Question
Does ivermectin, with a maximum targeted dose of 600 μg/kg daily for 6 days, compared with placebo, shorten symptom duration among adult (≥30 years) outpatients with symptomatic mild to moderate COVID-19?
Findings
In this double-blind, randomized, placebo-controlled platform trial including 1206 US adults with COVID-19 during February 2022 to July 2022, the median time to sustained recovery was 11 days in the ivermectin group and 11 days in the placebo group. In this largely vaccinated (84%) population, the posterior probability that ivermectin reduced symptom duration by more than 1 day was less than 0.1%.
Meaning
These findings do not support the use of ivermectin among outpatients with COVID-19.
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
Despite treatment advances for COVID-19, the evolution of SARS-CoV-2 variants and subvariants has shifted therapeutic options, including the recent loss of effectiveness of monoclonal antibodies. Novel oral antivirals have been authorized for high-risk individuals in high-income countries.1,2 However, efficacy of these antivirals in those vaccinated or with prior SARS-CoV-2 infection remains unclear. Interest remains for the potential of repurposed drugs to improve symptoms and clinical outcomes among patients with COVID-19.
Numerous repurposed drugs have been investigated for COVID-19 management, with several large randomized outpatient trials published.3–5 Trial results have been mixed. Trials of some drugs suggest possible benefit by reducing emergency department (ED) visits or hospitalizations, including fluvoxamine dosed at 100 mg twice daily3 and immediate-release metformin.6 Others have failed to show a reduction in ED visits or hospitalizations, such as fluvoxamine 50 mg twice daily.6,7 Although recently completed trials benefit from the increasing representation of vaccinated people, which is more relevant to the pandemic’s current state, the results have not affected treatment guidelines largely due to study design limitations, including definitions of outcomes that were of unclear significance in the US health care setting.8–10
Ivermectin, an antiparasitic drug used worldwide for onchocerciasis and strongyloidiasis, emerged in 2020 as a potential repurposed drug for COVID-19 initially informed by an in vitro study suggesting possible antiviral activity.11 The interest for ivermectin as a therapy for COVID-19 has remained high and, although there have been numerous ivermectin studies, its use has become controversial due to a lack of high-quality adequately powered randomized trials and article retractions of some of the earlier and most positive studies.12–15 Three large randomized outpatient trials of people with symptomatic mild or moderate COVID-19 failed to identify a clinical benefit of ivermectin when dosed at 400 μg/kg daily for 3 days.16–18 One possibility is that the dose and duration studied were too low and too short, missing the therapeutic window for ivermectin. A combination of modeling studies and a proof-of-concept clinical study have suggested doses up to 600 μg/kg daily may achieve system levels sufficient for in vitro antiviral activity.18,19 For this reason we tested ivermectin, with a maximum targeted dose of 600 μg/kg daily, for 6 days from February 16, 2022, through July 22, 2022. This report describes the effectiveness of this dose and duration of ivermectin compared with placebo for the treatment of early mild to moderate COVID-19. The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms, and secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28.
Trial Design and Oversight
Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) is an ongoing, fully remote (decentralized), double-blind, randomized placebo-controlled platform trial investigating repurposed drugs for the treatment of mild to moderate COVID-19 in the outpatient setting. The platform protocol is designed to be flexible, allowing enrollment across a wide range of settings within health care systems and the community, as well as virtually. The platform enrolls outpatients with mild to moderate COVID-19 with a confirmed positive SARS-CoV-2 test result. The full trial protocol and statistical analysis plan are available in Supplement 1 and Supplement 2.
The trial protocol was approved by each site’s institutional review board. Participants provided informed consent either via written consent or an electronic consent process. An independent data monitoring committee oversaw participant safety and trial conduct.
Recruitment into the platform trial opened on June 11, 2021, and ivermectin 600 μg/kg was included on the platform beginning on February 16, 2022. Enrollment into the ivermectin 600 μg/kg group was stopped on July 22, 2022, when 1206 participants had received their study drug, identical matched placebo, or contributing placebo. Participants were either identified by sites or self-identified by contacting a central study telephone hotline or website.
Study staff verified eligibility criteria including age of 30 years or older, SARS-CoV-2 infection within 10 days (positive polymerase chain reaction or antigen test result, including home-based tests), and experiencing at least 2 symptoms of acute COVID-19 for no more than 7 days from enrollment. The protocol defined “mild to moderate” as having symptoms as noted above self-reported at the time of enrollment, and symptoms were graded by participants as none, mild, moderate, or severe. Symptoms included fatigue, dyspnea, fever, cough, nausea, vomiting, diarrhea, body aches, chills, headache, sore throat, nasal symptoms, and new loss of sense of taste or smell. Exclusion criteria included hospitalization, ivermectin use within 14 days, and known allergy or contraindication to the study drug (Supplement 1). Vaccination against SARS-CoV-2 was allowable, as was concurrent use of standard therapies for COVID-19 available under US Food and Drug Administration Emergency Use Authorization or approval.
Participants were randomized using a random number generator in a 2-step process (Figure 1). First, participants were randomized to receive an active agent or placebo in a ratio of m:1, where m is the number of study drugs for which the participant was eligible; the other study drug under investigation during this period was fluvoxamine 50 mg twice daily for 10 days. Participants could choose to opt out of specific study drug groups during the consent process if they or the site investigator did not feel there was equipoise or if there was a contraindication to any study drug on the platform. 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 more study drugs a participant was eligible for, the greater the chance of receiving an active agent. Participants who were eligible to receive both ivermectin and fluvoxamine 50 mg but were randomized to the fluvoxamine-matched placebo group were included in and contributed to the placebo group for ivermectin.
A central pharmacy supplied ivermectin or placebo to participants via direct home delivery. Ivermectin was supplied as a bottle of 7-mg tablets. Participants were instructed to take a prespecified number of tablets for 6 consecutive days based on their weight for a maximum targeted daily dose of approximately 600 μg/kg. The dosing schedule was based on weight ranges as follows: those weighing 35 to 52 kg received a 21-mg daily dose; 53 to 69 kg, 28-mg daily dose; 70 to 89 kg, 42-mg daily dose; 90 to 109 kg, 49-mg daily dose; 110 to 129 kg, 56-mg daily dose; and more than 129 kg, 70-mg daily dose. This schedule resulted in a range of doses from 400 to 600 μg/kg (eFigure 1 in Supplement 3) and a median (IQR) dose of 498 (465-532) μg/kg per day. The median daily dose was calculated among participants randomized to receive ivermectin. Packaging for the matched placebo was identical to ivermectin and packaging for the contributing placebos was identical to that of the associated study drug, which in this case was fluvoxamine 50 mg twice daily.
The primary measure of effectiveness was time to sustained recovery, defined as the number of days between study drug receipt and the third of 3 consecutive days without symptoms. This outcome was selected a priori from among the 2 co–primary end points that remain available to other study drugs in the platform (Supplement 2). The key secondary outcome was the composite of hospitalization or death by day 28. Other secondary outcomes included mean time unwell, estimated from a longitudinal ordinal model; COVID-19 Clinical Progression Scale score on days 7, 14, and 28; mortality through day 28; and the composite of urgent or emergency care visits, hospitalizations, or death through day 28. The final secondary outcome, the Patient-Reported Outcomes Measurement Information System 29 profile, was to be assessed through day 90 and is not reported in this article because of the longer follow-up.
The study was designed as a fully remote, or decentralized, trial. Screening and eligibility confirmation were participant-reported and site-confirmed. A positive SARS-CoV-2 polymerase chain reaction or antigen test result was verified prior to randomization via uploading into the participant portal and reviewal by the site. At screening, participant-reported demographic information was collected and included race and ethnicity, eligibility criteria, medical history, concomitant medications, symptom reporting, and quality-of-life questionnaires.
A central investigational pharmacy distributed the study drug (either active or placebo) using a next-day priority shipping service. Delivery was tracked and participants needed to have received the study drug within 7 days of enrollment to be included. Confirmation that the study drug was delivered to the participant’s address was required for the participant to be included in the analysis. Receipt of study drug was defined as study day 1.
Participants were asked to c
