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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

Khoo, Saye H, Fitzgerald, Richard, Fletcher, Tom, Ewings, Sean, Jaki, Thomas, Lyon, Rebecca, Downs, Nicola, Walker, Lauren, Tansley-Hancock, Olana, Greenhalf, William, Woods, Christie, Reynolds, Helen, Marwood, Ellice, Mozgunov, Pavel, Adams, Emily ORCID: https://orcid.org/0000-0002-0816-2835, Bullock, Katie, Holman, Wayne, Bula, Marcin D, Gibney, Jennifer L, Saunders, Geoffrey, Corkhill, Andrea, Hale, Colin, Thorne, Kerensa, Chiong, Justin, Condie, Susannah, Pertinez, Henry, Painter, Wendy, Wrixon, Emma, Johnson, Lucy, Yeats, Sara, Mallaerd, Kim, Radford, Mike, Fines, Keira, Shaw, Victoria, Owen, Andrew, Lalloo, David ORCID: https://orcid.org/0000-0001-7680-2200, 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. (In Press)

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Abstract

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.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 268.5 Antiviral agents (General)
QW Microbiology and Immunology > Viruses > QW 160 Viruses (General). Virology
W General Medicine. Health Professions > W 20.5 Biomedical research
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI): https://doi.org/10.1093/jac/dkab318/6358705
Depositing User: Debbie Jenkins
Date Deposited: 30 Sep 2021 08:30
Last Modified: 30 Sep 2021 08:30
URI: https://archive.lstmed.ac.uk/id/eprint/18887

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