A randomized controlled Phase I de-escalation trial of molnupiravir and nirmatrelvir/ritonavir combination for mild-moderate SARS-CoV-2 infection
Year: 2026
Type: article
Study designs: Randomized Controlled Trial, Clinical Trial
Abstract: Objectives The AGILE CST-8 (NCT04746183) Phase I de-escalation trial evaluated the safety and tolerability of combination molnupiravir and nirmatrelvir/ritonavir for mild-moderate COVID-19. Methods Adult outpatients with SARS-CoV-2 infection within 5 days of symptoms were randomly assigned 2:1 to receive molnupiravir [starting at 800 mg twice daily (BD) reducing to 600 and 400 mg if necessary] in combination with nirmatrelvir (300 mg)/ritonavir (100 mg) BD for 5 days versus standard of care. Using a dose de-escalation, open-label, Bayesian adaptive Phase I trial, a combination dose was considered unsafe if the probability of 30% or greater dose-limiting toxicity risk (DLT—the primary outcome) over standard of care was 25% or higher. Secondary endpoints included tolerability, clinical progression, pharmacokinetics and virological responses. Results Of 49 participants screened, 24 were enrolled (16 combination, 8 standard of care) between January 2023 and September 2023. For the primary endpoint, to Day 11, no participant starting molnupiravir at 800 mg BD in combination with nirmatrelvir/ritonavir reported a DLT by Day 11 (primary endpoint) or by Day 29; dose de-escalation was not required. No participants reported severe adverse events (grade ≥3). Although proportions of swab PCR negativity at Day 5 and Day 11 were not statistically different, faster initial viral clearance was observed with treatment. Penetration of nirmatrelvir into saliva, nasal secretions and tears was 19%, 65% and 91% that of plasma. Conclusions Molnupiravir in combination with nirmatrelvir/ritonavir was safe and well-tolerated; later phase trials should evaluate combination therapy at currently recommended doses for each drug.
DOI: 10.1093/jac/dkag180
Authors: Saye H Khoo, Richard FitzGerald, Christopher J Edwards, Shazaad Ahmad, Geoffrey Saunders, Laura J Else, Victoria Shaw, Pavel Mozgunov, Joshua Northey, Laura Dickinson, Emma Knox, Amanda Buadi, Colin Hale, Helen E Reynolds, Calley Middleton, Katie Bullock, Lauren Walker, Michelle Tetlow, Rebecca Lyon, Jennifer Gibney, Alieu Amara, William Greenhalf, Abigail Burdon, Jan Dixon, Thomas Jaki, Justin Chiong, David G Lalloo, Andew Owen, Michael Jacobs, Thomas Fletcher, Gareth Griffiths, the AGILE CST-8 study group, Nicholas Paton, Fred Hayden, Janet Darbyshire, Amy Lucas, Ulrika Lorch, Andrew Freedman, Richard Knight, Steven Julious, Thomas Edwards, Christopher Myerscough, Nuala Tainton, Oliver Edwards, Kerensa Thorne, Sujan Dily Penchala, Rachel Carter, Callum Kelly, Kate Dodd, Callum Docherty, Charlotte Boe, Alasdair Munro, Dan Owens, Mihaela Pacurar, Gavin Babbage, Liza Shiner-Clark
Institutions: University of Liverpool, Liverpool University Hospitals NHS Foundation Trust, University Hospital Southampton NHS Foundation Trust, University of Manchester, NIHR Manchester Clinical Research Facility, University of Southampton, University of Cambridge, MRC Biostatistics Unit, University of Regensburg, Liverpool School of Tropical Medicine, Centre of Excellence for Long-acting Therapeutics, University of Oxford
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,784
Funders: Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Gilead Sciences, Wellcome Trust, ViiV Healthcare, Celldex Therapeutics, Astex Pharmaceuticals, UK Research and Innovation, Cancer Research UK, National Institute for Health and Care Research, Asthma and Lung UK, Medical Research Council Canada, Blood Cancer UK, National Institute for Health Research Southampton Biomedical Research Centre, Medical Research Council, Cilag
Awards: Bringing Innovative Methods for Early Phase Precision Medicine Trials Into Practice, AGILE: Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 treatment, G3223687611, AGILE: Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 treatment, AGILE: Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 treatment, G866144867, G915645594
OpenAlex ID: W7164933945