NeuroCognition After Carotid Recanalization

Study Overview
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Brief Summary
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Complete occlusion of the Internal carotid artery (ICA) by atherosclerotic disease (COICA) causes approximately 15%-25% of ischemic strokes in the carotid artery distribution. Patients treated with medical therapy have a 7%-10% risk of recurrent stroke per year for any stroke and a 5%-8% risk per year for ipsilateral ischemic stroke during the first 2 years after ICA occlusion. Internal carotid artery occlusion causes an estimated 61,000 first-ever strokes per year in the US an incidence more than twice the annual occurrence of ruptured intracranial aneurysms Additionally, 40% of subjects with COICA who present with transient ischemic attack (TIA) and 70% of COICA who present with stroke have cognitive decline with increased risk of vascular dementia and Alzheimer's' disease (AD) with time (2,3). Symptomatic COICA subjects are at increased risk of developing cognitive impairment and progressive development of vascular dementia and AD with time. Our proposal leverages several compelling retrospective and prospective preliminary data from human to perform this exploratory trial with go/no-go criteria to proceed to a phase 3 based on the data generated

Detailed Description
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Study Design: Prospective randomized open blinded end-point (PROBE) study This is a phase 2 randomized single-center open label clinical trial with randomization of 1:1 to either best medical management vs. best medical management and endovascular revascularization of COICA. Screening, Enrolling, & Randomization: All subjects who presents to our tertiary hospital with a diagnosis of COICA will undergo full evaluation including 1) documenting previous history of transient ischemic attack (TIA) and/or stroke; 2) cervical and brain CT angiography (CTA) to document complete occlusion; 3) CT perfusion (CTP) to assess for presence of penumbra evident by increased mean transient time (MTT) in the ipsilateral side of COICA; and 4) Montreal cognitive assessment (MoCA) score. If any subject is found to have complete occlusion of COICA, evident of abnormal/prolongation of MTT on CTP, previous history of TIA and or stroke, and MoCA <26 or abnormal response on another neuropsychological assessment preformed in the screening battery, then further evaluation is obtained including: MRI spectroscopy to assess for presence/absence of lactate in the ipsilateral watershed area (centrum semiovale), and size of ipsilateral hippocampus and amygdala, additional cognitive testing battery, and digital subtraction angiography (DSA) to document adequately the type of COICA the subject have (type A-D). If a subject meets all inclusion criteria (complete occlusion, MoCA <26 and/or abnormal other neuropsychological test result, abnormal CTP) they will be randomized, after consent is obtained. If all inclusion criteria are met other than the CTP, they will be enrolled but not randomized. These subjects will only be eligible for best medical management- not surgical intervention. If any subject does not have complete occlusion or abnormal MoCA >26 or other neuropsychological assessment, then the subject is excluded and no further testing needed (see exclusion criteria). If the subject meets all inclusion criteria, then a baseline of complete neurological testing, full demographics, CTA or MRA, CTP, MoCA, additional neurological testing, MRI spectroscopy and DSA are obtained and subject is randomized 1:1 to either best medical management or best medical management + endovascular balloon angioplasty and stenting. Follow up clinic visits are arranged at 6 and 12 months. Repeat testing of MoCA and additional cognitive testing battery are done at these clinical follow-up visits (6 and 12 months). MRI of the brain and is done at 6 and 12 months. DSA is performed at 1 year follow-up for intervention subjects to assess brain bio-markers and revascularization respectively.

Official Title
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Neurocognitive Impairment Assessment in Symptomatic Carotid Occlusion Recanalized Endovascularly

Conditions
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Cognition Disorder, Stroke, Occlusion Carotid

Intervention / Treatment
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* Procedure: Endovascular intervention
* Drug: Aspirin and Clopidogrel (maximal medical Therapy)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 21 Complete occlusion of cervical ICA on imaging studies (MRA or CTA) and confirmed with DSA History of TIA or stroke Increased MTT and/or time to peak (TTP) on CT perfusion as defined as T Max threshold of > 10cc > 4 seconds in the territory of the occluded carotid specifically in the MCA territory when compared to the opposite unaffected hemisphere (not required for observational cohort) All occlusion is due to atherosclerotic disease MoCA < 26 or abnormal result on another test in the battery (abnormal defined as 1.5 SD below age/ gender/ education matched norms). Baseline MoCA assessed by the neurosurgery team or neuropsychology team Failed best medical treatment (defined below) Class A and B on COICA Classification Study team able to gain consent from subject or legal adult representative (LAR) Exclusion Criteria: Non-atherosclerotic occlusive disease that may have caused the occlusion, including moyamoya, dissection, trauma or other causes Tandem occlusion No evidence of penumbra on CT perfusion Severe co-morbid diseases: Chronic Kidney Disease (CKD) stages 4 or 5, end-stage renal disease, liver cirrhosis; Chronic Obstructive Pulmonary Disease (COPD) requiring home oxygen; terminal illness such as cancer; Parkinson disease or other neurodegenerative diseases; severe congestive heart failure; seizures; debilitating stroke, Modified Rankin Score (mRS) ≥ 3 Short life expectancy due to cancer or other co-morbid diseases Class D on COICA classification Normal neuropychological battery test results Subject unwilling to randomized to surgical procedure Pregnant or risk of becoming pregnant

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1 randomization, 1 non-randomized active comparator arm
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Endovascular arm<br>Subjects meet all inclusion criteria and were randomized to intervention | Procedure: Endovascular intervention<br>* Endovascular angioplasty of the occluded carotid using balloon angioplasty and reconstruction with stents: coronary stents distally (Rebel, Boston Scientific; Vision, Abbott Vascular) and carotid stents proximal (Acculink and Xcat, Abbott Vascular) Patients will stay on their aspirin 325 mg and clopidogrel 75 mg<br>|
| Active Comparator: Medical arm<br>Subjects meet all inclusion criteria and were randomized to best medical management | Drug: Aspirin and Clopidogrel (maximal medical Therapy)<br>* Best Medical Management: daily dual antiplatelet therapy (aspirin: 325 mg p.o. qd and Clopidogrel: 75 mg p.o. qd), optimization of systolic blood pressure (120 -140 mmHg), and smoking cessation.<br>|
| Active Comparator: Non-Randomized Arm<br>Subject meets all inclusion criteria EXCEPT abnormal CTP. Subjects are not randomized and are eligible for only best medical management | Drug: Aspirin and Clopidogrel (maximal medical Therapy)<br>* Best Medical Management: daily dual antiplatelet therapy (aspirin: 325 mg p.o. qd and Clopidogrel: 75 mg p.o. qd), optimization of systolic blood pressure (120 -140 mmHg), and smoking cessation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MoCA Score | Cognitive outcome assessed by the MontReal Cognitive Assessment score | 12-month | 
| Composite Cognitive Score | This is one outcome that reflects the overall cognition. The composite cognitive score at 12-month follow-up is assessed by a composite z score based on average z score for the tests for each subject (sum of the z scores divided by the number of tests included) from a specifically designed battery of 14 cognitive tests. Scores from tests in the proposed neuropsychological battery will be converted to z-scores. This is the following battery: Montreal Cognitive Assessment (MoCA),Wide Range Achievement Test-5 (WRAT-5); Wechsler Adult Intelligence Scale - IV (WAIS-IV); WAIS-IV, Coding subtest; WAIS-IV, Matrix Reasoning subtest; Hopkins Verbal Learning Test ; Benton Visual Retention Test (BVRT) ; Controlled Oral Word Association (COWA) Test; Boston Naming Test;Boston Diagnostic Aphasia Examination, Complex Ideational Material subtest;Trail-Making Test, part A and part B; Beck Depression Inventory-Fast Screen (BDI-FS);Iowa Scales of Personality Change (ISPC). | 12-month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroke | Incidence of ipsilateral stroke | 12-month | 
| Hemorrhage | Incidence of ipsilateral cerebral hemorrhage | 12-month | 
| Death | Rate death | 12-months |