Efficacy and Safety of MRI-based Thrombolysis in Wake-up Stroke (WAKE-UP)

Universitätsklinikum Hamburg-Eppendorf

Status and phase

Completed

Phase 3

Conditions

Stroke

Treatments

Drug: Placebo

Drug: Alteplase

Study type

Interventional

Funder types

Other

Identifiers

NCT01525290

WAKE-UP

Details and patient eligibility

About

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.

Full 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.

Enrollment

501 patients

Sex

All

Ages

18 to 80 years old

Volunteers

No Healthy Volunteers

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