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

Stroke Clinical Trial

— WAKE-UP  

Official title:

Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke: a Randomised, Double-blind, Placebo-controlled Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01525290
• Other study ID #: WAKE-UP
• Status: Completed
• Phase: Phase 3
• Start date: September 2012
• Est. completion date: October 2018

Study information

• Verified date: October 2018
• Source: Universitätsklinikum Hamburg-Eppendorf
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

WAKE-UP is a 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. Intravenous thrombolysis with Alteplase is available as effective and safe treatment of acute stroke within 4.5 hours of symptom onset. However, in about 20% of acute stroke patients time of symptom onset is unknown. This large group of patients is currently excluded from treatment with Alteplase. The objective of the research proposed in the WAKE-UP project is to provide effective treatment options for this large group of acute stroke patients.

WAKE-UP is designed 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. Patients will be enrolled based on MRI findings indicative of acute ischemic stroke less than 4.5 hours of age.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 501
• Est. completion date: October 2018
• Est. primary completion date: October 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

Clinical Inclusion Criteria

• 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

Imaging Inclusion Criteria:

• 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

Exclusion Criteria:

Clinical Exclusion Criteria

• 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)

• Blood glucose < 50 or > 400 mg/dl (< 2.8 or 22.2 mmol/l)

• Severe uncontrolled hypertension, i.e. systolic blood pressure > 185 mmHg or diastolic blood pressure >110 mmHg or requiring aggressive medication to maintain blood pressure within these limits (routine medical treatment is allowed to lower the blood pressure below these limits)

• Manifest or recent bacterial endocarditis, pericarditis

• Manifest or recent acute pancreatitis

• Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformations

• Neoplasm with increased bleeding risk

• Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension and active hepatitis

• Major surgery or significant trauma in past 3 months

• Stroke within 30 days

• Life expectancy 6 months or less by judgement of the investigator

• Any condition associated with a significantly increased risk of severe bleeding not mentioned above

• Any contraindication to MRI (e.g. cardiac pacemaker)

Imaging Exclusion Criteria:

• Poor MRI quality precluding interpretation according to the study protocol

• Any sign of intracranial haemorrhage on baseline MRI

• FLAIR showing a marked parenchymal hyperintensity in a region corresponding to the acute DWI lesion indicative of an acute ischemic lesion with a high likelihood of being > 4.5 hours old

• Large DWI lesion volume > 1/3 of the MCA or > 50% of the anterior cerebral artery (ACA) or posterior cerebral artery (PCA) territory (visual inspection) or > 100 ml

• Any MRI findings indicative of a high risk of symptomatic intracranial haemorrhage related to potential IV-tPA treatment in the judgement of the investigator

Related Conditions & MeSH terms

• Stroke

Intervention

Drug:
• Alteplase
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
• Placebo
lyophilised powder to be reconstituted as solution indistinguishable from the active drug

Locations

Country	Name	City	State
Belgium	Katholieke Universitet Leuven	Leuven
Denmark	Aarhus Universitetshospital, Aahrhus Sygehus	Aarhus
France	Hospices Civils de Lyon	Bron Cedex
Germany	Charite - Universitätsmedizin Berlin	Berlin
Germany	University Medical Center Hamburg-Eppendorf	Hamburg
Spain	Institut d'Investigacio Biomedica de Girona Doctor Josep Trueta	Girona
United Kingdom	University of Glasgow	Glasgow

Sponsors (1)

Lead Sponsor	Collaborator
Universitätsklinikum Hamburg-Eppendorf

Countries where clinical trial is conducted

Belgium,  Denmark,  France,  Germany,  Spain,  United Kingdom, 

References & Publications (1)

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, Günther M, Guibernau J, Häusler KG, Hennerici M, Kemmling A, Marstrand J, Modrau B, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy	Favourable outcome (Modified Rankin Scale 0-1)	90 day after stroke
Primary	Safety	Mortality; Death or dependency (Modified Rankin Scale 4-6)	90 day after stroke
Secondary	Efficacy	Global outcome score; Responder analysis (Modified Rankin Scale 0, 0-1 or 0-2 depending on severity of symptoms assessed by the National Institutes of Health Stroke Scale on admission); Outcome across all disability ranges (categorical shift in Modified Rankin Scale score); Infarct volume (measured 22-36 hours after treatment); Functional health status and quality of life; Use of health care system resources	90 days after stroke
Secondary	Safety	Symptomatic intracranial haemorrhage (SICH) as defined in SITS-MOST; SICH as defined ECASS II; SICH as defined in NINDS; Parenchymal haemorrhage type 2 (PH-2)	90 days after stroke

External Links

•   Publication of primary trial results.