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Itraconazole for COVID-19: Preclinical Studies and a Proof-of-Concept Pilot Clinical Study

32 Pages Posted: 10 Dec 2020

See all articles by Laurens Liesenborghs

Laurens Liesenborghs

KU Leuven - Rega Institute for Medical Research

Isabel Spriet

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven

Dirk Jochmans

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven

Ann Belmans

KU Leuven

Iwein Gyselinck

Department of Respiratory Diseases, UZ Leuven and CHROMETA, Research group BREATHE, KU Leuven

Laure-Anne Teuwen

Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven

Sebastiaan ter Horst

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven

E Dreesen

KU Leuven - Department of Clinical Pharmacology and Pharmacotherapy

Tatjana Geukens

Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven

Matthias Engelen

Department of Cardiovascular Sciences, UZ and KU Leuven

Ewout Landeloos

Department of Oncology, Laboratory for molecular Cancer biology, VIB-KULeuven

Vincent Geldhof

Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven

Helga Ceunen

Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven

Barbara Debaveye

Department of Cardiovascular Sciences, UZ and KU Leuven

Bert Vandenberk

Department of Cardiovascular Sciences, UZ and KU Leuven

Lorenz Van der Linden

Pharmacy Department University Hospitals Leuven and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven

Sofie Jacobs

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven

Lana Langendries

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven

Robbert Boudewijns

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven

Birgit Weynand

Translational Cell and Tissue Research, Department of Imaging and Pathology, Katholieke Universiteit Leuven

Thomas Vanassche

Department of Cardiovascular Sciences, UZ and KU Leuven

Timothy Devos

Pharmacy Department University Hospitals Leuven and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven

Geert Meyfroidt

Department of Cellular and Molecular Medicine, Laboratory of Intensive Care Medicine, UZ and KU Leuven

Wim Janssens

KU Leuven- Respiratory Division and Rehabilitation

Robin Vos

Department of Respiratory Diseases, UZ Leuven and CHROMETA, Research group BREATHE, KU Leuven

Pieter Vermeersch

Department of Cardiovascular Sciences and Clinical Department of Laboratory Medicine, KU Leuven

Joost Wauters

Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven

Geert Verbeke

KU Leuven

Paul De Munter

Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven

Suzanne J. F. Kaptein

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven

Joana Duarte Rocha-Pereira

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven

Leen Delang

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven

Eric Van Wijngaerden

Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven

J Neyts

KU Leuven - Laboratory of Virology and Chemotherapy

Peter Verhamme

Department of Cardiovascular Sciences, UZ and KU Leuven

More...

Abstract

Background: Drug repurposing is an attractive strategy to rapidly develop affordable therapy against COVID-19. The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 comparable to that of hydroxychloroquine. 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 patients with COVID-19 were randomly assigned to receive standard of care with or without itraconazole. The 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. Other outcomes included time to sustained clinical improvement, duration of supplemental oxygen and evolution of nasopharyngeal viral load. 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 interim analysis that showed no trends 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), median time to clinical improvement 10 vs 9 days, hazard ratio 0.94 (95% CI 0.56 to 1.60) for itraconazole vs standard of care. 

Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. A proof-of-concept clinical study was ended prematurely because of futility. 

Trial Registration: (EudraCT 2020-001243-15)

Funding: Covid-19-Fund KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation

Declaration of Interests: Initial dug screening and discovery of the antiviral effect of itraconazole was done in collaboration with Johnson & Johnson and described in a separate manuscript. Scientists from Johnson & Johnson also performed drug measurements on hamster samples and provided guidance on the dosing regimens for the preclinical studies. The company had no role in the design, execution, analysis, publication or funding of the clinical trial.

Author Conflict of Interests: None to declare.

Ethics Approval Statement: The institutional Ethical Committee approved all animal experiments (license P065-2020).

The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the institutional Ethics Committee and by the Belgian Federal Agency for Medicines and Health Products (EudraCT 2020-001243-15). The trial was part of the DAWn clinical studies.

Keywords: COVID-19, SARS-CoV-2, itraconazole, drug repurposing, antivirals

Suggested Citation

Liesenborghs, Laurens and Spriet, Isabel and Jochmans, Dirk and Belmans, Ann and Gyselinck, Iwein and Teuwen, Laure-Anne and ter Horst, Sebastiaan and Dreesen, E and Geukens, Tatjana and Engelen, Matthias and Landeloos, Ewout and Geldhof, Vincent and Ceunen, Helga and Debaveye, Barbara and Vandenberk, Bert and Van der Linden, Lorenz and Jacobs, Sofie and Langendries, Lana and Boudewijns, Robbert and Weynand, Birgit and Vanassche, Thomas and Devos, Timothy and Meyfroidt, Geert and Janssens, Wim and Vos, Robin and Vermeersch, Pieter and Wauters, Joost and Verbeke, Geert and De Munter, Paul and Kaptein, Suzanne J. F. and Rocha-Pereira, Joana Duarte and Delang, Leen and Van Wijngaerden, Eric and Neyts, J and Verhamme, Peter, Itraconazole for COVID-19: Preclinical Studies and a Proof-of-Concept Pilot Clinical Study. Available at SSRN: https://ssrn.com/abstract=3731461 or http://dx.doi.org/10.2139/ssrn.3731461

Laurens Liesenborghs (Contact Author)

KU Leuven - Rega Institute for Medical Research ( email )

Leuven
Belgium

Isabel Spriet

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven ( email )

Dirk Jochmans

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven ( email )

Ann Belmans

KU Leuven ( email )

Iwein Gyselinck

Department of Respiratory Diseases, UZ Leuven and CHROMETA, Research group BREATHE, KU Leuven ( email )

Laure-Anne Teuwen

Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven ( email )

Sebastiaan Ter Horst

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven ( email )

E Dreesen

KU Leuven - Department of Clinical Pharmacology and Pharmacotherapy ( email )

Oude Markt 13
Leuven, Vlaams-Brabant 3000
Belgium

Tatjana Geukens

Department of Oncology, Laboratory for Translational Breast Cancer Research, KU Leuven ( email )

Matthias Engelen

Department of Cardiovascular Sciences, UZ and KU Leuven ( email )

Ewout Landeloos

Department of Oncology, Laboratory for molecular Cancer biology, VIB-KULeuven ( email )

Vincent Geldhof

Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, Leuven Cancer Institute, KU Leuven ( email )

Helga Ceunen

Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven ( email )

Barbara Debaveye

Department of Cardiovascular Sciences, UZ and KU Leuven ( email )

Bert Vandenberk

Department of Cardiovascular Sciences, UZ and KU Leuven ( email )

Lorenz Van der Linden

Pharmacy Department University Hospitals Leuven and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven ( email )

Sofie Jacobs

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven ( email )

Lana Langendries

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven ( email )

Robbert Boudewijns

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven ( email )

Birgit Weynand

Translational Cell and Tissue Research, Department of Imaging and Pathology, Katholieke Universiteit Leuven ( email )

Thomas Vanassche

Department of Cardiovascular Sciences, UZ and KU Leuven ( email )

Timothy Devos

Pharmacy Department University Hospitals Leuven and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven ( email )

Geert Meyfroidt

Department of Cellular and Molecular Medicine, Laboratory of Intensive Care Medicine, UZ and KU Leuven ( email )

Wim Janssens

KU Leuven- Respiratory Division and Rehabilitation

Leuven
Belgium

Robin Vos

Department of Respiratory Diseases, UZ Leuven and CHROMETA, Research group BREATHE, KU Leuven ( email )

Pieter Vermeersch

Department of Cardiovascular Sciences and Clinical Department of Laboratory Medicine, KU Leuven ( email )

Joost Wauters

Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven ( email )

Geert Verbeke

KU Leuven ( email )

Oude Markt 13
Leuven, Vlaams-Brabant 3000
Belgium

Paul De Munter

Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven ( email )

Suzanne J. F. Kaptein

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven ( email )

Joana Duarte Rocha-Pereira

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven ( email )

Leen Delang

Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven ( email )

Eric Van Wijngaerden

Department of General Internal Medicine, UZ Leuven and Department of Microbiology, Immunology and Transplantation, KU Leuven ( email )

J Neyts

KU Leuven - Laboratory of Virology and Chemotherapy ( email )

Oude Markt 13
Leuven, Vlaams-Brabant 3000
Belgium

Peter Verhamme

Department of Cardiovascular Sciences, UZ and KU Leuven ( email )

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