Liesenborghs Laurens, Spriet Isabel, Jochmans Dirk, Belmans Ann, Gyselinck Iwein, Teuwen Laure-Anne, Ter Horst Sebastiaan, Dreesen Erwin, Geukens Tatjana, Engelen Matthias M, Landeloos Ewout, Geldhof Vincent, Ceunen Helga, Debaveye Barbara, Vandenberk Bert, Van der Linden Lorenz, Jacobs Sofie, Langendries Lana, Boudewijns Robbert, Do Thuc Nguyen Dan, Chiu Winston, Wang Xinyu, Zhang Xin, Weynand Birgit, Vanassche Thomas, Devos Timothy, Meyfroidt Geert, Janssens Wim, Vos Robin, Vermeersch Pieter, Wauters Joost, Verbeke Geert, De Munter Paul, Kaptein Suzanne J F, Rocha-Pereira Joana, Delang Leen, Van Wijngaerden Eric, Neyts Johan, Verhamme Peter
Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium; The Outbreak Research Team, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
Pharmacy Department University Hospitals Leuven and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
EBioMedicine. 2021 Apr;66:103288. doi: 10.1016/j.ebiom.2021.103288. Epub 2021 Mar 19.
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.
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.
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.
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.
KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.
抗真菌药物伊曲康唑在体外对Vero细胞和人Caco - 2细胞中的新型冠状病毒2（SARS-CoV-2）具有活性。需要进行临床前和临床研究来调查伊曲康唑是否对治疗和/或预防2019冠状病毒病（COVID-19）有效。
由于最初缺乏临床前模型，在一项临床概念验证、开放标签、单中心研究中探索了伊曲康唑的作用，该研究将住院的COVID-19患者随机分配至接受或不接受伊曲康唑治疗的标准治疗组。主要结局是根据世界卫生组织的7分序贯量表得出的至第15天临床状态的累积评分。同时，一旦新建立的急性SARS-CoV-2感染和传播仓鼠模型得到验证，便对伊曲康唑进行评估。
在仓鼠急性感染模型中，尽管血浆和肺组织中的药物浓度足够，但伊曲康唑并未降低肺、粪便或回肠中的病毒载量。在传播模型中，伊曲康唑未能预防病毒传播。在对临床前研究进行评估后，且由于一项中期分析显示伊曲康唑未显示出更有利结局的信号（临床状态的平均累积评分：伊曲康唑组为49分，标准治疗组为47分，几何均数比为1.01（95%置信区间为0.85至1.19）），该临床试验提前终止。
尽管伊曲康唑在体外具有活性，但在临床前COVID-19仓鼠模型中无效。这促使了概念验证临床研究的提前终止。
鲁汶大学、弗拉芒研究基金会（FWO）、“地平线2020”计划、比尔及梅琳达·盖茨基金会。
