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. 2023 Mar 21;329(11):888-897.
doi: 10.1001/jama.2023.1650.

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19: A Randomized Clinical Trial

Susanna Naggie  1   2 , David R Boulware  3 , Christopher J Lindsell  4 , Thomas G Stewart  5 , Alex J Slandzicki  6 , Stephen C Lim  7 , Jonathan Cohen  8 , David Kavtaradze  9 , Arch P Amon  10 , Ahab Gabriel  11 , Nina Gentile  12 , G Michael Felker  1   2 , Dushyantha Jayaweera  13 , Matthew W McCarthy  14 , Mark Sulkowski  15 , Russell L Rothman  4 , Sybil Wilson  1 , Allison DeLong  1 , April Remaly  1 , Rhonda Wilder  1 , Sean Collins  4   16 , Sarah E Dunsmore  17 , Stacey J Adam  18 , Florence Thicklin  19 , George J Hanna  20 , Adit A Ginde  21 , Mario Castro  22 , Kathleen McTigue  23 , Elizabeth Shenkman  24 , Adrian F Hernandez  1   2 ; Accelerating Covid-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators
Collaborators, Affiliations

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19: A Randomized Clinical Trial

Susanna Naggie et al. JAMA. .

Erratum in

Abstract

Importance: It is unknown whether ivermectin, with a maximum targeted dose of 600 μg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19.

Objective: To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19.

Design, setting, and participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022.

Interventions: Participants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 μg/kg (n = 602) daily, or placebo (n = 604) for 6 days.

Main outcomes and measures: The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28.

Results: Among 1206 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%) reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups.

Conclusions and relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo did not improve time to sustained 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 receiving grants from Gilead Sciences and AbbVie; receiving personal fees from Pardes Biosciences and Silverback Therapeutics for consulting; serving as a scientific advisor for and having stock options in Vir Biotechnology; receiving personal fees from and serving on a data and safety monitoring board for Personal Health Insights; and serving on an event adjudication committee for Bristol Myers Squibb/PRA Health Sciences outside the submitted work. Dr Boulware reported receiving grants from the NIH (#U24TR001608) as co-chair of the ACTIV-6 trial steering committee during the conduct of the study. Dr Lindsell reported receiving grants to the institution from the National Center for Advancing Translational Sciences (NCATS) to the institution during the conduct of the study and grants to the institution from NIH and Department of Defense and research funds to the institution from the CDC, bioMerieux, AstraZeneca, AbbVie, Entegrion Inc, and Endpoint Health outside the submitted work; having a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center; and having stock options in Bioscape Digital unrelated to the current work. Dr Stewart reported receiving grants from Duke University as a subaward for ACTIV-6 from NIH during the conduct of the study and grants from NIH supported by grants from NCATS and NIDDK and research support from the Abdominal Core Health Quality Collaborative, a 501(c)(3) nonprofit organization, outside the submitted work. Dr Lim reported receiving a subaward from NCATS to the institution during the conduct of the study. Dr Gentile reported receiving personal fees from Duke University for ACTIV-6 protocol development committee membership during the conduct of the study. Dr Felker reported receiving grants from NIH during the conduct of the study. Dr Jayaweera reported receiving grants from NCATS during the conduct of the study and grants from Gilead, ViiV Healthcare, and Janssen and personal fees from Theratechnologies outside the submitted work. Dr Sulkowski reported receiving grants to the institution from Janssen, Vir, and GSK; personal fees for serving on a scientific advisory board from GSK, AbbVie, Antios, Assembly Bio, Atea, Gilead; personal fees for serving on a data and safety monitoring board from Precision Bio and Immunocore; personal fees as an editor for Journal of Viral Hepatitis; and personal fees from NIH (K24DA034621) outside the submitted work. Dr Rothman reported receiving grants from the NIH during the conduct of the study and spouse owning a small amount of stock in Moderna. Dr Wilson reported receiving grants from NCATS (3U24TR001608) during the conduct of the study. Dr DeLong reported receiving grants from NCATS (3U24TR001608) during the conduct of the study. Dr Collins reported receiving grants from NCATS during the conduct of the study and personal fees from Vir Biotechnology and Enanta Pharmaceuticals and grants from NHLBI outside the submitted work. Dr Adam reported receiving US Government funding through Operation Warp Speed during the conduct of the study. Dr Hanna reported receiving grants from US Biomedical Advanced Research & Development Authority contract to Tunnell Government Services for consulting services during the conduct of the study and personal fees from Merck & Co and AbPro outside the submitted work. Dr Ginde reported receiving contracts from NIH during the conduct of the study and grants from NIH, Centers for Disease Control and Prevention, Department of Defense, Faron Pharmaceuticals, and AbbVie outside the submitted work. Dr Castro reported receiving grants from NIH during the conduct of the study and grants from ALA, PCORI, AstraZeneca, Gala Therapeutics, Genentech, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi, and Theravance and personal fees from Genentech, Teva, Sanofi-Aventis, Merck, Novartis, Arrowhead, Allakos, Amgen, OM Pharma, Pfizer, Pioneering Medicines, GSK, and Regeneron and having stock options in Aer Therapeutics outside the submitted work. Dr McTigue reported receiving grants from University of Pittsburgh for ACTIV-6 research funding during the conduct of the study. Dr Hernandez reported receiving grants from AstraZeneca, Merck, and Pfizer outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow in a Trial of Higher-Dose Ivermectin for Mild to Moderate COVID-19
In this platform trial with multiple study drugs, participants were able to choose what agents they were willing to be randomized to receive. Participants were first randomized in a ratio of m:1, where m is the number of study drugs for which the participant was eligible. After randomization to receive an active agent vs placebo, participants were randomized with equal probability among the study drugs for which they were eligible. The consort diagram illustrates a sequential exclusion process, where each step of exclusion was applied to ensure that the reasons for participant removal were mutually exclusive. As a result, each participant was excluded for 1 reason even though multiple exclusions may have been present.
Figure 2.
Figure 2.. Time to Sustained Recovery, Hospitalization, Urgent or Emergency Care Visits, or Death, and 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.. Primary Outcome of Time to Sustained Recovery
Recovery was defined as the third of 3 consecutive days without symptoms. Fifty-nine participants did not provide any follow-up data beyond day 1 and were immediately censored. Fourty-seven participants were censored after some follow-up. All other participantss were followed up until recovery, death, or the end of short-term 28-day follow-up. Median (IQR) time to recovery was 11 (11-12) days in the ivermectin group and 12 (11-12) days in the placebo group. Shaded regions denote the pointwise 95% CIs.
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Comment in

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