Pharmacometrics of high-dose ivermectin in early COVID-19 from an open label, randomized, controlled adaptive platform trial (PLATCOV)

Abstract

Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has clinically 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 oral ivermectin (600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population (mITT). This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. 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. Following ivermectin the mean estimated rate of SARS-CoV-2 viral clearance was 9.1% slower [95%CI -27.2% to +11.8%; n=45] than in the no drug arm [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. Pharmacometric evaluation of viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a highly efficient and well tolerated method of assessing SARS CoV-2 antiviral 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 supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.Clinical trial number: ClinicalTrials.gov (NCT05041907).

Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV)

“…Under the linear model analysing viral clearance rates over 7 days, the meta-analysis including all unblinded drugs (not concurrently randomised) and adjusting for calendar time and viral variants, estimated that fluoxetine increased viral clearance by 16% (95% CrI 3 to 32%) compared to the no study drug group (Figure 4). Fluoxetine treatment resulted in a higher viral clearance rate than two interventions previously reported to have no clinical antiviral effect; ivermectin 25 and favipiravir. 27 The treatment effect of fluoxetine was lower than that of casirivimab/imdevimab, 26 remdesivir, 26 molnupiravir, 2 and substantially lower than ritonavirboosted nirmatrelvir, 2 with the probabilities of 0.88, 0.94, 0.98, and 1.00, respectively.…”

“…Initially, the following drugs were studied: ivermectin, favipiravir, remdesivir, and casirivimab/imdevimab (monoclonal antibody cocktail). These groups have already reached the prespecified stopping rules for efficacy or lack of efficacy and so have been stopped 2,[25][26][27] . Additional groups; ensitrelvir, molnupiravir, ritonavirboosted nirmatrelvir, and the tixagevimab/cilgavimab monoclonal antibody cocktail, were introduced later.…”

“…Further information on how to apply is found here: https://www.tropmedres.ac/units/morubangkok/bioethics-engagement/data-sharing. 25…”

“…The PLATCOV trial methodology can evaluate antiviral activity rapidly and compare available treatments quantitatively. 2,[25][26][27] Here we report the results for fluoxetine and contextualise this by pooling all unblinded data from the platform and comparing fluoxetine with the other assessed antiviral interventions.…”

Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a randomised, controlled, adaptive platform study (PLATCOV)

“…An alternative approach is to use rates of in-vivo viral clearance to characterise and compare antiviral efficacies [12]. This is relatively straightforward and requires orders of magnitude fewer patients [13]. PLATCOV is an ongoing multicentre phase 2 adaptive, open label, randomised, pharmacometric platform trial in symptomatic low risk adults with COVID-19 (NCT05041907) [13].…”