Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial

Laurens Liesenborghs; Isabel Spriet; Dirk Jochmans; Ann Belmans; Iwein Gyselinck; Laure-Anne Teuwen; Sebastiaan ter Horst; Erwin Dreesen; Tatjana Geukens; Matthias M. Engelen; Ewout Landeloos; Vincent Geldhof; Helga Ceunen; Barbara Debaveye; Bert Vandenberk; Lorenz van der Linden; Sofie Jacobs; Lana Langendries; Robbert Boudewijns; Thuc Nguyen Dan Do; Winston Chiu; Xinyu Wang; Xin Zhang; Birgit Weynand; Thomas Vanassche; Timothy Devos; Geert Meyfroidt; Wim Janssens; Robin Vos; Pieter Vermeersch; Joost Wauters; Geert Verbeke; Paul De Munter; Suzanne J. F. Kaptein; Joana Rocha-Pereira; Leen Delang; Eric Van Wijngaerden; Johan Neyts; Peter Verhamme

doi:10.1016/j.ebiom.2021.103288

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial

Laurens Liesenborghs, Isabel Spriet, Dirk Jochmans, Ann Belmans, Iwein Gyselinck, Laure-Anne Teuwen, Sebastiaan ter Horst, Erwin Dreesen, Tatjana Geukens, Matthias M. Engelen, Ewout Landeloos, Vincent Geldhof, Helga Ceunen, Barbara Debaveye, Bert Vandenberk, Lorenz van der Linden, Sofie Jacobs, Lana Langendries, Robbert Boudewijns, Thuc Nguyen Dan DoWinston Chiu, Xinyu Wang, Xin Zhang, Birgit Weynand, Thomas Vanassche, Timothy Devos, Geert Meyfroidt, Wim Janssens, Robin Vos, Pieter Vermeersch, Joost Wauters, Geert Verbeke, Paul De Munter, Suzanne J. F. Kaptein, Joana Rocha-Pereira, Leen Delang, Eric Van Wijngaerden, Johan Neyts, Peter Verhamme

Neglected Tropical Diseases

Research output: Contribution to journal › A1: Web of Science-article › peer-review

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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.

Original language	English
Article number	103288
Journal	EBioMedicine
Volume	66
Number of pages	11
ISSN	2352-3964
DOIs	https://doi.org/10.1016/j.ebiom.2021.103288
Publication status	Published - 2021

Keywords

Animals
Antiviral Agents/administration & dosage
COVID-19/drug therapy
Chlorocebus aethiops
Disease Models, Animal
Drug Evaluation, Preclinical
Female
Humans
Itraconazole/administration & dosage
Male
Mesocricetus
Middle Aged
Pneumonia, Viral/drug therapy
Proof of Concept Study
SARS-CoV-2/drug effects
Treatment Outcome
Vero Cells

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Liesenborghs, L., Spriet, I., Jochmans, D., Belmans, A., Gyselinck, I., Teuwen, L.-A., ter Horst, S., Dreesen, E., Geukens, T., Engelen, M. M., Landeloos, E., Geldhof, V., Ceunen, H., Debaveye, B., Vandenberk, B., van der Linden, L., Jacobs, S., Langendries, L., Boudewijns, R., ... Verhamme, P. (2021). Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial. EBioMedicine, 66, Article 103288. https://doi.org/10.1016/j.ebiom.2021.103288

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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.",

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author = "Laurens Liesenborghs and Isabel Spriet and Dirk Jochmans and Ann Belmans and Iwein Gyselinck and Laure-Anne Teuwen and {ter Horst}, Sebastiaan and Erwin Dreesen and Tatjana Geukens and Engelen, {Matthias M.} and Ewout Landeloos and Vincent Geldhof and Helga Ceunen and Barbara Debaveye and Bert Vandenberk and {van der Linden}, Lorenz and Sofie Jacobs and Lana Langendries and Robbert Boudewijns and Do, {Thuc Nguyen Dan} and Winston Chiu and Xinyu Wang and Xin Zhang and Birgit Weynand and Thomas Vanassche and Timothy Devos and Geert Meyfroidt and Wim Janssens and Robin Vos and Pieter Vermeersch and Joost Wauters and Geert Verbeke and {De Munter}, Paul and Kaptein, {Suzanne J. F.} and Joana Rocha-Pereira and Leen Delang and {Van Wijngaerden}, Eric and Johan Neyts and Peter Verhamme",

note = "FTX; DOAJ; (CC BY 4.0)",

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doi = "10.1016/j.ebiom.2021.103288",

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volume = "66",

journal = "EBioMedicine",

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Liesenborghs, L, Spriet, I, Jochmans, D, Belmans, A, Gyselinck, I, Teuwen, L-A, 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, X, Zhang, X, Weynand, B, Vanassche, T, Devos, T, Meyfroidt, G, Janssens, W, Vos, R, Vermeersch, P, Wauters, J, Verbeke, G, De Munter, P, Kaptein, SJF, Rocha-Pereira, J, Delang, L, Van Wijngaerden, E, Neyts, J & Verhamme, P 2021, 'Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial', EBioMedicine, vol. 66, 103288. https://doi.org/10.1016/j.ebiom.2021.103288

TY - JOUR

T1 - Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial

AU - Liesenborghs, Laurens

AU - Spriet, Isabel

AU - Jochmans, Dirk

AU - Belmans, Ann

AU - Gyselinck, Iwein

AU - Teuwen, Laure-Anne

AU - ter Horst, Sebastiaan

AU - Dreesen, Erwin

AU - Geukens, Tatjana

AU - Engelen, Matthias M.

AU - Landeloos, Ewout

AU - Geldhof, Vincent

AU - Ceunen, Helga

AU - Debaveye, Barbara

AU - Vandenberk, Bert

AU - van der Linden, Lorenz

AU - Jacobs, Sofie

AU - Langendries, Lana

AU - Boudewijns, Robbert

AU - Do, Thuc Nguyen Dan

AU - Chiu, Winston

AU - Wang, Xinyu

AU - Zhang, Xin

AU - Weynand, Birgit

AU - Vanassche, Thomas

AU - Devos, Timothy

AU - Meyfroidt, Geert

AU - Janssens, Wim

AU - Vos, Robin

AU - Vermeersch, Pieter

AU - Wauters, Joost

AU - Verbeke, Geert

AU - De Munter, Paul

AU - Kaptein, Suzanne J. F.

AU - Rocha-Pereira, Joana

AU - Delang, Leen

AU - Van Wijngaerden, Eric

AU - Neyts, Johan

AU - Verhamme, Peter

N1 - FTX; DOAJ; (CC BY 4.0)

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Animals

KW - Antiviral Agents/administration & dosage

KW - COVID-19/drug therapy

KW - Chlorocebus aethiops

KW - Disease Models, Animal

KW - Drug Evaluation, Preclinical

KW - Female

KW - Humans

KW - Itraconazole/administration & dosage

KW - Male

KW - Mesocricetus

KW - Middle Aged

KW - Pneumonia, Viral/drug therapy

KW - Proof of Concept Study

KW - SARS-CoV-2/drug effects

KW - Treatment Outcome

KW - Vero Cells

U2 - 10.1016/j.ebiom.2021.103288

DO - 10.1016/j.ebiom.2021.103288

M3 - A1: Web of Science-article

C2 - 33752127

SN - 2352-3964

VL - 66

JO - EBioMedicine

JF - EBioMedicine

M1 - 103288

ER -

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial

Abstract

Keywords

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