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

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

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 (SpO(2) ≥ 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 (SpO(2)), 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40121-021-00517-4.