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Ivermectin for COVID-19 in adults in the community (PRINCIPLE): an open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes

Hayward et al., Journal of Infection, doi:10.1016/j.jinf.2024.106130, PRINCIPLE, ISRCTN86534580

Feb 2024

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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.

Lower risk for mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral clearance.

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. c19ivm.org

Ivermectin and the Research Cartel

Four Years Later – The Toughest COVID Pill to Swallow

Can Scientific Misconduct Be Criminally Prosecuted?

Significantly improved recovery and significantly lower risk of long COVID with ivermectin, despite very late treatment, low-risk patients, and poor administration.

36% lower ongoing persistent COVID-19 specific symptoms, p<0.0001 (details below). The primary recovery outcome shows superiority of ivermectin (probability of superiority > 0.999), missing from the abstract (details below). The p values for sustained recovery, early sustained recovery, alleviation of all symptoms, and sustained alleviation are all < 0.0001.

The efficacy seen for ivermectin here is despite the trial being the most clearly designed to fail trial, with major bias in design, operation, analysis, and reporting. This trial is a great example of bias in clinical trials which will be covered in detail in the future.

c19early.org

	Molnupiravir PANORAMIC Gbinigie, isrctn.com	Ivermectin PRINCIPLE isrctn.com (B)
Investigator	Prof. Chris Butler	Prof. Chris Butler
Delay	≤5 days from onset median 2 days	≤14 days from onset median unknown
Population	50+ or 18+ w/comorbidities	18+ (mid-trial change)
Treatment	5 days, 2x per day	3 days, 1x per day, dose below real-world use
Administration	Per recommendation (with or without food)	Directed to take opposite of recommendation for COVID-19 - without food, greatly reducing concentration c19ivm.org, Guzzo
Patients	25,783	3,963 (inc. concurrent control)
Publication delay	4 months	19 months (26 months from expected end)
Enrollment	Dec 2021 - Apr 2022	May 2021 - Jul 2022
Mutagenic	Yes	No
Cost	$707 fiercepharma.com	<$1 medrxiv.org
Merck profit	>$7.2B sales to date merck.com, estimated $18 to produce theintercept.com	~$0 (potential, unlikely competitive with low cost manufacturers)
Design better for showing efficacy
Design better for hiding efficacy

Severity	Issue (most recent update 42 days ago)
CRITICAL	1. 36% lower long COVID hidden in appendix (45 days ago)
CRITICAL	2. False claims for long-term outcomes and recovery (45 days ago)
CRITICAL	3. Significantly improved recovery is strongly associated with significantly lower mortality (45 days ago)
CRITICAL	4. Superiority of ivermectin hidden (45 days ago)
CRITICAL	5. Mid-trial allowance of mAbs/antivirals corrupts hospitalization/death data (42 days ago)
CRITICAL	6. Superiority of budesonide not hidden (45 days ago)
CRITICAL	7. Budesonide press release within 12 days (44 days ago)
CRITICAL	8. Similar results, opposite conclusion (45 days ago)
CRITICAL	9. Pre-specified "meaningful effect" only for interim futility (45 days ago)
CRITICAL	10. Meaningful effect was 1.5 days for other arms (45 days ago)
CRITICAL	11. Pre-specified "meaningful effect" probability changed 0.01->0.25 (45 days ago)
CRITICAL	12. Hospitalization/death probability of meaningful effect (44 days ago)
CRITICAL	13. 10x lower accuracy in reported results (44 days ago)
CRITICAL	14. Adverse event data missing (44 days ago)
CRITICAL	15. Mortality results missing for concurrent control arm (45 days ago)
CRITICAL	16. Details of hospitalizations and deaths not provided (45 days ago)
CRITICAL	17. False claim on administration
CRITICAL	18. Results delayed 600 days (44 days ago)
CRITICAL	19. Authors coverage of prior research extremely biased and cherry-picked (45 days ago)
CRITICAL	20. Very late treatment
CRITICAL	21. Inclusion changed from 50+ to 18+ w/COVID dyspnea or comorbidity before start of ivermectin arm
CRITICAL	22. Mid-trial change to include lower risk patients
CRITICAL	23. Exteme conflict of interest
CRITICAL	24. Pause due to supply but medicine was stored at every study site
CRITICAL	25. Supply issue contradicated by manufacturer
CRITICAL	26. Design favors null result in contrast to molnupiravir trial by the same chief investigator
CRITICAL	27. Other arm results not released over 1,400 days later
CRITICAL	28. Inclusion changed from 7 to 14 days
CRITICAL	29. "Gate-keeping" protection of serious outcome evaluation
CRITICAL	30. Long delay between registration and enrollment
CRITICAL	31. Subject to participant fraud
CRITICAL	32. Inconsistent analysis - Bayesian vs. frequentist statistics (48 days ago)
CRITICAL	33. Age 65+ reduced from 47% to 16% for ivermectin (45 days ago)
SERIOUS	34. Delivery delay reduces perceived effect (45 days ago)
SERIOUS	35. Recovery subgroup forest plot for all arms except ivermectin (45 days ago)
SERIOUS	36. Even faster recovery with greater baseline severity (45 days ago)
SERIOUS	37. Lack of recovery inverted to reduce effect size (48 days ago)
SERIOUS	38. Slow delivery
SERIOUS	39. Administration on an empty stomach
SERIOUS	40. Mismatch with original proposal
SERIOUS	41. Eligibility criteria worse than concurrent favipiravir arm
SERIOUS	42. Recruitment questions varied
MAJOR	43. Ivermectin from source chosen has shown lower efficacy
MAJOR	44. Ability to pickup medication quickly removed from information sheet
MAJOR	45. Only three different doses, lower μg/kg dose for higher weights
MINOR	46. Duration == 7 missing (45 days ago)
COMMENT	47. Efficacy not due to open label design (44 days ago)

Responses: authors have not responded to any of these issues.

36% lower long COVID hidden in appendix. Page 358 in the appendix shows 36% lower ongoing persistent COVID-19 specific symptoms (p<0.0001) when combining the individual symptom results. The paper reports a 28% reduction (p=0.015), not mentioned in the abstract or conclusion. This appears to be a one of any symptom analysis, effectively increasing the weight of the more common “fatigue”, reducing the perceived effect (the difference does not appear to be due to adjustments - the adjustments in Table S6 to Table S39 make minimal difference). This is for very late and poorly administered treatment taken by only 89% of patients in a relatively low-risk population - benefits may be much greater with recommended usage and in high-risk patients.

False claims for long-term outcomes and recovery. Authors claim that ivermectin is "unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes", which is contradicted by their results. 36% (or the 28% from the author's calculation) lower long COVID is clearly clinical and very meaningful - it would represent an enormous global reduction in morbidity if adopted. The significantly faster recovery is also clearly clinically meaningful.

Significantly improved recovery is strongly associated with significantly lower mortality. Authors report highly statistically significant improved recovery but claim no clinical relevance. Across all 69 treatments we cover, improved recovery is very significantly associated with lower mortality, p<0.000000001 (from all studies that report both).

Superiority of ivermectin hidden. The protocol states "If the Bayesian posterior probability of superiority (a log hazards ratio greater than 0 corresponding to quicker recovery) for a treatment versus Usual Care is sufficiently large (e.g. ≥ 0.99), the null hypothesis will be rejected and the intervention will be deemed superior..". The intervention is superior (probability > 0.9999), yet there was no press release and immediate call for use, and this is not even mentioned in the abstract or conclusion.

Mid-trial allowance of mAbs/antivirals corrupts hospitalization/death data. Authors note: "From 16 Dec 2021, a minority of extremely clinically vulnerable patients could also access antiviral treatment or a monoclonal antibody infusion". However, there is no information on treatments provided or procedures for determining eligibility. This change corrupts hospitalization/death data after 16 Dec 2021. Hospitalization/death events occured in a small minority of patients and are expected to be strongly biased towards the extremely clinically vulnerable patients. Patients randomized to usual care are more likely to obtain alternative treatment. During the trial extension period sotrovimab was the most common treatment, with paxlovid and molnupiravir also being used england.nhs.uk. Sotrovimab showed very high efficacy during this period Behzad, De Vito. It is normal to provide details of other treatments used in cases like this, the lack of disclosure suggests that the data confirms alternative treatment use significantly biased the results.

Superiority of budesonide not hidden. The same trial's budesonide arm did not hide the superiority: "There was a benefit in time to first self-reported recovery ... with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99" (in the abstract).

Budesonide press release within 12 days. The superiority for recovery for budesonide was announced within 12 days of trial completion ox.ac.uk, principletrial.org (C). Slow but perhaps acceptable. Ethical and moral obligations mandate release as soon as possible. However for ivermectin, the results were hidden for around 600 days, and then misrepresented.

Similar results, opposite conclusion. Of the 5 arms reporting results (HCQ and favipiravir are still missing), only two show superiority on the primary recovery outcome, with probabiliy of superiority >0.999 for both ivermectin and budesonide, and similar results. Several individual recovery results are better for ivermectin than budesonide - concurrent and COVID+: time to allevation of all symptoms, time to sustained alleviation of all symptoms, WHO5 wellbeing at day 28, all concurrent: time to allevation of all symptoms, time to sustained alleviation of all symptoms, and time to initial reduction of severity all show better results for ivermectin than budesonide. However the conclusions for each are the opposite - for budesonide authors concluded superiority, for ivermectin they conclude that ivermectin "is unlikely to provide clinically meaningful improvement in recovery". Note improvements are higher with ivermectin and the primary recovery outcome for several subgroups related to baseline severity - illness duration, baseline severity, and respiratory illness.

Pre-specified "meaningful effect" only for interim futility. The protocol (even the post-hoc versions) only mentions clinically meaningful effects in terms of interim futility analyses: "If the Bayesian posterior probability of a clinically meaningful treatment effect is sufficiently small (e.g. < 0.01) for the first co-primary endpoint (time to recovery), the intervention arm may be dropped from the study for futility". In the body of the paper authors do note that the pre-specified HR of ≥1.2 was only for futility evaluation, however the abstract drops this, implying that there was a pre-specified HR of 1.2 for superiority.

Meaningful effect was 1.5 days for other arms. Authors did not mention a "meaningful effect" for budesonide, but added a "meaningful effect" of 1.5 days for colchicine, azithromycin, and doxycycline - which was sufficient to ensure very low probabilities for those arms. For ivermectin they show an improvement of 2.06 days, i.e., clinically meaningful according to the authors for all prior arms (for most other people, smaller improvements are also clinically meaningful, and as above the improvements translate into lower mortality for high-risk patients). Additionally, the poor design of the trial means the actual improvement for recommended usage is likely much greater.

Pre-specified "meaningful effect" probability changed 0.01->0.25. In June 2022, in view of interim (if not all at the time) results, authors changed the 0.01 probability to 0.25 (just above the 0.22 for the one outcome at the time). Authors note this change is only for ivermectin and favipiravir, and will return to 0.01 for future arms (appendix page 169). Authors claim a rationale for the change is in "Appendix A" but this appears to be missing.

Hospitalization/death probability of meaningful effect. For hospitalization/death authors previously used a threshold of 2% for calculating the probability of meaningful effect. For ivermectin they changed it to 20%. Consider the families of 20% or 2% of COVID-19 deaths, perhaps 4 million or 400,000 people based on an estimated 20 million total. Do they believe those deaths were not clinically meaningful?

10x lower accuracy in reported results. For budesonide authors reported key results with 10x greater accuracy, for example 10.9 vs. 13.3 days time to recovery, wherease for ivermectin all times are reported as integers, e.g., 14 vs. 16 days. This may be used to hide differences and to reduce efficacy (e.g., 3.6 vs. 5.4 becomes 4 vs. 5 and 3.6 vs. 4.4 becomes 4 vs. 4).

Adverse event data missing. Other than a count of hospitalizations, no adverse event data was reported.

Mortality results missing for concurrent control arm. Authors do not provide the main mortality results for the concurrent control arm.

Details of hospitalizations and deaths not provided. Authors provide no details on the hospitalizations and deaths. Given the remote nature of the trial, the enrollment of very late stage patients, the very low event rate, and the very delayed time between patients signing up and actual enrollment indicated by some participants, many of the hospitalizations may have happened before medication was delivered and taken. This is supported by the subgroup analysis showing that patients >7 days from onset (likely >8-9 days to treatment initiation) contributed more to the ivermectin events.

False claim on administration. Authors falsely claim that "the influence of food on absorption is not known" c19ivm.org. Guzzo et al. Guzzo show that the plasma concentration of ivermectin is much higher when administered with food (geometric mean AUC 2.6 times higher). This is from 2002 and well-known among ivermectin researchers.

Results delayed 600 days. Results were delayed around 600 days from the expected announcement time, with no reasonable excuse for hiding such positive results (or any results).

Authors coverage of prior research extremely biased and cherry-picked. Authors perform extreme cherry-picking on their discussion of previous research, and even then highly misrepresent those studies. For example, authors discuss the TOGETHER trial, without mentioning the known impossible data, refusal to release data despite pledging to, external sharing of results during the trial, randomization/blinding failure, and many protocol violations; and without mentioning that the principal investigator said that "There is a clear signal that IVM works in COVID patients.." in private Reis.

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+ w/COVID dyspnea or comorbidity 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. The move to low-risk patients was specific to the ivermectin and favipiravir arms only webcache.googleusercontent.com.

Mid-trial change to include lower risk patients. Inclusion criteria were modified mid-trial to allow enrolling anyone 18+, i.e. very low risk patients. This change is first seen in protocol 9.0 on July 12, 2021 c19ivm.org (D)

Exteme conflict of interest. The chief investigator is also chief investigator for the PANORAMIC molnupiravir trial, with overlapping dates, and 7.2B+ financial conflict of interest between the two treatments.

Pause due to supply but medicine was stored at every study site. The trial claimed to pause due to a supply problem but medicine was stored at every site dcricollab.dcri.duke.edu, It is unlikely that all sites would have run out, if there was no supply in some locations, recruitment could have continued at other locations.

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, administration, 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 1,400 days later. The HCQ arm results have not been released over 1,400 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.

"Gate-keeping" protection of serious outcome evaluation. Authors declare a "gate-keeping" strategy to prevent evaluation of hospitalization/death if the recovery time difference is not significant c19ivm.org. Authors claim benefit for serious outcomes is unlikely without statistically significant benefit for recovery time, which is not logical, especially with low prevalence of progression - consider for example an intervention that prevented progression to mortality by 100%, but has no effect on resolution of a specific symptom, e.g., cough. The trial did not always have this gate-keeping strategy - protocol 4.0 had hospitalization/death as the primary outcome and protocol 5.0 added the new strategy (this was a post-hoc change for azithromycin and doxycycline related to the recruitment of low-risk patients and low event rates).

Long delay between registration and enrollment. One participant reports filling out a form for the trial at the time of receiving a positive PCR result and not being called until much later on day 11 of COVID to complete enrollment twitter.com (C). A second participant reports waiting 9 days after online registration to receive an enrollment phone call twitter.com (D), twitter.com (E).

Subject to participant fraud. There is no requirement for participants to have a face-to-face visit as part of trial participation. The self-reported design and the potential lack of professional medical examination results for many patients opens this kind of remote trial to participant fraud, which may be significant due to extreme politicization in the study country. Participant fraud has been reported for two other remote trials academic.oup.com, Lindsell, involving submission of fake surveys and repeated signups. Authors do not provide any information on attempts to limit participant fraud.

Inconsistent analysis - Bayesian vs. frequentist statistics. The protocol specifies Bayesian analysis which is used for some outcomes. However, authors have used frequentist statistics for other outcomes, with no known reason. This results in avoiding reporting Bayesian probability of superiority showing superiority of treatment for those outcomes.

Age 65+ reduced from 47% to 16% for ivermectin. From the non-concurrent to concurrent populations (Table 1), we can see a dramatic change in the population. 47% of patients were over 65 in the control group prior to the ivermectin arm. For ivermectin this was reduced to 16% (focusing on low-risk patients is one method to reduce the chance of showing a benefit).

Delivery delay reduces perceived effect. Recovery is defined as the time from randomization, however there are additional delays between randomization and delivery, and between delivery and the patient taking the medication. This has the effect of reducing the perceived effect of treatment. For example, the median time to alleviation of all symptoms was 4 and 5 days respectively, or 20% faster with treatment. If the delay until treatment is one day, this becomes 3 and 4 days, for 25% improvement, with progressively greater improvement with longer delays. The patient information sheet for molnupiravir states that medication will be delivered by the next day c19ivm.org (H), Gbinigie, while the patient information sheet for ivermectin has deleted "next day" only stating that medication will be delivered c19ivm.org (I).

Recovery subgroup forest plot for all arms except ivermectin. The main paper shows a forest plot with subgroups of the primary recovery outcome for all arms (colchicine, budesonide, azithromycin, doxycycline) except ivermectin. For ivermectin, authors only show the hospitalization/death forest plot in the main paper. The recovery results show superiority of ivermectin.

Even faster recovery with greater baseline severity. Figure S2a shows that longer duration, at least one baseline major severity item, and respiratory illness all show greater improvement for recovery, consistent with the greater room for improvement in more severe cases. If authors truly believed that HR 1.2 is a required and valid threshold, they should not be ruling out use for higher-risk cases.

Lack of recovery inverted to reduce effect size. Authors report the number of patients fully recovered at 3, 6, 12 months. It is typical to compare the risk of bad outcomes (failure to recover, hospitalization, death, etc.), however authors compare good outcomes. Authors method shows a significant improvement of 6% at 12 months, however the typical analysis shows a much larger 18% reduction in failure to recover. Consider a recovery rate of 90% in the control group, by the author's method it would be impossible for any intervention to create the HR ≥1.2 that they added.

Slow delivery. The patient information sheet for molnupiravir states that medication will be delivered by the next day c19ivm.org (H), Gbinigie, while the patient information sheet for ivermectin has deleted "next day" only stating that medication will be delivered c19ivm.org (I).

Administration on an empty stomach. Authors instructed patients that "no food should be taken two hours before or after administration" c19ivm.org. Guzzo et al. Guzzo, from 2002 and well known to ivermectin investigators, shows 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+.

Eligibility criteria worse than concurrent favipiravir arm. In addition to inferior eligibility compared with molnupiravir, eligibility was even inferior to the concurrent favipiravir arm, with ivermectin further favoring a null result. As of July 8, 2021 favipiravir started at 50+ while ivermectin started at 18+ w/dyspnea or comorbidity as per the trial newsletter .

Recruitment questions varied. Recruitment questions varied, for example the video instructions for ambulatory care show the system asking about only two symptons - cough and fever. Notably, cough may be less responsive to treatment and increased enrollment based on cough may reduce the chance of showing efficacy youtube.com (C).

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.

Ability to pickup medication quickly removed from information sheet. Earlier versions of the patient information sheet (e.g., v3.1 c19ivm.org (K)) allowed patients to pickup the medication from a local pharmacy instead of waiting for delivery. This was removed sometime before the ivermectin arm and the sheet now only lists delivery, excluding the possibility of very quick pickup of the medication after enrollment c19ivm.org (L).

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) c19ivm.org. Patients with higher weights will have progressively lower μg/kg dosing.

Duration == 7 missing. The subgroup forest plot shows illness duration <7 and >7, without specifying what happens with == 7. The papers for other arms shows ≤7 and >7.

Efficacy not due to open label design. Some people with strong prior claims of no efficacy have claimed that the efficacy here is due to the open label design. Moustgaard et al. showed there was no evidence to support this from analysis of 142 meta-analyses covering 1,153 trials. However, in this case we have multiple arms from the same exact trial that show this is not the case (which authors acknowledge in the paper, noting no evidence from the other arms). Moreover, any effect would be reversed because at the time and in the study country, the government and almost all media claimed that ivermectin was ineffective (and contrary information was censored).

The PANORAMIC trial for molnupiravir and the PRINCIPLE trial for ivermectin provide a good example of extreme bias in trial design. For molnupiravir investigators randomized 25,000 patients a median of 2 days from onset Butler. For ivermectin, they allow inclusion up to 14 days after onset — a delay incompatible with the recommended use of antiviral treatments, and incompatible with current real-world protocols. This delay alone would normally be more than enough to guarantee a null effect for an early treatment. However, authors also bias the population, treatment dose and duration, treatment administration, and sample size to favor a null result with ivermectin.

PANORAMIC and PRINCIPLE have the same chief investigator and primary contact isrctn.com, isrctn.com (B), and the molnupiravir and ivermectin arms overlap in time.

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 were delayed 19 months 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, favipiravir, 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 c19ivm.org (B), Henderson.

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, participants received standard standard foil strips dailymed.nlm.nih.gov, twitter.com (B).

The trial later restarted the ivermectin arm. 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.

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	Change
PRINCIPLE trial timeline
March 22, 2020	Inclusion ≤7 days, age 50+ w/comorbidity or 65+.
June 16, 2020	Inclusion changed to ≤14 days.
February 14, 2021	Inclusion changed to 18+ w/COVID dyspnea or comorbidity or 65+ c19ivm.org (C).
May 12, 2021	Ivermectin listed as current intervention in protocol web.archive.org.
June 2021	Ivermectin added according to web site principletrial.org.
Jul 12, 2021	Inclusion changed to 18+ c19ivm.org (D).
December 2021	Anticipated completion of ivermectin arm.
December 3, 2021	Ivermectin arm ends, removed from web site between Dec 2 and Dec 3 twitter.com, web.archive.org (F), web.archive.org (G).
December 2021	No press release or rapid top-tier publication, indicating positive results.
December 9, 2021	Ivermectin added back to web site with claim of pause due to supply issues.
December 14, 2021	Trial does not respond to MedPage Today regarding supply problems. A statement from Merck is dramatically different to their previous position and is consistent with them knowing that a trial they cannot ignore has positive results and them being unsure if they can suppress the results medpagetoday.com.
December 25, 2021	The trial supplier, Edenbridge, denies any supply issue. Prof. Chris Butler declines to comment web.archive.org (H). The trial used standard widely available tablets dailymed.nlm.nih.gov, twitter.com (B).
January 14, 2022	Prof. Paul Little, TSC chair, is removed from the trial in protocol version 13 c19ivm.org (E). The TSC is responsible for reporting ethical issues.
January 27, 2022	Trial paused without explanation c19ivm.org (F).
February 11, 2022	Trial only open intermittently (twice daily between Sunday and Thursday), adding further enrollment delays c19ivm.org (G).
July 8, 2022	Extended ivermectin arm ends web.archive.org (I).
July 2022	No press release or rapid top-tier publication, indicating positive results.
June 2, 2023	Sometime between May 2 and June 2, authors add a note on the web site indicating that, against protocol, they are delaying and will release in a rigorous and transparent way after extended 1 year followup ends in July web.archive.org (J), web.archive.org (K). Note that the analysis code for professional trials is written and tested in advance.
November 6, 2023	Links to the protocol, amendments, and other supporting documents were removed from the web site.
December 2023	Still no results or update. A link was added to a version 14 of the protocol dated August 8, 2022 (after all arms had completed). The link does not work, pointing to an internal University of Oxford site. The latest version available is 13.0, dated January 14, 2022 c19ivm.org (E) (during the ivermectin arm, after the expected end in December 2021).

Treatment	Treatment patients	Duration	Results delay
PRINCIPLE trial treatments
HCQ	393-408 dcricollab.dcri.duke.edu	2 months	over 1,300 days principletrial.org (B)
Azithromycin thelancet.com	540	6 months	56 days nihr.ac.uk
Budesonide thelancet.com (B)	1,073	4 months	12 days principletrial.org (C)
Doxycycline thelancet.com (C)	780	5 months	42 days nihr.ac.uk
Colchicine bjgp.org	156	3 months	120 days medrxiv.org (B)
Ivermectin	2,157	14 months	600 days (810 days from ~1,000 per arm enrollment)
Favipiravir	~2,250	15 months	over 600 days (over 800 days from ~1,000 per arm enrollment)

This is the 48th of 49 COVID-19 RCTs for ivermectin, which collectively show efficacy with p=0.00000038.

This is the 101st of 102 COVID-19 controlled studies for ivermectin, which collectively show efficacy with p<0.0000000001 (1 in 560 quintillion).

1. academic.oup.com, academic.oup.com/ofid/article/7/7/ofaa277/5868216.academic.oup.com/ofid/article/7/7/ofaa277/5868216.

2. Behzad et al., Real world Effectiveness of Sotrovimab in Preventing COVID-19–related Hospitalisation or Death in Patients Infected with Omicron BA.2, Journal of Infection and Public Health, doi:10.1016/j.jiph.2023.11.029.sciencedirect.com, doi.org.

3. bjgp.org, bjgp.org/content/72/720/e446.bjgp.org/content/72/720/e446.

4. Butler et al., Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial, The Lancet, doi:10.1016/S0140-6736(22)02597-1.sciencedirect.com, doi.org.

5. c19ivm.org, c19ivm.org/pdf/principle-protocol-8.1.pdf.c19ivm.org/pdf/principle-protocol-8.1.pdf.

6. c19ivm.org (B), c19ivm.org/meta.html#merck.c19ivm.org/meta.html#merck.

7. c19ivm.org (C), c19ivm.org/pdf/principle-protocol-7.0.pdf.c19ivm.org/pdf/principle-protocol-7.0.pdf.

8. c19ivm.org (D), c19ivm.org/pdf/principle-protocol-9.0.pdf.c19ivm.org/pdf/principle-protocol-9.0.pdf.

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Important missing comments or errors? Let us know.

risk of death/hospitalization, 1.0% higher, HR 1.01, p = 0.97, treatment 34 of 2,157 (1.6%), control 27 of 1,806 (1.5%), concurrent and eligible, primary outcome.

risk of death, 62.3% lower, RR 0.38, p = 0.18, treatment 3 of 2,157 (0.1%), control 12 of 3,256 (0.4%), NNT 436, non-concurrent, authors do not provide details for concurrent deaths.

risk of mechanical ventilation, 151.4% higher, RR 2.51, p = 0.63, treatment 3 of 2,149 (0.1%), control 1 of 1,801 (0.1%).

risk of ICU admission, 319.0% higher, RR 4.19, p = 0.23, treatment 5 of 2,149 (0.2%), control 1 of 1,801 (0.1%).

time to sustained recovery, 16.0% lower, HR 0.84, p < 0.001, treatment 2,157, control 1,806, inverted to make HR<1 favor treatment, concurrent and eligible.

early sustained recovery, 23.1% lower, HR 0.77, p < 0.001, treatment 2,154, control 1,805, inverted to make HR<1 favor treatment, concurrent and eligible.

sustained alleviation, 17.4% lower, HR 0.83, p < 0.001, treatment 1,826, control 1,535, inverted to make HR<1 favor treatment, concurrent and eligible.

alleviation of all symptoms, 16.0% lower, HR 0.84, p < 0.001, treatment 2,154, control 1,805, inverted to make HR<1 favor treatment, concurrent and eligible.

first reported recovery, 13.0% lower, HR 0.87, p < 0.001, treatment 2,157, control 1,806, inverted to make HR<1 favor treatment, concurrent and eligible, primary outcome.

no recovery at 3/6/12 months, 28.0% lower, HR 0.72, p = 0.02, treatment 94 of 1,941 (4.8%), control 109 of 1,624 (6.7%), NNT 54.

risk of no recovery, 17.6% lower, RR 0.82, p = 0.001, treatment 417 of 1,848 (22.6%), control 420 of 1,533 (27.4%), NNT 21, day 365.

risk of PASC, 36.3% lower, RR 0.64, p < 0.001, treatment 1,886, control 1,567, all symptoms combined.

risk of PASC, 63.2% higher, RR 1.63, p = 1.00, treatment 2 of 1,507 (0.1%), control 1 of 1,230 (0.1%), ongoing/persistent, fever.

risk of PASC, 72.7% lower, RR 0.27, p = 0.33, treatment 1 of 1,819 (0.1%), control 3 of 1,489 (0.2%), NNT 683, ongoing/persistent, cough.

risk of PASC, 50.1% lower, RR 0.50, p = 0.04, treatment 15 of 1,886 (0.8%), control 25 of 1,567 (1.6%), NNT 125, ongoing/persistent, dyspnea.

risk of PASC, 35.3% higher, RR 1.35, p = 0.74, treatment 5 of 1,808 (0.3%), control 3 of 1,468 (0.2%), ongoing/persistent, chest pain.

risk of PASC, 25.2% lower, RR 0.75, p = 0.36, treatment 21 of 1,831 (1.1%), control 23 of 1,501 (1.5%), NNT 259, ongoing/persistent, smell.

risk of PASC, 58.7% lower, RR 0.41, p = 0.42, treatment 2 of 1,821 (0.1%), control 4 of 1,503 (0.3%), NNT 640, ongoing/persistent, diarrhoea.

risk of PASC, 70.2% lower, RR 0.30, p < 0.001, treatment 10 of 1,739 (0.6%), control 27 of 1,400 (1.9%), NNT 74, ongoing/persistent, headache.

risk of PASC, 29.8% lower, RR 0.70, p = 0.25, treatment 23 of 1,739 (1.3%), control 27 of 1,433 (1.9%), NNT 178, ongoing/persistent, muscle ache.

risk of PASC, 47.1% lower, RR 0.53, p = 0.03, treatment 19 of 1,724 (1.1%), control 30 of 1,441 (2.1%), NNT 102, ongoing/persistent, generally unwell.

risk of PASC, 20.1% lower, RR 0.80, p = 0.19, treatment 66 of 1,876 (3.5%), control 69 of 1,567 (4.4%), NNT 113, ongoing/persistent, fatigue.

risk of PASC, 28.5% lower, RR 0.72, p < 0.001, treatment 1,513, control 1,238, all symptoms combined.

risk of PASC, 39.9% lower, RR 0.60, p = 0.01, treatment 46 of 1,435 (3.2%), control 51 of 1,136 (4.5%), relatedness (yes + unsure) 9.1% (treatment) 11.2% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, cough.

risk of PASC, 41.6% lower, RR 0.58, p < 0.001, treatment 96 of 1,513 (6.3%), control 106 of 1,238 (8.6%), relatedness (yes + unsure) 14.4% (treatment) 18.5% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, shortness of breath.

risk of PASC, 22.2% lower, RR 0.78, p = 0.27, treatment 39 of 1,426 (2.7%), control 36 of 1,117 (3.2%), relatedness (yes + unsure) 7.6% (treatment) 8.4% (control) , NNT 205, adjusted per study and for relatedness, moderate/major symptoms at 12 months, chest pain.

risk of PASC, 38.0% lower, RR 0.62, p = 0.02, treatment 46 of 1,427 (3.2%), control 44 of 1,140 (3.9%), relatedness (yes + unsure) 7.7% (treatment) 10.3% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, palpitations.

risk of PASC, 11.5% higher, RR 1.12, p = 0.52, treatment 77 of 1,403 (5.5%), control 57 of 1,131 (5.0%), relatedness (yes + unsure) 13.2% (treatment) 12.9% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, smell.

risk of PASC, 36.4% lower, RR 0.64, p = 0.02, treatment 51 of 1,375 (3.7%), control 51 of 1,116 (4.6%), relatedness (yes + unsure) 1.1% (treatment) 1.4% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, taste.

risk of PASC, 22.1% lower, RR 0.78, p = 0.37, treatment 26 of 1,290 (2.0%), control 25 of 1,057 (2.4%), relatedness (yes + unsure) 4.8% (treatment) 5.3% (control) , NNT 286, adjusted per study and for relatedness, moderate/major symptoms at 12 months, ear ache.

risk of PASC, 9.6% higher, RR 1.10, p = 0.73, treatment 37 of 1,325 (2.8%), control 25 of 1,089 (2.3%), relatedness (yes + unsure) 6.7% (treatment) 7.4% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, sore throat.

risk of PASC, 34.8% lower, RR 0.65, p = 0.12, treatment 24 of 1,308 (1.8%), control 27 of 1,077 (2.5%), relatedness (yes + unsure) 6.0% (treatment) 6.9% (control) , NNT 149, adjusted per study and for relatedness, moderate/major symptoms at 12 months, hoarse voice.

risk of PASC, 16.6% higher, RR 1.17, p = 0.42, treatment 60 of 1,341 (4.5%), control 46 of 1,082 (4.3%), relatedness (yes + unsure) 8.3% (treatment) 7.4% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, tinnitus.

risk of PASC, 34.7% lower, RR 0.65, p = 0.29, treatment 13 of 1,382 (0.9%), control 12 of 1,139 (1.1%), relatedness (yes + unsure) 2.2% (treatment) 3.0% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, vomiting.

risk of PASC, 46.5% higher, RR 1.46, p = 0.12, treatment 44 of 1,439 (3.1%), control 25 of 1,175 (2.1%), relatedness (yes + unsure) 5.9% (treatment) 5.8% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, abdominal pain.

risk of PASC, 1.6% lower, RR 0.98, p = 0.95, treatment 33 of 1,416 (2.3%), control 24 of 1,167 (2.1%), relatedness (yes + unsure) 4.4% (treatment) 5.1% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, diarrhoea.

risk of PASC, 43.8% higher, RR 1.44, p = 0.23, treatment 30 of 1,417 (2.1%), control 17 of 1,160 (1.5%), relatedness (yes + unsure) 4.5% (treatment) 4.6% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, reduced appetite.

risk of PASC, 89.8% higher, RR 1.90, p = 0.27, treatment 11 of 1,375 (0.8%), control 4 of 1,129 (0.4%), relatedness (yes + unsure) 1.8% (treatment) 2.2% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, weight loss.

risk of PASC, 41.3% lower, RR 0.59, p < 0.001, treatment 89 of 1,287 (6.9%), control 94 of 973 (9.7%), relatedness (yes + unsure) 13.2% (treatment) 16.2% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, anxiety.

risk of PASC, 38.6% lower, RR 0.61, p < 0.001, treatment 95 of 1,298 (7.3%), control 92 of 992 (9.3%), relatedness (yes + unsure) 13.7% (treatment) 17.4% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, depression.

risk of PASC, 49.0% lower, RR 0.51, p < 0.001, treatment 129 of 1,376 (9.4%), control 143 of 1,105 (12.9%), relatedness (yes + unsure) 19.6% (treatment) 27.3% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, brain fog.

risk of PASC, 32.9% lower, RR 0.67, p = 0.08, treatment 37 of 1,187 (3.1%), control 33 of 874 (3.8%), relatedness (yes + unsure) 7.1% (treatment) 9.2% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, confusion.

risk of PASC, 41.9% lower, RR 0.58, p < 0.001, treatment 78 of 1,278 (6.1%), control 81 of 964 (8.4%), relatedness (yes + unsure) 12.5% (treatment) 15.7% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, headache.

risk of PASC, 45.4% lower, RR 0.55, p = 0.001, treatment 53 of 1,254 (4.2%), control 54 of 955 (5.7%), relatedness (yes + unsure) 11.5% (treatment) 15.8% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, dizziness.

risk of PASC, 73.5% lower, RR 0.27, p = 0.10, treatment 3 of 1,105 (0.3%), control 3 of 802 (0.4%), relatedness (yes + unsure) 0.4% (treatment) 1.1% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, fainting.

risk of PASC, 38.7% lower, RR 0.61, p = 0.02, treatment 42 of 1,200 (3.5%), control 39 of 894 (4.4%), relatedness (yes + unsure) 7.9% (treatment) 10.7% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, numbness.

risk of PASC, 42.1% lower, RR 0.58, p < 0.001, treatment 123 of 1,288 (9.5%), control 121 of 982 (12.3%), relatedness (yes + unsure) 13.9% (treatment) 18.5% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, sleeping problems.

risk of PASC, 11.8% lower, RR 0.88, p = 0.37, treatment 99 of 1,180 (8.4%), control 88 of 967 (9.1%), relatedness (yes + unsure) 15.1% (treatment) 16.1% (control) , NNT 141, adjusted per study and for relatedness, moderate/major symptoms at 12 months, body pains.

risk of PASC, 32.2% lower, RR 0.68, p < 0.001, treatment 136 of 1,220 (11.1%), control 146 of 1,034 (14.1%), relatedness (yes + unsure) 16.1% (treatment) 19.0% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, joint pains.

risk of PASC, 30.2% lower, RR 0.70, p < 0.001, treatment 205 of 1,398 (14.7%), control 209 of 1,181 (17.7%), relatedness (yes + unsure) 24.1% (treatment) 28.3% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, fatigue.

risk of PASC, 31.9% lower, RR 0.68, p = 0.006, treatment 91 of 1,208 (7.5%), control 89 of 997 (8.9%), relatedness (yes + unsure) 14.5% (treatment) 18.1% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, weakness.

risk of PASC, 35.9% lower, RR 0.64, p < 0.001, treatment 99 of 1,211 (8.2%), control 107 of 1,002 (10.7%), relatedness (yes + unsure) 14.3% (treatment) 17.4% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, generally unwell.

risk of PASC, 9.2% lower, RR 0.91, p = 0.81, treatment 16 of 1,066 (1.5%), control 11 of 855 (1.3%), relatedness (yes + unsure) 3.0% (treatment) 3.8% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, fever.

risk of PASC, 42.4% lower, RR 0.58, p = 0.21, treatment 10 of 1,065 (0.9%), control 11 of 853 (1.3%), relatedness (yes + unsure) 3.0% (treatment) 3.7% (control) , adjusted per study and for relatedness, moderate/major symptoms at 12 months, rashes.

risk of PASC, 10.0% lower, RR 0.90, p = 0.62, treatment 47 of 1,090 (4.3%), control 41 of 873 (4.7%), NNT 260, adjusted per study, moderate/major symptoms at 12 months, other.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Hayward et al., 29 Feb 2024, Randomized Controlled Trial, placebo-controlled, United Kingdom, preprint, 25 authors, study period 23 June, 2021 - 1 July, 2022, trial ISRCTN86534580 (PRINCIPLE). Contact: principle@phc.ox.ac.uk.

This Paper Ivermectin All

Ivermectin for COVID-19 in adults in the community (PRINCIPLE): an open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes

Gail Hayward, Ly-Mee Yu, Paul Little, Oghenekome Gbinigie, PhD Milensu Shanyinde, PhD Victoria Harris, Jienchi Dorward, Benjamin R Saville, Nicholas Berry, Philip H Evans, Nicholas Pb Thomas, Mahendra G Patel, Duncan Richards, Oliver Van Hecke, PhD Michelle A Detry, PhD Christina Saunders, PhD Mark Fitzgerald, Jared Robinson, Charlotte Latimer-Bell, Julie Allen, PhD Emma Ogburn, Jenna Grabey, FD Simon De Lusignan, Fd Richard Hobbs, FD Christopher C Butler

Journal of Infection, doi:10.1016/j.jinf.2024.106130

Background The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. Methods In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 g/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. Trial registration: ISRCTN86534580. Findings The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n=2157), usual care (n=3256), and other treatments (n=3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1•15 [95% Bayesian credible interval, 1•07 to 1•23], median decrease 2.06 days [1•00 to 3•06]), probability of meaningful effect (pre-specified hazard ratio 1.2) 0•192). COVID-19-related J o u r n a l P r e -p r o o f 4 hospitalisations/deaths (odds ratio 1•02 [0•63 to 1•62]; estimated percentage difference 0% [-1% to 0•6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74•3% and 71•2% respectively (RR = 1•05, [1•02 to 1•08]) and also at 3 and 12 months.,. Interpretation Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted.

Conflict of 0% (-0•9% to 0•6%) 3 J o u r n a l P r e -p r o o f ivermectin. Pr(Superiority) is the probability of superiority and treatment superiority is declared if Pr(superiority) ≥ 0•975 versus usual care. Pr(Meaningful) is the probability that the odds ratio for Ivermectin versus usual care is 0.80 or smaller. 4 All secondary outcome analyses were conducted on the concurrent and eligible randomisation SARS-CoV-2 positive population, but restricted to those who are in the ivermectin and usual care group only. Secondary outcomes were analysed using frequentist statistics. 5 Defined as recovered within 14 days and reports feeling recovered for the next 14 days (or recovered at 14 and 28 days if only call data available) 6 Relative risks adjusted for age, comorbidity at baseline, duration of illness, and vaccination status at baseline. 7 Estimated hazard ratio derived from a Cox proportional hazard model adjusted for age, comorbidity at baseline, duration of illness, and vaccination status at baseline, with 95% confidence interval. 8 Mixed effect model adjusting age, comorbidity, duration of illness, vaccination status at baseline, and time. Participant was fitted as a random effect. WHO well-being score was also adjusted for the score at baseline 9 Unadjusted relative risks due to low event rate. --Ivermectin versus concurrent and eligible usual care. 1 Relative risks (RR), derived from frequentist approach mixed effect logistic regression model, adjusted..

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Late treatment
is less effective

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