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Randomized Controlled Trial
. 2022 Oct 25;328(16):1595-1603.
doi: 10.1001/jama.2022.18590.

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

Susanna Naggie  1   2 , David R Boulware  3 , Christopher J Lindsell  4 , Thomas G Stewart  4 , Nina Gentile  5 , Sean Collins  4 , Matthew William McCarthy  6 , Dushyantha Jayaweera  7 , Mario Castro  8 , Mark Sulkowski  9 , Kathleen McTigue  10 , Florence Thicklin  11 , G Michael Felker  1   2 , Adit A Ginde  12 , Carolyn T Bramante  3 , Alex J Slandzicki  13 , Ahab Gabriel  14 , Nirav S Shah  15 , Leslie A Lenert  16 , Sarah E Dunsmore  17 , Stacey J Adam  18 , Allison DeLong  1 , George Hanna  19 , April Remaly  1 , Rhonda Wilder  1 , Sybil Wilson  1 , Elizabeth Shenkman  20 , Adrian F Hernandez  1   2 ; Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) Study Group and Investigators
Collaborators, Affiliations
Randomized Controlled Trial

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

Susanna Naggie et al. JAMA. .

Erratum in

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Naggie reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study and grants from Gilead Sciences and AbbVie; personal fees from Pardes Biosciences, Personal Health Insights Inc, and Bristol Myers Squibb/PRA Health Services; and stock options from Vir Biotechnology as well as providing unpaid consultation to Silverback Therapeutics outside the submitted work. Dr Boulware reported receiving grants from the NIH during the conduct of the study. Dr Lindsell reported receiving grants from the National Center for Advancing Translational Sciences (NCATS) during the conduct of the study and grants from the NIH, Centers for Disease Control and Prevention, and Department of Defense to his institution and contracts to his institution for research services from Endpoint Health, bioMerieux, Entegrion Inc, AbbVie, and AstraZeneca outside the submitted work. In addition, Dr Lindsell had a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center. Dr Stewart reported receiving grants from the NIH NCATS during the conduct of the study and grants from the NIH outside the submitted work. Dr Gentile reported receiving personal fees from Duke University during the conduct of the study and grants from the NIH outside the submitted work. Dr Collins reported receiving personal fees from Vir Biotechnology during the conduct of the study. Dr Jayaweera reported receiving grants from NCATS during the conduct of the study and grants from Gilead, Pfizer, Janssen, and ViiV and serving as a consultant for Theratechnologies outside the submitted work. Dr Castro reported receiving grants from the NIH, American Lung Association, Patient-Centered Outcomes Research Institute, AstraZeneca, GlaxoSmithKline, Novartis, Pulmatrix, Sanofi, and Shionogi and personal fees from Genentech, Teva, Sanofi, Merck, Novartis, Arrowhead, OM Pharma, Allakos, Amgen, AstraZeneca, GlaxoSmithKline, Regeneron, and Elsevier outside the submitted work. Dr Sulkowski reported receiving personal fees from AbbVie, Gilead, GlaxoSmithKline, Atea Pharmaceuticals, Antios Therapeutics, Precision BioSciences, Viiv, and Virion and grants from Janssen to Johns Hopkins University outside the submitted work. Dr McTigue reported receiving grants to her institution from the NIH during the conduct of the study and research contracts to her institution from Pfizer and Janssen outside the submitted work. Dr Felker reported receiving grants from the NIH during the conduct of the study and grants from Novartis outside the submitted work. Dr Ginde reported receiving grants from the NIH during the conduct of the study and grants from the NIH, Centers for Disease Control and Prevention, Department of Defense, AbbVie (investigator-initiated), and Faron Pharmaceuticals (investigator-initiated) outside the submitted work. Dr Adam reported receiving funding from the US government (funding through Operation Warp Speed) during the conduct of the study. Dr DeLong reported receiving grants from NCATS during the conduct of the study. Dr Hanna reported receiving grants from the US Biomedical Advanced Research and Development Authority during the conduct of the study and personal fees from Merck & Co and AbPro outside the submitted work. Dr Remaly reported receiving grants from NCATS during the conduct of the study. Dr Wilder reported receiving grants from NCATS during the conduct of the study. Dr Wilson reported receiving grants from NCATS during the conduct of the study. Dr Hernandez reported receiving grants from American Regent, Amgen, Boehringer Ingelheim, Merck, Verily, Somologic, and Pfizer, and personal fees from AstraZeneca, Boston Scientific, Bristol Myers Squibb, Cytokinetics, and Merck outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of Participants in the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) Trial
aIn this platform trial with multiple study drugs, participants were able to choose to which agents they were willing to be randomized. Participants were first randomized 1:m between placebo and study drug, where m was the number of study groups for which the participant was eligible and consented to participate. Then, participants were randomized with 1/m probability among the study drugs for which they were eligible.
Figure 2.
Figure 2.. Posterior Distributions of Effects for (A) Time to Sustained Recovery (1257 Observed Events); (B) Hospitalization, Urgent Care Visits, Emergency Department Visits, or Death (60 Observed Events); and (C) Mean Time Unwell
Thick vertical lines denote the estimated mean of the posterior distribution. Density is the relative likelihood of posterior probability distribution. Outcomes with higher density are more likely than outcomes with lower density.
Figure 3.
Figure 3.. Kaplan-Meier Curve for Primary Outcome of Time to Recovery
Recovery occurs on the third of 3 consecutive days without symptoms. Sixty-six participants were censored for nonresponse, and all others were followed up until recovery, death, or the end of short-term 28-day follow-up.
See this image and copyright information in PMC

Update of

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