Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial
PRINCIPLE Trial Collaborative Group None., Dorward J., Yu L-M., Hayward G., Saville B., Gbinigie O., Van Hecke O., Ogburn E., Evans P., Thomas NPB., Patel M., Richards D., Berry N., Detry M., Saunders C., Fitzgerald M., Harris V., Shanyinde M., de Lusignan S., Andersson M., Butler C., Hobbs FDR.
Objectives Colchicine has been proposed as a COVID-19 treatment, but its effect on time to recovery is unknown. We aimed to determine whether colchicine is effective at reducing time to recovery and COVID-19 related hospitalisations/deaths among people in the community. Design Prospective, multicentre, open-label, multi-arm, adaptive Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE). Setting National trial run remotely from a central trial site and at multiple primary care centres across the United Kingdom. Participants Adults aged ≥65, or ≥18 years with comorbidities or shortness of breath, and unwell ≤14 days with suspected COVID-19 in the community. Interventions Participants were randomised to usual care, usual care plus colchicine (500µg daily for 14 days), or usual care plus other interventions. Main outcome measures The co-primary endpoints were time to first self-reported recovery, and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. The hypothesis for the time to recovery endpoint is evaluated first, and if superiority is declared on time to recovery, the hypothesis for the second co-primary endpoint of hospitalisation/death is then evaluated. To determine futility, we pre-specified a clinically meaningful benefit in time to first reported recovery as a hazard ratio of 1.2 or larger (equating to approximately 1.5 days benefit in the colchicine arm, assuming 9 days recovery in the usual care arm). Results The trial opened on April 2, 2020, with randomisation to colchicine starting on March 04, 2021 and stopping on May 26, 2021, because the pre-specified time to recovery futility criterion was met. The primary analysis model included 2755 SARS-CoV-2 positive participants, randomised to colchicine (n=156), usual care (n=1145), and other treatments (n=1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.919 [95% credible interval 0.72 to 1.16] and an estimated increase of 1.14 days [−1.86 to 5.21] in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. Results were similar in comparisons with concurrent controls. COVID-19 related hospitalisations/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 [0.28 to 1.89] and an estimated difference of −0.4% [−2.7% to 2.4]. One serious adverse event occurred in the colchicine group and one in usual care. Conclusions Colchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community. Trial registration ISRCTN86534580.