivity cardiac troponin; ICU: intensive care unit; IQR: interquartile range; IL: interleukin; min: minute; n: number; NA: not applicable; n: number; NR: not reported; PaO₂: arterial blood partial pressure of oxygen; RT‐PCR: reverse transcription polymerase chain reaction; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus type 2; WHO: World Health Organization.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
CTRI/2020/08/027102	Colchicine for prevention of COVID‐19
CTRI/2020/09/028088	Intervention group received a combination of medicines (colchicine, aspirin, and montelukast)
IRCT20150623022884N3	Colchicine only given in combination with other medications (thymoquinone and thymol‐rich fractions)
Mareev 2021	Not an RCT: only 5/21 participants of the control group were truly randomised, the remaining 17 were retrospectively matched
NCT04359095	Intervention groups received a combination of medicines (colchicine, rosuvatatin/colchicine, rosuvatatin, emtricitabine, tenofovir)
NCT04392141	Colchicine in combination with another medicine vs standard care alone
NCT04492358	Wrong intervention: colchicine only combined with prednisone, not separately analysable
NCT04603690	Withdrawn

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COVID‐19: coronavirus disease 2019; RCT: randomised controlled trial.

Characteristics of studies awaiting classification [ordered by study ID]

IRCT20190804044429N5.

Methods	Trial design: 2‐arm parallel‐group randomised, double‐blind trial Sample size: 110 Setting: Hospitalised Country: Iran Language: English Number of centres: 1
Participants	Inclusion criteria Age > 18 years Diagnosis of COVID‐19 based on clinical criteria (presence of any symptoms of cough, shortness of breath, fever, and CT scan of the lungs for evidence of involvement consistent with COVID‐19 infection) or PCR and had clinical symptoms of COVID‐19 within 2 weeks Exclusion Pregnancy and lactation Severe hepatic insufficiency (Child‐Pugh C) Renal insufficiency (GFR < 30 mL/min/1.73 m²) Allergy history of colchicine Thrombocytopenia (platelets < 100,000/mm³) Not consent
Interventions	Intervention group Colchicine 2 mg tablet as loading dose then 1 mg daily for 7 days Route of administration: oral Comparator group Placebo Concomitant therapy Interferon‐1β 250 μg subcutaneous injection every other day for ≥ 3 doses Remdesivir 200 mg as first dose then 100 mg daily for 5 days Treatment cross‐overs: NR
Outcomes	Primary study outcomes (duration of follow‐up NR) Respiratory rate Blood oxygen saturation Fever recovery Therapeutic regimen safety CRP Lymphocyte count Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes, but duration of follow‐up NR Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up): unclear, maybe derivable from "respiratory rate," see primary study outcomes Duration of hospitalisation, or time to discharge from hospital: yes, but duration of follow‐up NR Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: probably yes, but duration of follow‐up NR Serious adverse events, defined as number of participants with event: probably yes, but duration of follow‐up NR Additional study outcomes: none
Notes	Recruitment status: recruitment complete Prospective completion date: NR Sponsor/funding: Mazandaran University of Medical Sciences

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IRCT20190810044500N5.

Methods	Trial design: double‐blind, randomised controlled trial Sample size: 152 reached (200 planned) Setting: Non‐hospitalised and hospitalised Country: Iran Language: English Number of centres: 2
Participants	Inclusion criteria Age 18–70 years Detection of COVID‐19 in the last 24–48 hours Candidate for hospitalisation (oxygensaturation < 93% or respiratory rate > 24 breaths/min or PaO₂/FiO₂ < 300) People with COVID‐19 hospitalised with hospital indications according to the guideline of the country People with pulmonary infiltration on CT scan Not pregnant or becoming pregnant until 30 days after the end of the study No consumption of colchicine during the last week Exclusion criteria History of Crohn's or ulcerative colitis, diarrhoea, or chronic malabsorption Neuromuscular diseases GFR < 30 mL/min/1.73 m² History of cirrhosis, hepatitis, and severe liver disease Receiving chemotherapy for cancer Currently receiving colchicine for other uses History of allergies to colchicine Pregnancy and lactation
Interventions	Intervention group Colchicine 0.5 mg/day for 1–3 days, and 1 mg/day for the next 12 days Route of administration: probably oral Comparator group Placebo from the first to the third day, 2 tablets of placebo and for the next 12 days, 1 daily dose Concomitant therapy: standard care including hydroxychloroquine 200 mg daily Treatment cross‐overs: NR
Outcomes	Primary study outcomes Clinical symptoms including fever, cough, shortness of breath (days 1, 3, 6–8, 14) Pulmonary infiltration findings on CT scan (2 weeks, 6–8 weeks) Oxygen saturation at the time of hospitalisation and discharge (days 1,3, 6–8, 14) Laboratory symptoms (ESR, CRP, NLR, LDH, ferritin, D‐dimer, CBC differential) (during hospitalisation, at discharge) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: probably yes (at discharge, follow‐up until day 14) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up): unclear, maybe derivable from primary study outcome (clinical symptoms) Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: yes (days 1, 3, 7, 6–8, 14) Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes: none
Notes	Recruitment status: recruitment completed Actual completion date: 14 January 2021 Sponsor/funding: Yazd University of Medical Sciences Colchicine dose reduced after day 3 (from 1 mg to 0.5 mg), while number of placebo tablets doubled at this time point (1 tablet to 2 tablets) Follow‐up/timings of measurement mistakably described in study registry

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IRCT20200408046990N2.

Methods	Trial design: randomised, triple‐blind, parallel‐group trial Sample size: 40 Setting: Hospitalised Country: Iran Language: English Number of centres: 1
Participants	Inclusion criteria Clinical or laboratory diagnosis of mild to moderate COVID‐19 Age 18–85 years Written consent Exclusion criteria Use of protease inhibitors History of allergy to colchicine Pregnancy or lactation Hepatic failure (Child‐Pugh C), kidney failure (GFR < 30 mL/min/1.73 m²), or heart failure with ejection fraction < 40% Concomitant use of CYP3A4 or P‐glycoprotein potent inhibitors Concomitant use of statins except rosuvastatin Active gastrointestinal disturbances such as active peptic ulcers Transmission of patients to ICU ward or his/her intubation Treatment of Behçet's disease with colchicine Mediterranean fever or gout History of neuromuscular disease, chronic diarrhoea, or malabsorption
Interventions	Intervention group Colchicine 1 mg tablet daily for 2 weeks Route of administration: orally Comparator group Placebo with same appearance of colchicine tablet, once daily for 2 weeks Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcomes Fever (daily, duration of follow‐up NR) Clinical response to treatment, including improvement of cough, myalgia, headache, olfactory and taste disorders (daily, duration of follow‐up NR) Radiological response, lung CT scan (14 days after treatment) Serum level of CRP and CBC with differential (weekly, duration of follow‐up NR) Adverse reactions (daily, duration of follow‐up NR) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: unclear, probably yes "Patients' clinical outcome at end of treatment" Clinical status, assessed by need for respiratory support with standardised scales: unclear, probably yes "Patients' clinical outcome at end of treatment" Duration of hospitalisation, or time to discharge from hospital: reported Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes: none
Notes	Recruitment status: completed Contact: Sepideh Elyasi, elyasis@mums.ac.ir Sponsor/funding: Mashhad University of Medical Sciences Duration of follow‐up unclear for several outcomes

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NCT04322565.

Methods	Trial design: randomised, controlled, open trial Sample size: 310 Setting: Hospitalised Language: English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Positive nasopharyngeal swab for COVID‐19 Asymptomatic or paucisymptomatic Aged ≥ 70 years or with clinical risk factors for poor outcome (clinically relevant chronic lung disease, diabetes, heart disease, or a combination of these), or both Symptomatic with respiratory or systemic symptoms Clinically stable (MEWS < 3) with CT imaging showing viral pneumonia and positive or pending pharyngonasal swab for COVID‐19 Temperature 38 °C or intensive cough, or both Respiratory rate < 25 breaths/min Oxygen saturation (pulse oximetry) > 95% Positive swab for COVID‐19 with respiratory or systemic symptoms, or both Initial mild respiratory failure with objective signs of lung involvement Stable conditions (MEWS < 3) Temperature > 38 °C or intensive cough, or both Respiratory rate ≥ 25 breaths/min Oxygen saturation 94–95% in room air Exclusion criteria Pregnant or breastfeeding MEWS ≥ 3 Hepatic failure (Child‐Pugh C) Enrolment in other pharmacological studies Ongoing treatment with colchicine Ongoing treatment with antiviral drugs that include ritonavir or cobicistat Any medical condition or disease which in the opinion of the Investigator may place the person at unacceptable risk for study participation
Interventions	Intervention group Colchicine 1 mg (or 0.5 mg in CKD)/day Route of administration: NR (probably oral) Comparator group Standard care Dose, route of administration): NR Concomitant therapy: standard care Treatment cross‐overs: NR
Outcomes	Primary study outcomes Clinical improvement of 2 points from the status at randomisation on a 7‐category ordinary scale (no reference reported) (day 28) Hospital discharge (day 28) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes for day 28 Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up: probably no (no reference to clinical status scale) Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020b) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): probably yes (need for mechanical ventilation, day 28) Weaning/liberation from mechanical ventilation: probably yes (need for mechanical ventilation, day 28) Worsening of clinical status Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): probably yes (need for mechanical ventilation, day 28) Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): NR Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): NR Duration of hospitalisation, or time to discharge from hospital: yes (days of hospitalisation) (day 28) Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Time to death (day 28) Time to negative test (day 21) Remission of fever in patients with temperature > 37.5 °C at enrolment (days 1, 4, 7, 14, 21, 28)
Notes	Recruitment status: completed, according to personal communication to the author Prospective completion date: 20 December 2020 Date last update was posted: 10 July 2020 Sponsor/funding: Azienda Ospedaliero‐Universitaria di Parma

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NCT04328480.

Methods	Trial design: simple, pragmatic randomised open controlled trial Sample size: 1279 Setting: Hospitalised Language: English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Consenting adults age ≥ 18 years COVID‐19 suspicious Admitted to hospital or already in hospital SARS with dyspnoea or image of typical or atypical pneumonia or oxygen desaturation (oxygen saturation ≤ 93%) Exclusion criteria Clear indication or contraindication for the use of colchicine Pregnant or breastfeeding women Chronic renal disease with creatinine clearance < 15 mL/min/m² Negative PCR test for SARS‐COV‐2
Interventions	Intervention group Dose: varying: Participants not receiving lopinavir/ritonavir: loading dose colchicine 1.5 mg followed by 0.5 mg after 2 hours (day 1). The next day 0.5 mg twice daily for 14 days or until discharge Participants receiving lopinavir/ritonavir: loading dose colchicine 0.5 mg (day 1). After 72 hours from the loading dose, 0.5 mg every 72 hours for 14 days or until discharge Treatment with colchicine but starting with lopinavir/ritonavir: dose colchicine 0.5 mg 72 hours after starting lopinavir/ritonavir. Continue with 0.5 mg every 72 hours for 14 days or until discharge Route of administration: oral or nasogastric tube (exception) Comparator group Standard care Dose, route of administration: NR Concomitant therapy: lopinavir/ritonavir Treatment cross‐overs: NR
Outcomes	Primary study outcome Composite outcome: new requirement for mechanical ventilation or death (day 28) Mortality (day 28) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: partially (up to day 28) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up: unclear (mean WHO descriptive score of COVID‐19 during hospitalisation, up to day 28) Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020b) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): NR Weaning or liberation from invasive mechanical ventilation in surviving participants, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7): NR Worsening of clinical status Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): NR Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): NR Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): yes (new requirement for mechanical ventilation, day 28) Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes New requirement for mechanical ventilation or death from respiratory failure (day 28) New requirement for mechanical ventilation or death from non‐respiratory failure (day 28) Mortality due to respiratory failure (day 28) Mortality due to non‐respiratory failure (day 28) In hospital: number of participants who require intubation for mechanical ventilation or die (day 28) In hospital: mortality (day 28) Number of participants who were not intubated at randomisation and require new intubation for mechanical ventilation or die (day 28) Mortality evaluated in non‐intubated population (day 28) Highest WHO descriptive score of COVID‐19 during hospitalisation (day 28)
Notes	Recruitment status: completed Prospective completion date: 30 March 2021 Date last update was posted: 27 April 2021 Sponsor/funding: Estudios Clínicos Latino América, Population Health Research Institute

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NCT04350320.

Methods	Trial design: prospective, randomised, controlled, open‐label trial Sample size: 102 Setting: Hospitalised Language: Spanish, English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria SARS‐CoV‐2 infection confirmed by PCR Admitted to hospital in previous 48 hours, with WHO clinical status 3, 4, or 5 Age > 18 years Informed written consent Exclusion criteria Invasive mechanical ventilation needed Established limitation of the therapeutic effort Inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhoea, or malabsorption Previous neuromuscular disease Other disease with an estimated vital prognosis < 1 year Severe renal insufficiency (GFR < 30 mL/min/1.73 m²) Medical records of cirrhosis, active chronic hepatitis, or severe hepatic disease defined by AST or ALT levels 3 times above the normal upper limit Previous colchicine treatment for other diseases. Clearance period will not be required for patients treated with colchicine who stopped the treatment before randomisation. History of allergic reaction or significant sensitivity to colchicine Treatment with immunosuppressive agents, corticoids, or interleukin‐1 antagonists for 6 months before inclusion Pregnant or breastfeeding women, confirmed by a positive result in the human chorionic gonadotropin test Fertile woman, or postmenopausal for < 1 year and non‐surgically sterilised. Women of fertile age may be included if using ≥ 1 contraceptive method and preferably 2 complementary contraceptive methods Use of other investigational drugs in the moment of inclusion, or for 30 days previous to inclusion
Interventions	Intervention group Dose: normal: colchicine initial dose 1.5 mg (1 mg and 0.5 mg 2 hours after), 0.5 mg every 12 hours for next 7 days and 0.5 mg every 24 hours until completion of 28 days of total treatment participants receiving ritonavir or lopinavir or with reduced renal clearance (< 50 mL/min/1.37 m²), weight < 70 kg or age > 75 years: half that dose Route of administration: tablet (oral) Comparator group Standard care Concomitant therapy: ritonavir, lopinavir Treatment cross‐overs: NR
Outcomes	Primary study outcome Changes in clinical status on 7‐point ordinal scale WHO R&D Blueprint expert group (days 7, 14, 28) Changes in IL‐6 concentrations (day 28) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: partially yes (up to day 28) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020b) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): NR Weaning or liberation from invasive mechanical ventilation in surviving participants, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7): NR Worsening of clinical status Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): NR Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): probably yes (number of days with high flow oxygen therapy, day 28) Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): yes (number of days with invasive mechanical ventilation, day 28) Duration of hospitalisation, or time to discharge from hospital: yes (day 28) Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: yes (day 28) Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Time needed to reduce ≥ 2 points in the 7‐point Ordinal Scale for Clinical Improvement by WHO R&D Blueprint expert group (up to day 28) Changes in the score for the Sequential Organ Failure Assessment score (day 28) Changes in the punctuation in the National Early Warning Score (day 28) Changes in other inflammatory markers (CRP, TNF‐alpha, GDF‐15, IL‐1β) (day 28) Changes in severity markers (D‐dimer, leukocytes, lymphocytes, platelets, LDH, ferritin) (day 28) Changes in myocardial damage (hsTnT, NT‐proBNP) (day 28) Time until reaching a COVID‐19‐negative status (day 28)
Notes	Recruitment status: completed Prospective completion date: 30 December 2020 Date last update was posted: 12 January 2021 Sponsor/funding: Fundacion para la Formacion e Investigacion Sanitarias de la Region de Murcia

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NCT04355143.

Methods	Trial design: open‐label, randomised controlled trial Sample size: 150 Setting: Hospitalised Language: English Number of centres: 2 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Confirmed COVID‐19 infection by PCR Cardiac injury, including any of the following Elevated troponin level Elevated BNP level New ischaemic or arrhythmogenic changes on ECG/telemetry New decrease in left ventricular ejection fraction or new pericardial effusion on echocardiogram Able to provide informed consent Exclusion criteria Pregnancy, breastfeeding mothers, and women of childbearing age who are unable to use 2 forms of contraception, which includes intrauterine devices, contraceptive implants, or tubal sterilisation hormone methods with a barrier method 2 barrier methods if a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must also be used in conjunction Co‐administration of CYPA3A4 and P‐glycoprotein transport system inhibitors Concurrent use of strong CYP3A4 or P‐glycoprotein inhibitors in people with renal or hepatic impairment Severe haematological or neuromuscular disorders Severe renal impairment with concomitant hepatic impairment
Interventions	Intervention group Colchicine 0.6 mg twice daily for 30 days Route of administration: oral Comparator group Current care per University of California, Los Angeles physicians alone Concomitant therapy: allowed: investigational drugs for COVID‐19 as new science emerges Treatment cross‐overs: NR
Outcomes	Primary study outcome Composite of all‐cause mortality, need for mechanical ventilation, or need for mechanical circulatory support (90 days) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes (up to 90 days) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up Worsening of clinical status Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): yes (90 days) Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): NR Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): NR Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020b) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): NR Weaning or liberation from invasive mechanical ventilation in surviving patients, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7): NR, may be indirect (number of participants requiring mechanical ventilation, day 90) Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Delta (peak minus baseline) troponin level (day 1, 30; day 3 and 7 if hospitalised) Delta (baseline to peak) BNP level (day 1, 30, day 3 and 7 if hospitalised) Change in left ventricular ejection fraction on echocardiography (day 1, 30) Delta (peak minus baseline) CRP inflammatory biomarker level (day 1, 30; day 3 and 7 if hospitalised) Delta (peak minus baseline) D‐dimer inflammatory biomarker level (day 1, 30; day 3 and 7 if hospitalised) Time (days) to primary study endpoint (day 90) Number of participants requiring mechanical circulatory support (day 90) Rehospitalisation (day 90) All‐cause mortality (day 90)
Notes	Recruitment status: recruiting Prospective completion date: 25 April 2021 Date last update was posted: 21 May 2020 Sponsor/funding: University of California, Los Angeles Other NCTs: NCT04762771, NCT04510038. The trial is registered 3 times (but is 2 times "suspended" due to RECOVERY evidence): first registration with placebo, second with standard care, third with other author name and double number of participants.

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NCT04510038.

Methods	Trial design: unblinded, randomised study Sample size: 75 Setting: Hospitalised Language: English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Age ≥ 18 years Cardiac injury (any of the following) Elevated troponin level Elevated BNP level New ischaemic or arrhythmogenic ECG/telemetry changes New decrease in LVEF or new pericardial effusion on echocardiogram Able to provide informed consent Exclusion criteria Pregnancy, breastfeeding mothers, and women of childbearing age who are unable to use adequate contraception including if a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must also be used in conjunction 2 barrier methods hormone method with a barrier method IUD, contraceptive implants, or tubal sterilisation History of severe haematological or neuromuscular disorder Co‐administration of CYPA3A4 and P‐glycoprotein transport inhibitor Severe renal impairment with concomitant hepatic impairment Concurrent use of colchicine and strong or P‐glycoprotein inhibitor with renal or hepatic impairment
Interventions	Intervention group Dose Standard: colchicine 0.6 mg twice daily for 30 days If gastrointestinal intolerance: colchicine 0.3–0.6 mg daily or every other day If weak or moderate CYP3A4 inhibitor: colchicine 0.6 mg daily If strong CYP3A4, P‐glycoprotein inhibitors, or protease inhibitors: colchicine 0.3 mg daily If CKD stage ≥ 4 (creatinine clearance ≤ 30 mL/min) or liver failure (AST/ALT > 3 × normal): colchicine 0.3 mg daily If ESRD or requiring dialysis: colchicine 0.6 mg every 14 days Route of administration: oral Comparator group Standard care as per treating physician Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcomes All‐cause mortality (90 days) Need for mechanical ventilation (90 days) Need for mechanical circulatory support (90 days) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes (up to day 90) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): NR Weaning or liberation from invasive mechanical ventilation in surviving participants, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7): probably yes (need for mechanical ventilation (90 days)) Worsening of clinical status Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): probably yes (need for mechanical ventilation (90 days)) Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): NR Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): NR Duration of hospitalisation, or time to discharge from hospital: yes (length of hospital stay, 90 days) Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Time to deterioration (90 days) Number of participants with treatment‐related adverse events as assessed by CTCAE v4.0 (90 days) Peak troponin levels (90 days) Troponin levels change from baseline (90 days) Change from baseline on BNP levels (90 days) Changes from baseline on CRP (90 days) Rehospitalisation rates (90 days) Changes in D‐dimer from baseline (90 days)
Notes	Recruitment status: suspended Prospective completion date: 1 January 2022 Date last update was posted: 21 February 2021 Sponsor/funding: Miami Cardiac and Vascular Institute Study acronym: COLHEART‐19

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NCT04527562.

Methods	Trial design: double (triple) blind, randomised, placebo‐controlled trial Sample size: 299 Setting: Hospitalised Language: English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Men and women age ≥ 18 years Able to swallow tablets Competent and willing to provide informed consent Diagnosis of COVID‐19 infection with positive RT‐PCR for SARS‐CoV‐2 within the last 3 days Moderate symptoms (according to National Guidelines on Clinical Management of Coronavirus Disease 2019 (COVID‐ 19). Version 7.0. 2020, DGHS, MOHFW, Government of the People's Republic of Bangladesh). Following features of moderate COVID‐19 must be present: Fever or history of fever Cough or shortness of breath, or both Oxygen saturation ≥ 94% Pneumonia – pulmonary consolidations on chest imaging (chest x‐ray or CT scan of chest) involving < 50% of lungs CRB 65 score 0 Exclusion criteria Pregnancy and breastfeeding Known hypersensitivity to colchicine Known chronic illness, e.g. hepatic failure, CKD (eGFR < 30 mL/min/1.73 m²), decompensated heart failure, long QT syndrome (QTc > 450 mseconds) Inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhoea, or malabsorption Currently receiving colchicine for other indications (mainly chronic indications represented by familial Mediterranean fever or gout) Undergoing chemotherapy for cancer Considered by the investigator, for any reason, to be an unsuitable candidate for the study.
Interventions	Intervention group Colchicine 1.2 mg (2 tablets of 0.6 mg) single or 12 hourly divided dose. After that: colchicine 0.6 mg daily for 13 days Route of administration: oral Comparator Placebo 2 tablets of placebo, single or 12 hourly divided doses. After that, they will take 1 placebo tablet daily for 13 days. Placebo tablet will be identical in appearance to the colchicine tablet. Concomitant therapy: supportive care (symptomatic treatment with paracetamol, fexofenadine, steam inhalation/gurgle of lukewarm water, monitoring by the attending nurses) Treatment cross‐overs: NR
Outcomes	Primary study outcome Clinical worsening assessed by 7‐category ordinal scale (WHO 2020d) (day 14) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes (day 14) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐u– Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020c) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): yes (day 14) Weaning or liberation from invasive mechanical ventilation in surviving participants, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7): yes (day 14) Worsening of clinical status Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): yes (day 14) Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): yes (day 14) Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): yes (day 14) Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR
Notes	Recruitment status: completed Prospective completion date: 10 December 2020 Date last update was posted: 11 January 2021 Sponsor/funding: Dhaka Medical College

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NCT04762771.

Methods	Trial design: open‐label unblinded, randomised trial Sample size: 75 Setting: Hospitalised Country: US Language: English Number of centres: 1
Participants	Inclusion criteria Age ≥ 18 years Covid‐19 positive Hospitalised patients able to provide informed consent Cardiac injury (as evidenced by any of the following) Elevated troponin level Elevated BNP level New ischaemic or arrhythmogenic ECG/telemetry changes New decrease in LVEF or new pericardial effusion on echocardiogram Exclusion criteria Pregnancy, breastfeeding mothers, and women of childbearing age who are unable to use adequate contraception, including IUD, contraceptive implants, or tubal sterilisation Hormone method with a barrier method 2 barrier methods If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must also be used in conjunction History of severe haematological or neuromuscular disorder Co‐administration of CYPA3A4 and P‐glycoprotein transport inhibitor Severe renal impairment with concomitant hepatic impairment Concurrent use of colchicine and strong or P‐glycoprotein inhibitor with renal or hepatic impairment
Interventions	Intervention group Dose Normal: colchicine 0.6 mg twice daily for 30 days If gastrointestinal intolerance: colchicine 0.3–0.6 mg daily or every other day If weak or moderate CYP3A4 inhibitor: colchicine 0.6 mg daily If strong CYP3A4, P‐glycoprotein inhibitors, or protease inhibitors; or CKD stage ≥ 4 (creatinine clearance ≤ 30 mL/min) or liver failure (AST/ALT > 3 × normal): colchicine 0.3 mg daily If ESRD or requiring dialysis: colchicine 0.6 mg every 14 days Route of administration: oral Comparator group Standard care Dose, route of administration: NR Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcomes All‐cause mortality (day 90) Need for mechanical ventilation (day 90) Need for mechanical circulatory support (day 90) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes (day 90) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020c) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): NR Weaning or liberation from invasive mechanical ventilation in surviving participants, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7): NR Worsening of clinical status Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): yes (day 90) Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): NR Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): NR Duration of hospitalisation, or time to discharge from hospital: yes (90 days) Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Time to either mortality or need for mechanical ventilation or mechanical circulatory support (90 days) Time of peak and delta (change from baseline) troponin level (90 days) Baseline BNP level (90 days) Baseline and delta (change from baseline) of CRP and D‐dimer (90 days) Need for rehospitalisation (90 days)
Notes	Recruitment status: suspended Actual completion date: 12 March 2021 Sponsor/funding: Baptist Health South Florida; University of California, Los Angeles Other NCT: NCT04355143

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Salehdazeh 2020.

Methods	Trial design: randomised, single‐blind (participants blind), placebo‐controlled trial Type of publication: preprint, Research Square Setting: probably hospitalised Recruitment dates: 21 May to 20 June 2020 Country: Iran Language: English Number of centres: 1 Trial registration number: IRCT20200418047126N1 Date of trial registration: 14 May 2020
Participants	Age (median): colchicine group: 56.56; control group: 55.56 Sex (n male): colchicine group: 19 (38%); control group: 22 (44%) Ethnicity: NR n recruited/allocated/evaluated: 100/100/100 Participants with positive SARS‐CoV‐2 RT‐PCR test result (n): NR (RT‐PCR positivity was an inclusion criterion) Severity of condition according to study definition: hospitalised participants (unclear whether this refers to disease severity) Severity of condition according to WHO score: NR Co‐morbidities (colchicine group vs control group, n): diabetes mellitus: 5 (10%) vs 6 (12%); ischaemic heart disease: 6 (12%) vs 9 (18%); hypertension: 3 (6%) vs 8 (16%); cancer/neoplasia: 1 (2%) vs 1 (2%); COPD: 0 (0%) vs 4 (8%); renal failure: 4 (8%) vs 1 (2%); hypothyroidism: 1 (2%) vs 1 (2%) Inclusion criteria Pulmonary involvement seen in CT scan compatible with COVID‐19 Positive PCR for COVID‐19 Exclusion criteria Sensitivity to any medications of regimens Renal failure Heart failure Pregnancy Participating in another clinical study Refusal to participate in the study before or during the follow‐up period Previous treatments: NR
Interventions	Intervention group Colchicine 1 mg daily for 6 days Route of administration: oral Comparator group Placebo Tablet Concomitant therapy Hydroxychloroquine for 6 days and azithromycin in the therapy period (no details) Duration of follow‐up: unclear Treatment cross‐overs: NR Compliance with assigned treatment: NR
Outcomes	Primary study outcomes Length of hospitalisation symptoms Co‐existing diseases Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: NR Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up: NR Duration of hospitalisation, or time to discharge from hospital: reported, but very suspicious: same numbers in table 1 for "time from suffering to enrolment" Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Mortality and morbidity (14 days after hospital discharge) Re‐admission (14 days after hospital discharge) Symptoms (14 days after hospital discharge)
Notes	Date of publication: preprint 21 September 2020 Sponsor/funding: "Authors declare any private funding in this study" Very suspicious: same numbers in table 1 for at "time from suffering to enrolment" Duration of follow‐up unclear Secondary endpoints only partly reported Data concerning chronic obstructive pulmonary disease not plausible No answer to our questions via email Preprint posted in September 2020, but no peer‐reviewed publication available until now

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ALT: alanine aminotransferase; AST: aspartate transaminase; BNP: B‐type natriuretic peptide; CBC: complete blood count; CKD: chronic kidney disease; COVID‐19: coronavirus disease 2019; CRB: confusion, respiratory rate, blood pressure; CRP: C‐reactive protein; CT: computer tomography; CTCAE v4.0: Common Terminology Criteria for Adverse Events Version 4.0; ECG: electrocardiogram; eGFR: estimated glomerular filtration rate; ESR: erythrocyte sedimentation rate; ESRD: end‐stage renal disease; FiO₂: fraction of inspired oxygen; GDF: growth/differentiation factor; GFR: glomerular filtration rate; hsTnT: high‐sensitive troponin T; ICU: intensive care unit; IL: interleukin; IUD: intrauterine device; LDH: lactose dehydrogenase; LVEF: left ventricular ejection fraction; MEWS: Modified early warning score; min: minute; NLR: neutrophil to lymphocyte ratio; NR: not reported; NT‐proBNP: N‐terminal pro B‐type natriuretic peptide; PaO₂: partial pressure of oxygen; PCR: polymerase chain reaction; SARS: severe acute respiratory syndrome; TNF: tumour necrosis factor; WHO: World Health Organization.

Characteristics of ongoing studies [ordered by study ID]

EUCTR2020‐001511‐25.

Study name	Randomized open‐blind controlled trial to study the benefit of colchicine in patients with COVID‐19
Methods	Trial design: controlled, randomised, open trial Sample size: 102 Setting: Hospitalised Language: Spanish, English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Infection confirmed by SARS‐CoV‐2 by RT‐PCR Hospital admission in the previous 48 hours for clinical involvement in groups 3, 4 or 5 of the WHO clinical scale Age > 18 years Granting of informed consent in writing Exclusion criteria Need for invasive ventilatory support Limitation of therapeutic effort due to poor vital prognosis Inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhoea, or malabsorption Previous neuromuscular disease Different disease with estimated life prognosis < 1 year Severe kidney failure (GFR < 30 mL/min/1.73 m²) History of cirrhosis, active chronic hepatitis, or severe liver disease defined by AST or ALT values that exceed 3 × upper limit of normal Receiving colchicine for other indications (mainly chronic prescriptions for family Mediterranean fever or gout) (no washout period will be required for participants who have been treated with colchicine and have stopped treatment before randomisation) History of allergic reactions or significant sensitivity to colchicine Treatment with immunosuppressants, corticosteroids, IL‐1 antagonists in the 6 months prior to inclusion Pregnant or lactating women Fertile, or postmenopausal for < 1 year and not surgically sterilised Women of childbearing potential who are using ≥ 1 contraceptive method and preferably 2 complementary methods of contraception, including a barrier method (male or female condoms, spermicides, sponges, foams, contraceptive gels, diaphragms, intrauterine device) may be included throughout the entire study and up to 30 days after the end of the study Use of other investigational drugs at the time of enrolment, or during the 30 days prior to enrolment
Interventions	Intervention group Colchicine 0.5 mg tablet Route of administration: oral Comparator group Other medicinal product(s), not further described Dose, route of administration: NR Concomitant therapy: NR Treatment cross‐overs: none
Outcomes	Primary study outcomes Changes in the clinical status of participants on the 7‐point ordinal scale (WHO R&D Blueprint expert group) at 7, 14, and 28 days Change in IL‐6 concentrations up to 28 days Review outcomes All‐cause mortality at day 28 day 60, and up to longest follow‐up: probably yes (all‐cause mortality, timing of measurement unclear "end of study") Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up): probably yes (7‐point ordinal scale (WHO R&D Blueprint expert group)) Duration of hospitalisation, or time to discharge from hospital: yes Admission to ICU: yes Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Improvement of clinical status defined as time to reduction of ≥ 2 points on the WHO 7‐point ordinal scale Changes in the Sequential Organ Failure Scale during hospitalisation and time to 50% reduction with respect to randomisation Changes in NEWS severity scale score during hospitalisation and time to NEWS score ≤ 2 or 50% reduction from randomisation Number of days in invasive mechanical ventilation or ECMO Number of days with oxygen at high flow Changes of other inflammatory markers: CRP, TNF‐alpha, GDF‐15, IL‐1β up to 28 days with respect to randomisation Changes in severity markers: D‐dimer, leukocytes, lymphocytes, platelets, LDH and ferritin up to 28 days with respect to randomisation Changes in markers of myocardial damage: hsTnT and NT‐proBNP up to 28 days with respect to randomisation Time to viral negative by RT‐PCR
Starting date	Unclear, first registered 15 April 2020
Contact information	Corresponding author: NR Contact point designated by the sponsor Name of organisation: FFIS Email: Lola.serna@carm.es
Notes	Recruitment status: ongoing Prospective completion date: unclear, study duration: 6 months Sponsor/funding: ISCarlos iii, FFIS Other: use of old WHO 7‐Scale (R&E Blueprint)

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EUCTR2020‐001841‐38.

Study name	Colchicine for the treatment of hyperinflammation associated with pneumonia due to COVID‐19
Methods	Trial design: controlled, randomised, open trial Sample size: 240 Setting: Hospitalised Language: Spanish, English Number of centres: 8 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria People hospitalised for COVID‐19 (microbiological confirmation and chest X‐ray compatible with pneumonia are required) Hyperinflammation Verbal informed consent (written consent on paper would carry a risk of contagion for healthcare personnel) (model consent is given). Participant's consent will be noted in the patient's medical record. Exclusion criteria Haemodynamically instability Already receiving invasive or non‐invasive ventilation (CPAP/BiPAP) Pregnant, lactating, or considering pregnancy in the following 6 months. In women with the possibility of undiagnosed pregnancy, pregnancy should be ruled out using a urine test Indication of treatment with kaletra Included in other clinical trials Cirrhosis, active hepatitis, or severe liver failure Chronic inflammatory disease in active phase Diarrhoea that does not respond to diet or medication Chronic immunosuppressive treatment Neutrophils < 500 cell/mm³ or platelets < 50,000 cell/mm³, or both Severe renal failure (renal glomerular filtration < 30 mL/min/1.7m²) Already under treatment with colchicine Age < 18 years
Interventions	Intervention group Dose: colchicine 0.5–1 mg Route of administration: oral Comparator group Other medicinal product(s) Concomitant therapy: NR Treatment cross‐overs: none
Outcomes	Primary study outcomes (days 0, 2, and 5) Support compound with CPAP/BiPAP (non‐invasive ventilation) ICU admission Invasive ventilation Death Cytokine levels (IL‐6) and inflammatory parameters (PCR, ESR, ferritin, fibrinogen, blood count) at recruitment, at 48 hours and on the fifth day of treatment. Ultrasensitive troponin on the fifth day of treatment Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: death (timing and method of measurement unclear) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up): probably yes (see primary study outcomes) Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: yes Length of stay on ICU, or time to discharge from ICU: yes (admission to ICU) Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: partially, only for admission to hospital for venous or arterial thromboembolism (up to day 60)
Starting date	Unclear, first registered on 26 May 2020
Contact information	Corresponding author: NR Contact point designated by the sponsor Name of organisation: Sociedad Española de Cardiología Name of contact: Alberto Cecconi Email: alberto.cecconi@salud.madrid.org
Notes	Recruitment status: ongoing Prospective completion date: 4 months anticipated, registered May 2020 Date last update was posted: 1 January 2021 Sponsor/funding: Sociedad Española de Cardiología

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ISRCTN86534580.

Study name	A trial evaluating treatments for suspected coronavirus infection in people aged 50 years and above with pre‐existing conditions and those aged 65 years and above
Methods	Trial design: platform randomised trial Sample size: NR Setting: NR Country: UK Language: English Number of centres: NR
Participants	Inclusion criteria Tested positive for COVID‐19 or with COVID‐19 symptoms Within the first 14 days of COVID‐19 illness Age > 65 years or age 18–64 years with shortness of breath from the illness or certain underlying health conditions that put them at risk of severe illness Exclusion criteria Women who are pregnant or breastfeeding People taking certain medications People with inflammatory bowel disease
Interventions	Intervention group Colchicine 500 μg tablets for 14‐days Route of administration: oral Comparator group Standard care Dose, route of administration: NR Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	NR Follow‐up will be 28 days
Starting date	NR
Contact information	NR
Notes	Recruitment status: recruiting Prospective completion date: NR Sponsor/funding: University of Oxford/Clinical Trials and Research Governance Waiting for updated protocol or trial registration, current information extracted from press release "PRINCIPLE COVID‐19 treatments trial widens to under 50s and adds colchicine"

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jRCT2071200078.

Study name	A randomized double‐blind placebo controlled phase 2 clinical trial to assess anti‐inflammatory effect of colchicine (DRC3633) in mild to moderately severe COVID‐19 patients (DRC‐06C)
Methods	Trial design: randomised double‐blind placebo‐controlled phase 2 trial Sample size: 100 Setting: Hospitalised Country: Japan Language: English Number of centres: 1
Participants	Inclusion criteria Definitive diagnosis of COVID‐19 and written informed consent Oxygen saturation > 94% at room air and having ≥ 1 of the following pneumonia shadow on chest imaging > 1 risk factors of the following: diabetes mellitus, cardiovascular disease (coronary disease, stroke, peripheral arterial disease, heart failure), chronic obstructive pulmonary disease, chronic kidney disease (30 mL/min/1.73 m² ≤ eGFR < 60 mL/min/1.73 m²), obesity (BMI ≥ 30), age ≥ 65 years Hospitalised within 5 days after the onset of symptoms and with the ability of administrating the investigational drug by the second day of hospitalisation Age > 20 years at informed consent Participants or partners of participants agreed to prevent pregnancy for 90 days from the day of initiating investigational drug Able to understand and willing to sign an IRB approved written informed consent document Exclusion criteria Asymptomatic people People previously diagnosed COVID‐19 Known allergy or intolerance to colchicine Receiving colchicine within the past 30 days of consent date Receiving biological drug within the past 30 days of consent date Receiving oral or intravenous corticosteroids within the past 30 days of informed consent date Liver cirrhosis Clinical cholestasis Renal failure (eGFR < 30 mL/min/1.73 m²) Active or history of malignant disease Receiving the following medicines: medicines strongly inhibiting CYP3A4: atazanavir, clarithromycin, indinavir, itraconazole, nelfinavir, ritonavir, saquinavir, darunavir, telithromycin, telaprevir, drugs containing kobishistat medicines moderately inhibiting CYP3A4: amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil medicines inhibiting P glycoprotein: ciclosporin receiving amiodarone or quinidine Pregnant, possibly pregnant, or willing to become pregnant women; breastfeeding women Registered in other clinical trials/studies at informed consent date or in the past 30 days of informed consent date Considered inappropriate by attending physicians
Interventions	Intervention group Colchicine 1.5 mg on day 1, then once daily colchicine 0.5 mg days 2–28 Route of administration: oral Comparator group Placebo Dose, route of administration): 1.5 mg placebo on day 1, then once daily oral administration of from day 2 to 28 Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcome Area under the curve of amount of change of serum CRP from baseline at 1, 2, and 4 weeks after initiating investigational drug Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: NR Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up: NR Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Amount of change and area under the curve of neutrophil counts and lymphocyte counts (and its ratio), IL‐1β, IL‐6, TNF‐alpha, D‐dimer, ferritin, von Willebrand factor, troponin, NT‐proBNP, LDH from baseline at 1, 2, and 4 weeks after initiating investigational drug
Starting date	13 January 2021
Contact information	Corresponding author Name: Kinjo Takeshi Affiliation: University of the Ryukyus Graduate School of Medicine Full Address: 207, Uehara, Nakagami, Nishihara, Okinawa Email: drc‐06c@ml.u‐ryukyu.ac.jp
Notes	Recruitment status: recruiting Prospective completion date: NR Sponsor/funding: NR

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NCT04324463.

Study name	Anti‐coronavirus therapies to prevent progression of coronavirus disease 2019 (COVID‐19) trial (ACTCOVID19)
Methods	Trial design: open‐label, parallel group, factorial, randomised controlled trial Sample size: 4000 Setting: Non‐hospitalisedand hospitalised Country: Brazil, Canada, Chile, Colombia, Ecuador, Egypt, India, Pakistan, Russia, Saudi Arabia, United Arab Emirates Language: English Number of centres: 71
Participants	Non‐hospitalised setting Inclusion criteria Symptomatic and laboratory‐confirmed diagnosis of COVID‐19 Age ≥ 18 years High risk: either age ≥ 70 years or 1 of the following: male; obesity (BMI ≥ 30); chronic cardiovascular, respiratory or renal disease; active cancer; diabetes Within 7 days (ideally 72 hours) of diagnosis, or worsening clinically Exclusion criteria General: advanced kidney disease; advanced liver disease; pregnancy (known or potential) or lactation Colchicine: allergy or planned use; current or planned use of cyclosporin, verapamil, HIV protease inhibitor, azole antifungal, or macrolide antibiotic (except azithromycin) Aspirin: allergy; high risk of bleeding, current or planned use of other anti‐thrombotic drugs (e.g. P2Y12 inhibitors, direct oral anticoagulants, vitamin K antagonists, heparins) Hospitalised setting Inclusion criteria Symptomatic and laboratory‐confirmed diagnosis of COVID‐19 Age ≥ 18 years Within 72 hours (ideally 24 hours) of admission, or worsening clinically Exclusion criteria General: advanced kidney disease; advanced liver disease, pregnancy (known or potential) or lactation, already ventilated for > 72 hours Interferon‐β: known monoclonal gammopathy, history of severe depression/anxiety Colchicine: allergy or planned use; current or planned use of cyclosporin, verapamil, HIV protease inhibitors, azole antifungals, or macrolide antibiotics (except azithromycin) Aspirin and rivaroxaban: allergy; high risk of bleeding; estimated GFR < 15 mL/min/1.73 m²; current or planned use of P2Y12 inhibitors or therapeutic doses of anticoagulants* (e.g. direct oral anticoagulants, vitamin K antagonists, heparin, low‐molecular weight heparin), current or planned use of strong inhibitors of both CYP 3A4 and P‐glycoprotein (e.g. lopinavir/ritonavir, carbamazepine, ketoconazole). *Note that prophylactic doses of anticoagulants can be used in people who are randomised to control
Interventions	Intervention group Dose Non‐hospitalised: colchicine 0.6 mg twice daily for 3 days, then 0.6 mg once daily for 25 days (total 28 days) Hospitalised: colchicine 1.2 mg followed by 0.6 mg 2 hours later, then 0.6 mg twice daily for 28 days Route of administration: oral Comparator group Standard care Dose, route of administration: no constraints for treating physicians on the therapies within the standard care group Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Non‐hospitalised setting Primary study outcome Composite outcome of hospitalisation or death (45 days) Review outcomes All‐cause mortality at day 28, day 60, and up to longest follow‐up: probably yes (day 45), if composite primary outcome is reported separately Development of moderate to severe clinical COVID‐19 symptoms, defined as WHO Clinical Progression Scale ≥ 4 (WHO 2020c), up to longest follow‐up: unclear, maybe derivable from "Disease progression scale," see additional study outcomes Quality of life, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 30 days, and longest follow‐up available: NR Admission to hospital: probably yes (day 45), if composite primary outcome is reported separately Time to symptom onset: NR Length of hospital stay, for subgroup of participants hospitalised during course of disease: NR Admission to ICU: unclear, maybe derivable from "Disease progression scale," see additional study outcomes Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Disease progression by 2 points on a 7‐point scale (day 45) Hospitalised setting Primary study outcome Composite outcome of invasive mechanical ventilation or death Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: probably yes (day 45), if composite primary outcome is reported separately Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up) Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020b) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): unclear, maybe derivable from "Disease progression scale," see additional study outcomes Weaning or liberation from invasive mechanical ventilation in surviving participants, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7); unclear, maybe derivable from "Disease progression scale," see additional study outcomes Worsening of clinical status Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): probably yes (day 45), if composite primary outcome is reported separately Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): unclear, maybe derivable from "Disease progression scale," see additional study outcomes Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): unclear, maybe derivable from "Disease progression scale," see additional study outcomes Duration of hospitalisation, or time to discharge from hospital: NR Serious adverse events, defined as number of participants with event: NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Need for dialysis (at up to 28 days): NR Admission to ICU: unclear, maybe derivable from "Disease progression scale," see additional study outcomes Length of stay on ICU, or time to discharge from ICU: NR Additional study outcomes Disease progression by 2 points on a 7‐point scale (day 45)
Starting date	21 April 2020
Contact information	Contact information ACT COVID‐19 study co‐ordinator Email: ACT.ProjectTeam@PHRI.ca
Notes	Recruitment status: recruiting Prospective completion date: 30 June 2021 Sponsor/funding: Population Health Research Institute, Bayer

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NCT04360980.

Study name	The effects of standard protocol with or without colchicine in Covid‐19 infection
Methods	Trial design: randomised, double‐blind (no placebo, risk of unblinding) Sample size: 80 Setting: Hospitalised Language: English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Age > 18 years Nasopharyngeal swab confirmed COVID‐19 PCR CT involvement compatible with COVID‐19 Fever and dyspnoea without hypoxaemia Exclusion criteria Unwilling to enter in study Known hypersensitivity to colchicine Hepatic failure Renal failure with eGFR < 20 mL/min/1.73 m²
Interventions	Intervention group Colchicine 1.5 mg loading then 0.5 mg twice daily Route of administration: oral Comparator group Standard care Dose, route of administration: vitamin C 3 g daily, tiamine 400 mg, selenium, omega‐3 500 mg daily, vitamin A, vitamin D, azithromycin, ceftriaxone, kaletra 400 twice daily for 10 days) Concomitant therapy: standard treatment protocol including essential minerals, vitamins as antioxidants, antibiotics, and kaletra (lopinavir/ritonavir) Treatment cross‐overs: NR
Outcomes	Primary study outcomes CRPxN/R ratio change (day 14) Clinical deterioration by WHO definition (not referenced), including change in fever or oxygen saturation (day 14) PCR viral load (day 14) CT severity involvement index (day 14) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: NR Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up): unclear ("Clinical deterioration by the WHO definition," not referenced) Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes LDH change (day 14)
Starting date	20 March 2020
Contact information	Corresponding author Name: Nooshin Dalili Affiliation: CKDRC,SBMU Full Address: NR Email: nooshindalili4@gmail.com
Notes	Recruitment status: recruiting Prospective completion date: 30 November 2021 Date last update was posted: 31 December 2020 Sponsor/funding: Shahid Beheshti University of Medical Sciences

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NCT04363437.

Study name	Colchicine in moderate‐severe hospitalized patients before ARDS to treat COVID‐19 (COMBATCOVID19)
Methods	Trial design: prospective, randomised, open‐label, controlled study Sample size: 70 Setting: Hospitalised Language: English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Age ≥ 18 years Willing and able to provide written informed consent prior to performing study procedures Currently hospitalised and requiring medical care for COVID‐19 Significant COVID‐19 symptom, or judged by the treating provider to be at high risk of progression to severe COVID‐19 infection Dyspnoea, respiratory rate ≥ 30 breaths/min, blood oxygen saturation ≤ 93% AND ≥ 1 of the following: positive PCR test or positive antibodies or CT/chest X‐ray consistent with COVID‐19 infection or anosmia Exclusion criteria Requirement of oxygen supplementation > 8 L nasal cannula Pregnancy Known hypersensitivity to colchicine Currently in shock or with haemodynamic instability requiring pressors History of cirrhosis ALT or AST > 5 × upper limit of normal Severe renal disease, creatinine clearance < 30mL/min Requiring invasive mechanical ventilation at screening or clinical estimation that the person will require mechanical respiratory support within 24 hours Currently taking colchicine for other indications (gout or familial Mediterranean fever) Received remdesivir, sarilumab, tocilizumab, lopinavir/ritonavir or other immunomodulator given for COVID‐19 treatment (note: convalescent plasma infusion is not an exclusion) On (and cannot discontinue) a strong CYP3A4 inhibitor (e.g. clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, atazanavir), a moderate CYP3A4 inhibitor (e.g. diltiazem, verapamil, fluconazole, amprenavir, aprepitant, fosamprenavir) or a P‐glycoprotein inhibitor (e.g. cyclosporin, ranolazine) Chemotherapy for cancer Patient is considered by the investigator, for any reason, to be unsuitable candidate for the study
Interventions	Intervention group Dose colchicine 1.2 mg followed by 0.6 mg after 2 hours if without significant gastrointestinal symptoms next day: 0.6 mg twice daily for 14 days or until discharge participants who are receiving HMG‐CoA reductase inhibitors (atorvastatin, fluvastatin, pravastatin, simvastatin), fibrates, gemfibrozil, amiodarone, dronedarone or digoxin, colchicine 0.6 mg followed by 0.3 mg after 2 hours followed by 0.3 mg twice daily for 14 days or until discharge Route of administration: NR Comparator group Usual medical therapy (can include medications such as hydroxychloroquine, azithromycin) Dose, route of administration: NR Concomitant therapy: NR Treatment cross‐over: NR
Outcomes	Primary study outcome Percentage of participants requiring supplemental oxygen beyond 8 L nasal cannula (2 months) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up) Improvement of clinical status Liberation from supplemental oxygen in surviving patients, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020b) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): NR Weaning or liberation from invasive mechanical ventilation in surviving participants, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7): probably yes (percentage of participants who will require mechanical ventilation, 2 months) Worsening of clinical status Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): probably yes (percentage of patients who will require mechanical ventilation, 2 months) Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): NR Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): NR Duration of hospitalisation, or time to discharge from hospital: yes (hospital length of stay, 2 months) Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Maximum CRP (2 months) Maximum troponin elevation (2 months)
Starting date	26 April 2020
Contact information	Corresponding author Name: Felix Yang, MD Affiliation: Maimonides Medical Center Full address: Brooklyn, New York, US, 11219 Email: fyang@maimonidesmed.org
Notes	Recruitment status: recruiting Prospective completion date: 14 June 2020 Date last update was posted: 8 May 2020 Sponsor/funding: Maimonides Medical Center

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NCT04367168.

Study name	Colchicine twice daily for 10 days as an option for the treatment of symptoms induced by inflammation in patients with mild and severe coronavirus disease (ColchiVID)
Methods	Trial design: randomised, placebo‐controlled double‐blind trial Sample size: 174 Setting: Hospitalised Language: Spanish, English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Age > 18 years Diagnosed with COVID‐19 with mild or severe disease In‐hospital care at the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran Able to take tablets orally Exclusion criteria Concomitant participation in another clinical trial Hypersensitivity to colchicine Pregnancy and lactation Age > 70 years Kidney failure with creatinine clearance < 30 mL/min Known liver failure Concomitant medication that has interactions with colchicine and that due to its indication cannot be suspended or substituted
Interventions	Intervention group Colchicine 1 mg, 1½ tablets in day 1 and ½ tablet twice daily for 10 days Route of administration: NR Comparator group Placebo Dose, route of administration: placebo, 1½ tablets in day 1 and ½ tablet twice daily for 10 days Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcomes Number of participants with improvement in body temperature, myalgia, arthralgia, total lymphocyte count, D‐dimer, fibrinogen and ferritin levels (24 days) Progression to severe disease (≥ 1 of the following: respiratory failure, respiratory rate > 30 breaths/min, oxygen saturation < 92%, PaO₂/FiO₂ < 300 mmHg) (10 days) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: partially (up to day 28): NR Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up): unclear (mean WHO descriptive score of COVID‐19 during hospitalisation, up to day 28): NR Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR
Starting date	27 May 2020
Contact information	Corresponding author Name: José J Torres‐Ruiz, MD, MSc Affiliation: Instituto Nacional de Ciencias Medicas y Nutricion Full Address: Mexico City, Mexico, 14080 Email: josetorresruiz85@gmail.com
Notes	Recruitment status: recruiting Prospective completion date: 27 April 2021 Date last update was posted: 28 May 2020 Sponsor/funding: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

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NCT04375202.

Study name	Colchicine in COVID‐19: a pilot study (COLVID‐19)
Methods	Trial design: interventional, pilot, multicentre, randomised, open‐label, phase II study Sample size: 308 Setting: Hospitalised Language: English Number of centres: 9 Type of intervention (treatment/prevention): treatment (phase II)
Participants	Inclusion criteria Informed consent for participation in the study Virological diagnosis of SARS‐CoV‐2 infection (RT‐PCR) Hospitalised due to clinical/instrumental diagnosis of pneumonia Oxygen saturation at rest in ambient air ≤ 94%, PaO₂/FiO₂ ratio 350:200 Exclusion criteria Hypersensitivity to colchicine or its excipients Severe diarrhoea Cannot take oral therapy Pregnant and lactating women Severe cardiac, renal insufficiency (creatinine clearance < 30 mL/min) Kidney or liver damage (AST or ALT > 5 times the normal limits in International Units); or are taking CYP3A4 enzyme – P‐glycoprotein inhibitors Known other clinical condition that contraindicates colchicine and cannot be treated or solved according to the judgement of the clinician Neutrophil count < 1000/mm³ Platelet count < 50,000/mm³ Bowel diverticulitis or perforation Already in ICU or requiring mechanical ventilation Receiving tocilizumab Already enrolled in other clinical trials
Interventions	Intervention group Dose: weight < 100 kg: colchicine 0.5 mg 3 times a day weight > 100 kg: colchicine 1 mg twice a day for 30 days or up to discharge reduce based on gastrointestinal symptoms appearance at discretion of the Investigator Route of administration: oral Comparator group Current care Dose, route of administration): NR Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcome Rate of entering the critical stage (30 days) (combined outcome) Respiratory failure occurs and requires mechanical ventilation Other organ failure needing ICU monitoring and treatment Death Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes (day 28), if reported separately (see primary study outcome) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up): NR on standardised scale, need for non‐invasive ventilation and need for mechanical ventilation combined with other outcomes (see additional study outcome) Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: yes (day 28), if reported separately (see primary study outcome) Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes White blood cell count Change of Sequential Organ failure Assessment Rate of biochemical criterion (creatine kinase, ALT, ferritin) recovery Rate of disease remission (combined outcome, any of the following) No fever, cough, and other symptoms Oxygen saturation > 94% or PaO₂/FiO₂ > 350 mmHg without oxygen inhalation
Starting date	18 April 2020
Contact information	Corresponding author Name: Carlo Perricone Affiliation: Reumatologia, Dipartimento di Medicina, Università degli Studi di Perugia Email: carlo.perricone@unipg.it
Notes	Recruitment status: recruiting Prospective completion date: 31 October 2021 Date last update was posted: 5 November 2020 Sponsor/funding: University of Perugia

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NCT04416334.

Study name	Preemptive therapy with colchicine in patients older than 60 years with high risk of severe pneumoniae due to coronavirus (COLCHI‐COVID)
Methods	Trial design: phase III clinical trial, randomised, single‐centre, opened, controlled study Sample size: 954 Setting: Non‐hospitalised Language: Spanish, English Number of centres: "single‐centre" according to study authors but 4 locations named Type of intervention (treatment/prevention): prevention
Participants	Inclusion criteria Age ≥ 60 years Diagnosis of COVID‐19 infection in the last 72 hours and confirmed by PCR Patient in outpatient follow‐up or institutionalised in senior centres/residences ≥ 2 of the following high‐risk criteria Age ≥ 60 years Any of the following: diabetes mellitus, hypertension, pulmonary disease (including asthma or chronic obstructive pulmonary disease), heart failure, coronary disease, bicytopenia, pancytopenia, or the existence of simultaneous neutrophilia and lymphopenia Must be able and willing to comply with the requirements of this study protocol Exclusion criteria Hospitalised person or under immediate consideration of doing so Receiving colchicine for other indications History of allergic reaction or sensitivity to colchicine Inflammatory bowel disease, gastric ulcer, chronic diarrhoea, or malabsorption Pre‐existing progressive neuromuscular disease Kidney damage and eGFR < 30 mL/min/1.73 m² Undergoing chemotherapy for cancer, including haematological malignancies Being treated with CYP3A4 or glycoprotein inhibitor drugs, or both Immunosuppressive treatment History of cirrhosis, chronic active hepatitis, severe chronic disease defined by AST or ALT values exceeding 3 times the upper limit of normal If the investigator considers it, for any reason, to be an inadequate candidate Patient or legal representative have not signed the informed consent form
Interventions	Intervention group Colchicine 0.5 mg orally twice daily for the first 3 days and then once daily for the last 18 days Route of administration: oral Comparator group Standard care Dose, route of administration: NR Concomitant therapy: symptomatic treatment (paracetamol or best symptomatic treatment based on doctor recommendations) Treatment cross‐overs: NR
Outcomes	Primary study outcome Number of participants who die due to COVID‐19 infection (21 days) Number of participants who require hospitalisation due to COVID‐19 infection (21 days) Review outcomes All‐cause mortality at day 28, day 60, and up to longest follow‐up: NR Development of moderate to severe clinical COVID‐19 symptoms, defined as WHO Clinical Progression Scale ≥ 4 (WHO 2020c), up to longest follow‐up: NR Quality of life, assessed with standardised scales: NR Admission to hospital: NR (specific for hospitalisation due to COVID‐19 infection) Time to symptom onset: NR Length of hospital stay, for subgroup of participants hospitalised during course of disease: NR Admission to ICU: NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes: none
Starting date	19 August 2020
Contact information	Corresponding author Name: Carlos Richard Affiliation: Instituto de Investigación Marqués de Valdecilla Email: carlos.richard@scsalud.es
Notes	Recruitment status: recruiting Prospective completion date: 31 December 2021 Date last update was posted: 20 November 2020 Sponsor/funding: Instituto de Investigación Marqués de Valdecilla

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NCT04516941.

Study name	Coronavirus edoxaban colchicine (CONVINCE) COVID‐19
Methods	Trial design: randomised, open, 2 × 2 factorial design Sample size: 420 Setting: Non‐hospitalised Language: English Number of centres: 2 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Laboratory confirmed SARS‐CoV‐2 infection (with RT‐PCR) Managed at home or in another out‐of‐hospital setting Exclusion criteria Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including Child‐Pugh C cirrhosis with portal hypertension Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration; presence of malignant neoplasms at high risk of bleeding; recent brain or spinal injury; recent brain, spinal, or ophthalmic surgery; recent intracranial haemorrhage; known or suspected oesophageal varices; arteriovenous malformations; vascular aneurysms or major intraspinal or intracerebral vascular abnormalities Uncontrolled severe hypertension Ongoing or planned treatment with parenteral or oral anticoagulants Unilateral or bilateral above knee lower extremity amputation. Inability to take oral medication or otherwise unable or unwilling to undergo/perform study‐specified procedures Have received or will receive an experimental drug or used an experimental medical device within 30 days before the planned start of treatment Pregnancy or breastfeeding or any plan to become pregnant during the study. Women (and men, for colchicine group only) with childbearing potential not using adequate contraception method (note: if oral contraception is not feasible, both partners should use adequate barrier contraceptives) Need for dual anti‐platelet therapy consisting of aspirin and an oral P2Y12 inhibitor Inflammatory bowel disease, chronic diarrhoea, or neuromuscular disease Creatinine clearance < 15 mL/min Anticipated use of hydroxychloroquine Participation in any other clinical trial Inability to understand the requirements of the study and to provide informed consent
Interventions	Intervention group Colchicine 0.5 mg twice daily for the first 3 days, then once daily from randomisation to day 14 (SD 3) days. Treatment could be continued to day 25 (SD 3 days) Route of administration: oral Comparator groups Active comparator: edoxaban tablets Active comparator: edoxaban tablets combined with colchicine Control: no intervention Dose, route of administration: edoxaban tablets: 60 mg once daily, or 30 mg once daily in people with creatinine clearance ≤ 50 mL/min or bodyweight ≤ 60 kg from randomisation to end of study visit at day 25 (SD 3 days), taken orally Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcome Composite endpoint (edoxaban vs no active treatment, day 22–28) of asymptomatic proximal deep‐vein thrombosis symptomatic proximal or distal deep‐vein thrombosis symptomatic pulmonary embolism or thrombosis myocardial infarction ischemic stroke non‐CNS systemic embolism or death Composite endpoint (colchicine vs no active treatment, day 11–17) of Viral clearance (RT‐PCR) death or hospitalisation Review outcomes All‐cause mortality at day 28, day 60, and up to longest follow‐up: NR (only cause‐specific deaths) Development of moderate to severe clinical COVID‐19 symptoms, defined as WHO Clinical Progression Scale ≥ 4 (WHO 2020c), up to longest follow‐up: NR Need for invasive mechanical ventilation, non‐invasive mechanical ventilation or high flow, i.e. WHO ≥ 6, severe disease: probably yes (need for non‐invasive or invasive ventilation, day 25) Need for hospitalisation with or without supplemental oxygen, i.e. WHO 4–5, moderate disease: NR Quality of life, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days, up to 30 days, and longest follow‐up available: NR Admission to hospital: NR Time to symptom onset: NR Length of hospital stay, for subgroup of participants hospitalised during course of disease: NR Admission to ICU: NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Number of participants with asymptomatic proximal deep‐vein thrombosis Number of participants with symptomatic proximal or distal deep‐vein thrombosis Number of participants with symptomatic pulmonary embolism or thrombosis Number of participants with myocardial infarction Number of participants with ischaemic stroke Number of participants with non‐central nervous system systemic embolism Number of deaths (classified in 5 categories with respect to cause: thromboembolism, cardiovascular, bleeding, pulmonary, other known cause. In general, all deaths will be assumed to be due to thromboembolism or pulmonary in nature unless another cause is obvious)
Starting date	1 October 2020
Contact information	Corresponding author Name: Prof Dr Stephan Windecker Affiliation: Bern University Hospital Full Address: Bern University Hospital, Bern, Switzerland, 3010 Email: mailto:Stephan.Windecker%40insel.ch?subject=NCT04516941, CONVINCE Version 1.0 12052020, CorONa Virus edoxabaN ColchicinE (CONVINCE) COVID‐19
Notes	Recruitment status: not yet recruiting Prospective completion date: 31 December 2021 Date last update was posted: 18 August 2020 Sponsor/funding: University Hospital Inselspital, Berne, Collaborator: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company

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NCT04539873.

Study name	Impact of colchicine in hospitalised Colombian patients with COVID‐19 (COLCOVID19)
Methods	Trial design: phase IIIa, prospective, open‐label, randomised, parallel‐group study Sample size: 128 Setting: Hospitalised Language: Spanish, English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Age ≥ 18 years Nasopharyngeal swab by positive RT‐PCR in last 48 hours Hospital admission for COVID‐19 in previous 48 hours Clinical stage 3 (no supplemental oxygen requirement) or 4 (supplemental oxygen requirement for nasal contact lenses or mask) of the WHO classification Able and willing to provide informed written consent Exclusion criteria Pregnancy, nursing mothers, and women of childbearing potential who are unable to use adequate contraception Known hypersensitivity or other clear contraindication to the use of colchicine History of end‐stage renal disease (eGFR < 30 mL/min/1.73 m²) Medical history of cirrhosis (Child‐Pugh C), liver failure, chronic active hepatitis, or severe liver disease defined by ALT or AST > 5 times the upper limit of normal History of pre‐existing neuromuscular disease Previous severe haematological disease or bleeding disorders Inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhoea, or malabsorptive syndrome Colchicine treatment for other indications Treatment with immunosuppressive/immunomodulatory agents, including glucocorticoids, antivirals, antimalarials, and IL‐6 antagonists for 30 days prior to enrolment Use of other investigational drugs at the time of inclusion, or during the 30 days prior to inclusion Any medical condition or disease that, in the opinion of the investigator, may place the patient at unacceptable risk to participate in the study
Interventions	Intervention group Colchicine initial dose 1.5 mg on the first day, followed by 0.5 mg every 12 hours on days 2 to 7 and continuing with 0.5 mg a day until completing 14 days (SD 1 day) Route of administration: orally Comparator group Standard care Dose, route of administration: treatment in adherence to the Colombian guidelines (Colombian Consensus of the Colombian Association of Infectious Diseases), and to standard treatment Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcome Admission to ICU (15 days) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes (15 days) Clinical status, assessed by the need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d) at up to day 28, day 60, and up to longest follow‐up: NR Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with the event: NR Serious adverse events, defined as the number of participants with the event: NR Additional study outcomes: none
Starting date	15 March 2021
Contact information	Corresponding author Name: Giovanni Montealegre Email: giosurg@hotmail.com
Notes	Recruitment status: not yet recruiting Prospective completion date: 15 September 2021 Date last update was posted: 23 April 2021 Sponsor/funding: Fundación Universitaria de Ciencias de la Salud

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NCT04667780.

Study name	Study to investigate the treatment effect of colchicine in patients with COVID‐19
Methods	Trial design: phase III, prospective, pragmatic, randomised, controlled and open‐label trial Sample size: 102 Setting: Hospitalised Language: English Number of centres: 1 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria SARS‐CoV‐2 infection confirmed by PCR Admitted to hospital in the previous 48 hours, with WHO clinical status 3, 4, or 5 Age > 18 years Informed written consent Exclusion criteria Invasive mechanical ventilation needed Established limitation of the therapeutic effort Inflammatory bowel disease (Crohn's disease or ulcerative colitis), chronic diarrhoea, or malabsorption Previous neuromuscular disease Other disease with an estimated vital prognosis < 1 year Severe renal insufficiency (GFR < 30 mL/min/1.73 m²) Medical records of cirrhosis, active chronic hepatitis or severe hepatic disease defined by AST or ALT levels 3 times above the normal upper limit Previous colchicine treatment for other diseases, clearance period will not be required for patients treated with colchicine who stopped the treatment before the randomisation History of allergic reaction or significant sensitivity to colchicine Treatment with immunosuppressive agents, corticoids or IL‐1 antagonists for 6 months before inclusion Pregnant or breastfeeding women, confirmed by a positive result in the human chorionic gonadotropin test Fertile woman, or postmenopausal women for < 1 year and non‐surgically sterilised. Women of fertile age may be included if using ≥ 1 contraceptive method and preferably 2 complementary contraceptive methods Use of other investigational drugs in the moment of inclusion, or during 30 days previous to inclusion
Interventions	Intervention group Dose Normal: initial dose of colchicine 1.5 mg (1 mg and 0.5 mg 2 hours after), followed by 0.5 mg every 12 hours for the next 7 days and 0.5 mg every 24 hours until the completion of 14 days of total treatment Participants receiving ritonavir or lopinavir or with reduced renal clearance (< 50 mL/min/1.37 m²), weight < 70 kg or age > 75 years: dose will be halved Route of administration: NR Comparator group Standard care Dose, route of administration): NR Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcomes Changes in clinical status assessed by 7‐category ordinal scale (WHO 2020d) (14 days) Changes in IL‐6 concentrations (14 days) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes (14 days) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020b), WHO Ordinal Scale for Clinical Improvement (WHO 2020c) at up to day 28, day 60, and up to longest follow‐up) Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020b) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): yes (14 days) Weaning or liberation from invasive mechanical ventilation in surviving participants, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7): yes (14 days) Worsening of clinical status Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): yes (14 days) Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): yes (14 days) Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): yes (14 days) Duration of hospitalisation, or time to discharge from hospital: yes (14 days) Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: yes (number of days in ICU, 14 days) Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Changes in Sequential Organ Failure Assessment score (14 days) Changes in the punctuation in the NEWS scale (14 days) Changes in other inflammatory markers (CRP) (14 days) Changes in severity markers (D‐dimer, leukocytes, lymphocytes, platelets, LDH, ferritin) (14 days) Changes in myocardial damage (hsTnT, NT‐proBNP) (14 days) Time until reaching a COVID‐19 virus‐negative status (14 days)
Starting date	10 December 2020
Contact information	Corresponding author Name: Dr Zeeshan Haroon Affiliation: Ayub Teaching Hospital Full Address: Abbottabad, Khyber Pakhtunkhwa, Pakistan, 22010 Email: mailto:zeeshanharoon%40yahoo.com?subject=NCT04667780, ATH/IRB/Colchicine/25.11.2020, Study to Investigate the Treatment Effect of Colchicine in Patients With COVID‐19
Notes	Recruitment status: recruiting Prospective completion date: 9 July 2021 Date last update was posted: 16 December 2020 Sponsor/funding: Ayub Teaching Hospital, Universidad de Murcia

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NCT04724629.

Study name	Survival trial using cytokines in COVID‐19 (STRUCK)
Methods	Trial design: multicentre, adaptive, open‐label, randomised study (1: 1: 1: 1 ratio) Sample size: 60 Setting: Hospitalised (severe to critical) Language: English Number of centres: 2 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Positive result in the quantitative real‐time PCR (qPCR) test for SARS‐CoV‐2 in the respiratory tract Pneumonia confirmed by chest imaging Respiratory rate ≥ 24 IRPM (for adults) or O2 saturation < 93% or No improvement in oxygen saturation, despite oxygen supply or Arterial hypotension; or Changes in capillary filling time; or Changes in level of consciousness; or Oliguria Exclusion criteria Age <18 years Refuse to sign the informed consent form Patient's decision that their involvement is not in their interest Severe known liver disease (e.g. cirrhosis, with aminotransferase levels > 5 times the reference value limit) Pregnancy or breastfeeding Severe bacterial infection Severe diarrhoea Diverticulitis or intestinal perforation HIV Presence of 1 of the following uncontrolled or unstable cardiovascular diseases: stroke, ECG‐confirmed acute ischemia or myocardial infarction, clinically significant dysrhythmia History of gastrointestinal bleeding, uncontrolled peptic ulcer, or uncontrolled duodenal ulcer History of haemophilia or other bleeding disorders History of organ transplantation, congenital immunodeficiency
Interventions	Intervention group Colchicine 0.5 mg every 8 hours for 3 days, followed by 4 weeks (SD 7 days) 0.5 mg twice daily Route of administration: oral Comparator group Ixekizumab 80 mg per week, (SC) once a week for 4 weeks or until discharge; or 1.5 million IU per day (SC) for 7 days or until discharge. Patients will receive study medication Aldesleukin 1.5 million IU per day (SC), for 7 days or until discharge; standard treatment, supplementation of oxygen ventilation + standard treatment of the institution, which may include Dexamethasone, Corticoids, and antiretrovirals Concomitant therapy: NR Treatment cross‐over: NR
Outcomes	Primary study outcome Proportion of participants with clinical improvement, defined by an increase of 2 points in the ordinal scale of 7 WHO categories (day 21) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes (day 30) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d) at up to day 28, day 60, and up to longest follow‐up Improvement of clinical status Liberation from supplemental oxygen in surviving patients, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020b) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): yes (time until independence from oxygen therapy in days) (day 30) Weaning or liberation from invasive mechanical ventilation in surviving patients, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7): probably yes Worsening of clinical status: yes (worsening pulmonary involvement: need to increase FIO₂ to keep oxygen saturation stable or the need for mechanical ventilation; increase in the number or extension of affected lung areas on chest CT, or both) (days 7, 14, and 28) Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): probably yes (In patients who needed mechanical ventilation, time to indicate mechanical ventilation, day 0–45) Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): yes Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): yes Duration of hospitalisation, or time to discharge from hospital: yes (day 28) Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Ventilator‐free days (day 30) Analysis of in‐hospital mortality (day 0–45) Changes from baseline of cytokine storm surrogate markers (days 0, 2, 4, 7, 14, 21, and 28) Change in Score for Sepsis score (days 7 and 14) Analysis of secondary infections (day 30) Qualitative and quantitative assessment of treatment‐ related adverse effects assessed by the Common Terminology Criteria for Adverse Event version 5.0 (day 30)
Starting date	5 January 2021
Contact information	Corresponding author Name: Poliana Goulart Affiliation: Hospital e Maternidade Christovão da Gama Email: qualidade@svriglobal.com
Notes	Recruitment status: recruiting Prospective completion date: 30 July 2021 Date last update was posted: 26 January 2021 Sponsor/funding: University of Sao Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Science Valley Research Institute

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NCT04756128.

Study name	Impact of colchicine and low‐dose naltrexone on COVID‐19 (COLTREXONE)
Methods	Trial design: 4‐arm, prospective, randomised, open‐label trial Sample size: 164 Setting: Hospitalised Language: English Number of centres: 2 Type of intervention (treatment/prevention): treatment
Participants	Inclusion criteria Men and non‐pregnant, non‐breastfeeding women aged ≥ 18 years Requiring admission to Methodist or Regions Hospital due to laboratory‐confirmed COVID‐19 Meets criteria of only up to moderate COVID‐19 disease as defined by a clinical score of 2 or 3 at the time of enrolment, and ≥ 1 of the following: dyspnoea limiting usual activities on baseline oxygen needs respiratory rate ≥ 30 breaths/min on oxygen or room air blood oxygen saturations < 94% on room air (or on baseline oxygen needs if on supplemental oxygen prior to presentation at the hospital for a condition unrelated to COVID‐19) requiring supplemental oxygen above baseline needs (i.e. prior to presentation at hospital) Ability to provide written informed consent Exclusion criteria Severe/critical COVID‐19 as defined by study protocol or requiring oxygen supplementation ≥ 6L nasal cannula at screening In shock as defined by haemodynamic instability requiring vasopressors Current hospitalisation for COVID‐19 ≥ 7 days at the time of screening Require mechanical respiratory support within 48 hours of enrolment Person will be discharged within 48 hours of enrolment EITHER symptom onset OR a positive COVID‐19 laboratory test occurred > 10 days prior to enrolment Concomitant influenza A or B at time of hospitalisation if tested as part of emergency department/hospital admission Pregnant or breastfeeding at time of hospital admission Diagnosis of chronic kidney disease stage ≥ 4 Creatinine clearance < 30 mL/min or requiring renal replacement therapy History of cirrhosis or advanced liver disease, or active hepatic viral infection Transplant of kidney, lung, heart, or liver in the past 2 years Uncontrolled severe gastrointestinal disorders, Crohn's disease, ulcerative colitis, chronic diarrhoea, diarrhoea predominant irritable bowel syndrome, active stomach or intestinal ulcer, or one that was treated within the last 6 months Currently receiving P‐glycoprotein AND strong CYP3A4 inhibitors with creatinine clearance < 60 mL/min, or any combination of drug interactions that is not amenable to dosage adjustment Actively undergoing chemotherapy for an active malignancy, or history of haematological malignancies Chronic or current use of colchicine or any μ‐opioid antagonist Chronic, scheduled opioid therapy (i.e. not intermittent as‐needed use), or, prior to enrolment, an acute condition requiring continued pain control that is unattainable without ongoing opioid therapy Pre‐existing condition treated with tocilizumab, anakinra, sarilumab, other IL antagonists, TNF inhibitors, or JAK inhibitors Participation in any other clinical trial of an experimental treatment for COVID‐19, note: while convalescent plasma is no longer recommended, it can be given if deemed appropriate by the medical team once ≥ 24 hours has elapsed since enrolment; patients previously enrolled in the C3PO study can enrol in this study, as any convalescent plasma received would have been outpatient; remdesivir is allowed per standard protocol; dexamethasone is allowed per standard protocol Actively enrolled in hospice or who are 'do not intubate' or on palliative care History of hypersensitivity reaction to colchicine or its inactive ingredients History of hypersensitivity reaction to naltrexone or its inactive ingredients Incarcerated or a ward of the state Considered an unsuitable candidate, for any reason, by study investigators
Interventions	Intervention group Colchicine 0.6 mg twice daily for up to 28 days Route: oral Comparator groups Colchicine 0.6 mg twice daily for up to 28 days (oral) AND naltrexone 4.5 mg once daily for up to 28 days (oral suspension) Naltrexone 4.5 mg once daily for up to 28 days (oral suspension) Standard care, may include remdesivir treatment Concomitant therapy: NR Treatment cross‐over: NR
Outcomes	Primary study outcome Progression from 'moderate' to 'severe/critical' on WHO ordinal scale (day 14) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: yes (at hospital discharge) Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020b), WHO Ordinal Scale for Clinical Improvement (WHO 2020c) at up to day 28, day 60, and up to longest follow‐up Improvement of clinical status Liberation from supplemental oxygen in surviving participants, i.e. WHO ≤ 4 on the Clinical Progression Scale (WHO 2020b) (for the subgroup of participants requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≥ 5): yes (total duration of time above baseline oxygen requirements) Weaning or liberation from invasive mechanical ventilation in surviving patients, i.e. WHO ≤ 6 (for the subgroup of participants requiring invasive mechanical ventilation at baseline, i.e. WHO ≥ 7) Worsening of clinical status: yes (see primary endpoint) Need for invasive mechanical ventilation, i.e. WHO 7–9 (for the subgroup of participants not requiring invasive mechanical ventilation at baseline, i.e. WHO ≤ 6): yes (total duration of intubation) Need for non‐invasive mechanical ventilation or high flow, i.e. WHO 6 (for the subgroup of participants not requiring non‐invasive or non‐invasive mechanical ventilation, or high flow oxygen at baseline, i.e. WHO ≤ 5): probably yes (total duration of time spent on HFNC or NIPPV) Need for oxygen by mask or nasal prongs, i.e. WHO 5 (for the subgroup of participants not requiring any supplemental oxygen or ventilator support at baseline, i.e. WHO ≤ 4): yes (total duration of time above baseline oxygen requirements) Duration of hospitalisation, or time to discharge from hospital: yes (total amount of time (in hours) participant spent in hospital from admission to discharge AND from first dose of any study medication to discharge) Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: yes Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Total duration of time above baseline oxygen requirements In hospital days with a fever ≥ 38 °C Incidence of adverse events associated with the study drug (day 60) Incidence of significant adverse outcomes associated with/attributable to COVID‐19 (day 60) Acute respiratory distress syndrome Thromboembolic disease Myocardial injury Acute kidney injury Myocardial injury Encephalopathic delirium Cumulative dose of corticosteroids received Discharge anticoagulation needs Continuous laboratory results: BNP, CRP, D‐dimer, ferritin, serum creatinine, procalcitonin, troponin, ALT/AST/alkaline phosphatase, bilirubin, protein/albumin, red blood cell count, white blood cell count, platelets, neutrophil, absolute lymphocyte, absolute monocytes, absolute eosinophils, absolute basophils, absolute haematocrit, % immature granulocytes (%), haemoglobin (g/dL)
Starting date	25 January 2021
Contact information	Corresponding author Name: Dan Delaney Affiliation: PharmDPark Nicollet Methodist Hospital Email: NR
Notes	Recruitment status: enrolling by invitation Prospective completion date: 31 December 2021 Date last update was posted: 18 February 2021 Sponsor/funding: HealthPartners Institute, Park Nicollet Foundation

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NCT04818489.

Study name	Colchicine and post‐COVID‐19 pulmonary fibrosis
Methods	Trial design: open‐label, randomised controlled trial Sample size: 250 Setting: not defined, probably hospitalised Country: Egypt Language: English Number of centres: 1
Participants	oInclusion criteria Confirmed COVID‐19 clinically, radiologically, and PCR Age > 18 years Informed written consent Exclusion criteria History of hypersensitivity to colchicine Pregnancy or breastfeeding women Severe renal impairment (creatinine clearance < 30 mL/min) Severe hepatic impairment (AST or ALT > 5 times the normal limits Blood dyscrasias, neutrophils < 1000/mm³ or platelets < 50,000/mm³ History of severe cardiac insufficiency History of pulmonary fibrosis Severe diarrhoea, bowel diverticulitis, or perforation Cannot take oral therapy Already in ICU or requiring mechanical ventilation Already enrolled in other clinical trials Taking P‐glycoprotein inhibitor (e.g. ciclosporin, verapamil, or quinidine) or a CYP3A4 inhibitor (e.g. ritonavir, remdesivir, atazanavir, indinavir, clarithromycin, telithromycin, itraconazole, or ketaconazole) or tocilizumab
Interventions	Intervention group Colchicine 0.5 mg twice per day as a loading dose, followed by 1 tablet 0.5 mg twice per day for 3 weeks Route of administration: oral Comparator group Standard care. Local standard protocol for COVID‐19 Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcome Clinical status on a 7‐category ordinal scale (day 14) Pulmonary fibrosis at week 2 (day 14) Pulmonary fibrosis at 45 days (day 45) Review outcomes All‐cause mortality at day 28, day 60, and hospital discharge: NR, unclear whether assessed by clinical status scale Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale (WHO 2020c), WHO Ordinal Scale for Clinical Improvement (WHO 2020d)) at up to day 28, day 60, and up to longest follow‐up: NR, unclear whether assessed by clinical status scale Duration of hospitalisation, or time to discharge from hospital: NR Admission to ICU: NR, unclear whether assessed by clinical status scale Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional study outcomes Change in CRP (day 14) Change in ferritin (day 14) Change in ESR (day 14) Change in LDH (day 14) Adverse reactions ("adverse events related to the study medication") (day 45) Pulmonary function test: FVC (day 45) Pulmonary function test: FEV₁ (day 45)
Starting date	25 March 2021
Contact information	Corresponding author Name: Mariam Maged, MD Affiliation: El‐Demerdash Hospital, Cairo, Egypt Email: mailto:mariamaged%40yahoo.com?subject=NCT04818489, PR00202, Colchicine and Post‐COVID‐19 Pulmonary Fibrosis
Notes	Recruitment status: recruiting Prospective completion date: 25 May 2021 Sponsor/funding: ClinAmygate

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NCT04867226.

Study name	Effectiveness of colchicine among patients with COVID‐19 infection
Methods	Trial design: open‐label, randomised controlled trial Sample size: 100 Setting: Hospitalised and non‐hospitalised Country: Iraq Language: English Number of centres: 1
Participants	Inclusion criteria Diagnosed clinically or by RT‐PCR test or lung involvement confirmed by CT scan compatible with people with COVID‐19, or both Age 18–70 years Bodyweight > 50 kg Written informed consent from participants or relatives Exclusion criteria Sensitivity to any medications of regimens GFR < 30 mL/min/1.73 m² Pregnancy Malignancy Participating in another clinical study and refusing to participate in the study at a later date or later, and they are already taking colchicine for other diseases
Interventions	Intervention group Dose Normal: colchicine 0.5 mg twice daily, for 14 days or until symptoms subside Low bodyweight or adverse effects: reduced to 0.5 mg/day, for 14 days or until symptoms subside Route of administration: orally Comparator group Standard care Dose and treatment details: NR Concomitant therapy: none Treatment cross‐overs: NR
Outcomes	Primary study outcome Number of participants needing supplemental oxygen (14 days) Number of participants admitted to hospital and duration of stay (14 days) Number of participants needing invasive mechanical ventilation (14 days) Mortality (14 days) Review outcomes for people with moderate to severe disease (hospitalised setting) All‐cause mortality at day 28, day 60, and hospital discharge: NR Clinical status, assessed by need for respiratory support with standardised scales Improvement of clinical status: NR Worsening of clinical status Need for invasive mechanical ventilation: yes (14 days) Need for non‐invasive mechanical ventilation or high flow: NR Need for oxygen by mask or nasal prongs: NR Duration of hospitalisation, or time to discharge from hospital: yes (14 days) Admission to ICU: NR Length of stay on ICU, or time to discharge from ICU: NR Need for dialysis (at up to 28 days): NR Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event: NR Serious adverse events, defined as number of participants with event: NR Additional/other review outcomes for asymptomatic people or people with mild disease (non‐hospitalised setting) All‐cause mortality at day 28, day 60, and up to longest follow‐up: NR Development of moderate to severe clinical COVID‐19 symptoms: NR Need for hospitalisation with or without supplemental oxygen, i.e. WHO 4–5, moderate disease: NR Quality of life: NR Admission to hospital: yes (14 days) Time to symptom onset: NR Length of hospital stay: yes (14 days) Additional study outcomes Oxygen saturation measurement (14 days) Back pain and myalgia measure by patient analogue scale of pain (14 days) Change of CRP (14 days) Change of ferritin (14 days) Change of D‐dimer (14 days) Change of leukocytes (14 days) Number of participants who develop adverse effects with treatment (14 days)
Starting date	8 May 2021
Contact information	Corresponding author Name: Aryan MF Jalal, M.B.ch.B Affiliation: Hawler medical university, Rozhawa Emergency Hospital Full Address: Hawler Medical University, Rozhawa Emergency Hospital, Erbil, Iraq, 44001 Email: aryan.jalal87@yahoo.com
Notes	Recruitment status: recruiting Prospective completion date: June 2021 Sponsor/funding: Hawler Medical University

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ALT: alanine aminotransferase; AST: aspartate transaminase; BiPAP: bilevel positive airway pressure; BMI: body‐mass index; COVID‐19: coronavirus disease 2019; CPAP: continuous positive airway pressure; CRP: C‐reactive protein; ECG: electrocardiogram; ECMO: extracorporeal membrane oxygenation; ESR: erythrocyte sedimentation rate; FEV₁: forced expiratory volume in one second; FiO₂: fraction of inspired oxygen; FVC: forced vital capacity; GDF: growth/differentiation factor; GFR: glomerular filtration rate; HFNC: high‐flow nasal cannula; HMG‐CoA: β‐hydroxy β‐methylglutaryl‐CoA; hsTnT: high‐sensitive troponin T; ICU: intensive care unit; IL: interleukin; IRB: institutional review board; LDH: lactate dehydrogenase; min: minute; NEWS: National Early Warning Score; NIPPV: non‐invasive positive‐pressure ventilation; NT‐proBNP: N‐terminal pro B‐type natriuretic peptide; PaO₂: partial pressure of oxygen;PCR: polymerase chain reaction; RT‐PCR: reverse transcription polymerase chain reaction; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; SD: standard deviation; TNF: tumour necrosis factor; WHO: World Health Organization.

Differences between protocol and review

Types of outcome measures

As part of the German COVID‐19 Evidence Ecosystem (CEOsys), we aim to generate several reviews about COVID‐19 treatment with a consistent core outcome set, that was updated 23 June 2021, confronting the competing risk of death in our prespecified outcome parameters. We decided to revise the outcome domain targeting the clinical status of participants and take death as a competing event into account. This change resulted in a revision of primary outcomes and outcome definitions. Additionally, we revised the wording of outcome definitions in the light of the changing World Health Organization definitions on clinical progression, so that they remain self‐explanatory.

We performed the following adaptations.

Revised outcomes, included in the review	Previous outcome set, defined at protocol stage	Amendments and justification
People with COVID‐19 and moderate to severe disease
All‐cause mortality up to day 28, day 60, time‐to‐event, and at hospital discharge.	All‐cause mortality at day 28, day 60, and up to longest follow‐up.	Definition of longest follow‐up revised to time‐to‐event, and time point of hospital discharge included following expert consensus.
Included in primary outcomes Clinical status up to day 28, day 60, and up to longest follow‐up, including: worsening of clinical status; i.e. participants with clinical deterioration, defined as new need for invasive mechanical ventilation or death; improvement of clinical status; i.e. participants discharged alive. Participants should be discharged without clinical deterioration or death. Included in secondary outcomes Clinical status at up to day 28, day 60, and up to longest follow‐up, including: worsening of clinical status: new need for invasive mechanical ventilation; new need for non‐invasive mechanical ventilation or high flow; new need for oxygen by mask or nasal prongs; improvement of clinical status: weaned or liberated from invasive mechanical ventilation, and surviving, in subgroup of participants requiring invasive mechanical ventilation at baseline; ventilator‐free days; duration to liberation from invasive mechanical ventilation; liberation from supplemental oxygen in surviving patients, including the liberation from invasive mechanical ventilation; duration to liberation from supplemental oxygen.	Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale, WHO Ordinal Scale for Clinical Improvement) up to 7 days, 8 to 15 days, 16 to 30 days; including: ventilator‐free days and need for intubation or IV (day 28, day 60, and up to longest follow‐up); weaning/liberation from mechanical ventilation; increase of WHO score (WHO clinical progression scale), for subgroup of patients without the respective need for respiratory support at baseline: need for invasive ventilation, i.e. WHO 7–9; need for non‐invasive ventilation or high flow, i.e. WHO 6; need for oxygen by mask or nasal prongs, i.e. WHO 5; need for hospitalisation without oxygen therapy, i.e. WHO 4; need for dialysis (up to 28 days) for subgroup of severely ill people.	Outcomes separated into primary and secondary outcomes. Primary outcomes revised to include competing event of death. Secondary outcomes still included to scope disease progression; however, competing events not considered, and data were not pooled across studies.
Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) up to 7 days, up to 28 days, and longest follow‐up available.	Neurological function or functional independence.	Outcome definition amended to include neurological functioning as a component of quality of life, and to increase consistency across reviews and included populations.
Adverse events (any grade) during the study period, defined as number of participants with any event.	Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event.	Definition edited, and grades of severity removed, as grading system relates to oncology research and is not commonly used in infectious diseases (CTCAE 2021).
Serious adverse events during the study period, defined as number of participants with any event.	Serious adverse events, defined as number of participants with event.	Definition edited.
Need for new dialysis up to 28 days.	—	Outcome added due to expert consensus and to increase consistency across reviews.
Admission to ICU up to day 28.	—	Outcome added due to expert consensus and to increase consistency across reviews.
Duration of hospitalisation.	Duration of hospitalisation.	No changes.
Improvement of clinical status; i.e. participants discharged alive.	Time to discharge from hospital.	Time to event measurement considered as part of revised primary outcome 'Improvement of clinical status; i.e. participants discharged alive.'
Improvement of clinical status; i.e. participants discharged alive.	Time to symptom resolution (WHO ≤ 4).	Definition edited to revised primary outcome 'Improvement of clinical status; i.e. participants discharged alive.'
Viral clearance, assessed with reverse transcription polymerase chain reaction (RT‐PCR) test for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days.	Viral clearance (at day 3, 7, or 15).	Definition edited.
Incidence of abdominal pain during the study period, defined as number of participants with any event.	—	Added due to expert consensus as intervention‐related outcome.
Incidence of diarrhoea during the study period, defined as number of participants with any event.	—	Added due to expert consensus as intervention‐related outcome.
Incidence of nausea and vomiting during the study period, defined as number of participants with any event.	—	Added due to expert consensus as intervention‐related outcome.
People with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19
All‐cause mortality up to day 28, day 60, time‐to‐event, and up to longest follow‐up.	All‐cause mortality at day 28, day 60, and up to longest follow‐up.	—
Admission to hospital or death within 28 days.	Admission to hospital (WHO ≥ 4).	Competing event of death considered.
Clinical status up to day 28 and up to longest follow‐up: worsening of clinical status (moderate to severe COVID‐19 symptoms): need for invasive mechanical ventilation; need for non‐invasive mechanical ventilation or high flow; need for hospitalisation with need for oxygen by mask or nasal prongs; need for hospitalisation without oxygen therapy.	Development of severe clinical COVID‐19 symptoms, defined as WHO Clinical Progression Scale ≥ 6, up to longest follow‐up.	Outcomes included as secondary outcomes to scope disease progression. However, competing event is not considered, and data were not pooled across studies.
Symptom resolution; i.e. all initial symptoms resolved (asymptomatic) at day 14, day 28, and up to longest follow‐up.	Time to symptom resolution (no need for oxygen support; WHO Scale ≤ 4).	Time to event measurement considered as part of revised primary outcome 'Symptom resolution; i.e. all initial symptoms resolved (participant asymptomatic).'
Duration to symptom resolution.	Time to symptom resolution (no need for oxygen support; WHO Scale ≤ 4).	Definition edited to include continuous outcome measurement.
Quality of life, including fatigue and neurological status, assessed with standardised scales (e.g. WHOQOL‐100) up to 7 days, up to 28 days, and longest follow‐up available.	Quality of life, assessed with standardised scales (e.g. WHOQOL‐100) up to 7 days, up to 30 days, and longest follow‐up available.	Definition amended to include neurological functioning and fatigue as components of quality of life, and to increase consistency across reviews and included populations.
Adverse events (any grade) during the study period, defined as number of participants with any event.	Adverse events (any grade, grade 1–2, grade 3–4), defined as number of participants with event.	Definition edited, and grades of severity removed, as grading system relates to oncology research and is not commonly used in infectious diseases (CTCAE 2021).
Serious adverse events during the study period, defined as number of participants with any event.	Serious adverse events, defined as number of participants with event.	Definition edited.
Clinical status up to day 28 and up to longest follow‐up; worsening of clinical status (moderate to severe COVID‐19 symptoms): need for invasive mechanical ventilation; need for non‐invasive mechanical ventilation or high flow; need for hospitalisation with need for oxygen by mask or nasal prongs; need for hospitalisation without oxygen therapy.	Clinical status, assessed by need for respiratory support with standardised scales (e.g. WHO Clinical Progression Scale, WHO Ordinal Scale for Clinical Improvement) up to 7 days, 8–15 days, 16–30 days; including: ventilator‐free days and need for intubation or IV (at day 28, day 60, and up to longest follow‐up); weaning/liberation from mechanical ventilation; increase of WHO score (WHO clinical progression scale), for subgroup of patients without the respective need for respiratory support at baseline: need for invasive ventilation, i.e. WHO 7–9; need for non‐invasive ventilation or high flow, i.e. WHO 6; need for oxygen by mask or nasal prongs, i.e. WHO 5; need for hospitalisation without oxygen therapy, i.e. WHO 4.	Outcomes included as secondary outcomes to scope disease progression. However, competing event not considered, and data were not pooled across studies. Some outcomes addressing clinical status (i.e. ventilator‐free days and need for intubation or IV, weaning/liberation from mechanical ventilation) removed as deemed of low‐priority for target population.
—	Need for dialysis (up to 28 days), for subgroup of participants developing severe disease (WHO 6–9).	Outcome removed as deemed of low‐priority for target population.
—	Need for renal monitoring (e.g. with renal function tests in the community).	Outcome removed as deemed of low‐priority for target population.
—	Duration of hospitalisation, for subgroup of participants hospitalised during course of disease.	Outcome removed as deemed of low‐priority for target population.
—	Time to hospital discharge, for subgroup of participants hospitalised during course of disease.	Outcome removed as deemed of low‐priority for target population.
Viral clearance, assessed with RT‐PCR for SARS‐CoV‐2 at baseline, up to 3, 7, and 14 days.	—	Outcome added due to expert consensus.
Incidence of abdominal pain during the study period, defined as number of participants with any event.	—	Added due to expert consensus as intervention‐related outcome.
Incidence of diarrhoea during the study period, defined as number of participants with any event.	—	Added due to expert consensus as intervention‐related outcome.
Incidence of nausea and vomiting during the study period, defined as number of participants with any event.	—	Added due to expert consensus as intervention‐related outcome.

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Measures of treatment effect

For binary outcomes, we had planned at protocol stage to perform all analyses using the Mantel‐Haenszel method under a random‐effects model to report pooled risk ratios with 95% CIs. However, for some outcomes, the number of observed events was small (less than 5% of sample per group) and we reported the Peto odds ratio (OR) with 95% CI instead, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2021).

Summary of findings and assessment of the certainty of the evidence

Methods for future updates

At protocol stage, this review was not planned to be a living systematic review. As we identified multiple ongoing studies that could potentially reveal important results for our review question in the future, we agreed together with the Cochrane editorial team to plan future updates for this review.

Contributions of authors

AM: clinical expertise, conception and writing of the review, contact with the authors of the included studies, data extraction, risk of bias assessments.

ALF: clinical expertise, conception and writing of the review, contact with the authors of the included studies and studies awaiting classification, data extraction, risk of bias, GRADE assessments.

VP: methodological expertise, study selection, conception and writing of the review, data extraction, risk of bias, GRADE assessments.

AMu: clinical expertise, conception, writing of the review.

MIM: development of the search strategy.

MB: data extraction.

ED: study selection, data extraction, risk of bias assessment, writing of the review.

RLP: methodological expertise, writing of the review.

ALCM: methodological expertise, writing of the review.

RR: methodological expertise, writing of the review.

NS: methodological expertise and advice, study selection, conception, writing, proof‐reading of the manuscript.

MS: clinical expertise and advice, writing, proof‐reading of the manuscript.

Sources of support

Internal sources

University Hospital of Cologne, Germany

Cochrane Cancer, Department I of Internal Medicine
University Hospital Leipzig, Germany

Department of Anaesthesia and Intensive care
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt‐Universität zu Berlin, Berlin, Germany, Germany

Department of Infectious Diseases and Respiratory Medicine

External sources

Federal Ministry of Education and Research, Germany

This review is part of the CEOsys project funded by the Network of University Medicine (Nationales Forschungsnetzwerk der Universitätsmedizin (NUM)) by the Federal Ministry of Education and Research of Germany (Bundesministerium für Bildung und Forschung (BMBF)), grant number 01KX2021.

Declarations of interest

AM: none.

ALF: is funded by the Federal Ministry of Education and Research, Germany (NaFoUniMedCovid19, funding number: 01KX2021; part of the project "CEOSys", which was paid to the institution).

VP: is funded by the Federal Ministry of Education and Research, Germany (NaFoUniMedCovid19, funding number: 01KX2021; part of the project "CEOSys", which was paid to the institution).

AMu: none.

MIM: none.

MB: none.

ED: none.

RLP: none.

ALCM: none.

RR: none.

NS: none.

MS: none.

Contributed equally (first author)

Contributed equally (last author)

New

References

References to studies included in this review

Deftereos 2020 {published data only}2020‐001455‐40

Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Network Open 2020;3(6):14. [DOI: 10.1001/jamanetworkopen.2020.13136] [DOI] [PMC free article] [PubMed] [Google Scholar]
Deftereos SG, Siasos G, Giannopoulos G, Vrachatis DA, Angelidis C, Giotaki SG, et al. The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): rationale and study design. Hellenic Journal of Cardiology 2020;61(1):42-5. [DOI: 10.1016/j.hjc.2020.03.002] [DOI] [PMC free article] [PubMed] [Google Scholar]

Horby 2021 {published data only}

Colchicine in patients admitted to hospital with 3 COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. medRxiv. [DOI: ] [DOI] [PMC free article] [PubMed]

Lopes 2021 {published data only}

Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD open 2021;7(1):e001455. [DOI: 10.1136/ rmdopen-2020-001455] [DOI] [PMC free article] [PubMed] [Google Scholar]

Tardif 2021 {published data only}2020‐001689‐12

Tardif JC, Bouabdallaoui N, L'Allier PL, Gaudet D, Shah B, Pillinger MH, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respiratory Medicine 2021;9(8):924-32. [DOI] [PMC free article] [PubMed] [Google Scholar]
Tardif JC, Bouabdallaoui N, L'Allier PL, Gaudet D, Shah B, Pillinger MH, et al. Efficacy of colchicine in non-hospitalized patients with COVID-19. www.medrxiv.org 2021. [DOI: ]

References to studies excluded from this review

CTRI/2020/08/027102 {published data only}CTRI/2020/08/027102

Colchichine use for preventing COVID infection in haemodialysis patients. ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=45658 (first received 13 August 2020).

CTRI/2020/09/028088 {published data only}CTRI/2020/09/028088

CTRI/2020/09/028088. Open label randomized trial of colchicine, aspirin and montelukast in Covid-19. www.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2020/09/028088 (first received 28 September 2020).

IRCT20150623022884N3 {published data only}

IRCT20150623022884N3. Evaluation of therapeutic effect of MAB98 including thymolic fraction of trachyspermum ammi, thymoquinone fraction of nigella sativa and colchicine of colchicum autumnale in Covid 19 patients. www.irct.ir/trial/49249 (first received 18 November 2020). [IRCT: IRCT20150623022884N3]

Mareev 2021 {published data only}

Mareev VY, Orlova YA, Plisyk AG, Pavlikova EP, Akopyan ZA, Matskeplishvili SТ, et al. Proactive anti-inflammatory therapy with colchicine in the treatment of advanced stages of new coronavirus infection. The first results of the COLORIT study. Kardiologiia 2021;61(2):15-27. [DOI: ] [DOI] [PubMed] [Google Scholar]

NCT04359095 {published data only}

NCT04359095. Effectiveness and safety of medical treatment for SARS-CoV-2 (COVID-19) in Colombia. clinicaltrials.gov/ct2/show/NCT04359095 (first received 24 April 2020).

NCT04392141 {published data only}

NCT04392141. Colchicine plus phenolic monoterpenes to treat COVID-19. clinicaltrials.gov/ct2/show/NCT04392141 (first received 18 May 2020).

NCT04492358 {published data only}

Treatment for moderate/severe COVID-19 in a fragile and vulnerable population, admitted to a geriatric hospital unit or in a transicional care center. clinicaltrials.gov/show/NCT04492358 (first received 30 July 2020).

NCT04603690 {published data only}

NCT04603690. Study to investigate the benefits of colchicine in patients with COVID-19. clinicaltrials.gov/show/NCT04603690 (first received 27 October 2020).

References to studies awaiting assessment

IRCT20190804044429N5 {published data only}20190804044429N5

IRCT20190804044429N5. Efficacy and safety of colchicine on clinical improvement in patients with COVID-19: a randomized, double blind clinical trial. www.irct.ir/trial/54385 (first received 18 February 2021).

IRCT20190810044500N5 {published data only}20190810044500N5

20190810044500N5. Investigation of the efficacy and safety of colchicine In combination with standard treatment on covid-19 patients: a clinical trial. www.irct.ir/trial/46867 (first received 18 May 2020).

IRCT20200408046990N2 {published data only}

IRCT20200408046990N2. Evaluation of colchicine tablet efficacy as an adjuvant treatment for patients with mild to moderate COVID-19 in Qaem Hospital, Mashhad: a triple-blind randomized placebo controlled clinical trial. en.irct.ir/trial/47468 (first received 25 April 2020). [IRCT: IRCT20200408046990N2]

NCT04322565 {published data only}2020‐001258‐23

NCT04322565. Colchicine efficacy in COVID-19 pneumonia. clinicaltrials.gov/ct2/show/NCT04322565 (first received 26 March 2020).

NCT04328480 {published data only}

NCT04328480. The ECLA PHRI COLCOVID trial. Effects of colchicine on moderate/high-risk hospitalized COVID-19 patients (COLCOVID). clinicaltrials.gov/show/NCT04328480 (first received 31 March 2020).

NCT04350320 {published data only}2020‐001511‐25

NCT04350320. Trial to study the benefit of colchicine in patients with COVID-19 (COL-COVID). clinicaltrials.gov/show/NCT04350320 (first received 17 April 2020).

NCT04355143 {published data only}

NCT04355143. Colchicine to reduce myocardial injury in COVID-19 (COLHEART-19). clinicaltrials.gov/show/NCT04355143 (first received 21 April 2020).

NCT04510038 {published data only}

NCT04510038. Colchicine vs current standard of care in hospitalized patients with COVID-19 and cardiac injury. clinicaltrials.gov/show/NCT04510038 (first received 12 August 2020).

NCT04527562 {published data only}

NCT04527562. Colchicine in moderate symptomatic COVID-19 patients: double blind, randomized, placebo controlled trial to observe the efficacy. clinicaltrials.gov/show/NCT04527562 (first received 26 August 2020).
NCT04527562. Efficacy of colchicine in moderately symptomatic COVID-19 patients: a study protocol for a double-blind, randomized, placebo-controlled trial [International Journal of Clinical Trials]. 2021;8:1. [DOI: dx.doi.org/10.18203/2349 - 3259.ijct2021 0144] [DOI: ]

NCT04762771 {published data only}

NCT04762771. Colchicine for the treatment of cardiac injury in hospitalized patients with COVID-19 (COLHEART-19). clinicaltrials.gov/ct2/show/NCT04762771 (first received 21 February 2021).

Salehdazeh 2020 {published data only}IRCT20200418047126N1

Salehdazeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients; a clinical trial study. www.researchsquare.com/article/rs-69374/v1 (accessed prior to 21 September 2020). [DOI: 10.21203/rs.3.rs-69374/v1] [DOI]

References to ongoing studies

EUCTR2020‐001511‐25 {published data only}

EUCTR2020-001511-25. Randomized open-blind controlled trial to study the benefit of colchicine in patients with COVID-19. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-001511-25 (first received 15 April 2020).

EUCTR2020‐001841‐38 {published data only}

EUCTR2020-001841-38-ES. Colchicine for the treatment of hyperinflammation associated with pneumonia due to COVID-19. www.clinicaltrialsregister.eu/ctr-search/trial/2020-001841-38/ES (first received 26 May 2020).

ISRCTN86534580 {published data only}

ISRCTN86534580. A trial evaluating treatments for suspected coronavirus infection in people aged 50 years and above with pre-existing conditions and those aged 65 years and above. www.isrctn.com/ISRCTN86534580 (first received 20 March 2020). [DOI: ]
ISRCTN86534580. PRINCIPLE COVID-19 treatments trial widens to under 50s and adds colchicine. www.principletrial.org/news/principle-covid-19-treatments-trial-widens-to-under-50s-adds-colchicine?ref=image 3 March 2021.

jRCT2071200078 {published data only}2071200078

jRCT2071200078. A randomized double-blind placebo controlled phase 2 clinical trial to assess anti-inflammatory effect of colchicine (DRC3633) in mild to moderately severe COVID-19 patients (DRC-06C). jrct.niph.go.jp/en-latest-detail/jRCT2071200078 (first received 7 January 2021).

NCT04324463 {published data only}

NCT04324463. Anti-coronavirus therapies to prevent progression of coronavirus disease 2019 (COVID-19) Trial (ACTCOVID19). clinicaltrials.gov/ct2/show/NCT04324463 (first received 27 March 2020).

NCT04360980 {published data only}

Dalili N, Kashefizadeh A, Nafar M, Poorrezagholi F, Firouzan A, Samadian F, et al. Adding colchicine to the antiretroviral medication – lopinavir/ritonavir (Kaletra) in hospitalized patients with non-severe Covid-19 pneumonia: a structured summary of a study protocol for a randomized controlled trial. Trials 2020;21(1):489. [DOI] [PMC free article] [PubMed] [Google Scholar]
NCT04360980. The effects of standard protocol with or without colchicine in Covid-19 infection. clinicaltrials.gov/show/NCT04360980 (first received 24 April 2020).

NCT04363437 {published data only}

NCT04363437. Colchicine in moderate-severe hospitalized patients before ARDS to treat COVID-19 (COMBATCOVID19). clinicaltrials.gov/show/NCT04363437 (first received 27 April 2020).

NCT04367168 {published data only}

NCT04367168. Colchicine twice daily during 10 days as an option for the treatment of symptoms induced by inflammation in patients with mild and severe coronavirus disease (ColchiVID). clinicaltrials.gov/show/NCT04367168 (first received 29 April 2020).

NCT04375202 {published data only}2020‐001475‐33

EUCTR2020-001475-33. Treatment with colchicine of patients affected by COVID-19: a pilot study. www.clinicaltrialsregister.eu/ctr-search/trial/2020-001475-33/IT (first received 24 June 2020).
NCT04375202. Colchicine in COVID-19: a pilot study (COLVID-19). clinicaltrials.gov/show/NCT04375202 (first received 5 May 2020).

NCT04416334 {published data only}

EUCTR2020-001603-16. A randomization, multicentric, open-label, controlled, clinical trial to investigate the effectiveness of early colchicine administration in patients over 70 years of age with high risk of developing severe pulmonary complications associated with Coronavirus disease pneumonia (Covid-19). www.clinicaltrialsregister.eu/ctr-search/trial/2020-001603-16/ES (first received 8 May 2020).
NCT04416334. Preemptive therapy with colchicine in patients older than 60 years with high risk of severe pneumoniae due to coronavirus (COLCHI-COVID). clinicaltrials.gov/show/NCT04416334 (first received 4 June 2020).

NCT04516941 {published data only}2020‐002234‐32

NCT04516941. Coronavirus edoxaban colchicine (CONVINCE) COVID-19. clinicaltrials.gov/show/NCT04516941 (first received 18 August 2020).

NCT04539873 {published data only}

NCT04539873. Impact of colchicine in hospitalized Colombian patients with COVID-19 (COLCOVID19). clinicaltrials.gov/show/NCT04539873 (first received 7 September 2020).

NCT04667780 {published data only}

NCT04667780. Study to investigate the treatment effect of colchicine in patients with COVID-19. clinicaltrials.gov/show/NCT04667780 (first received 16 December 2020).

NCT04724629 {published data only}

NCT04724629. Survival trial using cytokines in COVID-19 (STRUCK). clinicaltrials.gov/show/NCT04724629 (first received 26 January 2021).

NCT04756128 {published data only}

NCT04756128. Impact of colchicine and low-dose naltrexone on COVID-19. clinicaltrials.gov/show/NCT04756128 (first received 16 February 2021).

NCT04818489 {published data only}

NCT04818489. Colchicine and post-COVID-19 pulmonary fibrosis. clinicaltrials.gov/ct2/show/NCT04818489 (first received 26 March 2021).

NCT04867226 {published data only}

Effectiveness of colchicine among patients with COVID-19 infection. clinicaltrials.gov/ct2/show/NCT04867226 (first received 30 April 2021).

Additional references

Alabed 2014

Alabed S, Cabello JB, Irving GJ, Qintar M, Burls A. Colchicine for pericarditis. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No: CD010652. [DOI: 10.1002/14651858.CD010652.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

Angelidis 2018

Angelidis C, Kotsialou Z, Kossyvakis C, Vrettou AR, Zacharoulis A, Kolokathis F, et al. Colchicine pharmacokinetics and mechanism of action. Current Pharmaceutical Design 2018;24(6):659-63. [DOI: 10.2174/1381612824666180123110042] [DOI] [PubMed] [Google Scholar]

Buitrago‐Garcia 2020

Buitrago-Garcia D, Egli-Gany D, Counotte MJ, Hossmann S, Imeri H, Ipekci Aziz M, et al. Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: a living systematic review and meta-analysis. PLoS Medicine 2020;17(9):e1003346. [DOI] [PMC free article] [PubMed] [Google Scholar]

Castaño‐Rodriguez 2018

Castaño-Rodriguez C, Honrubia JM, Gutiérrez-Álvarez J, DeDiego ML, Nieto-Torres JL, Jimenez-Guardeño JM, et al. Role of severe acute respiratory syndrome coronavirus viroporins E, 3a, and 8a in replication and pathogenesis. mBio 2018;9(3):e02325-17. [DOI: 10.1128/mBio.02325-17] [DOI] [PMC free article] [PubMed] [Google Scholar]

Chen 2020

Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368:m1091. [DOI] [PMC free article] [PubMed] [Google Scholar]

Cochrane LSR

Guidance for the production and publication of Cochrane living systematic reviews: Cochrane Reviews in living mode. community.cochrane.org/review-production/production-resources/living-systematic-reviews (accessed 3 June 2021).

COMET 2021

Core outcome set developers’ response to COVID-19. www.comet-initiative.org/Studies/Details/1538 (accessed 3 June 2021).

Conti 2020

Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. Journal of Biological Regulators and Homeostatic Agents 2020;34(2):327-31. [DOI: 10.23812/CONTI-E] [DOI] [PubMed] [Google Scholar]

CTCAE 2021

Common terminology criteria for adverse events (CTCAE). ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm (accessed 3 June 2021).

Deeks 2021

Deeks JJ, Higgins JP, Altman DG. Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

Della‐Torre 2020

Della-Torre E, Della-Torre F, Kusanovic M, Scotti R, Ramirez GA, Dagna L, et al. Treating COVID-19 with colchicine in community healthcare setting. Clinical Immunology 2020;217:108490. [DOI: 10.1016/j.clim.2020.108490] [DOI] [PMC free article] [PubMed] [Google Scholar]

Dupuis 2020

Dupuis J, Sirois MG, Rhéaume E, Nguyen QT, Clavet-Lanthier ME, Brand G, et al. Colchicine reduces lung injury in experimental acute respiratory distress syndrome. PloS One 2020;15(12):e0242318. [DOI: 10.1371/journal.pone.0242318] [DOI] [PMC free article] [PubMed] [Google Scholar]

EndNote X9 [Computer program]

EndNote X9. London (UK): Clarivate, 2013.

Finkelstein 2010

Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Dubnov-Raz G, et al. Colchicine poisoning: the dark side of an ancient drug. Clinical Toxicology 2010;48(5):407-14. [DOI: 10.3109/15563650.2010.495348] [DOI] [PubMed] [Google Scholar]

Funk 2021

Funk T, Pharris A, Spiteri G, Bundle N, Melidou A, Carr M, et al. Characteristics of SARS-CoV-2 variants of concern B.1.1.7, B.1.351 or P.1: data from seven EU/EEA countries, weeks 38/2020 to 10/2021. Eurosurveillance 2021;26(16):2100348. [DOI] [PMC free article] [PubMed] [Google Scholar]

Hariyanto 2021

Hariyanto TI, Halim DA, Jodhinata C, Yanto TA, Kurniawan A. Colchicine treatment can improve outcomes of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Clinical and Experimental Pharmacology and Physiology 2021;48(6):823-30. [DOI] [PMC free article] [PubMed] [Google Scholar]

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

Higgins 2021a

Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook. [DOI] [PMC free article] [PubMed]

Higgins 2021b

Higgins JP, Eldridge S, Li T. Chapter 23: Including variants on randomized trials. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

Higgins 2021c

Higgins JP, Lasserson T, Chandler J, Tovey D, Thomas J, Flemyng E, et al. Methodological expectations of Cochrane intervention reviews. www.community.cochrane.org/mecir-manual/ (accessed 3 June 2021).

Higgins 2021d

Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Chapter 8: Assessing risk of bias in a randomized trial. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

Higgins 2021e

Higgins JP, Tianging L, Deeks JJ. Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

Huang 2020

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395(10223):497-506. [DOI] [PMC free article] [PubMed] [Google Scholar]

Imazio 2007

Imazio M, Cecchi E, Ierna S, Trinchero R. CORP (COlchicine for Recurrent Pericarditis) and CORP-2 trials – two randomized placebo-controlled trials evaluating the clinical benefits of colchicine as adjunct to conventional therapy in the treatment and prevention of recurrent pericarditis: study design and rationale. Journal of Cardiovascular Medicine (Hagerstown) 2007;8(10):830-4. [DOI] [PubMed] [Google Scholar]

Karagiannidis 2020

Karagiannidis C, Mostert C, Hentschker C, Voshaar T, Malzahn J, Schillinger G, et al. Case characteristics, resource use, and outcomes of 10 021 patients with COVID-19 admitted to 920 German hospitals: an observational study. Lancet Respiratory Medicine 2020;8(9):853-62. [DOI] [PMC free article] [PubMed] [Google Scholar]

Kreuzberger 2021

Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, et al. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database of Systematic Reviews 2021, Issue 9. Art. No: CD013825. [DOI: 10.1002/14651858.CD013825.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

Lamontagne 2021

Lamontagne F, Agoritsas T, Siemieniuk R, Rochwerg B, Bartoszko J, Askie L, et al. A living WHO guideline on drugs to prevent COVID-19. BMJ 2021;372:n526. [DOI: 10.1136/bmj.n526] [DOI] [PubMed] [Google Scholar]

Lauer 2020

Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application. Annals of Internal Medicine 2020;172(9):577–82. [DOI: 10.7326/M20-0504] [DOI] [PMC free article] [PubMed] [Google Scholar]

Leung 2015

Leung YY, Yao Hui LL, Kraus VB. Colchicine – update on mechanisms of action and therapeutic uses. Seminars in Arthritis and Rheumatism 2015;45(3):341-50. [DOI] [PMC free article] [PubMed] [Google Scholar]

Li 2021

Li T, Higgins JP, Deeks JJ. Chapter 5: Collecting data. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

Liang 2020

Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncology 2020;21(3):335-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

MAGICapp [Computer program]

MAGICapp. Brønnøysund (NOR): Norwegian MAGIC Evidence Ecosystem Foundation (powered by UserVoice Inc.), 2020. Available at magicapp.org.

Martínez 2018

Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis 2018;269:262-71. [DOI: 10.1016/j.atherosclerosis.2017.12.027] [DOI] [PubMed] [Google Scholar]

McCullough 2021

McCullough PA, Kelly RJ, Ruocco G, Lerma E, Tumlin J, Wheelan KR, et al. Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection. American Journal of Medicine 2021;134(1):16-22. [DOI] [PMC free article] [PubMed] [Google Scholar]

Microsoft 2018 [Computer program]

Microsoft Excel. Microsoft Corporation. Microsoft Corporation, 2018. office.microsoft.com/excel.

Misawa 2013

Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nature Immunology 2013;14(5):454-60. [DOI: 10.1038/ni.2550] [DOI] [PubMed] [Google Scholar]

Moher 2009

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Journal of Clinical Epidemiology 2009;62(10):1006-12. [DOI] [PubMed] [Google Scholar]

Nawangsih 2021

Nawangsih EN, Kusmala YY, Rakhmat II, Handayani DR, Juliastuti H, Wibowo A, et al. Colchicine and mortality in patients with coronavirus disease 2019 (COVID-19) pneumonia: a systematic review, meta-analysis, and meta-regression. International Immunopharmacology 2021;96:107723. [DOI] [PMC free article] [PubMed] [Google Scholar]

NICE 2021

National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing COVID-19, 2021. www.nice.org.uk/guidance/ng191 (accessed prior to 22 September 2021).

Nieto‐Torres 2015

Nieto-Torres JL, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, Castaño-Rodriguez C, Fernandez-Delgado R, et al. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 2015;485:330-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

Nuki 2008

Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Current Rheumatology Reports 2008;10(3):218-27. [DOI] [PubMed] [Google Scholar]

Oran 2020

Oran DP, Topol EJ. Prevalence of asymptomatic SARS-CoV-2 Infection: a narrative review. Annals of Internal Medicine 2020;173(5):362-7. [DOI: 10.7326/M20-3012] [DOI] [PMC free article] [PubMed] [Google Scholar]

Page 2021

Page MJ, Higgins JP, Sterne JA. Chapter 13: Assessing risk of bias due to missing results in a synthesis. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.

Parmar 1998

Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17(24):2815-34. [DOI: ] [DOI] [PubMed] [Google Scholar]

Piechotta 2021

Piechotta V, Iannizzi C, Chai KL, Valk SJ, Kimber C, Dorando E, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review. Cochrane Database of Systematic Reviews 2021, Issue 5. Art. No: CD013600. [DOI: 10.1002/14651858.CD013600.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]

Potere 2020

Potere N, Valeriani E, Candeloro M, Tana M, Porreca E, Abbate A, et al. Acute complications and mortality in hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Critical Care 2020;24(1):389. [DOI] [PMC free article] [PubMed] [Google Scholar]

RevMan Web 2019 [Computer program]

Review Manager Web (RevMan Web). Version 3.9.0. The Cochrane Collaboration, 2019. revman.cochrane.org.

Reyes 2021

Reyes AZ, Hu KA, Teperman J, Wampler Muskardin TL, Tardif JC, Shah B, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Annals of Rheumatic Diseases 2021;80:550-7. [DOI: 10.1136/annrheumdis-2020-219174] [DOI] [PMC free article] [PubMed] [Google Scholar]

Richardson 2020

Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323(20):2052-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

Santesso 2020

Santesso N, Glenton C, Dahm P, Garner P, Akl A, Alper B, et al. GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions. Journal of Clinical Epidemiology 2020;119:126-35. [DOI: 10.1016/j.jclinepi.2019.10.014] [DOI] [PubMed] [Google Scholar]

Schünemann 2021

Schünemann HJ, Higgins JP, Vist GE, Glasziou P, Akl EA, Skoetz N, et al. Chapter 14: Completing ‘Summary of findings’ tables and grading the certainty of the evidence. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.

Siemieniuk 2020

Siemieniuk RA, Bartoszko JJ, Ge L, Zeraatkar D, Izcovich A, Kum E, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ 2020;370:m2980. [DOI: 10.1136/bmj.m2980] [DOI] [PMC free article] [PubMed] [Google Scholar]

Simmonds 2017

Simmonds M, Salanti G, McKenzie J, Elliott J, Living Systematic Review Network. Living systematic reviews: 3. Statistical methods for updating meta-analyses. Journal of Clinical Epidemiology 2017;91:38-46. [DOI: 10.1016/j.jclinepi.2017.08.008] [PMID: ] [DOI] [PubMed] [Google Scholar]

Skoetz 2020

Skoetz N, Goldkuhle M, Dalen EC, Akl EA, Trivella M, Mustafa RA, et al. GRADE guidelines 27: how to calculate absolute effects for time-to-event outcomes in summary of findings tables and evidence profiles. Journal of Clinical Epidemiology 2020;118:124-31. [DOI: 10.1016/j.jclinepi.2019.10.015] [DOI] [PubMed] [Google Scholar]

Sterne 2019

Sterne JA, Savovic J, Page MJ, Elbers RG, Blencowe N, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. [DOI: 10.1136/bmj.l4898] [DOI] [PubMed] [Google Scholar]

Struyf 2020

Struyf T, Deeks JJ, Dinnes J, Takwoingi Y, Davenport C, Leeflang MM, et al. Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease. Cochrane Database of Systematic Reviews 2020, Issue 7. Art. No: CD013665. [DOI: 10.1002/14651858.CD013665] [DOI] [PMC free article] [PubMed] [Google Scholar]

Tierney 2007

Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16. [DOI: 10.1186/1745-6215-8-16] [DOI] [PMC free article] [PubMed] [Google Scholar]

Toldo 2018

Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nature Reviews. Cardiology 2018;15(4):203-14. [DOI: 10.1038/nrcardio.2017.161] [DOI] [PubMed] [Google Scholar]

van Echteld 2014

Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No: CD006190. [DOI: 10.1002/14651858.CD006190.pub2] [DOI] [PubMed] [Google Scholar]

Wagner 2021

Wagner C, Griesel M, Mikolajewska A, Mueller A, Nothacker M, Kley K, et al. Systemic corticosteroids for the treatment of COVID‐19. Cochrane Database of Systematic Reviews 2021, Issue 8. Art. No: CD014963. [DOI: 10.1002/14651858.CD014963] [DOI] [PMC free article] [PubMed] [Google Scholar]

WHO 2007

World Health Organization. Cumulative number of reported probable cases of SARS. www.who.int/csr/sars/country/2003_07_11/en (accessed 3 June 2021).

WHO 2019

World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV). www.who.int/emergencies/mers-cov/en (accessed 3 June 2021).

WHO 2020a

World Health Organization. Report of the WHO‐China Joint Mission on coronavirus disease 2019 (COVID‐19). www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report (accessed 3 June 2021).

WHO 2020b

WHO working group on the clinical characterisation and management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infectious Diseases 2020;20(8):e192-7. [DOI] [PMC free article] [PubMed]

WHO 2020c

World Health Organization. Corticosteroids for COVID-19 – living guidance 2 September 2020. www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1 (accessed 3 June 2021).

WHO 2020d

World Health Organization. Draft landscape of COVID-19 candidate vaccines. www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines (accessed 3 June 2021).

WHO 2021a

World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. covid19.who.int (accessed 3 June 2021).

WHO 2021b

World Health Organization. Coronavirus disease (COVID-19)/COVID-19 vaccines/Explainers. www.who.int/emergencies/diseases/novel-coronavirus-2019/covid-19-vaccines/explainers (accessed 14 July 2021).

Williamson 2020

Williamson E, Walker AJ, Bhaskaran KJ, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584:430-6. [DOI: 10.1038/s41586-020-2521-4] [DOI] [PMC free article] [PubMed] [Google Scholar]

Wu 2020

Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323(13):1239-42. [DOI: 10.1001/jama.2020.2648] [DOI] [PubMed] [Google Scholar]

References to other published versions of this review

Mikolajewska 2021a

Mikolajewska A, Piechotta V, Mueller A, Metzendorf M-I, Fischer A-L, Skoetz N, et al. Colchicin for the treatment of COVID-19 (part of German Ecosystem CEO-Sys). PROSPERO 2021 CRD42021239107 Available from: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021239107.

Mikolajewska 2021b

Mikolajewska A, Fischer A-L, Piechotta V, Mueller A, Metzendorf M-I, Becker M, Dorando E, et al. Risk of bias assessment for the Cochrane review "Colchicine for the treatment of COVID-19". zenodo.org/record/5377507 2021. [DOI: 10.5281/zenodo.5377507] [DOI] [PMC free article] [PubMed]

[CD015045-bib-0001] Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial. JAMA Network Open 2020;3(6):14. [DOI: 10.1001/jamanetworkopen.2020.13136] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0002] Deftereos SG, Siasos G, Giannopoulos G, Vrachatis DA, Angelidis C, Giotaki SG, et al. The Greek study in the effects of colchicine in COvid-19 complications prevention (GRECCO-19 study): rationale and study design. Hellenic Journal of Cardiology 2020;61(1):42-5. [DOI: 10.1016/j.hjc.2020.03.002] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0003] Colchicine in patients admitted to hospital with 3 COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. medRxiv. [DOI: ] [DOI] [PMC free article] [PubMed]

[CD015045-bib-0004] Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, et al. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD open 2021;7(1):e001455. [DOI: 10.1136/ rmdopen-2020-001455] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0005] Tardif JC, Bouabdallaoui N, L'Allier PL, Gaudet D, Shah B, Pillinger MH, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respiratory Medicine 2021;9(8):924-32. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0006] Tardif JC, Bouabdallaoui N, L'Allier PL, Gaudet D, Shah B, Pillinger MH, et al. Efficacy of colchicine in non-hospitalized patients with COVID-19. www.medrxiv.org 2021. [DOI: ]

[CD015045-bib-0007] Colchichine use for preventing COVID infection in haemodialysis patients. ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=45658 (first received 13 August 2020).

[CD015045-bib-0008] CTRI/2020/09/028088. Open label randomized trial of colchicine, aspirin and montelukast in Covid-19. www.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2020/09/028088 (first received 28 September 2020).

[CD015045-bib-0009] IRCT20150623022884N3. Evaluation of therapeutic effect of MAB98 including thymolic fraction of trachyspermum ammi, thymoquinone fraction of nigella sativa and colchicine of colchicum autumnale in Covid 19 patients. www.irct.ir/trial/49249 (first received 18 November 2020). [IRCT: IRCT20150623022884N3]

[CD015045-bib-0010] Mareev VY, Orlova YA, Plisyk AG, Pavlikova EP, Akopyan ZA, Matskeplishvili SТ, et al. Proactive anti-inflammatory therapy with colchicine in the treatment of advanced stages of new coronavirus infection. The first results of the COLORIT study. Kardiologiia 2021;61(2):15-27. [DOI: ] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0011] NCT04359095. Effectiveness and safety of medical treatment for SARS-CoV-2 (COVID-19) in Colombia. clinicaltrials.gov/ct2/show/NCT04359095 (first received 24 April 2020).

[CD015045-bib-0012] NCT04392141. Colchicine plus phenolic monoterpenes to treat COVID-19. clinicaltrials.gov/ct2/show/NCT04392141 (first received 18 May 2020).

[CD015045-bib-0013] Treatment for moderate/severe COVID-19 in a fragile and vulnerable population, admitted to a geriatric hospital unit or in a transicional care center. clinicaltrials.gov/show/NCT04492358 (first received 30 July 2020).

[CD015045-bib-0014] NCT04603690. Study to investigate the benefits of colchicine in patients with COVID-19. clinicaltrials.gov/show/NCT04603690 (first received 27 October 2020).

[CD015045-bib-0015] IRCT20190804044429N5. Efficacy and safety of colchicine on clinical improvement in patients with COVID-19: a randomized, double blind clinical trial. www.irct.ir/trial/54385 (first received 18 February 2021).

[CD015045-bib-0016] 20190810044500N5. Investigation of the efficacy and safety of colchicine In combination with standard treatment on covid-19 patients: a clinical trial. www.irct.ir/trial/46867 (first received 18 May 2020).

[CD015045-bib-0017] IRCT20200408046990N2. Evaluation of colchicine tablet efficacy as an adjuvant treatment for patients with mild to moderate COVID-19 in Qaem Hospital, Mashhad: a triple-blind randomized placebo controlled clinical trial. en.irct.ir/trial/47468 (first received 25 April 2020). [IRCT: IRCT20200408046990N2]

[CD015045-bib-0018] NCT04322565. Colchicine efficacy in COVID-19 pneumonia. clinicaltrials.gov/ct2/show/NCT04322565 (first received 26 March 2020).

[CD015045-bib-0019] NCT04328480. The ECLA PHRI COLCOVID trial. Effects of colchicine on moderate/high-risk hospitalized COVID-19 patients (COLCOVID). clinicaltrials.gov/show/NCT04328480 (first received 31 March 2020).

[CD015045-bib-0020] NCT04350320. Trial to study the benefit of colchicine in patients with COVID-19 (COL-COVID). clinicaltrials.gov/show/NCT04350320 (first received 17 April 2020).

[CD015045-bib-0021] NCT04355143. Colchicine to reduce myocardial injury in COVID-19 (COLHEART-19). clinicaltrials.gov/show/NCT04355143 (first received 21 April 2020).

[CD015045-bib-0022] NCT04510038. Colchicine vs current standard of care in hospitalized patients with COVID-19 and cardiac injury. clinicaltrials.gov/show/NCT04510038 (first received 12 August 2020).

[CD015045-bib-0023] NCT04527562. Colchicine in moderate symptomatic COVID-19 patients: double blind, randomized, placebo controlled trial to observe the efficacy. clinicaltrials.gov/show/NCT04527562 (first received 26 August 2020).

[CD015045-bib-0024] NCT04527562. Efficacy of colchicine in moderately symptomatic COVID-19 patients: a study protocol for a double-blind, randomized, placebo-controlled trial [International Journal of Clinical Trials]. 2021;8:1. [DOI: dx.doi.org/10.18203/2349 - 3259.ijct2021 0144] [DOI: ]

[CD015045-bib-0025] NCT04762771. Colchicine for the treatment of cardiac injury in hospitalized patients with COVID-19 (COLHEART-19). clinicaltrials.gov/ct2/show/NCT04762771 (first received 21 February 2021).

[CD015045-bib-0026] Salehdazeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients; a clinical trial study. www.researchsquare.com/article/rs-69374/v1 (accessed prior to 21 September 2020). [DOI: 10.21203/rs.3.rs-69374/v1] [DOI]

[CD015045-bib-0027] EUCTR2020-001511-25. Randomized open-blind controlled trial to study the benefit of colchicine in patients with COVID-19. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-001511-25 (first received 15 April 2020).

[CD015045-bib-0028] EUCTR2020-001841-38-ES. Colchicine for the treatment of hyperinflammation associated with pneumonia due to COVID-19. www.clinicaltrialsregister.eu/ctr-search/trial/2020-001841-38/ES (first received 26 May 2020).

[CD015045-bib-0029] ISRCTN86534580. A trial evaluating treatments for suspected coronavirus infection in people aged 50 years and above with pre-existing conditions and those aged 65 years and above. www.isrctn.com/ISRCTN86534580 (first received 20 March 2020). [DOI: ]

[CD015045-bib-0030] ISRCTN86534580. PRINCIPLE COVID-19 treatments trial widens to under 50s and adds colchicine. www.principletrial.org/news/principle-covid-19-treatments-trial-widens-to-under-50s-adds-colchicine?ref=image 3 March 2021.

[CD015045-bib-0031] jRCT2071200078. A randomized double-blind placebo controlled phase 2 clinical trial to assess anti-inflammatory effect of colchicine (DRC3633) in mild to moderately severe COVID-19 patients (DRC-06C). jrct.niph.go.jp/en-latest-detail/jRCT2071200078 (first received 7 January 2021).

[CD015045-bib-0032] NCT04324463. Anti-coronavirus therapies to prevent progression of coronavirus disease 2019 (COVID-19) Trial (ACTCOVID19). clinicaltrials.gov/ct2/show/NCT04324463 (first received 27 March 2020).

[CD015045-bib-0033] Dalili N, Kashefizadeh A, Nafar M, Poorrezagholi F, Firouzan A, Samadian F, et al. Adding colchicine to the antiretroviral medication – lopinavir/ritonavir (Kaletra) in hospitalized patients with non-severe Covid-19 pneumonia: a structured summary of a study protocol for a randomized controlled trial. Trials 2020;21(1):489. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0034] NCT04360980. The effects of standard protocol with or without colchicine in Covid-19 infection. clinicaltrials.gov/show/NCT04360980 (first received 24 April 2020).

[CD015045-bib-0035] NCT04363437. Colchicine in moderate-severe hospitalized patients before ARDS to treat COVID-19 (COMBATCOVID19). clinicaltrials.gov/show/NCT04363437 (first received 27 April 2020).

[CD015045-bib-0036] NCT04367168. Colchicine twice daily during 10 days as an option for the treatment of symptoms induced by inflammation in patients with mild and severe coronavirus disease (ColchiVID). clinicaltrials.gov/show/NCT04367168 (first received 29 April 2020).

[CD015045-bib-0037] EUCTR2020-001475-33. Treatment with colchicine of patients affected by COVID-19: a pilot study. www.clinicaltrialsregister.eu/ctr-search/trial/2020-001475-33/IT (first received 24 June 2020).

[CD015045-bib-0038] NCT04375202. Colchicine in COVID-19: a pilot study (COLVID-19). clinicaltrials.gov/show/NCT04375202 (first received 5 May 2020).

[CD015045-bib-0039] EUCTR2020-001603-16. A randomization, multicentric, open-label, controlled, clinical trial to investigate the effectiveness of early colchicine administration in patients over 70 years of age with high risk of developing severe pulmonary complications associated with Coronavirus disease pneumonia (Covid-19). www.clinicaltrialsregister.eu/ctr-search/trial/2020-001603-16/ES (first received 8 May 2020).

[CD015045-bib-0040] NCT04416334. Preemptive therapy with colchicine in patients older than 60 years with high risk of severe pneumoniae due to coronavirus (COLCHI-COVID). clinicaltrials.gov/show/NCT04416334 (first received 4 June 2020).

[CD015045-bib-0041] NCT04516941. Coronavirus edoxaban colchicine (CONVINCE) COVID-19. clinicaltrials.gov/show/NCT04516941 (first received 18 August 2020).

[CD015045-bib-0042] NCT04539873. Impact of colchicine in hospitalized Colombian patients with COVID-19 (COLCOVID19). clinicaltrials.gov/show/NCT04539873 (first received 7 September 2020).

[CD015045-bib-0043] NCT04667780. Study to investigate the treatment effect of colchicine in patients with COVID-19. clinicaltrials.gov/show/NCT04667780 (first received 16 December 2020).

[CD015045-bib-0044] NCT04724629. Survival trial using cytokines in COVID-19 (STRUCK). clinicaltrials.gov/show/NCT04724629 (first received 26 January 2021).

[CD015045-bib-0045] NCT04756128. Impact of colchicine and low-dose naltrexone on COVID-19. clinicaltrials.gov/show/NCT04756128 (first received 16 February 2021).

[CD015045-bib-0046] NCT04818489. Colchicine and post-COVID-19 pulmonary fibrosis. clinicaltrials.gov/ct2/show/NCT04818489 (first received 26 March 2021).

[CD015045-bib-0047] Effectiveness of colchicine among patients with COVID-19 infection. clinicaltrials.gov/ct2/show/NCT04867226 (first received 30 April 2021).

[CD015045-bib-0048] Alabed S, Cabello JB, Irving GJ, Qintar M, Burls A. Colchicine for pericarditis. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No: CD010652. [DOI: 10.1002/14651858.CD010652.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0049] Angelidis C, Kotsialou Z, Kossyvakis C, Vrettou AR, Zacharoulis A, Kolokathis F, et al. Colchicine pharmacokinetics and mechanism of action. Current Pharmaceutical Design 2018;24(6):659-63. [DOI: 10.2174/1381612824666180123110042] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0050] Buitrago-Garcia D, Egli-Gany D, Counotte MJ, Hossmann S, Imeri H, Ipekci Aziz M, et al. Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: a living systematic review and meta-analysis. PLoS Medicine 2020;17(9):e1003346. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0051] Castaño-Rodriguez C, Honrubia JM, Gutiérrez-Álvarez J, DeDiego ML, Nieto-Torres JL, Jimenez-Guardeño JM, et al. Role of severe acute respiratory syndrome coronavirus viroporins E, 3a, and 8a in replication and pathogenesis. mBio 2018;9(3):e02325-17. [DOI: 10.1128/mBio.02325-17] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0052] Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368:m1091. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0053] Guidance for the production and publication of Cochrane living systematic reviews: Cochrane Reviews in living mode. community.cochrane.org/review-production/production-resources/living-systematic-reviews (accessed 3 June 2021).

[CD015045-bib-0054] Core outcome set developers’ response to COVID-19. www.comet-initiative.org/Studies/Details/1538 (accessed 3 June 2021).

[CD015045-bib-0055] Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. Journal of Biological Regulators and Homeostatic Agents 2020;34(2):327-31. [DOI: 10.23812/CONTI-E] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0056] Common terminology criteria for adverse events (CTCAE). ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm (accessed 3 June 2021).

[CD015045-bib-0057] Deeks JJ, Higgins JP, Altman DG. Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

[CD015045-bib-0058] Della-Torre E, Della-Torre F, Kusanovic M, Scotti R, Ramirez GA, Dagna L, et al. Treating COVID-19 with colchicine in community healthcare setting. Clinical Immunology 2020;217:108490. [DOI: 10.1016/j.clim.2020.108490] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0059] Dupuis J, Sirois MG, Rhéaume E, Nguyen QT, Clavet-Lanthier ME, Brand G, et al. Colchicine reduces lung injury in experimental acute respiratory distress syndrome. PloS One 2020;15(12):e0242318. [DOI: 10.1371/journal.pone.0242318] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0060] EndNote X9. London (UK): Clarivate, 2013.

[CD015045-bib-0061] Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Dubnov-Raz G, et al. Colchicine poisoning: the dark side of an ancient drug. Clinical Toxicology 2010;48(5):407-14. [DOI: 10.3109/15563650.2010.495348] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0062] Funk T, Pharris A, Spiteri G, Bundle N, Melidou A, Carr M, et al. Characteristics of SARS-CoV-2 variants of concern B.1.1.7, B.1.351 or P.1: data from seven EU/EEA countries, weeks 38/2020 to 10/2021. Eurosurveillance 2021;26(16):2100348. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0063] Hariyanto TI, Halim DA, Jodhinata C, Yanto TA, Kurniawan A. Colchicine treatment can improve outcomes of coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Clinical and Experimental Pharmacology and Physiology 2021;48(6):823-30. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0064] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0065] Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook. [DOI] [PMC free article] [PubMed]

[CD015045-bib-0066] Higgins JP, Eldridge S, Li T. Chapter 23: Including variants on randomized trials. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

[CD015045-bib-0067] Higgins JP, Lasserson T, Chandler J, Tovey D, Thomas J, Flemyng E, et al. Methodological expectations of Cochrane intervention reviews. www.community.cochrane.org/mecir-manual/ (accessed 3 June 2021).

[CD015045-bib-0068] Higgins JP, Savović J, Page MJ, Elbers RG, Sterne JA. Chapter 8: Assessing risk of bias in a randomized trial. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

[CD015045-bib-0069] Higgins JP, Tianging L, Deeks JJ. Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

[CD015045-bib-0070] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395(10223):497-506. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0071] Imazio M, Cecchi E, Ierna S, Trinchero R. CORP (COlchicine for Recurrent Pericarditis) and CORP-2 trials – two randomized placebo-controlled trials evaluating the clinical benefits of colchicine as adjunct to conventional therapy in the treatment and prevention of recurrent pericarditis: study design and rationale. Journal of Cardiovascular Medicine (Hagerstown) 2007;8(10):830-4. [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0072] Karagiannidis C, Mostert C, Hentschker C, Voshaar T, Malzahn J, Schillinger G, et al. Case characteristics, resource use, and outcomes of 10 021 patients with COVID-19 admitted to 920 German hospitals: an observational study. Lancet Respiratory Medicine 2020;8(9):853-62. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0073] Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, et al. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database of Systematic Reviews 2021, Issue 9. Art. No: CD013825. [DOI: 10.1002/14651858.CD013825.pub2] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0074] Lamontagne F, Agoritsas T, Siemieniuk R, Rochwerg B, Bartoszko J, Askie L, et al. A living WHO guideline on drugs to prevent COVID-19. BMJ 2021;372:n526. [DOI: 10.1136/bmj.n526] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0075] Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application. Annals of Internal Medicine 2020;172(9):577–82. [DOI: 10.7326/M20-0504] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0076] Leung YY, Yao Hui LL, Kraus VB. Colchicine – update on mechanisms of action and therapeutic uses. Seminars in Arthritis and Rheumatism 2015;45(3):341-50. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0077] Li T, Higgins JP, Deeks JJ. Chapter 5: Collecting data. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (updated February 2021). Cochrane, 2021. Available from training.cochrane.org/handbook.

[CD015045-bib-0078] Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncology 2020;21(3):335-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0079] MAGICapp. Brønnøysund (NOR): Norwegian MAGIC Evidence Ecosystem Foundation (powered by UserVoice Inc.), 2020. Available at magicapp.org.

[CD015045-bib-0080] Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis 2018;269:262-71. [DOI: 10.1016/j.atherosclerosis.2017.12.027] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0081] McCullough PA, Kelly RJ, Ruocco G, Lerma E, Tumlin J, Wheelan KR, et al. Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection. American Journal of Medicine 2021;134(1):16-22. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0082] Microsoft Excel. Microsoft Corporation. Microsoft Corporation, 2018. office.microsoft.com/excel.

[CD015045-bib-0083] Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nature Immunology 2013;14(5):454-60. [DOI: 10.1038/ni.2550] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0084] Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Journal of Clinical Epidemiology 2009;62(10):1006-12. [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0085] Nawangsih EN, Kusmala YY, Rakhmat II, Handayani DR, Juliastuti H, Wibowo A, et al. Colchicine and mortality in patients with coronavirus disease 2019 (COVID-19) pneumonia: a systematic review, meta-analysis, and meta-regression. International Immunopharmacology 2021;96:107723. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0086] National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing COVID-19, 2021. www.nice.org.uk/guidance/ng191 (accessed prior to 22 September 2021).

[CD015045-bib-0087] Nieto-Torres JL, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, Castaño-Rodriguez C, Fernandez-Delgado R, et al. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 2015;485:330-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0088] Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Current Rheumatology Reports 2008;10(3):218-27. [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0089] Oran DP, Topol EJ. Prevalence of asymptomatic SARS-CoV-2 Infection: a narrative review. Annals of Internal Medicine 2020;173(5):362-7. [DOI: 10.7326/M20-3012] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0090] Page MJ, Higgins JP, Sterne JA. Chapter 13: Assessing risk of bias due to missing results in a synthesis. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.

[CD015045-bib-0091] Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17(24):2815-34. [DOI: ] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0092] Piechotta V, Iannizzi C, Chai KL, Valk SJ, Kimber C, Dorando E, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review. Cochrane Database of Systematic Reviews 2021, Issue 5. Art. No: CD013600. [DOI: 10.1002/14651858.CD013600.pub4] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0093] Potere N, Valeriani E, Candeloro M, Tana M, Porreca E, Abbate A, et al. Acute complications and mortality in hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis. Critical Care 2020;24(1):389. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0094] Review Manager Web (RevMan Web). Version 3.9.0. The Cochrane Collaboration, 2019. revman.cochrane.org.

[CD015045-bib-0095] Reyes AZ, Hu KA, Teperman J, Wampler Muskardin TL, Tardif JC, Shah B, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Annals of Rheumatic Diseases 2021;80:550-7. [DOI: 10.1136/annrheumdis-2020-219174] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0096] Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323(20):2052-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0097] Santesso N, Glenton C, Dahm P, Garner P, Akl A, Alper B, et al. GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions. Journal of Clinical Epidemiology 2020;119:126-35. [DOI: 10.1016/j.jclinepi.2019.10.014] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0098] Schünemann HJ, Higgins JP, Vist GE, Glasziou P, Akl EA, Skoetz N, et al. Chapter 14: Completing ‘Summary of findings’ tables and grading the certainty of the evidence. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.

[CD015045-bib-0099] Siemieniuk RA, Bartoszko JJ, Ge L, Zeraatkar D, Izcovich A, Kum E, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ 2020;370:m2980. [DOI: 10.1136/bmj.m2980] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0100] Simmonds M, Salanti G, McKenzie J, Elliott J, Living Systematic Review Network. Living systematic reviews: 3. Statistical methods for updating meta-analyses. Journal of Clinical Epidemiology 2017;91:38-46. [DOI: 10.1016/j.jclinepi.2017.08.008] [PMID: ] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0101] Skoetz N, Goldkuhle M, Dalen EC, Akl EA, Trivella M, Mustafa RA, et al. GRADE guidelines 27: how to calculate absolute effects for time-to-event outcomes in summary of findings tables and evidence profiles. Journal of Clinical Epidemiology 2020;118:124-31. [DOI: 10.1016/j.jclinepi.2019.10.015] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0102] Sterne JA, Savovic J, Page MJ, Elbers RG, Blencowe N, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. [DOI: 10.1136/bmj.l4898] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0103] Struyf T, Deeks JJ, Dinnes J, Takwoingi Y, Davenport C, Leeflang MM, et al. Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease. Cochrane Database of Systematic Reviews 2020, Issue 7. Art. No: CD013665. [DOI: 10.1002/14651858.CD013665] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0104] Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16. [DOI: 10.1186/1745-6215-8-16] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0105] Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nature Reviews. Cardiology 2018;15(4):203-14. [DOI: 10.1038/nrcardio.2017.161] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0106] Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database of Systematic Reviews 2014, Issue 8. Art. No: CD006190. [DOI: 10.1002/14651858.CD006190.pub2] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0107] Wagner C, Griesel M, Mikolajewska A, Mueller A, Nothacker M, Kley K, et al. Systemic corticosteroids for the treatment of COVID‐19. Cochrane Database of Systematic Reviews 2021, Issue 8. Art. No: CD014963. [DOI: 10.1002/14651858.CD014963] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0108] World Health Organization. Cumulative number of reported probable cases of SARS. www.who.int/csr/sars/country/2003_07_11/en (accessed 3 June 2021).

[CD015045-bib-0109] World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV). www.who.int/emergencies/mers-cov/en (accessed 3 June 2021).

[CD015045-bib-0110] World Health Organization. Report of the WHO‐China Joint Mission on coronavirus disease 2019 (COVID‐19). www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report (accessed 3 June 2021).

[CD015045-bib-0111] WHO working group on the clinical characterisation and management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infectious Diseases 2020;20(8):e192-7. [DOI] [PMC free article] [PubMed]

[CD015045-bib-0112] World Health Organization. Corticosteroids for COVID-19 – living guidance 2 September 2020. www.who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1 (accessed 3 June 2021).

[CD015045-bib-0113] World Health Organization. Draft landscape of COVID-19 candidate vaccines. www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines (accessed 3 June 2021).

[CD015045-bib-0114] World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. covid19.who.int (accessed 3 June 2021).

[CD015045-bib-0115] World Health Organization. Coronavirus disease (COVID-19)/COVID-19 vaccines/Explainers. www.who.int/emergencies/diseases/novel-coronavirus-2019/covid-19-vaccines/explainers (accessed 14 July 2021).

[CD015045-bib-0116] Williamson E, Walker AJ, Bhaskaran KJ, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584:430-6. [DOI: 10.1038/s41586-020-2521-4] [DOI] [PMC free article] [PubMed] [Google Scholar]

[CD015045-bib-0117] Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020;323(13):1239-42. [DOI: 10.1001/jama.2020.2648] [DOI] [PubMed] [Google Scholar]

[CD015045-bib-0118] Mikolajewska A, Piechotta V, Mueller A, Metzendorf M-I, Fischer A-L, Skoetz N, et al. Colchicin for the treatment of COVID-19 (part of German Ecosystem CEO-Sys). PROSPERO 2021 CRD42021239107 Available from: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021239107.

[CD015045-bib-0119] Mikolajewska A, Fischer A-L, Piechotta V, Mueller A, Metzendorf M-I, Becker M, Dorando E, et al. Risk of bias assessment for the Cochrane review "Colchicine for the treatment of COVID-19". zenodo.org/record/5377507 2021. [DOI: 10.5281/zenodo.5377507] [DOI] [PMC free article] [PubMed]

PERMALINK

Colchicine for the treatment of COVID‐19

Agata Mikolajewska

Anna-Lena Fischer

Vanessa Piechotta

Anika Mueller

Maria-Inti Metzendorf

Marie Becker

Elena Dorando

Rafael L Pacheco

Ana Luiza C Martimbianco

Rachel Riera

Nicole Skoetz

Miriam Stegemann

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Colchicine plus standard care compared to standard care (plus/minus placebo) for hospitalised patients with COVID‐19 and moderate to severe disease.

Summary of findings 2. Colchicine compared to placebo or standard care alone for non‐hospitalised patients with asymptomatic SARS‐CoV‐2 infection or mild COVID‐19.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Timing of outcome measurement

Hospitalised people with moderate to severe COVID‐19

Non‐hospitalised people with SARS‐CoV‐2 infection and asymptomatic or mild disease

Hospitalised people with moderate to severe COVID‐19

Non‐hospitalised people with SARS‐CoV‐2 infection and asymptomatic or mild disease

Search methods for identification of studies

Electronic searches

Living systematic review considerations

Searching other resources

Living systematic review considerations

Data collection and analysis

Selection of studies

Living systematic review considerations

Data extraction and management

Living systematic review considerations

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Studies with multiple treatment groups

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Living systematic review consideration

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Summary of findings

Hospitalised people with a confirmed or suspected diagnosis of COVID‐19 and moderate to severe disease

Non‐hospitalised managed individuals with a confirmed or suspected diagnosis of SARS‐CoV‐2 infection and asymptomatic or mild disease

Assessment of the certainty in the evidence

Methods for future updates – living systematic review considerations

When review methods will be reviewed

Conditions under which the review will no longer be maintained as a living systematic review

Results

Description of studies

Results of the search

1.

Obtaining additional data

Study design

Setting

Participants