Ivermectin for COVID-19 in adults in the community (PRINCIPLE): an open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.
Hayward G., Yu L-M., Little P., Gbinigie O., Shanyinde M., Harris V., Dorward J., Saville BR., Berry N., Evans PH., Thomas NP., Patel MG., Richards D., Hecke OV., Detry MA., Saunders C., Fitzgerald M., Robinson J., Latimer-Bell C., Allen J., Ogburn E., Grabey J., de Lusignan S., Hobbs FR., Butler CC., PRINCIPLE Trial Collaborative Group None.
BACKGROUND: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. METHODS: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 μg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n=2157), usual care (n=3256), and other treatments (n=3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months.,. INTERPRETATION: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. FUNDING: UKRI / National Institute of Health Research (MC_PC_19079).