Original Article from The New England Journal of Medicine — Effect of Early Treatment with Ivermectin among Patients with Covid-19
www.nejm.org
Effect of Early Treatment with Ivermectin among Patients with Covid-19
Discussion
We did not find a significantly or clinically meaningful lower risk of medical admission to a hospital or prolonged emergency department observation (primary composite outcome) with ivermectin administered for 3 days at a dose of 400 μg per kilogram per day than with placebo. We found no important effects of treatment with ivermectin on the secondary outcomes.
The evidence supporting the role of ivermectin in the treatment of Covid-19 is inconsistent. At least three meta-analyses of ivermectin trials have strongly indicated a treatment benefit, and others have concluded that there was no benefit.
7,8,18-20 Although the number of included trials involving outpatients varies among the meta-analyses, the overall number of events that occurred in our trial is larger than the number of all the combined events in these meta-analyses. The results of this trial will, therefore, reduce the effect size of the meta-analyses that have indicated any benefits. In addition, a reported trial of ivermectin treatment for Covid-19 was suspected of malfeasance and was withdrawn from publication,
9and other trials have been weakened by concerns about quality.
8 A large collaboration of clinical trialists working on ivermectin treatment for Covid-19 has conducted a meta-analysis of trials and has concluded that ivermectin did not offer a treatment benefit when trials that were considered to be of moderate or better quality were examined.
6 The WHO has concluded, on the basis of results obtained before our trial, that there existed only very-low-certainty evidence regarding ivermectin and thus recommended against the use of ivermectin for the treatment of patients with Covid-19 outside the clinical trial setting.
21 The findings in our trial are consistent with these conclusions.
Major strengths of our trial include the rapid recruitment and enrollment of high-risk patients. We enrolled only patients who had a confirmed diagnosis of Covid-19 and less than 7 days of symptoms, and we did not enroll asymptomatic SARS-CoV-2–positive persons. The primary outcome was a composite of hospitalization for adjudicated Covid-19 as well as retention in a Covid-19 emergency setting for physician observation for more than 6 hours. Patients in these settings would typically have been hospitalized but were prevented from doing so because of limited capacity in hospitals.
When we began this trial, we randomly assigned patients to receive a 1-day dose of ivermectin, as is most commonly used for the treatment of parasitic diseases. We responded to feedback from advocacy groups regarding this administration schedule and adapted the duration of ivermectin administration to 3 days at a relatively high dose as compared with most other trials of this drug. Ivermectin has been used off-label widely since the original in vitro study by Caly et al. describing ivermectin activity against SARS-CoV-2,
22 and in Brazil, in particular, the use of ivermectin for the treatment of Covid-19 has been widely promoted. We ensured that trial participants did not have a history of ivermectin use for the treatment of Covid-19 by means of extensive screening of potential participants about this issue. Given the public interest in ivermectin and the support of its use by paramedical groups, we suspect that there will be additional criticism that our administration regimen was inadequate. Details of the pharmacologic rationale and mechanistic hypotheses for ivermectin use are provided in the
Supplementary Appendix.
In this randomized trial, the administration of ivermectin did not result in a lower incidence of medical admission to a hospital or prolonged emergency department observation for Covid-19 among outpatients at high risk for serious illness.