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Background: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. Methods: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome assessed in a modified intention-to-treat population (mITT) was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial is registered at ClinicalTrials.gov (NCT05041907). Results: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients administered favipiravir and patients receiving no study drug -1% (95% CI: -14 to 14% change). High dose favipiravir was well tolerated. Interpretation: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19.

BackgroundUncertainty over the therapeutic benefit provided by parenteral remdesivir in COVID-19 has resulted in varying treatment guidelines. Early in the pandemic the monoclonal antibody cocktail, casirivimab/imdevimab, proved highly effective in clinical trials but because of weak or absentin vitroactivity against the SARS-CoV-2 Omicron BA.1 subvariant, it is no longer recommended.MethodsIn a multicenter open label, randomized, controlled adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to one of eight treatment arms including intravenous remdesivir (200mg followed by 100mg daily for five days), casirivimab/imdevimab (600mg/600mg), and no study drug. The primary outcome was the viral clearance rate in the modified intention-to-treat population derived from daily log10viral densities (days 0-7) in standardized duplicate oropharyngeal swab eluates. This ongoing adaptive trial is registered atClinicalTrials.gov(NCT05041907).ResultsAcceleration in mean estimated SARS-CoV-2 viral clearance, compared with the contemporaneous no study drug arm (n=64), was 42% (95%CI 18 to 73%) for remdesivir (n=67). Acceleration with casirivimab/imdevimab was 58% (95%CI: 10 to 120) in Delta (n=13), and 20% (95%CI: 3 to 43) in Omicron variant (n=61) infections compared with contemporaneous no study drug arm (n=84). In apost hocsubgroup analysis viral clearance was accelerated by 8% in BA.1 (95%CI: −21 to 59) and 23% (95%CI: 3 to 49) in BA.2 and BA.5 Omicron subvariants.ConclusionsParenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Despite substantially reducedin vitroactivities, casirivimab/imdevimab retainsin vivoantiviral activity against COVID-19 infections caused by currently prevalent Omicron subvariants.Brief summaryIn early symptomatic COVID-19 remdesivir accelerated viral clearance by 42% while the monoclonal antibody cocktail casirivimab/imdevimab accelerated clearance by approximately 60% in SARS-CoV-2 Delta variant infections, and by approximately 25% in infections with Omicron subvariants BA.2 and BA.5.

BackgroundThere is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infection. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has significant antiviral activity in vivo is uncertain.MethodsIn a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high dose ivermectin (600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. Viral clearance rates were derived from daily duplicate oropharyngeal quantitative PCR measurements. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907).ResultsRandomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Compared with the no study drug arm, the mean estimated SARS-CoV-2 viral clearance following ivermectin was 9.1% slower [95%CI -27.2% to +11.8%; n=45 versus n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus n=41].ConclusionsHigh dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Measured in this way viral clearance rate is a valuable pharmacodynamic measure in assessing antiviral COVID-19 therapeutics in vivo.Funding“Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)” is funded by the Wellcome Therapeutics Accelerator (223195/Z/21/Z).ImpactRate of viral clearance determined from daily duplicate oropharyngeal swabs over one week is an efficient measure of antiviral efficacy in early COVID-19 infection.High dose ivermectin did not demonstrate measurable antiviral activity in early symptomatic COVID-19 infection.