|Chief investigator||Prof. Chris Butler||Prof. Chris
|Randomization delay||Median 2 days, ≤5 days from
onset||≤14 days from onset (median unknown)|
|Population||50+ or 18+ w/comorbidities||18+ (mid-trial change, prev. 18+ w/dyspnea or comorbidity,
|Treatment||5 days, 2x per day||3
days, 1x per day, dosage below real-world protocols and recent
|Enrollment period||Dec 8, 2021 - Apr 27,
2022||May 12, 2021 - Jul 8, 2022 (est.)|
|Cost||$707||<$1 (off patent)|
|Merck profit||$5.4B sales to June 30, 2022 (2021,
$17.74 to produce.||~$0 (potential, unlikely
competitive with low cost manafacturers)|
|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
(June 2021 according to
and favipiravir on April 26, 2021
4,731 patients were enrolled as of April 8, 2021
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,
[, web.archive.org (C)]
suggesting that enrollment was complete and results would be available shortly
By Dec 9 ivermectin was added back to the list
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
investigators did not respond to journalist queries, there was reportedly no
response to Freedom of Information requests
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
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
Enrollment ended with 11,768 patients which was reached on or
before July 8, 2022
giving an estimated 2,250 patients per arm. No results have been released
over 334 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).
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 1,111 days later.
The HCQ arm results have not been released over 1,111 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]
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.
PRINCIPLE et al., 10 Oct 2022, Randomized Controlled Trial, preprint, 1 author, trial ISRCTN86534580