Please select the eligibility criteria that correspond to the clinical trial below.
Title: Extending the Time for Thrombolysis in Emergency Neurological Deficits
Brief Summary: 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.


Options:
A: Inclusion criteria

* Symptoms and signs compatible with ischemia in the basilar artery territory.
* Basilar artery occlusion (BAO) confirmed by CTA or MRA.
* Age 18 years or older (i.e., candidates must have had their 18th birthday).
* If IVT is considered as part of best medical management, IVT should be started within 4.5 hours of estimated time of BAO. (Estimated time of BAO is defined as time of onset of acute symptoms leading to clinical diagnosis of BAO or if not known last time patient was seen normal prior to onset of these symptoms).
* Initiation of IAT should be feasible within 6 hours of estimated time of BAO.

Exclusion criteria

* Pre-existing dependency with mRankin ≥3.
* Females of childbearing potential who are known to be pregnant and/or lactating or who have positive pregnancy tests on admission.
* Patients who require hemodialysis or peritoneal dialysis.
* Other serious, advanced, or terminal illness.
* Any other condition that the investigator feels would pose a significant hazard to the patient if thrombolytic therapy is initiated.
* Current participation in another research drug treatment protocol (patient cannot start another experimental agent until after 90 days).
* Informed consent is not or cannot be obtained.

Imaging exclusion criteria

* High-density lesion consistent with hemorrhage of any degree.
* Significant cerebellar mass effect or acute hydrocephalus.
* Bilateral extended brainstem ischemia.
B: 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
C: Inclusion Criteria:

* Patients presenting with hemispheric acute ischaemic stroke
* Patient, family member or legally responsible person depending on local ethics requirements has given informed consent
* Patient's age is ≥18 years (or as per local requirements)
* Treatment onset can commence within 4.5 - 9 hours after stroke onset according to registered product information, or within 3 - 9 hours according to locally accepted guidelines.
* 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.
* Significant neurological deficit (eg. NIHSS score of ≥ 4 - 26) with clinical signs of hemispheric infarction.
* Penumbral mismatch - A "hypo-perfusion to core" volume ratio of greater than 1.2, and an absolute difference greater than 10ml (using a Magnetic Resonance (MR) or Computed Tomography (CT) Tmax \> 6 second delay), between perfusion lesion and MR-DWI or Computed Tomography-Cerebral Blood Flow (CT-CBF) core lesion.
* An infarct core lesion of less than or equal to 70ml using MR-DWI or CT-CBF

Exclusion Criteria:

* Intracranial haemorrhage (ICH) identified by CT or MRI
* 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
* Pre-stroke MRS score of ≥ 2 (indicating previous disability)
* Contra indication to imaging with contrast agents
* Infarct core \>1/3 Middle Cerebral Artery (MCA) territory qualitatively
* Participation in any investigational study in the previous 30 days
* Any terminal illness such that patient would not be expected to survive more than 1 year
* 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.
* Pregnant women (clinically evident)
* Previous stroke within last three months
* 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.
* Current use of oral anticoagulants or a prolonged prothrombin time (INR \> 1.7) if the patient is on warfarin
* Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hours and a prolonged activated thromboplastin time exceeding the upper limit of the local laboratory normal range.
* 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.
* Clinically significant hypoglycaemia.
* 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.
* Hereditary or acquired haemorrhagic diathesis
* Gastrointestinal or urinary bleeding within the preceding 21 days
* Major surgery within the preceding 14 days which poses risk in the opinion of the investigator.
* Exposure to a thrombolytic agent within the previous 72 hours
* Clinically deemed eligible for Endovascular Clot Retrieval (ECR) treatment by the treating team
D: 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

Answer: B