Please select the eligibility criteria that correspond to the clinical trial below.
Title: Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3
Brief Summary: This is a study to evaluate the hypothesis that FDA cleared thrombectomy devices plus medical management leads to superior clinical outcomes in acute ischemic stroke patients at 90 days when compared to medical management alone in appropriately selected subjects with the Target mismatch profile and an MCA (M1 segment) or ICA occlusion who can be randomized and have endovascular treatment initiated between 6-16 hours after last seen well.


Options:
A: 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
B: Clinical Inclusion Criteria:

1. Signs \& symptoms consistent w/ the diagnosis of acute anterior circulation ischemic stroke
2. Age 18-90 years
3. Baseline NIHSSS is ≥ 6 and remains ≥6 immediately prior to randomization
4. Endovascular treatment can be initiated (femoral puncture) between 6 and 16 hours of stroke onset. Stroke onset is defined as the time the patient was last known to be at their neurologic baseline (wake-up strokes are eligible if they meet the above time limits).
5. modified Rankin Scale less than or equal to 2 prior to qualifying stroke (functionally independent for all ADLs)
6. Patient/Legally Authorized Representative has signed the Informed Consent form.

Clinical Exclusion Criteria:

1. Other serious, advanced, or terminal illness (investigator judgment) or life expectancy is less than 6 months.
2. Pre-existing medical, neurological or psychiatric disease that would confound the neurological or functional evaluations
3. Pregnant
4. Unable to undergo a contrast brain perfusion scan with either MRI or CT
5. Known allergy to iodine that precludes an endovascular procedure
6. Treated with tPA \>4.5 hours after time last known well
7. Treated with tPA 3-4.5 hours after last known well AND any of the following; age \>80, current anticoagulant use, history of diabetes or prior stroke, NIHSS \>25
8. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR \> 3 (recent use of one of the new oral anticoagulants is not an exclusion if estimated GFR \> 30 ml/min).
9. Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS
10. Baseline blood glucose of \<50mg/dL (2.78 mmol) or \>400mg/dL (22.20 mmol)
11. Baseline platelet count \< 50,000/uL
12. Severe, sustained hypertension (Systolic BP \>185 mmHg or Diastolic BP \>110 mmHg)
13. Current participation in another investigational drug or device study
14. Presumed septic embolus; suspicion of bacterial endocarditis
15. Clot retrieval attempted using a neurothrombectomy device prior to 6 hrs from symptom onset
16. Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the subject if an endovascular procedure was performed.

Neuroimaging Inclusion Criteria:

1. ICA or MCA-M1 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA or CTA

   AND
2. Target Mismatch Profile on CT perfusion or MRI (ischemic core volume is \< 70 ml, mismatch ratio is \>/= 1.8 and mismatch volume\* is \>/= 15 ml)

Alternative neuroimaging inclusion criteria (if perfusion imaging or CTA/MRA is technically inadequate):

A) If CTA (or MRA) is technically inadequate:

Tmax\>6s perfusion deficit consistent with an ICA or MCA-M1 occlusion AND Target Mismatch Profile (ischemic core volume is \< 70 ml, mismatch ratio is \>1.8 and mismatch volume is \>15 ml as determined by RAPID software)

B) If MRP is technically inadequate:

ICA or MCA-M1 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a CTA was performed within 60 minutes prior to the MRI) AND DWI lesion volume \< 25 ml

C) If CTP is technically inadequate:

Patient can be screened with MRI and randomized if neuroimaging criteria are met.

Neuroimaging Exclusion Criteria:

1. ASPECTS score \<6 on non-contrast CT (if patient is enrolled based on CT perfusion criteria)
2. Evidence of intracranial tumor (except small meningioma) acute intracranial hemorrhage, neoplasm, or arteriovenous malformation
3. Significant mass effect with midline shift
4. Evidence of internal carotid artery dissection that is flow limiting or aortic dissection
5. Intracranial stent implanted in the same vascular territory that precludes the safe deployment/removal of the neurothrombectomy device
6. Acute symptomatic arterial occlusions in more than one vascular territory confirmed on CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion).
C: 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.
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: B