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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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.
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SciScore for 10.1101/2021.05.03.21256309: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: All participants provided written informed consent before enrolment.
IRB: The study protocol was reviewed and approved by the UK Medicines and Healthcare product Regulatory Agency (MHRA) and West Midlands Edgbaston Research Ethics Committee.
Field Sample Permit: All samples were rapidly cooled on wet ice and centrifuged (2000g for 10min) within 30 min of sample collection.Sex as a biological variable Eligible participants were men and women aged ≥18 years with PCR-confirmed SARS-CoV-2 infection who were within 5 days of symptom onset, free of uncontrolled chronic conditions, and ambulant in the community with mild or moderate disease. Randomization Study design and Participants: This … SciScore for 10.1101/2021.05.03.21256309: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: All participants provided written informed consent before enrolment.
IRB: The study protocol was reviewed and approved by the UK Medicines and Healthcare product Regulatory Agency (MHRA) and West Midlands Edgbaston Research Ethics Committee.
Field Sample Permit: All samples were rapidly cooled on wet ice and centrifuged (2000g for 10min) within 30 min of sample collection.Sex as a biological variable Eligible participants were men and women aged ≥18 years with PCR-confirmed SARS-CoV-2 infection who were within 5 days of symptom onset, free of uncontrolled chronic conditions, and ambulant in the community with mild or moderate disease. Randomization Study design and Participants: This dose-escalation phase I study (NCT04746183) was designed as an open label, randomised, controlled Bayesian adaptive trial in adult early infection in the community, coordinated by the National Institute for Health Research (NIHR) Southampton Clinical Trials Unit with participants recruited into the NIHR Royal Liverpool and Broadgreen Clinical Research Facility (UK). Blinding not detected. Power Analysis The sample size was flexible, based on the need for the study to adapt to accruing safety data. Table 2: Resources
Software and Algorithms Sentences Resources Drug concentrations were measured using a validated LC-MS/MS assay at Covance Clinical Laboratories, Leeds, Covance Clinical Laboratoriessuggested: NoneKey pharmacokinetic (PK) parameters such as area under the concentration-time curve 0-4 h (AUC0-4), maximum concentration (Cmax) and time to maximum concentration (Tmax) were determined by non-compartmental modelling methods (WinNonlin, Phoenix, v. 8.3, Pharsight, Mountain View, CA, USA) on day 1 and day 5 for each dose and summarised descriptively. Phoenixsuggested: (Phoenix, RRID:SCR_003163), STATA version 16 and R version 3·6 ·0. STATAsuggested: (Stata, RRID:SCR_012763)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04746183 Recruiting AGILE (Early Phase Platform Trial for COVID-19) NCT04392219 Completed COVID-19 First In Human Study to Evaluate Safety, Tolerabili… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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