Waiting for PRINCIPLE
Sixteen months on, no results have been published from the UK’s large Oxford-backed platform trial
It’s been more than a year since PRINCIPLE, the Oxford-led large randomized platform trial on early COVID treatments, completed its ivermectin and favipiravir arms.
While the results for all the other drugs assessed by the UK trial were published within a short turnaround, no results have been announced, and no study published, for ivermectin and favipiravir.
In a response to an email I sent on Nov. 2, a spokesperson for PRINCIPLE said the team is in the “final stages of site closure and report/paper completion”. Below is the full response, which is nearly identical to the statement currently up on their website:
“The study paused recruitment in July 2022, at c10,000 participants, and we have been continuing to collect the data we need for the analysis of the Ivermectin and Favipiravir arms of the trial since this date.
“As a result, we have not yet published the results for these two treatments. Participants in the trial are followed up for a full year, so that we are able to answer the critically important questions about the effect of treating acute SARS-Cov-2 infection on symptoms and well-being over the longer term.
“The team collected the one year follow up data to the end of July 2023. Following on from this, queries were made, and the data fully cleaned prior to complex analyses. We are now in the final stages of site closure and report/paper completion according to our published protocol.
“You will, of course, be able to find the results on our website as soon as they become available, and we will submit scientific papers describing this rigorous, independent evaluation of these medicines to peer reviewed journals as soon as possible.”
My follow-up questions were not answered. Unfortunately, the response poses more questions than it answers.
Just like TOGETHER, PRINCIPLE is a platform trial. That means it’s focused on a single disease and can evaluate multiple treatments against the same control group, with the ability to also change the treatments during active enrolment.
In the case of PRINCIPLE, the trial was focused on COVID-19, randomized but not blinded, and entirely remote, with patients self-reporting symptoms and PCR or lateral flow tests. Instead of placebo, patients in the control group received usual care. the trial evaluated six drugs: Inhaled budesonide, azithromycin, doxycycline, colchicine, favipiravir and ivermectin. (It initially kicked off assessing hydroxychloroquine, but that trial was suspended upon request from authorities. For more on this issue, I recommend Phil Harper’s coverage, e.g. here).
As you can see in the table below, the results for the first four of these drugs were published and/or announced very shortly upon completion, ranging from barely two weeks after study end in the case of budesonide to up to four months for colchicine.
But for ivermectin and favipiravir, nothing has been announced, or published. So, what is going on? There are a few head scratchers in the response from PRINCIPLE.
Why a year follow-up?
For one, the answer talks of collating data from a full year of follow-up. Why is that? PRINCIPLE was specifically set up to investigate early treatments, and to obtain rapid answers. To quote the trial’s Chief Investigator Professor Chris Butler (emphasis mine):
“PRINCIPLE will enable researchers to rapidly evaluate different treatments that could stem the progression of COVID-19 symptoms in older people and help ease the burden on hospitals.”
In the same quote, from April 2020, Butler further emphasized the importance of speed (again, emphasis mine):
“What’s unique about the PRINCIPLE trial platform is that it’s so flexible. By setting up a nationwide primary care research network across the NHS, we’re able to rapidly evaluate potential new treatments for COVID-19. This trial will allow us to make treatments that are proven to be effective as widely, and as rapidly available as possible.”
How does a year of follow-up come into this? Why not publish the immediate or interim results and then a follow-up, if the latter is deemed useful? And why is this being done for ivermectin and favipiravir and not the other treatments?
Perhaps a clue is in the protocol. PRINCIPLE has iterated through 14 protocol versions since its start, and while they’re no longer on its website, most are recoverable thanks to Web Archive. The ISRCTN entry also has a summary of key changes over time.
From this we can make out that version 5 from September 2020 makes no mention of a 12 month follow-up (see point 2.9 Subsequent visits). However, version 6 from November 2020 has this addition under point 2.9:
“We will seek consent from participants to contact them on a monthly basis for up to 12 months after enrolment (via email, text message or phone call) to collect information about any ongoing symptoms, hospitalisations and well-being. We will re-consent those already enrolled in the trial.”
By then, azithromycin was almost completed, and doxycycline was two-thirds through. Budesonide and colchicine had not started yet. Yet, all of these were still published within a few months of study end, regardless of this new criterion. So this change doesn’t seem to provide a useful clue.
Maybe the more relevant change is that from version 13 from January 14 2022. In that version, the end of trial definition is changed to September 2023, from the previous date of March 2022 (See point 2.12 Definition of End of Trial). A note dated April 12 2022 from the ISRCTN registry also says the target number of participants and target enrolment was changed from 9,000 to 12,000, while the intention to publish was postponed by a whole year to March 3 2023.
The year-long delay is just one of multiple oddities with PRINCIPLE’s ivermectin arm.
Dosage capped
Readers of this Substack will remember how the TOGETHER trial capped its dosing for ivermectin, so that patients of more than 90kg were seriously underdosed. We see the same phenomenon with PRINCIPLE. Per their protocol, ivermectin was dosed at around 0.3mg per kilo of bodyweight:
Up to 90kg, that is. Anyone weighing more than that was still receiving only 30mg. So say you weighed 120kg, your actual dosage was 0.25mg per kg. This may seem trivial as the average weight of UK males and females is around 85kg and 72kg, respectively, and the higher the weight the lower the dose goes. Here is the dosing per kg of the PRINCIPLE trial mapped against the dosing in the TOGETHER trial.
However, those most at risk for severe COVID-19 symptoms are the overweight, so under-dosing specifically this group of people is obviously counterproductive. We have covered the implications of such underdosing those most at risk previously. No matter how much we have searched for any medical justification of such concerning design decisions, none has been forthcoming.
From older people… to anyone over 18
Another head scratcher: Mid-way through the trial, PRINCIPLE changed its protocol to include younger people, and eventually anyone over 18. (Sounds familiar? Hello, TOGETHER!).
At the onset, PRINCIPLE was set up to investigate COVID treatments in older people. In fact, its original name stood for “Platform Randomised trial of INterventions against COVID-19 in older peoPLE”. Yet as of 27/01/2022, the recruitment age was changed to anyone 18 years and older:
In other words, anyone 18 and older with a sore throat or “general feeling of being unwell” and claim to have a positive COVID test would have been admitted to the study.
What a far cry from examining “participants who are most at risk of serious COVID-19 illness, either due to their age, symptoms, or an underlying health condition” — to use their own words.
At this late stage, the change only affected the ivermectin and favipiravir trials.
The age had already been lowered as of April 2021 in version 8 of the protocol, to include anyone over 65, and anyone over 18 *with* shortness of breath or a comorbidity. This change – which would have again affected the favipiravir and ivermectin arms, and possibly also the last portion of the colchicine study – is not as incongruous, since a comorbidity and shortness of breath are compatible with being more at risk of COVID-19 complications. Reflecting this change, version 8 also changed the name of the trial, dropping the mention of older people: “Platform Randomised trIal of treatmeNts in the Community for epIdemic and Pandemic iLlnEsses.”1
Symptoms within 14 days
Unlike many trials for COVID-19 that focused on severe symptoms, PRINCIPLE was focused on early treatment for mild symptoms that didn’t need hospitalization. As described in this press release:
“Unlike many other clinical trials for COVID-19, which are mostly focussed on providing treatment to those who already have serious symptoms and are admitted to hospital, the PRINCIPLE trial looks to identify treatments that can be prescribed by community-based GPs to slow or halt the progression of the disease and prevent the need for hospitalisation.”
Even so, the trial was focused on identifying early treatments. Yet, the inclusion criteria allowed for anyone that had a positive COVID test and ongoing symptoms that started within the past 14 days. Knowing that enrolment was open to anyone above 18, that most young people recover quickly from COVID, and that anti-virals such as ivermectin have the most chance of working if taken as soon as possible, it is unclear how allowing for such a long window of symptoms would allow for any meaningful conclusions.
Compare this to the PANORAMIC trial, also led by Chris Butler. In that trial, evaluating the commercial drug Molnupiravir, participants had to be less than 5 days from symptoms onset.
Supply issues and unexplained pauses
Finally and possibly the strangest part of PRINCIPLE’s ivermectin (and favipiravir) trial is the timeline itself. While the other arms all lasted between 3 to 6 months, PRINCIPLE reported that enrolment for favipiravir and ivermectin ended on July 1, 2022. That’s a whole 15 and 12 months after these arms started, respectively – far longer than any of the others.
There also appear to have been unexplained gaps and pauses in the ivermectin trial. On December 3, 2021, ivermectin was no longer listed on the list of treatments assessed, though favipiravir was still there. This suggested that recruitment for the arm was done, which would tally with the length of the trials for the other arms.
But then, ivermectin re-appeared sometime by December 9. This time, a note said the arm was paused “due to temporary supply issues”.
On December 14, 2021, MedPage Today reported on the pause, and said the trial press team didn’t respond to a request to comment on the issue. MedPage reached out to Merck, which manufactures ivermectin, but the manufacturer didn’t comment on the issues. PRINCIPLE’s protocol actually lists Edenbridge Pharmaceuticals, not Merck, as the supplier of ivermectin. Another newspaper, Epoch Times, contacted Edenbridge for comment at the time, who said they weren’t experiencing any issues.
Using Web Archive screenshots, it appears the mention of supply issues was removed between December 22 and 25, while the entire trial was on pause for a ‘festive break’ from December 22 to January 4.
Then again, it seems both arms were paused on January 27, according to this screenshot saved by IVM Meta. As of February 11, the trial was open intermittently (twice daily between Sunday and Thursday), again according to a screenshot from IVM Meta.
In conclusion
So where does that leave us? A trial that inexplicably went on for a whole year, that has been declared completed for well over 15 months now but the authors still haven’t announced any findings, despite its purpose being to rapidly assess treatments for COVID-19. In contrast, the other four other drugs that they assessed were evaluated in a few months, with studies published within a year of trial start. We’re now at over two years since trial start for ivermectin and favipiravir.
The same trial was supposed to focus on people at risk of severe COVID but it underdosed overweight participants and changed its protocol mid-way to accept anyone over 18. It also accepted anyone with any range of mild symptoms that started within 14 days, despite being focused on early treatment. Finally, it appears to have had several unexplained pauses in its timeline and recruitment, in part citing supply issues that the manufacturer itself denied.
PRINCIPLE trials: Timeline
2020
Mar 22: PRINCIPLE registered on ISRCTN (ISRCTN86534580).
Mar 27: Version 1 of protocol published.
May 22: HCQ arm suspended. Last patient randomized.
May 23: Azithromycin starts.
Jul 24: Doxycycline starts
Nov 2: Protocol v6 adds option for a 12 month follow-up
Nov 27: Budesonide starts
Nov 30: Azithromycin ends
Dec 14: Doxycycline ends
2021:
Mar 4: Colchicine starts
Mar 31: Budesonide ends
Apr 8: Recruitment started for favipiravir according to version 4 appendix.
Apr 12: Protocol v 8.1 (couldn’t locate 8.0). Name is changed to Platform Randomised trIal of treatmeNts in the Community for epIdemic and Pandemic iLlnEsses, i.e. dropping the mention of older people. Age for inclusion changed to: over 65 or above 18 with shortness of breath or comorbidity. Previously: anyone over 65, or over 50 with comorbidity.
May 26: Colchicine ends
Jun 23: Ivermectin starts according to version 4 appendix. (On ISRTNC they say May 12)
Dec 2: PRINCIPLE website shows enrolment still open, and assessing favipiravir and ivermectin. By then, displays 8,010 patients enrolled.
Dec 3: Ivermectin no longer listed on list of active treatments.
Dec 9: ivermectin back on website, with a note saying “this arm is currently paused due to temporary supply issues”. Shows 8,251 patients enrolled.
Dec 14: MedPage Today reports on the pause, PRINCIPLE doesn’t comment.
Dec 22: PRINCIPLE website says recruitment is paused for ‘festive break’ until Jan. 4.
Dec 24-25: Epoch Times reports that Edenbridge (which supplied ivermectin to PRINCIPLE) said they hadn’t experienced supply issues. PRINCIPLE website no longer mentions supply issues. Now shows 8,523 patients enrolled.
2022
Jan 5: Festive break is over.
Jan 14: Protocol v13 changes inclusion criteria to anyone above 18, no comorbidities or shortness of breath required. End of trial date is postponed by a year to September 30, 2023.
Jan. 27: Trial paused without explanation.
Feb 11 (until ?): Trial open twice daily between Sunday and Thursday.
Apr 12: Intention to publish date is postponed by a year to March 23 2023. Recruitment end date is moved from March 30 to September 30 2022. Source: ISRCTN.
2023:
May: Sometime in May, website is updated to mention the data for ivermectin and favipiravir is still being collected and should be complete by the end of July. See screenshot from May 2 and June 2.
Nov 6: IVM Meta says links to the protocol, amendments, and other supporting documents are removed from the website. This is confirmed if you compare a screenshot from Oct. 21 with Nov. 7 (the closest range available). All the links to the protocols and amendments used to be included on the website, under the section For health & care professionals. That same link (https://www.principletrial.org/health-professionals) no longer works.
As a sidenote, both the ivermectin and favipiravir arms (as well as colchicine) excluded pregnant women, as well as women of childbearing potential *and* men with partners of women of childbearing potential, unless willing to use “highly effective contraceptive” for the 28-day duration of the trial. Methods qualifying as “highly effective” were defined as those with failure rates of below 1%, including sterilization and intrauterine devices and implants. Alternatively, couples using e.g. the pill could enroll as long as they were willing to use an additional barrier such as condoms. Just using condoms didn’t qualify.
In effect, this could plausibly have ruled out a large swath of women under 50 and male partners of women under 50. Though, the trial was remote and would have been dependent on patients’ own honesty about their contraception usage.
I’d guess ivermectin was so successful, they are trying to figure out ways of gaming the results to reduce the overall effectiveness or render it “inconclusive”.
If results had been to ANY extent negative or even neutral regarding Ivermectin effectiveness, we would not be still waiting. On the contrary, media outlets the world over would be celebrating more "Science" showing how dumb the non-believers of "The Science" were for using Ivermectin.