Early ivermectin use does not confer benefit for COVID-19

In outpatients with an early diagnosis of COVID-19 at high risk for serious illness, treatment with the antiparasitic ivermectin did not reduce the incidence of hospital admission due to disease progression or of prolonged emergency department observation, findings from the TOGETHER trial suggest.

This adaptive platform study comprised 3,515 symptomatic SARS-CoV-2-positive adults (median age 49 years, 58 percent female) recruited from public health clinics in Brazil. Participants were randomized to receive ivermectin (400 μg/kg of body weight) QD for 3 days (n=679), placebo (n=679), or another intervention (n=2,157). [N Engl J Med 2022;386:1721-1731]

Overall, similar fractions of ivermectin and placebo recipients had a primary outcome event (15 percent vs 16 percent; relative risk [RR], 0.90). These findings aligned with that of the primary analysis evaluating patients who have received at least one dose of ivermectin or placebo (RR, 0.89) and those who reported 100-percent adherence to their assigned regimen (RR, 0.94).

There were also no significant differences between the ivermectin and the placebo arms in terms of viral clearance at day 7 (RR, 1.00); risk of hospitalization for any cause (RR, 0.83) or of death (RR, 0.88); time to hospitalization (hazard ratio [HR], 0.83), clinical recovery (HR, 1.05), or death (HR, 0.88); and median number of days in hospital (1 day) and with mechanical ventilation (1.06 days).

Apart from the higher incidence of grade 3/4 general disorders and administration site conditions in the ivermectin vs the placebo arm (7 percent vs 1 percent), other safety outcomes were generally similar between arms, as were the quality-of-life outcomes as reflected by the PROMIS* Global-10 scores measured on day 28 (mean differences, −0.4 and 6.1** points for the respective physical and mental components).

Ivermectin has gained public interest owing to evidence demonstrating its efficacy against various infections and a spectrum of viruses. [Biochem Pharmacol 2002;63:1061-1068; J Antibiot (Tokyo) 2020;73:593-602] For COVID-19 however, trials on ivermectin treatment have reflected discordant results. [Lancet Digit Health 2020;2:e286-e287; Open Forum Infect Dis 2022;9:ofab645; Am J Ther 2021;28:e434-e460; BMJ 2020;370:m2980]

“[Based on the] results obtained before our trial, [the WHO has concluded] that there existed only very-low-certainty evidence regarding ivermectin and thus recommended against the use of ivermectin for the treatment of COVID-19 patients outside the clinical trial setting,” said the researchers.

“[Our results] are consistent with these conclusions … 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,” they said. “We also found no important effects of treatment with ivermectin on the secondary outcomes.”

“[However,] given the public interest in ivermectin and the support of its use by paramedical groups … there [might] be additional criticism that our administration regimen was inadequate,” they noted.