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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\u2014the 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\u2005mg 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 \u22653). 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>","DOI":"10.1093\/jac\/dkag180","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T11:46:07Z","timestamp":1778154367000},"source":"Crossref","is-referenced-by-count":0,"title":["A randomized controlled Phase I de-escalation trial of molnupiravir and nirmatrelvir\/ritonavir combination for mild-moderate SARS-CoV-2 infection"],"prefix":"10.1093","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2769-0967","authenticated-orcid":false,"given":"Saye 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