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

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