Favipiravir Treatment of Uncomplicated Influenza in Adults: Results of Two Phase 3, Randomized, Double-Blind, Placebo-Controlled Trials

Abstract

Background: We conducted double-blind, placebo-controlled trials assessing the efficacy and tolerability of favipiravir in acute influenza.

Methods: Otherwise healthy adults with influenza-like symptoms and fever of ≤48 hours were randomized to favipiravir (1800 mg twice daily [BID] on day 1, 800 mg BID on days 2-5) or placebo tablets (1:1 in US316; 3:1 in US317). The primary efficacy endpoint was the time to illness alleviation when 6 influenza symptoms were self-rated as absent or mild and fever was absent in the intention-to-treat, influenza-infected participants.

Results: In US316 (301 favipiravir, 322 placebo), favipiravir was associated with a 14.4-hour reduction (median, 84.2 vs 98.6 hours; P = .004) in time to illness alleviation vs placebo. In US317 (526 favipiravir, 169 placebo), favipiravir did not significantly reduce time to alleviation (median, 77.8 vs 83.9 hours). In both trials favipiravir was associated with reduced viral titers, RNA load area under the curve over days 1-5, and median times to cessation of virus detection (P < .001). Aside from asymptomatic hyperuricemia, no important differences in adverse events were found.

Conclusions: This favipiravir dosing regimen demonstrated significant antiviral efficacy but inconsistent illness alleviation in uncomplicated influenza. Studies of higher doses and antiviral combinations for treating serious influenza and other RNA viral infections are warranted. Clinical Trials Registration. NCT02026349; NCT02008344.

Keywords: antiviral; favipiravir; influenza; pharmacokinetics; treatment.

Conflict of interest statement

Potential conflicts of interest. F. G. H. has served as unpaid consultant to Medivector and Fujifilm during the clinical development of favipiravir and to other companies involved in developing influenza therapeutics or vaccines (Appili, Gilead, GSK, Janssen/J&J, MedImmune, Merck, Ridgeback, Roche/Genentech, Versatope, Vir, Visterra). Cidara, Enanta, Shionogi, and Versatope have made charitable donations for his consulting, and both Shionogi and Roche have provided meeting travel support. All of the other co-authors were employees of Medivector at the time of the trials but are no longer employees. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.

Kaplan–Meier estimates for the primary endpoint of time to alleviation of 6 influenza symptoms and resolution of fever in US316 (A) and US317 (B). The estimated probability of persistence of symptoms (failure to have achieved alleviation) as a function of time (hours) from the start of dosing is shown.

Figure 2.

Mean ± standard error of the mean (SEM) infectious virus titers (median tissue culture infectious dose [TCID50]/mL) in respiratory tract samples from favipiravir and placebo recipients in US316 (A) and US317 (B). The lower limit of quantification (LLOQ) in the TCID50 assay (0.7852, LLOQ = 0.75 TCID50/mL) is indicated by the dashed horizontal line.