Abstract: Journal Pre-proof
Ivermectin and COVID-19
Christopher C Butler, F D Richard Hobbs
Paul Little
Duncan Richards
Benjamin R Saville
Ly-Mee Yu
For the PRINCIPLE Trial Collaborative Group
PII:
S0163-4453(25)00124-0
DOI:
https://doi.org/10.1016/j.jinf.2025.106530
Reference:
YJINF106530
To appear in: Journal of Infection
Please cite this article as: Christopher C Butler, F D Richard Hobbs, Paul Little,
Duncan Richards, Benjamin R Saville, Ly-Mee Yu and For the PRINCIPLE
Trial Collaborative Group, Ivermectin and COVID-19, Journal of Infection,
(2025) doi:https://doi.org/10.1016/j.jinf.2025.106530
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© 2025 Published by Elsevier Ltd on behalf of The British Infection Association.
Ivermectin and COVID-19
Authors
Christopher C Butler (1)
F D Richard Hobbs (1)
Paul Little (2)
Duncan Richards (3)
of
Benjamin R Saville (4)
For the PRINCIPLE Trial Collaborative Group
ro
Ly-Mee Yu (1)
lP
re
-p
1. Nuffield Department of Primary Care Health Sciences, University of Oxford,
Oxford, UK ( Prof CC Butler FMedSci, Prof FDR Hobbs FMedSci, Prof Ly-Mee Yu
PhD)
2. Primary Care Research Centre, University of Southampton (Prof P Little FMedSci)
3. Oxford Clinical Trials Research Unit, Botnar Research Centre, University of
Oxford, Oxford, UK (Prof D Richards FRCP)
4 Berry Consultants, Austin, Texas, USA, and Department of Biostatistics, Vanderbilt
University School of Medicine, Tennessee, USA (Benjamin R Saville PhD)
Jo
u
rn
a
Corresponding author:
Professors Christopher C Butler, FD Richard Hobbs
Address: Nuffield Department of Primary Care Health Sciences, University of Oxford,
Gibson Building 1st Floor, Radcliffe Observatory Quarter, Woodstock Road, Oxford,
OX2 6GG
Email: christopher.butler@phc.ox.ac.uk
Telephone: +44 (0)1865 289670
Dear Editor,
Fordham and colleagues are correct that, as we reported, the PRINCIPLE Trial found
statistically significant differences time taken for recovery between those randomised to
receive usual care plus ivermectin versus usual care alone.(1) However, we disagree that our
conclusion that the magnitude of this difference was not clinically meaningful, is arbitrary
and unsupported by our data.(2) The authors are correct that the meaningful effect
threshold of 1.2 was defined in the context of a futility rule. It was pre-specified that if the
true HR was unlikely to exceed 1.2, the treatment was unlikely to provide clinically
meaningful benefit and the study would be considered futile. This pre-specified effect size
can and should be used to help interpret the magnitude of estimated benefit in the context
of “statistical significance”. It is widely known that large sample sizes can lead to statistically
significant results that lack clinical meaning. In addition, the American Statistical Association
has warned against drawing scientific conclusions or making policy decisions based on p-
values or “statistical significance” alone.(3) Hence, one should..
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