Clinical effectiveness, safety and viral mutagenicity of oral favipiravir for COVID-19: Results from a phase II/III trial.

<bold>Introduction:</bold> Early community treatment may reduce severe COVID-19 incidence and associated societal disruption. We evaluated favipiravir for the early treatment of mild COVID-19. <bold>Methods:</bold> We performed an open-label, community-based, phase II/III randomised trial, recruiting non-hospitalised adults with mild COVID-19 (WHO ordinal severity scale (OSS)≤3). Public health data was used to invite positive cases to web-based self-screening. Exclusion criteria: symptoms >7 days, pregnancy/breastfeeding, severe renal/liver disease, gout, licensed antiviral eligibility. Participants were randomised 1:1 to favipiravir (Day 1:3600mg; Days 2-10:1600mg) or no additional treatment. The primary endpoint was worst recorded OSS up to & including day 15 (intention-to-treat). Secondary endpoints included adverse event (AE) rate, time-to-viral clearance (TTVC), time-to-symptom resolution (TTSR) & SARSCoV2 sequencing variant rate (≥5% frequency) at day 15. Registration <ext-link>ISRCTN31062548</ext-link>. <bold>Results:</bold> 84,546 individuals were pre-screened (December 2020-July 2022). 302(0.35%) were randomised (favipiravir (n=152), standard care (n=150)). Mean age was 47(13.2), 230/302(76%) were vaccinated. Severe outcomes were infrequent, with no ICU admissions/deaths. There was no difference in the primary endpoint (OR 1.29 (95%CI 0.81-2.04)), TTSR (HR 0.97 (95% CI 0.76-1.24)) or TTVC (HR 1.13 (95% CI 0.65-1.97)). AE rate was similar in both study arms. Favipiravir was associated with increased variant frequency, including C-to-U mutations. <bold>Conclusions:</bold> Community administration of favipiravir for mild COVID19 was not associated with clinical benefits or safety concerns but was associated with SARSCoV2 mutagenicity.