Abstract: Clinical Infectious Diseases SC RI PT RESEARCH ARTICLE Efficacy and safety of ensitrelvir in patients with mild-tomoderate COVID-19: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study U Hiroshi Mukae1, Hiroshi Yotsuyanagi2, Norio Ohmagari3, Yohei Doi4,5, Hiroki Sakaguchi6, Takuhiro Sonoyama6, Genki Ichihashi6, Takao Sanaki7, Keiko Baba7, Yuko Tsuge6, Takeki Uehara6* 1 TE D M A N Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 2The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 3Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan; 4Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; 5Departments of Microbiology and Infectious Diseases, Fujita Health University School of Medicine, Toyoake, Japan; 6Drug Development and Regulatory Science Division, Shionogi & Co., Ltd., Osaka, Japan; 7Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan EP Background. This phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron epidemic. A CC —————————————————————————————————————— *Corresponding author: Takeki Uehara Drug Development and Regulatory Science Division, Shionogi & Co., Ltd. Address: 8F, Nissay Yodoyabashi East, 3-3-13 Imabashi, Chuo-ku, Osaka 541-0042, Japan Email: takeki.uehara@shionogi.co.jp © The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/cid/ciac933 1 SC RI PT Methods. Patients were randomized (1:1:1) to orally receive ensitrelvir fumaric acid 125 mg (375 mg on day 1) or 250 mg (750 mg on day 1) or placebo once daily for 5 days. The co-primary endpoints were the change from baseline in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer on day 4 and time-weighted average change from baseline up to 120 hours in the total score of predefined 12 COVID-19 symptoms. Safety was assessed through adverse events. N U Results. A total of 341 patients (ensitrelvir 125 mg group, 114; ensitrelvir 250 mg group, 116; and placebo group, 111; male, 53.5%–64.9%; mean age, 35.3–37.3 years) were included in the efficacy analyses. The change from baseline in the SARS-CoV-2 titer on day 4 was significantly greater with both ensitrelvir doses than with placebo (differences from placebo: -0.41 log10 50% tissue-culture infectious dose/mL, P<0.0001 for both). The total score of the 12 COVID-19 symptoms did not show a significant difference between the ensitrelvir groups and placebo group. The time-weighted average change from baseline up to 120 hours was significantly greater with ensitrelvir versus placebo in several subtotal scores, including acute symptoms and respiratory symptoms. Most adverse events were mild in severity. A Conclusions. Ensitrelvir treatment demonstrated a..