tetano
Editor, Senior Moderator
J Antimicrob Chemother
. 2026 Jun 3;81(7):dkag180.
doi: 10.1093/jac/dkag180.
A randomized controlled Phase I de-escalation trial of molnupiravir and nirmatrelvir/ritonavir combination for mild-moderate SARS-CoV-2 infection
Saye H Khoo[SUP] 1 2 [/SUP], Richard FitzGerald[SUP] 1 2 [/SUP], Christopher J Edwards[SUP] 3 [/SUP], Shazaad Ahmad[SUP] 4 [/SUP], Geoffrey Saunders[SUP] 5 [/SUP], Laura J Else[SUP] 1 [/SUP], Victoria Shaw[SUP] 6 [/SUP], Pavel Mozgunov[SUP] 7 [/SUP], Joshua Northey[SUP] 5 [/SUP], Laura Dickinson[SUP] 1 [/SUP], Emma Knox[SUP] 5 [/SUP], Amanda Buadi[SUP] 3 [/SUP], Colin Hale[SUP] 2 [/SUP], Helen E Reynolds[SUP] 1 [/SUP], Calley Middleton[SUP] 5 [/SUP], Katie Bullock[SUP] 8 [/SUP], Lauren Walker[SUP] 1 2 [/SUP], Michelle Tetlow[SUP] 1 [/SUP], Rebecca Lyon[SUP] 2 [/SUP], Jennifer Gibney[SUP] 2 [/SUP], Alieu Amara[SUP] 1 [/SUP], William Greenhalf[SUP] 8 [/SUP], Abigail Burdon[SUP] 7 [/SUP], Jan Dixon[SUP] 1 [/SUP], Thomas Jaki[SUP] 7 9 [/SUP], Justin Chiong[SUP] 1 [/SUP], David G Lalloo[SUP] 10 [/SUP], Andew Owen[SUP] 11 [/SUP], Michael Jacobs[SUP] 10 12 [/SUP], Thomas Fletcher[SUP] 10 [/SUP], Gareth Griffiths[SUP] 5 [/SUP]; AGILE CST-8 study group
Collaborators, Affiliations
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.
. 2026 Jun 3;81(7):dkag180.
doi: 10.1093/jac/dkag180.
A randomized controlled Phase I de-escalation trial of molnupiravir and nirmatrelvir/ritonavir combination for mild-moderate SARS-CoV-2 infection
Saye H Khoo[SUP] 1 2 [/SUP], Richard FitzGerald[SUP] 1 2 [/SUP], Christopher J Edwards[SUP] 3 [/SUP], Shazaad Ahmad[SUP] 4 [/SUP], Geoffrey Saunders[SUP] 5 [/SUP], Laura J Else[SUP] 1 [/SUP], Victoria Shaw[SUP] 6 [/SUP], Pavel Mozgunov[SUP] 7 [/SUP], Joshua Northey[SUP] 5 [/SUP], Laura Dickinson[SUP] 1 [/SUP], Emma Knox[SUP] 5 [/SUP], Amanda Buadi[SUP] 3 [/SUP], Colin Hale[SUP] 2 [/SUP], Helen E Reynolds[SUP] 1 [/SUP], Calley Middleton[SUP] 5 [/SUP], Katie Bullock[SUP] 8 [/SUP], Lauren Walker[SUP] 1 2 [/SUP], Michelle Tetlow[SUP] 1 [/SUP], Rebecca Lyon[SUP] 2 [/SUP], Jennifer Gibney[SUP] 2 [/SUP], Alieu Amara[SUP] 1 [/SUP], William Greenhalf[SUP] 8 [/SUP], Abigail Burdon[SUP] 7 [/SUP], Jan Dixon[SUP] 1 [/SUP], Thomas Jaki[SUP] 7 9 [/SUP], Justin Chiong[SUP] 1 [/SUP], David G Lalloo[SUP] 10 [/SUP], Andew Owen[SUP] 11 [/SUP], Michael Jacobs[SUP] 10 12 [/SUP], Thomas Fletcher[SUP] 10 [/SUP], Gareth Griffiths[SUP] 5 [/SUP]; AGILE CST-8 study group
Collaborators, Affiliations
- PMID: 42301199
- PMCID: PMC13270479
- DOI: 10.1093/jac/dkag180
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.