Effect of Early Treatment with Ivermectin among Patients with Covid-19

Abstract

Background: The efficacy of ivermectin in preventing hospitalization or extended observation in an emergency setting among outpatients with acutely symptomatic coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is unclear.

Methods: We conducted a double-blind, randomized, placebo-controlled, adaptive platform trial involving symptomatic SARS-CoV-2-positive adults recruited from 12 public health clinics in Brazil. Patients who had had symptoms of Covid-19 for up to 7 days and had at least one risk factor for disease progression were randomly assigned to receive ivermectin (400 μg per kilogram of body weight) once daily for 3 days or placebo. (The trial also involved other interventions that are not reported here.) The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization.

Results: A total of 3515 patients were randomly assigned to receive ivermectin (679 patients), placebo (679), or another intervention (2157). Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, as compared with 111 (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16). Of the 211 primary-outcome events, 171 (81.0%) were hospital admissions. Findings were similar to the primary analysis in a modified intention-to-treat analysis that included only patients who received at least one dose of ivermectin or placebo (relative risk, 0.89; 95% Bayesian credible interval, 0.69 to 1.15) and in a per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen (relative risk, 0.94; 95% Bayesian credible interval, 0.67 to 1.35). There were no significant effects of ivermectin use on secondary outcomes or adverse events.

Conclusions: Treatment with ivermectin did not result in a lower incidence of medical admission to a hospital due to progression of Covid-19 or of prolonged emergency department observation among outpatients with an early diagnosis of Covid-19. (Funded by FastGrants and the Rainwater Charitable Foundation; TOGETHER ClinicalTrials.gov number, NCT04727424.).

Figure 1. Randomization and Follow-up of the Patients.

Outpatients with symptoms of coronavirus disease 2019 (Covid-19) were assessed for eligibility. The intention-to-treat population included all the patients who had undergone randomization. The modified intention-to-treat population included all the patients who received ivermectin or placebo for at least 24 hours before a primary-outcome event (hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19, defined as the participant remaining under observation for >6 hours); if the event occurred before 24 hours after randomization, the patient was not included in this population. The per-protocol population included only patients who reported 100% adherence to the assigned regimen. Only the results in the 3-day ivermectin group as compared with the concurrent placebo group are reported in this article. Participants in the placebo group received placebo for 1, 3, 10, or 14 days, comparable to the active-treatment groups in the trial. Although all the participants who had been assigned to receive any placebo were included in the intention-to-treat population, only those in the 3-day placebo groups were included in the per-protocol population.

Figure 2. Subgroup Analyses of Ivermectin as Compared with Placebo for the Prevention of Covid-19–Related Hospitalization or Prolonged Observation in an Emergency Setting.

The primary composite outcome was hospitalization due to Covid-19 within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization. Arrows indicate that the 95% Bayesian credible interval extends outside the graphed range.