Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19

Abstract

Background: Favipiravir is an antiviral drug, an inhibitor of RNA dependent RNA polymerase that is preliminarily effective against SARS-CoV-2 virus. The aim of this study was to evaluate the efficacy and safety of favipiravir for treatment of mild to moderate coronavirus disease (COVID-19).

Methods: We conducted an open-labeled, randomized, active-controlled multicenter trial of an oral dosage form of favipiravir in out- and hospitalized patients with mild to moderate COVID-19. The study was organized in 10 clinical centers in Russia. Eligible patients had laboratory confirmed by PCR test infection of SARS-CoV-2 and were aged 18-60 years. Patients were randomly assigned (in a 2:1 ratio) to receive either favipiravir (1800 mg BID on day 1, followed by 800 mg BID for up to 9 days), or standard of care (SOC) treatment (umifenovir + intranasal interferon alpha-2b, or hydroxychloroquine) for up to 10 days. Randomization was performed using a web-response system after stratification by COVID-19 severity, age and CT severity at enrollment. The co-primary outcomes were the time to clinical improvement and the time to viral clearance. An efficacy analysis was performed in intent-to-treat population. The safety population included all participants who received at least one dose of favipiravir or SOC.

Findings: Between May 23, 2020, and June 30, 2020, 190 patients were assessed for eligibility, of whom 168 were randomly assigned to receive either favipiravir (n = 112), or SOC (n = 56). The median time to clinical improvement was 6.0 (IQR 4·0; 9·3) days in favipiravir group and 10.0 (IQR 5·0; 21·0) days in SOC group; the median difference was 4 days (HR 1·63; 95% CI 1·14-2·34, p = 0·007). The statistically significant difference in the median time to viral clearance was observed only in the hospitalized cohort of patients: 3·0 (IQR 3·0; 3·0) vs. 5·0 (IQR 4·5; 5·5), respectively (HR 2·11; 95% CI 1·04-4·31; p = 0·038). However, the rate of viral elimination on Day 5 in the favipiravir group was significantly higher in the whole population: 81·2% vs. 67·9% respectively (RR 1·22; 05% CI 1·00-1·48; p = 0.022). The rate of clinical improvement on Day 7 in the favipiravir group was 1.5-fold higher compared to SOC: 52·7% vs. 35·8% (RR 1·50; 95% CI 1·02-2·22; p = 0·020). Favipiravir was well tolerated: most of the adverse events (AE) were mild. Any AEs were reported in 74·1% of patients in the favipiravir group vs. 60·0% in the SOC group. Among the most common adverse reactions was asymptomatic hyperuricemia, transient elevation of ALT & AST, and gastrointestinal disorders (diarrhea, nausea, abdominal pain).

Interpretation: Favipiravir was superior to SOC in shortening the time to clinical improvement in patients with mild to moderate COVID-19.

Trial Registration: The trial is registered on ClinicalTrials.gov, identifier: NCT04501783.

Funding: Funded by R-Pharm Group of Companies

Declaration of Interests: ENK, MYS, MVN, VAR, AVZ, and OVF were employees of R-Pharm Group of Companies during the study and received compensation as part of their employment. All other authors declare no competing interests.

Ethics Approval Statement: The trial protocol was approved by the Russian Ministry of Health (MoH) (permission #201 dated by May 20, 202010), including Central Ethics Council, and by the appropriate local ethics committees at each center. Enrollment in this trial was done on the10 trial sites in Russia, including hospitals and outpatient sites. All of the patients provided written informed consent (IC) before the enrollment.

Keywords: coronavirus disease, COVID-19, SARS-CoV-2 virus, favipiravir, phase 3 study