• Aspire
• Captiva
• Imperative
• Most
• Presta
• RESCUE
• Saturn
• SleepSmart
• Discovery
• Comets
• Domino
• Serial MRIs in LVOs
• Slam
• CH in LVAD
• Optical Biomarkers of CVD
• PRECISE
• OCEANIC

All Inpatient Strokes –

OCEANIC– Caroline

INCLUSION CRITERIA:

1. 18 years of age or older (at legal age of consent according to local legislation) at the time of signing the informed consent.

• Participants who have an acute onset of neurological deficit attributed to non- cardioembolic focal brain ischemia due to either:
  • Non-cardioembolic ischemic stroke with NIHSS ≤ 15 at randomization and either of the following:
    • Persistent signs and symptoms of stroke lasting for ≥ 24 hours OR
    • Acute ischemic brain infarction documented by magnetic resonance imaging (MRI; diffusion weight imaging), standard computed tomography (CT) or perfusion CT1 that could account for the clinical presentation.

OR

• High-risk TIA with complete resolution of symptoms within < 24 hours and an ABCD2 score ≥ 6 with negative neuroimaging (CT or MRI) for acute ischemia.
  • All participants must have at least one of the following criteria a – c:
• Cerebrovascular atherosclerosis defined as vascular imaging (CTA, MRA, ultrasound, DSA) showing atherosclerotic plaque involving intracranial or extracranial cerebral arteries or the aortic arch2,

OR

• Medical history of atherosclerosis:
  • CAD or AMI with documented coronary atherosclerotic disease, prior CABG, or prior PCI
  • PAD requiring previous bypass surgery, or percutaneous transluminal angioplasty revascularization, limb or foot amputation for arterial vascular disease (i.e., excludes trauma), OR history of intermittent claudication and one or more of the following: 1) an ankle/arm blood pressure (BP) ratio < 0.90, or 2) documented peripheral artery stenosis
  • Carotid stenosis ≥ 50% or previous carotid revascularization
  • Documented aortic plaque

1 CT perfusion with deficits that resolve after EVT and/or thrombolysis are eligible and will be considered as imaging evidence of ischemic stroke. Also participants who undergo EVT and have all symptoms/signs resolve within 24 hours of onset and without imaging evidence of infarction are eligible and will be considered to have (aborted) brain infarction.

2 Qualifying plaques are those that clearly protrude into the vessel lumen as interpreted by the local investigator                                                                                                                 

• Brain imaging demonstrating an acute non-lacunar infarct (CT, CT perfusion or DWI MRI) defined as cortical location and/or size >20 mm for DWI and

>15 mm for CT.

• If no brain infarct is documented prior to randomization (i.e. clinical diagnosis of stroke or TIA with negative imaging) at least one of the following needs to be present that is not otherwise explainable and is related to the acute ischemic stroke/TIA event: motor deficits, speech deficits (aphasia/dysarthria), visual deficits (hemianopsia) and/or neglect. Thus, patients with isolated dizziness/vertigo or isolated numbness are not eligible.
  • Imaging of brain (CT or MRI) prior to randomization ruling out hemorrhagic stroke or another pathology that could explain symptoms (e.g. brain tumor, abscess)
  • 6.  Plan for secondary prevention of stroke/TIA with single or dual antiplatelet therapy including ASA, clopidogrel, ticagrelor, prasugrel, cilostazol and dipyridamole and in line with local guidelines.

Other Inclusions

• Able to be randomized within 72 hours after the onset of symptoms of the index event (or after patients were last known to be without symptoms in case of wake- up stroke).

NOTE: In case of endovascular therapy (mechanical thrombectomy) and / or thrombolysis, randomization can only occur > 24 hours after endovascular therapy and in case of thrombolysis only after 24 hours and standard clinical imaging has been performed post thrombolysis to exclude hemorrhage.

Sex and Contraceptive/Barrier Requirements

• Male or female

Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

• Male participants: there are no measures required for the study
• Female participants: a female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
  • is a woman of nonchildbearing potential (WONCBP) as defined in Appendix 4

OR

• is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Appendix 4 during the study intervention period and for at least 4 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (e.g. noncompliance, recently initiated) in relationship to the first dose of study intervention.
  • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) before randomization, see Section 8.3.8. If a urine test cannot be confirmed as negative (e.g. an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.                                                                                                                  

• Additional requirements for pregnancy testing during and after study intervention are located in Section 8.3.8. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

• EXCLUSION CRITERIA:
• Recent ischemic stroke within 7 days before index stroke event
  1. Strokes (index event) following procedures (e.g. TAVI, CABG) or strokes due to other rare causes (e.g. bacterial endocarditis, vertebral artery dissections)Known premorbid (before index event) mRS ≥ 4Dysphagia with inability to safely swallow study medication at time of randomization5.                   History of atrial fibrillation / flutter, left ventricular thrombus, mechanical valve or other cardioembolic source of stroke requiring anticoagulation6.                   Sustained uncontrolled hypertension after index stroke/TIA event3Known vascular malformation of the brain with high risk for bleeding (except isolated cavernoma, aneurysm treated and secured, or aneurysm with diameter <5 mm)Active non-trivial bleeding (including PH1 or PH2 hemorrhagic transformation of the index stroke event, if known before randomization4); known chronic bleeding disorder (e.g. von Willebrand disease); history of non-traumatic intracranial hemorrhage (does not include cerebral microbleeds or asymptomatic hemorrhagic transformation of an ischemic stroke); other non-traumatic major bleeding or clinically significant gastrointestinal bleeding within last 6 months before randomization
• 1. Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis, or signs of coagulopathy) or known hepatic insufficiency classified as Child-Pugh B or C at randomization5
  1. End stage renal disease requiring dialysis or expected to be started on dialysis within the next 12 months

Acute Ischemic Stroke

IMPERATIVE – Nichole

• INCLUSION CRITERIA:
  1. Age 18 and older
  2. NIHSS >=6
  3. The operator feels that the stroke can be treated with endovascular thrombectomy approaches and the interventionalist estimates that groin puncture can be achieved within 8 hours from time last seen well
  4. Pre-event mRS scale 0-1
  5. Large vessel occlusion of the intracranial internal carotid artery (ICA) or middle cerebral artery (MCA)-M1 and M2 segments, basilar and vertebral arteries as evidenced by MRA or CTA
  6. For strokes in anterior circulation, ASPECTS >=6; For strokes in posterior circulation, pc-ASPECTS >=8
  7. Non-contrast CT/CTA or MRI/MRA for trial eligibility performed or repeated at treating stroke center or outside medical facility within two hours of treatment initiation – IF REPEAT IMAGING IS NEEDED, HEAD CT ALONE ON ANGIO TABLE IS SUFFICIENT – CTA DOES NOT NEED TO BE REPEATED
  8. If indicated, IV t-PA should be administered as soon as possible, but no later than 3 hours from onset of stroke symptoms (onset time is defined as the last time when the patient was witnessed to be at baseline)
  9. Consenting requirements met according to local IRB or ethics committee
• EXCLUSION CRITERIA:
  1. Female known to be pregnant at time of admission
  2. Patient has suffered a stroke in the past 3 months
  3. Presence of an existing or pre-existing large territory infarction
  4. Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluation, e.g., dementia with prescribed anti-cholinesterase inhibitor
  5. Known history of severe contrast allergy or absolute contraindication to iodinated contrast.
  6. Clinical history, past imaging or clinical judgement suggest that the intracranial occlusion is chronic
  7. Life expectancy of less than 6 months prior to stroke onset
  8. Clinical symptoms suggestive of bilateral stroke or stroke in multiple territories
  9. Subject participating in another clinical trial involving an investigational device or drug
  10. Known cancer with metastases
  11. Evidence of active systemic infection
  12. Any known hemorrhagic or coagulation deficiency
• IMAGING EXCLUSION CRITERIA:
  13. Evidence of intracranial hemorrhage on CT/MRI
  14. CTA or MRA evidence of carotid stenosis requiring treatment for intracranial access
  15. Excessive vascular access tortuosity or target vessel size that will likely prevent endovascular access with the Imperative Care 0.088” ID Catheters
  16. Intracranial stent implanted in the same vascular territory that would preclude the safe deployment/removal of the thrombectomy devices
  17. 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 as determined by the treating physician
  18. Significant mass effect with midline shift as confirmed on CT/MRI
  19. Evidence of intracranial tumor (except small meningioma defined as ≤ 3cm and asymptomatic) as confirmed on CT/MRI
  20. Angiographic evidence of pre-existing arterial injury, such as carotid dissection, complete cervical carotid occlusion, or vasculitis

Acute Intracerebral Hemorrhage

Investigator Initiated Trials

COMETS: Sarah

• INCLUSION CRITERIA:
  1. Age ≥ 18 years
  2. Acute ischemic stroke with radiographic evidence of occlusion of the internal carotid artery and/or middle cerebral artery on either side of the brain
  3. Patient will undergoing mechanical thrombectomy for acute stroke
  4. Willingness and ability to sign informed consent by patient or legally acceptable surrogate decision-maker
• EXCLUSION CRITERIA:
  1. Bilateral arterial occlusion
  2. Hemicraniectomy or other skull defect that would interfere with monitoring.
  3. History of brain mass (other than meningioma)
  4. Pregnancy
     1. Women of child-bearing age must have a negative pregnancy test (urine or serum) prior to enrollment (which is performed as part of standard care)
  5. Any other illness or condition that the investigator feels would pose a hazard to the subject from participation in the study

DOMINO: Steph

• INCLUSION CRITERIA:
  1. Age > 18
  2. Acute ischemic stroke in the territory of the anterior, middle, or posterior cerebral artery, on either side of the brain
  3. Study can be initiated within 72 hours of stroke symptom onset
  4. Ability and willingness to sign informed consent
• EXCLUSION CRITERIA:
  1. History of any neurological disease
  2. History of stroke or transient ischemic attack
  3. Known cerebrovascular abnormality
  4. History of congestive heart failure
  5. History of chronic pulmonary disease such as asthma or COPD
  6. Presence of pneumonia or active pulmonary infection
  7. Current use of any NO donor medication (sodium nitroprusside or nitroglycerin)
  8. Age < 18 years
  9. Skull defect that would interfere with CBF monitoring
  10. Pregnancy (urine or blood tests will not be performed)
  11. Structural brain lesion
  12. Prior neurosurgical procedure
  13. History of psychiatric disease
  14. Any medical condition that the clinical investigator feels would pose a hazard to the subject if he/she participated in the study
  15. Cognitive impairment

SERIAL MRIs IN LVOs: Sarah

• INCLUSION CRITERIA:
  1. Age at least 18 years
  2. Occlusion of ICA (cervical or intracranial), M1, or M2.
  3. Symptom onset <24 hours
  4. NIHSS <6
  5. Not going for EVT at the time of enrollment (you are welcome to change treatment plan at any time, for any reason)

• EXCLUSION CRITERIA:
  1. Contraindication to MRI (use MRI screening form)
  2. Inability to lie flat 
  3. Inability to obtain consent from patient or surrogate
  4. Considered by the investigator to have a condition that precludes safe participation 

SLAM: Steph

• INCLUSION CRITERIA:
  1. Age > 18
  2. For cases, admission to the Stroke Inpatient Service with a diagnosis of acute ischemic stroke. NIHSS≥1, including at least 1 point for limb weakness.  At least half of the stroke patients must have at least 2 points on the NIHSS for limb weakness.
  3. For controls, admission to the hospital with a TIA, normal MRI, and normal neurologic exam, admission to the Epilepsy Monitoring Unit for differential diagnosis of transient neurologic spells with a normal MRI and normal neurologic exam, or recent cardiac surgery.
• EXCLUSION CRITERIA:
  1. Any medical or psychological conditions that, in the opinion of the investigator, would compromise the subject’s safety or successful participation in the study.
  2. A limb amputation above the wrist in the upper extremities and the ankle in the lower extremities.
  3. For controls:
     1. History of prior stroke
     2. Evidence of prior brain injury on MRI when this data is available, excluding mild small vessel ischemic disease
     3. Evidence of any focal neurologic findings on exam including asymmetric limb weakness or neglect

CH in LVAD: Sarah

• INCLUSION CRITERIA:
  1. Advanced heart failure with plan to treat with LVAD
  2. Over 18 years of age
  3. Patients must be able to read and understand English
  4. Patient must sign the informed consent form
• EXCLUSION CRITERIA:
  1. History of ischemic stroke
  2. History of intracerebral hemorrhage
  3. Known >70% stenosis of the internal carotid artery
  4. Known >70% stenosis of the middle cerebral artery
  5. Skull defect or skull surgery that will preclude monitoring
  6. Unable or unwilling to remain in bed for 30 minutes (to tolerate TCD monitoring)
  7. Unable or unwilling to return for 3-month study visit
  8. INTERMACS profile 1 (critically ill patients requiring temporary assist devices such as ECMO, Impella, aortic balloon pump)

OPTICAL BIOMARKERS of CVD: Sarah

• HEALTHY SUBJECTS:
  • INCLUSION CRITERIA:
    1. Age 18-49
    2. No history of hypertension, hyperlipidemia, peripheral artery disease, prior stroke, coronary artery disease, chronic kidney disease, congestive heart failure, dementia, or current tobacco use.
  • EXCLUSION CRITERIA:
    1. Hemicraniectomy or other skull defect that would interfere with monitoring. 
    2. Any other illness or condition that the investigator feels would pose a hazard to the subject from participation in the study
    3. Pregnant women* and prisoners are excluded
• CCOD SUBJECTS:
  • INCLUSION CRITERIA:
    1. Age ≥ 35
    2. Unilateral carotid stenosis or occlusion, defined as any of the following:
       • Carotid ultrasound with a peak systolic velocity >230 cm/s, and either EDV>100 cm/s, or internal to common carotid artery ratio >4.0
       • CT Angiography showing a ≥70% stenosis per NASCET criteria.⁶⁵
       • MR angiography showing a ≥70% stenosis per NASCET criteria
       • Digital subtraction angiography with a ≥70% stenosis per NASCET criteria
  • EXCLUSION CRITERIA:
    1. Contralateral carotid artery stenosis ≥70% stenosis, using the above definitions
    2. Contralateral carotid artery occlusion
    3. Prior history of carotid territory ischemic stroke or intraparenchymal hemorrhage at any time
    4. History of dementia
    5. Hemicraniectomy or other skull defect that would interfere with monitoring. 
    6. Any other illness or condition that the investigator feels would pose a hazard to the subject from participation in the study
    7. Pregnant women* and prisoners are excluded
• SVID SUBJECTS:
  • INCLUSION CRITERIA:
    1. Age ≥ 35
    2. Cerebral small vessel disease, defined by:
       • Prior lacunar infarction, <15mm in size and with subcortical location
       • AND
       • Confluent or beginning confluent cerebral white matter hyperintensities, corresponding to Fazekas visual rating scale⁶⁶ score of 2 or 3 in the periventricular or subcortical white matter on MRI obtained for clinical purposes prior to enrollment.
  • EXCLUSION CRITERIA:
    1. Prior history of intraparenchymal hemorrhage
    2. History of dementia
    3. Hemicraniectomy or other skull defect that would interfere with monitoring. 
    4. Any other illness or condition that the investigator feels would pose a hazard to the subject from participation in the study
    5. Pregnant women* and prisoners are excluded

* Pregnancy Testing: The MRI screening questionnaire will be administered to each patient at the time of check in for the MRI appointment.  The questionnaire will ask each female patient about their “pregnancy” status before each MRI session.  Consistent with clinical care standards, attestation of pregnancy status will be accepted at the time of MRI screening for this study. 

PRECISE: Nichole

INCLUSION CRITERIA

1. Signs and symptoms consistent with an acute posterior circulation ischemic stroke
2. mRS 0-2 at baseline for patients age 18-89. Patients ≥90 should be fully independent in all of their activities of daily living prior to stroke onset.
3. Age ≥18 years; patients ≥90 years must be fully independent in all activities of daily living prior to the stroke.
4. Baseline National Institutes of Health Stroke Scale Score ≥4 and remains ≥4 immediately prior to thrombectomy treatment
5. Stroke symptoms began within 48 hours of thrombectomy treatment. Stroke onset is defined as the time the patient was last known to be at his/her neurologic baseline. Wake-up strokes are eligible if they meet the above time limits.
6. Endovascular thrombectomy for PC-LVO planned as standard-of-care therapy. Patients may be treated by endovascular therapy that includes aspiration or mechanical thrombectomy, angioplasty, stent placement, or intravenous/intra-arterial GPIIb/IIIa inhibitor infusion
7. Time of arterial puncture (femoral or radial artery) occurred (or expected to occur) within 120 minutes of CT or MR imaging study completion
8. Patient or Legally Authorized Representative has signed the study Informed Consent form

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 outcomes evaluation
3. Any 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

IMAGING INCLUSION CRITERIA

1. Planned to undergo standard neuroimaging evaluation by computed tomography (CT) or magnetic resonance (MR) imaging that includes CT or MR angiography or the intracranial circulation and cerebral perfusion imaging prior to thrombectomy
2. Vertebral artery or basilar artery occlusion or severe stenosis on CTA or MRA. (Alternative assessment if MRA/CTA technically inadequate or > 120 minutes old is cerebral perfusion imaging consistent with a basilar or vertebral artery occlusion)
3. Absence of cerebral hemorrhage on baseline CT or MRI

IMAGING EXCLUSION CRITERIA

1. Acute symptomatic arterial occlusions in more than one vascular territory on CTA (ie – associated anterior circulation LVO of the internal, middle, or anterior cerebral artery
2. Evidence of intracranial tumor (except small meningioma), acute intracranial hemorrhage, neoplasm or arteriovenous malformation
3. Mass effect with significant herniation above the cerebral tentorium or below the foramen magnum
4. Intracranial stent implanted in the same vascular territory that precludes safe deployment/removal of neurothrombectomy device