Background The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. Methods Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. Findings In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. Interpretation Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. Funding: KU Leuven, Research Foundation – Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation
【저자키워드】 COVID-19, Drug repurposing, SARS-CoV-2, antivirals, itraconazole, breath, 【초록키워드】 Treatment, clinical trial, Open-label, SARS-COV-2 infection, itraconazole, lung, Transmission, outcome, clinical status, Stool, Viral, Viral load, acute infection, Lungs, Clinical studies, Viral transmission, Transmission model, funding, preclinical study, hospitalized COVID-19 patient, Ordinal Scale, clinical study, in vitro activity, Vero, Caco-2, Melinda Gates, Health Organization, preclinical studies, not effective, World Health Organization, Standard of care, Primary outcome, Geometric means, hospitalized COVID-19 patients, 95% CI, 7-point ordinal scale, foundation, interim analysis, acute SARS-CoV-2 infection, antifungal drug itraconazole, cumulative score, Horizon, ileum, premature termination, proof-of-concept clinical study, single-center study, stools, viral load in lungs, finding, Prevent, effective, drug concentrations, Randomly, prevention of COVID-19, initial, evaluated, required, absence, assigned, did not reduce, adequate plasma, geometric, human Caco-2 cells, Leuven, Melinda Gate, Preclinical, showed no signal, 【제목키워드】 randomized clinical trial, itraconazole, preclinical study,