Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial
M. Holubar, A. K. Subramanian, N. Purington, H. Hedlin, B. Bunning, K. Walter, H. Bonilla, A. Boumis, M. Chen, K. Clinton, L. Dewhurst, C. Epstein, P. Jagannathan, R. Kaszynski, L. Panu, J. Parsonnet, E. Ponder, O. Quintero, E. Sefton, U. Singh, L. Soberanis, H. Truong, J. Andrews, M. Desai, C. Khosla, Y. Maldonado,
Abstract
Background: Favipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries. Methods: We conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1:1 to receive placebo or favipiravir (1800 mg BID Day 1, 800mg BID Days 2-10). The primary outcome was SARS-CoV2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV2 deep sequencing, we assessed the impact of favipiravir on mutagenesis. Results: From July 8, 2020 to March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48 - 1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54 - 1.29; sustained: HR 0.87, 95% CI 0.52 - 1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment. Conclusions: Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.
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