Effectiveness of Favipiravir on Nonsevere, Early-Stage COVID-19 in Japan: A Large Observational Study Using the COVID-19 Registry Japan
Shinya Tsuzuki, Kayoko Hayakawa, Yohei Doi, Tomohiro Shinozaki, Yukari Uemura, Nobuaki Matsunaga, Mari Terada, Setsuko Suzuki, Yusuke Asai, Gen Yamada, Sho Saito, Taro Shibata, Masashi Kondo, Kazuo Izumi, Masayuki Hojo, Tetsuya Mizoue, Kazuhisa Yokota, Fukumi Nakamura-Uchiyama, Fumitake Saito, Wataru Sugiura, Norio Ohmagari
Infectious Diseases and Therapy, doi:10.1007/s40121-022-00617-9
Introduction: Several randomized controlled trials have compared the effectiveness of favipiravir with that of placebo. However, evidence regarding its effect on nonsevere, early-stage coronavirus disease 2019 (COVID-19) remains insufficient. Methods: We used the COVID-19 Registry Japan, a nationwide registry of inpatients with COVID-19, for evaluating the effectiveness of favipiravir on patients with nonsevere, earlystage COVID-19. Eligible patients, who did not need supplementary oxygen therapy at admission, were classified according to two regimens (starting favipiravir therapy within 4 days from admission vs. no favipiravir during hospitalization) and were then compared using a threestep method (cloning, censoring, and
Ethics Author Contributions. Shinya Tsuzuki, Kayoko Hayakawa, Yohei Doi, Wataru Sugiura, and Norio Ohmagari conceived the study. Tomohiro Shinozaki and Yukari Uemura designed analysis. Nobuaki Matsunaga, Mari Terada, Setsuko Suzuki, Yusuke Asai, Taro Shibata, Masahi Kondo, Kazuo Izumi, Masahiro Hojo, Tetsuya Mizoue, Kazuhisa Yokota, Fukumi Nakamura-Uchiyama, and Fumitake Saito collected the data. Shinya Tsuzuki, Kayoko Hayakawa, Yohei Doi, Tomohiro Shinozaki, Yukari Uemura, Sho Saito, and Gen Yamada analyzed and interpreted the data. Shinya Tsuzuki wrote the first draft, which was subsequently revised by all authors. All authors read and approved the final manuscript. Disclosures. Yohei Doi received scholarship donation from Shionogi & Co., Ltd., honorarium from Merck & Co., Shionogi & Co., Ltd., FUJIFILM Toyama Chemical Co., Ltd., and Teijin Pharma Limited, consultant fee from Shionogi & Co., Ltd., Meiji Seika Pharma Co., Ltd., Gilead Sciences, Inc., bioMe ´rieux S.A., GlaxoSmithKline plc, Merck & Co., and Chugai Pharmaceutical Co., Ltd. Shinya Tsuzuki, Kayoko Hayakawa, Tomohiro Shinozaki, Yukari Uemura, Nobuaki Matsunaga, Mari Terada, Setsuko Suzuki, Yusuke Asai, Gen Yamada, Sho Saito, Taro Shibata, Masashi Kondo, Kazuo Izumi, Masayuki Hojo, Tetsuya Mizoue, Kazuhisa Yokota, Fukumi Nakamura-Uchiyama, Fumitake Saito, Wataru Sugiura, Norio Ohmagari all have nothing to disclose. Compliance with Ethics Guidelines. This study was approved by the NCGM ethics..
References
Bai, Mu, Kargbo, Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)-Sierra Leone, 2014, Clin Infect Dis
Bosaeed, Alharbi, Favipiravir and hydroxychloroquine combination therapy in patients with moderate to severe COVID-19 (FACCT Trial): an open-label, multicenter, randomized, controlled trial, Infect Dis Ther
Bosaeed, Alharbi, Mahmoud, Efficacy of favipiravir in adults with mild COVID-19: a randomized, double-blind, multicentre, placebo-controlled clinical trial, Clin Microbiol Infect,
doi:10.1016/j.cmi.2021.12.026Core, R: a language and environment for statistical computing
Cunningham, Vaduganathan, Claggett, Clinical outcomes in young US adults hospitalized with COVID-19, JAMA Intern Med
Delang, Abdelnabi, Neyts, Favipiravir as a potential countermeasure against neglected and emerging RNA viruses, Antivir Res
Doi, Hibino, Hase, A prospective, randomized, open-label trial of early versus late favipiravir therapy in hospitalized patients with COVID-19, Antimicrob Agents Chemother
Finberg, Ashraf, Julg, US201 study: a phase 2, randomized proof-of-concept trial of favipiravir for the treatment of COVID-19, Open Forum Infect Dis
Furuta, Komeno, Nakamura, Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase, Proc Jpn Acad Ser B Phys Biol Sci
Harris, Taylor, Thielke, Payne, Gonzalez et al., Research electronic data capture (RED-Cap)-a metadata-driven methodology and workflow process for providing translational research informatics support, J Biomed Inform
Hashemian, Farhadi, Velayati, A review on favipiravir: the properties, function, and usefulness to treat COVID-19, Expert Rev Anti Infect Ther
Herna ´n, How to estimate the effect of treatment duration on survival outcomes using observational data, BMJ
Herna ´n, Sauer, Herna ´ndez-Dı ´az, Platt, Shrier, Specifying a target trial prevents immortal time bias and other self-inflicted injuries in observational analyses, J Clin Epidemiol
Ito, Ohmagari, Mikami, Sugiura, Major ongoing clinical trials for COVID-19 treatment and studies currently being conducted or scheduled in Japan, Glob Health Med
Ivashchenko, Dmitriev, Vostokova, AVIFAVIR for treatment of patients with moderate coronavirus disease 2019 (COVID-19): interim results of a phase II/III multicenter randomized clinical trial, Clin Infect Dis
Lai, Chao, Hsueh, Clinical efficacy of antiviral agents against coronavirus disease 2019: a systematic review of randomized controlled trials, J Microbiol Immunol Infect
Lighter, Phillips, Hochman, Obesity in patients younger than 60 years is a risk factor for COVID-19 hospital admission, Clin Infect Dis
Matsunaga, Hayakawa, Terada, Clinical epidemiology of hospitalized patients with COVID-19 in Japan: report of the COVID-19 Registry Japan, Clin Infect Dis
Petrilli, Jones, Yang, Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study, BMJ
Pilkington, Pepperrell, Hill, A review of the safety of favipiravir-a potential treatment in the COVID-19 pandemic?, J Virus Erad
Ritchie, Mathieu, ´s-Guirao, Coronavirus pandemic (COVID-19)
Robins, Finkelstein, Correcting for noncompliance and dependent censoring in an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-rank tests, Biometrics
Rosenbaum, Db, The central role of the propensity score in observational studies for causal effects, Biometrilca
Shinkai, Tsushima, Tanaka, Efficacy and safety of favipiravir in moderate COVID-19 pneumonia patients without oxygen therapy: a randomized, phase III clinical trial, Infect Dis Ther
Sissoko, Laouenan, Folkesson, Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in guinea, PLoS Med
Suissa, Dell'aniello, Time-related biases in pharmacoepidemiology, Pharmacoepidemiol Drug Saf
Tartof, Qian, Hong, Obesity and mortality among patients diagnosed with COVID-19: Infect Dis Ther results from an integrated health care organization, Ann Intern Med
Tsuzuki, Hayakawa, Uemura, Efficacy of remdesivir in hospitalised COVID-19 patients in Japan: a large observational study using the COVID-19 Registry Japan,
doi:10.1101/2021.03.09.21253183v2Udwadia, Singh, Barkate, Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: a randomized, comparative, open-label, multicenter, phase 3 clinical trial, Int J Infect Dis
Williamson, Walker, Bhaskaran, Factors associated with COVID-19-related death using OpenSAFELY, Nature
Wu, Mcgoogan, Characteristics of and Important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention, JAMA
