| Title: |
Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial |
| Authors: |
Liesenborghs , L; Spriet, I; Jochmans, D; Belmans , A; Gyselinck, I; Teuwen, LA; ter Horst, S; Dreesen , E; Geukens , T; Engelen, MM; Landeloos, E; Geldhof, V; Ceunen, H; Debaveye, B; Vandenberk , B; van der Linden , L; Jacobs, S; Langendries , L; Boudewijns, R; Do, TND; Chiu, W; Wang , XY; Zhang, X; Weynand, B; Vanassche, T; Devos , T; Meyfroidt, G; Janssens , W; Vos, R; Vermeersch, P; Wauters, J; VERBEKE, Geert; De Munter , P; Kaptein, SJF; Rocha-Pereira, J; Delang , L; Van Wijngaerden, E; Neyts, J; Verhamme, P |
| Contributors: |
Liesenborghs , L; Spriet, I; Jochmans, D; Belmans , A; Gyselinck, I; Teuwen, LA; ter Horst, S; Dreesen , E; Geukens , T; Engelen, MM; Landeloos, E; Geldhof, V; Ceunen, H; Debaveye, B; Vandenberk , B; van der Linden , L; Jacobs, S; Langendries , L; Boudewijns, R; Do, TND; Chiu, W; Wang , XY; Zhang, X; Weynand, B; Vanassche, T; Devos , T; Meyfroidt, G; Janssens , W; Vos, R; Vermeersch, P; Wauters, J; VERBEKE, Geert; De Munter , P; Kaptein, SJF; Rocha-Pereira, J; Delang , L; Van Wijngaerden, E; Neyts, J; Verhamme, P |
| Publisher Information: |
ELSEVIER |
| Publication Year: |
2021 |
| Collection: |
Document Server@UHasselt (Universiteit Hasselt) |
| Subject Terms: |
COVID-19; SARS-CoV-2; itraconazole; drug repurposing; antivirals |
| Description: |
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. (C) 2021 The Authors. Published by Elsevier B.V. ; This project has received funding from the Covid-19-Fund KU Leuven / University Hospitals Leuven, the COVID-19 call of the Research Foundation - Flanders (FWO) (grant G0G4820N), the European Union's Horizon 2020 research and innovation program (Grant 101003627, Swift COronavirus therapeutics REsponse project) and the Bill and Melinda Gates Foundation (Grant INV-00636). LLi is ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
info:eu-repo/grantAgreement/EC/H2020/101003627; EBioMedicine, 66 (Art N° 103288); https://hdl.handle.net/1942/35835; 66; 000647447600003 |
| DOI: |
10.1016/j.ebiom.2021.103288 |
| Availability: |
https://hdl.handle.net/1942/35835; https://doi.org/10.1016/j.ebiom.2021.103288 |
| Accession Number: |
edsbas.24DEB6DF |
| Database: |
BASE |