Colchicine is a commonly used drug to treat gout. It has been shown to produce an inhibitory effect on NLRP3 inflammasome. Inflammasomes play a role in inducing inflammation, and they are activated in coronavirus disease (COVID-19), with disease severity correlating with the extent of activation.
Study: Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial. Image Credit: Sonis Photography/ Shutterstock
Earlier studies have suggested that colchicine may be an effective treatment for COVID-19. The large RECOVERY trial showed that colchicine did not show any significant benefit when compared to usual care. The COLCORONA randomized controlled trial was terminated early, and no clear evidence was obtained about colchicine's effect on COVID-19 related hospitalizations or death.
Another trial revealed a slightly significant reduction in COVID-19 related hospitalization and death. Pulmonary emboli and gastrointestinal side events were higher in the colchicine-treated group, and time to recovery was not evaluated in this trial.
The present randomized clinical trial published on the medRxiv* server attempted to study if colchicine will effectively hasten recovery and reduce COVID-19 associated hospitalizations or death amongst the people in the community.
A preprint version of the study is available on the medRxiv* server while the article undergoes peer review.
The study was remotely conducted nationally in the United Kingdom involving multiple primary care centers with a main trial site. The participants were randomized to the usual care group and a usual care with colchicine group, which was administered 500 μg of colchicine daily for 14 days and usual care along with other interventions.
The participants had to be unwell for ≤14 days with suspected COVID-19 symptoms. Two primary outcome measures were chosen, time to first self-reported recovery and COVID-19 related hospitalization or death within 28 days.
The outcome measures were analyzed using Bayesian models. The time to recovery endpoint is first evaluated. If the results show that colchicine has a statistically significant benefit on this endpoint, then the second primary endpoint measure of COVID-19 related hospitalizations or death is evaluated.
The futility criterion was also fixed based on the pre-specified time to first reported recovery as a hazard ratio of 1.2 or larger, which was considered clinically significant (1.5 days benefit in the colchicine treated arm assuming a nine day time to recovery in the usual care group).
Study participant characteristics
Of the 4997 participants randomized into PRINCIPLE, 212 were segregated to the colchicine group, 2081 to usual care alone. 86.5% of eligible participants had a SARS-CoV-2 test result, of which 68.7% tested positive.
Amongst the participants randomized to colchicine and usual care, the average age of participants was 61 years, 91.2% of participants were white, 84.4% of participants were suffering from comorbidities.
At six days median time from symptom onset, the participants were randomized. The baseline characteristics between the groups were similar. 7% of participants in the colchicine arm and 10% of those in the usual care arm had taken inhaled corticosteroids which were reported at randomization or during follow-up.
One hundred eighty-four participants in the colchicine group had provided information about their medication utilization, and of these, 75% reported taking colchicine for at least seven days.
Colchicine did not show any significant benefit on the primary outcomes
Amongst the primary analysis population that was SARS-CoV-2 positive, the median time to the first recovery was 15 days in the colchicine group and 14 days in the usual care group. Amongst the concurrent randomization analysis population, the median time to the first recovery was 15 days in the colchicine treated group and 14 days in the usual care group. The Bayesian primary analysis model showed no evidence of colchicine improving the time-to-first-recovery compared to the usual care. A lack of clinically significant treatment effect was seen in the concurrent randomization and the overall study participants.
The second primary endpoint of COVID-19 related hospitalizations/death in the colchicine and the usual care group were assessed. Amongst the SARS-CoV-2 positive primary analysis population, the colchicine group reported 3.8% of COVID-19 related hospitalizations/death 10.4% was reported in the usual care group, which is explained by the high event rate in the primary analysis population before the colchicine arm was started.
The Bayesian primary analysis model showed no difference in the COVID-19 related hospitalization/deaths in the colchicine group compared to the usual care group. It was found that there was no clinically significant evidence of benefit rendered by colchicine treatment on hospitalizations/death due to COVID-19 in concurrent randomization population and overall study population.
Colchicine did not show any significant benefit on the secondary outcomes
The concurrent randomization and eligible SARS-Cov-2 positive population were analyzed for secondary outcomes, including binary outcome for early sustained recovery, rating of 1-10 on how patients feel, time to initial symptom recovery, time to sustained symptom recovery, and contact with hospital services.
It was found that colchicine treatment did not provide any significant benefit on any of the secondary outcomes. Subgroup analyses was also performed, and it showed that factors like duration of symptoms before randomization, baseline illness severity score, corticosteroid use as an inhalant, age, or comorbidities did not show statistically significant influence on the effect of colchicine on time to first reported recovery.
The vaccination status of the participants also did not influence the effect of colchicine treatment on the outcomes assessed. Sub-analyses of the COVID-19 related hospitalization/death outcome was not conducted due to low event rates.
Findings from the randomized clinical trial
Analysis of the present randomized clinical trial reveals that in COVID-19 patients with complications, colchicine did not provide statistically significant improvement in time to the first recovery compared to the group receiving usual care. It was also found that there was no difference between the groups in secondary outcome measures of symptoms, well-being, sustained recovery, or healthcare recovery use.
As the futility criterion was achieved on time to recovery, the colchicine treatment arm was terminated even before enough data was obtained on COVID-19 hospitalizations or death. Evidence from the study shows that colchicine cannot be used as a treatment for COVID-19 symptoms.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Dorward, J. et al. (2021) "Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial". medRxiv. doi: 10.1101/2021.09.20.21263828.
Posted in: Medical Science News | Medical Research News | Disease/Infection News
Tags: Clinical Trial, Colchicine, Coronavirus, Coronavirus Disease COVID-19, Corticosteroid, Gout, Healthcare, Hospital, Inflammasome, Inflammation, Primary Care, SARS, SARS-CoV-2
Dr. Maheswari Rajasekaran
Maheswari started her science career with an undergraduate degree in Pharmacy and later went on to complete a master’s degree in Biotechnology in India. She then pursued a Ph.D. at the University of Arkansas for Medical Sciences in the USA.
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