Study design

We performed a randomised placebo-controlled phase 2 trial of favipiravir versus matched placebo ({"type":"clinical-trial","attrs":{"text":"NCT04445467","term_id":"NCT04445467"}}NCT04445467) in individuals infected with COVID-19.¹¹ The study was approved by the Alfred Ethics Committee (No 406/20) and all participants provided informed consent. The trial was overseen by an independent safety monitoring committee (SMC). Eligible participants with confirmed COVID-19 were randomised 1:1 to favipiravir or placebo for 14 days in addition to standard of care. Participants were recruited from July 2020 to September 2021 and were followed for a minimum of 28 days. Participants could be either in the community or a hospital inpatient at time of recruitment.

The sample size calculation was based on estimates from two studies available prior to the trial commencing.^9,10 One randomised trial of 236 patients reported 61% of people receiving favipiravir compared to 52% of people receiving umifenovir met the primary clinical recovery endpoint by day 7.¹⁰ In a non-randomised study of 80 people (subsequently retracted), 90% of the favipiravir group achieved viral clearance compared to 57% of those on lopinavir/ritonavir, with a significantly faster rate of clearance in patients who received favipiravir (Hazard Ratio (HR) 3.43, 95% CI 1.16 to 10.1).⁹ We assumed 80% of patients on favipiravir and 60% of patients in the placebo arm would reach virological cure with twice as fast a rate of cure occurring in the favipiravir arm (HR 2.0). Assuming an alpha of 0.05, 86 participants in each arm would allow a log rank comparison with 80% power. Allowing for 10% lost to follow-up, we aimed to recruit 190 participants.

Favipiravir dosing was based on a 50% effective concentration or EC₅₀ of 61.88 μM (9.7 μg/ml) in vitro⁸ and the knowledge that mean daily trough levels over 20 μg/ml are achieved with the same dosing proposed in this trial.¹² Participants were given 1800 mg of favipiravir twice daily on Day 1 followed by 800 mg twice daily or identical placebo tablets. Duration of dosing was 14 days based on reports from available published trials at study initiation.^9,10