Please select the eligibility criteria that correspond to the clinical trial below.
Title: The THERAPY Trial: The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke
Brief Summary: The purpose of this trial is to assess the safety and effectiveness of the Penumbra System as an adjunctive treatment to intravenous (IV) recombinant human tissue plasminogen activator (rtPA)in patients with acute ischemic stroke from large vessel occlusion in the brain. IV rtPA is the only drug approved for the treatment of acute ischemic stroke but it does not work very well in cases where the stroke is caused by a large vessel occlusion. The hypothesis being tested is to determine if the addition of a treatment by a mechanical thrombectomy device like the Penumbra System can improve the clinical outcome of the patient over just using IV rtPA alone.


Options:
A: General Inclusion Criteria:

1. Clinical signs and symptoms consistent with the diagnosis of an acute ischemic stroke, and subject belongs to one of the following subgroups:

   1. Subject has failed IV t-PA therapy (defined as a confirmed persistent occlusion 60 min after administration)
   2. Subject is contraindicated for IV t-PA administration
2. Age ≥18
3. Baseline NIHSS ≥10 (assessed within one hour of measuring core infarct volume)
4. Subject can be randomized between with 6 to 24 hours after time last known well
5. No significant pre-stroke disability (pre-stroke mRS must be 0 or 1)
6. Anticipated life expectancy of at least 6 months
7. Subject willing/able to return for protocol required follow up visits
8. Subject or subject's Legally Authorized Representative (LAR) has signed the study Informed Consent form\*

   * If approved by local ethics committee and country regulations, the investigator is allowed to enroll a patient utilizing emergency informed consent procedures if neither the patient nor the representative or person of trust is available to sign the informed consent form. However, as soon as possible, the patient is informed and his/her consent is requested for the possible continuation of this research. (Not applicable to U.S. Sites.)

Imaging Inclusion Criteria:

1. \< 1/3 MCA territory involved, as evidenced by CT or MRI
2. Occlusion of the intracranial ICA and/or MCA-M1 as evidenced by MRA or CTA
3. Clinical Imaging Mismatch (CIM) defined as one of the following on MR-DWI or CTP-rCBF maps:

   1. 0-\<21 cc core infarct and NIHSS ≥ 10 (and age ≥ 80 years old)
   2. 0-\<31 cc core infarct and NIHSS ≥ 10 (and age \< 80 years old)
   3. 31 cc to \<51 cc core infarct and NIHSS ≥ 20 (and age \< 80 years old)

General Exclusion Criteria:

1. History of severe head injury within past 90 days with residual neurological deficit, as determined by medical history
2. Rapid improvement in neurological status to an NIHSS \<10 or evidence of vessel recanalization prior to randomization
3. Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, e.g. dementia with prescribed anti-cholinesterase inhibitor (e.g. Aricept)
4. Seizures at stroke onset if it makes the diagnosis of stroke doubtful and precludes obtaining an accurate baseline NIHSS assessment
5. Baseline blood glucose of \<50mg/dL (2.78 mmol) or \>400mg/dL (22.20 mmol)
6. Baseline hemoglobin counts of \<7 mmol/L
7. Baseline platelet count \< 50,000/uL
8. Abnormal baseline electrolyte parameters as defined by sodium concentration \<130 mmol/L, potassium concentration \<3 mEq/L or \>6 mEq/L
9. Renal failure as defined by a serum creatinine \>3.0 mg/dL (264 µmol/L) NOTE: subjects on renal dialysis may be treated regardless of serum creatinine levels
10. Known hemorrhagic diathesis, coagulation factor deficiency, or on anticoagulant therapy with INR \> 3.0 or PTT \> 3 times normal. Patients on factor Xa inhibitor for 24-48 hours ago must have a normal PTT.
11. Any active or recent hemorrhage within the past 30 days
12. History of severe allergy (more than rash) to contrast medium
13. Severe, sustained hypertension (Systolic Blood Pressure \>185 mmHg or Diastolic Blood Pressure \>110 mmHg) NOTE: If the blood pressure can be successfully reduced and maintained at the acceptable level using medication the subject can be enrolled
14. Female who is pregnant or lactating at time of admission
15. Current participation in another investigational drug or device study
16. Presumed septic embolus, or suspicion of bacterial endocarditis
17. Treatment with any cleared thrombectomy devices or other intra-arterial (neurovascular) therapies prior to randomization

Imaging Exclusion Criteria:

1. Evidence of intracranial hemorrhage on CT/MRI
2. CTA or MRA evidence of flow limiting carotid dissection, high-grade stenosis, or complete cervical carotid occlusion requiring stenting at the time of the index procedure (i.e., mechanical thrombectomy).
3. Excessive tortuosity of cervical vessels on CTA/MRA that would likely preclude device delivery/deployment
4. Suspected cerebral vasculitis based on medical history and CTA/MRA
5. Suspected aortic dissection based on medical history and CTA/MRA
6. Intracranial stent implanted in the same vascular territory that would preclude the safe deployment/removal of the Trevo device
7. Occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior circulation/vertebrobasilar system) as confirmed on CTA/MRA, or clinical evidence of bilateral strokes or strokes in multiple territories
8. Significant mass effect with midline shift as confirmed on CT/MRI
9. Evidence of intracranial tumor (except small meningioma) as confirmed on CT/MRI
B: Inclusion Criteria:

* New focal disabling neurologic deficit consistent with acute cerebral ischemia (NIHSS \>/= 6)
* Age \>/= 18 ≤ 85
* Clot retrieval procedure can be initiated within 8 hours from onset
* Large vessel proximal anterior circulation occlusion on MR or CT angiography (internal carotid, M1 or M2 MCA)
* Pretreatment MRI performed according to MR RESCUE protocol
* Signed informed consent obtained from the patient or patient's legally authorized representative
* Premorbid modified Rankin score of 0-2
* Allowed but not required: patients treated with IV tPA (tissue plasminogen activator) up to 4.5 hours from symptom onset with persistent target occlusion on post-treatment MR RESCUE MR or CT protocol performed at the completion of drug infusion (Note: Rapidly improving neurological signs prior to randomization is an exclusion)

Exclusion Criteria:

* NIHSS \>/= 30
* Contraindication to MRI (pacemaker etc)
* Acute intracranial hemorrhage
* Coma
* Rapidly improving neurological signs prior to randomization
* Pre-existing medical, neurological or psychiatric disease that would confound the neurological, functional, or imaging evaluations
* Pregnancy
* Known allergy to iodine previously refractory to pretreatment medications
* Current participation in another experimental treatment protocol
* Contrast-Enhanced Neck MRA (magnetic resonance angiography) or CTA (computed tomography angiography) suggests proximal ICA occlusion, proximal carotid stenosis \> 67%, or dissection
* INR \> 3.0 (international normalized ratio)
* PTT \> 3 x Normal (partial thromboplastin time)
* Imaging data cannot be processed by the MR RESCUE computer
* Renal Failure (serum creatinine \> 2.0 or Glomerular Filtration Rate \[GFR\] \< 30)

MRI Exclusion Criteria:

* Contraindication to MRI (pacemaker, etc)

CT Exclusion Criteria:

* Contraindication to iodinated contrast\*\*

  \*\*Examples of possible iodinated contrast contraindications include:
* Hyperthyroidism
* History of severe allergic reaction to iodinated contrast material
* History of sever kidney disease as an adult, including tumor or transplant surgery, or family history of kidney failure
* Paraproteinemia syndromes or multiple myeloma
* Collagen vascular disease
* Severe cardiac insufficiency
* Severely compromised liver function
* Current therapy with metformin, aminoglycosides
C: Inclusion Criteria:

* Sudden focal neurological deficit attributable to a stroke
* Clearly defined time of onset, allowing initiation of intravenous treatment within 3 hours of symptoms onset and intra-arterial treatment within 6 hour of symptoms onset.
* Age greater than 18 years

Exclusion Criteria:

* Disability preceding stroke consistent with a modified Rankin scale score of 2-4
* Coma at onset
* Rapidly improving neurological deficit
* Seizure at onset
* Clinical presentation suggestive of a subarachnoid hemorrhage
* Previous history of intracranial hemorrhage
* Septic embolism
* Arterial puncture at a non compressible site within the previous 7 days
* Any traumatic brain injury within the previous 14 days
* Surgery of the central nervous system in the previous 3 months
* Gastrointestinal hemorrhage or urinary tract hemorrhage within the previous 14 days.
* Current therapy with intravenous or subcutaneous heparin to rise the clotting time
* Known hereditary or acquired hemorrhagic diathesis, baseline INR greater than 1.5, aPTT more than 1.5 times normal, or baseline platelet count less than 100,000 per cubic millimeter
* Baseline blood glucose concentrations below 2.75 mm/L (50 mg/dL).
* Known contrast sensitivity.
* Women of childbearing potential (unless pregnancy impossible) or known to be breastfeeding. Uncontrolled hypertension defined by a blood pressure greater or equal 185 mmHg systolic or diastolic greater or equal 110 mm Hg in 3 separate occasions at least 10 minutes apart or requiring continuous IV therapy.
* Prognosis very poor regardless of therapy; likely to be dead within months.
* Unlikely to be available for follow-up (eg, no fixed home address, visitor from overseas).
* Any other condition which local investigators feels would pose a significant hazard in terms of risk/benefit to the patient, or if therapies are impracticable.

COMPUTED TOMOGRAPHIC (CT) SCAN EXCLUSION CRITERIA

* Intracranial tumors except small meningioma
* Hemorrhage of any degree
* Acute infarction (since this may be an indicator that the time of onset is uncorrected)
D: Inclusion Criteria:

1. From 18 to 85 years of age
2. Present with symptoms consistent with an acute ischemic stroke and eligible for IV rtPA therapy (patients presenting 3-4.5 hrs from symptom onset are not eligible if they are \>80 yrs of age, have a history of stroke and diabetes, anticoagulant use (even if INR is \<1.7) and have a NIHSS score \>25
3. Evidence of a large vessel occlusion in the anterior circulation with a clot length of 8mm or longer
4. NIH Stroke Scale (NIHSS) score 8 or greater or aphasic at presentation
5. Signed informed consent

Exclusion Criteria:

1. History of stroke in the past 3 months.
2. Females who are pregnant
3. Pre-existing neurological or psychiatric disease that could confound the study results such as a pre-stroke mRS score 1 or greater
4. Known severe allergy to contrast media
5. Uncontrolled hypertension (defined as systolic blood pressure \>185 mmHg or diastolic blood pressure \>110 mmHg)
6. CT evidence of the following conditions at randomization:

   * Significant mass effect with midline shift
   * Any acute ischemic changes in \>1/3 of the affected middle cerebral artery territory
   * Evidence of intracranial hemorrhage
7. Angiographic evidence of tantem extracranial occlusion or an arterial stenosis proximal to the occlusion that requires treatment prior to thrombus removal. Moderate stenosis not requiring treatment is not an exclusion
8. Angiographic evidence of preexisting arterial injury
9. Rapidly improving neurological status prior to randomization
10. Bilateral stroke
11. Intracranial tumors
12. Known history of cerebral aneurysm or arteriovenous malfunction
13. Known hemorrhagic diathesis, coagulation deficiency, or on anticoagulant therapy with an International Normalized Ratio (INR) of \>1.7
14. Baseline platelets \<50,000
15. Use of IV heparin in the past 48 hours with PPT \>1.5 times the normalized ratio
16. Pre-treatment glucose \<50mg/dL or \>300mg/dL
17. Life expectancy less than 90 days prior to stroke onset
18. Participation in another clinical investigation that could confound the evaluation of the study device

Answer: D