Multicenter, single-blind, randomized controlled study of the efficacy and safety of favipiravir and nafamostat mesilate in patients with COVID-19 pneumonia

Mahoko Ikeda; Shu Okugawa; Kosuke Kashiwabara; Takashi Moritoyo; Yoshiaki Kanno; Daisuke Jubishi; Hideki Hashimoto; Koh Okamoto; Kenji Tsushima; Yasuki Uchida; Takahiro Mitsumura; Hidetoshi Igari; Takeya Tsutsumi; Hideki Araoka; Kazuhiro Yatera; Yoshihiro Yamamoto; Yuki Nakamura; Amato Otani; Marie Yamashita; Yuji Wakimoto; Takayuki Shinohara; Maho Adachi-Katayama; Tatsunori Oyabu; Aoi Kanematsu; Sohei Harada; Yuichiro Takeshita; Yasutaka Nakano; Yasunari Miyazaki; Seiichiro Sakao; Makoto Saito; Sho Ogura; Kei Yamasaki; Hitoshi Kawasuji; Osamu Hataji; Jun-Ichiro Inoue; Yasuyuki Seto; Kyoji Moriya

doi:10.1016/j.ijid.2022.12.039

Multicenter, single-blind, randomized controlled study of the efficacy and safety of favipiravir and nafamostat mesilate in patients with COVID-19 pneumonia

Int J Infect Dis. 2023 Mar:128:355-363. doi: 10.1016/j.ijid.2022.12.039. Epub 2023 Jan 4.

Authors

Mahoko Ikeda¹, Shu Okugawa², Kosuke Kashiwabara³, Takashi Moritoyo³, Yoshiaki Kanno², Daisuke Jubishi², Hideki Hashimoto², Koh Okamoto², Kenji Tsushima⁴, Yasuki Uchida⁵, Takahiro Mitsumura⁶, Hidetoshi Igari⁷, Takeya Tsutsumi⁸, Hideki Araoka⁹, Kazuhiro Yatera¹⁰, Yoshihiro Yamamoto¹¹, Yuki Nakamura¹², Amato Otani¹³, Marie Yamashita², Yuji Wakimoto², Takayuki Shinohara², Maho Adachi-Katayama², Tatsunori Oyabu², Aoi Kanematsu², Sohei Harada¹⁴, Yuichiro Takeshita⁴, Yasutaka Nakano⁵, Yasunari Miyazaki⁶, Seiichiro Sakao⁷, Makoto Saito¹⁵, Sho Ogura⁹, Kei Yamasaki¹⁰, Hitoshi Kawasuji¹¹, Osamu Hataji¹², Jun-Ichiro Inoue¹³, Yasuyuki Seto¹⁶, Kyoji Moriya¹⁷

Affiliations

¹ Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan; Department of Infection Control and Prevention, The University of Tokyo Hospital, Tokyo, Japan.
² Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan.
³ Clinical Research Promotion Center, The University of Tokyo Hospital, Tokyo, Japan.
⁴ Department of Pulmonary Medicine, International University of Health and Welfare, Narita Hospital, Chiba, Japan.
⁵ Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Shiga, Japan.
⁶ Department of Respiratory Medicine, Tokyo Medical and Dental University Hospital, Tokyo, Japan.
⁷ Department of Infection Control, Chiba University Hospital, Chiba, Japan.
⁸ Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan; Division of Infectious Diseases, Advanced Clinical Research Center, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁹ Department of Infectious Diseases, Toranomon Hospital, Tokyo, Japan.
¹⁰ Department of Respiratory Medicine, Hospital of the University of Occupational and Environmental Health, Fukuoka, Japan.
¹¹ Department of Clinical Infectious Diseases, Toyama University Hospital, Toyama, Japan.
¹² Respiratory Center, Matsusaka Municipal Hospital, Mie, Japan.
¹³ Research Platform Office, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁴ Department of Infection Control and Prevention, The University of Tokyo Hospital, Tokyo, Japan.
¹⁵ Division of Infectious Diseases, Advanced Clinical Research Center, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁶ Department of Stomach and Esophageal Surgery, The University of Tokyo Hospital, Tokyo, Japan.
¹⁷ Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan; Department of Infection Control and Prevention, The University of Tokyo Hospital, Tokyo, Japan. Electronic address: moriyakyojl0720@gmail.com.

Abstract

Objectives: To evaluate the efficacy and safety of nafamostat combined with favipiravir for the treatment of COVID-19.

Methods: We conducted a multicenter, randomized, single-blind, placebo-controlled, parallel assignment study in hospitalized patients with mild-to-moderate COVID-19 pneumonia. Patients were randomly assigned to receive favipiravir alone (n = 24) or nafamostat with favipiravir (n = 21). The outcomes included changes in the World Health Organization clinical progression scale score, time to improvement in body temperature, and improvement in oxygen saturation (SpO₂).

Results: There was no significant difference in the changes in the clinical progression scale between nafamostat with favipiravir and favipiravir alone groups (median, -0.444 vs -0.150, respectively; least-squares mean difference, -0.294; P = 0.364). The time to improvement in body temperature was significantly shorter in the combination group (5.0 days; 95% confidence interval, 4.0-7.0) than in the favipiravir group (9.0 days; 95% confidence interval, 7.0-18.0; P =0.009). The changes in SpO₂ were greater in the combination group than in the favipiravir group (0.526% vs -1.304%, respectively; least-squares mean difference, 1.831; P = 0.022). No serious adverse events or deaths were reported, but phlebitis occurred in 57.1% of the patients in the combination group.

Conclusion: Although our study showed no differences in clinical progression, earlier defervescence, and recovery of SpO₂ were observed in the combination group.

Keywords: COVID-19; Favipiravir; Nafamostat mesilate; Pneumonia; SARS-CoV-2.

Publication types

Randomized Controlled Trial
Multicenter Study

MeSH terms

Antiviral Agents / therapeutic use
COVID-19*
Disease Progression
Humans
SARS-CoV-2
Single-Blind Method
Treatment Outcome

Substances

nafamostat
favipiravir
Antiviral Agents