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.
-
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.
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.
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.
Metrics
-
- 6,348
- views
-
- 265
- downloads
-
- 12
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Medicine
- Neuroscience
Monomethyl fumarate (MMF) and its prodrug dimethyl fumarate (DMF) are currently the most widely used agents for the treatment of multiple sclerosis (MS). However, not all patients benefit from DMF. We hypothesized that the variable response of patients may be due to their diet. In support of this hypothesis, mice subjected to experimental autoimmune encephalomyelitis (EAE), a model of MS, did not benefit from DMF treatment when fed a lauric acid-rich (LA) diet. Mice on normal chow (NC) diet, in contrast, and even more so mice on high-fiber (HFb) diet showed the expected protective DMF effect. DMF lacked efficacy in the LA diet-fed group despite similar resorption and preserved effects on plasma lipids. When mice were fed the permissive HFb diet, the protective effect of DMF treatment depended on hydroxycarboxylic receptor 2 (HCAR2) which is highly expressed in neutrophil granulocytes. Indeed, deletion of Hcar2 in neutrophils abrogated DMF protective effects in EAE. Diet had a profound effect on the transcriptional profile of neutrophils and modulated their response to MMF. In summary, DMF required HCAR2 on neutrophils as well as permissive dietary effects for its therapeutic action. Translating the dietary intervention into the clinic may improve MS therapy.
-
- Medicine
- Neuroscience
Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selected zizyphi spinosi semen (ZSS), a medicinal herb used in traditional Chinese medicine. Oral administration of ZSS hot water extract ameliorated Aβ and tau pathology and cognitive impairment in mouse models of Alzheimer’s disease and frontotemporal dementia. Non-extracted ZSS simple crush powder showed stronger effects than the extract and improved α-synuclein pathology and cognitive/motor function in Parkinson’s disease model mice. Furthermore, when administered to normal aged mice, the ZSS powder suppressed cellular senescence, reduced DNA oxidation, promoted brain-derived neurotrophic factor expression and neurogenesis, and enhanced cognition to levels similar to those in young mice. The quantity of known active ingredients of ZSS, jujuboside A, jujuboside B, and spinosin was not proportional to the nootropic activity of ZSS. These results suggest that ZSS simple crush powder is a promising dietary material for the prevention of neurodegenerative diseases and brain aging.
