Early ivermectin does not prevent progression to severe COVID-19

The early addition of ivermectin to standard of care (SoC)* in high-risk patients with mild-to-moderate COVID-19 did not prevent progression to severe disease compared with SoC alone, according to results of the I-TECH** trial conducted in Malaysia.

“The study findings do not support the use of ivermectin for patients with COVID-19,” the researchers pointed out.

This multicentre, open-label trial was conducted between May 31 and October 25, 2021. A total of 490 patients aged ≥50 years (mean age 62.5 years, 54.5 percent female, 51.8 percent had received two doses of COVID-19 vaccine) with RT-PCR- or antigen test-confirmed COVID-19, mild-to-moderate disease, and comorbidities were enrolled within 1 week of symptom onset (mean 5.1 days). Patients were randomized 1:1 to receive SoC alone (control group) or in addition to oral ivermectin (0.4 mg/kg/day for 5 days).

Common comorbidities in the study population were hypertension, diabetes mellitus, dyslipidaemia, and obesity (75.3, 53.5, 37.6, and 23.9 percent, respectively).

Progression to severe disease (hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation of ≥95 percent) did not significantly differ between patients who received ivermectin–SoC compared with SoC alone (21.6 percent vs 17.3 percent; relative risk [RR], 1.25, 95 percent confidence interval [CI], 0.87–1.80; p=0.25). [JAMA Intern Med 2022;doi:10.1001/jamainternmed.2022.0189]

The rates of mechanical ventilation were relatively low and did not significantly differ between the ivermectin–SoC and control groups (1.7 percent vs 4.0 percent; RR, 0.41, 95 percent CI, 0.13–1.30; p=0.17), nor did rates of intensive care unit admission (2.5 percent vs 3.2 percent; RR, 0.78, 95 percent CI, 0.27–2.20; p=0.79).

Time to progression to severe disease was similar between the ivermectin–SoC and control groups (mean 3.2 vs 2.9 days; p=0.51) and patients had a comparable duration of hospitalization (mean 7.7 vs 7.3 days; p=0.38). 

There were three in-hospital deaths within 28 days in the ivermectin–SoC group and 10 in the control group, with no significant difference between groups (1.2 percent vs 4.0 percent; RR, 0.31, 95 percent CI, 0.09–1.11; p=0.09). Severe COVID-19 pneumonia was the principal cause of death in nine cases, and four deaths in the control group were due to nosocomial sepsis. None of the deaths were deemed related to ivermectin.

Repeat assessment at day 5 showed a comparable rate of complete symptom resolution between the ivermectin–SoC and control groups (51.3 percent vs 53.0 percent; RR, 0.97; p=0.72), with 25.6 and 24.9 percent, respectively, having normal chest radiography findings (RR, 1.03; p=0.92).

Nine percent of patients (n=44) experienced adverse events (AEs), with 33 of the 55 events occurring in the ivermectin–SoC group. The most common AE was diarrhoea (5.8 percent [ivermectin–SoC] vs 1.6 percent [control]). Five serious AEs were documented, four in the ivermectin–SoC group and one in the control group. Six patients discontinued ivermectin, and three withdrew from the study due to AEs.

Antivirals, anti-inflammatory drugs, and monoclonal antibodies have shown benefits at different stages of COVID-19, said the researchers.

“In Malaysia, about 95 percent of patients with COVID-19 present early with mild disease, and less than 5 percent progress to a hypoxic state requiring oxygen supplementation,” they said. Antivirals such as molnupiravir and nirmatrelvir/ritonavir, while effective in early COVID-19, may not be an affordable option “for widespread use in resource-limited settings,” they added.

“Although some early clinical studies suggested the potential efficacy of ivermectin in the treatment and prevention of COVID-19 … we found no evidence that ivermectin was efficacious in reducing the risk of severe disease,” they concluded.

The open-label study design may have led to underreporting of AEs in the control group, the researchers acknowledged. Nonetheless, the greater AE rate with ivermectin as seen in this study “raises concerns about the use of this drug outside of trial settings and without medical supervision.”