Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study
Saye H Khoo, Richard Fitzgerald, Thomas Fletcher, Sean Ewings, Thomas Jaki, 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
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.
Author contributions S.H.K., G.G., T.J., S.E., R.F. and P.M. contributed to study design. S.H.K., G.G., T.J., S.E., G.S., K.T., P.M. and H.P. contributed to data analysis and interpretation. R.F. led clinical conduct as the principal investigator of the clinical site. T.F., L.W., R.L. and M.D.B. participated in clinical assessment and data collection. K.F. participated in the management of pharmacovigilance. S.C., E.W., M.R. and L.J. contributed to the digital data collection and data management of the trial. M.R. led set-up of the randomization system. W.G., T.F., V.S., E.A., K.B. and C.H. contributed to study bioanalysis. A.C., N.D., E.M., O.T.-H., S.Y., H.R., J.C., R.L., C.W., J.L.G., A.O., M.J. and D.G.L. contributed to study management and execution. K.M. contributed to monitoring activities. W.P. and W.H. contributed preclinical and safety data on molnupiravir. S.H.K., G.G., M.J., A.O. and D.G.L. were involved in primary manuscript writing. All authors contributed to the final version of the manuscript. The statisticians S.E., G.S. and K.T. had full access to all the data in the study and S.H.K. and G.G. had final responsibility for the decision to submit for publication.
Disclaimer The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Supplementary data Supplement S1 and Supplement S2 are available as Supplementary data at JAC Online.
References
Cevik, Tate, Lloyd, SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis, Lancet Microbe
Cox, Wolf, Plemper, Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets, Nat Microbiol
Griffiths, Fitzgerald, Jaki, AGILE-ACCORD: a randomized, multicentre, seamless, adaptive phase I/II platform study to determine the optimal dose, safety and efficacy of multiple candidate agents for the treatment of COVID-19: a structured summary of a study protocol for a randomised platform trial, Trials
Mozgunov, Jaki, Paoletti, Randomized dose-escalation designs for drug combination cancer trials with immunotherapy, J Biopharm Stat
Painter, Holman, Bush, Human safety, tolerability, and pharmacokinetics of a novel broad-spectrum oral antiviral compound, molnupiravir, with activity against SARS-CoV-2, Antimicrob Agents Chemother
Painter, Sheahan, Baric, Reduction in infectious SARS-CoV-2 in treatment study of COVID-19 with molnupiravir
Rosenke, Hansen, Schwarz, Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model, Nat Commun
Wahl, Gralinski, Johnson, SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801, Nature
DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Objectives</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>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%.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.</jats:p>\n </jats:sec>",
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