Please select the eligibility criteria that correspond to the clinical trial below.
Title: Synthesis Expansion: A Randomized Controlled Trial on Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke
Brief Summary: SYNTHESIS is a pragmatic multicenter randomized controlled trial (RCT), open-label, with blinded follow-up aiming to determine whether loco-regional intra-arterial (IA) with recombinant tissue-plasminogen activator (rt-PA) and/or mechanical devices, as compared with systemic intravenous (I.V.) infusion of rt-PA within 3 hours of ischemic stroke, increases the proportion of independent survivors at 3 months.


Options:
A: 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)
B: Inclusion Criteria:

1. Subject or subject's legally authorized representative has signed and dated an Informed Consent Form
2. Age ≥ 18 and \< 85
3. Clinical signs consistent with acute ischemic stroke
4. Thrombolysis in Cerebral Infarction (TICI) 0 or TICI 1 flow in the proximal anterior intracranial vasculature (M1 or M2 of Middle Cerebral Artery (MCA), Internal Carotid Artery (ICA) intracranial, Internal Carotid Artery (ICA) terminal)
5. Presentation within 8 hours of stroke onset according to local stroke protocol
6. If stroke presentation within 4.5 hours, one of these conditions can be met:

   * Bridging protocol (starting intravenous and continuing with intra-arterial) (Up to maximum 0.9 mg/kg)
   * Failed intravenous thrombolysis
   * Direct Intra-arterial treatment (according to institution guidelines)
7. Subject is willing to conduct follow-up visits.
8. National Institutes of Health Stroke Scale (NIHSS) ≥ 8 and ≤ 30
9. Modified Rankin Scale (mRS) ≤ 2 prior to stroke onset

Exclusion Criteria:

1. Females who are pregnant or lactating
2. Known serious sensitivity to radiographic contrast agents
3. Neurological signs that are rapidly improving prior to or at time of treatment
4. Current participation in another investigational drug or device study
5. Life expectancy of less than 90 days
6. National Institutes of Health Stroke Scale (NIHSS) \> 30 or coma
7. Uncontrolled hypertension defined as systolic blood pressure \> 185 or diastolic blood pressure \> 110 that cannot be controlled except with continuous parenteral antihypertensive medication
8. Use of warfarin anticoagulation with International Normalised Ratio (INR) \> 3.0
9. Platelet count \< 30,000
10. Glucose \< 400 mg/dL
11. Previous stroke within 30 days
12. Time of symptom onset unknown
13. Seizure at the onset of stroke
14. Myocardial infarction or infection (sepsis or endocarditis)
15. Arterial tortuosity that would prevent the device from reaching the target vessel
16. Known hypersensitivity to nickel-titanium

    Imaging Exclusion Criteria:
17. Angiographic evidence of carotid dissection, complete cervical carotid occlusions, or vasculitis
18. Stenosis proximal to thrombus site that may preclude safe recovery of the device
19. Brain computed tomography (CT) with signs of hemorrhage, arteriovenous venous malformations, or aneurysm
20. Early ischemic changes greater than 1/3 of the middle cerebral artery (MCA) territory or according to brain computed tomography (CT) Alberta Stroke Program Early CT (ASPECT) score ≤ 6 or according to magnetic resonance diffusion weighted imaging (MR DWI) ASPECT score \<5
C: 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
D: Inclusion Criteria:

* 1. Acute ischemic stroke where patient is ineligible for IV thrombolytic treatment or the treatment is contraindicated (e.g., subject presents beyond recommended time from symptom onset), or where patient has received IV thrombolytic therapy without recanalization after a minimum of 30 min from start of iv tPA infusion
* 2. No significant pre-stroke functional disability (mRS ≤ 1)
* 3. Baseline NIHSS score obtained prior to randomization must be equal or higher than 6 points
* 4. Age ≥18 and ≤ 85.
* 5. Occlusion (TICI 0-1) of the intracranial ICA (distal ICA or T occlusions), MCA-M1 segment or tandem proximal ICA/MCA-M1 suitable for endovascular treatment, as evidenced by CTA, MRA or angiogram, with or without concomitant cervical carotid occlusion or stenosis
* 6. Patient treatable within eight hours of symptom onset. Symptoms onset is defined as point in time the patient was last seen well (at baseline). Treatment start is defined as groin puncture.
* 7. Informed consent obtained from patient or acceptable patient surrogate

Exclusion Criteria:

* Clinical criteria
* 1. Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR \> 3.0
* 2. Baseline platelet count \< 30.000/µL
* 3. Baseline blood glucose of \< 50mg/dL or \>400mg/dl
* 4. Severe, sustained hypertension (SBP \> 185 mm Hg or DBP \> 110 mm Hg)
* 5. Patients in coma (NIHSS item of consciousness \>1) (Intubated patients for transfer could be randomized only in case an NIHSS is obtained by a neurologist prior transportation).
* 6. Seizures at stroke onset which would preclude obtaining a baseline NIHSS
* 7. Serious, advanced, or terminal illness with anticipated life expectancy of less than one year.
* 8. History of life threatening allergy (more than rash) to contrast medium
* 9. Subjects who has received iv t-PA treatment beyond 4,5 hours from the beginning of the symptoms
* 10. Renal insufficiency with creatinine ≥ 3 mg/dl
* 11. Woman of childbearing potential who is known to be pregnant or lactating or who has a positive pregnancy test on admission.
* 12. Subject participating in a study involving an investigational drug or device that would impact this study.
* 13. Cerebral vasculitis
* 14. Patients with a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, mRS score at baseline must be ≤ 1. This excludes patients who are severely demented, require constant assistance in a nursing home type setting or who live at home but are not fully independent in activities of daily living (toileting, dressing, eating, cooking and preparing meals, etc.)
* 15. Unlikely to be available for 90-day follow-up (e.g. no fixed home address, visitor from overseas).

Neuroimaging criteria:

* 16. Hypodensity on CT or restricted diffusion amounting to an ASPECTS score of \<7 on NCCT or \<6 on DWI MRI. Patients 81 to 85 years old with ASPECTS score on non-contrast CT or DWI MRI \<9 must be excluded. ASPECTS must be evaluated by CBV maps of CT Perfusion, CTA source imaging (CTA-SI) or DWI-MR in patients whose vascular occlusion study (CTA/MRA) confirming qualifying occlusion, is performed beyond 4.5 hours of last seen well.
* 17. CT or MR evidence of hemorrhage (the presence of microbleeds is allowed).
* 18. Significant mass effect with midline shift.
* 19. Evidence of ipsilateral carotid occlusion, high grade stenosis or arterial dissection in the extracranial or petrous segment of the internal carotid artery that cannot be treated or will prevent access to the intracranial clot or excessive tortuosity of cervical vessels precluding device delivery/deployment
* 20. Subjects with occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior/posterior circulation)
* 21. Evidence of intracranial tumor (except small meningioma).

Answer: A