Ensitrelvir for the treatment of hospitalized adults with COVID-19: an international phase 3 randomized placebo-controlled trial

DOI record: { "DOI": "10.1093/cid/ciag272", "ISSN": [ "1058-4838", "1537-6591" ], "URL": "http://dx.doi.org/10.1093/cid/ciag272", "abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>Antivirals remain an important treatment strategy for persons who experience severe and life-threatening COVID-19. Ensitrelvir is an oral 3CL protease inhibitor with potent antiviral activity.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>We conducted an international randomized, placebo-controlled trial of ensitrelvir with standard of care (SOC) among adults hospitalized for COVID-19. The primary outcome was clinical recovery assessed by the Days to Recovery Scale through Day 60 (DRS-60), analyzed using a Van Elteren test.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>From 2023 to 2025, 589 participants received blinded study treatment (293 ensitrelvir and 296 placebo). Median age was 69 years, 49% were female, 68% were White, and SOC commonly included corticosteroids (61% and 54%) and remdesivir (62% and 60%) in ensitrelvir and placebo groups, respectively. Median DRS-60 category was 6 (IQR: 3-15) in the ensitrelvir and 5.5 (IQR: 3-12) in the placebo group (p=0.19), and the OR was 0.82 (95% CI: 0.62-1.09) for a better DRS-60 category with ensitrelvir. Ensitrelvir participants had lower detectable viral antigen in plasma at Day 5 (13.4% vs 25.1%; p&amp;lt;0.001). There was no difference in secondary clinical outcomes or pre-specified safety outcomes, though the mortality rate was 6.1% vs 4.4% and the frequency of hemorrhagic events was 3.4% vs 0.3% among ensitrelvir and placebo groups, respectively.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>Ensitrelvir treatment did not improve clinical recovery in addition to SOC for adults hospitalized for COVID-19. The lower illness severity in the Omicron era compared to earlier periods in the COVID-19 pandemic, and high use of remdesivir and corticosteroids, may have contributed to the lack of clinical benefit.</jats:p>\n </jats:sec>", "article-number": "ciag272", "author": [ { "ORCID": "https://orcid.org/0000-0002-5542-1545", "affiliation": [ { "name": "Infectious Diseases, Hennepin Healthcare, Department of Medicine, University of Minnesota , Minneapolis, Minnesota ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Baker", "given": "Jason V", "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0001-9440-9146", "affiliation": [ { "name": "Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota , Minneapolis, Minnesota ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Siegel", "given": "Lianne", "sequence": "additional" }, { "affiliation": [ { "name": "CICAL, Fundación IBIS , Buenos Aires ,", "place": [ "Argentina" ] }, { "name": "Hospital General de Agudos Jose Maria Ramos Mejía , Buenos Aires ,", "place": [ "Argentina" ] } ], "family": "Losso", "given": "Marcelo", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-1431-0945", "affiliation": [ { "name": "Virginia Tech Carilion School of Medicine , Salem, Virginia ,", "place": [ "USA" ] }, { "name": "Department of Medicine, Salem VA Medical Center, U.S. Department of Veterans Affairs , Salem, Virginia ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Vasudeva", "given": "Shikha", "sequence": "additional" }, { "ORCID": "https://orcid.org/0009-0005-6339-1701", "affiliation": [ { "name": "Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota , Minneapolis, Minnesota ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Nordwall", "given": "Jacqueline A", "sequence": "additional" }, { "ORCID": "https://orcid.org/0009-0003-4052-7974", "affiliation": [ { "name": "Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota , Minneapolis, Minnesota ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Harper", "given": "Katrina", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-4275-7880", "affiliation": [ { "name": "Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota , Minneapolis, Minnesota ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Grund", "given": "Birgit", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-9894-615X", "affiliation": [ { "name": "College of Pharmacy, University of Nebraska Medical Center , Omaha, Nebraska ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Havens", "given": "Joshua P", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-3703-7849", "affiliation": [ { "name": "Antiviral Pharmacology Laboratory, University of Nebraska Medical Center , Omaha, Nebraska ,", "place": [ "USA" ] } ], "authenticated-orcid": false, "family": "Fletcher", "given": "Courtney V", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-4302-2405", "affiliation": [ { "name": "Central City Clinical Hospital of Ivano-Frankivsk City Council , Ivano-Frankivsk ,", "place": [ "Ukraine" ] } ], "authenticated-orcid": false, "family": "Fishchuk", "given": "Roman", "sequence": "additional" }, { "affiliation": [ { "name": "Central City Clinical Hospital of Ivano-Frankivsk City Council , Ivano-Frankivsk ,", "place": [ "Ukraine" ] } ], "family": "Kobrynska", "given": "Olena", "sequence": "additional" }, { "affiliation": [ { "name": "T. 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