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.

The following data sets were generated
    1. Watson
    2. J
    (2022) PLATCOV Ivermectin
    https://github.com/jwatowatson/PLATCOV-Ivermectin.

Article and author information

Author details

  1. William HK Schilling

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    For correspondence
    william@tropmedres.ac
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6328-8748
  2. Podjanee Jittamala

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  3. James A Watson

    Nuffield Department of Medicine, Oxford University Clinical Research Unit, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5524-0325
  4. Maneerat Ekkapongpisit

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  5. Tanaya Siripoon

    Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  6. Thundon Ngamprasertchai

    Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  7. Viravarn Luvira

    Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9270-3720
  8. Sasithorn Pongwilai

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  9. Cintia Valeria Cruz

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8393-8536
  10. James J Callery

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3218-2166
  11. Simon Boyd

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  12. Varaporn Kruabkontho

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  13. Thatsanun Ngernseng

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  14. Jaruwan Tubprasert

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  15. Mohammad Yazid Abdad

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  16. Nattaporn Piaraksa

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  17. Kanokon Suwannasin

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  18. Pongtorn Hanboonkunupakarn

    Bangplee Hospital, Ministry of Public Health, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  19. Borimas Hanboonkunupakarn

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  20. Sakol Sookprome

    Bangplee Hospital, Ministry of Public Health, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  21. Kittiyod Poovorawan

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  22. Janjira Thaipadungpanit

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6184-3381
  23. Stuart Blacksell

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  24. Mallika Imwong

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  25. Joel Tarning

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4566-4030
  26. Walter RJ Taylor

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  27. Vasin Chotivanich

    Faculty of Medicine, Navamindradhiraj University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  28. Chunlanee Sangketchon

    Faculty of Science and Health Technology, Navamindradhiraj University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  29. Wiroj Ruksakul

    Faculty of Medicine, Navamindradhiraj University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  30. Kesinee Chotivanich

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  31. Mauro Martins Teixeira

    Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
    Competing interests
    Mauro Martins Teixeira, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6944-3008
  32. Sasithon Pukrittayakamee

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  33. Arjen M Dondorp

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5190-2395
  34. Nicholas PJ Day

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2309-1171
  35. Watcharapong Piyaphanee

    Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  36. Weerapong Phumratanaprapin

    Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand
    Competing interests
    No competing interests declared.
  37. Nicholas J White

    Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
    For correspondence
    nickw@tropmedres.ac
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1897-1978

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

  • 6,327
    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)

  1. William HK Schilling
  2. Podjanee Jittamala
  3. James A Watson
  4. Maneerat Ekkapongpisit
  5. Tanaya Siripoon
  6. Thundon Ngamprasertchai
  7. Viravarn Luvira
  8. Sasithorn Pongwilai
  9. Cintia Valeria Cruz
  10. James J Callery
  11. Simon Boyd
  12. Varaporn Kruabkontho
  13. Thatsanun Ngernseng
  14. Jaruwan Tubprasert
  15. Mohammad Yazid Abdad
  16. Nattaporn Piaraksa
  17. Kanokon Suwannasin
  18. Pongtorn Hanboonkunupakarn
  19. Borimas Hanboonkunupakarn
  20. Sakol Sookprome
  21. Kittiyod Poovorawan
  22. Janjira Thaipadungpanit
  23. Stuart Blacksell
  24. Mallika Imwong
  25. Joel Tarning
  26. Walter RJ Taylor
  27. Vasin Chotivanich
  28. Chunlanee Sangketchon
  29. Wiroj Ruksakul
  30. Kesinee Chotivanich
  31. Mauro Martins Teixeira
  32. Sasithon Pukrittayakamee
  33. Arjen M Dondorp
  34. Nicholas PJ Day
  35. Watcharapong Piyaphanee
  36. Weerapong Phumratanaprapin
  37. Nicholas J White
  38. on behalf of the PLATCOV Collaborative Group
(2023)
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

Share this article

https://doi.org/10.7554/eLife.83201

Further reading

    1. Immunology and Inflammation
    2. Medicine
    Haiyi Fei, Xiaowen Lu ... Lingling Jiang
    Research Article

    Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RACCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3CCR7+HeliosCD127CD8+) and pro-inflam Macs (CD206CD163CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206 pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.

    1. Medicine
    Gabriel O Heckerman, Eileen Tzng ... Adrienne Mueller
    Research Article

    Background: Several fields have described low reproducibility of scientific research and poor accessibility in research reporting practices. Although previous reports have investigated accessible reporting practices that lead to reproducible research in other fields, to date, no study has explored the extent of accessible and reproducible research practices in cardiovascular science literature.

    Methods: To study accessibility and reproducibility in cardiovascular research reporting, we screened 639 randomly selected articles published in 2019 in three top cardiovascular science publications: Circulation, the European Heart Journal, and the Journal of the American College of Cardiology (JACC). Of those 639 articles, 393 were empirical research articles. We screened each paper for accessible and reproducible research practices using a set of accessibility criteria including protocol, materials, data, and analysis script availability, as well as accessibility of the publication itself. We also quantified the consistency of open research practices within and across cardiovascular study types and journal formats.

    Results: We identified that fewer than 2% of cardiovascular research publications provide sufficient resources (materials, methods, data, and analysis scripts) to fully reproduce their studies. Of the 639 articles screened, 393 were empirical research studies for which reproducibility could be assessed using our protocol, as opposed to commentaries or reviews. After calculating an accessibility score as a measure of the extent to which an article makes its resources available, we also showed that the level of accessibility varies across study types with a score of 0.08 for Case Studies or Case Series and 0.39 for Clinical Trials (p = 5.500E-5) and across journals (0.19 through 0.34, p = 1.230E-2). We further showed that there are significant differences in which study types share which resources.

    Conclusion: Although the degree to which reproducible reporting practices are present in publications varies significantly across journals and study types, current cardiovascular science reports frequently do not provide sufficient materials, protocols, data, or analysis information to reproduce a study. In the future, having higher standards of accessibility mandated by either journals or funding bodies will help increase the reproducibility of cardiovascular research.

    Funding: Authors Gabriel Heckerman, Arely Campos-Melendez, and Chisomaga Ekwueme were supported by an NIH R25 grant from the National Heart, Lung and Blood Institute (R25HL147666). Eileen Tzng was supported by an AHA Institutional Training Award fellowship (18UFEL33960207).