But no significant results seen in overall COLCORONA cohort

Colchicine had no statistically significant effects on overall clinical events related to Covid-19 infection in community-treated patients, according to results from the COLCORONA trial—however, in a subgroup of patients with Covid-19 confirmed by PCR, it did bring about lower rates of the composite of death or hospital admission compared with placebo, they reported in The Lancet Respiratory Medicine.

“Given the absence of orally administered therapies to prevent Covid-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven Covid-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended,” wrote Jean-Claude Tardif, MD, of the Montreal Heart Institute, Québec, Canada, and fellow COLCORONA investigators.

“Colchicine is a potent anti-inflammatory agent used to treat gout, viral pericarditis, coronary disease, and familial Mediterranean fever. Its mechanism of action is through the inhibition of tubulin polymerization, with effects on the inflammasome, cellular adhesion molecules, and inflammatory chemokines,” they explained. “In an experimental model of acute respiratory distress syndrome, colchicine was shown to reduce inflammatory lung injury and respiratory failure by interfering with leukocyte activation and recruitment. Substantial clinical benefits of colchicine have also been reported in observational studies and two randomized controlled trials of patients admitted to hospital with Covid-19.”

Enrollment for this phase III, randomized, double-blind, adaptive, placebo-controlled, multicenter study ran from March 23, 2020, through Dec. 22, 2020, during which Tardif and colleagues enrolled 4,488 patients and randomized them to treatment with oral colchicine (0.5 mg twice daily for 3 days, and then once daily for 27 days; n=2235) or placebo (n=2253). Patients were followed up for 30 days.

Inclusion criteria included age of at least 40 years, receiving a diagnosis of Covid-19 within 24 hours of enrollment, no current in-hospital treatment, and no consideration for hospital treatment or admission, and presentation of at least one of the following high-risk criteria: age ≥70 years, obesity, diabetes, uncontrolled hypertension, known respiratory disease, known heart failure, known coronary disease, fever of at least 38.4° C within the past 48 hours, dyspnea on presentation, bicytopenia, pancytopenia, or combination of high neutrophil/low lymphocyte counts.

A composite of death or hospital admission for Covid-19 was the primary efficacy endpoint, and occurred in 4.7% of patients treated with colchicine, compared with 5.8% of those treated with placebo (OR: 0.79; 95.1% CI: 0.61-1.03; P=0.081).

Covid-19 was confirmed via PCR testing in a subgroup of 4,159 patients, among whom 4.6% of those treated with colchicine experienced the primary endpoint, compared with 6.0% of those treated with placebo (OR: 0.75; 0.57-0.99; P=0.042); death occurred in 0.2% vs 0.4%, respectively, and hospitalization in 4.5% vs 5.9%. The secondary endpoint—the need for mechanical ventilation—occurred in 0.5% of patients treated with colchicine, vs 1.0% of those treated with placebo.

Serious adverse events occurred in 4.9% of those in the colchicine group, compared with 6.3% in the placebo group (P=0.51). Pneumonia was seen in significantly fewer patients treated with colchicine compared with placebo (2.9% vs 4.1%, respectively P=0.021), but significantly more colchicine-treated patients experienced pulmonary embolism (0.5% vs 0.1%) and diarrhea (13.7% vs 7.3%; P˂0.0001).

“Despite this apparent imbalance, the numbers of hospital admissions, use of mechanical ventilation, and deaths were numerically lower in the colchicine group than in the placebo group,” noted researchers.

No patients in either group developed deep venous thrombosis.

“In COLCORONA, the risk of the primary composite efficacy endpoint of death or hospital admission due to Covid-19 infection in the 30 days following randomization was not statistically significantly lower among the patients who were randomly assigned to receive colchicine than in those who received placebo,” concluded Tardif et al.

Yet despite these disappointing results, the COLCORONA study provides some glimmers of hope for the treatment of Covid-19, according to Clark D. Russell, MBChB, and PhD student, University of Edinburgh Center for Inflammation Research, The Queen’s Medical Research Institute, Edinburgh, U.K.

“The authors found no difference in the primary endpoint between the two treatment groups. However, in a subgroup analysis restricted to patients with PCR-confirmed SARS-CoV-2 infection (4,159 [92.7%] of 4488 participants) colchicine was associated with a reduction in hospital admission and death (4.6 vs 6.0%, odds ratio 0.75, 95% CI 0.57–0.99), with a number needed to treat of 70 (95% CI 36–1,842),” wrote Russell in an accompanying editorial. “The COLCORONA trial is a valuable addition to the clinical investigation of Covid-19. Is colchicine likely to become a first-line treatment for community management of early Covid-19? The answer is probably not. The effect size was small and the NNT large, although further investigation in a higher-risk cohort might be warranted, aiming to recruit patients closer to symptom onset and possibly dosing colchicine closer to the recommendations for familial Mediterranean fever,” he added. “This trial does however add proof of principle of two important therapeutic concepts—progression of Covid-19 lung injury can be inhibited to prevent hospital admission and anti-inflammatory therapy can achieve this.”

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Russell concluded: “There is observational evidence that an early window of opportunity exists in which to modify the inflammatory trajectory in Covid-19 with the aim of preventing hospital admission. Encouragingly, these findings are now supported by emerging evidence from outpatient clinical trials. As has been the case in trials with patients admitted to hospital, evaluation of multiple agents will probably be required before highly efficacious outpatient therapy is identified. COLCORONA represents the beginning of this important process.”

Limitations of the COLCORONA trial include early termination at 75% planned recruitment, short follow-up, failure to assess persistent Covid-19 symptoms and effects of longer-term colchicine treatment, failure to assess benefits of a shorter course of colchicine, and the non-generalizability of study results.

Editorialist Russell also commented on the median patient age of 53 years and the large percentage of women that comprised this cohort.

“Given that increasing age and male sex have the largest effect sizes for risk of mortality in people who are admitted to hospital, the cohort studied in the COLCORONA trial cannot be considered to be in the highest-risk category,” he wrote.

  1. Among a subgroup of patients with PCR-confirmed Covid-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo.

  2. Note that colchicine did not show a statistically significant benefit over placebo for Covid-19-related events when applied to the overall study cohort.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

The COLCORONA trial was funded by the Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.

Tardif reports grants from Government of Quebec, the National Heart, Lung, and Blood Institute of the US National Institutes of Health (NIH), the Montreal Heart Institute Foundation, the Bill & Melinda Gates Foundation, Amarin, Esperion, Ionis, Servier, and RegenXBio, along with grants and personal fees from AstraZeneca, Sanofi, and Servier, and grants, personal fees, and minor equity interests from Dalcor. In addition, Tardif’s institution has submitted a pending patent for a method of treating a coronavirus infection using colchicine, and a pending patent on early administration of low-dose colchicine after myocardial infarction. Tardif has waived his rights in all patents related to colchicine and does not stand to benefit financially if colchicine becomes used as a treatment for COVID-19. Tardif and a co-author also have a patent method for treating or preventing cardiovascular disorders and lowering risk of cardiovascular events issued to Dalcor, no royalties received, a patent genetic markers for predicting responsiveness to therapy with HDL-raising or HDL mimicking agent issued to Dalcor, no royalties received, and a patent method for using low-dose colchicine after myocardial infarction with royalties paid to invention assigned to the Montreal Heart Institute.

Russell declared no conflicts of interest.

Cat ID: 190

Topic ID: 79,190,730,933,190,926,192,927,151,928,925,934