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
- University of Liverpool, 70 Pembroke Place, Liverpool, UK
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- Richard Fitzgerald
- Liverpool University Hospital NHS Foundation Trust, Prescot Road, Liverpool, UK
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- Thomas Fletcher
- Liverpool University Hospital NHS Foundation Trust, Prescot Road, Liverpool, UK
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- Sean Ewings
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Thomas Jaki
- University of Lancaster, Bailrigg, Lancaster, UK
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- Rebecca Lyon
- Liverpool University Hospital NHS Foundation Trust, Prescot Road, Liverpool, UK
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- Nichola Downs
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Lauren Walker
- University of Liverpool, 70 Pembroke Place, Liverpool, UK
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- Olana Tansley-Hancock
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- William Greenhalf
- University of Liverpool, 70 Pembroke Place, Liverpool, UK
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- Christie Woods
- Liverpool University Hospital NHS Foundation Trust, Prescot Road, Liverpool, UK
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- Helen Reynolds
- University of Liverpool, 70 Pembroke Place, Liverpool, UK
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- Ellice Marwood
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Pavel Mozgunov
- University of Lancaster, Bailrigg, Lancaster, UK
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- Emily Adams
- Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK
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- Katie Bullock
- University of Liverpool, 70 Pembroke Place, Liverpool, UK
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- Wayne Holman
- Ridgeback Biotherapeutics, 3480 Main Highway, Miami, FL, USA
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- Marcin D Bula
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Jennifer L Gibney
- Liverpool University Hospital NHS Foundation Trust, Prescot Road, Liverpool, UK
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- Geoffrey Saunders
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Andrea Corkhill
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Colin Hale
- Liverpool University Hospital NHS Foundation Trust, Prescot Road, Liverpool, UK
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- Kerensa Thorne
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Justin Chiong
- University of Liverpool, 70 Pembroke Place, Liverpool, UK
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- Susannah Condie
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Henry Pertinez
- University of Liverpool, 70 Pembroke Place, Liverpool, UK
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- Wendy Painter
- Ridgeback Biotherapeutics, 3480 Main Highway, Miami, FL, USA
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- Emma Wrixon
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Lucy Johnson
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Sara Yeats
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Kim Mallard
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Mike Radford
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Keira Fines
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
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- Victoria Shaw
- University of Liverpool, 70 Pembroke Place, Liverpool, UK
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- Andrew Owen
- University of Liverpool, 70 Pembroke Place, Liverpool, UK
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- David G Lalloo
- Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK
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- Michael Jacobs
- Royal Free London NHS Foundation Trust, Pond Street, London, UK
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- Gareth Griffiths
- Southampton Clinical Trials Unit, University of Southampton, Tremona Road, Southampton, UK
抄録
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Objectives</jats:title> <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> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <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> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <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> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <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> </jats:sec>
収録刊行物
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- Journal of Antimicrobial Chemotherapy
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Journal of Antimicrobial Chemotherapy 76 (12), 3286-3295, 2021-08-27
Oxford University Press (OUP)