Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial
MD MS Marisa Holubar, MD Aruna Subramanian, PhD Natasha Purington, PhD Haley Hedlin, MS Bryan Bunning, PhD Katharine S Walter, MD Hector Bonilla, Athanasia Boumis, MD Michael Chen, Kimberly Clinton, Liisa Dewhurst, MD Carol Epstein, MD Prasanna Jagannathan, MD Richard H Kaszynski, Lori Panu, MD Julie Parsonnet, PhD Elizabeth L Ponder, MD Orlando Quintero, PhD Elizabeth Sefton, MD Upinder Singh, Luke Soberanis, PharmD Henry Truong, MD Jason R Andrews, PhD Manisha Desai, PhD Chaitan Khosla, MD Yvonne Maldonado
doi:10.1093/cid/ciac312/6572081
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 1:1 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 amplicon-based 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.
Participants We enrolled asymptomatic or symptomatic adults without respiratory distress who had a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) collected within 72 hours of enrollment. We excluded individuals who required renal replacement therapy, had liver impairment, were immunocompromised, or were pregnant or breast-feeding. See Supplementary Appendix for full criteria. Participants were randomized 1:1 to favipiravir or placebo using block, REDCap-implemented, randomization stratified by age (>=50 and <50 years old) and sex. [4, 5]
Procedures Participants received placebo or favipiravir 1800 mg BID on day 1, then 800mg BID on days 2-10. Favipiravir and placebo tablets were identical in appearance to maintain blinding. We followed participants for 28 days and performed a clinical assessment (including vital signs and targeted physical exams) and collected oropharyngeal (OP) swabs and blood samples at each visit. Staff-collected OP specimens underwent RT-PCR (Viroclinics Biosciences, Rotterdam, The Netherlands). Anti-SARSCoV-2 serology was performed using a virus plaque reduction neutralization assay (Viroclinics Biosciences, Rotterdam, The Netherlands). Participants self-collected daily anterior nasal swabs on days 1-10, 14, 21, and 28 and submitted them directly for RT-PCR with an assay that targeted the viral nucleocapsid gene's N1 and N3 regions (Quest Diagnostics, Secaucus, New Jersey). Participants also completed..
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DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>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 1: 1 to receive placebo or favipiravir (1800mg BID Day 1, 800 mg 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 amplicon-based sequencing, we assessed favipiravir’s impact on mutagenesis.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusions</jats:title>\n <jats:p>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.</jats:p>\n </jats:sec>",
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