Khoo, Saye H 
ORCID: 0000-0002-2769-0967, FitzGerald, Richard, Edwards, Christopher J, Ahmad, Shazaad, Saunders, Geoffrey, Else, Laura J, Shaw, Victoria ORCID: 0000-0002-0429-0186, Mozgunov, Pavel, Northey, Joshua, Dickinson, Laura ORCID: 0000-0001-5557-9396 et al (show 21 more authors)
(2026)
A randomized controlled Phase I de-escalation trial of molnupiravir and nirmatrelvir/ritonavir combination for mild-moderate SARS-CoV-2 infection
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 81 (7).
dkag180-.
ISSN 0305-7453, 1460-2091
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | AGILE CST-8 study group , Humans, Hydroxylamines, Ritonavir, Ornithine, Leucine, Proline, Cytidine, Antiviral Agents, Treatment Outcome, Drug Therapy, Combination, Adult, Aged, Middle Aged, Female, Male, COVID-19, SARS-CoV-2, COVID-19 Drug Treatment |
| Divisions: | Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Infection, Vet & Ecological Sciences Faculty of Health & Life Sciences > Inst. Infection, Vet & Ecological Sciences > Clinical Infection, Microbiology & Immunology Faculty of Health & Life Sciences > Clinical Directorate Faculty of Health & Life Sciences > Clinical Directorate > Clinical Directorate Prof Svcs Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology (T&R Staff) Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > SMIB Professional Services Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Molecular & Clinical Cancer Medicine Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Pharmacology & Therapeutics |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 24 Jun 2026 13:12 |
| Last Modified: | 23 Jul 2026 22:17 |
| DOI: | 10.1093/jac/dkag180 |
| Open Access URL: | https://doi.org/10.1093/jac/dkag180 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3199123 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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