US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19
Robert W Finberg, Madiha Ashraf, Boris Julg, Folusakin Ayoade, Jai G Marathe, Nicolas C Issa, MD Jennifer P Wang, Siraya Jaijakul, Lindsey R Baden, Carol Epstein
Open Forum Infectious Diseases, doi:10.1093/ofid/ofab563
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 . Patients were randomized to standard of care (SOC) or favipiravir treatment (1800 mg per os twice a day [b.i.d.] on day 1, followed by 1000 mg 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. ClinicalTrials.gov registration. NCT04358549.
References
Bank, Renzette, Liu, An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy, Evolution
Cai, Yang, Liu, Experimental treatment with favipiravir for COVID-19: an open-label control study, Engineering
Cohen, Monoclonal antibodies to disrupt progression of early Covid-19 infection, N Engl J Med
Driouich, Cochin, Lingas, Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model, Nat Commun
Hung, Ghula, Aziz, The efficacy and adverse effects of favipiravir on COVID-19 patients: a systematic review and meta-analysis of published clinical trials and observational studies, Lancet,
doi:10.2139/ssrn.3889346Jensen, Lynch, Considering mutational meltdown as a potential SARS-CoV-2 treatment strategy, Heredity (Edinb)
Kaptein, Jacobs, Langendries, Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity, Proc Natl Acad Sci U S A
Naydenova, Muir, Wu, Structure of the SARS-CoV-2 RNAdependent RNA polymerase in the presence of favipiravir-RTP, Proc Natl Acad Sci U S A
Ormond, Liu, Matuszewski, The combined effect of oseltamivir and favipiravir on influenza a virus evolution, Genome Biol Evol
Peng, Peng, Yuan, Structural basis of SARS-CoV-2 polymerase inhibition by favipiravir, Innovation
Sada, Saraya, Ishii, Detailed molecular interactions of favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza virus polymerases in silico, Microorganisms
Shinkai, Tsushima, Tanaka, Efficacy and safety of favipiravir in moderate COVID-19 pneumonia patients without oxygen therapy: a randomized, phase III clinical trial, Infect Dis Ther
Simonis, Theobald, Fätkenheuer, A comparative analysis of remdesivir and other repurposed antivirals against SARS-CoV-2, EMBO Mol Med
Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res
