Higher ivermectin dose, longer duration still futile for COVID, trial finds

Sleeping man meds on nightstand

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A randomized, controlled trial (RCT) shows that even at a higher dose and longer treatment duration, the antimalarial drug ivermectin didn't shorten the time to a sustained recovery from COVID-19.

In the double-blind trial, published yesterday in JAMA, a team led by Duke University researchers evaluated time to sustained recovery among 1,206 COVID-19 patients at 93 US sites from Feb 16 to Jul 22, 2022, with follow-up until Nov 10, 2022. Sustained recovery was considered at least 3 days without symptoms.

Patients were at least 30 years old and had two or more symptoms for no more than 7 days, 59.1% were women, and 83.5% reported receiving two or more COVID-19 vaccine doses.

The trial was part of the ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6), which was designed to assess the effectiveness of repurposed drugs such as ivermectin in the treatment of mild to moderate COVID-19.

Of all participants, 602 were randomly assigned to receive 600 micrograms per kilogram (μg/kg) of ivermectin once daily for 6 days, and 604 received a placebo. The dose used in previous RCTs showing futility of ivermectin for COVID-19 was 400 μg/kg once daily for 3 days, which some experts suggested was insufficient.

Both groups recovered in about 11 days

The median time to sustained recovery was 11 days in both the ivermectin and placebo groups (hazard ratio [HR], 1.02). Of the ivermectin recipients, 5.7% were hospitalized, died, or visited an urgent care center or emergency department, compared with 6.0% of placebo recipients (HR, 1.0).

One ivermectin recipient died, and 4 (0.8%) were hospitalized. Among placebo recipients, 2 (0.3%) were hospitalized, and none died. Adverse events were rare in both groups.

Despite the lack of efficacy in randomized, controlled trials, media reports and clinical experience suggests that some healthcare providers in the United States and abroad still prescribe ivermectin for their COVID-19 patients, according to an editor's note by Kirsten Bibbins-Domingo, PhD, MD, and Preeti Malani, MD, JAMA editor-in-chief and deputy editor, respectively.

The continued practice, they wrote, is "fueled in part by real or perceived lack of access to effective therapies, continued confusion or misinformation, and active disinformation about ivermectin's efficacy, including by physicians. More must be done in partnership with others to address the misinformation that continues as we embark on the fourth year of the COVID-19 pandemic."

Are more ivermectin trials needed?

In a related editorial, Alex John London, PhD, of Carnegie Mellon University, and Christopher Seymour, MD, of the University of Pittsburgh, noted that while evidence against ivermectin for this indication is likely sufficient, more than 10 ivermectin trials are still recruiting participants on ClinicalTrials.gov.

Despite the lack of efficacy in randomized, controlled trials, media reports and clinical experience suggests that some healthcare providers in the United States and abroad still prescribe ivermectin for their COVID-19 patients.

The number of ongoing trials on a drug already proven futile, and their inherent resource use and ethical dilemmas, beg the question of clinical equipoise, they said.

"The equipoise requirement holds that (1) research that addresses uncertainty or conflicting medical judgments of conscientious and informed experts is likely to have social value and (2) allocating individuals to interventions that are subject to such conflict or uncertainty is consistent with respect for their rights or welfare," they wrote.

London and Seymour argue that uncertainty alone is not enough to ensure that studies fill a knowledge gap that would help clinicians and health systems effectively and equitably promote the best interests of patients.

"After considering factors that can influence the persistence of clinical equipoise, we argue that decisions about what investigations to undertake must be responsive to the relative social value of continuing to reduce uncertainty around one intervention, and stakeholders must consider whether scarce time, resources, and participant effort could be better invested examining other questions," they wrote.

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