New COVID-19 drug, same playbook: Like hydroxychloroquine, ivermectin lacks 'strong data'
The FDA is clear about the use of ivermectin, a drug used primarily to treat intestinal strongyloidiasis and onchocerciasis, as a potential therapy for COVID-19: It is not approved.
Moreover, the drug is not currently recommended by any professional organization. However, the pressures of the pandemic have forced doctors worldwide to make decisions they might not normally make. The on-again, off-again use of hydroxychloroquine is emblematic of that phenomenon.
With hydroxychloroquine effectively sidelined due to insufficient data showing its efficacy, history is repeating itself. Another cheap, commonly-available antiparasitic drug, ivermectin (Stromectol, Merck), is being used widely before the data show that it is ready for primetime.
“People looked at ivermectin because it is approved for other infectious diseases, so there is some comfort level there,” Amesh A. Adalja, MD, an infectious disease, bioterrorism and emergency medicine specialist and senior scholar at Johns Hopkins Center for Health Security, told Healio Rheumatology. “As with hydroxychloroquine, ivermectin was touted because it had some in vitro activity against the virus.”
The key point for Adalja is that the results were seen in vitro rather than in vivo. He suggested that this anti-inflammatory activity was largely seen in “labs and test tubes,” and not in actual patients.
Adarsh Bhimraj, MD, FIDSA, chair of the Infectious Diseases Society of America Guidelines Expert Panel on the treatment and management of COVID-19 and head of the section of neurologic infectious diseases at the Cleveland Clinic, explained the problem with this thinking. “How a drug works in a patient might be more complicated,” he said in an interview. “You should not base the use of a drug solely on in vitro data.”
While the NIH also contraindicates ivermectin in COVID-19, it offered some rationale for use of the drug in its COVID-19 guidelines. “Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to enhance infection by suppressing the host’s antiviral response,” the guideline authors wrote. “In addition, ivermectin docking may interfere with the attachment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein to the human cell membrane.”
Bhimraj had a simple thought about this potential mechanism of action, based primarily on the fact that the bulk of the data have been in vitro. “It’s mechanistic and theoretical reasoning,” he said.
If there is another key concern for Bhimraj, it is that the drug is being used in COVID not for its antiviral properties, but for its putative anti-inflammatory properties. “Rheumatologists love cytokines, but it is still mechanistic reasoning,” he said. “We need efficacy data from RCTs.”
Despite these obvious issues, ivermectin is being used extensively in COVID-19 hot zones such as India and other parts of the Indian subcontinent, and in South America, with mixed results. This kind of widespread, unregulated usage will only serve to complicate the picture of the role ivermectin may or may not ultimately play in the pandemic.
A number of organizations have made strong statements about ivermectin in COVID-19.
The FDA left little room for interpretation: “FDA has not approved ivermectin for use in treating or preventing COVID-19 in humans.”
From WHO: “The current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive. Until more data is available, WHO recommends that the drug only be used within clinical trials.”
The NIH offered a similar statement. “There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of ivermectin for the treatment of COVID-19.”
The IDSA suggested “against ivermectin use outside of the context of a clinical trial,” noting that this was a conditional recommendation with very low certainty of evidence.
Merck, the manufacturer of ivermectin, is also clear about the utility of the drug in COVID-19, noting on its website that there is “no scientific basis for a potential therapeutic effect against COVID-19 from preclinical studies; no meaningful evidence for clinical activity or clinical efficacy in patients with COVID-19 disease; a concerning lack of safety data in the majority of studies. We do not believe that the data available support the safety and efficacy of ivermectin beyond the doses and populations indicated in the regulatory agency-approved prescribing information.”
Experts like Adalja and Bhimraj have taken these warnings to heart and are skeptical of ivermectin as a COVID-19 therapy. Both are clear that further, rigorous study is warranted even as new data are emerging.
If there is one clinical trial that has garnered the most attention, it is the one conducted by Lopez-Medina and colleagues and published in JAMA. The double-blind, randomized controlled trial included 476 adult patients who experienced mild COVID-19 disease and symptoms for 7 days or fewer. Enrollment occurred between July 15, 2020, and Nov. 30, 2020, with follow-up being conducted through Dec. 21, 2020.
The researchers randomly assigned 200 patients ivermectin at 300 g/kg of body weight per day for 5 days and 200 patients to the placebo arm. Time to resolution of symptoms within a 21-day follow-up period served as the primary outcome measure.
Results showed a median time to resolution of symptoms of 10 days (interquartile range, 9-13 days) in the ivermectin group and 12 days (IQR, 9-13 days) in the placebo group (HR = 1.07; P =.53). Results at day 21 showed that 82% of patients treated with ivermectin and 79% those who received placebo showed resolution of symptoms.
“Among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms,” the researchers concluded. “The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.”
“This was a well-done, but small trial in patients with mild or moderate disease,” Bhimraj said. He suggested that this is a negative study for a non-mortality outcome, but because the numbers were small, it might not have produced a statistically significant difference in effect size. The evidence is not enough to warrant a recommendation for the use of ivermectin.
Adalja also put the findings in context. “As with hydroxychloroquine, there are not strong data supporting ivermectin’s use,” he said. “It is so important to study these drugs in COVID-19 to understand if or why they do work.”
For Bhimraj, it comes down to a couple of critical ifs and whys. “It is important for us to be intellectually honest,” Bhimraj said. “By that, I mean that saying something works when you do not have the data is not accurate. But saying something doesn’t work when you do not have data is also intellectually dishonest.”
As part of the IDSA guideline committee, Bhimraj had occasion to comb through individual studies and meta-analyses alike. “A lot of the trials were labeled randomized, controlled trials, but they were not, really,” he said. “Either they had no placebo group, or the patients, physicians or outcome assessors were not blinded. We saw significant risk of bias that makes them more prone to an erroneous conclusion about the efficacy and safety of ivermectin.”
Bhimraj was less than enthusiastic about the pooled “positive results” from meta-analyses of such studies with methodological limitations. Combining heterogeneous studies with a high risk of bias can produce a “significant result” but still reflects the potential biases inherent in them.
Muddying the Waters
It is not just biased and poorly designed trials that can make it difficult for experts to arrive at a firm conclusion about a drug. Bhimraj noted that there have been anecdotes of judges and other non-clinical parties encouraging or ordering clinicians to use ivermectin. “We are also seeing the use of doses much higher than we have traditionally used,” he said. “We have limited safety data on higher doses.”
Of particular concern are the aforementioned regions like India and certain pockets in South America, where clinicians are using ivermectin extensively, according to Bhimraj. “I would strongly encourage people to stop using this drug routinely and encourage them to conduct trials,” he said. “If we start adopting a treatment prematurely, we will never get the much-needed evidence on ivermectin’s efficacy and safety in COVID-19.”
But this is exactly what is happening. Huge numbers of patients are being treated off-label with varying doses. This prevents researchers from understanding if ivermectin might have a role in treating COVID-19, and in which patients, and at what dosing level.
Despite these concerns, Bhimraj believes that the drug should be studied, for one simple reason: “We still do not have highly effective therapies for COVID-19,” he said.
While Adalja acknowledged the dearth of drugs to treat the virus, he does not believe ivermectin is, or will be, the answer. “We will eventually get better antivirals,” he said.
For more information:
Amesh Adalja, MD, can be reached at 621 E. Pratt Street, Suite 210, Baltimore, Maryland 21202; email: firstname.lastname@example.org.
Adarsh Bhimraj, MD, can be reached at 1730 W 25th St, Cleveland, OH 44113; email: email@example.com.