Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities

Abstract

IMPORTANCEIvermectin, an inexpensive and widely available antiparasitic drug, is prescribed to treat COVID-19. Evidence-based data to recommend either for or against the use of ivermectin are needed. OBJECTIVE To determine the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS The Ivermectin Treatment Efficacy in COVID-19 High-Risk Patients (I-TECH) study was an open-label randomized clinical trial conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia between May 31 and October 25, 2021. Within the first week of patients' symptom onset, the study enrolled patients 50 years and older with laboratory-confirmed COVID-19, comorbidities, and mild to moderate disease. INTERVENTIONS Patients were randomized in a 1:1 ratio to receive either 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). The standard of care consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging. MAIN OUTCOMES AND MEASURESThe primary outcome was the proportion of patients who progressed to severe disease, defined as the hypoxic stage requiring supplemental oxygen to maintain pulse oximetry oxygen saturation of 95% or higher. Secondary outcomes of the trial included the rates of mechanical ventilation, intensive care unit admission, 28-day in-hospital mortality, and adverse events. RESULTS Among 490 patients included in the primary analysis (mean [SD] age, 62.5 [8.7] years; 267 women [54.5%]), 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% CI, 0.87-1.80; P = .25). For all prespecified secondary outcomes, there were no significant differences between groups. Mechanical ventilation occurred in 4 (1.7%) vs 10 (4.0%) (RR, 0.41; 95% CI, 0.13-1.30; P = .17), intensive care unit admission in 6 (2.4%) vs 8 (3.2%) (RR, 0.78; 95% CI, 0.27-2.20; P = .79), and 28-day in-hospital death in 3 (1.2%) vs 10 (4.0%) (RR, 0.31; 95% CI, 0.09-1.11; P = .09). The most common adverse event reported was diarrhea (14 [5.8%] in the ivermectin group and 4 [1.6%] in the control group). CONCLUSIONS AND RELEVANCEIn this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study findings do not support the use of ivermectin for patients with COVID-19.TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04920942

Clinical update on COVID-19 for the emergency and critical care clinician: Medical management

“…Ivermectin is an effective antiparasitic with multiple proposed mechanisms of action against SARS-CoV-2, including inhibition of viral transfer and replication in vitro and anti-inflammatory effects based on prior studies of other viruses (e.g., Zika, Dengue) [ [146] , [147] , [148] , [149] , [150] ]. Current evidence based on higher quality data suggests no benefit [ [151] , [152] , [153] ]. While several early studies suggested reduced mortality, shortened recovery time, and decreased transmissibility benefits with ivermectin in the treatment of COVID-19 patients, these studies suffered from major limitations, including wide heterogeneity, poor subject allocation, limited or no blinding, and inadequate controls with risk of confounding [ 10 , [146] , [147] , [148] , [149] , [150] , [151] , [152] , [153] ].…”

“…Current evidence based on higher quality data suggests no benefit [ [151] , [152] , [153] ]. While several early studies suggested reduced mortality, shortened recovery time, and decreased transmissibility benefits with ivermectin in the treatment of COVID-19 patients, these studies suffered from major limitations, including wide heterogeneity, poor subject allocation, limited or no blinding, and inadequate controls with risk of confounding [ 10 , [146] , [147] , [148] , [149] , [150] , [151] , [152] , [153] ]. Additionally, many studies employed dosing regimens larger than those previously approved for parasitic infections, increasing the risks of side effects [ 10 , 148 , 152 ].…”

“…A meta-analysis released in 2021 including 10 RCTs found no improvement in all-cause mortality, length of stay, or viral clearance in patients with mild COVID-19 [ 151 ]. An RCT including 409 patients 50 years and older with mild-to-moderate COVID-19 within 7 days of symptom onset found no change in progression to severe disease (RR 1.25, 95% CI 0.87 to 1.80), as well as no difference in ICU admission, mechanical ventilation, and 28-day in-hospital death with ivermectin [ 153 ]. Furthermore, the IDSA and NIH recommend against its use in both inpatient and outpatient settings for COVID-19 [ 10 , 154 ].…”

Ivermectin and Zuranolone: A Double Standard in the Literature

“…Highly clinically significant benefits are cited as evidence that ivermectin does not work for COVID-19 because the results were not statistically significant. In a recent study [3], ivermectin was added to standard care for 241 participants while standard care was provided to 249 participants. The authors concluded that, "The study findings do not support the use of ivermectin for patients with COVID-19."…”

Interaction of the new inhibitor paxlovid (PF-07321332) and ivermectin with the monomer of the main protease SARS-CoV-2: A volumetric study based on molecular dynamics, elastic networks, classical thermodynamics and SPT

“…The proteins are dynamic molecules ( Laage et al, 2017 , Lee, 1983 ), and at thermal equilibrium, the intrinsic volume (geometric component) and the hydration or interaction volume are constantly fluctuacting around their mean values and Laage et al, 2017 , Lee, 1983 , Lee, 1983 , Liang et al, 2020 , Lim et al, 2022 , Lindow et al, 2013 , Lockbaum et al, 2021 .The structural dynamic is very important for biological function of protein and stability ( Lee, 1983 , Lockbaum et al, 2021 , Low et al, 2022 , Luong et al, 2015 , Macchiagodena et al, 2022 , Madhavi et al, 2021 , Mahdian et al, 2021 , Marchi, 2003 , Mejía-Tamayo et al, 2018 , Monkos, 2013 ). The intrinsic protein flexibility is relevant to interaction with ligand and can contribute to the binding process ( Lindow et al, 2013 , Lockbaum et al, 2021 , Monkos, 2004 , Mori et al, 2006 , Morris et al, 2009 , Osipiuk et al, 2021 , O’Boyle et al, 2011 ).…”