Ivermectin is a macrocyclical lactone obtained by hydrogenating the products of Streptomyces avermitilis fermentation1 and approved by the Food and Drug Administration for the treatment of scabies, onchocerciasis, and helminthiases in humans.2 In 2020 and 2021, ivermectin was used in the management of COVID-19 infection, first on an empirical basis and then based on data from small sample clinical trials and observational cohorts.2 The National Institutes of Health, in its COVID-19 treatment guidelines, last updated in April 2022, recommended against the use of ivermectin.2 This position has been endorsed by the US Centers for Disease Control and Prevention.3

In 2021, the American Journal of Therapeutics hosted a vigorous debate regarding the quality of the primary data used by systematic reviewers to justify the therapeutic use of ivermectin for COVID-19.5–11 We indicated at the time that the value of ivermectin for COVID-19 remained to be established by carefully designed and executed randomized, double-blinded, placebo-controlled trials.12

To follow up on our suggestion, we searched Medline on September 15, 2022 using the key words “ivermectin”, “controlled trials” and COVID-19 and identified six reports of such trials13–18 (Table 1).

Table 1. - Randomized, double-blind, placebo-controlled trials of ivermectin for COVID-19 published in 2022. Authors, Country Publication month, year COVID-19 severity Ivermectin group Placebo group Ivermectin dose Treatment duration Clinical outcomes Ivermectin better than placebo Beltran Gonzalez et al,13 Mexico March, 2022 Hospitalized patients with COVID-19 induced pneumonia 36 37 12 mg or 18 mg, according to weight (<80 kg>) N/A Duration of hospitalization; respiratory deterioration; death No Reis et al,14 Brazil May 2022 Acutely symptomatic outpatients 679 679 400 µg/kg 3 days Admission to the hospital or prolonged emergency department observation No Rezai et al,15 Iran June, 2022 Moderate-to-severe COVID-19 infection in hospitalized patients; outpatients without pneumonia or hypoxia 447 444 400 µg/kg 3 days Clinical improvement, admission to ICU, need for invasive ventilation, death No Activ-6 Study Group,16 USA August, 2022 Preprint Early, mild-to-moderate COVID-19 infection in outpatients 817 774 400 µg/kg 3 days Incidence of hospitalization or death No Manumaipiboon et al,17 Thailand August, 2022 Hospitalized patients with mild-to moderate COVID 19 infection 36 36 12 mg 5 days Duration of hospitalization, clinical worsening, death No Bramante et al, USA August 2022 Non-hospitalized adults (52% vaccinated) 410 398 390-470 µg/kg 3 days Severe Covid-19 through 14 days (hypoxia, emergency department visit, hospitalization, death) No

The trials published in 2022 were performed in 3 continents (North America, South America and Asia) and involved 2,425 patients treated with ivermectin and 2,368 patients who received placebo. The severity spectrum of COVID-19 infection was wide, and included asymptomatic persons, outpatients and hospitalized patients with mild-to moderate severity, as well as individuals with confirmed COVID-19 pneumonias. None of these trials indicated that ivermectin was better than placebo regarding mortality and frequency of severe presentations of the infection. Ivermectin is not effective and should not be prescribed for acute COVID-19 infection.

1. Lasota JA, Dybas RA. Avermectins, a novel class of compounds: implications for use in arthropod pest control. Annu Rev Entomol. 1991;36:91–117. 3. Available at: https://emergency.cdc.gov/newsletters/coca/020122.htm. Updated February 1, 2022. Accessed September 16, 2022. 4. Kory P, GU Meduri, Varon J, et al. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. Am J Ther. 2021 Apr 22;28(3):e299-e318. doi: 10.1097/MJT.0000000000001377. Erratum in: Am J Ther. 2021;28:e813. 5. Bryant A, Lawrie TA, Dowswell T, et al. Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical Guidelines. Am J Ther. 2021;28:e434–e460. 6. Kow CS, Hasan SS. Pitfalls in reporting sample size calculation across randomized controlled trials involving ivermectin for the treatment of COVID-19. Am J Ther. 2021;28:e616–e619. 7. Neil M, Fenton N. Bayesian hypothesis testing and hierarchical modeling of ivermectin effectiveness. Am J Ther. 2021;28:e576–e579. 8. Marik PE, Kory P. Ivermectin, A reanalysis of the data. Am J Ther. 2021;28:e579–e580. 9. Rothrock SG, Weber KD, Giordano PA, et al. Meta-analyses do not establish improved mortality with ivermectin use in COVID-19. Am J Ther. 2022;29:e237–e244. 10. Bryant A, Lawrie TA, Fordham EJ, et al. Re: “Commentary” by Rothrock et al. “Meta-Analyses Did Not Establish Improved Mortality With Ivermectin Use in COVID-19”. Am J Ther. 2021;29:e233–e237. 11. Bryant A, Lawrie TA, Fordham EJ, et al. Re: expression of concern for Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, Tham TC. Ivermectin for prevention and treatment of COVID-19 infection. Am J Ther. 2022;29:e232. Am J Ther. 2022;294:455–459. 12. Manu P. Ivermectin research should not Be used to promote vaccine opposition. Am J Ther. 2021;28:e680. 13. Beltran Gonzalez JL, González Gámez M, Mendoza Enciso EA, et al. Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19: a randomized controlled trial. Infect Dis Rep. 2022;14:160–168. 14. Reis G, Silva EASM, Silva DCM, et al. Effect of early treatment with ivermectin among patients with covid-19. N Engl J Med. 2022;386:1721–1731. 15. Rezai MS, Ahangarkani F, Hill A, et al. Non-effectiveness of ivermectin on inpatients and outpatients with COVID-19; results of two randomized, double-blinded, placebo-controlled clinical trials. Front Med (Lausanne). 2022;9:919708. 16. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group, Naggie S. Ivermectin for treatment of mild-to-moderate COVID-19 in the outpatient setting: a decentralized, placebo-controlled, randomized, platform clinical trial. medRxiv [Preprint]. 2022;2022.06.10.22276252. 17. Manomaipiboon A, Pholtawornkulchai K, Poopipatpab S, et al. Efficacy and safety of ivermectin in the treatment of mild to moderate COVID-19 infection: a randomized, double-blind, placebo-controlled trial. Trials. 2022;23(1):714. 18. Bramante CT, Huling JD, Tignanelli CJ, et al. Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N Engl J Med. 2022;387(7):599–610.