Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes

Gail Hayward; Ly-Mee Yu; Paul Little; Oghenekome Gbinigie; Milensu Shanyinde; Victoria Harris; Jienchi Dorward; Benjamin R Saville; Nicholas Berry; Philip H Evans; Nicholas P B Thomas; Mahendra G Patel; Duncan Richards; Oliver V Hecke; Michelle A Detry; Christina Saunders; Mark Fitzgerald; Jared Robinson; Charlotte Latimer-Bell; Julie Allen; Emma Ogburn; Jenna Grabey; Simon de Lusignan; Fd Richard Hobbs; Christopher C Butler; PRINCIPLE Trial Collaborative Group

doi:10.1016/j.jinf.2024.106130

Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes

J Infect. 2024 Apr;88(4):106130. doi: 10.1016/j.jinf.2024.106130. Epub 2024 Feb 29.

Authors

Gail Hayward¹, Ly-Mee Yu¹, Paul Little², Oghenekome Gbinigie¹, Milensu Shanyinde¹, Victoria Harris¹, Jienchi Dorward³, Benjamin R Saville⁴, Nicholas Berry⁵, Philip H Evans⁶, Nicholas P B Thomas⁷, Mahendra G Patel¹, Duncan Richards⁸, Oliver V Hecke¹, Michelle A Detry⁵, Christina Saunders⁵, Mark Fitzgerald⁵, Jared Robinson¹, Charlotte Latimer-Bell¹, Julie Allen¹, Emma Ogburn¹, Jenna Grabey¹, Simon de Lusignan¹, Fd Richard Hobbs⁹, Christopher C Butler⁹; PRINCIPLE Trial Collaborative Group

Affiliations

¹ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
² Primary Care Research Centre, University of Southampton, Southampton, UK.
³ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
⁴ Berry Consultants, TX, USA; Department of Biostatistics, Vanderbilt University School of Medicine, TN, USA.
⁵ Berry Consultants, TX, USA.
⁶ College of Medicine and Health, University of Exeter, Exeter, UK; National Institute for Health Research (NIHR) Clinical Research Network, National Institute for Health Research, London, UK.
⁷ National Institute for Health Research (NIHR) Clinical Research Network, National Institute for Health Research, London, UK.
⁸ Royal College of General Practitioners, London, UK; Oxford Clinical Trials Research Unit, Botnar Research Centre, University of Oxford, Oxford, UK.
⁹ Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK. Electronic address: principle@phc.ox.ac.uk.

Abstract

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).

Keywords: COVID-19; Clinical trial; Ivermectin; Long-term follow up; SARS-Cov2.

Publication types

Randomized Controlled Trial
Multicenter Study

MeSH terms

Adolescent
Adult
Bayes Theorem
COVID-19*
Humans
Ivermectin / therapeutic use
SARS-CoV-2
Treatment Outcome

Substances

Ivermectin