Ongoing Clinical Trials Will Decide Whether (or Not) Ivermectin Is Safe, Effective for COVID-19
By Catalina Jaramillo
Posted on September 16, 2021
Studies on whether ivermectin is beneficial in treating COVID-19 patients haven’t been conclusive, and health officials have warned people not to self-medicate. But multiple large trials are continuing to assess the antiparasitic drug. Yet, Sen. Rand Paul reportedly said researchers were “unwilling to objectively study” it because of “hatred” for Donald Trump. He later acknowledged studies are being done. Here we review the research.
The Food and Drug Administration has not approved the use of ivermectin, an antiparasitic medication, to treat or prevent COVID-19, the disease caused by the SARS-CoV-2 virus. 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.
Although the National Institutes of Health counts over 70 studies evaluating the safety and effectiveness of ivermectin to treat or prevent COVID-19 in humans, the FDA says “currently available data do not show ivermectin is effective against COVID-19,” and using the medication for this purpose in humans or animals “can be highly dangerous” in some instances.
Yet, at a town hall, Kentucky Sen. Rand Paul said the drug was not officially available because researchers were “unwilling to objectively study” the use of ivermectin to treat COVID-19 out of “hatred” for former President Donald Trump.
“The hatred for Trump deranged these people so much that they’re unwilling to objectively study it,” Paul told constituents on Friday, Aug. 27, after a woman asked why ivermectin wasn’t more available, according to the Cincinnati Enquirer’s report of the gathering. “So someone like me that’s in the middle on it, I can’t tell you because they will not study ivermectin.”
In a subsequent opinion piece published by the Enquirer on Sept. 8, Paul said the paper did not report what he said “accurately.” He said his point was that “we don’t yet know the full story on whether” ivermectin “is effective,” and he acknowledged the drug was in “several studies including a Phase 3 trial for COVID right now.” “I never recommended anyone take Ivermectin,” he wrote.
Paul’s remarks came almost a week after the FDA used Twitter to scold those who have been self-medicating with ivermectin to treat or prevent COVID-19, and a day after the Centers for Disease Control and Prevention issued a health advisory showing a rapid and worrisome increase of both ivermectin prescriptions and severe illness associated with its use.
The FDA said the agency received “multiple reports” of people requiring “medical attention, including hospitalization,” after ingesting ivermectin intended for livestock, which comes in doses that can be toxic for humans. Animal ivermectin, which is different from the one intended for people, helps prevent heartworm disease and other parasites in different animal species.
Both the World Health Organization and the National Institutes of Health have not recommended the use of ivermectin for the treatment of COVID-19 outside of clinical trials, citing insufficient evidence. The Infectious Diseases Society of America also suggested against the use of the drug outside of a trial, since there is a “very low certainty of evidence” and “concerns with risk of bias (i.e., study limitations) and imprecision” on 15 studies reviewed by the end of July.
On Sept. 1, worried about an alarming increase of calls to poison control centers after ivermectin ingestion, the American Medical Association, American Pharmacists Association and American Society of Health-System Pharmacists called for an “immediate end to the prescribing, dispensing, and use of ivermectin for the prevention and treatment of COVID-19 outside of a clinical trial,” adding that the use of the drug for this purpose “has been demonstrated to be harmful to patients.”
“My recommendation is, if people are interested in ivermectin and helping prove what its effect is — and is there a benefit or is there not a benefit — participate in a clinical trial,” Dr. David Boulware, a professor of medicine at the University of Minnesota Medical School and a practicing infectious disease physician, told us in a phone interview. “That will help our society get the answers, you know, as quick as possible.”
Preliminary Results from International Trial
Researchers in the U.S. and across the world have shown great interest in trying to find out if ivermectin, a cheap and widely used antiparasitic drug, could be effectively and safely used to treat COVID-19 patients. As of now, there are 77 studies assessing the use of ivermectin to treat or prevent COVID-19 registered in clinicaltrials.gov, and 139 trials listed in the WHO’s International Clinical Trials Registry Platform.
“Everybody wanted to do what they could when COVID first struck,” said Edward Mills, a Canadian researcher co-leading one of the largest clinical trials on repurposed treatments to be completed yet. “And those of us working in clinical research, we did what we could too.” Mills was speaking on Aug. 6 while presenting the results for the first time during an event sponsored by the National Institutes of Health.
The Together trial, co-led by Mills, professor of health research methods, evidence and impact at McMaster University in Canada, and Dr. Gilmar Reis, associate professor of medicine at Pontifícia Universidade Católica de Minas Gerais, Brazil, started in June 2020 and was set in 10 cities in the state of Minas Gerais, Brazil. This randomized adaptive platform trial started looking at the effectiveness of ivermectin for the treatment of COVID-19 among high-risk adult nonhospitalized patients on Jan. 15, 2021. The study analyzed whether patients’ health became worse and required hospitalization or more than six hours of observation in an emergency room, within 28 days of randomization.
According to the preliminary results presented by Mills, the study found no indication of benefit on the use of ivermectin — nor with hydroxychloroquine or lopinavir-ritonavir, or metformin. The ivermectin arm had 1,500 patients: 677 of them received a daily dose of the medication, and 678 others were given a placebo, for three days.
“We found that it had no effect whatsoever on our primary outcomes,” Mills said.
According to the results presented, 86 patients in the ivermectin group required extended emergency room observation or hospitalization versus 95 in the placebo group. Both the differences in relative risk and mortality relative risk between the two groups were not statistically significant. These results have not been peer-reviewed yet.
“In our specific trial, outpatient, we do not see the treatment benefit that a lot of advocates believe should have been” seen, Mills said.
The study did find benefits in the use of fluvoxamine, an inexpensive antidepressant, which reduced the relative risk for hospitalization and extended emergency room attention by 29%, with 77 patients needing either in the fluvoxamine group compared with 108 in the placebo.
Boulware, who provides advice for two large, ongoing clinical trials in the U.S., told us hearing these results changed his opinion on ivermectin.
“Whereas before I was kind of very open-minded, now I’m sort of the proof is really, is starting to generate that there may not be much of an effect at all,” he said in a phone interview.
Enthusiasm around the use of the drug started last year when researchers found that ivermectin inhibited SARS-CoV-2 replication in cell cultures. Countries without access to vaccines or other treatments started using ivermectin to treat COVID-19 last year, and disinformation about ivermectin as a miracle cure spread all across the world, as we’ve reported. But according to the NIH, studies suggest that to achieve the plasma levels needed to replicate the antiviral effect detected in petri dishes in the human body “would require administration of doses up to 100-fold higher than those approved for use in humans.”
And even though some studies on ivermectin and COVID-19 have presented promising results, the NIH says most of the studies completed as of July 19 “had incomplete information and significant methodological limitations.”
One of the papers that increased the hope for ivermectin, which included 400 people with symptoms of COVID-19, was retracted on July 14, after concerns about plagiarism and inconsistencies in the data. According to Nature, before being withdrawn, the paper was viewed more than 150,000 times, cited more than 30 times and included in several meta-analyses, creating a ripple effect of misinformation. Researchers, experts and health officials agree on the need for more data and larger trials to really understand the effects of the use of the drug in COVID-19 patients.
Trials Ongoing in U.S.
As we said, two large clinical trials are being conducted in the U.S.
“As much as we want to think that the answer is already there … it doesn’t seem like the question is answered about whether or not ivermectin is better than placebo,” Dr. Carolyn Bramante, the principal researcher of the first randomized double-blind placebo-controlled clinical trial studying ivermectin use for COVID-19 patients in the U.S., told us in a phone interview.
The study, led by the University of Minnesota Medical School, where Bramante is an assistant professor of internal medicine and pediatrics, started studying the use of ivermectin and of the antidepressant fluvoxamine in nonhospitalized people with COVID-19 in May. The study was an expansion to an ongoing trial looking at outpatient use of metformin, a medication for type 2 diabetes, to prevent hospitalization and long COVID, which the CDC describes as “long-term effects of COVID.”
Bramante said the study, which is still recruiting volunteers nationwide, expects to include 1,124 people and will randomly assign patients to six groups, in which every volunteer takes the medications or a placebo at home, twice a day, for 14 days, and then completes a survey. Volunteers must have had a positive COVID test within the prior three days and be between 30 and 85 years old.
She said looking at the Together trial results has been helpful, but not discouraging.
“Our trial is a little bit different than the Together trial in some ways, so we might have different results from them or we might have the same results from them. But I think that’s why it’s always good to have a couple of trials on important topics,” Bramante said.
Researchers expect to have preliminary results by December.
The second large study taking place in the U.S., named ACTIV-6 — the sixth of a series of studies funded by the National Institutes of Health called Accelerating COVID-19 Therapeutic Interventions and Vaccines — started in April and included ivermectin in August. It is enrolling participants who are at least 30 years old, have a positive SARS-CoV-2 test within the past 10 days and have at least two symptoms. Participants will need to take a medication and complete online surveys for symptoms over 90 days.
The study, a double-blind randomized phase 3 trial led by the Duke Clinical Research Institute, is evaluating the use of ivermectin, fluvoxamine and fluticasone, an inhaled steroid commonly used to treat asthma, to reduce symptoms of nonhospitalized volunteers with mild and moderate COVID-19. If the drugs demonstrate efficacy, they will be further studied for effects on hospitalization, mortality and long COVID-19. According to the trial’s protocols, it expects to include up to 15,000 adults and have a duration of two years, with an estimated completion date of 2023.
“An independent data monitoring and safety committee are monitoring the ongoing ACTIV-6 results and will provide recommendations based on the internal and external data,” Dr. Adrian Hernandez, the study’s administrative principal investigator and executive director of the DCRI, told FactCheck.org in an email.
Hernandez had said one of the goals of the study is to rigorously evaluate how safe and effective ivermectin and the other repurposed drugs are, so that people can have easy access to an affordable, at-home treatment for mild to moderate COVID-19.
The U.K. Study
Researchers in the U.K. are also studying ivermectin. In June, Oxford University researchers added the drug to their PRINCIPLE trial, or Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses, which analyses possible COVID-19 treatments for nonhospitalized patients. The study has so far recruited over 6,000 volunteers in the United Kingdom. Those receiving ivermectin, people between 18 and 64 years old with underlying conditions or people over 65 with COVID-19, will receive three daily doses of the antiparasitic drug and be followed for 28 days. The results will be compared with patients who received standard care.
The study’s rationale says that even though the concentrations of ivermectin needed to inhibit the replication of SARS-CoV-2 in cell cultures “may be difficult to attain” in humans “the relationship between in vitro inhibitory effects and clinical efficacy is not clear.”
“By including ivermectin in a large-scale trial like PRINCIPLE, we hope to generate robust evidence to determine how effective the treatment is against Covid-19, and whether there are benefits or harms associated with its use,” said Chris Butler, the lead researcher for the trial, in June.
Boulware, from the University of Minnesota, said the results of all these large trials will finally provide more definitive data on the use of ivermectin as a treatment for COVID-19 patients. The results of one trial could be discussed, but “if you have two trials that show the same thing, that’s pretty hard to dismiss,” he said.
Editor’s note: SciCheck’s COVID-19/Vaccination Project is made possible by a grant from the Robert Wood Johnson Foundation. The foundation has no control over FactCheck.org’s editorial decisions, and the views expressed in our articles do not necessarily reflect the views of the foundation. The goal of the project is to increase exposure to accurate information about COVID-19 and vaccines, while decreasing the impact of misinformation.
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