Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study
Khoo et al.,
Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label,..,
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkab318, NCT04746183
Dose and safety study of molnupiravir with 18 participants, finding no serious adverse events in short-term followup. There was no significant difference in clinical outcomes.
NCT04746183 (history).
Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer [Hadj Hassine, Swanstrom]. See [Fountain-Jones, Sanderson, ] for analysis of variants potentially created by molnupiravir.
risk of no recovery, 33.3% higher, RR 1.33, p = 0.63, treatment 8 of 12 (66.7%), control 3 of 6 (50.0%), all dosages, symptomatic at day 15.
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risk of no recovery, 100% higher, RR 2.00, p = 0.61, treatment 4 of 12 (33.3%), control 1 of 6 (16.7%), all dosages, symptomatic at day 29.
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risk of no recovery, 100% higher, RR 2.00, p = 0.20, treatment 4 of 4 (100.0%), control 3 of 6 (50.0%), 800mg, symptomatic at day 15.
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risk of no recovery, no change, RR 1.00, p = 1.00, treatment 2 of 4 (50.0%), control 3 of 6 (50.0%), 600mg, symptomatic at day 15.
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risk of no recovery, no change, RR 1.00, p = 1.00, treatment 2 of 4 (50.0%), control 3 of 6 (50.0%), 300mg, symptomatic at day 15.
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risk of no recovery, 50.0% higher, RR 1.50, p = 1.00, treatment 1 of 4 (25.0%), control 1 of 6 (16.7%), 800mg, symptomatic at day 29.
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risk of no recovery, 200.0% higher, RR 3.00, p = 0.50, treatment 2 of 4 (50.0%), control 1 of 6 (16.7%), 600mg, symptomatic at day 29.
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risk of no recovery, 50.0% higher, RR 1.50, p = 1.00, treatment 1 of 4 (25.0%), control 1 of 6 (16.7%), 300mg, symptomatic at day 29.
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Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
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Khoo et al., 27 Aug 2021, Randomized Controlled Trial, United Kingdom, peer-reviewed, 38 authors, average treatment delay 4.0 days, trial
NCT04746183 (history).
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.
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