43 Pages Posted: 17 Oct 2022

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Oxford Respiratory Trials Unit; University of Oxford - NIHR Biomedical Research Unit Oxford; University of Oxford - Chinese Academy of Medical Science Oxford Institute (COI)

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS)

University of Oxford - Nuffield Department of Primary Care Health Sciences; University of KwaZulu-Natal - Centre for the AIDS Programme of Research in South Africa (CAPRISA)

University College London - UCL Institute of Immunity and Transplantation

University College London - Department of Infection, Inflammation and Immunity; Great Ormond Street Hospital for Children - Department of Pharmacy

University College London - Department of Infection, Inflammation and Immunity

University of Liverpool - Department of Molecular and Clinical Pharmacology

University of Oxford - Nuffield Department of Primary Care Health Sciences

Cardiff University - Centre for Trials Research

University of Nottingham - Division of Epidemiology and Public Health

University of Oxford - Nuffield Department of Primary Care Health Sciences

Berry Consultants, LLC; Vanderbilt University - Department of Biostatistics

Berry Consultants, LLC

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Southampton - Primary Care Research Centre

Windrush Medical Practice; National Institute for Health and Care Research - CRN Thames Valley and South Midlands; Royal College of General Practitioners

University of Exeter - Faculty of Health and Life Sciences; National Institute for Health and Care Research

University of Oxford - Oxford Respiratory Trials Unit

Cardiff University - Centre for Trials Research

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Southampton - Primary Care Research Centre

University of Oxford - Nuffield Department of Primary Care Health Sciences

Berry Consultants, LLC

Berry Consultants, LLC

Berry Consultants, LLC

Berry Consultants, LLC

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Glasgow - Institute of Health and Wellbeing

Queen's University Belfast - School of Medicine, Dentistry & Biomedical Science

Queen's University Belfast - School of Medicine, Dentistry & Biomedical Science

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

NHS Foundation Trust - Oxford University Hospitals

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Oxford - Nuffield Department of Primary Care Health Sciences

North Manchester General Hospital - Regional Infectious Diseases Unit

Cardiff University - Centre for Trials Research

University of Oxford - Nuffield Department of Primary Care Health Sciences

University of Southampton - Primary Care and Population Science

Date Written: October 4, 2022

Background: The safety, effectiveness and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, in patients in the community who are multiply-vaccinated and at increased risk of morbidity and mortality from COVID-19, has not been established. We aimed to determine whether molnupiravir added to usual care reduced hospital admissions/deaths among people at higher risk from COVID-19, and here report our preliminary analyses.

Methods: Participants in this UK multicentre, open-label, adaptive, multi-arm, platform, randomised controlled trial were aged ≥50, or ≥18 years with comorbidities, and unwell ≤5 days with confirmed COVID-19 in the community, and were randomised to usual care or usual care plus molnupiravir (800mg twice daily for 5 days). The primary outcome measure was all-cause hospitalisation/death within 28 days, analysed using Bayesian models. The main secondary outcome measure was time to first self-reported recovery. A sub-set of participants in each group were assessed for the virology primary outcome measure of day seven SARS-CoV-2 viral load. Trial registration: ISRCTN30448031

Findings: Between December 8, 2021 and April 27, 2022, 25783 participants were randomised to molnupiravir plus usual care (n=12821) or usual care alone (n=12962). Mean (range) age of participants was 56·6 years (18 to 99), 58·6% were female, and 99% had at least one dose of a SARS-CoV-2 vaccine. The median duration of symptoms prior to randomisation was two days (IQR 1 – 3), the median number of days from symptom onset to starting to take the medication was three days (IQR 3 – 4), 87% (11109/11997) received their medication within five days of symptom onset, and 95·4% (n=11857) of participants randomised to molnupiravir reported taking molnupiravir for five days. Primary outcome measure data were available in 25000 (97%) participants and included in this analysis. 103/12516 (0·8%) hospitalisations/deaths occurred in the molnupiravir group versus 96/12484 (0·8%) in usual care alone with a posterior probability of superiority of 0·34 (adjusted odds ratio 1·061 (95% Bayesian credible interval [BCI]) 0·80 to 1·40). Estimates were similar for all subgroups. The observed median (IQR) time-to-first-recovery from randomisation was 9 (5–23) days in molnupiravir and 15 (7–not reached) days in usual care. There was an estimated benefit of 4·2 (95% BCI: 3·8 – 4·6) days in time-to-first-recovery (TTR) giving a posterior probability of superiority of >0·999 (estimated median TTR 10·3 [10·2 – 10·6] days vs 14·5 [14·2 – 14·9] days respectively; hazard ratio [95% BCI], 1·36 [1·3–1·4] days), which met the pre-specified superiority threshold. On day 7, SARS-CoV-2 virus was below detection levels in 7/34 (21%) of the molnupiravir group, versus 1/39 (3%) in the usual care group (p=0.039), and mean viral load was lower in the molnupiravir group compared with those receiving usual care [(SD) of log10(viral load) 3·82 (1·40) in the molnupiravir group and 4.93 (1·38) in the usual care group, (P