SciCheck Digest
Randomized clinical trials have repeatedly found that ivermectin does not benefit COVID-19 patients. The National Institutes of Health recommends against its use for COVID-19. Ivermectin enthusiasts continue to falsely claim the contrary. 
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The latest results of several large, randomized controlled trials show no benefit in using the antiparasitic drug ivermectin to treat COVID-19, the disease caused by the coronavirus, or SARS-CoV-2. The results are consistent with existing evidence that shows the cheap and accessible drug does not work to treat COVID-19.
But a recently published study from Brazil that claims ivermectin decreased COVID-19 hospitalization by 100% and COVID-19 mortality by 92% is giving new wings to those touting ivermectin as a miracle drug. The observational study contains methodological flaws, and is authored by ivermectin activists. And its results are completely inconsistent with stronger studies that did not identify any benefit of using the drug for COVID-19.
“From multiple, large well-conducted, double-blind randomized clinical trials of now thousands of participants, ivermectin has not been shown to have any meaningful clinical benefit for the early, outpatient treatment of COVID-19,” Dr. David Boulware, a professor of medicine at the University of Minnesota Medical School and an adviser for two large trials in the U.S., told us in an email.
“Specifically, two large, multi-site randomized clinical trials (Covid-Out; ACTIV-6) have been completed in the United States. These two trials both failed to detect any statistically significant benefit of ivermectin,” Boulware added.
In addition, the flawed study got intertwined with a false rumor that the National Institutes of Health COVID-19 treatment guidelines website had “now” added ivermectin as a recommended treatment. But that’s not accurate. The drug has been listed on the NIH’s page for antiviral treatments for a while (here’s an archived capture from June 12, 2021) as a medication “that is being evaluated to treat COVID-19.” But the NIH recommends against the use of ivermectin for the treatment of COVID-19 outside of clinical trials.
“Yesterday the National institute of health added Ivermectin to the list of covid treatment,” former martial arts fighter Jake Shields wrote on Twitter. “Looks like the conspiracy theorist were right and the ‘experts’ wrong once again,” he said, later referencing the problematic study. His tweet got over 42,000 likes and 13,000 retweets in three days.
On Sept. 3, the conservative website The Blaze published a story titled “Ivermectin reduces COVID death risk by 92%, peer-reviewed study finds,” which got over 1,000 shares. The same day, Robby Starbuck, a former Republican congressional candidate in Tennessee, referenced both the study and the supposed addition of ivermectin to the NIH’s website in posts across his social media.
“Now’s a good time to think about the mass censorship campaign carried out against those who used it or advocated for the freedom to use it, pharmacists who refused to fill doctors prescriptions and the unending hate people got for treating COVID with it. The attacks on it were all about lining Big Pharma and politicians pockets,” he wrote in a Facebook post. A capture of the post on his Instagram got over 26,000 likes in four days.
As we said, there has been no recent change to the NIH website to recommend ivermectin as a treatment. The page on ivermectin, which clearly states that the agency’s guidelines recommend against the use of the drug to treat COVID-19, was last updated on April 29.
The antiparasitic drug has not been approved or authorized by the Food and Drug Administration to prevent or treat COVID-19. Ivermectin is approved for human use only to treat some conditions caused by parasites, such as intestinal strongyloidiasis and onchocerciasis, head lice, and skin conditions. The FDA has warned that the use of large doses of the drug or of ivermectin for animals is dangerous.
Most Recent Results of Large Clinical Trials Show No Benefit
More than 80 studies around the world have examined the use of ivermectin to treat or prevent COVID-19. But as we’ve reported, over and over, randomized controlled trials have shown no evidence of a clinical benefit for ivermectin.
Here are some of the latest results of large clinical trials we’ve been following.
In May, researchers of the Together trial in Brazil concluded that treatment with a moderate daily ivermectin dose for three days “did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19.” This study had a total of 3,515 patients with a SARS-CoV-2 infection, where 679 received ivermectin, 679 got a placebo, and 2,157 received another intervention.
In June, the ACTIV-6 trial, funded by the NIH, reported that a moderate daily ivermectin dose for three days “resulted in less than one day of shortening of symptoms and did not lower incidence of hospitalization or death among outpatients with COVID-19 in the United States during the delta and omicron variant time periods.” The ivermectin arm of the study had 1,591 participants with a SARS-CoV-2 infection, with 817 assigned to the ivermectin group and 774 to the placebo.
Finally, in August, researchers of the University of Minnesota Covid-Out trial, which studied the use of ivermectin, metformin and fluvoxamine for COVID-19 in 1,323 patients with a SARS-CoV-2 infection, reported that none of the three medications “prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19.”
“At the dose we used, which was a median of 430 micrograms per kilo, per day, for three days, there was no effect on reducing severe COVID-19 in this population — and our population was adults over age 30 with a BMI greater than 25,” said Dr. Carolyn T. Bramante, an assistant professor of medicine at the University of Minnesota, in a video responding to the question of whether ivermectin was effective in reducing the severity of COVID-19.
Boulware, who provided advice for the trial, told us that investigators found there was no difference in the duration of symptoms between the participants who took ivermectin and those who took the placebo, and that numerically the ivermectin group patients had more ER visits and hospitalizations than the placebo group.
Problematic Study
The study that revived claims about ivermectin for COVID-19 used data from a citywide program in Itajaí, a city in southeastern Brazil, in which residents were offered ivermectin to prevent COVID-19 between July and December 2020.
In March, we explained that a previous observational study by the same team, using the same dataset, had multiple methodological flaws. Both papers were published in Cureus, an open-access online medical journal that allows researchers to publish studies faster than the traditional peer-reviewed journals. The peer-review process for the most recent paper took five days. In other journals, the peer-review process typically takes more than a month.
The team reported multiple conflicts of interest: Two of the authors have financial ties with an ivermectin manufacturer, and four of them work for organizations that promote ivermectin as a treatment for COVID-19.
Neither of the studies, the first published in January and the second published in August, were randomized placebo-controlled clinical trials. Instead, the researchers looked back at data collected by clinics and health centers where ivermectin was offered. According to the study’s methodology, people without COVID-19 symptoms could opt to get a prescription to take a low dose (about half of the dose given in the previously mentioned clinical trials) of ivermectin for two consecutive days every 15 days over the course of 150 days. Those who then got COVID-19 were medically followed, and data on hospitalizations and deaths were registered. The study grouped the participants by non-users (residents who didn’t use ivermectin), irregular users (those who took up to 10 tablets), and regular users (took more than 30 tablets), and compared their outcomes.
“The regular use of ivermectin decreased hospitalization for COVID-19 by 100%, mortality by 92%, and the risk of dying from COVID-19 by 86% when compared to non-users,” the paper concluded. “Protection from COVID-19-related outcomes was observed across all levels of ivermectin use, with a notable reduction in risk of death in the over 50-year-old population and those with comorbidities.”
But experts have identified numerous problems with the study, which as an observational study can at most only claim to have found an association between regular ivermectin use and better outcomes — not that the drug reduced hospitalizations or mortality.
“The main flaw is that it’s an uncontrolled epidemiological trial using a small quantity of routinely collected clinical data in a somewhat useless way,” Gideon Meyerowitz-Katz, an epidemiologist from the University of Wollongong in Australia, told us in an email. “In this sort of study, you have to spend a great deal of time looking for alternate explanations for why you might be seeing a relationship, like residual confounding, immortal time bias, or survivorship bias as others have mentioned, but instead the authors simply decided to run a biased analysis and call it a day.” (Click on the links for more information about residual confounding, immortal time bias and survivorship bias.)
The study, for example, attempted to control for some factors that might explain the outcomes of the different groups, such as sex, age and some underlying health conditions — but not for other factors related to infection risk, including income. Those could have skewed the results.
The inability to control for differences in groups is always a problem for observational studies — and that’s why randomized controlled trials, which randomly assign individuals to the treatment and control groups from the start, are considered more reliable and a higher level of evidence.
Perhaps most critically, as Greg Tucker-Kellogg, a biology professor in practice at the National University of Singapore, and Kyle Sheldrick, a medical researcher in Australia, have noted, the study suffers from survivorship bias because once a participant contracted COVID-19 they were advised not to use ivermectin.
This is important because the study’s purported finding is about “regular” ivermectin users who took at least 30 tablets of the drug. This means that most of the people who took ivermectin in the study who got sick were not included in the analysis because they couldn’t have taken enough pills to be considered a “regular” user, Tucker-Kellogg explains in a video. In contrast, no one in the non-ivermectin group was removed from that group if they got sick earlier in the study.
“By definition, ‘regular users’ would almost always be people who didn’t get infected,” Meyerowitz-Katz told us, “that’s simply how the study has been designed.”
Or, as Tucker-Kellogg put it, “This is a way to game the system. This is basically gaming the outcome so that the strictly regular ivermectin users have an extremely low rate of sickness and death, because basically most of the people who got sick are not counted in that group.”
In the study’s comments, Cadegiani, one of the authors, dismissed these issues.
But Meyerowitz-Katz said that even if the paper didn’t have methodology problems, it still wouldn’t be useful at this point, when there is higher-quality evidence that ivermectin doesn’t work.
“I could go on with issues and errors, but there’s not that much point. When it comes to ivermectin, a poorly-conducted study with errors *in the title* is not going to move the dial on what the evidence says at all,” he said on Twitter. “Current best evidence shows that ivermectin is unlikely to have a clinically meaningful benefit in the treatment of COVID-19, and there’s not much evidence for its use as a prophylactic.”
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Meyerowitz-Katz, Gideon. Epidemiologist from the University of Wollongong in Australia. Email sent to FactCheck.com. 12 Sep 2022.
Meyerowitz-Katz, Gideon. “15/n I could go on with issues and errors, but there’s not that much point. When it comes to ivermectin, a poorly-conducted study with errors *in the title* is not going to move the dial on what the evidence says at all.” Twitter thread. 15 Dec 2021.
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