Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2:a Phase I, open-label, dose-escalating, randomized controlled study

Khoo, Saye H and Fitzgerald, Richard and Fletcher, Thomas and Ewings, Sean and Jaki, Thomas and Lyon, Rebecca and Downs, Nichola and Walker, Lauren and Tansley-Hancock, Olana and Greenhalf, William and Woods, Christie and Reynolds, Helen and Marwood, Ellice and Mozgunov, Pavel and Adams, Emily and Bullock, Katie and Holman, Wayne and Bula, Marcin D and Gibney, Jennifer L and Saunders, Geoffrey and Corkhill, Andrea and Hale, Colin and Thorne, Kerensa and Chiong, Justin and Condie, Susannah and Pertinez, Henry and Painter, Wendy and Wrixon, Emma and Johnson, Lucy and Yeats, Sara and Mallard, Kim and Radford, Mike and Fines, Keira and Shaw, Victoria and Owen, Andrew and Lalloo, David G and Jacobs, Michael and Griffiths, Gareth (2021) Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2:a Phase I, open-label, dose-escalating, randomized controlled study. Journal of Antimicrobial Chemotherapy, 76 (12). pp. 3286-3295. ISSN 0305-7453

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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.

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Journal Article
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Journal of Antimicrobial Chemotherapy
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21 Feb 2022 12:15
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20 Sep 2023 01:48