US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19

Abstract

Background: Favipiravir is used to treat influenza, and studies demonstrate that it has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: We performed a randomized, open-label, multicenter, phase 2 proof-of-concept trial of favipiravir in hospitalized adult patients with polymerase chain reaction (PCR)-positive coronavirus disease 2019 (COVID-19). Patients were randomized to standard of care (SOC) or favipiravir treatment (1800mg per os twice a day [b.i.d.] on day 1, followed by 1000mg b.i.d. for 13 days). The primary end point was time to viral clearance on day 29.

Results: Fifty patients were enrolled and stratified by disease severity (critical disease, severe disease, or mild to moderate disease). Nineteen patients were censored from the event of viral clearance based on being SARS-CoV-2 PCR-negative at the study outset, being PCR-positive at day 29, or because of loss to follow-up. Data from the 31 remaining patients who achieved viral clearance show enhanced viral clearance in the favipiravir group compared with the SOC group by day 29, with 72% of the favipiravir group and 52% of the SOC group being evaluable for viral clearance through day 29. The median time to viral clearance was 16.0 days (90% CI, 12.0 to 29.0) in the favipiravir group and 30.0 days (90% CI, 12.0 to 31.0) in the SOC group. A post hoc analysis revealed an effect in the subgroup of patients who were neutralizing antibody-negative at randomization. Treatment-emergent adverse events were equally distributed between the groups.

Conclusions: We demonstrate that favipiravir can be safely administered to hospitalized adults with COVID-19 and believe that further studies are warranted.

Clinicaltrialsgov registration: NCT04358549.

Keywords: COVID-19; favipiravir; hospitalized; human.

© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.

Primary and secondary end points of US201 favipiravir study. A, US201 primary end point (viral clearance). B, Clinical status over time on study-specific 6-point ordinal scale (ITT population). Stacked box plot showing the proportion of subjects in each of the 6 clinical status categories over time for the favipiravir treatment group and the standard-of-care group. Abbreviations: ECMO, extracorporeal membrane oxygenation; FAV, favipiravir; ITT, intention to treat; RT-PCR, reverse transcription polymerase chain reaction; SOC, standard of care.

Figure 2.

Post hoc subgroup analysis. A, Subgroup analysis by neutralizing antibody at day 1 predose. Time to viral clearance measured in patients with neutralizing antibodies to SARS-CoV-2 that were lower than the LLOQ (left panel) or higher than the LLOQ (right panel). B, Subgroup analysis by days from symptom onset to randomization. Time to viral clearance (by PCR) was measured in patients grouped on the basis of the time between development of COVID-19 symptoms and randomization to the favipiravir plus SOC group or the SOC alone group. Abbreviations: COVID-19, coronavirus disease 2019; LLOQ, lower limit of quantification; PCR, polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SOC, standard of care.