Laurens Liesenborghs1, Isabel Spriet2, Dirk Jochmans3, Ann Belmans4, Iwein Gyselinck5, Laure-Anne Teuwen6, Sebastiaan Ter Horst3, Erwin Dreesen7, Tatjana Geukens8, Matthias M Engelen9, Ewout Landeloos10, Vincent Geldhof6, Helga Ceunen11, Barbara Debaveye9, Bert Vandenberk9, Lorenz Van der Linden2, Sofie Jacobs3, Lana Langendries3, Robbert Boudewijns3, Thuc Nguyen Dan Do3, Winston Chiu3, Xinyu Wang3, Xin Zhang3, Birgit Weynand12, Thomas Vanassche9, Timothy Devos13, Geert Meyfroidt14, Wim Janssens5, Robin Vos5, Pieter Vermeersch15, Joost Wauters16, Geert Verbeke4, Paul De Munter11, Suzanne J F Kaptein3, Joana Rocha-Pereira3, Leen Delang3, Eric Van Wijngaerden11, Johan Neyts3, Peter Verhamme9. 1. 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. Electronic address: lliesenborghs@itg.be. 2. Pharmacy Department University Hospitals Leuven and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium. 3. Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium. 4. KU Leuven - University of Leuven & Universiteit Hasselt, I-BioStat, Leuven, Belgium. 5. Department of Respiratory Diseases, UZ Leuven and CHROMETA, Research group BREATHE, KU Leuven, Leuven, Belgium. 6. Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium. 7. Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium. 8. Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven, Belgium. 9. Department of Cardiovascular Sciences, UZ and KU Leuven, Belgium. 10. Department of Oncology, Laboratory for molecular Cancer biology, VIB-KU Leuven, Belgium. 11. Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium. 12. Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Belgium. 13. Department of Hematology, UZ Leuven and Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Belgium. 14. Department and Laboratory of Intensive Care Medicine, UZ and KU Leuven, Belgium. 15. Department of Cardiovascular Sciences and Clinical Department of Laboratory Medicine, KU Leuven, Belgium. 16. Medical Intensive Care Unit, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium.
Abstract
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.
RCT Entities:
BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and humanCaco-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-19patients 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 hamsteracute 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-19hamster 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.
Authors: Iwein Gyselinck; Laurens Liesenborghs; Ann Belmans; Matthias M Engelen; Albrecht Betrains; Quentin Van Thillo; Pham Anh Hong Nguyen; Pieter Goeminne; Ann-Catherine Soenen; Nikolaas De Maeyer; Charles Pilette; Emmanuelle Papleux; Eef Vanderhelst; Aurélie Derweduwen; Patrick Alexander; Bernard Bouckaert; Jean-Benoît Martinot; Lynn Decoster; Kurt Vandeurzen; Rob Schildermans; Peter Verhamme; Wim Janssens; Robin Vos Journal: ERJ Open Res Date: 2022-02-28