Disclaimer: The aim of these rapid reviews is to retrieve, appraise, summarize and update the available evidence on COVID-related health technology. The reviews have not been externally peer- reviewed; they should not replace individual clinical judgement and the sources cited should be checked. The views expressed represent the views of the authors and not necessarily those of their host institutions. The views are not a substitute for professional medical advice.

Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

Colchicine is perhaps one of the oldest drugs in use today dating back since 1820.1 It has been approved by the FDA for use on gout flares, Behcet’s disease and Familial Mediterranean Fever,1,2

Colchicine has a unique anti-inflammatory property with a prolonged anti-inflammatory effect even after discontinuation.1 According to a study by Leung (2015), the mechanisms of action of colchicine on the immune system includes inhibition of neutrophil chemotaxis, adhesion and mobilization, and superoxide production as well as inhibition of NACHT-LRRPYD-containing protein 3 (NALP3) inflammasomes and interluekin (IL) 1β processing and release.3 It’s primary mechanism is tubulin disruption leading to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity.3 It is this inflammatory mechanism that may potentially have an effect on the clinical course of the patient with COVID-19 in terms of developing pneumonia and other cardiac complications.

The use of colchicine for gout has already been well established4 with a strong recommendation based on high quality evidence for clinicians to use it in acute gout.5 Its use on Neuro-Behcet’s or Behcet’s syndrome still needs further evidence in randomized or controlled clinical trials.6,7

Should Colchicine be used in the treatment of COVID-19?

In Familial Mediterranean Fever, colchicine appears to reduce the number of people experiencing attacks, but well designed and robust randomized controlled trials are still needed for a more comprehensive concusion.8 The Food and Drug Administration has approved colchicine use for these three indications, though only for gout does it seem to have high quality of evidence.

In recent years, Colchicine has been studied for cardiovascular and cerebrovascular diseases. Initially it was seen to reduce rates of recurrent pericarditis and post-pericardiotomy syndrome, and because of these, the European Society of Cardiology has listed this treatment in their 2015 pericardial diseases guidelines.9,10 Colchicine may have benefit in reducing myocardial infarction in selected high-risk populations.11 It also showed efficacy versus usual care in preventing atrial fibrillation after cardiac surgery and was associated with decreased hospital stay.12 It was noted to decrease stroke risk in patients with history of coronary artery disease2 and high cardiovascular risk.13 Thus the use of colchicine seems to expand as studies on its effectiveness for other indications beyond the initial ones are released.

Adverse events during oral colchicine use were also explored in a recent systematic review of randomized controlled trials.14 Methodologic quality was noted to be high on assessment of the primary studies. The meta- analysis showed that colchicine increases the rate of diarrhea and gastrointestinal adverse events. It did not observe an increase in the rate of liver, sensory, muscle, infectious or hematology adverse event and even death.

Clinical trials that investigate the efficacy and safety of colchicine for COVID-19 patients are still ongoing.

This rapid review summarizes the available evidence on the efficacy and safety of colchicine in treating patients with COVID-19.

METHODS

See General Methods Section.

Articles were selected based on the following inclusion criteria:

•Population: COVID-19 patients of any age, with any co-morbidities, any severity

•Intervention: Colchicine any dose, any duration

•Comparator: placebo, any active control, no intervention

•Outcomes: mortality, complications, respiratory distress, adverse events, length of hospitalization

•Study designs: randomized controlled trials (RCTs), non-randomized studies

RESULTS

Characteristics of Included Studies

There are currently no studies or clinical trials specifically answering the question on whether colchicine can be used

for the treatment of COVID-19 patients. There are however 4 ongoing trials listed in ClinicalTrials.gov to specifically answer that question, namely GRECCO-19, Colchicine Efficacy in COVID-19 Pneumonia, COLCOVID and COLCORONA. The 2 latter studies originated from Canada and are both Phase 3 studies while GRECCO-19 from Greece and Colchicine Efficacy in COVID-19 Pneumonia from Italy are both Phase 2 studies. Only the COLCORONA study has started recruitment at this time.

The interventions for the trials include colchicine on top of standard therapy compared to current standard therapy, except for COLCORONA where colchicine is compared to placebo. COLCORONA includes COVID-19 patients in the out-patient setting while the three other trials will recruit hospitalized patients. Completion dates have been targeted from the period of May 2020 up to September 2020. Details on the trials and outcomes are seen on the Table of Ongoing Clinical Trials in the Appendix.

Recommendations from Other Guidelines

There are currently no specific recommendations for the use of colchicine for COVID-19 patients in the WHO Interim Guidance, the US CDC Interim Clinical Guidance and Chinese Clinical Guidance.

CONCLUSION

Although its use as an anti-inflammatory agent for gout is firmly established and its use for cerebrovascular and cardiovascular disease is continually being confirmed by randomized controlled trials, this is not the case yet for COVID-19. Thus there is currently insufficient evidence for the use of colchicine for COVID-19 patients at this time. The ongoing trials will be assessed and reported as soon as it is completed.

Declaration of Conflict of Interest

No conflict of interest.

REFERENCES

1.Yan BP, Tan GM. What’s old is new again - a review of the current evidence of colchicine in cardiovascular medicine. Curr Cardiol Rev. 2017; 13(2):130-138.

2.Katsanos AH, Palaiodimou L, Price C, Giannopoulos S, Lemmens R, Kosmidou M, et al. Colchicine for stroke prevention in patients with coronary artery disease: a systematic review and meta-analysis. Eur J Neurol. 2020 Mar 5. doi: 10.1111/ene.14198.

3.Leung YY, Yao Hui LL, Kraus VB. Colchicine — Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015; 45(3):341-50.

4.Shekelle PG, Newberry SJ, FitzGerald JD, Motala A, O'Hanlon CE, Tariq A, et al. Management of gout: a systematic review in support of an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2017;166(1):37-51. doi: 10.7326/M16-0461.

5.Qaseem A, Harris RP, Forciea MA for the Clinical Guidelines Committee of the American College of Physicians. Management of acute and recurrent gout: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017; 166(1):58-68.

6.Nava F, Ghilotti F, Maggi L, Hatemi G, Del Bianco A, Merlo C, et al. Biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha for Neuro-Behçet's Syndrome. Cochrane Database Syst Rev. 2014;(12):CD010729. doi: 10.1002/14651858.CD010729. pub2.

7.Saenz A, Ausejo M, Shea B, Wells G, Welch V, Tugwell P. Pharmacotherapy for Behcet's syndrome. Cochrane Database Syst Rev. 2000; (2):CD001084.

8.Wu B, Xu T, Li Y, Yin X. Interventions for reducing inflammation in familial Mediterranean fever. Cochrane Database Syst Rev. 2018; 10:CD010893. doi: 10.1002/14651858.CD010893.pub3.

9.Verma S, Eikelboom JW, Nidorf SM, Al-Omran M, Gupta N, Teoh H, et al. Colchicine in cardiac disease: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2015; 15:96. doi: 10.1186/s12872-015-0068-3.

10.Adler Y, Charron P, Imazio M, Badano L, Barón-Esquivias G, Bogaert J, et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases. Eur Heart J. 2015; 36(42):2921-2964.

11.Hemkens LG, Ewald H, Gloy VL, Arpagaus A, Olu KK, Nidorf M, et al. Colchicine for prevention of cardiovascular events. Cochrane Database Syst Rev. 2016; (1):CD011047. doi: 10.1002/14651858. CD011047.pub2.

12.Lennerz C, Barman M, Tantawy M, Sopher M, Whittaker P. Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis. Int J Cardiol. 2017; 249:127-137. doi: 10.1016/j.ijcard.2017.08.039.

13.Masson W, Lobo M, Molinero G, Masson G, Lavalle-Cobo A. Role of colchicine in stroke prevention: an updated meta-analysis. J Stroke Cerebrovasc Dis. 2020; 29(5):104756. https://doi.org/ 10.1016/j.jstrokecerebrovasdis.2020.104756

14.Stewart S, Yang KCK, Atkins K, Dalbeth N, Robinson PC. Adverse events during oral colchicine use:a systematic review and meta-analysis of randomised controlled trials. Arthritis Res Ther. 2020. 22:28.

Local standard care plus colchicine with specific dosage schedule

Local standard of care for COVID-19 SARS moderate / high-risk patients

Primary Outcome Measures:

All-cause mortality (Time Frame: During hospitalization or until death, whichever comes first, assessed up to 30 days)

Secondary Outcome Measures:

Composite of intubation for mechanical ventilation or death. (Time Frame: During hospitalization or until death, whichever comes first, assessed up to 30 days) Number of participants who require intubation for mechanical ventilation or die

Colchicine 0.5mg twice daily for first 3 days and then once daily for the last 27 days

Placebo twice daily for the first 3 days and then once daily for the last 27 days

Primary Outcome Measures:

Number of participants who die or require hospitalization due to COVID-19 infection (Time Frame: 30 days post randomization)

The primary endpoint will be the composite of death or the need for hospitalization due to COVID-19 infection in the first 30 days after randomization.

Secondary Outcome Measures:

Number of participants who die (Time Frame: 30 days post randomization) The secondary endpoint is the occurrence of death in the 30 days following randomization.

Number of participants requiring hospitalization due to COVID-19 infection (Time Frame: 30 days post randomization)

The secondary endpoint is the need for hospitalization due to COVID-19 infection in the 30 days following randomization.

Number of participants requiring mechanical ventilation (Time Frame: 30 days post randomization)

The secondary endpoint is the need for mechanical ventilation in the 30 days following randomization.

Database	Search strategy / search terms
Medline	“Coronavirus Infections"[Mesh]) OR "Coronavirus"[Mesh]) OR
	coronavirus) OR novel coronavirus) OR NCOV) OR "COVID-19"
	[Supplementary Concept]) OR covid19) OR covid 19) OR covid-19) OR
	"severe acute respiratory syndrome coronavirus 2" [Supplementary
	Concept]) OR severe acute respiratory syndrome coronavirus 2) OR
	SARS2) OR SARS 2) OR SARS COV2) OR SARS COV 2) OR SARS-
	COV-2)) AND (("Colchicine"[Mesh]) OR colchicine)

Date and time	Results
of search	Yield	Eligible
01 April 2020	13	0
10:00:35