eLife (Feb 2023)

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

  • William HK Schilling,
  • Podjanee Jittamala,
  • James A Watson,
  • Maneerat Ekkapongpisit,
  • Tanaya Siripoon,
  • Thundon Ngamprasertchai,
  • Viravarn Luvira,
  • Sasithorn Pongwilai,
  • Cintia Cruz,
  • James J Callery,
  • Simon Boyd,
  • Varaporn Kruabkontho,
  • Thatsanun Ngernseng,
  • Jaruwan Tubprasert,
  • Mohammad Yazid Abdad,
  • Nattaporn Piaraksa,
  • Kanokon Suwannasin,
  • Pongtorn Hanboonkunupakarn,
  • Borimas Hanboonkunupakarn,
  • Sakol Sookprome,
  • Kittiyod Poovorawan,
  • Janjira Thaipadungpanit,
  • Stuart Blacksell,
  • Mallika Imwong,
  • Joel Tarning,
  • Walter RJ Taylor,
  • Vasin Chotivanich,
  • Chunlanee Sangketchon,
  • Wiroj Ruksakul,
  • Kesinee Chotivanich,
  • Mauro Martins Teixeira,
  • Sasithon Pukrittayakamee,
  • Arjen M Dondorp,
  • Nicholas PJ Day,
  • Watcharapong Piyaphanee,
  • Weerapong Phumratanaprapin,
  • Nicholas J White,
  • on behalf of the PLATCOV Collaborative Group

DOI
https://doi.org/10.7554/eLife.83201
Journal volume & issue
Vol. 12

Abstract

Read online

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 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: NCT05041907.

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