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When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Reliable Conclusions: Three Examples

Scheim et al., Journal of Clinical Medicine, doi:10.3390/jcm12113625
May 2023  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now known with p < 0.00000000001 from 102 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
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
7 meta analyses show significant improvements with ivermectin for mortality Bryant, Hariyanto, Kory, Lawrie, Nardelli, Zein, hospitalization Schwartz, recovery Kory, and cases Kory.
Currently there are 102 ivermectin for COVID-19 studies, showing 49% lower mortality [35‑60%], 29% lower ventilation [12‑42%], 35% lower ICU admission [7‑54%], 34% lower hospitalization [20‑45%], and 81% fewer cases [71‑87%].
Scheim et al., 23 May 2023, Australia, peer-reviewed, 5 authors. Contact: (corresponding author).
This PaperIvermectinAll
When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Reliable Conclusions: Three Examples
David E Scheim, Colleen Aldous, Barbara Osimani, Edmund J Fordham, Wendy E Hoy
Journal of Clinical Medicine, doi:10.3390/jcm12113625
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.
Author Contributions: Methodology, B.O., C.A., E.J.F., D.E.S. and W.E.H.; formal analysis, D.E.S. and E.J.F.; writing-original draft preparation, D.E.S.; writing-review and editing, B.O., C.A., E.J.F., D.E.S. and W.E.H.; All authors have read and agreed to the published version of the manuscript. Conflicts of Interest: The authors declare no conflict of interest. Abbreviations The The DSS of the study as published on this date promised access to its "complete de-identified data set" at the ICODA data repository beginning "immediately after publication" [26] . 10 May 2022. A letter from 66 scientists and physicians requesting the study's four outcome numbers of key importance, PP death and hospitalization rates, IVM vs. placebo, was emailed to study coauthors, and copied to 39 scientists and science journalists [24] . 10 May 2022. TOGETHER trial coauthor David Boulware replied, declining to provide those outcome numbers and directing the letter signatories to the ICODA data repository [25] . 7 June 2022. An ICODA manager sent an email to a scientist who had inquired about this data, stating "ICODA does not hold the data and we have requested that the authors update the data sharing agreement to reflect that" [28] . 8 June 2022. Three of us (DES, CA, EJF) emailed the TOGETHER trial coauthors and cc's of the above-cited email thread, quoting the above statement from that ICODA manager, that ICODA never hosted the study's data [24] . The..
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