Abstract: J Antimicrob Chemother doi:10.1093/jac/dkab318 Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study 1 University of Liverpool, 70 Pembroke Place, Liverpool, UK; 2Liverpool University Hospital NHS Foundation Trust, Prescot Road, Liverpool, UK; 3Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK; 4Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK; 5University of Lancaster, Bailrigg, Lancaster, UK; 6MRC Biostatistics Unit, University of Cambridge, Cambridge, UK; 7Ridgeback Biotherapeutics, 3480 Main Highway, Miami, FL, USA; 8Royal Free London NHS Foundation Trust, Pond Street, London, UK *Corresponding author. E-mail: khoo@liverpool.ac.uk †Contributed equally. Received 15 June 2021; accepted 4 August 2021 Objectives: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. Methods: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. Results: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (grade 2). The probability of 30% excess toxicity over controls at 800 mg was estimated at 0.9%. Conclusions: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.