Original Investigation 

October 21, 2022

Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial

Susanna Naggie, David R. Boulware, Christopher J. Lindsell, et al

JAMA. Published online October 21, 2022. doi:10.1001/jama.2022.18590

Key Points

Question  Does ivermectin, 400 μg/kg, daily for 3 days, compared with placebo, shorten symptom duration among adult (≥30 years) outpatients in the US with symptomatic mild to moderate COVID-19?

Findings  In this double-blinded, randomized, placebo-controlled platform trial conducted in the US during a period of Delta and Omicron variant predominance, and that included 1591 adult outpatients with COVID-19, the posterior probability of improvement in time to recovery in those treated with ivermectin vs placebo had a hazard ratio of 1.07, with a posterior probability of benefit of .91. This did not meet the prespecified threshold of posterior probability greater than .95.

Meaning  These findings do not support the use of ivermectin in outpatients with mild to moderate COVID-19.

Abstract

Importance  The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown.

Objective  To evaluate the efficacy of ivermectin, 400 μg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19.

Design, Setting, and Participants  ACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US.

Interventions  Participants were randomized to receive ivermectin, 400 μg/kg (n = 817), daily for 3 days or placebo (n = 774).

Main Outcomes and Measures  Time to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28.

Results  Among 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5]).

Conclusions and Relevance  Among outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19.

Trial Registration  ClinicalTrials.gov Identifier: NCT04885530