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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

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 (...

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Autores principales: Khoo, Saye H, Fitzgerald, Richard, Fletcher, Thomas, Ewings, Sean, Jaki, Thomas, Lyon, Rebecca, Downs, Nichola, Walker, Lauren, Tansley-Hancock, Olana, Greenhalf, William, Woods, Christie, Reynolds, Helen, Marwood, Ellice, Mozgunov, Pavel, Adams, Emily, 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, Mallard, Kim, Radford, Mike, Fines, Keira, Shaw, Victoria, Owen, Andrew, Lalloo, David G, Jacobs, Michael, Griffiths, Gareth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598307/
https://www.ncbi.nlm.nih.gov/pubmed/34450619
http://dx.doi.org/10.1093/jac/dkab318
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author Khoo, Saye H
Fitzgerald, Richard
Fletcher, Thomas
Ewings, Sean
Jaki, Thomas
Lyon, Rebecca
Downs, Nichola
Walker, Lauren
Tansley-Hancock, Olana
Greenhalf, William
Woods, Christie
Reynolds, Helen
Marwood, Ellice
Mozgunov, Pavel
Adams, Emily
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
Mallard, Kim
Radford, Mike
Fines, Keira
Shaw, Victoria
Owen, Andrew
Lalloo, David G
Jacobs, Michael
Griffiths, Gareth
author_facet Khoo, Saye H
Fitzgerald, Richard
Fletcher, Thomas
Ewings, Sean
Jaki, Thomas
Lyon, Rebecca
Downs, Nichola
Walker, Lauren
Tansley-Hancock, Olana
Greenhalf, William
Woods, Christie
Reynolds, Helen
Marwood, Ellice
Mozgunov, Pavel
Adams, Emily
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
Mallard, Kim
Radford, Mike
Fines, Keira
Shaw, Victoria
Owen, Andrew
Lalloo, David G
Jacobs, Michael
Griffiths, Gareth
author_sort Khoo, Saye H
collection PubMed
description 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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spelling pubmed-85983072021-11-18 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, Thomas Ewings, Sean Jaki, Thomas Lyon, Rebecca Downs, Nichola Walker, Lauren Tansley-Hancock, Olana Greenhalf, William Woods, Christie Reynolds, Helen Marwood, Ellice Mozgunov, Pavel Adams, Emily 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 Mallard, Kim Radford, Mike Fines, Keira Shaw, Victoria Owen, Andrew Lalloo, David G Jacobs, Michael Griffiths, Gareth J Antimicrob Chemother Original Research 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. Oxford University Press 2021-08-27 /pmc/articles/PMC8598307/ /pubmed/34450619 http://dx.doi.org/10.1093/jac/dkab318 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Khoo, Saye H
Fitzgerald, Richard
Fletcher, Thomas
Ewings, Sean
Jaki, Thomas
Lyon, Rebecca
Downs, Nichola
Walker, Lauren
Tansley-Hancock, Olana
Greenhalf, William
Woods, Christie
Reynolds, Helen
Marwood, Ellice
Mozgunov, Pavel
Adams, Emily
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
Mallard, Kim
Radford, Mike
Fines, Keira
Shaw, Victoria
Owen, Andrew
Lalloo, David G
Jacobs, Michael
Griffiths, Gareth
Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study
title Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study
title_full Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study
title_fullStr Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study
title_full_unstemmed Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study
title_short Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study
title_sort optimal dose and safety of molnupiravir in patients with early sars-cov-2: a phase i, open-label, dose-escalating, randomized controlled study
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598307/
https://www.ncbi.nlm.nih.gov/pubmed/34450619
http://dx.doi.org/10.1093/jac/dkab318
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