Pharmacometric assessment of the in vivo antiviral activity of ivermectin in early symptomatic COVID-19

  1. William HK Schilling
  2. Podjanee Jittamala
  3. James A Watson
  4. Maneerat Ekkapongpisit
  5. Tanaya Siripoon
  6. Thundon Ngamprasertchai
  7. Viravarn Luvira
  8. Sasithon Pongwilai
  9. Cintia 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 M Teixeira
  32. Sasithon Pukrittayakamee
  33. Arjen M Dondorp
  34. Nicholas PJ Day
  35. Watcharapong Piyaphanee
  36. Weerapong Phumratanaprapin
  37. Nicholas J White
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Abstract

Background

There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infection. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has 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 ivermectin (600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. Viral clearance rates were derived from daily duplicate oropharyngeal quantitative PCR measurements. This ongoing trial is registered at <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</ext-link> ( <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT05041907">NCT05041907</ext-link> ).

Results

Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Compared with the no study drug arm, the mean estimated SARS-CoV-2 viral clearance following ivermectin was 9.1% slower [95%CI -27.2% to +11.8%; n=45 versus 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. Measured in this way viral clearance rate is a valuable pharmacodynamic measure in assessing antiviral COVID-19 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 funded by the Wellcome Therapeutics Accelerator (223195/Z/21/Z).

Impact

  • Rate of viral clearance determined from daily duplicate oropharyngeal swabs over one week is an efficient measure of antiviral efficacy in early COVID-19 infection.

  • High dose ivermectin did not demonstrate measurable antiviral activity in early symptomatic COVID-19 infection.

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