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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

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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, Thomas et al.
In: Journal of Antimicrobial Chemotherapy, Vol. 76, No. 12, 12.11.2021, p. 3286-3295.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Khoo, SH, Fitzgerald, R, Fletcher, T, Ewings, S, Jaki, T, Lyon, R, Downs, N, Walker, L, Tansley-Hancock, O, Greenhalf, W, Woods, C, Reynolds, H, Marwood, E, Mozgunov, P, Adams, E, Bullock, K, Holman, W, Bula, MD, Gibney, JL, Saunders, G, Corkhill, A, Hale, C, Thorne, K, Chiong, J, Condie, S, Pertinez, H, Painter, W, Wrixon, E, Johnson, L, Yeats, S, Mallard, K, Radford, M, Fines, K, Shaw, V, Owen, A, Lalloo, DG, Jacobs, M & Griffiths, G 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, vol. 76, no. 12, pp. 3286-3295. https://doi.org/10.1093/jac/dkab318

APA

Khoo, S. H., Fitzgerald, R., Fletcher, T., Ewings, S., Jaki, T., Lyon, R., Downs, N., Walker, L., Tansley-Hancock, O., Greenhalf, W., Woods, C., Reynolds, H., Marwood, E., Mozgunov, P., Adams, E., Bullock, K., Holman, W., Bula, M. D., Gibney, J. L., ... Griffiths, G. (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, 76(12), 3286-3295. https://doi.org/10.1093/jac/dkab318

Vancouver

Khoo SH, Fitzgerald R, Fletcher T, Ewings S, Jaki T, Lyon R et al. 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. 2021 Nov 12;76(12):3286-3295. Epub 2021 Aug 27. doi: 10.1093/jac/dkab318

Author

Khoo, Saye H ; Fitzgerald, Richard ; Fletcher, Thomas et al. / Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2 : a Phase I, open-label, dose-escalating, randomized controlled study. In: Journal of Antimicrobial Chemotherapy. 2021 ; Vol. 76, No. 12. pp. 3286-3295.

Bibtex

@article{4f036128f3994e0587623bb496e211d2,
title = "Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study",
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.",
keywords = "Infectious Diseases, Pharmacology (medical), Pharmacology, Microbiology (medical)",
author = "Khoo, {Saye H} and Richard Fitzgerald and Thomas Fletcher and Sean Ewings and Thomas Jaki and Rebecca Lyon and Nichola Downs and Lauren Walker and Olana Tansley-Hancock and William Greenhalf and Christie Woods and Helen Reynolds and Ellice Marwood and Pavel Mozgunov and Emily Adams and Katie Bullock and Wayne Holman and Bula, {Marcin D} and Gibney, {Jennifer L} and Geoffrey Saunders and Andrea Corkhill and Colin Hale and Kerensa Thorne and Justin Chiong and Susannah Condie and Henry Pertinez and Wendy Painter and Emma Wrixon and Lucy Johnson and Sara Yeats and Kim Mallard and Mike Radford and Keira Fines and Victoria Shaw and Andrew Owen and Lalloo, {David G} and Michael Jacobs and Gareth Griffiths",
year = "2021",
month = nov,
day = "12",
doi = "10.1093/jac/dkab318",
language = "English",
volume = "76",
pages = "3286--3295",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "12",

}

RIS

TY - JOUR

T1 - Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2

T2 - a Phase I, open-label, dose-escalating, randomized controlled study

AU - Khoo, Saye H

AU - Fitzgerald, Richard

AU - Fletcher, Thomas

AU - Ewings, Sean

AU - Jaki, Thomas

AU - Lyon, Rebecca

AU - Downs, Nichola

AU - Walker, Lauren

AU - Tansley-Hancock, Olana

AU - Greenhalf, William

AU - Woods, Christie

AU - Reynolds, Helen

AU - Marwood, Ellice

AU - Mozgunov, Pavel

AU - Adams, Emily

AU - Bullock, Katie

AU - Holman, Wayne

AU - Bula, Marcin D

AU - Gibney, Jennifer L

AU - Saunders, Geoffrey

AU - Corkhill, Andrea

AU - Hale, Colin

AU - Thorne, Kerensa

AU - Chiong, Justin

AU - Condie, Susannah

AU - Pertinez, Henry

AU - Painter, Wendy

AU - Wrixon, Emma

AU - Johnson, Lucy

AU - Yeats, Sara

AU - Mallard, Kim

AU - Radford, Mike

AU - Fines, Keira

AU - Shaw, Victoria

AU - Owen, Andrew

AU - Lalloo, David G

AU - Jacobs, Michael

AU - Griffiths, Gareth

PY - 2021/11/12

Y1 - 2021/11/12

N2 - 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.

AB - 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.

KW - Infectious Diseases

KW - Pharmacology (medical)

KW - Pharmacology

KW - Microbiology (medical)

U2 - 10.1093/jac/dkab318

DO - 10.1093/jac/dkab318

M3 - Journal article

VL - 76

SP - 3286

EP - 3295

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 12

ER -