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

William H K 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 R J Taylor; Vasin Chotivanich; Chunlanee Sangketchon; Wiroj Ruksakul; Kesinee Chotivanich; Mauro Martins Teixeira; Sasithon Pukrittayakamee; Arjen M Dondorp; Nicholas P J Day; Watcharapong Piyaphanee; Weerapong Phumratanaprapin; Nicholas J White; PLATCOV Collaborative Group

doi:10.7554/eLife.83201

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

Elife. 2023 Feb 21:12:e83201. doi: 10.7554/eLife.83201.

Authors

William H K Schilling^#^{1

2}, Podjanee Jittamala^#^{1

3}, James A Watson^{1

2}, Maneerat Ekkapongpisit¹, Tanaya Siripoon⁴, Thundon Ngamprasertchai⁴, Viravarn Luvira⁴, Sasithorn Pongwilai¹, Cintia Cruz^{1

2}, James J Callery^{1

2}, Simon Boyd^{1

2}, Varaporn Kruabkontho¹, Thatsanun Ngernseng¹, Jaruwan Tubprasert¹, Mohammad Yazid Abdad^{1

2}, Nattaporn Piaraksa¹, Kanokon Suwannasin¹, Pongtorn Hanboonkunupakarn⁵, Borimas Hanboonkunupakarn^{1

4}, Sakol Sookprome⁵, Kittiyod Poovorawan^{1

4}, Janjira Thaipadungpanit^{1

4}, Stuart Blacksell^{1

2}, Mallika Imwong^{1

6}, Joel Tarning^{1

2}, Walter R J Taylor^{1

2}, Vasin Chotivanich⁷, Chunlanee Sangketchon⁸, Wiroj Ruksakul⁷, Kesinee Chotivanich^{1

4}, Mauro Martins Teixeira⁹, Sasithon Pukrittayakamee^{1

4}, Arjen M Dondorp^{1

2}, Nicholas P J Day^{1

2}, Watcharapong Piyaphanee⁴, Weerapong Phumratanaprapin⁴, Nicholas J White^{1

2}; PLATCOV Collaborative Group

Collaborator

PLATCOV Collaborative Group:
On Behalf Of The Platcov Collaborative Group

Affiliations

¹ Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
² Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom.
³ Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
⁴ Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
⁵ Bangplee Hospital, Ministry of Public Health, Bangkok, Thailand.
⁶ Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
⁷ Faculty of Medicine, Navamindradhiraj University, Bangkok, Thailand.
⁸ Faculty of Science and Health Technology, Navamindradhiraj University, Bangkok, Thailand.
⁹ Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

^# Contributed equally.

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 (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.

Keywords: COVID-19; antivirals; bayesian hierarchical linear regression; human; medicine; pharmacometric assessment; rate of viral clearance.

Publication types

Randomized Controlled Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antiviral Agents / therapeutic use
COVID-19*
Humans
Ivermectin / therapeutic use
SARS-CoV-2
Treatment Outcome

Substances

Ivermectin
Antiviral Agents

Supplementary concepts

SARS-CoV-2 variants

Associated data