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

Autor: Schilling, WHK, Jittamala, P, Watson, JA, Ekkapongpisit, M, Siripoon, T, Ngamprasertchai, T, Luvira, V, Pongwilai, S, Cruz, CV, Callery, JJ, Boyd, S, Kruabkontho, V, Ngernseng, T, Tubprasert, J, Abdad, MY, Piaraksa, N, Suwannasin, K, Hanboonkunupakarn, P, Hanboonkunupakarn, B, Sookprome, S, Poovorawan, K, Thaipadungpanit, J, Blacksell, S, Imwong, M, Tarning, J, Taylor, WRJ, Chotivanich, V, Sangketchon, C, Ruksakul, W, Chotivanich, K, Teixeira, MM, Pukrittayakamee, S, Dondorp, AM, Day, NPJ, Piyaphanee, W, Phumratanaprapin, W, White, NJ
Přispěvatelé: Group, PLATCOV Collaborative
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Popis: 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 (600 µg/kg daily for 7 days), the monoclonal antibodies casirivimab and imdevimab (600 mg/600 mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population. This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. This ongoing trial is registered at https://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% confidence interval [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) vs. 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 vitro.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:NCT05041907.
Databáze: OpenAIRE