A randomized controlled Phase I de-escalation trial of molnupiravir and nirmatrelvir/ritonavir combination for mild-moderate SARS-CoV-2 infection
et al., Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkag180, NCT04746183, Jun 2026
Phase I RCT of 24 outpatients (16 combination therapy, 8 standard of care) showing that molnupiravir (800 mg twice daily) combined with nirmatrelvir/ritonavir (300/100 mg twice daily) for 5 days was safe and well-tolerated in mild-to-moderate COVID-19.
Clinical outcomes are missing. Authors collected "symptom, health and medication questionnaires" on Days 1, 2, 3, 4, 5, 8, and 29, but have not reported the results. There were no deaths, hospitalizations or any new requirement for oxygen therapy for any participant.
Although PCR negativity rates at day 5 and day 11 were not significantly different between arms, a bi-exponential virological clearance model detected a significantly faster initial viral decay in the combination arm.
Study covers molnupiravir and paxlovid.
Khoo et al., 3 Jun 2026, Randomized Controlled Trial, United Kingdom, peer-reviewed, 56 authors, study period January 2023 - September 2023, trial NCT04746183 (history).
Contact: khoo@liverpool.ac.uk.
Abstract:
A randomized controlled Phase I de-escalation trial of molnupiravir and nirmatrelvir/ritonavir combination for mild-moderate SARS-CoV-2 infection
Saye H. Khoo 1,2 *, Richard FitzGerald 1,2 , Christopher J. Edwards 3 , Shazaad Ahmad 4 , Geoffrey Saunders 5 , Laura J. Else 1 , Victoria Shaw 6 , Pavel Mozgunov 7 , Joshua Northey 5 , Laura Dickinson 1 , Emma Knox 5 , Amanda Buadi 3 , Colin Hale 2 , Helen E. Reynolds 1 , Calley Middleton 5 , Katie Bullock 8 , Lauren Walker 1,2 , Michelle Tetlow 1 , Rebecca Lyon 2 , Jennifer Gibney 2 , Alieu Amara 1 , William Greenhalf 8 , Abigail Burdon 7 , Jan Dixon 1 , Thomas Jaki 7,9 , Justin Chiong 1 , David G. Lalloo 10 , Andew Owen 11 , Michael Jacobs 10,12 , Thomas Fletcher 10 and Gareth Griffiths 5 † on behalf of the AGILE CST-8 study group
1 Centre for Experimental Therapeutics (TherEx), University of Liverpool, Liverpool, UK; 2 NIHR Liverpool Clinical Research Facility, NHS University Hospitals of Liverpool Group, Liverpool, UK; 3 NIHR Southampton Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, UK; 4 NIHR Manchester Clinical Research Facility, University of Manchester, Manchester, UK; 5 Southampton Clinical Trials Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK; 6 Clinical Directorate, University of Liverpool, Liverpool, UK; 7 MRC Biostatistics Unit, University of Cambridge, Cambridge, UK; 8 Molecular & Clinical Cancer Medicine, University of Liverpool, Liverpool, UK; 9 Computational Statistics, University of Regensburg, Regensburg, Germany; 10 Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK; 11 Centre of Excellence for Long-Acting Therapeutics, University of Liverpool, Liverpool, UK; 12 Keble College, University of Oxford, Oxford, UK
*Corresponding author. E-mail: khoo@liverpool.ac.uk † Members are listed in the Acknowledgements section.
Received 19 November 2025; accepted 17 April 2026
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 deescalation 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,..
DOI record:
{
"DOI": "10.1093/jac/dkag180",
"ISSN": [
"0305-7453",
"1460-2091"
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"URL": "http://dx.doi.org/10.1093/jac/dkag180",
"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Objectives</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>",
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