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Timely Administration of Tocilizumab Improves Survival of Hospitalized COVID-19 Patients

20 Pages Posted: 27 Apr 2021

See all articles by Abraham Rutgers

Abraham Rutgers

University of Groningen - University Medical Center Groningen (UMCG)

Peter E. Westerweel

Albert Schweitzer Hospital

Bronno van der Holt

Erasmus University Rotterdam (EUR) - Clinical Trial Center; Erasmus University Rotterdam (EUR) - HOVON Data Center

Simone Postma

University of Groningen - University Medical Center Groningen (UMCG)

Marit G.A. van Vonderen

Medical Center Leeuwarden

Djura P. Piersma

Medisch Spectrum Twente

Douwe Postma

University of Groningen - University Medical Center Groningen (UMCG)

Maarten van den Berge

University of Groningen - Groningen Research Institute for Asthma and COPD

Eefje Jong

Meander Medical Center

Marten de Vries

Tjongerschans

Leonie van der Burg

Antonius Zorggroep - Antonius Hospital Sneek

Dennis Huugen

Deventer Ziekenhuis - Deventer Hospital

Marjolein van der Poel

Maastricht University - Medical Center

Linda M. Kampschreur

Medical Center Leeuwarden

Marcel Nijland

University of Groningen - Department of Hematology and Oncology

Jaap H. Strijbos

Independent

Menno Tamminga

University of Groningen - Department of Pulmonary Diseases

Pim G. N. J. Mutsaers

Erasmus University Rotterdam (EUR) - Erasmus Medical Center (MC)

Suzanne Schol-Gelok

Albert Schweitzer Hospital

Margriet Dijkstra-Tiekstra

University of Groningen - University Medical Center Groningen (UMCG)

Grigory Sidorenkov

University of Groningen - Department of Epidemiology; University of Groningen - University Medical Center Groningen (UMCG)

Julien Vincenten

Albert Schweitzer Hospital

Wouter H. van Geffen

Medical Center Leeuwarden

Marjolein Knoester

University of Groningen - University Medical Center Groningen (UMCG)

Jos Kosterink

University of Groningen - University Medical Center Groningen (UMCG)

Reinold Gans

University of Groningen - University Medical Center Groningen (UMCG)

Coen Stegeman

University of Groningen - University Medical Center Groningen (UMCG)

Gerwin Huls

University of Groningen - University Medical Center Groningen (UMCG)

Tom van Meerten

University of Groningen - Department of Hematology and Oncology

More...

Abstract

Background: Accumulating evidence points to an overactive immune response in Covid-19 disease and potential clinical benefit of the interleukin-6 inhibitor tocilizumab. We assessed the efficacy of early tocilizumab treatment for hospitalized patients in a randomized phase II study.

Methods: Patients admitted to the general ward with proven Covid-19 and in need of supplemental oxygen were randomly assigned to receive standard of care with or without intravenous tocilizumab 8 mg/kg (maximal 800 mg). A second dose of tocilizumab was permitted if hypoxia persisted after 8 hrs. 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.

Findings: 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). 21% of patients were admitted to the ICU in each arm (p=0.89). The median stay in the ICU was 16 days (IQR 8-30) in the standard arm versus 9 days (IQR 5-16) in the tocilizumab arm (p=0.025). 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).

Interpretation: Various studies have suggested a beneficial effect of tocilizumab in the treatment of COVID-19. This randomized phase II study, which met its primary endpoint, confirms these observations and demonstrates a clinically meaningful efficacy when given early in the disease course in hospitalized patients who need oxygen support, even when concomitantly treated with dexamethasone.

Trial Registration: The trial was designed as a prospective randomized (1:1) open label phase II trial and was registered in the Netherlands Trial register (https://www.trialregister.nl/trial/8504).

Funding Statement: Academic study, funded by participating hospitals. Roche supplied tocilizumab.

Declaration of Interests: None to declare.

Ethics Approval Statement: The trial was approved by the relevant medical ethical committee and was performed in accordance with Good Clinical Practice guidelines and the Helsinki Declaration.

Suggested Citation

Rutgers, Abraham and Westerweel, Peter E. and van der Holt, Bronno and Postma, Simone and van Vonderen, Marit G.A. and Piersma, Djura P. and Postma, Douwe and van den Berge, Maarten and Jong, Eefje and de Vries, Marten and van der Burg, Leonie and Huugen, Dennis and van der Poel, Marjolein and Kampschreur, Linda M. and Nijland, Marcel and Strijbos, Jaap H. and Tamminga, Menno and Mutsaers, Pim G. N. J. and Schol-Gelok, Suzanne and Dijkstra-Tiekstra, Margriet and Sidorenkov, Grigory and Vincenten, Julien and van Geffen, Wouter H. and Knoester, Marjolein and Kosterink, Jos and Gans, Reinold and Stegeman, Coen and Huls, Gerwin and van Meerten, Tom, Timely Administration of Tocilizumab Improves Survival of Hospitalized COVID-19 Patients. Available at SSRN: https://ssrn.com/abstract=3834311 or http://dx.doi.org/10.2139/ssrn.3834311

Abraham Rutgers

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Peter E. Westerweel

Albert Schweitzer Hospital ( email )

Netherlands

Bronno Van der Holt

Erasmus University Rotterdam (EUR) - Clinical Trial Center ( email )

Doctor Molewaterplein 40
Rotterdam, South Holland
Netherlands

Erasmus University Rotterdam (EUR) - HOVON Data Center ( email )

Netherlands

Simone Postma

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Marit G.A. Van Vonderen

Medical Center Leeuwarden ( email )

Leeuwarden
Netherlands

Djura P. Piersma

Medisch Spectrum Twente

Netherlands

Douwe Postma

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Maarten Van den Berge

University of Groningen - Groningen Research Institute for Asthma and COPD ( email )

Groningen
Netherlands

Eefje Jong

Meander Medical Center ( email )

Amersfoort
Netherlands

Marten De Vries

Tjongerschans ( email )

Netherlands

Leonie Van der Burg

Antonius Zorggroep - Antonius Hospital Sneek ( email )

Netherlands

Dennis Huugen

Deventer Ziekenhuis - Deventer Hospital ( email )

Netherlands

Marjolein Van der Poel

Maastricht University - Medical Center ( email )

Maastricht
Netherlands

Linda M. Kampschreur

Medical Center Leeuwarden ( email )

Leeuwarden
Netherlands

Marcel Nijland

University of Groningen - Department of Hematology and Oncology

Netherlands

Jaap H. Strijbos

Independent ( email )

Menno Tamminga

University of Groningen - Department of Pulmonary Diseases ( email )

Netherlands

Pim G. N. J. Mutsaers

Erasmus University Rotterdam (EUR) - Erasmus Medical Center (MC) ( email )

Doctor Molewaterplein 40
Rotterdam, South Holland 3015 GD
Netherlands

Suzanne Schol-Gelok

Albert Schweitzer Hospital ( email )

Netherlands

Margriet Dijkstra-Tiekstra

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Grigory Sidorenkov

University of Groningen - Department of Epidemiology ( email )

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Julien Vincenten

Albert Schweitzer Hospital ( email )

Netherlands

Wouter H. Van Geffen

Medical Center Leeuwarden ( email )

Leeuwarden
Netherlands

Marjolein Knoester

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Jos Kosterink

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Reinold Gans

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Coen Stegeman

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Gerwin Huls

University of Groningen - University Medical Center Groningen (UMCG) ( email )

Hanzeplein 1
Groningen, 9713
Netherlands

Tom Van Meerten (Contact Author)

University of Groningen - Department of Hematology and Oncology ( email )

Netherlands

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