When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Reliable Conclusions: Three Examples
Scheim et al.,
When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw..,
Journal of Clinical Medicine, doi:10.3390/jcm12113625 (meta analysis)
Analysis of PP vs. ITT results in three RCTs, including discussion of multiple critical issues with the ivermectin arm of the TOGETHER trial
[Reis]:
- conflicting and inconsistent decreases in PP vs. ITT groups between different tables and between the treatment and control arms
- refusal to release per-protocol mortality and hospitalization results although they were reported for fluvoxamine and their importance was emphasized by coauthor Dr. Boulware
- false statements and ethical violations regarding the availability of the data
- blinding failure with placebo patients that received an injection
- censorship of scientists reporting issues with the trial
- conflicting descriptions of the placebo group
- continued refusal to release the data
- problems with mixed-day placebos
Currently there are
97 ivermectin studies and meta analysis shows:
Scheim et al., 23 May 2023, Australia, peer-reviewed, 5 authors.
Contact:
dscheim@alum.mit.edu (corresponding author).
Abstract: Journal of
Clinical Medicine
Opinion
When Characteristics of Clinical Trials Require Per-Protocol as
Well as Intention-to-Treat Outcomes to Draw Reliable
Conclusions: Three Examples
David E. Scheim 1, * , Colleen Aldous 2 , Barbara Osimani 3 , Edmund J. Fordham 4
1
2
3
4
5
*
Citation: Scheim, D.E.; Aldous, C.;
Osimani, B.; Fordham, E.J.; Hoy, W.E.
When Characteristics of Clinical
and Wendy E. Hoy 5
US Public Health Service, Commissioned Corps, Inactive Reserve, Blacksburg, VA 24060, USA
College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa
Center for Philosophy, Science, and Policy, Faculty of Medicine, Marche Polytechnic University,
60121 Ancona, Italy
EbMCsquared CIC, Bath BA2 4BL, UK
Centre of Chronic Disease, Faculty of Medicine, University of Queensland, Brisbane 4072, Australia
Correspondence: dscheim@alum.mit.edu
Abstract: Under exceptional circumstances, including high rates of protocol non-compliance, perprotocol (PP) analysis can better indicate the real-world benefits of a medical intervention than
intention-to-treat (ITT) analysis. Exemplifying this, the first randomized clinical trial (RCT) considered
found that colonoscopy screenings were marginally beneficial, based upon ITT analysis, with only
42% of the intervention group actually undergoing the procedure. However, the study authors
themselves concluded that the medical efficacy of that screening was a 50% reduction in colorectal
cancer deaths among that 42% PP group. The second RCT found a ten-fold reduction in mortality
for a COVID-19 treatment drug vs. placebo by PP analysis, but only a minor benefit by ITT analysis.
The third RCT, conducted as an arm of the same platform trial as the second RCT, tested another
COVID-19 treatment drug and reported no significant benefit by ITT analysis. Inconsistencies and
irregularities in the reporting of protocol compliance for this study required consideration of PP
outcomes for deaths and hospitalizations, yet the study coauthors refused to disclose them, instead
directing inquiring scientists to a data repository which never held the study’s data. These three
RCTs illustrate conditions under which PP outcomes may differ significantly from ITT outcomes and
the need for data transparency when these reported or indicated discrepancies arise.
Trials Require Per-Protocol as Well as
Intention-to-Treat Outcomes to Draw
Keywords: intention-to-treat; per-protocol; colonoscopy; fluvoxamine; ivermectin; COVID-19
Reliable Conclusions: Three
Examples. J. Clin. Med. 2023, 12, 3625.
https://doi.org/10.3390/jcm12113625
Academic Editor:
Giuseppe Migliaretti
Received: 4 April 2023
Revised: 10 May 2023
Accepted: 19 May 2023
Published: 23 May 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
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