Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients

Abraham Rutgers; Peter E Westerweel; Bronno van der Holt; Simone Postma; Marit G A van Vonderen; Djura P Piersma; Douwe Postma; Maarten van den Berge; Eefje Jong; Marten de Vries; Leonie van der Burg; Dennis Huugen; Marjolein van der Poel; Linda M Kampschreur; Marcel Nijland; Jaap H Strijbos; Menno Tamminga; Pim G N J Mutsaers; Suzanne Schol-Gelok; Margriet Dijkstra-Tiekstra; Grigory Sidorenkov; Julien Vincenten; Wouter H van Geffen; Marjolein Knoester; Jos Kosterink; Reinold Gans; Coen Stegeman; Gerwin Huls; Tom van Meerten

doi:10.1371/journal.pone.0271807

Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients

Abraham Rutgers^*, Peter E Westerweel, Bronno van der Holt, Simone Postma, Marit G A van Vonderen, Djura P Piersma, Douwe Postma, Maarten van den Berge, Eefje Jong, Marten de Vries, Leonie van der Burg, Dennis Huugen, Marjolein van der Poel, Linda M Kampschreur, Marcel Nijland, Jaap H Strijbos, Menno Tamminga, Pim G N J Mutsaers, Suzanne Schol-Gelok, Margriet Dijkstra-TiekstraGrigory Sidorenkov, Julien Vincenten, Wouter H van Geffen, Marjolein Knoester, Jos Kosterink, Reinold Gans, Coen Stegeman, Gerwin Huls, Tom van Meerten

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

INTRODUCTION: The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease.

METHODS: Open-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation.

RESULTS: A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39-0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9-28) in the standard arm versus 9 days (IQR 5-14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98; p = 0.042).

CONCLUSIONS: This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone.

TRIAL REGISTRATION: https://www.trialregister.nl/trial/8504.

Original language	English
Article number	e0271807
Number of pages	13
Journal	PLOS ONE
Volume	17
Issue number	8
DOIs	https://doi.org/10.1371/journal.pone.0271807
Publication status	Published - 12 Aug 2022

Keywords

Aged
Antibodies, Monoclonal, Humanized
COVID-19/drug therapy
Dexamethasone/therapeutic use
Female
Humans
Male
Oxygen
Respiration, Artificial
SARS-CoV-2
Treatment Outcome

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Cite this

Rutgers, A., Westerweel, P. E., van der Holt, B., Postma, S., van Vonderen, M. G. A., Piersma, D. P., Postma, D., van den Berge, M., Jong, E., de Vries, M., van der Burg, L., Huugen, D., van der Poel, M., Kampschreur, L. M., Nijland, M., Strijbos, J. H., Tamminga, M., Mutsaers, P. G. N. J., Schol-Gelok, S., ... van Meerten, T. (2022). Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients. PLOS ONE, 17(8), Article e0271807. https://doi.org/10.1371/journal.pone.0271807

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abstract = "INTRODUCTION: The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease.METHODS: Open-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation.RESULTS: A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39-0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9-28) in the standard arm versus 9 days (IQR 5-14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98; p = 0.042).CONCLUSIONS: This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone.TRIAL REGISTRATION: https://www.trialregister.nl/trial/8504.",

keywords = "Aged, Antibodies, Monoclonal, Humanized, COVID-19/drug therapy, Dexamethasone/therapeutic use, Female, Humans, Male, Oxygen, Respiration, Artificial, SARS-CoV-2, Treatment Outcome",

author = "Abraham Rutgers and Westerweel, {Peter E} and {van der Holt}, Bronno and Simone Postma and {van Vonderen}, {Marit G A} and Piersma, {Djura P} and Douwe Postma and {van den Berge}, Maarten and Eefje Jong and {de Vries}, Marten and {van der Burg}, Leonie and Dennis Huugen and {van der Poel}, Marjolein and Kampschreur, {Linda M} and Marcel Nijland and Strijbos, {Jaap H} and Menno Tamminga and Mutsaers, {Pim G N J} and Suzanne Schol-Gelok and Margriet Dijkstra-Tiekstra and Grigory Sidorenkov and Julien Vincenten and {van Geffen}, {Wouter H} and Marjolein Knoester and Jos Kosterink and Reinold Gans and Coen Stegeman and Gerwin Huls and {van Meerten}, Tom",

note = "Publisher Copyright: Copyright: {\textcopyright} 2022 Rutgers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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Rutgers, A, Westerweel, PE, van der Holt, B, Postma, S, van Vonderen, MGA, Piersma, DP, Postma, D, van den Berge, M, Jong, E, de Vries, M, van der Burg, L, Huugen, D, van der Poel, M, Kampschreur, LM, Nijland, M, Strijbos, JH, Tamminga, M, Mutsaers, PGNJ, Schol-Gelok, S, Dijkstra-Tiekstra, M, Sidorenkov, G, Vincenten, J, van Geffen, WH, Knoester, M, Kosterink, J, Gans, R, Stegeman, C, Huls, G & van Meerten, T 2022, 'Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients', PLOS ONE, vol. 17, no. 8, e0271807. https://doi.org/10.1371/journal.pone.0271807

TY - JOUR

T1 - Timely administration of tocilizumab improves outcome of hospitalized COVID-19 patients

AU - Rutgers, Abraham

AU - Westerweel, Peter E

AU - van der Holt, Bronno

AU - Postma, Simone

AU - van Vonderen, Marit G A

AU - Piersma, Djura P

AU - Postma, Douwe

AU - van den Berge, Maarten

AU - Jong, Eefje

AU - de Vries, Marten

AU - van der Burg, Leonie

AU - Huugen, Dennis

AU - van der Poel, Marjolein

AU - Kampschreur, Linda M

AU - Nijland, Marcel

AU - Strijbos, Jaap H

AU - Tamminga, Menno

AU - Mutsaers, Pim G N J

AU - Schol-Gelok, Suzanne

AU - Dijkstra-Tiekstra, Margriet

AU - Sidorenkov, Grigory

AU - Vincenten, Julien

AU - van Geffen, Wouter H

AU - Knoester, Marjolein

AU - Kosterink, Jos

AU - Gans, Reinold

AU - Stegeman, Coen

AU - Huls, Gerwin

AU - van Meerten, Tom

N1 - Publisher Copyright: Copyright: © 2022 Rutgers et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2022/8/12

Y1 - 2022/8/12

N2 - INTRODUCTION: The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease.METHODS: Open-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation.RESULTS: A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39-0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9-28) in the standard arm versus 9 days (IQR 5-14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98; p = 0.042).CONCLUSIONS: This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone.TRIAL REGISTRATION: https://www.trialregister.nl/trial/8504.

AB - INTRODUCTION: The aim of this study was to determine the efficacy of early tocilizumab treatment for hospitalized patients with COVID-19 disease.METHODS: Open-label randomized phase II clinical trial investigating tocilizumab in patients with proven COVID-19 admitted to the general ward and in need of supplemental oxygen. The primary endpoint of the study was 30-day mortality with a prespecified 2-sided significance level of α = 0.10. A post-hoc analysis was performed for a combined endpoint of mechanical ventilation or death at 30 days. Secondary objectives included comparing the duration of hospital stay, ICU admittance and duration of ICU stay and the duration of mechanical ventilation.RESULTS: A total of 354 patients (67% men; median age 66 years) were enrolled of whom 88% received dexamethasone. Thirty-day mortality was 19% (95% CI 14%-26%) in the standard arm versus 12% (95% CI: 8%-18%) in the tocilizumab arm, hazard ratio (HR) = 0.62 (90% CI 0.39-0.98; p = 0.086). 17% of patients were admitted to the ICU in each arm (p = 0.89). The median stay in the ICU was 14 days (IQR 9-28) in the standard arm versus 9 days (IQR 5-14) in the tocilizumab arm (p = 0.014). Mechanical ventilation or death at thirty days was 31% (95% CI 24%-38%) in the standard arm versus 21% (95% CI 16%-28%) in the tocilizumab arm, HR = 0.65 (95% CI 0.42-0.98; p = 0.042).CONCLUSIONS: This randomized phase II study supports efficacy for tocilizumab when given early in the disease course in hospitalized patients who need oxygen support, especially when concomitantly treated with dexamethasone.TRIAL REGISTRATION: https://www.trialregister.nl/trial/8504.

KW - Aged

KW - Antibodies, Monoclonal, Humanized

KW - COVID-19/drug therapy

KW - Dexamethasone/therapeutic use

KW - Female

KW - Humans

KW - Male

KW - Oxygen

KW - Respiration, Artificial

KW - SARS-CoV-2

KW - Treatment Outcome

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DO - 10.1371/journal.pone.0271807

M3 - Article

C2 - 35960720

SN - 1932-6203

VL - 17

JO - PLOS ONE

JF - PLOS ONE

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M1 - e0271807

ER -