Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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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
Аннотация
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.