Ivermectin treatment given to high-risk patients with mild-to-moderate COVID-19 during the first week of illness did not prevent progression to severe disease, according to results from a randomized clinical trial.

“The study findings do not support the use of ivermectin for patients with COVID-19,” researchers conclude in the paper published online today in JAMA Internal Medicine.

The open-label trial was conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. It was led by Steven Chee Loon Lim, MRCP, Department of Medicine, Raja Permaisuri Bainun Hospital, Perak, Malaysia.

Among 490 patients in the primary analysis, 52 of 241 patients (21.6%) in the ivermectin group and 43 of 249 patients (17.3%) in the control group progressed to severe disease (relative risk [RR], 1.25; 95% confidence interval [CI], 0.87 – 1.80; P = .25). All major ethnic groups in Malaysia were well represented, the researchers write.

Participants (average age 62.5 and 54.5% women) were randomly assigned 1:1 to receive either a 5-day course of oral ivermectin (0.4 mg/kg body weight daily for 5 days) plus standard of care (n = 241) or standard of care alone (n = 249). Standard of care included symptomatic therapy and monitoring for early deterioration, based on clinical findings, laboratory tests, and chest imaging.

Secondary Outcomes

Secondary outcomes included rates of mechanical ventilation, intensive care unit (ICU) admission, 28-day in-hospital mortality, and side effects.

In all the secondary outcomes, there were no significant differences between groups.

Mechanical ventilation occurred in four patients on the ivermectin protocol (1.7%) vs 10 patients in the control group (4.0%) (RR, 0.41; 95% CI, 0.13 – 1.30; P = .17); ICU admission occurred in six (2.4%) vs eight (3.2%) (RR, 0.78; 95% CI, 0.27 – 2.20; P = .79); and 28-day in-hospital death occurred in three (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09).

The most common adverse event was diarrhea, reported by 5.8% in the ivermectin group and 1.6% in the control group.

No Difference by Vaccine Status

The researchers conducted a subgroup analysis to evaluate any differences in whether participants were vaccinated. They said that analysis was “unremarkable.”

Just more than half of participants (51.8%) were fully vaccinated with two doses of COVID-19 vaccines. Among the fully vaccinated patients, 17.7% in the ivermectin group and 9.2% in the control group developed severe disease (RR, 1.92; 95% CI, 0.99 – 3.71; P = .06).

Ivermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19, but has not been approved by the US Food and Drug Administration for that purpose. Evidence-based data for or against use has been sparse.

The authors write, “Although some early clinical studies suggested the potential efficacy of ivermectin in the treatment and prevention of COVID-19, these studies had methodologic weaknesses.”

Lim and colleagues point out that their findings are consistent with those of the IVERCOR-COVID19 trial, which found ivermectin ineffective in reducing hospitalization risk.

Previous randomized trials of ivermectin for COVID-19 patients that have included at least 400 patients have focused on outpatients.

In the current study, the authors note, patients were hospitalized, which allowed investigators to observe administration of ivermectin with a high adherence rate. Additionally, the researchers used clearly defined criteria for determining progression to severe disease.

Limitations of the current study include that the open-label design might lead to underreporting of adverse events in the control group while overestimating the drug effects of ivermectin. The study also was not designed to assess the effects of ivermectin on mortality from COVID-19.