The Journal of antimicrobial chemotherapy · 2026
A randomized controlled Phase I de-escalation trial of molnupiravir and nirmatrelvir/ritonavir combination for mild-moderate SARS-CoV-2 infection.
Клиническое исследование I фазыСтатьяМногоцентровое исследованиеРандомизированное исследованиеНазвание и аннотация: Перевод пока не подготовлен
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Khoo Saye H, FitzGerald Richard, Edwards Christopher J, Ahmad Shazaad, Saunders Geoffrey, Else Laura J, Shaw Victoria, Mozgunov Pavel, Northey Joshua, Dickinson Laura, Knox Emma, Buadi Amanda, Hale Colin, Reynolds Helen E, Middleton Calley, Bullock Katie, Walker Lauren, Tetlow Michelle, Lyon Rebecca, Gibney Jennifer, Amara Alieu, Greenhalf William, Burdon Abigail, Dixon Jan, Jaki Thomas, Chiong Justin, Lalloo David G, Owen Andew, Jacobs Michael, Fletcher Thomas, Griffiths Gareth, AGILE CST-8 study group
Аннотация
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.
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.