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SEATTLE -- A higher dose of ivermectin given for a longer duration still failed to offer any benefit in mild to moderate COVID-19, data from a large randomized U.S. trial showed.

In the ACTIV-6 trial of more than 1,200 largely vaccinated outpatients, the median time to sustained recovery was an identical 11 days with either 6 days of ivermectin at a targeted daily dose of 600 μg/kg or placebo (P=0.68), reported Susanna Naggie, MD, MHS, of the Duke University School of Medicine in Durham, North Carolina.

And no difference was seen for the secondary endpoint of hospitalization, urgent or emergency department care visits, or death, at 5.7% with ivermectin compared with 6% with placebo (P=0.53), according to findings detailed at the Conference on Retroviruses and Opportunistic Infections annual meeting.

"These findings do not support the use of ivermectin in outpatients with COVID-19," said Naggie.

One death and four hospitalizations occurred in the ivermectin group versus no deaths and two hospitalizations in the placebo group. Overall, adverse events (AEs) were uncommon in both arms.

Results of the trial were published simultaneously in .

In an accompanying , JAMA Editor-in-Chief Kirsten Bibbins-Domingo, MD, PhD, and Preeti Malani, MD, MSJ, the journal's deputy editor, pointed out that a 2022 of 11 eligible studies showed no benefit with ivermectin for COVID-19, and that three randomized trials since then have all reached the same conclusion.

Yet the negative trials failed to silence proponents of the controversial antiparasitic, with criticism often lobbed at the dosage selected or duration of treatment used in trials.

"Today JAMA publishes a new trial of ivermectin treatment for mild to moderate COVID-19 that addresses the possibility that the existing literature may have missed the efficacy of ivermectin because the previously tested dose -- approximately 400 μg/kg daily for 3 days -- was insufficient," they wrote. "At a higher treatment dose -- 600 μg/kg daily and longer treatment duration of 6 days, Naggie and colleagues again conclude that ivermectin is not beneficial for the treatment of COVID-19."

Although AEs were not significantly different between the ivermectin and placebo groups, Bibbins-Domingo and Malani cautioned that ivermectin treatment for COVID-19 could still be harmful, particularly if it delays the use of other proven interventions.

Naggie's group said a strength of the current study was that 83.5% had received at least two doses of vaccine, "thus representing a highly relevant study population," noting that past ivermectin trials had excluded vaccinated participants. No different effect by vaccination status was seen for the primary endpoint of time to sustained recovery, which was defined as at least 3 consecutive days without symptoms.

In an accompanying , Alex John London, PhD, of Carnegie Mellon University in Pittsburgh, and Christopher Seymour, MD, of the University of Pittsburgh, highlighted that despite all the evidence against it thus far, ivermectin studies continued, perhaps at the expense of other more fruitful endeavors.

"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.

The current arm of the ACTIV-6 platform trial recruited from February 2022 to July 2022 at 93 sites in the U.S., and ultimately included 1,206 participants with confirmed COVID-19. Participants were randomized to ivermectin at a daily targeted maximum dose of 600 μg/kg for 6 days (n=602) or placebo (n=604).

Participants had a median age of 48 years, about 60% were women, and three-fourths were white. About a quarter of the individuals had hypertension, 13-16% had asthma, and 9% had diabetes.

Participants had to have at least two COVID-19 symptoms for no longer than 7 days before enrollment. From symptom onset, the median time to enrollment was 3 and 60% received treatment within 5 days. Exclusion criteria included hospitalization, ivermectin use within the past 14 days, and known allergy or contraindication to the study drug.

Concurrent use of standard therapies for COVID-19 was allowed. Here, 2.5% of patients on the ivermectin arm received nirmatrelvir-ritonavir (Paxlovid) versus 4.3% of placebo patients. Other treatments included the use of monoclonal antibodies in 4.2% and 3.6%, respectively, and molnupiravir in 0.2% and 0.8%.