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All Studies   Meta Analysis   Recent: 
PRINCIPLE Trial Ivermectin arm: unexplained delay and extension
PRINCIPLE (Preprint), PRINCIPLE, ISRCTN86534580
10 Oct 2022    Source   PDF   Share   Tweet
MolnupiravirIvermectin
TrialPANORAMICPRINCIPLE
Chief investigatorProf. Chris ButlerProf. Chris Butler
Randomization delayMedian 2 days, ≤5 days from onset≤14 days from onset (median unknown)
Population50+ or 18+ w/comorbidities18+ (mid-trial change, prev. 18+ w/dyspnea or comorbidity, 65+)
Treatment5 days, 2x per day3 days, 1x per day, dosage below real-world protocols and recent trials
Patients randomized25,783est. 4,500
Enrollment periodDec 8, 2021 - Apr 27, 2022May 12, 2021 - Jul 8, 2022 (est.)
Cost$707<$1 (off patent)
Merck profit$5.4B sales to June 30, 2022 (2021, 2022). Estimated $17.74 to produce.~$0 (potential, unlikely competitive with low cost manafacturers)
MutagenicYesNo
Design better for showing efficacy
Design worse for showing efficacy
The PANORAMIC trial for molnupiravir randomized 25,000 patients a median of 2 days from onset [Butler]. The PRINCIPLE trial for ivermectin enrolled patients up to 14 days from onset, a delay incompatible with the recommended use of antiviral treatments, and incompatible with current real-world protocols.
Despite the contrasting approach of these two trials, they have the same chief investigator and primary contact [isrctn.com, isrctn.com (B)].
It is unclear why results were not released December 2021, why a reported supply issue was contradicted by the manufacturer, why the trial continued, and why results have still not been released [youtube.com].
Ivermectin was added to the PRINCIPLE trial on May 12, 2021 [web.archive.org] (June 2021 according to [principletrial.org]), and favipiravir on April 26, 2021 [web.archive.org]. 4,731 patients were enrolled as of April 8, 2021 [web.archive.org (B)], by which time the azithromycin, doxycycline, and budesonide arms had completed. The colchicine arm had been running for one month and was later terminated with 156 patients. With an estimated enrollment of 1,000 per arm for ivermectin, favipirar, and concurrent control, the trial would end when total enrollment reached around 8,000.
8,010 patients were enrolled and ivermectin was removed from the list of treatments under investigation on the website on or before Dec 2, 2021 [twitter.com, web.archive.org (C)], suggesting that enrollment was complete and results would be available shortly thereafter.
By Dec 9 ivermectin was added back to the list [web.archive.org (D)] with a note that the arm was paused due to supply issues. MedPage Today reported on the pause on Dec 14 [Henderson]. Notably, Merck's statement at the time shows a significantly softer stance compared to their previous comments [Henderson, ivmmeta.com].
The reported supply issue is unusual - trials normally secure medication in advance, the reported trial manufacturer stated there were no supply issues [web.archive.org (E)], investigators did not respond to journalist queries, there was reportedly no response to Freedom of Information requests [youtube.com (B)], alternate sources of ivermectin in the specified dosage were readily available, and there was no need for an identical match in appearance. The trial manufacturer was Edenbridge [cdn.factcheck.org]
The trial later restarted the ivermectin arm, although modifications were made. On or before January 27, 2022, the inclusion criteria were changed to enroll any patient 18+. As of January 27, 2022, the trial was paused without explanation. As of February 11, 2022, the trial was open intermittently (twice daily between Sunday and Thursday), a change which further decreases the chance of participants receiving relatively early treatment. Delaying and restarting the trial at a later time may also reduce observed efficacy due to less severe variants in combination with the trial design.
Enrollment ended with 11,768 patients which was reached on or before July 8, 2022 [web.archive.org (F)], giving an estimated 2,250 patients per arm. No results have been released over 153 days later.
We are pre-specifying subgroup analysis for enrollment up to Dec 2, 2021, for treatment within 2 days of onset, and for treatment of high risk patients (as originally defined by the trial).
TreatmentTreatment patientsDurationResults delay
HCQn/a (523 trial total on Jun 16)2 monthsover 930 days [principletrial.org (B)]
Azithromycin [thelancet.com]5406 months56 days [nihr.ac.uk]
Doxycycline [thelancet.com (B)]7805 months42 days [nihr.ac.uk]
Budesonide [thelancet.com (C)]1,0734 months12 days [principletrial.org (C)]
Colchicine [bjgp.org]1563 months120 days [medrxiv.org]
Ivermectin~2,25014 monthsover 153 days (over 371 days from ~1,000 per arm enrollment)
Favipiravir~2,25015 monthsover 153 days (over 371 days from ~1,000 per arm enrollment)
Very late treatment. Patients were enrolled up to 14 days after the onset of symptoms. Extensive research for COVID-19 and other viral diseases show that early antiviral treatment is critical.
Inclusion changed from 50+ to 18+ before start of ivermectin arm. Inclusion was originally 50+ w/comorbidity or 65+, but was changed to 18+ w/COVID dyspnea or comorbidity or 65+ before the start of the ivermectin arm.
Exteme conflict of interest. The chief investigator is also chief investigator for the PANORAMIC molnupiravir trial, with overlapping dates.
Mid-trial change to include lower risk patients. Inclusion criteria were modified mid-trial to allow enrolling anyone 18+.
Supply issue contradicated by manufacturer. The trial was paused with a reported supply issue, however the manufacturer stated that there were no supply issues.
Design favors null result in contrast to molnupiravir trial by the same chief investigator. Treatment delay, inclusion criteria, dosing, and target size all show a design better for efficacy for molnupiravir, and worse for efficacy for ivermectin. Both trials have the same chief investigator and overlapping dates.
Other arm results not released over 930 days later. The HCQ arm results have not been released over 930 days later [principletrial.org (B)].
Inclusion changed from 7 to 14 days. Inclusion was originally within 7 days of symptoms, but was changed to 14 days, compared to the molnupiravir trial which was started with 5 days [clinicaltrialsregister.eu].
Administration on an empty stomach. Authors instructed patients that "no food should be taken two hours before or after administration" [cdn.factcheck.org]. [Guzzo] show that the plasma concentration of ivermectin is much higher when administered with food (geometric mean AUC 2.6 times higher).
Mismatch with original proposal. The original proposal for the trial starts with: "COVID-19 disproportionately affects people over 50 years old with comorbidities and those over 65 years old. The infection causes considerable morbidity and mortality in this population group in particular." [hra.nhs.uk], yet authors later modified the trial to include anyone 18+.
Ivermectin from source chosen has shown lower efficacy. Authors chose to source ivermectin from Edenbridge, which ranked 7 out of 11 brands in In Vitro tests for antiparasitic efficacy [Williams], requiring 5 days compared to 2 days for the best performing brand, and 3 days for 4 other brands.
Only three different doses, lower μg/kg dose for higher weights. Only three different doses were used: 45-64kg (18mg), 65-84kg (24mg), and ≥84kg (30mg) [cdn.factcheck.org]. Patients with higher weights will have progressively lower μg/kg dosing.
DateRandomization delayInclusion criteria
Mar 22, 2020≤7 days50+ w/comorbidity, 65+
Jun 16, 2020≤14 days50+ w/comorbidity, 65+
Apr 12, 2021≤14 days18+ w/COVID dyspnea or comorbidity, 65+
Jul 12, 2021≤14 days18+ according to web ad updated from previous ad
Jan 27, 2022≤14 days18+
PRINCIPLE et al., 10 Oct 2022, Randomized Controlled Trial, preprint, 1 author, trial ISRCTN86534580 (PRINCIPLE).
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Late treatment
is less effective
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