Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of phase 2 antiviral studies (preprint)

BackgroundEffective antiviral drugs prevent hospitalisation and death in COVID-19. Antiviral efficacy can be assessed efficiently in-vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral densities measured in nasopharyngeal or oropharyngeal swab eluates. The changing epidemiology of SARS-CoV-2 infection has substantially affected viral clearance kinetics and thus the optimal design and interpretation of antiviral pharmacometric evaluations. MethodsSerial viral density data were analysed from patients enrolled in a large multicentre randomised adaptive pharmacodynamic platform trial (PLATCOV) comparing antiviral interventions for SARS-CoV-2. Viral clearance rates over one week were estimated and boot-strap re-sampling was used to assess the optimal duration of follow-up for pharmacometric assessment, where optimal is defined as maximising the expected z-score. ResultsBetween 29 September 2021 and 20 October 2023, 1264 patients were randomised. Unblinded data were available from 800 patients (16,818 oropharyngeal viral qPCR measurements). SARS-CoV-2 viral clearance was biphasic (bi-exponential). The first phase () was accelerated by effective interventions. For all the effective interventions studied, maximum discriminative power (maximum expected z-score) was obtained when evaluating serial data from the first 5 days after enrolment. Over the two year period studied, median viral clearance half-lives estimated over 7 days have shortened from 16.8 hours in September 2021 to 9.3 hours in October 2023 in patients receiving no antiviral drugs, equivalent to a relative reduction of 44% [95% credible interval (CrI): 17 to 67%]. A parallel trend was observed in treated patients. In the ritonavir-boosted nirmatrelvir arm the median clearance half-life declined from 6.6 hours in June 2022 to 4.8 hours in October 2023, a relative reduction of 26% [95%CrI: -4 to 42%]. ConclusionsSARS-CoV-2 viral clearance kinetics in symptomatic vaccinated individuals have accelerated substantially over the past two years. Antiviral efficacy in COVID-19 can now be assessed efficiently in-vivo using serial qPCRs from duplicate oropharyngeal swab eluates taken daily for 5 days after drug administration. FundingWellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.

Pharmacometric assessment of the in-vivo antiviral activity of ivermectin in early symptomatic COVID-19 (preprint)

Background: There 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. Methods: In 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 (600micrograms/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). Results: Randomization 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]. Conclusions: High dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Measured in this way viral clearance rate is a valuable