MR WITNESS: A Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients

This study was jointly developed and is jointly led by Massachusetts General Hospital and
the NINDS. This is a multi-center, open-label, Phase IIa safety study in adult acute
ischemic stroke patients to determine if it is safe to extend intravenous thrombolytic
treatment to subjects who are evaluated within 24 hours from last known well ("stroke
onset") and eligible to receive thrombolytic treatment within 4.5 hours from symptom
discovery with the assistance of an MRI-based "witness" when no human witness of stroke
onset is available. The study is designed to investigate the safety in using standard
diagnostic MRI in selecting patients for thrombolytic therapy when the last known well time
places the patient beyond the current IV thrombolytic time-window.

Inclusion Criteria:

- Age, 18 to 85 years inclusive

- Brain MRI findings consistent with early stroke onset

- Clinical diagnosis of acute ischemic stroke with disabling neurological deficit

- Stroke symptoms present for at least 30 minutes with no significant improvement
before treatment

- Be last known well (without stroke symptoms) within 24 hours of triage

- Be able to receive IV rt-PA within 4.5 hours from the time the symptoms were
discovered.

- MRI diagnostic of acute ischemic stroke and consistent with clinical syndrome

- Time between completion of qualifying MRI studies to treatment initiation ≤ 1 hour

Exclusion Criteria:

- History of intracranial hemorrhage

- Symptoms rapidly improving or only minor before start of study drug.

- Severe stroke as assessed clinically (e.g., NIHSS score >25) or by appropriate
imaging techniques (lesion volume > one-third of MCA by visual inspection or >100 cm3
using the ellipsoid estimation formula of ABC/2)

- Stroke or serious head trauma within the previous 3 months

- Administration of heparin within the 48 hours preceding the onset of stroke, with an
activated partial-thromboplastin time at presentation exceeding the upper limit of
the normal range

- Platelet count of less than 100,000 per cubic millimeter

- Uncontrolled hypertension defined as systolic blood pressure > 185 mm Hg or diastolic
blood pressure > 110 mm Hg that cannot be controlled except with continuous
parenteral antihypertensive medication

- Blood glucose less than 50 mg per deciliter or greater than 400 mg per deciliter

- Symptoms suggestive of subarachnoid hemorrhage, even if CT/MRI scan was normal

- Oral anticoagulant treatment, regardless of INR.

- Major surgery or severe trauma within the previous 3 months

- Other major disorders associated with an increased risk of bleeding

- Eligible for rt-PA therapy per institutional protocol as part of routine clinical
practice

- Non-ischemic etiology demonstrated by neuroimaging

- Neuroimaging (CT or gradient echo MRI) evidence of acute or chronic ICH
(non-microbleed)

- Presence of 10 or more microbleeds on GRE (suggestive of amyloid angiopathy)

- Any contraindication for MRI, e.g. presence of a pacemaker, ferromagnetic aneurysm
clip, etc, pre-menopausal women with a positive pregnancy blood test, or severe
claustrophobia.

- Poor quality MRI- images are not interpretable

- In the opinion of the investigator, the patient is not an appropriate candidate for
IV rt-PA

- Women known to be pregnant, lactating or having a positive or indeterminate pregnancy
test.