Extending the Time for Thrombolysis in Emergency Neurological Deficits
Extending the Time for Thrombolysis in Emergency Neurological Deficits
The primary hypothesis being tested in this trial is that ischaemic stroke patients selected
 with significant penumbral mismatch (measured by MRI criteria) at 3 - 9 hours post onset of
 stroke will have improved clinical outcomes when given intravenous tissue plasminogen
 activator (tPA) compared to placebo.
Inclusion Criteria:

 1. Patients presenting with hemispheric acute ischaemic stroke

 2. Patient, family member or legally responsible person depending on local ethics
 requirements has given informed consent

 3. Patient's age is ≥18 years

 4. Treatment onset can commence within ≥ 3 - 9 hours after stroke onset according to
 registered product information, or within 4.5 - 9 hours according to locally accepted
 guidelines*.

 (*Guidelines are currently under international review - advisory statement issued by
 the Stroke Council, American Heart Association and American Stroke Association)

 5. Patients who wake with stroke may be included if neurological and other exclusion
 criteria are satisfied. These 'wake up' strokes are defined as having no symptoms at
 sleep onset, but stroke symptoms on waking. The time of stroke onset is to be taken as
 the mid-point between sleep onset (or last known to be normal) and time of waking. The
 maximum time window for randomisation is then 9 hours from the mid-point as described.

 6. NIHSS score of ≥ 4 - 26 with clinical signs of hemispheric infarction.

 7. Penumbral mismatch - A "hypo-perfusion to core" volume ratio of greater than 1.2 and
 an absolute difference greater than 10mL (using a MR or CT Tmax > 6 second delay)
 between perfusion lesion and MR-DWI or CT-CBF core lesion.

 8. An ischaemic core lesion volume of less than or equal to 70 ml using MR-DWI or CT-CBF
 ** Patients may be consented before or after penumbral screening depending upon local
 practice. The entire cohort of patients consented onto the study will be followed up
 with clinical assessments and biomarker studies regardless of eligibility for
 randomisation to treatment based on penumbral mismatch criteria

 Exclusion Criteria:

 1. Intracranial haemorrhage (ICH) identified by CT or MRI

 2. Rapidly improving symptoms, particularly if in the judgment of the managing clinician
 that the improvement is likely to result in the patient having an NIHSS score of < 4
 at randomization

 3. Pre-stroke MRS score of ≥ 2 (indicating previous disability)

 4. Contra indication to imaging with MR with contrast agents

 5. Infarct core >1/3 MCA territory qualitatively

 6. Participation in any investigational study in the previous 30 days

 7. Any terminal illness such that patient would not be expected to survive more than 1
 year

 8. Any condition that could impose hazards to the patient if study therapy is initiated
 or affect the participation of the patient in the study (this applies to patients with
 severe microangiopathy such as haemolytic uremic syndrome or thrombotic
 thrombocytopenic purpura). The judgment is left to the discretion of the Investigator.

 9. Pregnant women (clinically evident)

 10. Previous stroke within last three months

 11. Recent past history or clinical presentation of ICH, subarachnoid haemorrhage (SAH),
 arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm. At the discretion of
 each Investigator.

 12. Current use of oral anticoagulants or a prolonged prothrombin time (INR > 1.7) if the
 patient is on warfarin

 13. Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hours and
 an activated prolonged partial thromboplastin time exceeding the upper limit of the
 local laboratory normal range.

 14. Use of glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of single or
 dual agent oral platelet inhibitors (clopidogrel and/or low-dose aspirin) prior to
 study entry is permitted.

 15. Clinically significant hypoglycaemia.

 16. Uncontrolled hypertension defined by a blood pressure > 185 mmHg systolic or >110 mmHg
 diastolic on at least 2 separate occasions at least 10 minutes apart, or requiring
 aggressive treatment to reduce the blood pressure to within these limits. The
 definition of "aggressive treatment" is left to the discretion of the responsible
 Investigator.

 17. Hereditary or acquired haemorrhagic diathesis

 18. Gastrointestinal or urinary bleeding within the preceding 21 days

 19. Major surgery within the preceding 14 days which poses risk in the opinion of the
 investigator.

 20. Exposure to a thrombolytic agent within the previous 72 hours

 21. Clinically deemed eligible for Endovascular Clot Retrieval (ECR) treatment by the
 treating team