The Promise, Hope & Disappointment of the PRINCIPLE Trial as Design Concerns Throw Latest Study In Serious Doubt
The University of Oxford PRINCIPLE trial had to evaluate the potential of repurposed drugs such as Ivermectin, Fluvoxamine, Favipiravir, and many more for early COVID-19 treatment. TrialSite first reported on the rumblings from the press in the U.K. back on January 23rd, 2021. We first declared that ivermectin was now a study drug, but we quickly had to change the title to a “consideration.” Well, half a year passed, and with more rumblings, media snippets, and a few discussions in our network, we reported on June 23rd that the trial now would include ivermectin. While TrialSite again emphasized this study was late in the pandemic response (given so many other ivermectin studies showed some promise), we nevertheless expressed enthusiasm that the University of Oxford was moving forward. But dozens of researchers, physicians, and scientists with a commitment to economic, early-stage treatments for COVID-19 picked up on some concerning, perhaps even problematic, insight into this particular program associated with the PRINCIPLE trial. TrialSite investigated, interacted with, and elicited some concerns and included them as a summary herein.
The Study’s Promise
The PRINCIPLE Trial in the U.K. hopes to determine if favipiravir and ivermectin could impact the COVID pandemic. That is, if the trial is ere performed reliably. Antiviral agents can only be
expected to act in the early symptomatic stage of the disease, when
viral replication is the driving force. But the UK-wide clinical study offered such hope, led by the venerable University of Oxford. The study would bring the potential COVID-19 treatments right to the patient at home. These medicines can help people with their COVID-19 symptoms get better faster, while reducing the need for hospitalization. What a grand promise.
The Only Treatments: Costly & Cumbersome to Administer
How badly are antivirals or similar treatments used as an early-stage treatment for COVID-19 needed? The crisis in Thailand indicates just how important these treatments are as vaccination programs have been horribly mismanaged. The demand for Favipiravir, an antiviral used around the world targeting COVID-19, far outstrips supply during this latest delta variant-driven surge.
The need for early treatment, and there are numerous ones to consider, can be a matter of life and death during the COVID-19 pandemic. That’s because when the immune reaction takes hold in the inflammatory phase of COVID-19, viral levels have declined and are not the main problem. At this point, the primary effective antiviral agents are the Lilly and Regeneron anti-SARS-Cov-2 monoclonal antibodies, proven beneficial in studies targeting the initial three days of COVID-19. Note that the Lilly product isn’t in use now in America as the U.S. Food and Drug Administration (FDA) revoked the emergency use authorization (EUA).
The monoclonal antibodies must be administered intravenously, making their use impractical for every person at the time of initial COVID-19 diagnosis. What has been needed for a long time and evidenced in select National Institutes of Health (NIH)-supported clinical trials is a need for early treatments, even prophylaxis.
The Dire Need for Oral Antiviral Therapy
TrialSite has emphasized for 15 months now the critical need for easy-to-administrate and ideally low-cost options targeting early care of COVID-19. Why? Because 90%+ of SARS-CoV-2 cases are either asymptomatic or mild-to-moderate symptomatically. Many TrialSite advisors have known this, from prominent physicians on the front lines to scientists at some top universities. Early on, TrialSite interviewed researchers and physicians involved with ivermectin studies—case series, observational studies, and randomized controlled trials—worldwide. The promise seemed infectious alone, but the results seemed too many to ignore. With 62 studies completed now—and a majority of them showing some considerable promise—the critical need for publicly-financed studies far earlier in the pandemic was clear. Of course, the mainstream media, led by the preordained “thought leaders,” completely ignored any positive results. Still, as soon as any neutral to negative data points availed, they pounced to pop any balloon of ivermectin hope. That, unfortunately, will continue toward a hydroxychloroquine-type outcome. But based on the many dozens of interviews, considerable and available data scrutinized, and even some of our own experiences with using the generic treatment successfully early on to treat COVID-19, we suspect the calculus for efficacy and safety is significantly positive for ivermectin and several other repurposed candidates.
Billions of U.S. Taxpayer Dollars Directed to a Few Players
In America, many billions of taxpayer dollars got funneled during the first several months of the COVID-19 pandemic to either vaccine or monoclonal antibody developers. One antiviral drug maker secured subsidies for clinical trials and what many suspect was preferential treatment during clinical trials.
During a pivotal remdesivir trial, Dr. Anthony Fauci’s National Institutes of Allergy and Infectious Diseases (NIAID) made an unorthodox move of changing the endpoint toward the end of the study. While Fauci declared there was a “new standard” of treatment, he moderated the position to say it’s “no knock out drug.”
That last statement didn’t matter nor did the WHO Solidarity trial results declaring that remdesivir had no desirable effect on the study population.
The winner was selected, and in the first nine months of the pandemic, Gilead generated about $3 billion on a drug that’s been heavily subsidized with public monies. The drug couldn’t be used for early ambulatory or home care, was costly, and required administration in a hospital or clinic. TrialSite did marvel at the business acumen and prowess of Gilead operating early on in an intense crisis, which led to what we term “Remdesivir-envy” when referring to other pharmaceutical companies that sought to replicate that success.
TrialSite learned some hard lessons of just how much bias favoring novel and expensive drug development exists even in the worst of crisis with so many people dying. Led by the National Institutes of Health (NIH) and its ACTIV program, the entire apparatus favored expensive and novel branded therapy development over economic repurposed drug investigations. For example it’s a known problem at the National Center for Advancing Translational Sciences (NCATS). TrialSite started chronicling who was getting paid what. The money flow, the accumulation of wealth by select vaccine makers, and a true winner-take-all environment unfolded amid the worst pandemic in a century.
The Feds ‘See the Light’
But by June 2021, the federal government saw the light, that is, the need for antivirals to address early-onset care. But it would appear to be more of the same, including subsidizing more pharmaceuticals that had questionable, lengthy, and expensive, publicly supported roads. For example, Merck secured $356 million and then another $1.2 billion from the current administration in guaranteed purchases. Other companies pursuing this market include Pfizer and Roche. Fauci recently went even further, declaring exactly what kind of pill he desired from the companies.
In the meantime, countries around the world were testing Favipiravir. In fact, drug regulators authorized the use in dozens of countries, from Russia and China to Turkey. However, there was scant news associated with those milestones in the American or British press. A trio of organizations even submitted an authorization to market a version of Favipiravir to Health Canada, but still, there were crickets in the news. The same thing happened when a lab associated with the Chinese People’s Liberation Army patented Favipiravir, a hostile act to the drug maker across the East China Sea to the west in Japan. But the goals were clear as the Chinese saw a massive market for early-onset, relatively low-cost treatments. Would the powers-that-be clear the path for pharmaceutical domination in the lucrative West while Russian and Chinese firms get the low-and-middle-income countries (LMICs)? If that’s the case, the NIH will have served its function.
NIH Changes the Guidelines and the Industry Gloves Come Off
The Ivermectin experience has been quite similar, but there are some differences to note. At first, as TrialSite reported on positive study after positive study, the mainstream news and everyone else was silent. But then the National Institute of Health (NIH) COVID-19 Treatment Guidelines Panel met with ivermectin researchers from the Front-Line COVID-19 Critical Care Alliance (FLCCC) as well as Dr. Andrew Hill from the U.K. Shortly thereafter, the globally influential NIH group changed their recommendation association with ivermectin, from recommended only for research to a neutral position, which TrialSite reported.
A lot has happened since then, including a mounting campaign hostile to the use of the drug—even for research. Established media like the Los Angeles Times outright spew mountains of misinformation, as evidenced by this TrialSite piece. But many in academia and industry were already high fiving; the next hydroxychloroquine pathway was inevitable.
The Principle Study—Tailored for Failure
Yes, there is a need for oral antiviral therapy and economical ones that can help care for the world. We have seen what happens with the vaccination programs. While the richest countries secure surplus products now, most low-to middle-income countries (LMICs) really struggle to secure quality vaccination products. Yet, in the meantime, places like Thailand are betting life or death on Favipiravir.
Drs. Chris Butler and Richard Hobbs, the leaders of the outpatient PRINCIPLE Trial, recognized the need and have introduced ivermectin and favipiravir as arms in their study. However, the PRINCIPLE Trial admits patients with up to a 14-day duration of symptoms. It is impossible for antiviral treatment to show a benefit over such a long time span. Furthermore, participation of both vaccinated and unvaccinated individuals further clouds the statistical analysis. A number of thought leaders have attempted to engage Drs. Hobbs and Butler to suggest a separate statistical analysis of short duration versus longer duration and vaccinated versus unvaccinated patients.
Such a change would require much larger sample sizes than PRINCIPLE has ever had to date. COVID studies have suffered from small sample sizes, so effects are only observable by aggregating the results in meta-analyses as done with ivermectin. In contrast to the U.K. RECOVERY Trials in hospitalized patients, which have enrolled tens of thousands of patients, PRINCIPLE had only entered about 5000 patients before the delta variant outbreak. With such small numbers in a trial with such broad enrollment criteria, it is unlikely that the PRINCIPLE effort will be worthwhile. It is hoped that a major media effort could increase interest and enrollment in PRINCIPLE to get legitimate answers on the use of early-stage antiviral treatment.
TrialSite was able to interact with a prominent physician and principal investigator from Argentina, Dr. Hector E. Carvallo, Department of Internal Medicine at Buenos Aires University. Dr. Carvallo led the IVERCAR study at Eurnekian Public Hospital, evidencing positive results for generic drug use in Argentina. In an email sent to TrialSite, Dr. Carvallo shared some thoughts about what he knows about the PRINCIPLE trial:
“Regarding the PRINCIPLE trial, the method seems to be entirely designed to fail. Enrolling subjects up to 14 days of infection will only prove that ANY treatment, when applied too late, has reduced chances of success. In a scathing critique of this study, Carvallo continued, “Thus, it not only disregards one of the dogmas of modern Medicine, but it also weakens the patients’ right to be treated properly.”
Moreover, he continued, “The placebo-matched studies, in a potentially dangerous (and even life-threatening) condition, also disregards Helsinki Protocols for such a situation, depriving subjects from available chances.”
Dr. Carvallo pondered the meaning of this trial based on his understanding of the protocol design and obvious limitations was. What was behind this clinical trial design—”ignorance, some hidden intentions or a little of both,” articulated the Argentinian physician and research scientist.
These are strong and profound statements from a highly respected, world-class researcher.
TrialSite also reached out to a renowned cardiologist, one that’s put his own position on the line to fight for his patients. Dr. Peter McCullough is highly accomplished, one of the most published principal investigators in the nation. The M.D. and MPH has published the results of hundreds of studies, founded and led the Cardio Renal Society of America, served as co-editor-in-chief of the journal Cardiorenal Medicine, and led editorial for Reviews in Cardiovascular Medicine. An expert in conducting various types of cardiovascular studies, he uncovered a cardiovascular condition in high endurance athletes among many investigational breakthroughs.
Since the beginning of the pandemic, Dr. McCullough has been first and foremost concerned with delivering early care to his patients. TrialSite asked the Texas-based physician and cardiologist, research scientist, and epidemiologist to share his thoughts on the matter, which he did via email:
“It is unclear if PRINCIPLE included some of the burgeoning numbers of vaccine breakthroughs which appear to have a similar COVID-19 syndrome as those who are unvaccinated and should be considered equally eligible for medical therapy to reduce the chances of poor outcomes after the vaccine has failed.”
A Top-Down System—Doctors Now Pawns
TrialSite was aware of numerous futile attempts by dozens of physicians/researchers and other committed health care professionals concerned about this study design; eliciting a response from the prominent University of Oxford principal investigators was met with crickets. This is an unfortunate and all too familiar reality during the polarized age of COVID-19. That is, those in positions of power, privilege, and access to lots of money aren’t open to any criticism or real constructive challenge from physicians in the field, for example. A top-down, corporatized, hierarchical system of academic elites, industry executives, and government gatekeepers ensures that so many diverse, authentic, and committed caregiving voices are never heard again. Doctors have become pawns in some new form of a highly corporate, top-down ecosystem, where money, power, and stifling processes supersedes the fundamentals of doctoring and patient care. This problem unfolded long before COVID-19; the pandemic merely exposed the cancerous metastasis now spreading throughout society’s body.
