Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial

DOI record: { "DOI": "10.1001/jamanetworkopen.2023.54991", "ISSN": [ "2574-3805" ], "URL": "http://dx.doi.org/10.1001/jamanetworkopen.2023.54991", "abstract": "<jats:sec><jats:title>Importance</jats:title><jats:p>Treatment options for COVID-19 are warranted irrespective of the presence of risk factors for severe disease.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To assess the efficacy and safety of ensitrelvir in patients with mild to moderate COVID-19.</jats:p></jats:sec><jats:sec><jats:title>Design, Setting, and Participants</jats:title><jats:p>This phase 3 part of a phase 2/3, double-blind, placebo-controlled randomized clinical trial was conducted from February 10 to July 10, 2022, with a 28-day follow-up period, at 92 institutions in Japan, Vietnam, and South Korea. Patients (aged 12 to &amp;amp;lt;70 years) with mild to moderate COVID-19 within 120 hours of positive viral test results were studied.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>Patients were randomized (1:1:1) to receive 125 mg of once-daily ensitrelvir (375 mg on day 1), 250 mg of once-daily ensitrelvir (750 mg on day 1), or placebo for 5 days.</jats:p></jats:sec><jats:sec><jats:title>Main Outcomes and Measures</jats:title><jats:p>The primary end point was the time to resolution of the composite of 5 characteristic symptoms of SARS-CoV-2 Omicron infection, assessed using a Peto-Prentice generalized Wilcoxon test stratified by vaccination history. Virologic efficacy and safety were also assessed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 1821 patients were randomized, of whom 1030 (347 in the 125-mg ensitrelvir group, 340 in the 250-mg ensitrelvir group, and 343 in the placebo group) were randomized in less than 72 hours of disease onset (primary analysis population). The mean (SD) age in this population was 35.2 (12.3) years, and 552 (53.6%) were men. A significant difference was observed between the 125-mg ensitrelvir group and the placebo group (<jats:italic>P</jats:italic> = .04 with a Peto-Prentice generalized Wilcoxon test). The difference in median time was approximately 1 day between the 125-mg ensitrelvir group and the placebo group (167.9 vs 192.2 hours; difference, −24.3 hours; 95% CI, −78.7 to 11.7 hours). Adverse events were observed in 267 of 604 patients (44.2%) in the 125-mg ensitrelvir group, 321 of 599 patients (53.6%) in the 250-mg ensitrelvir group, and 150 of 605 patients (24.8%) in the placebo group, which included a decrease in high-density lipoprotein level (188 [31.1%] in the 125-mg ensitrelvir group, 231 [38.6%] in the 250-mg ensitrelvir group, and 23 [3.8%] in the placebo group). No treatment-related serious adverse events were reported.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Relevance</jats:title><jats:p>In this randomized clinical trial, 125-mg ensitrelvir treatment reduced the time to resolution of the 5 typical COVID-19 symptoms compared with placebo in patients treated in less than 72 hours of disease onset; the absolute difference in median time to resolution was approximately 1 day. Ensitrelvir demonstrated clinical and antiviral efficacy without new safety concerns. Generalizability to populations outside Asia should be confirmed.</jats:p></jats:sec><jats:sec><jats:title>Trial Registration</jats:title><jats:p>Japan Registry of Clinical Trials Identifier: <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://jrct.niph.go.jp/en-latest-detail/jRCT2031210350\">jRCT2031210350</jats:ext-link></jats:p></jats:sec>", "author": [ { "affiliation": [ { "name": "The Institute of Medical Science, The University of Tokyo, Tokyo, Japan" } ], "family": "Yotsuyanagi", "given": "Hiroshi", "sequence": "first" }, { "affiliation": [ { "name": "Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan" } ], "family": "Ohmagari", "given": "Norio", "sequence": "additional" }, { "affiliation": [ { "name": "Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania" }, { "name": "Departments of Microbiology and Infectious Diseases, Fujita Health University School of Medicine, Toyoake, Japan" } ], "family": "Doi", "given": "Yohei", "sequence": "additional" }, { "affiliation": [ { "name": "Infectious Diseases Center, Rinku General Medical Center, Izumisano, Japan" } ], "family": "Yamato", "given": "Masaya", "sequence": "additional" }, { "affiliation": [ { "name": "Endoscopic Surgery Training Center, University Medical Center, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam" } ], "family": "Bac", "given": "Nguyen Hoang", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, Chung-Ang Medical Health Care System Hyundae Hospital, Gyeonggi-do, Republic of Korea" } ], "family": "Cha", "given": "Bong Ki", "sequence": "additional" }, { "affiliation": [ { "name": "Drug Development and Regulatory Science Division, Shionogi & Co, Ltd, Osaka, Japan" } ], "family": "Imamura", "given": "Takumi", "sequence": "additional" }, { "affiliation": [ { "name": "Drug Development and Regulatory Science Division, Shionogi & Co, Ltd, Osaka, Japan" } ], "family": "Sonoyama", "given": "Takuhiro", "sequence": "additional" }, { "affiliation": [ { "name": "Drug Development and Regulatory Science Division, Shionogi & Co, Ltd, Osaka, Japan" } ], "family": "Ichihashi", "given": "Genki", "sequence": "additional" }, { "affiliation": [ { "name": "Research Division, Shionogi & Co, Ltd, Toyonaka, Japan" } ], "family": "Sanaki", "given": "Takao", "sequence": "additional" }, { "affiliation": [ { "name": "Drug Development and Regulatory Science Division, Shionogi & Co, Ltd, Osaka, Japan" } ], "family": "Tsuge", "given": "Yuko", "sequence": "additional" }, { "affiliation": [ { "name": "Drug Development and Regulatory Science Division, Shionogi & Co, Ltd, Osaka, Japan" } ], "family": "Uehara", "given": "Takeki", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan" } ], "family": 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"10.1021/acs.jmedchem.2c00117", "article-title": "Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19.", "author": "Unoh", "doi-asserted-by": "publisher", "first-page": "6499", "issue": "9", "journal-title": "J Med Chem", "key": "zoi231613r14", "volume": "65", "year": "2022" }, { "DOI": "10.1038/s41586-022-04856-1", "article-title": "Characterization and antiviral susceptibility of SARS-CoV-2 Omicron BA.2.", "author": "Uraki", "doi-asserted-by": "publisher", "first-page": "119", "issue": "7917", "journal-title": "Nature", "key": "zoi231613r15", "volume": "607", "year": "2022" }, { "DOI": "10.1126/scitranslmed.abq4064", "article-title": "S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters.", "author": "Sasaki", "doi-asserted-by": "publisher", "issue": "679", "journal-title": "Sci Transl Med", "key": "zoi231613r16", "volume": "15", "year": "2023" }, { "DOI": 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"Antimicrob Agents Chemother", "key": "zoi231613r19", "volume": "66", "year": "2022" }, { "DOI": "10.1093/cid/ciac933", "article-title": "Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study.", "author": "Mukae", "doi-asserted-by": "publisher", "first-page": "1403", "issue": "8", "journal-title": "Clin Infect Dis", "key": "zoi231613r20", "volume": "76", "year": "2023" }, { "DOI": "10.1001/jama.2013.281053", "article-title": "World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.", "author": "World Medical Association", "doi-asserted-by": "publisher", "first-page": "2191", "issue": "20", "journal-title": "JAMA", "key": "zoi231613r21", "volume": "310", "year": "2013" }, { "DOI": "10.1097/MD.0000000000033024", "article-title": "A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part).", "author": "Yotsuyanagi", "doi-asserted-by": "publisher", "issue": "8", "journal-title": "Medicine (Baltimore)", "key": "zoi231613r22", "volume": "102", "year": "2023" }, { "DOI": "10.1200/JCO.19.01681", "article-title": "Methods for accommodating nonproportional hazards in clinical trials: ready for the primary analysis?", "author": "Freidlin", "doi-asserted-by": "publisher", "first-page": "3455", "issue": "35", "journal-title": "J Clin Oncol", "key": "zoi231613r25", "volume": "37", "year": "2019" }, { "DOI": "10.1128/aac.00632-22", "article-title": "Safety, tolerability, and pharmacokinetics of the novel antiviral agent ensitrelvir fumaric acid, a SARS-CoV-2 3CL protease inhibitor, in healthy adults.", "author": "Shimizu", "doi-asserted-by": "publisher", "issue": "10", "journal-title": "Antimicrob Agents Chemother", "key": "zoi231613r26", "volume": "66", "year": "2022" }, { "DOI": "10.1016/j.lanepe.2022.100556", "article-title": "Severity of Omicron (B.1.1.529) and Delta (B.1.617.2) SARS-CoV-2 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