PRINCIPLE Trial Ivermectin arm: unexplained delay and extension

	Molnupiravir	Ivermectin
Trial	PANORAMIC	PRINCIPLE
Chief investigator	Prof. Chris Butler	Prof. Chris Butler
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, 65+)
Treatment	5 days, 2x per day	3 days, 1x per day, dosage below real-world protocols and recent trials
Patients randomized	25,783	est. 4,500
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, 2022). Estimated $17.74 to produce.	~$0 (potential, unlikely competitive with low cost manafacturers)
Mutagenic	Yes	No
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 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).

Date	Randomization delay	Inclusion criteria
Mar 22, 2020	≤7 days	50+ w/comorbidity, 65+
Jun 16, 2020	≤14 days	50+ w/comorbidity, 65+
Apr 12, 2021	≤14 days	18+ w/COVID dyspnea or comorbidity, 65+
Jul 12, 2021	≤14 days	18+ according to web ad updated from previous ad
Jan 27, 2022	≤14 days	18+