Clinical effectiveness, safety and viral mutagenicity of oral favipiravir for COVID-19: results from a community-based, open-label, randomised, phase III trial - Repository

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: https://doi.org/10.1128/aac.00054-25

Abstract

Early community treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may reduce severe coronavirus disease (COVID-19) incidence. We evaluated clinical effectiveness, safety, and SARS-CoV-2 mutagenicity of favipiravir, an oral viral RNA polymerase inhibitor. We performed an open-label, community-based, randomized Phase III trial, recruiting non-hospitalized adults with mild COVID-19 (WHO ordinal severity score [OSS] ≤ 3). Positive cases were invited to web-based self-screening within 24 h using public health data. Exclusion criteria included symptoms for >7 days, pregnancy/breastfeeding, severe renal/liver disease, gout, and licensed antiviral eligibility. Participants were randomized 1:1 to 10 days favipiravir (Day 1: 3,600 mg; days 2-10: 1,600 mg) or no additional treatment. The primary endpoint was worst recorded OSS up to and including Day 15 (intention-to-treat). The target recruitment was 302. Secondary endpoints included adverse event (AE) rate to Day 60, time-to-viral clearance (TTVC), time-to-symptom resolution (TTSR), and SARS-CoV-2 sequencing variant rate (≥5% frequency) at Day 15 (registration ISRCTN: 31062548; EudraCT: 2020-001904-41). A total of 68,788 adults were invited, and 302 (0.4%) were subsequently randomized between December 2020 and July 2022 (favipiravir [n = 152]: standard care [n = 150]). Mean (SD) age was 47.2 (13.2), and 230/302 (76%) were vaccinated. Severe outcomes were infrequent, with no intensive care unit admissions/deaths. There was no difference in the primary endpoint: odds ratio 1.18 (95% confidence interval [CI] 0.63–2.20), TTSR (HR 1.03 [95% CI 0.81–1.31]), or TTVC (HR 1.13 [95% CI 0.65–1.97]). Favipiravir was well tolerated with few AEs but was associated with increased variant frequency, including C-to-U mutations. Community administration of favipiravir for mild COVID-19 was not associated with clinical benefits or safety concerns but was associated with SARS-CoV-2 mutagenicity.

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Tate, M., Illingworth, C., MacGregor, G., Cunningham, L., Divers, L., McCartney, E., Paterson, L., Kelly, C., Shaw, A., Perkins, J., Silva, V., Holland, P., Dalton, C., Carmichael, S., Douglas, E., Surtees, P., Scott, J., Berry, C., Vattipally, S., da Silva Filipe, A., Tong, L., Gunson, R., co-investigators, G., McInnes, I., Jones, R., Thomson, E. & Blyth, K. 2025, 'Clinical effectiveness, safety and viral mutagenicity of oral favipiravir for COVID-19: results from a community-based, open-label, randomised, phase III trial', Antimicrobial Agents and Chemotherapy. https://doi.org/10.1128/aac.00054-25

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DOI: https://doi.org/10.1128/aac.00054-25

Repository URI: https://eprints.gla.ac.uk/357376/