Largest Ivermectin Trial Fails to Show Benefit in COVID Outpatients

Early use of ivermectin in COVID-19 patients at high-risk for severe disease failed to lower the risk of hospitalization or prolonged emergency department (ED) observation, a large randomized trial showed.

In an adaptive platform trial in Brazil, an intention-to-treat (ITT) analysis found that 14.7% of patients in the ivermectin group and 16.3% of patients in the placebo group either required hospitalization or visited an ED within 28 days due to worsening COVID symptoms (relative risk 0.90, 95% Bayesian credible interval [CrI] 0.70-1.16), reported Craig Rayner, PharmD, of Monash University in Melbourne, Australia, and TOGETHER trial colleagues.

More than 60 randomized trials of ivermectin as COVID treatment have been registered, with findings reported for as many as 31 trials. However, most trials have either been small and a few have been "withdrawn from publication owing to concerns about credibility," they stated in the New England Journal of Medicine.

The TOGETHER trial is a randomized, placebo-controlled, adaptive platform trial, and this particular subset of data was from March 23, 2021 to Aug. 6, 2021. Patients were assigned to receive either 400 μg/kg of ivermectin or placebo for 3 days.

Participants were adults with high-risk medical conditions who presented to outpatient care with "an acute clinical condition consistent with Covid-19" within 7 days of symptom onset. "Patients who had been vaccinated against SARS-CoV-2 were eligible for participation in the trial," according to the authors.

Rayner's group also noted that while hospitalization within 28 days would have been the primary outcome, it was expanded to include ED visits, as patients who would've been hospitalized could not be due to limited capacity during peak COVID waves. They used observation in a COVID-19 emergency setting for over 6 hours as a proxy for hospitalization.

Overall, 1,358 patients were randomized 1:1 to receive either ivermectin or placebo. Median age was 49, 58% were women, nearly all identified as being mixed race, and 12% had type 2 diabetes, which was considered a high-risk condition for COVID progression. Mean number of days with COVID symptoms prior to randomization was about 4.

There were 100 patients in the ivermectin group and 111 in the placebo group who progressed to the primary outcome. These results were similar in a modified ITT, defined as at least one dose of the agent or placebo (RR 0.89, 95% Bayesian CrI 0.69-1.15), and a per-protocol analysis, which included only patients who reported 100% adherence to the assigned regimen (RR 0.94, 95% Bayesian CrI 0.67-1.35).

Of these primary outcome events, 81% were hospitalizations, and primary outcome events happened after a median of 5 days, the authors said.

There were no significant differences in viral clearance at day 7 between groups, nor were there differences in risk of hospitalization for any cause, time to hospitalization, and number of days in the hospital. Rayner's group noted there was also no significant difference in time to clinical recovery, risk of death, or days with mechanical ventilation.

The authors noted that some "meta-analyses of ivermectin trials have strongly indicated a treatment benefit, and others have concluded that there was no benefit," but they pointed out that the number of events in the current trial surpass all of the combined events in these meta-analyses. "The results of this trial will, therefore, reduce the effect size of the meta-analyses that have indicated any benefits," they added.

Rayner and colleagues appeared to brace themselves against potential criticism, due to the "public interest in ivermectin and support of its use by paramedical groups."

"We suspect that there will be additional criticism that our administration was inadequate," they said. When the trial first started, the investigators randomly assigned patients to a 1-day dose of ivermectin (common for treating parasitic diseases), but adjusted the administration to 3 days at a relatively high dose following "feedback from advocacy groups."

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