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

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