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Colchicine

Last Updated: April 21, 2021

Colchicine is an anti-inflammatory drug that is used to treat a variety of conditions, including gout, recurrent pericarditis, and familial Mediterranean fever.1 Recently, the drug has been studied for the prevention of major cardiovascular events in those with coronary artery disease.2 Colchicine has several potential mechanisms of action, including mechanisms that reduce the chemotaxis of neutrophils, inhibit inflammasome signaling, and decrease the production of cytokines such as interleukin-1 beta.3 When colchicine is administered early in the course of COVID-19, these mechanisms may potentially mitigate or prevent inflammation-associated manifestations of the disease. These anti-inflammatory properties (as well as the drug’s limited immunosuppressive potential, widespread availability, and favorable safety profile) have prompted investigation of colchicine for the treatment of COVID-19.

Recommendations

  • There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of colchicine for the treatment of nonhospitalized patients with COVID-19.
    • A large, randomized trial in outpatients, the Colchicine Coronavirus SARS-CoV-2 Trial (COLCORONA), did not reach its primary efficacy endpoint of reducing hospitalizations and death. However, a slight reduction in hospitalizations was observed in the subset of patients whose diagnosis was confirmed by a positive nasopharyngeal swab on a SARS-CoV-2 polymerase chain reaction (PCR) test.
  • The Panel recommends against the use of colchicine in hospitalized patients for the treatment of COVID-19, except in a clinical trial (AIII).

Clinical Data for COVID-19

Colchicine in Nonhospitalized Patients With COVID-19: The COLCORONA Trial

COLCORONA was a contactless, double-blind, placebo-controlled randomized trial in outpatients who were diagnosed with COVID-19 within 24 hours of enrollment.4 Participants had to have at least one risk factor for COVID-19 complications, including age ≥70 years, body mass index ≥30, diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart failure or coronary disease, fever ≥38.4°C within the last 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count. Participants were randomized 1:1 to receive colchicine 0.5 mg twice daily for 3 days and then once daily for 27 days or placebo. The primary endpoint was a composite of death or hospitalization by Day 30; secondary endpoints included components of the primary endpoint, as well as the need for mechanical ventilation by Day 30. Given the contactless design of the study, outcomes were ascertained by patient self-report via telephone at 15 and 30 days after randomization; in some cases, clinical data was confirmed by medical chart review.

Results

  • The study enrolled a total of 4,488 participants.
  • The primary endpoint was reached in 104 of 2,235 participants (4.7%) in the colchicine arm versus in 131 of 2,253 participants (5.8%) in the placebo arm (OR 0.79; 95% CI, 0.61–1.03; P = 0.08).
  • There were no statistically significant differences in the secondary outcomes between the arms.
  • In a prespecified analysis of 4,159 participants who had a SARS-CoV-2 diagnosis confirmed by a nasopharyngeal PCR test (93% of those enrolled), those in the colchicine arm were significantly less likely to reach the primary endpoint (96 of 2,075 participants [4.6%]) than those in the placebo arm (126 of 2,084 participants [6.0%]; OR 0.75; 95% CI, 0.57–0.99; P = 0.04). In this subgroup of patients who were SARS-CoV-2 positive, there were fewer hospitalizations (a secondary outcome) in the colchicine arm (4.5% of patients) than in the placebo arm (5.9% of patients; OR 0.75; 95% CI, 0.57–0.99).
  • More gastrointestinal adverse events occurred in the colchicine arm, including diarrhea (occurred in 13.7% of patients vs. in 7.3% of patients in the placebo arm; P <0.001). Unexpectedly, more pulmonary emboli were reported among patients in the colchicine arm (11 events [0.5% of patients] vs. 2 [0.1% of patients] in the placebo arm; P = 0.01).

Limitations

  • Due to logistical difficulties with staffing, the trial was stopped at approximately 75% of the target enrollment, which may have limited the study’s power to detect differences for the primary outcome.
  • There was uncertainty as to the accuracy of COVID-19 diagnoses in presumptive cases.
  • Patient-reported clinical outcomes were potentially misclassified.

Colchicine in Hospitalized Patients With COVID-19: The RECOVERY Trial

This study has not been published.

The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial randomized hospitalized patients with COVID-19 to receive colchicine (1 mg loading dose, followed by 0.5 mg 12 hours later, and then 0.5 mg twice daily for 9 days or until discharge) or usual care.5

Results

  • In a preliminary, unpublished report of results for 11,162 patients randomized to colchicine or usual care, there was no significant difference in the primary endpoint of 28-day mortality between the arms.
  • Of the 2,178 patients who died, 20% were in the colchicine arm versus 19% in the usual care arm (risk ratio 1.02; 95% CI, 0.94–1.11; P = 0.63).
  • Among the patients who died, 94% had received concomitant corticosteroids.

Study of the Effects of Colchicine in Hospitalized Patients With COVID-19: The GRECCO-19 Trial

The GReek Study in the Effects of Colchicine in Covid-19 cOmplications Prevention (GRECCO-19) was a small, prospective, open-label randomized clinical trial in 105 patients hospitalized with COVID-19 across 16 hospitals in Greece. Patients were assigned 1:1 to receive standard of care with colchicine (1.5 mg loading dose, followed by 0.5 mg after 60 minutes and then 0.5 mg twice daily until hospital discharge or up to 3 weeks) or standard of care alone.6

Results

  • Fewer patients in the colchicine arm (1 of 55 patients) than in the standard of care arm (7 of 50 patients) reached the primary clinical endpoint of deterioration in clinical status from baseline by two points on a seven-point clinical status scale (OR 0.11; 95% CI, 0.01–0.96).
  • Participants in the colchicine group were significantly more likely to experience diarrhea (occurred in 45.5% vs. 18.0% of participants in the colchicine and standard of care arms, respectively; P = 0.003).

Limitations

  • The number of clinical events reported for the trial was small.
  • The study design was open-label treatment assignment.

The results of several small randomized trials and retrospective cohort studies that have evaluated various doses and durations of colchicine in hospitalized patients with COVID-19 have been published in peer-reviewed journals or made available as preliminary, non-peer-reviewed reports.7-10 Some have shown benefits of colchicine use, including less need for supplemental oxygen, improvements in clinical status on an ordinal clinical scale, and reductions in certain inflammatory markers. In addition, some studies have reported higher discharge rates or fewer deaths among patients who received colchicine than among those who received comparator drugs or placebo. However, these studies also had significant design or methodological limitations, including small sample sizes, open-label designs, and differences between the treatment arms in participants’ clinical and demographic characteristics and the permitted use of various cotreatments (e.g., remdesivir, corticosteroids), that limit interpretability of the studies.

Adverse Effects, Monitoring, and Drug-Drug Interactions

Common side effects of colchicine include diarrhea, nausea, vomiting, cramping, abdominal pain, bloating, and loss of appetite. In rare cases, colchicine is associated with serious adverse events, such as neuromyotoxicity and blood dyscrasias. Use of colchicine should be avoided in patients with severe renal insufficiency, and patients with moderate renal insufficiency who receive the drug should be monitored for adverse effects. Caution should be used when colchicine is coadministered with drugs that inhibit cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) because such use may increase the risk of colchicine-induced adverse effects due to significant increases in colchicine plasma levels. The risk of myopathy may be increased with the concomitant use of certain HMG-CoA reductase inhibitors, such as atorvastatin, lovastatin, and simvastatin, due to potential competitive interactions mediated by CYP3A4 and P-gp pathways.11,12 Fatal colchicine toxicity has been reported in individuals with renal or hepatic impairment who received colchicine in conjunction with P-gp inhibitors or strong CYP3A4 inhibitors.

Considerations in Pregnancy

There are limited data on the use of colchicine in pregnancy. Fetal risk cannot be ruled out based on data from animal studies and the drug’s mechanism of action. Colchicine crosses the placenta and has antimitotic properties, which raises a theoretical concern for teratogenicity. However, a recent systematic review of the literature did not find higher rates of miscarriage or major fetal malformations in pregnant women who were exposed to colchicine than in pregnant women who were not exposed to the drug. There are no data for colchicine use in pregnant women with acute COVID-19. Risks of use should be balanced against potential benefits.11,13

Considerations in Children

Colchicine use in children is limited to the treatment of periodic fever syndromes, primarily familial Mediterranean fever. There are no data on the use of colchicine to treat pediatric acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C).

  1. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database Syst Rev. 2014(8):CD006190. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25123076.
  2. Xia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary artery disease. Am J Cardiol. 2021;140:33-38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33137319.
  3. Reyes AZ, Hu KA, Teperman J, et al. Anti-inflammatory therapy for COVID-19 infection: the case for colchicine. Ann Rheum Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33293273.
  4. Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Efficacy of colchicine in non-hospitalized patients with COVID-19. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.01.26.21250494v1.
  5. Randomised Evaluation of COVID-19 Therapy (RECOVERY). RECOVERY trial closes recruitment to colchicine treatment for patients hospitalised with COVID-19. 2021. https://www.recoverytrial.net/news/recovery-trial-closes-recruitment-to-colchicine-treatment-for-patients-hospitalised-with-covid-19. Accessed March 9, 2021.
  6. Deftereos SG, Giannopoulos G, Vrachatis DA, 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 Netw Open. 2020;3(6):e2013136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32579195.
  7. Brunetti L, Diawara O, Tsai A, et al. Colchicine to weather the cytokine storm in hospitalized patients with COVID-19. J Clin Med. 2020;9(9). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32937800.
  8. Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33133323.
  9. Lopes MI, Bonjorno LP, Giannini MC, 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). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33542047.
  10. Salehzadeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients; a clinical trial. Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-69374/v1.
  11. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf.
  12. American College of Cardiology. AHA statement on drug-drug interactions with statins. 2016. Available at: https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2016/10/20/21/53/recommendations-for-management-of-clinically-significant-drug. Accessed February 24, 2021.
  13. Indraratna PL, Virk S, Gurram D, Day RO. Use of colchicine in pregnancy: a systematic review and meta-analysis. Rheumatology (Oxford). 2018;57(2):382-387. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29029311.