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

Abstract

Objective: To assess the efficacy and safety of favipiravir in adults with mild-to-moderate coronavirus disease 2019 (COVID-19).

Methods: In this randomized, open-label, parallel-arm, multicenter, phase 3 trial, adults (18-75 years) with RT-PCR confirmed COVID-19 and mild-to-moderate symptoms (including asymptomatic) were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-14: 800 mg BID) plus standard supportive care versus supportive care alone. The primary endpoint was time to the cessation of viral shedding; time to clinical cure was also measured.

Results: From May 14 to July 3, 2020, 150 patients were randomized to favipiravir (n = 75) or control (n = 75). Median time to the cessation of viral shedding was 5 days (95% CI: 4 days, 7 days) versus 7 days (95% CI: 5 days, 8 days), P = 0.129, and median time to clinical cure was 3 days (95% CI: 3 days, 4 days) versus 5 days (95% CI: 4 days, 6 days), P = 0.030, for favipiravir and control, respectively. Adverse events were observed in 36% of favipiravir and 8% of control patients. One control patient died due to worsening disease.

Conclusion: The lack of statistical significance on the primary endpoint was confounded by limitations of the RT-PCR assay. Significant improvement in time to clinical cure suggests favipiravir may be beneficial in mild-to-moderate COVID-19.

Keywords: Antiviral; COVID-19; Coronavirus; Favipiravir; Randomized clinical trial; SARS-CoV-2.

Figure 1

CONSORT Diagram of Patient Disposition.

Figure 2

Kaplan–Meier Survival Curves for Primary and Secondary Endpoints, ITT Population. ITT, intent-to-treat. The ITT population excluded 2 subjects with no drug intake (favipiravir arm) and 1 subject with no post baseline efficacy assessment (favipiravir arm). The favipiravir arm received treatment with favipiravir + standard supportive care; the control arm received standard supportive care alone. Kaplan–Meier was used to estimate the median duration of time-to-event and 95% confidence intervals. The two treatment groups were compared using a log-rank test to estimate the P value. The hazard ratio of favipiravir/control and the corresponding P value were computed based on the Cox regression model with covariates of age, treatment, and baseline comorbidity. Subjects who terminated the study without documented event were censored at day 28. Subjects who died without the documented event were censored at day 28 or the date of death, whichever was later. Analyses of time to clinical cure and time to the first use of supplemental oxygen included, respectively, only patients who were symptomatic at baseline and patients who required the use of supplemental oxygen. Panel A: median of the time to events in days for favipiravir and control (95% CI): 5.0 (4.0, 7.0), 7.0 (5.0, 8.0); P value for favipiravir vs control: 0.1290; and hazard ratio (95% CI): 1.367 (0.944, 1.979), P = 0.098. Panel B: median of the time to events in days for favipiravir and control (95% CI): 3.0 (3.0, 4.0), 5.0 (4.0, 6.0); P value for favipiravir vs control: 0.0297; and hazard ratio (95% CI): 1.749 (1.096, 2.792), P = 0.019. Panel C: Median of the time to events in days for favipiravir and control (95% CI): 5.0 (1.0, 6.0), 2.0 (1.0, 4.0); P value for favipiravir vs control: 0.0653; and hazard ratio (95% CI): 0.065 (0.005, 0.809), P = 0.034; subjects who terminated the study without a documented event were excluded. Because most of the subjects did not require oxygen support, the censoring rate was too high for Kaplan–Meier analysis to estimate the median time-to-event; therefore, only results from noncensored data are presented for this endpoint. Panel D: Median of the time to events in days for favipiravir and control (95% CI): 9.0 (7.0, 10.0), 10.0 (8.0, 12.0); P value for favipiravir vs control: 0.1079; and hazard ratio (95% CI): 1.406 (0.974, 2.030), P = 0.069.

Figure 3

Rate of Events at Days 4, 7, 10, and 14.