Colchicine treatment in COVID-19: the remaining unsolved question.

Colchicine has been used to treat diverse pathologies in different areas of medicine, including rheumatology and cardiology. During the COVID-19 pandemic, colchicine has been considered a good therapeutic option because of its effects on the parts of the immune system involved in SARS-CoV-2 infection and acute respiratory distress syndrome (ARDS), including its effects on the chemotaxis of inflammatory cells, such as neutrophils and monocytes, and the intracellular transportation of vesicles. Colchicine also inhibits the inflammasome, expression of different molecules involved in leukocytes binding to endothelial cells, and the recruitment of mononuclear cells and neutrophils to inflamed tissue. Therefore, different clinical trials were initiated to test the hypothesis of its benefit in COVID-19. 11 studies enrolling 17 205 patients with COVID-19, most of whom were male, were included in a meta-analysis, published in 2021. Patients who received colchicine had a significantly lower risk of mortality (odds ratio 0·57 [95% CI 0·38–0·87]; I 2 72%; p<0·01) and a non-significantly lower rate of mechanical ventilation (odds ratio 0·67 [95% CI 0·39–1·15]; I 2 67%; p<0·01). Of note, the subgroup analysis involving randomised controlled trials showed no statistically significant difference in mortality between patients who received colchicine and those who did not. The COLCORONA trial, a study of more than 4000 non-hospitalised patients, was included in the meta-analysis, but this trial was stopped before the scheduled sample size had been fully enrolled due to logistical reasons and the result was not statistically significant.

In The Lancet Respiratory Medicine, the RECOVERY Collaborative Group report the results of a streamlined, randomised, controlled, open-label, platform trial, in which adult patients were randomly assigned (1:1) to receive either usual standard of care alone or usual standard of care plus colchicine. The primary outcome was all-cause mortality assessed at day 28. The study suggests that colchicine was not associated with reductions in 28-day mortality (rate ratio 1·01 [95% CI 0·93 to 1·10]; p=0·77), duration of hospital stay (10 days [IQR 5 to >28] in both groups), or risk of progressing to invasive mechanical ventilation or death (risk ratio 1·02 [95% CI 0·96 to 1·09]; p=0·47).

However, the study has important limitations. The maximum duration of colchicine was set at 10 days and in several patients the cause of premature discontinuation was not collected. The authors mention that a longer duration of therapy might have provided benefit, but most participants had stopped colchicine before day 10 either because of death, discharge from hospital, or at the discretion of the treating clinician. Moreover, information regarding the number of patients who received the treatment through a nasogastric tube and the number of patients whose dose frequency was halved because they were also receiving a moderate CYP3A4 was not collected. Additionally, information regarding chest radiographical findings was not gathered appearances was not collected. Furthermore, stratification based on disease severity or autoinflammatory markers was not done. Because of the study's design, it was not possible to know the outcome within the subgroup of patients that received colchicine plus steroids compared with those who received usual care plus steroids without receiving other available treatments. All this information should be considered when deciding the clinical context in which patients with COVID-19 should receive colchicine. Moreover, these factors should be considered when deciding whether new clinical studies are initiated, especially given the low costs and relative ease of administration of colchicine.

The outcome of the RECOVERY trial led us to analyse the difficulties that clinical trials have had, especially the need for a rapid but valid trial development in search of solutions for COVID-19. This situation has tested the question other researchers have asked: can we increase the rate of discovery while staying faithful to scientific method? There are already hundreds of COVID-19 trials registered worldwide, with numbers increasing daily. Several studies have already been reported during the COVID-19 pandemic, often as preprints to publish results quickly. Many of the randomised trials are flawed because of the many challenges associated with research during a pandemic, including ethical concerns. Furthermore, predefined platform trials, such as RECOVERY and SOLIDARITY, have been recognised as an efficient approach to knowledge acquisition, but the randomisation methods of these trials have been considered suboptimal for matching the studied groups based on disease severity in critically ill patients hospitalised with COVID-19—a population with high mortality rates.

Acknowledging the suboptimal randomisation strategies, the results of the RECOVERY trial regarding the use of colchicine in patients hospitalised with COVID-19 should only be applied to patients with very similar characteristics. However, previous published results from the RECOVERY trial showed three alternative effective options to reduce mortality: dexamethasone and tocilizumab in patients who were critically ill and those requiring oxygen therapy and the combination of monoclonal antibodies (casirivimab and imdevimab) for patients without detectable antibodies (seronegative). Questions remain to be resolved regarding the benefit of colchicine in different populations of patients with COVID-19, especially in outpatients with early stage disease.

AR-V, RP-M, and AG-L are currently researchers in the Impact of Colchicine in Hospitalized Colombian Patients With COVID-19 (COLCOVID19) clinical trial (ClinicalTrials.gov, NCT04539873). AR-V reports fees for conferences from Abbvie, Amgen, Biopas-UCB, Janssen, and Pfizer; and fees for Advisory Board membership from Alexion. All other authors declare no competing interest.