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Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.
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.
  • Liesenborghs L; 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: lli
  • Spriet I; Pharmacy Department University Hospitals Leuven and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
  • Jochmans D; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Belmans A; KU Leuven - University of Leuven & Universiteit Hasselt, I-BioStat, Leuven, Belgium.
  • Gyselinck I; Department of Respiratory Diseases, UZ Leuven and CHROMETA, Research group BREATHE, KU Leuven, Leuven, Belgium.
  • Teuwen LA; Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
  • Ter Horst S; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Dreesen E; Clinical Pharmacology and Pharmacotherapy Unit, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
  • Geukens T; Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven, Belgium.
  • Engelen MM; Department of Cardiovascular Sciences, UZ and KU Leuven, Belgium.
  • Landeloos E; Department of Oncology, Laboratory for molecular Cancer biology, VIB-KU Leuven, Belgium.
  • Geldhof V; Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
  • Ceunen H; Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium.
  • Debaveye B; Department of Cardiovascular Sciences, UZ and KU Leuven, Belgium.
  • Vandenberk B; Department of Cardiovascular Sciences, UZ and KU Leuven, Belgium.
  • Van der Linden L; Pharmacy Department University Hospitals Leuven and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium.
  • Jacobs S; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Langendries L; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Boudewijns R; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Do TND; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Chiu W; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Wang X; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Zhang X; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Weynand B; Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Belgium.
  • Vanassche T; Department of Cardiovascular Sciences, UZ and KU Leuven, Belgium.
  • Devos T; Department of Hematology, UZ Leuven and Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Belgium.
  • Meyfroidt G; Department and Laboratory of Intensive Care Medicine, UZ and KU Leuven, Belgium.
  • Janssens W; Department of Respiratory Diseases, UZ Leuven and CHROMETA, Research group BREATHE, KU Leuven, Leuven, Belgium.
  • Vos R; Department of Respiratory Diseases, UZ Leuven and CHROMETA, Research group BREATHE, KU Leuven, Leuven, Belgium.
  • Vermeersch P; Department of Cardiovascular Sciences and Clinical Department of Laboratory Medicine, KU Leuven, Belgium.
  • Wauters J; Medical Intensive Care Unit, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium.
  • Verbeke G; KU Leuven - University of Leuven & Universiteit Hasselt, I-BioStat, Leuven, Belgium.
  • De Munter P; Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium.
  • Kaptein SJF; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Rocha-Pereira J; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Delang L; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Van Wijngaerden E; Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven, Belgium.
  • Neyts J; Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • Verhamme P; Department of Cardiovascular Sciences, UZ and KU Leuven, Belgium.
EBioMedicine ; 66: 103288, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1141720
Semantic information from SemMedBD (by NLM)
1. itraconazole TREATS COVID-19
Subject
itraconazole
Predicate
TREATS
Object
COVID-19
2. Caco-2 Cells PART_OF Homo sapiens
Subject
Caco-2 Cells
Predicate
PART_OF
Object
Homo sapiens
3. itraconazole PREVENTS COVID-19
Subject
itraconazole
Predicate
PREVENTS
Object
COVID-19
4. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
5. Feces LOCATION_OF itraconazole
Subject
Feces
Predicate
LOCATION_OF
Object
itraconazole
6. ileum LOCATION_OF itraconazole
Subject
ileum
Predicate
LOCATION_OF
Object
itraconazole
7. Lung LOCATION_OF itraconazole
Subject
Lung
Predicate
LOCATION_OF
Object
itraconazole
8. itraconazole TREATS COVID-19
Subject
itraconazole
Predicate
TREATS
Object
COVID-19
9. Caco-2 Cells PART_OF Homo sapiens
Subject
Caco-2 Cells
Predicate
PART_OF
Object
Homo sapiens
10. itraconazole PREVENTS COVID-19
Subject
itraconazole
Predicate
PREVENTS
Object
COVID-19
11. COVID-19 PROCESS_OF Patients
Subject
COVID-19
Predicate
PROCESS_OF
Object
Patients
12. Feces LOCATION_OF itraconazole
Subject
Feces
Predicate
LOCATION_OF
Object
itraconazole
13. ileum LOCATION_OF itraconazole
Subject
ileum
Predicate
LOCATION_OF
Object
itraconazole
14. Lung LOCATION_OF itraconazole
Subject
Lung
Predicate
LOCATION_OF
Object
itraconazole
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Itraconazole / COVID-19 Type of study: Controlled clinical trial / Etiology study / Prognostic study / Randomized controlled trials Topics: Traditional medicine Limits: Animals / Female / Humans / Male / Middle aged Language: English Journal: EBioMedicine Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Itraconazole / COVID-19 Type of study: Controlled clinical trial / Etiology study / Prognostic study / Randomized controlled trials Topics: Traditional medicine Limits: Animals / Female / Humans / Male / Middle aged Language: English Journal: EBioMedicine Year: 2021 Document Type: Article