Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial

Masaharu Shinkai, Kenji Tsushima, Shingo Tanaka, Eri Hagiwara, Norihito Tarumoto, Ichiro Kawada, Yuji Hirai, Sho Fujiwara, Yuko Komase, Takeshi Saraya, Hidefumi Koh, Naho Kagiyama, Megumi Shimada, Daiki Kanou, Shinichi Antoku, Yujiro Uchida, Yutaka Tokue, Mikio Takamori, Yasuhiro Gon, Kenya IeYoshitaka Yamazaki, Kazumasa Harada, Naoki Miyao, Takashi Naka, Mitsunaga Iwata, Atsushi Nakagawa, Kazutoshi Hiyama, Yoshihiko Ogawa, Masahiro Shinoda, Shinichiro Ota, Takatomo Hirouchi, Jiro Terada, Shuichi Kawano, Takashi Ogura, Tsutomu Sakurai, Yoshihiko Matsumoto, Hiroyuki Kunishima, Osamu Kobayashi, Satoshi Iwata

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46 Citations (Scopus)


Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. Methods: COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. Results: A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. Conclusions: The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. Trial registration: Clinicaltrials.jp number: JapicCTI-205238.

Original languageEnglish
Pages (from-to)2489-2509
Number of pages21
JournalInfectious Diseases and Therapy
Issue number4
Publication statusPublished - 12-2021

All Science Journal Classification (ASJC) codes

  • Microbiology (medical)
  • Infectious Diseases


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