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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Stroke

Intervention / Treatment
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* Drug: Alteplase
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intravenous tissue plasminogen activator<br>Intervention drug: intravenous tissue plasminogen activator (tPA), alteplase | Drug: Alteplase<br>* 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<br>* Other names: rt-PA;|
| Placebo Comparator: Placebo<br>Intervention drug: placebo | Drug: Placebo<br>* lyophilised powder to be reconstituted as solution indistinguishable from the active drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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wake-up stroke, thrombolysis, magnetic resonance imaging (MRI), diffusion weighted imaging (DWI), fluid attenuated inversion recovery (FLAIR)