Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild-to-Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial
M.D Hiroshi Yotsuyanagi, M.D Norio Ohmagari, M.D Yohei Doi, M.D Masaya Yamato, M.D Nguyen Hoang Bac, M.D Bong Ki Cha, M.S Takumi Imamura, M.D Takuhiro Sonoyama, Genki Ichihashi, Ph.D Takao Sanaki, M.S Yuko Tsuge, Ph.D Takeki Uehara, M.D Hiroshi Mukae
doi:10.1101/2023.07.11.23292264
IMPORTANCE Treatment options for coronavirus disease 2019 (COVID-19) that can be used irrespective of risk factors for severe disease are warranted. OBJECTIVE To assess the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19. DESIGN The phase 3 part of a phase 2/3, double-blind, randomized, placebo-controlled study conducted from February 10 to July 10, 2022. SETTING A multicenter study conducted at 92 institutions in Japan, Vietnam, and South Korea. PARTICIPANTS Patients (aged 12 to <70 years) with mild-to-moderate COVID-19 within 120 hours of positive viral testing. INTERVENTIONS Patients were randomized (1:1:1) to receive once-daily ensitrelvir 125 mg (375 mg on day 1), 250 mg (750 mg on day 1), or placebo for 5 days. Among 1821 randomized patients, 1030 (347, 340, and 343 in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively) were randomized in less than 72 hours of disease onset and assessed as the primary analysis population.
MAIN OUTCOMES AND MEASURES The primary end point was the time to resolution of five COVID-19 symptoms (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness). Other end points included virologic efficacy and safety.
RESULTS The mean age was 35.7, 35.3, and 34.7 years, and 193 (55.6%), 185 (54.4%), and 174 (50.7%) patients were men in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively (intention-to-treat, primary analysis population). A significant difference (P=.04 with a Peto-Prentice generalized Wilcoxon test stratified by vaccination history) was observed in the primary end point between ensitrelvir 125 mg and placebo in the primary
References
Ancova, analysis of covariance; CI, confidence interval; COVID-19, coronavirus disease 2019; LS, least squares; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SE, standard error
Auvigne, Vaux, Strat, Severe hospital events following symptomatic infection with Sars-CoV-2 Omicron and Delta variants in France, EClinicalMedicine
Beigel, Tomashek, Dodd, Remdesivir for the treatment of Covid-19 -final report, N Engl J Med
Bernal, Da Silva, Musungaie, Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients, N Engl J Med
Butler, Hobbs, Gbinigie, Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial, Lancet
Clinicaltrials, Gov, Evaluation of protease inhibition for COVID-19 in standard-risk patients (EPIC-SR)
Covid-19, RNA, ribonucleic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
Hammond, Leister-Tebbe, Gardner, Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19, N Engl J Med
Hammond, Leister-Tebbe, Gardner, Sustained alleviation and resolution of targeted COVID-19 symptoms with nirmatrelvir/ritonavir versus placebo, Open Forum Infect Dis,
doi:10.1093/ofid/ofac492.994
Hyams, Challen, Marlow, Severity of Omicron (B.1.1.529) and Delta
Kawashima, Matsui, Adachi, Ensitrelvir is effective against SARS-CoV-2 3CL protease mutants circulating globally, Biochem Biophys Res Commun
Kopsidas, Karagiannidou, Kostaki, Global distribution, dispersal patterns, and trend of several Omicron subvariants of SARS-CoV-2 across the globe, Trop Med Infect Dis
Meng, Abdullahi, Ferreira, Altered TMPRSS2 usage by
Mukae, Yotsuyanagi, Ohmagari, A randomized phase 2/3 study of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mildto-moderate COVID-19 or asymptomatic SARS-CoV-2 infection: results of the phase 2a part, Antimicrob Agents Chemother
Mukae, Yotsuyanagi, Ohmagari, 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, Clin Infect Dis,
doi:10.1093/cid/ciac933
Najjar-Debbiny, Gronich, Weber, Effectiveness of molnupiravir in high-risk patients: a propensity score matched analysis, Clin Infect Dis
Nyberg, Ferguson, Nash, Comparative analysis of the risks of hospitalisation and death associated with SARS-CoV-2 omicron (B.1.1.529) and delta (B.1.617.2) variants in England: a cohort study, Lancet
Sasaki, Tabata, Kishimoto, S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters, Sci Transl Med
Shimizu, Sonoyama, Fukuhara, Kuwata, Matsuo et al., Safety, tolerability, and pharmacokinetics of the novel antiviral agent ensitrelvir fumaric acid, a SARS-CoV-2 3CL protease inhibitor, in healthy adults, Antimicrob Agents Chemother
Takashita, Yamayoshi, Simon, Efficacy of antibodies and antiviral drugs against Omicron BA.2.12.1, BA.4, and BA.5 subvariants, N Engl J Med
Unoh, Uehara, Nakahara, Discovery of S-217622, a noncovalent oral SARS-CoV-2 3CL protease inhibitor clinical candidate for treating COVID-19, J Med Chem
Uraki, Kiso, Iida, Characterization and antiviral susceptibility of
Wolter, Jassat, Walaza, Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study, Lancet
Yamasoba, Kosugi, Kimura, Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to therapeutic monoclonal antibodies, Lancet Infect Dis
Yotsuyanagi, Ohmagari, Doi, A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (phase 3 part), Medicine (Baltimore)