Ischemia Care Biomarkers of Acute Stroke Etiology (BASE)

Study Overview
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Brief Summary
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The proposed study will validate the clinical use of new biomarker blood tests to identify blood components that may differentiate between diverse stroke etiologies and clinical outcomes as listed below: Differentiate between cardioembolic and large artery atherosclerotic ischemic strokes, when hemorrhagic stroke is ruled out. In cases of ischemic strokes of unknown or cryptogenic etiology, determine the ability of biomarker blood tests to predict etiology between cardioembolic and large artery atherosclerotic. In cases of cardioembolic ischemic stroke, further differentiation of cardioembolic ischemic strokes into those caused by atrial fibrillation (AF) and those not caused by AF. Differentiate transient ischemic attacks (TIAs) from acute ischemic strokes. Differentiate TIAs from non-ischemic transient neurological events (TNE) with similar symptoms.

Detailed Description
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Acute ischemic stroke (AIS) is a leading cause of adult mortality and morbidity in the United States, affecting over 800,000 individuals, annually, leaving many with permanent disability. Furthermore, hundreds of thousands of Americans experience a transient ischemic attack (TIA), a momentary episode of neurologic dysfunction, which often precedes a major stroke and serves as a warning for future ischemic events. Despite symptoms resolving, experiencing a TIA increases the risk of stroke by 20% within 90 days. Emergent evaluation, prompt acute treatment, and identification of stroke etiology for secondary prevention are key to decreasing the morbidity and mortality associated with cerebrovascular disease. Key to treatment and prevention is the identification of stroke etiology - large vessel atherosclerosis, cardioembolic phenomenon, or in-situ small vessel cerebrovascular disease - since primary and secondary prevention measures differ based on stroke subtype. The diagnosis of ischemic stroke includes a combination of patient history, clinical assessment, and brain imaging. However, identifying the cause of cerebrovascular ischemia is challenging and routinely assigned of cryptogenic origin. Therefore, there is a great need to understand the pathogenesis of TIA and AIS events in order to develop more effective preventative measures. Recent studies have identified the differential expression of genes in whole blood that may differentiate the major ischemic stroke types. Such differences may help identify TIA and AIS events that are more likely to respond to therapy specifically tailored to the major stroke type. Furthermore, by establishing a more robust standard for secondary prevention, future stroke events may be avoided. BASE is a multisite prospective study with a estimated enrollment of up to 1100 subjects adult subjects and 100 age, gender and co-morbidity matched controls (Controls) will be recruited from patients who present to the Emergency Department (ED) or hospital with suspected AIS or TIA. Research personnel will identify potential patients by responding to Brain Attacks pages from the ED to the Stroke Team for patients who meet current Brain Attack criteria. Following evaluation by the ED and neurology physicians, the clinical coordinator will verify the patient had a suspected AIS or TIA and meets eligibility criteria. The patient or their legal surrogate will be approached for study participation. Written informed consent will be obtained for all subjects enrolled. There are two recruitment windows related to BASE determined by time of symptom onset, time of presentation at ED or hospital, and ability to consent: BASE - patients that present with suspected stroke symptoms within 18 hours of symptom onset or last known normal time OR BASE 24 - patients that present within 24 hours +/- 6 hours (i.e. 18 - 30 hour window) of symptom onset or last known normal time and clinical evidence suggesting Acute Ischemic Stroke.

Official Title
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Ischemia Care Biomarkers of Acute Stroke Etiology (BASE)

Conditions
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Ischemic Stroke, Atrial Fibrillation, Transient Ischemic Attacks, Transient Cerebrovascular Events, Thrombotic Stroke, Stroke of Basilar Artery, Cardioembolic Stroke

Intervention / Treatment
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* Other: Biomarker blood draw


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients >18 years of age Signs and symptoms suggestive of AIS or TIA One of the following: BASE - Arrival to the emergency department or hospital within 18 hrs of symptom onset or last known normal time BASE 24 - Arrival to the emergency department or hospital within 24 hours +/- 6 hours (i.e. 18 - 30 hour window) of symptom onset or last known normal time and clinical evidence suggesting Acute Ischemic Stroke. Head CT or MRI ruling out other pathology such as vascular malformation, hemorrhage, tumor or abscess which would likely be responsible for presenting neurologic symptoms Informed consent obtained Exclusion Criteria: Any central nervous system infection, i.e. meningitis or encephalitis in the past 30 days Any form of head trauma, stroke or intracranial hemorrhage in the past 30 days Known primary or metastatic cancer involving the brain Active Cancer defined as a diagnosis of cancer, within 6 months before enrollment, any treatment for cancer within the previous 6 months, or recurrent or metastatic cancer. Autoimmune diseases: such as lupus, rheumatoid arthritis, Crohn's disease, ulcerative colitis Active infectious diseases (eg. HIV/AIDS, hepatitis C) Any underlying medical condition which in the opinion of the investigator would prohibit the patient from providing informed consent Major surgery within three months prior to the index event

Ages Eligible for Study
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Minimum Age: 18 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Ischemic Stroke<br>Ischemic stroke subjects presenting within 24 hours from symptom onset will have serial PAX Gene Blood RNA tubes drawn within 18 hours of onset of symptoms upon arrival to the Emergency Department (if available) or hospital; 24 hours +/- 6 hours from symptom onset (if available) and 48 hours+/- 6 hours from symptom onset (if available). Biomarker blood draw | Other: Biomarker blood draw<br>* Comparison of gene expression profiles using RNA isolated from whole blood.<br>* Other names: PAX Gene Blood RNA tube, PreAnalytiX, Germnay;|
| TIA (Transient Ischemic Attack)<br>TIA subjects presenting within 24 hours from symptom onset will have serial PAX Gene Blood RNA tubes drawn within 18 hours of onset of symptoms upon arrival to the Emergency Department (if available) or hospital; 24 hours +/- 6 hours from symptom onset (if available) and 48 hours+/- 6 hours from symptom onset (if available). Biomarker blood draw | Other: Biomarker blood draw<br>* Comparison of gene expression profiles using RNA isolated from whole blood.<br>* Other names: PAX Gene Blood RNA tube, PreAnalytiX, Germnay;|
| Non-Ischemic TNE<br>Non-Ischemic Transient Neurological Event (TNE) subjects will have serial PAX Gene Blood RNA tubes drawn within 18 hours of onset of symptoms upon arrival to the Emergency Department or hospital. Biomarker blood draw | Other: Biomarker blood draw<br>* Comparison of gene expression profiles using RNA isolated from whole blood.<br>* Other names: PAX Gene Blood RNA tube, PreAnalytiX, Germnay;|
| Control<br>Control group subjects will have PAX Gene Blood RNA tubes drawn within 8 hours of arrival to the Emergency Department or hospital. Control group matched with ischemic stroke and TIA subjects for age, race, gender, smoking history with at least one of the following vascular risk factors: diabetes, hypertension, atrial fibrillation, hyperlipidemia. Biomarker blood draw | Other: Biomarker blood draw<br>* Comparison of gene expression profiles using RNA isolated from whole blood.<br>* Other names: PAX Gene Blood RNA tube, PreAnalytiX, Germnay;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardioembolic and large vessel stroke stiology | Determine the ability of ISCDX, a blood test, to differentiate between clinically diagnosed cardioembolic and large artery atherosclerotic ischemic stroke when hemorrhagic stroke is ruled out. | Up to 60 days. | 
| TIA differentiation from non ischemic events (TNE). | Determine the ability of TIADX, a blood test, to identify clinically diagnosed TIAs and differentiate these events from controls, which include TNEs. TNEs represent patients presenting with clinical symptoms similar to a TIA such as migraines, seizures and syncope, which are non-ischemic transient neurological events (TNE). | Up to 60 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cryptogenic stroke | Determine the ability of ISCDX to categorize strokes of cryptogenic strokes, as either cardioembolic or large artery atherosclerotic when best practice clinical diagnostic testing cannot determine the cause, suggesting the best treatment pathway. | Up to 60 days. | 
| Atrial fibrillation and stroke | Determine the ability of ISCDX to further sub-classify strokes diagnosed as cardioembolic into those caused by atrial fibrillation and those not caused by atrial fibrillation, such as structural defects in the heart. | Up to 60 days. | 
| Stroke and TIA, differentiation | Determine the ability of the ISCDX and TIADX tests to differentiate between a TIA and an ischemic stroke, much in the manner that Acute Coronary Syndrome is now viewed as part of a spectrum of cardiovascular diseases. | Up to 60 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ischemic Stroke, Transient Ischemic Attack, Transient Neurological Event, Atrial Fibrillation, Cryptogenic Stroke, Gene Expression, RNA, Anticoagulant, NOAC, Antiplatelet, Cardiac monitoring, Point of Care, tPA, Atheroembolic