Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial (preprint)

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 11 to receive placebo or favipiravir (1800 mg BID Day 1, 800mg BID Days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 deep sequencing, we assessed favipiravir’s impact on mutagenesis. Results From July 8, 2020 - March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The participants’ 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. Trial registration number NCT04346628 Summary In this phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or uncomplicated patients with COVID-19, we found no difference in time to shedding cessation or time to symptom resolution by treatment arm.