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This brief communication describes protocol violations in López-Medina et al., Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial (JAMA, 2021). This study switched ivermectin (IVM) and placebo doses for 38 patients; failed to maintain blinding between IVM and placebo doses; had distinctive IVM-associated adverse effects among the controls, matching those for the IVM group, indicating over-the-counter IVM use; and had blatant conflicts of interest for the lead investigator and two other investigators.

Background: Ivermectin has demonstrated different mechanisms of action that potentially protect from both coronavirus disease 2019 (COVID-19) infection and COVID-19-related comorbidities. Based on the studies suggesting efficacy in prophylaxis combined with the known safety profile of ivermectin, a citywide prevention program using ivermectin for COVID-19 was implemented in Itajaí, a southern city in Brazil in the state of Santa Catarina. The objective of this study was to evaluate the impact of regular ivermectin use on subsequent COVID-19 infection and mortality rates.Materials and methods: We analyzed data from a prospective, observational study of the citywide COVID-19 prevention with ivermectin program, which was conducted between July 2020 and December 2020 in Itajaí, Brazil. Study design, institutional review board approval, and analysis of registry data occurred after completion of the program. The program consisted of inviting the entire population of Itajaí to a medical visit to enroll in the program and to compile baseline, personal, demographic, and medical information. In the absence of contraindications, ivermectin was offered as an optional treatment to be taken for two consecutive days every 15 days at a dose of 0.2 mg/kg/day. In cases where a participating citizen of Itajaí became ill with COVID-19, they were recommended not to use ivermectin or any other medication in early outpatient treatment. Clinical outcomes of infection, hospitalization, and death were automatically reported and entered into the registry in real time. Study analysis consisted of comparing ivermectin users with non-users using cohorts of infected patients propensity score-matched by age, sex, and comorbidities. COVID-19 infection and mortality rates were analyzed with and without the use of propensity score matching (PSM).Results: Of the 223,128 citizens of Itajaí considered for the study, a total of 159,561 subjects were included in the analysis: 113,845 (71.3%) regular ivermectin users and 45,716 (23.3%) non-users. Of these, 4,311 ivermectin users were infected, among which 4,197 were from the city of Itajaí (3.7% infection rate), and 3,034 non-users (from Itajaí) were infected (6.6% infection rate), with a 44% reduction in COVID-19 infection rate (risk ratio [RR], 0.56; 95% confidence interval (95% CI), 0.53-0.58; p < 0.0001). Using PSM, two cohorts of 3,034 subjects suffering from COVID-19 infection were compared. The regular use of ivermectin led to a 68% reduction in COVID-19 mortality (25 [0.8%] versus 79 [2.6%] among ivermectin non-users; RR, 0.32; 95% CI, 0.20-0.49; p < 0.0001). When adjusted for residual variables, reduction in mortality rate was 70% (RR, 0.30; 95% CI, 0.19-0.46; p < 0.0001). There was a 56% reduction in hospitalization rate (44 versus 99 hospitalizations among ivermectin users and non-users, respectively; RR, 0.44; 95% CI, 0.31-0.63; p < 0.0001). After adjustment for residual variables, reduction in hospitalization rate was 67% (RR, 0.33; 95% CI, 023-0.66; p < 0.0001). Conclusion:In this large PS...

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Introduction. On May 8, 2020, Peru’s Ministry of Health approved ivermectin (IVM), a drug of Nobel Prize-honored distinction, for inpatient and outpatient treatment of COVID-19. As IVM treatments proceeded in that nation of 33 million residents, excess deaths decreased 14-fold over four months through December 1, 2020, consistent with clinical benefits of IVM for COVID-19 found in several RCTs. But after IVM use was sharply restricted under a new president, excess deaths then increased 13-fold. Methods. To evaluate possible IVM treatment effects suggested by these aggregate trends, excess deaths were analyzed by state for ages ≥ 60 in Peru’s 25 states. To identify potential confounding factors, Google mobility data, population densities, SARS-CoV-2 genetic variations and seropositivity rates were also examined.Results. The 25 states of Peru were grouped by extent of IVM distributions: maximal (mass IVM distributions through operation MOT, a broadside effort led by the army); medium (locally managed IVM distributions); and minimal (restrictive policies in one state, Lima). The mean reduction in excess deaths 30 days after peak deaths was 74% for the maximal IVM distribution group, 53% for the medium group and 25% for Lima. Reduction of excess deaths is correlated with extent of IVM distribution by state with a p value of 0.002 using the Kendall τb test, well below the confidence threshold of 0.05 for an established clinical effect.Conclusion. Mass treatments with IVM, a drug safely used in 3.7 billion doses worldwide since 1987, most likely caused the 14-fold reductions in excess deaths in Peru, prior to their 13-fold increase under reversed IVM policy. This strongly suggests that IVM treatments can likewise effectively complement immunizations to help eradicate COVID-19. The indicated biological mechanism of IVM, competitive binding with SARS-CoV-2 spike protein, is likely non-epitope specific, possibly yielding full efficacy against emerging viral mutant strains.