On November 13, a scientific review manuscript was posted to OSF, a medical pre-print server by Pierre Kory, MD, of the Front Line COVID-19 Critical Care Alliance (FLCCC). On November 3, TrialSite reported on the inclusion of the drug in the Alliance’s I-MASK+ protocol; the new manuscript comprehensively reviews the entirety of the emerging evidence from recent publications in journals, pre-print servers, and randomized trial results posted on clinicaltrials.gov. The FLCCC was created in March by Professor Paul Marik, MD, in order to continuously analyze the quickly-evolving science and clinical data for the purpose of creating COVID-19 treatment protocols. The corresponding author for the review is Pierre Kory, MD, MPA, an Associate Professor of Medicine at St. Luke’s Aurora Medical Center.
While Other Drugs Have Failed, Ivermectin Studies are Now Showing Consistent and Substantial Benefits
The Alliance writes that, to date, much of the research being conducted and the care being given has been plagued by the use of medicines at, “inappropriate time points during this now well-described multi-phase disease.” And at this point, due to either trial design errors or lack of efficacy, negative study results including the SOLIDARITY trial have almost eliminated any role for remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon, convalescent plasma, tocilizumab, or monoclonal antibody therapy, especially in later phases of the disease. In the face of these failures, “the FLCCC recently discovered that ivermectin, an anti-parasitic medicine, has highly potent real-world, anti-viral, and anti-inflammatory properties against SARS-CoV-2 and COVID-19.” They reached this opinion via a review of a wide range of studies, including many randomized and observational studies. FLCCC found repeated and substantial improvements in outcomes when ivermectin is utilized both as a prophylactic and in treatment for mild, moderate, and even severe COVID-19 cases.
Long List of Reasons
The FLCC expert panel reached consensus in advising that ivermectin should be “systematically and globally” used for both prevention and treatment of COVID-19 based on 11 factors, including: invitro studies over the past decade that show ivermectin slows or stops replication of many viruses, ivermectin inhibits SARS-CoV-2 replication in infected cell cultures, and it is a potent anti-inflammatory shown to inhibit cytokine production. The clinical data shows that it stops transmission in those exposed to patients with COVID-19, it quickens recovery and stops deterioration in those with mild to moderate disease who were treated early after symptoms, and it reduces ICU admission and death in hospitalized patients, even among those already critically ill. Finally, in several epidemiologic analyses, “striking reductions in case-fatality rates can be measured in regions with widespread use,” and it is proven safe with over billions of uses in history while being very low-cost.
Offering a compelling, comprehensive summary of evidence, scientific rational and a call to action, Dr. Pierre Kory recently participated in a Grand rounds, describing the accumulating case for ivermectin to the Associazone Naso Sano Provider ECM, a Rome-based international association of ENT physicians.
NIH Says NO to Ivermectin; World Expert Urges Caution
Not everyone in the medical community agrees that ivermectin should be used widely, however the FLCCC recommendation relies on previously unavailable evidence. In its last ivermectin update from August 27, NIH’s COVID-19 Treatment Guidelines Panel recommended, “against the use of ivermectin for the treatment of COVID-19, except in a clinical trial.” They argue that pharmacokinetic and pharmacodynamic studies suggest that doses up to 100 times that approved for humans would be needed to be comparable to levels shown to have in vitro effects and that clinical data are limited. Also on August 27, MedPage Today weighed in on ivermectin. They cite Carlos Chaccour, MD, PhD of the Barcelona Institute for Global Health (ISGlobal), who studies ivermectin in the treatment of tropical diseases. “The pandemic creates a sense of urgency and we tend to cut some corners, and that can be okay, but you don’t cut all corners,” offered the doctor. “There needs to be scientific rigor. People may say, ‘What do you have to lose? It’s a safe drug,’ but no drug is free from side effects,” he said. The article notes that ivermectin can lead to GI side effects or skin rashes and that in rare cases it is neurotoxic; also, RCT’s are needed before wide use of ivermectin should be allowed.
Since the last interviews and engagement with Chaccour, mounting evidence from both observational and randomized controlled studies pointing to the efficacy of ivermectin as some form of treatment for COVID-19 becomes ever harder to ignore.
Avoiding the Hydroxychloroquine Mistake
According to Matthew Spinelli, MD, of the University of California, San Francisco, the positive evidence, to the degree it is anecdotal, is “difficult to interpret given that most patients who are infected will get better on their own, and the clinical manifestations are so variable for COVID-19.” Another doctor urging caution is Zeno Bisoffi, MD, PhD, of the University of Verona, Italy. “There were some results from observational studies claiming that [hydroxychloroquine] worked, but in fact they were small studies with very heavy methodological flaws,” Bisoffi said. “Nevertheless, they were cited everywhere, so most clinicians around the world were using hydroxychloroquine with no evidence—-This is a mistake we want to avoid with ivermectin.
Q&A: Moral Hazard of Ivermectin; Low Cost Not a Factor
Turning back to ISGlobal and Dr. Chaccour, he penned a “Q&A” on ivermectin and COVID-19 on August 8. In it, he argues that the state of the evidence is “equipoise,” meaning that “there is a reasonable doubt of whether a drug might be of use or not. Testing of ivermectin against SARS-CoV-2 in clinical trials is warranted.” Key issues include the dose question as well as whether the drug might harm folks in proinflammatory states. Per Chaccour, “Given the absence of reasonable evidence that ivermectin has any efficacy against SARS-CoV-2, the risk-benefit analysis dictates that we should be prudent, i.e. evaluate the efficacy (and safety in this context) before taking ivermectin to the population level.” He also argues that there may be a “moral hazard” to ivermectin if people using it feel “safe” and quit using face masks, etc. Regarding whether big pharma may be wary of the low-cost of ivermectin, Chaccour argues that given the market size for a COVID-19 product, i.e. billions of people, adequate incentives exist for even a “cheap” drug.
Dr. Chaccour makes an important point here: a generic pharmaceutical company could potentially generate significant revenues based on a commercial, regulatory approved, version of ivermectin. There most certainly will be a large market for a low cost, widely available option targeting COVID-19 alongside vaccines and advanced therapies, such as monoclonal antibodies should they ultimately become proven safe and effective.
Is Ivermectin Too Good?
On balance, the arguments against thoughtful use of ivermectin outside of trials are unconvincing. The issue of whether a dangerous dose would be needed to fight COVID-19 is somewhat moot, in that many doctors around the world are using safe dose levels every day and seeing results. Moreover a number of studies have been completed, pointing to positive findings. And the implication that this is an “all or nothing” situation is not quite true. In between the scenarios of every COVID-19 patient being given ivermectin and the other extreme of strictly limiting the drug to RCT’s, there is much room for a wide variety of clinical and research strategies. If some doctors use ivermectin and some don’t, this will provide ongoing data to inform us down the road. From TrialSite’s perspective, the FLCCC makes a rational argument.
Why is ivermectin not being more widely studied and utilized? The most likely and most defensible reason is that it is due to the ignorance of the large and rapidly emerging amounts of recent data showing efficacy that was compiled by the FLCCC.
Another possibility is that a major benefit, the drug’s cheapness, has inhibited the commercial ecosystem from honing in on this promising medicine. Although here, TrialSite suggests that a substantial market opportunity for a generics healthcare venture in fact does exist. Or perhaps just as troubling, research hubris–a kind of investigational elitism–could serve as a rampart against the accumulating evidence produced by universities and health systems in both low and middle-income countries (LMICs), as well as from the clinic in wealthy countries (such as the United States and Australia). That is, only an elite faction associated with national research agencies, regulators and top academic medical centers–and pharmaceutical companies, can produce the answer to the COVID-19 pandemic crisis. Regardless, it is tragic given the COVID-19 death toll to date.