Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke

NCT01525290 | Completed Phase 3 DMC

• 1 other identifier: WAKE-UP
• Study Type: interventional
• Target: 501
• Locations: 6 countries
• Sites: 7

Brief Summary

WAKE-UP is an investigator initiated European multicenter randomized controlled clinical trial of MRI based thrombolysis in acute stroke patients with unknown time of symptom onset, e.g. due to recognition of stroke symptoms on awakening. Objective of WAKE-UP is to prove efficacy and safety of MRI-based intravenous thrombolysis with Alteplase in patients waking up with stroke symptoms or patients with otherwise unknown symptom onset.

Conditions

Stroke

Keywords

wake-up stroke; thrombolysis; magnetic resonance imaging (MRI); diffusion weighted imaging (DWI); fluid attenuated inversion recovery (FLAIR)

Outcome Measures

Primary Outcomes (2)

• Efficacy

  Favourable outcome (Modified Rankin Scale 0-1)

  90 day after stroke

• Safety

  * Mortality * Death or dependency (Modified Rankin Scale 4-6)

  90 day after stroke

Secondary Outcomes (2)

• Efficacy

  90 days after stroke

• Safety

  90 days after stroke

Study Arms (2)

intravenous tissue plasminogen activator

EXPERIMENTAL

Intervention drug: intravenous tissue plasminogen activator (tPA), alteplase

Drug: Alteplase

Placebo

PLACEBO COMPARATOR

Intervention drug: placebo

Drug: Placebo

Interventions

Alteplase DRUG

Intravenous tissue plasminogen activator (Alteplase) 0.9 mg/kg body-weight up to a maximum of 90 mg, 10% as bolus, 90% over 1 hour as infusion

Also known as: Actilyse, Activase, rt-PA

intravenous tissue plasminogen activator

Placebo DRUG

lyophilised powder to be reconstituted as solution indistinguishable from the active drug

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g., stroke symptoms recognized on awakening)
• Last known well (without neurological symptoms) \> 4.5 hours of treatment initiation
• Measurable disabling neurological deficit (defined as an impairment of one or more of the following: language, motor function, cognition, gaze, vision, neglect)
• Age 18-80 years
• Treatment can be started within 4.5 hours of symptom recognition (e.g., awakening)
• Written informed consent by patient or proxy
• Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) completed
• MRI showing a pattern of "DWI-FLAIR-mismatch", i.e. acute ischemic lesion visibly on DWI ("positive DWI") but no marked parenchymal hyperintensity visible on FLAIR ("negative FLAIR") indicative of an acute ischemic lesion ≤4.5 hours of age

You may not qualify if:

• Planned or anticipated treatment with endovascular reperfusion strategies (e.g. intra-arterial thrombolysis, mechanical recanalization techniques)
• Pre-stroke disability (inability to carry out all daily activities, requiring some help or supervision, i.e. slight disability corresponding to an MRS score \> 1)
• Participation in any investigational study in the previous 30 days
• Severe stroke by clinical assessment (e.g. NIHSS \> 25)
• Hypersensitivity to Alteplase or any of the excipients
• Pregnancy or lactating (formal testing needed in woman of childbearing potential; childbearing potential is assumed in women up to 55 years of age)
• Significant bleeding disorder at present or within past 6 months
• Known haemorrhagic diathesis
• Manifest or recent severe or dangerous bleeding
• Known history of or suspected intracranial haemorrhage
• Suspected subarachnoid haemorrhage (even if CT is negative) or condition after subarachnoid haemorrhage from aneurysm
• History of CNS damage (e.g. neoplasm, aneurysm, intracranial or spinal surgery)
• Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel
• Current use of anticoagulants (e.g. Phenprocoumon, Warfarin, new anticoagulants such as Dabigatran) or current use of heparin and elevated thromboplastin time (low-dose subcutaneous heparin is allowed)
• Platelet count \< 100.000/mm3 (\<100G/l)

Sponsors & Collaborators

• Universitätsklinikum Hamburg-Eppendorf: lead

Study Sites (7)

Katholieke Universitet Leuven

Leuven, 3000, Belgium

Location

Aarhus Universitetshospital, Aahrhus Sygehus

Aarhus, 8000, Denmark

Location

Hospices Civils de Lyon

Bron, 69677, France

Location

Charite - Universitätsmedizin Berlin

Berlin, 10117, Germany

Location

University Medical Center Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Institut d'Investigacio Biomedica de Girona Doctor Josep Trueta

Girona, 17007, Spain

Location

University of Glasgow

Glasgow, G12 8QQ, United Kingdom

Location

Related Publications (18)

• Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, Cheripelli B, Cho TH, Fazekas F, Fiehler J, Ford I, Galinovic I, Gellissen S, Golsari A, Gregori J, Gunther M, Guibernau J, Hausler KG, Hennerici M, Kemmling A, Marstrand J, Modrau B, Neeb L, Perez de la Ossa N, Puig J, Ringleb P, Roy P, Scheel E, Schonewille W, Serena J, Sunaert S, Villringer K, Wouters A, Thijs V, Ebinger M, Endres M, Fiebach JB, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Gerloff C; WAKE-UP Investigators. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018 Aug 16;379(7):611-622. doi: 10.1056/NEJMoa1804355. Epub 2018 May 16.

  PMID: 29766770 RESULT

• Nagele FL, Scheldeman L, Wouters A, Heinze M, Petersen M, Schlemm E, Schell M, Ebinger M, Endres M, Fiebach JB, Fiehler J, Galinovic I, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Puig J, Simonsen CZ, Thijs V, Thomalla G, Cheng B. Blood-Brain Barrier Leakage in the Penumbra Is Associated With Infarction on Follow-Up Imaging in Acute Ischemic Stroke. Stroke. 2025 Jul;56(7):1832-1842. doi: 10.1161/STROKEAHA.124.050171. Epub 2025 Apr 17.

  PMID: 40242873 DERIVED

• Galinovic I, Fiebach JB, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, Enzinger C, Fiehler J, Ford I, Gregori J, Gunther M, Lemmens R, Muir KW, Nighoghossian N, Roy P, Simonsen CZ, Thijs VN, Wouters A, Gerloff C, Thomalla G, Pedraza S; for WAKE-UP Investigators. Effect of IV Thrombolysis With Alteplase in Patients With Vessel Occlusion in the WAKE-UP Trial. Neurology. 2025 Jan 28;104(2):e209871. doi: 10.1212/WNL.0000000000209871. Epub 2024 Dec 20.

  PMID: 39705631 DERIVED

• Frey BM, Shenas F, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, Fiebach JB, Fiehler J, Galinovic I, Barow E, Konigsberg A, Schlemm E, Pedraza S, Lemmens R, Thijs V, Muir KW, Nighoghossian N, Simonsen CZ, Gerloff C, Thomalla G; WAKE-UP Investigators. Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial. Stroke. 2023 Jul;54(7):1718-1725. doi: 10.1161/STROKEAHA.122.040247. Epub 2023 May 25.

  PMID: 37226772 DERIVED

• Jensen M, Sehner S, Cheng B, Schlemm E, Quandt F, Barow E, Wegscheider K, Boutitie F, Ebinger M, Endres M, Fiebach JB, Thijs V, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Thomalla G, Gerloff C. Patient-Reported Quality of Life After Intravenous Alteplase for Stroke in the WAKE-UP Trial. Neurology. 2023 Jan 10;100(2):e154-e162. doi: 10.1212/WNL.0000000000201375. Epub 2022 Oct 27.

  PMID: 36302662 DERIVED

• Barow E, Quandt F, Cheng B, Gelderblom M, Jensen M, Konigsberg A, Boutitie F, Nighoghossian N, Ebinger M, Endres M, Fiebach JB, Thijs V, Lemmens R, Muir KW, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G. Association of White Blood Cell Count With Clinical Outcome Independent of Treatment With Alteplase in Acute Ischemic Stroke. Front Neurol. 2022 Jun 13;13:877367. doi: 10.3389/fneur.2022.877367. eCollection 2022.

  PMID: 35769368 DERIVED

• Schlemm L, Braemswig TB, Boutitie F, Vynckier J, Jensen M, Galinovic I, Simonsen CZ, Cheng B, Cho TH, Fiehler J, Puig J, Thijs V, Fiebach J, Muir K, Nighoghossian N, Ebinger M, Pedraza S, Thomalla G, Gerloff C, Endres M, Lemmens R, Nolte CH; WAKE-UP Investigators. Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial. Neurology. 2022 Jan 18;98(3):e302-e314. doi: 10.1212/WNL.0000000000013055. Epub 2021 Nov 15.

  PMID: 34782419 DERIVED

• Lettow I, Jensen M, Schlemm E, Boutitie F, Quandt F, Cheng B, Ebinger M, Endres M, Fiebach JB, Thijs V, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G; WAKE-UP Investigators. Serious Adverse Events and Their Impact on Functional Outcome in Acute Ischemic Stroke in the WAKE-UP Trial. Stroke. 2021 Dec;52(12):3768-3776. doi: 10.1161/STROKEAHA.120.033425. Epub 2021 Aug 26.

  PMID: 34433305 DERIVED

• Barow E, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, Fiebach JB, Fiehler J, Nickel A, Puig J, Roy P, Lemmens R, Thijs V, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G. 24-hour blood pressure variability and treatment effect of intravenous alteplase in acute ischaemic stroke. Eur Stroke J. 2021 Jun;6(2):168-175. doi: 10.1177/23969873211014758. Epub 2021 Jun 18.

  PMID: 34414292 DERIVED

• Scheldeman L, Wouters A, Dupont P, Christensen S, Boutitie F, Cheng B, Ebinger M, Endres M, Fiebach JB, Gerloff C, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Ringelstein EB, Chamorro A, Grond M, Laage R, Schneider A, Thomalla G, Thijs V, Lemmens R. Reversible Edema in the Penumbra Correlates With Severity of Hypoperfusion. Stroke. 2021 Jul;52(7):2338-2346. doi: 10.1161/STROKEAHA.120.033071. Epub 2021 May 13.

  PMID: 33980046 DERIVED

• Konigsberg A, Sehner S, Arlt S, Cheng B, Simonsen CZ, Boutitie F, Serena J, Thijs V, Ebinger M, Endres M, Fiebach JB, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Gerloff C, Thomalla G; WAKE-UP investigators. Effect of intravenous alteplase on post-stroke depression in the WAKE UP trial. Eur J Neurol. 2021 Jun;28(6):2017-2025. doi: 10.1111/ene.14797. Epub 2021 Mar 22.

  PMID: 33657675 DERIVED

• Grosch AS, Kufner A, Boutitie F, Cheng B, Ebinger M, Endres M, Fiebach JB, Fiehler J, Konigsberg A, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Siemonsen CZ, Thijs V, Wouters A, Gerloff C, Thomalla G, Galinovic I. Extent of FLAIR Hyperintense Vessels May Modify Treatment Effect of Thrombolysis: A Post hoc Analysis of the WAKE-UP Trial. Front Neurol. 2021 Feb 4;11:623881. doi: 10.3389/fneur.2020.623881. eCollection 2020.

  PMID: 33613422 DERIVED

• Barow E, Pinnschmidt H, Boutitie F, Konigsberg A, Ebinger M, Endres M, Fiebach JB, Fiehler J, Thijs V, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G, Cheng B; WAKE-UP investigators. Symptoms and probabilistic anatomical mapping of lacunar infarcts. Neurol Res Pract. 2020 Aug 3;2:21. doi: 10.1186/s42466-020-00068-y. eCollection 2020.

  PMID: 33324925 DERIVED

• Schlemm L, Kufner A, Boutitie F, Nave AH, Gerloff C, Thomalla G, Simonsen CZ, Ford I, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Ebinger M, Endres M. Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Post-hoc Analysis of the WAKE-UP Trial. Front Neurol. 2019 Nov 22;10:1239. doi: 10.3389/fneur.2019.01239. eCollection 2019.

  PMID: 31824412 DERIVED

• Barow E, Boutitie F, Cheng B, Cho TH, Ebinger M, Endres M, Fiebach JB, Fiehler J, Ford I, Galinovic I, Nickel A, Puig J, Roy P, Wouters A, Thijs V, Lemmens R, Muir KW, Nighoghossian N, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G; WAKE-UP investigators. Clinical Characteristics and Outcome of Patients with Lacunar Infarcts and Concurrent Embolic Ischemic Lesions. Clin Neuroradiol. 2020 Sep;30(3):511-516. doi: 10.1007/s00062-019-00800-5. Epub 2019 Jun 3.

  PMID: 31161343 DERIVED

• Thomalla G, Boutitie F, Fiebach JB, Simonsen CZ, Nighoghossian N, Pedraza S, Lemmens R, Roy P, Muir KW, Heesen C, Ebinger M, Ford I, Cheng B, Cho TH, Puig J, Thijs V, Endres M, Fiehler J, Gerloff C. Effect of informed consent on patient characteristics in a stroke thrombolysis trial. Neurology. 2017 Sep 26;89(13):1400-1407. doi: 10.1212/WNL.0000000000004414. Epub 2017 Aug 25.

  PMID: 28842449 DERIVED

• Thomalla G, Boutitie F, Fiebach JB, Simonsen CZ, Pedraza S, Lemmens R, Nighoghossian N, Roy P, Muir KW, Ebinger M, Ford I, Cheng B, Galinovic I, Cho TH, Puig J, Thijs V, Endres M, Fiehler J, Gerloff C. Clinical characteristics of unknown symptom onset stroke patients with and without diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch. Int J Stroke. 2018 Jan;13(1):66-73. doi: 10.1177/1747493017706245. Epub 2017 Apr 20.

  PMID: 28425349 DERIVED

• Thomalla G, Boutitie F, Fiebach JB, Simonsen CZ, Nighoghossian N, Pedraza S, Lemmens R, Roy P, Muir KW, Ebinger M, Ford I, Cheng B, Galinovic I, Cho TH, Puig J, Thijs V, Endres M, Fiehler J, Gerloff C; WAKE-UP Investigators. Stroke With Unknown Time of Symptom Onset: Baseline Clinical and Magnetic Resonance Imaging Data of the First Thousand Patients in WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial). Stroke. 2017 Mar;48(3):770-773. doi: 10.1161/STROKEAHA.116.015233. Epub 2017 Feb 7.

  PMID: 28174327 DERIVED

MeSH Terms

Conditions

Stroke; Ischemic Stroke

Interventions

Tissue Plasminogen Activator

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Serine Endopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Biological Factors

Study Officials

• Christian Gerloff, MD

  Universitätsklinikum Hamburg-Eppendorf

  STUDY CHAIR

• Goetz Thomalla, MD

  Universitätsklinikum Hamburg-Eppendorf

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Coordinating Investigator

Study Record Dates

• First Submitted: January 30, 2012
• First Posted: February 2, 2012
• Study Start: September 1, 2012
• Primary Completion: October 1, 2018
• Study Completion: October 1, 2018
• Last Updated: October 11, 2018

Record last verified: 2018-10

Locations

DK (1); FR (1); DE (2); ES (1); BE (1); GB (1)