A large global study indicates that treatment with colchicine is effective in reducing hospitalization and death among patients with COVID-19 confirmed through polymerase chain reaction (PCR) testing. In the study, treatment with colchicine led to a 25% lower incidence of death or hospital admission than placebo.
The COLCORONA study by Jean-Claude Tardif, MD, director of the Montreal Heart Institute, University of Montreal, and colleagues was initiated at the onset of the pandemic. At the time, there was a shortage of reagents for PCR tests, and the use of such tests was restricted. Therefore, the study was initially performed in patients with a diagnosis of probable COVID-19 through an epidemiological link or compatible symptoms. When the investigators considered only patients with a confirmed diagnosis of COVID-19, colchicine proved more beneficial than it was in those with a presumed diagnosis.
The treatment’s efficacy was limited to men. For non-hospitalized patients with COVID-19 who were men, treatment with colchicine was associated with a 33% lower incidence of death or hospital admission compared with placebo. It had no effect in women. Although colchicine also decreased the incidence of pneumonia, the study results did not reach statistical significance.
The results suggest colchicine is most effective in populations at higher risk for hospitalization from COVID-19. One such risk factor is sex, with men more likely to experience adverse outcomes from COVID-19 than women. The fact that colchicine was effective in men and not women may also reflect sex-related differences in immune responses against SARS-CoV-1. Men have higher plasma concentrations of interleukin (IL) 18 and IL-8, whereas women have stronger T-cell activation.
The findings, published online in The Lancet Respiratory Medicine on May 27, are important given the lack of orally administered therapies to prevent complications from COVID-19. The authors emphasize that colchicine is a safe and inexpensive anti-inflammatory agent that may be useful in patients at risk of complications of COVID-19 infection.1
Awareness
“It’s been a little frustrating, because the findings haven’t actually broken through to the public,” says Michael H. Pillinger, MD, a rheumatologist at New York University (NYU) Grossman School of Medicine and co-principal investigator of the study’s U.S. arm. According to Dr. Pillinger, colchicine is already being used to treat COVID-19 in Cypress and Greece, but not throughout the U.S. or Canada.
This study was funded by multiple sources, including the Government of Quebec, the National Heart Lung and Blood Institute of the U.S. National Institutes of Health, and by the Bill & Melinda Gates Foundation. After analyzing its results, the Gates Foundation recommended colchicine for consideration to regulatory bodies, stating “it could be a key treatment modality for high-risk patients with COVID-19 and mild disease. The low cost and oral route of administration make it attractive for use, especially in low- to middle-income countries.”
The U.S. Centers for Disease Control and Prevention (CDC) has not yet weighed in on the use of colchicine in non-hospitalized patients. The CDC’s most recent COVID-19 update on colchicine is from June 2020 and describes data from hospitalized patients.2
Dr. Pillinger thinks the study’s findings have been ignored because of the success of the COVID-19 vaccines. “We thought the problem was licked,” he says.
Unfortunately, the high rate of vaccine hesitancy and the spread of the delta variant means individuals are becoming infected with COVID-19 and suffering complications. Many of these patients, especially men, may benefit from treatment with colchicine.
“It’s a generally safe drug,” says Dr. Pillinger, adding, “The main problem is diarrhea.” Diarrhea was reported in 13.7% of patients in the study’s treatment group and 7.3% of of patients in the placebo group. However, Dr. Pillinger notes that, because colchicine is easy to stop, if the diarrhea becomes intolerable, the patient can discontinue treatment.
The treatment group had a greater incidence of pulmonary embolism than the placebo group (0.5% vs. 0.1%), but the pulmonary emboli did not necessitate mechanical ventilation or lead to death. Additionally, the physicians considered the pulmonary emboli to be unrelated to the study medication. Dr. Pillinger believes the pulmonary emboli were likely an artifact of how the study captured data.
In addition to being safe, Dr. Pillnger emphasizes colchicine is “dirt cheap.” In the U.S., the cost of 30 days of treatment is approximately $150. This amount compares favorably to the cost of one day of hospitalization, which can be $10,000.
Backstory
“Colchicine is one of the oldest drugs we rheumatologists have,” says Dr. Pillinger. Colchicine, originally isolated from the autumn crocus (Colchium autumnale) which first grew in Asia Minor, has been used medicinally for 2,000 years. It was first described as a treatment for rheumatism and swelling in an Egyptian medical papyrus, and Hippocrates later proposed it as a gout remedy.3 Jason and the Argonauts went to Colchis to capture the Golden Fleece, and according to Dr. Pillinger, some historians have proposed the Golden Fleece was the autumn crocus. Colchicine made its way to the U.S. when Benjamin Franklin brought it back from France to treat his gout. (For more information about colchicine, see “Colchicine: An Ancient Drug with Modern Uses.”)
The U.S. Food & Drug Administration (FDA) has approved colchicine to treat or prevent gout in adults, as well as to treat the genetic condition familial Mediterranean fever. It has been used successfully to reduce the inflammation associated with gout and cardiovascular conditions. However, it’s not a potent immunosuppressant—which Dr. Pillinger says is a potential advantage in its use to treat COVID-19.4
As the understanding of COVID-19 has evolved and the medical community has developed an appreciation for the role of cytokine overproduction in negative COVID-19 outcomes, rheumatologists and cardiologists around the world have asked: “Can we tap the brakes before things get bad?”
Dr. Pillinger says he and his colleagues designed this study to answer that question. Other studies have examined the treatment’s ability to help non-hospitalized patients with COVID-19. The first studies were small. Individual hospitals around the world tried colchicine, and the results were consistently positive.5 They found colchicine was helpful in reducing hospital stays and mortality, if given on the first day or two of arrival.
For this larger study, physicians around the world came together to create a phase 3, randomized double-blind, adaptive, placebo-controlled, multi-center clinical trial. Dr. Pillinger and his colleague in the U.S., Binita Shah, MD, a cardiologist at NYU, were among these physicians. Thus, he found himself not only at the epicenter of the U.S. pandemic, but also leading the U.S. arm of the international study.
Dr. Pillinger was pleased with the study results. “When we ran it through, it cut admissions by 25%. The higher the risk the patient, the more [colchicine] seemed to be effective,” he says.
Barriers to Adoption
“It’s not very sexy,” says Dr. Pillinger, noting colchicine is inexpensive—the poor cousin in a rheumatologist’s arsenal of expensive biologic drugs. The colchicine story was also not helped by the intense—and ultimately unsatisfying—focus on hydroxychloroquine (HCQ) in early 2020.
“The whole world got burned over the [HCQ] story,” says Dr. Pillinger, referencing how early in the pandemic U.S. President Donald Trump identified HCQ as a cure for COVID-19. Ultimately, however, the scientific data did not support this early claim. “The idea that another very old, pre-existing rheumatologic drug may be effective raised some skepticism.”
Dr. Pillinger also notes the COLCORONA study was different from most COVID-19 studies. “We were focused on outpatient [treatment], and everyone else was focused on inpatient,” he says.
The colchicine outpatient message was buried by data from the RECOVERY trial in the U.K. That study found that patients with COVID-19 who were receiving invasive mechanical ventilation or oxygen alone who were treated with dexamethasone experienced a lower 28-day mortality rate than those treated with placebo.6 The study continued by randomizing patients to receive other treatments, including REGN-COV2, a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein; aspirin; colchicine; or usual care alone, which may include a glucocorticoid, macrolide antibiotic, HCQ, lopinavir/ritonavir or IL-6 antagonist. The colchicine arm was stopped because preliminary analysis revealed no significant difference in the primary endpoint for the 28-day mortality rate.
With 4,488 patients, the COLCORONA study stands on par with the RECOVERY trial (N= 2,104). However, the RECOVERY trial focused on hospitalized patients, a population distinct from that studied in the COLCORONA trial. It also added colchicine to dexamethasone, and according to Dr. Pillinger, most rheumatologists would predict the combination to have little added value.
As another COVID-19 wave sweeps over North America, and hospitals in some regions are again becoming overwhelmed, Dr. Pillinger wants to draw the medical community’s attention to the benefits of colchicine in certain populations. He emphasizes the treatment is inexpensive, well-understood and can be stopped if ineffective. “Why would you not just go ahead and try it?” he asks.
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
References
- Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): A phase 3, randomized, double-blinded, adaptive, placebo-controlled, multi-centre trial. Lancet Respir Med. 2021 Aug;9(8):924–932.
- COVID-19 science update released: July 2, 2020, edition 27. U.S. Centers for Disease Control and Prevention. 2021 Jul 2.
- Nerlekar N, Beale A, Harper RW. Colchicine—a short history of an ancient drug. Med J Aust. 2014 Dec 11;201(11):687–688.
- Reyes AZ, Hu KA, Teperman J, et al. Anti-inflammatory therapy for COVID-19 infection: The case for colchicine. Ann Rheum Dis. 2021;80:550–557.
- Detereos SG, Giannapoulos 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 Network Open. 2020;3:e2013136.
- The RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021 Feb 25; 384(8):693–704.
