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.
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.
Among a largely vaccinated outpatient population with mild to moderate COVID-19, treatment with ivermectin, with a targeted maximum dose of 600 μg/kg daily for 6 days, compared with placebo was not shown to improve time to recovery in more than 1200 participants in the US during a period of Omicron variant/subvariant circulation. No evidence of benefit was observed for secondary clinical outcomes, including the composite of hospitalization, death, or acute care visits. Hospitalization and death were uncommon in this largely vaccinated population. These findings do not support the use of ivermectin in outpatients with COVID-19.
Multiple large double-blind randomized clinical trials have failed to identify a clinically meaningful benefit of ivermectin when used at a targeted dose of 400 μg/kg daily for 3 days.6,17 This large clinical trial addresses a potential gap in knowledge by testing (1) a higher daily dose (targeted maximum dose of 600 μg/kg) and (2) a longer (6-day) duration of ivermectin. Due to the lack of early-phase studies or animal-model studies to determine optimal dosing for a therapeutic drug, the appropriate dosing of ivermectin for COVID-19 was never determined. Modeling studies and a proof-of-concept clinical study have suggested that doses up to 600 μg/kg daily may achieve levels sufficient for in vitro antiviral activity18,19; however, a phase 2 trial testing ivermectin, 600 μg/kg daily for 7 days, and assessing a virologic end point of oropharyngeal SARS-CoV-2 polymerase chain reaction test result did not show measurable antiviral activity and was stopped for futility.21 With weight-based dosing, there is additional variability in the range for dosing and, in this study, the dosing per weight strata was targeted to a maximum dose of 600 μg/kg; thus, the median dose across the study population of approximately 500 μg/kg is meaningfully higher than that achieved in studies that targeted a maximum dose of 400 μg/kg. For example, a previous study from the current platform trial that had a maximum targeted dose of ivermectin 400 μg/kg achieved a median dose of 343 μg/kg. The 600-μg/kg dose was safe and generally well tolerated, with a higher prevalence of the known self-resolving visual disturbances in the intervention group previously reported with similar doses of ivermectin for parasitic infections.18,19
The notable difference in baseline characteristics between these 2 cohorts is the completed vaccination rate, which was 84% for this study and 47% for the prior ivermectin 400 μg/kg group.16 Hospitalizations and COVID-19–related clinical events were less common in this largely vaccinated cohort. The incidence of acute care visits, hospitalizations, or death was similar with ivermectin (5.7%) and placebo (6.0%), which was a result also observed in the 2 previous randomized trials of ivermectin 400 μg/kg in the US.6,16
This trial has several strengths. This was a double-blind, randomized, placebo-controlled nationwide trial with 93 enrolling sites and a call center that recruited participants from all 50 US states. The ivermectin 600 μg/kg group of the platform trial enrolled rapidly due to ongoing Omicron variant/subvariant surges and largely included vaccinated people, thus representing a highly relevant study population that also addresses a weakness of many other studies that excluded vaccinated people. Furthermore, standard-of-care therapies were allowable in this study, although utilization was low.
This study has limitations. Due to infrequent hospitalization, this study cannot assess the effect of the intervention on this clinical outcome. Also, due to the remote nature of the trial, 60% of participants received the study drug within 5 days of symptom onset. Most outpatient COVID-19 antiviral trials have limited enrollment to participants within 5 days of symptom onset.1,2 In this trial, no evidence of a differential treatment effect was observed based on shorter time to study drug receipt. Lastly, the primary end point–adjusted model did not include underlying comorbidities. Treatment effect was putatively expected to differ based on age and BMI, and these were included as covariates and evaluated for heterogeneity of treatment effect.
Among outpatients with mild or moderate COVID-19, treatment with ivermectin, with a targeted maximum dose of 600 μg/kg daily for 6 days, was not shown to improve time to sustained recovery compared with placebo. These findings do not support the use of ivermectin in outpatients with COVID-19.
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