Pharmacometrics of high dose ivermectin in early COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV)
- Mahidol University, Thailand
- Oxford University Clinical Research Unit, United Kingdom
- Ministry of Public Health, Thailand
- Navamindradhiraj University, Thailand
- Universidade Federal de Minas Gerais, Brazil
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).
Data availability
All code and data are openly accessible via GitHub: https://github.com/jwatowatson/PLATCOV-IvermectinSequencing data have been deposited in GISAID.
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PLATCOV Ivermectinhttps://github.com/jwatowatson/PLATCOV-Ivermectin.
Article and author information
Author details
William HK Schilling
Cintia Valeria Cruz
Janjira Thaipadungpanit
Mauro Martins Teixeira
Funding
Wellcome Trust (223195/Z/21/Z)
- Nicholas J White
Wellcome Trust (223195/Z/21/Z)
- William HK Schilling
Wellcome Trust (223195/Z/21/Z)
- William HK Schilling
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Joshua T Schiffer, Fred Hutchinson Cancer Research Center, United States
Ethics
Human subjects: The trial was approved by local and national research ethics boards in Thailand (Faculty of Tropical Medicine Ethics Committee, Mahidol University, FTMEC Ref: TMEC 21-058) and the Central Research Ethics Committee (CREC, Bangkok, Thailand, CREC Ref: CREC048/64BP-MED34) and by the Oxford University Tropical Research Ethics Committee (OxTREC, Oxford, UK, OxTREC Ref: 24-21). All patients provided fully informed written consent.
Version history
- Preprint posted: July 19, 2022 (view preprint)
- Received: September 2, 2022
- Accepted: February 3, 2023
- Accepted Manuscript published: February 21, 2023 (version 1)
- Version of Record published: March 6, 2023 (version 2)
- Version of Record updated: June 14, 2023 (version 3)
Copyright
© 2023, Schilling et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Pharmacometrics of high dose ivermectin in early COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV)
eLife 12:e83201.
https://doi.org/10.7554/eLife.83201
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