Recently, McMaster University’s Professor Ed Mills, principal investigator of the Together trial, highlighted interim analysis results evidencing no impact of ivermectin and some other repurposed study drugs while pointing to some promise for Fluvoxamine. TOGETHER is a randomized, Adaptive Platform trial investigating several possible treatments, including ivermectin. After many therapies disappointed, Fluvoxamine, an SSRI commonly used for depression, showed some promise as a repurposed treatment. The study isn’t completed, as there is still a 28-day monitoring period, but Mills recently presented the findings, which are already making the news rounds. While a disappointment for those tracking Ivermectin studies, those critical of the study raise legitimate points for consideration.

Dr. Ed Mills presented the study results during an August 6 event sponsored by the National Institutes of Health. Mills led this study that looked into several treatments, from hydroxychloroquine and lopinavir to ivermectin and Fluvoxamine. The trial was led by McMaster University, engaging with trial sites in Brazil. He was supported by Kristian Thorlung from McMaster University and Cytel, Inc. and locally in Brazil by Dr. Gilmur Reis from Pontifical Catholic University of Minas Gerais, Brazil.

Funding for the study originates from the Bill & Melinda Gates Foundation (hydroxychloroquine and lopinavir/ritonavir), Fast Grants (Ivermectin, Metformin and Fluvoxamine), and Rainwater (overall trial infrastructure).

Trial Site Locations

In order to enroll as many patients as possible, the study established a network of trial site locations in the Brazilian state of Minas Gerais, including ten (10) specific sites.

Summary of Findings

Mills provided some details early on in their findings covering hydroxychloroquine or lopinavir/ritonavir vs. placebo; Metformin vs. placebo; and ivermectin vs. placebo. The study team found no benefits involving either hydroxychloroquine or the combination of lopinavir/ritonavir on the outcome of hospitalization or standard of emergency care. Mills declared, “it just didn’t make a difference.” Metformin didn’t show any benefit, and thus, they stopped the study after 423 patients. Many observational studies involved this drug early on, showing that people weren’t dying of COVID-19. He suggests it could benefit if on for a long time.

In regards to the topic of ivermectin, Mills’ point of view is perhaps a little biased given the strong advocacy he has contended with around the world. He suggested in this presentation that perhaps his findings would disappoint those advocates or those in the “dark web” but regales the media attention clearly isn’t warranted to the Canadian professor.

The study started in January with a randomized single dose of ivermectin versus a single dose match of placebo.

He reported considerable criticism and ultimately increased the regimen to three days of 400 mcg/kg in 1,500 patients. Ultimately, the data indicate that the study drug didn’t significantly impact the study endpoints—composite ER and hospitalization. The results for ivermectin can be found here at 32:00. 

Mills reported that in this outpatient study, they just didn’t see the benefit that many of the ivermectin advocates were looking for, or thought should have been present. 

As far as Fluvoxamine, Mills saw potential good news with the results here. He noted 10 days worth of Fluvoxamine 200 mg per day costs $4, and thus, if the findings are correct, there is an intervention here at a low price point. They have up to 742 patients to date and 738 in the placebo group. Thus, Mills notes that the interim analysis must now be complete, the ongoing study ended as of the presentation, but the study team must follow up the patients for another 28 days.

These are preliminary findings, but he doesn’t believe they will change that much but perhaps slightly.

TrialSite Review

TrialSite engaged with several researchers and physicians involved with ivermectin to elicit some initial perspective on this study. Although, we emphasize the study hasn’t even been uploaded to the preprint server as of yet. Reviewers need to see the data in its entirety.

Ivermectin was dosed at initially one day and then three days, while Fluvoxamine was dosed at ten days. A review of ivermectin protocols from the Front Line COVID-19 Critical Care Alliance (FLCCC) involves considerably longer use of the drug, in that case, off-label use based on a discussion of the risks and rewards and consent between doctor and patient.

There has been much criticism of Dr. Mills by ivermectin proponents, for example. Still, TrialSite suggests Mills is a straight shooter, ethical and moral, and we don’t believe there was any agenda one way or another. Of course, we have chronicled numerous ivermectin studies that have demonstrated considerable results, and some of us have direct first-hand experience using it as an early treatment option for COVID-19.

But a number of factors could possibly help explain why ivermectin didn’t show results in Dr. Mills important study, including the following:

· Note sufficient duration of use—for instance, in a scenario where the study drug was dosed at .6mg/day at 14-day course commencing the first day of symptom onset, the results could have been materially different—but we can only speculate.

· Virulent variant—note that in Brazil, P1 is apparently strong, and as we have written recently, the FLCCC changes its protocol due to delta’s viral load and effects

· Early-onset treatments—a consensus of individuals we spoke with is that if one doesn’t treat P1 immediately upon symptoms, then the results may not be there

· Factoring in local use of ivermectin by participants into exclusion criteria

· Ensuring endpoints match protocol

Practicing Physicians and Researchers’ Point of View

In March of this year, Dr. Ira Bernstein, a family physician in Canada and advocate of early outpatient treatment, corresponded with Dr. Mills. Dr. Bernstein was supportive of the overall design of the trial after reviewing the protocol in detail, with one exception. Bernstein states, “I advised Dr. Mills of my concerns that there was no exclusion criteria for subjects having past exposure to ivermectin. Dr. Mills had indicated there isn’t much ivermectin use in the general community in Brazil and stated that the half-life was so short for ivermectin that it shouldn’t be a major concern. I advised Dr. Mills that ivermectin has longer tissue effects than just the half-life, which explains the prophylactic dosing of ivermectin. Additionally, I have family members who live in the same state of Minas Gerais where the study was being conducted, and who all contracted COVID-19. Eight family members took ivermectin at recommended doses all available without a prescription.” The concern expressed by Dr. Bernstein was that there was a risk of ivermectin contamination in any treatment arm, which has the risk to diminish differences in the treatment and placebo arms, similar to concerns raised in the Lopez study in Colombia. Regrettably, the protocol remained unchanged, and the data will need to be carefully scrutinized.

TrialSite also spoke with Dr. Pierre Kory, director of the Front Line COVID-19 Critical Care Alliance (FLCCC), who declared, “We appreciate the insight that the TOGETHER trial has brought to the fore, that a confluence of factors and forces necessitate evolving protocols to ensure Ivermectin continues to have the positive impact we have see to date.” Kory’s point is that TOGETHER contributes knowledge the FLCCC has already factored into their treatment regimen, but the doctor and researcher appreciated Mills and the team for taking on the topic.

How Studies can Fail

At least some well-respected researchers and early treatment advocates suggest that ivermectin may have failed in this study due to a combination of factors, including 1) too little a dose, 2) dosing starts too late, 3) not taken with a meal or shortly after, 4) length of continuation (or lack thereof), and 5) in Brazil, many people had already been taking the drug.

Steve Kirsch’s COVID-19 Early Treatment Fund (CETF) has supported clinical investigations into Fluvoxamine but also supports other therapies such as ivermectin

Kirsch’s CETF suggests, “Clinical trials on repurposed drugs should always be tested first on outpatients by physicians who prescribe on a shared decision-making basis. Once a protocol is found to be reliable, then it can be “locked” into a clinical trial for “proof” of efficacy. Sadly we do the opposite, which wastes a lot of time and money. We form a hypothesis and then invest millions to test it out in a large scale trial rather than on an outpatient basis.”

Some key failure points include Dose, Timing, Treatment Delay, Compliance, Duration, Deception, and many more here

Lead Research/Investigator TOMORROW trial

Ed Mills, Ph.D., FRCP, Professor Department of Health Research Methods, Evidence

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