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 (according to imaging criteria) at 4.5 (or 3 hours depending on local guidelines) - 9 hours post onset of stroke or after 'wake up stroke' (WUS) will have improved clinical outcomes when given intravenous tissue plasminogen activator (tPA) compared to placebo.


Options:
A: Inclusion Criteria:

* Randomization within 11 hours after stroke onset (if known) or last seen well.
* Endovascular treatment is expected to be finished within 12 hours after known symptom onset or last seen well by judgment of the interventional neuroradiologist in charge (if stroke onset is known).
* Patient must demonstrate clinical signs and symptoms attributable to target area of occlusion consistent with the diagnosis of ischemic stroke, including impairment of the following: language, motor function, sensation, cognition, gaze, and/or vision for at least 30 minutes without relevant improvement.
* Female and male patient above 18 years of age
* NIHSS Score of \<26
* Signed informed consent (IC) form by patient or legal guardian, or inclusion of patient's presumptive will by investigator under emergency situation, but after consultation of an independent physician who is familiar with these types of illness if the other options are not possible according to local approval.
* Prior to new focal neurological deficit, mRS score was ≤2.

Imaging Inclusion Criteria

* A new focal occlusion confirmed by imaging (MRA/CTA) to be accessible to the thrombectomy device, and located in the M1 of the middle cerebral artery (MCA) and/or the intracranial segment of the distal internal carotid artery (ICA).
* CT (non-contrast CT) or DWI with an ASPECT score of 3-5

Clinical exclusion criteria

* Patient is an active participant in another drug or device treatment trial for any disease state or patient is expected to start participation in another drug or device treatment trial while enrolled in this protocol, unless approved by Sponsor.
* Patient has pre-existing neurological or psychiatric disease that could impede the study results or would confound the neurological or functional evaluations.
* Patient has vascular disease preventing endovascular treatment (e.g. aortic dissection or aneurysm, no arterial transfemoral access)
* Patient has history of contraindication for contrast medium.
* Patient is known to have infective endocarditis
* Patient's anticipated life expectancy is less than 6 Months12 months

Imaging exclusion criteria

* ExtracaranialExtracranial CT scan or MR angiography showing high grade stenosis expected to require acute stent placement (especially e.g. ICAACI stenting) during the procedure to get access to the occlusion
* CT or MRI with evidence of: Mass mass effect or intracranial tumor, or hypodensity on unenhanced CT and
* If CT perfusion is done per institutional standard: CBV drop on CBV maps on CTP, or, alternatively as with an ASPECT score of 0-2
* If DWI is done per institutional standard,: restricted diffusion on DWI with an ASPECT score of 0-2, or above 5
B: Inclusion Criteria:

* Acute ischemic stroke patients who were treated with intravenous rt-PA therapy within 4.5 hours from onset and have persistent occlusion of IC and M1 proximal portion\* confirmed by cerebral angiography.

  \*: M1 proximal portion means the segment of MCA within 5mm from the internal carotid bifurcation.
* Patients who can receive endovascular treatment within 8 hours after the onset.
* Patients whose DWI-ASPECTS was 5 points and more, or CT-ASPECT was 6 points and more just before cerebral angiography.
* Patients whose NIHSS is between 8 and 29 points.
* Patients who are between 20 and 85 years.
* Gender does not matter.
* Consent of this study participants must be obtained from patients or legal representative in writing.

Exclusion Criteria:

* Patients whose neurological symptoms improved and NIHSS is eight points and less after intravenous rt-PA therapy.
* Patients whose mRS was 3 points and more before the onset. 3)Patients with past history of lumbar puncture or arterial puncture that were difficult of hemostasis.
* Patients with intracranial tumor
* Patients with hypersensitivity to contrast agent.
* Patients with serious renal disease.
* Patients with malignant tumor.
* Patients with pregnancy or suspect of pregnancy, or during lactation.
* Patients with findings of acute myocardial infarction or pericarditis after myocardial infarction.
* Patients who cannot be followed for 3 months.
* Patients with past history of cerebral aneurysm, cerebral arteriovenous malformation, cerebral venous thrombosis, or moyamoya disease.
* Patients with other occlusions besides ICA or M1 proximal portion.
* Patients with aortic dissection complicating endovascular treatment.
* Patients with tortuous arteries that prevent the navigation of the device to the target vessel.
* Patients considered inappropriate to participate in the study.
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 diagnosis of acute ischemic stroke with unknown symptom onset (e.g. acute wake-up ischemic stroke, acute ischemic stroke with unknown time of symptom onset)
* Last known well without neurological symptoms \>4.5 hours of treatment initiation
* Treatment can be started within 4.5 hours of symptom recognition (e.g. awaking)
* Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) completed
* Alberta Stroke Program Early CT score (ASPECTS) on initial DWI is 5 or more
* No marked parenchymal hyperintensity visible on FLAIR
* Initial NIHSS ≥2
* Written informed consent by patient or next of kin

Exclusion Criteria:

* Pre-stroke Modified Rankin Scale (mRS) \>1 (patients who have inability to carry out all daily activities and require some help or supervision)
* Contraindications in the Japanese guideline for the intravenous application of recombinant tissue-type plasminogen activator (alteplase)

  * History of nontraumatic intracranial hemorrhage
  * History of stroke within the last 1 month (excluding transient ischemic attack)
  * History of significant head/spinal injury or surgery within the last 3 months
  * History of gastrointestinal or urinary tract bleeding within the last 21 days
  * History of major surgery or significant trauma other than head injury within the last 14 days
  * Hypersensitivity to alteplase
  * Suspected subarachnoid hemorrhage
  * Concurrent acute aortic dissection
  * Concurrent hemorrhage (e.g., intracranial, gastrointestinal, urinary tract, or retroperitoneal, hemoptysis)
  * Systolic blood pressure ≥185 mmHg despite antihypertensive therapy
  * Diastolic blood pressure ≥110 mmhg despite antihypertensive therapy
  * Significant hepatic disorder
  * Acute pancreatitis
  * Blood glucose \<50mg/dL or \>400 mg/dL
  * Platelet count ≤100,000/mm3
  * International normalized ratio of prothrombin time (PT-INR) \>1.7 or Prolonged activated partial thromboplastin time (aPTT: \>1.5 times the baseline value \[\>approximately 40 seconds only as a guide\]) for patients on anticoagulation therapy or those with abnormal coagulation
* Any contraindication to MRI (e.g. cardiac pacemaker)
* Extensive early ischemic change in brain stem or cerebellum (e.g., more than half of brain stem or more than one hemisphere of cerebellum)
* Planned or anticipated treatment with surgery or endovascular reperfusion strategies (e.g., intra-arterial thrombolysis, mechanical recanalization techniques)
* Pregnant, lactating, or potentially pregnant
* Life expectancy 6 months or less by judgment of the investigator
* Inappropriate for study enrollment by judgment of the investigator

Answer: C