A Randomised -Controlled Phase 2 trial of Molnupiravir in Unvaccinated and Vaccinated Individuals with Early SARS-CoV-2

Background Molnupiravir was licensed for treating high-risk patients with COVID-19 based on data from unvaccinated adults. AGILE CST-2 ([NCT04746183][1]) Phase II reports safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals. Methods Adult out-patients with PCR-confirmed SARS-CoV-2 infection within five days of symptom onset were randomly assigned 1:1 to receive molnupiravir (800mg twice daily for five days) or placebo. The primary outcome was time to swab PCR-negativity, compared using a Bayesian model for estimating the probability of a superior virological response (Hazard Ratio>1) for molnupiravir over placebo. Secondary outcomes included change in viral titre at day 5, safety and tolerability, clinical progression and patient reported outcome measures. We analysed outcomes after the last participant reached day 29. Findings Of 180 participants randomised (90 molnupiravir, 90 placebo), 50% were vaccinated. Infections with SARS-CoV-2 variants Delta (40%), Alpha (21%), Omicron (21%) and EU1 (16%) were represented. The median time to negative-PCR was 8 versus 11 days for molnupiravir and placebo (HR=1·30, 95% CrI 0·92-1·71, p=0·07 by Logrank and p=0·03 by Breslow-Gehan tests). Although small numbers precluded subgroup analysis, no obvious differences were observed between vaccinated and unvaccinated participants. Using a two-point prior the probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was just below our defined threshold of 80% for establishing superiority. Using an uninformative continuous prior, the probability of HR>1 was 94·7%. As an exploratory analysis, the change in viral titre on day 5 (end of treatment) was significantly greater with molnupiravir compared with placebo. A total of 4 participants reported severe adverse events (grade 3+), 3 of whom were in the placebo arm. Interpretation We found molnupiravir to be well-tolerated, with evidence for high probability of antiviral efficacy in a population of vaccinated and unvaccinated individuals infected with a broad range of viral variants. Funding Funded by Ridgeback Biotherapeutics and UK National Institute for Health and Care Research infrastructure funding. The AGILE platform infrastructure is supported by the Medical Research Council (grant number MR/V028391/1) and the Wellcome Trust (grant number 221590/Z/20/Z). ### Competing Interest Statement SK has received research funding from ViiV Healthcare, and Merck for the Liverpool HIV Drug Interactions programme and for unrelated clinical studies. GG has received funding from Janssen-Cilag, Astra Zeneca, Novartis, Astex, Roche, Heartflow, Celldex, BMS, BionTech, Cancer Research UK, NIHR, British Lung Foundation, Unitaid, GSK for unrelated academic clinical trials and programme funding. WG has received funding from the Wellcome Trust. WH is a cofounder, owner and advisor of/to Ridgeback Biotherapeutics LP. WP is employed by Ridgeback Biotherapeutics. For the other authors we declare no competing interests. JP has received honoraria for lectures from Gilead and LIPS UK. JAH has received research funding from the United States Food and Drug Administration and payment for expert testimony from DAC Beachcroft and Clyde and Co. TE has received unrelated research funding from MRC, Wellcome Trust and Bloomsbury SET and travel grants from ECCMID. ### Clinical Trial NCT04746183; ISRCTN27106947 ### Clinical Protocols ### Funding Statement This study was funded by Ridgeback Biotherapeutics and UK National Institute for Health and Care Research infrastructure funding. The AGILE platform infrastructure is supported by the Medical Research Council (grant number MR/V028391/1) and the Wellcome Trust (grant number 221590/Z/20/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was reviewed and approved by the UK Medicines and Healthcare product Regulatory Agency (MHRA) (EudraCT 2020 001860 27) and West Midlands Edgbaston Research Ethics Committee (20/WM/0136). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04746183&atom=%2Fmedrxiv%2Fearly%2F2022%2F07%2F26%2F2022.07.20.22277797.atom