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A multicenter, randomized, double-blind, placebo-controlled trial to test efficacy and safety of magnetic resonance imaging-based thrombolysis in wake-up stroke (WAKE-UP)

Authors

  • Götz Thomalla,

    Corresponding author
    1. Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
    • Correspondence: Götz Thomalla*, Kopf- und Neurozentrum, Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.

      E-mail: thomalla@uke.uni-hamburg.de

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  • Jochen B. Fiebach,

    1. Centrum für Schlaganfallforschung Berlin (CSB), Charité-Universitätsmedizin Berlin, Berlin, Germany
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  • Leif Østergaard,

    1. Center of Functionally Integrative Neuroscience (CFIN), Aarhus University Hospital, Aarhus, Denmark
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  • Salvador Pedraza,

    1. Department of Radiology, Institut de Diagnostic per la Image (IDI), Hospital Dr Josep Trueta, Institut d'Investgació Biomèdica de Girona (IDIBGI), Girona, Spain
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  • Vincent Thijs,

    1. Department of Neurology, University HospitalsLeuven, Leuven, Belgium
    2. Vesalius Research Center, VIB, Leuven, Belgium
    3. Experimental Neurology and Leuven Research Institute for Neurodegenerative Diseases (LIND), University of Leuven, Leuven, Belgium
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  • Norbert Nighoghossian,

    1. Department of Neurology, Hospices Civils de Lyon, Lyon, France
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  • Pascal Roy,

    1. Service de Biostatistique, Centre d'Investigation Clinique, Hospices Civils de Lyon, Lyon, France
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  • Keith W. Muir,

    1. Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK
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  • Martin Ebinger,

    1. Centrum für Schlaganfallforschung Berlin (CSB), Charité-Universitätsmedizin Berlin, Berlin, Germany
    2. Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
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  • Bastian Cheng,

    1. Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
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  • Ivana Galinovic,

    1. Centrum für Schlaganfallforschung Berlin (CSB), Charité-Universitätsmedizin Berlin, Berlin, Germany
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  • Tae-Hee Cho,

    1. Department of Neurology, Hospices Civils de Lyon, Lyon, France
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  • Josep Puig,

    1. Department of Radiology, Institut de Diagnostic per la Image (IDI), Hospital Dr Josep Trueta, Institut d'Investgació Biomèdica de Girona (IDIBGI), Girona, Spain
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  • Florent Boutitie,

    1. Service de Biostatistique, Centre d'Investigation Clinique, Hospices Civils de Lyon, Lyon, France
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  • Claus Z. Simonsen,

    1. Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
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  • Matthias Endres,

    1. Centrum für Schlaganfallforschung Berlin (CSB), Charité-Universitätsmedizin Berlin, Berlin, Germany
    2. Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
    3. ExzellenzCluster NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany
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  • Jens Fiehler,

    1. Klinik und Poliklinik für Neuroradiologische Diagnostik und Intervention, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
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  • Christian Gerloff,

    1. Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
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  • WAKE-UP investigators


  • Conflicts of interest: Matthias Endres has received grant support from AstraZeneca and Sanofi Aventis, has participated in advisory board meetings of Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, and Sanofi, and has received honoraria from AstraZeneca, Bayer, Berlin Chemie, Bristol-Myers Squibb, Boehringer Ingelheim, Desitin, Eisei, Ever, Glaxo Smith Kline, MSD, Novartis, Pfizer, Sanofi, Takeda, Trommsdorff. Jochen B. Fiebach has received fees as a board member, consultant, or lecturer from Boehringer Ingelheim, Lundbeck, Siemens, Sygnis, and Synarc. Jens Fiehler has received fees as a consultant or lecture fees from Codman, Covidien, Siemens, and Stryker. Christian Gerloff has received fees as a consultant or lecture fees from Bayer Vital, Boehringer Ingelheim, EBS technologies, Glaxo Smith Kline, Lundbeck, Pfizer, Sanofi Aventis, Silk Road Medical, and UCB. Ivana Galinovic has received lecture fees from Lundbeck. Keith W. Muir has received support for travel to meetings from Boehringer Ingelheim and has received consultancy fees from Codman. Salvador Pedraza has received fees as a board member, consultant, or lecturer from Lundbeck and Synarc. Vincent Thijs has received fees as a steering committee member, consultant, adjudicator, or lecturer from Boehringer Ingelheim,Sygnis, Bayer, Pfizer, Merck, Shire, Medtronic, Abbott, Takeda. Florent Boutitier, Bastian Cheng, Tae-Hee Cho, Martin Ebinger, Norbert Nighoghossian, Leif Østergaard, Josep Puig, Pascal Roy, Claus Z. Simonsen, and Götz Thomalla have no conflicts of interest to report.
  • Funding: WAKE-UP receives funding from the European Union Seventh Framework Programme [FP7/2007–2013] under grant agreement no. 278276 (WAKE-UP).

Abstract

Rationale

In about 20% of acute ischemic stroke patients stroke occurs during sleep. These patients are generally excluded from intravenous thrombolysis. MRI can identify patients within the time-window for thrombolysis (≤4·5 h from symptom onset) by a mismatch between the acute ischemic lesion visible on diffusion weighted imaging (DWI) but not visible on fluid-attenuated inversion recovery (FLAIR) imaging.

Aims and hypothesis

The study aims to test the efficacy and safety of MRI-guided thrombolysis with tissue plasminogen activator (rtPA) in ischemic stroke patients with unknown time of symptom onset, e.g., waking up with stroke symptoms. We hypothesize that stroke patients with unknown time of symptom onset with a DWI-FLAIR-mismatch pattern on MRI will have improved outcome when treated with rtPA compared to placebo.

Design

WAKE-UP is an investigator initiated, European, multicentre, randomized, double-blind, placebo-controlled clinical trial. Patients with unknown time of symptom onset who fulfil clinical inclusion criteria (disabling neurological deficit, no contraindications against thrombolysis) will be studied by MRI. Patients with MRI findings of a DWI-FLAIR-mismatch will be randomised to either treatment with rtPA or placebo.

Study outcome

The primary efficacy endpoint will be favourable outcome defined by modified Rankin Scale 0–1 at day 90. The primary safety outcome measures will be mortality and death or dependency defined by modified Rankin Scale 4–6 at 90 days.

Discussion

If positive, WAKE-UP is expected to change clinical practice making effective and safe treatment available for a large group of acute stroke patients currently excluded from specific acute therapy.

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