Ivermectin Does Not Improve COVID-19 Outcomes

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Ivermectin is no more effective than placebo in reducing the severity of COVID-19 among newly diagnosed patients, according to the largest trial to date that has investigated this question.

Treatment with ivermectin failed to reduce hospital admissions for worsening COVID-19 and failed to shorten the time that patients with COVID-19 stayed as outpatients in the emergency room for observation.

"The main take-home [message] is ivermectin is not a drug that should be widely used for COVID," senior author Edward J. Mills, PhD, professor of health research methods, evidence, and impact at McMaster University in Hamilton, Canada, told Medscape Medical News.

"There were no ill effects that we noticed, and it's generally a very safe drug. And we cannot rule out that there's a small treatment effect, but if there is, it's a small treatment effect, and there are other options out there now that have larger benefits," Mills said.

The findings from the trial, which included 3515 patients from Brazil, were published March 30 in the New England Journal of Medicine.

Adaptive Platform Trial

Ivermectin, which is typically used as an antiparasitic agent, has been much in the news recently, and one of the reasons is that the repurposing of existing medicines that are widely available and reasonably safe has assumed greater importance with the emergence of COVID-19.

Ivermectin inhibits the chloride channels of helminthic parasites and has been shown to have clinical efficacy for the treatment of onchocerciasis, strongyloidiasis, and ectoparasitic infections such as scabies.

Ivermectin has also been studied in vitro for its potential antiviral properties in many viruses, including severe acute respiratory syndrome coronavirus 1 (SARS-1), HIV, dengue, Zika, yellow fever, West Nile, Hendra, chikungunya, Semliki Forest, Sindbis, and avian influenza viruses.

Patients were enrolled at 12 public health clinics in Brazil. Eligible patients had experienced symptoms for up to 7 days and had at least one risk factor for disease progression. These risk factors included age greater than 50 years, diabetes, hypertension requiring medication, cardiovascular and lung disease, smoking, obesity (defined as a BMI greater than 30), organ transplantation, chronic kidney disease (stage IV), or receipt of dialysis, immunosuppressive therapy (receipt of 10 mg or more of prednisone or equivalent daily), a diagnosis of cancer within the previous 6 months, or receipt of chemotherapy for cancer.

"The trial was designed and conducted to simultaneously test potential treatments for early COVID-19," said Mills. "Thus far, the TOGETHER investigators have evaluated hydroxychloroquine and lopinavir-ritonavir and metformin, ivermectin administered for 1 day, ivermectin administered for 3 days, doxazosin, pegylated interferon lambda, and fluvoxamine, compared with matching placebos."

The researchers randomly assigned 3515 participants to receive either ivermectin at a dose of 499 µg/kg for 3 days (n = 679), placebo (n = 679), or another intervention (n = 2157).

"This was an adaptive platform trial where we can test multiple drugs, either at the same time or adding and dropping," said Mills. "We have evaluated 11 different drugs and are currently evaluating three new ones. This was evaluating ivermectin; we are not reporting on other interventions here."

No Significant Effects

The primary composite outcome was hospitalization due to COVID-19 within 28 days after randomization or an emergency department visit as a result of clinical worsening of COVID-19 that lasted for more than 6 hours within 28 days after randomization.

Secondary outcomes included clearance of virus at day 3 and day 7, as assessed with quantitative reverse transcriptase-polymerase chain reaction laboratory testing; hospitalization for any cause; the time to hospitalization; the duration of hospitalization; the time to an emergency visit lasting more than 6 hours; the time to clinical recovery; death from any cause; the time to death; receipt of mechanical ventilation; the number of days with mechanical ventilation; health-related quality of life; and adverse reactions to ivermectin or placebo. All secondary outcomes were assessed through 28 days after randomization.

Overall, 100 patients (14.7%) in the ivermectin group had a primary-outcome event, compared with 111 patients (16.3%) in the placebo group (relative risk, 0.90; 95% Bayesian credible interval, 0.70 - 1.16).

Of the 211 primary outcome events, 171 (81.0%) were hospital admissions.

Findings were similar to those of 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 - 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 - 1.35).

There were no significant effects of ivermectin use on secondary outcomes or adverse events.

Ivermectin Not Recommended

"To be honest, those of us who spend plenty of time evaluating the benefits of various COVID therapeutics took ivermectin off the list of potentially beneficial treatments a while ago," Andrew Morris, MD, professor in the Division of Infectious Diseases at the University of Toronto, Canada, told Medscape Medical News.

The reasons for this include a minimal theoretical basis for concluding that benefits would outweigh potential harms, a track record of unreliable and downright fraudulent data supporting ivermectin, and the strong relationship between the quality of the clinical trial and finding of no benefit from ivermectin.

"This study has the added benefits of size — it is the largest study to date — and methodological rigor," said Morris, who was not involved with the TOGETHER study.

"Ivermectin should not be used for COVID-19 under any circumstances. Recommending it goes against the current state of knowledge," he concluded.

N Engl J Med. Published online March 30, 2022. Full text

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