Pragmatic design
The study design has been described in detail elsewhere [The ambition was to obtain a rapid efficacy readout for these promising drugs to address the healthcare emergency. Only favipiravir had been tested in COVID-19 patients in two hospital-based studies [An open-label design was necessary as matched placebos could not be sourced during a pandemic. Also, the high pill burden would increase complexity and undermine adherence. As our study was not designed to compare investigational arms but to compare each of the four parallel arms to a single SOC arm, and as there was an objective endpoint, there was little advantage to a blinded design [A low-risk patient population was targeted, aged ≥ 18 to ≤ 65 years and with mild-to-moderate symptoms [An objective primary endpoint was needed to drive efficiency of sample size. Virological clearance at day 7 was considered a feasible endpoint. At the time of study initiation, our opinion was that reliable data could be obtained as community-based reverse transcription polymerase chain reaction (RT-PCR) testing for confirmation of SARS-CoV-2-positivity had been rapidly adopted and expanded in South Africa [Published evidence suggesting that 20% of patients would have viral clearance at day 7 in the SOC arm, increasing to 50% with effective drug therapy, was used for power and sample size calculation [