Favipiravir for Treatment of Outpatients With Asymptomatic or Uncomplicated Coronavirus Disease 2019: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial

Abstract

Background

Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (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-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [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.

Results

We randomized 149 participants with 116 included in the mITT cohort. The participants’ mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48–1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54–1.29]; sustained: HR, 0.87 [95% CI, .52–1.45]) and no difference in transition mutation accumulation in the viral genome during treatment.

Conclusions

Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19.

Clinical Trials Registration

NCT04346628.

SciScore for 10.1101/2021.11.22.21266690: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Ethics	not detected.
Sex as a biological variable	not detected.
Randomization	Study Design: We conducted a Phase 2, double-blind, randomized, placebo-controlled phase 2 trial at Stanford Healthcare, California. Stanford University School of Medicine Panel on Human Subjects in Medical Research approved the study protocol.
Blinding	Favipiravir and placebo tablets were identical in appearance to maintain blinding.
Power Analysis	Sample size determination: Assuming 1:1 randomization and a two-sided log rank test at alpha□=□0.04999 level of significance for the final analysis, we anticipated 79 shedding cessation events, which provided 80% power to detect a hazard ratio of 2.03.

Table 2: Resources

…

SciScore for 10.1101/2021.11.22.21266690: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Ethics	not detected.
Sex as a biological variable	not detected.
Randomization	Study Design: We conducted a Phase 2, double-blind, randomized, placebo-controlled phase 2 trial at Stanford Healthcare, California. Stanford University School of Medicine Panel on Human Subjects in Medical Research approved the study protocol.
Blinding	Favipiravir and placebo tablets were identical in appearance to maintain blinding.
Power Analysis	Sample size determination: Assuming 1:1 randomization and a two-sided log rank test at alpha□=□0.04999 level of significance for the final analysis, we anticipated 79 shedding cessation events, which provided 80% power to detect a hazard ratio of 2.03.

Table 2: Resources

Software and Algorithms
Sentences	Resources
Study Design: We conducted a Phase 2, double-blind, randomized, placebo-controlled phase 2 trial at Stanford Healthcare, California. Stanford University School of Medicine Panel on Human Subjects in Medical Research approved the study protocol.	Stanford Healthcare suggested: None
Patients self-collected daily anterior nasal swabs on days 1-10, 14, 21, and 28 and submitted them directly for RT-PCR testing with an assay that targeted the viral nucleocapsid gene’s N1 and N3 regions (Quest Diagnostics, Secaucus, New Jersey).	Quest suggested: (QUEST, RRID:SCR_005210)
Patients also completed electronic daily symptom surveys and recorded temperature and oxygen saturation using study-provided devices; all data was collected using REDCap Cloud version 1.6 (REDCap Cloud, Encinitas, California).	REDCap suggested: (REDCap, RRID:SCR_003445)

Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

Of note, in vitro data suggests molnupiravir may also be mutagenic to mammalian cells.[19] Animal studies suggest that favipiravir administered in combination with molnupiravir may be an effective strategy to allow for lower molnupiravir doses and potentially avoid unintended consequences.[20] Our study has several limitations. Most therapeutic studies for COVID-19, like ours, assess antiviral efficacy by using RT-PCR to detect viral RNA from nasal, nasopharyngeal or oropharyngeal swabs. However, detectable RNA may not reflect actively replicating virus and individuals can continue to have detectable RNA intermittently and long after illness recovery.[21] Widespread use of cell culture to detect replication-competent virus and to establish viral clearance is limited by feasibility, cost, and safety considerations.[21] Although we use cycle threshold rather than viral load, our analysis was strengthened by serial testing from individuals. Our primary endpoint was based upon participant-collected nasal swabs, which may be less accurate than nasopharyngeal swabs.[22] However, we found similar results from a secondary analysis of study staff collected oropharyngeal swabs. Our study was powered to detect differences in shedding cessation, not symptom resolution. Our study was not designed to detect a difference in long COVID syndrome, but we found that nearly half of both favipiravir and placebo-treated patients continued to report symptoms 28-day after enrollment. Finally, our st...

Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

Identifier	Status	Title
NCT04346628	Completed	Oral Favipiravir Compared to Placebo in Subjects With Mild C…

Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

Results from JetFighter: We did not find any issues relating to colormaps.

Results from rtransparent:

Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
No protocol registration statement was detected.

Results from scite Reference Check: We found no unreliable references.

Read the original source