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)
- 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).
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.
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.
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.
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.