A randomized controlled Phase I de-escalation trial of molnupiravir and nirmatrelvir/ritonavir combination for mild-moderate SARS-CoV-2 infection

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.