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

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  • Saye H Khoo
  • Richard Fitzgerald
  • Thomas Fletcher
  • Sean Ewings
  • Rebecca Lyon
  • Nichola Downs
  • Lauren Walker
  • Olana Tansley-Hancock
  • William Greenhalf
  • Christie Woods
  • Helen Reynolds
  • Ellice Marwood
  • Pavel Mozgunov
  • Emily Adams
  • Katie Bullock
  • Wayne Holman
  • Marcin D Bula
  • Jennifer L Gibney
  • Geoffrey Saunders
  • Andrea Corkhill
  • Colin Hale
  • Kerensa Thorne
  • Justin Chiong
  • Susannah Condie
  • Henry Pertinez
  • Wendy Painter
  • Emma Wrixon
  • Lucy Johnson
  • Sara Yeats
  • Kim Mallard
  • Mike Radford
  • Keira Fines
  • Victoria Shaw
  • Andrew Owen
  • David G Lalloo
  • Michael Jacobs
  • Gareth Griffiths
<mark>Journal publication date</mark>12/11/2021
<mark>Journal</mark>Journal of Antimicrobial Chemotherapy
Issue number12
Number of pages10
Pages (from-to)3286-3295
Publication StatusPublished
Early online date27/08/21
<mark>Original language</mark>English


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.