Ischemia Care Biomarkers of Acute Stroke Etiology (BASE)

Atrial Fibrillation Clinical Trial

— BASE  

Official title:

Ischemia Care Biomarkers of Acute Stroke Etiology (BASE)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02014896
• Other study ID #: ISCH01
• Status: Completed
• Start date: December 2013
• Est. completion date: January 2020

Study information

• Verified date: July 2020
• Source: Ischemia Care LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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:

1. Differentiate between cardioembolic and large artery atherosclerotic ischemic strokes, when hemorrhagic stroke is ruled out.

2. 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.

3. 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.

4. Differentiate "transient ischemic attacks" (TIAs) from acute ischemic strokes.

5. Differentiate TIAs from non-ischemic "transient neurological events" (TNE) with similar symptoms.

Description:

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:

1. "BASE" - patients that present with suspected stroke symptoms within 18 hours of symptom onset or last known normal time OR

2. "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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1750
• Est. completion date: January 2020
• Est. primary completion date: November 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients >18 years of age

• Signs and symptoms suggestive of AIS or TIA

• One of the following:

1. BASE - Arrival to the emergency department or hospital within 18 hrs of symptom onset or last known normal time

2. 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

Related Conditions & MeSH terms

• Atrial Fibrillation
• Cardioembolic Stroke
• Ischemia
• Ischemic Attack, Transient
• Ischemic Stroke
• Stroke
• Stroke of Basilar Artery
• Thrombotic Stroke
• Transient Cerebrovascular Events
• Transient Ischemic Attacks

Intervention

Other:
• Biomarker blood draw
Comparison of gene expression profiles using RNA isolated from whole blood.

Locations

Country	Name	City	State
United States	Montefiore Medical Center (University Hospital for Albert Einstein College of Medicine)	Bronx	New York
United States	University of North Carolina Department of Neurology - Stroke Division	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Chattanooga Center for Neurologic Research	Chattanooga	Tennessee
United States	Cleveland Clinic	Cleveland	Ohio
United States	Riverside Methodist Hospital/ Ohio Health Research Institute	Columbus	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Baylor College of Medicine	Houston	Texas
United States	UT Health Department of Neurology	Houston	Texas
United States	Kettering Medical Center	Kettering	Ohio
United States	The Stroke Center at Saint Barnabas Medical Center	Livingston	New Jersey
United States	University of Pennsylvania Medical Center	Philadelphia	Pennsylvania
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Providence Health and Services	Portland	Oregon
United States	William Beaumont Hospital - Beaumont Health System	Royal Oak	Michigan
United States	Dignity Health Mercury San Juan	Sacramento	California
United States	Washington University, University Hospital in St Louis	Saint Louis	Missouri
United States	University of California San Francisco Medical Center Hospital	San Francisco	California
United States	Zuckerberg San Francisco General Hospital (UCSF)	San Francisco	California
United States	Wake Forest School of Medicine	Winston-Salem	North Carolina
United States	Genesis Healthcare System	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Ischemia Care LLC

Country where clinical trial is conducted

United States, 

References & Publications (18)

Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993 Jan;24(1):35-41. — View Citation

Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, Halperin JL, Johnston SC, Katzan I, Kernan WN, Mitchell PH, Ovbiagele B, Palesch YY, Sacco RL, Schwamm LH, Wassertheil-Smoller S, Turan TN, Wentworth D; American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2011 Jan;42(1):227-76. doi: 10.1161/STR.0b013e3181f7d043. Epub 2010 Oct 21. — View Citation

Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007 Jun 19;146(12):857-67. — View Citation

Ionita CC, Xavier AR, Kirmani JF, Dash S, Divani AA, Qureshi AI. What proportion of stroke is not explained by classic risk factors? Prev Cardiol. 2005 Winter;8(1):41-6. Review. — View Citation

Jauch EC, Barreto AD, Broderick JP, Char DM, Cucchiara BL, Devlin TG, Haddock AJ, Hicks WJ, Hiestand BC, Jickling GC, June J, Liebeskind DS, Lowenkopf TJ, Miller JB, O'Neill J, Schoonover TL, Sharp FR, Peacock WF. Biomarkers of Acute Stroke Etiology (BASE) Study Methodology. Transl Stroke Res. 2017 May 5. doi: 10.1007/s12975-017-0537-3. [Epub ahead of print] — View Citation

Jickling GC, Stamova B, Ander BP, Zhan X, Liu D, Sison SM, Verro P, Sharp FR. Prediction of cardioembolic, arterial, and lacunar causes of cryptogenic stroke by gene expression and infarct location. Stroke. 2012 Aug;43(8):2036-41. doi: 10.1161/STROKEAHA.111.648725. Epub 2012 May 24. — View Citation

Jickling GC, Stamova B, Ander BP, Zhan X, Tian Y, Liu D, Xu H, Johnston SC, Verro P, Sharp FR. Profiles of lacunar and nonlacunar stroke. Ann Neurol. 2011 Sep;70(3):477-85. doi: 10.1002/ana.22497. Epub 2011 Jul 27. — View Citation

Jickling GC, Xu H, Stamova B, Ander BP, Zhan X, Tian Y, Liu D, Turner RJ, Mesias M, Verro P, Khoury J, Jauch EC, Pancioli A, Broderick JP, Sharp FR. Signatures of cardioembolic and large-vessel ischemic stroke. Ann Neurol. 2010 Nov;68(5):681-92. doi: 10.1002/ana.22187. — View Citation

Jickling GC, Zhan X, Stamova B, Ander BP, Tian Y, Liu D, Sison SM, Verro P, Johnston SC, Sharp FR. Ischemic transient neurological events identified by immune response to cerebral ischemia. Stroke. 2012 Apr;43(4):1006-12. doi: 10.1161/STROKEAHA.111.638577. Epub 2012 Feb 2. — View Citation

Kamel et al. J Stroke Cerebrolvasc Dis; 2009 Nov-Dec;18(6):453-7. The risk of stroke recurrence is four times greater among prior stroke patients with newly detected AF.

Ovbiagele B, Saver JL, Fredieu A, Suzuki S, Selco S, Rajajee V, McNair N, Razinia T, Kidwell CS. In-hospital initiation of secondary stroke prevention therapies yields high rates of adherence at follow-up. Stroke. 2004 Dec;35(12):2879-83. Epub 2004 Oct 28. — View Citation

Stamova B, Xu H, Jickling G, Bushnell C, Tian Y, Ander BP, Zhan X, Liu D, Turner R, Adamczyk P, Khoury JC, Pancioli A, Jauch E, Broderick JP, Sharp FR. Gene expression profiling of blood for the prediction of ischemic stroke. Stroke. 2010 Oct;41(10):2171-7. doi: 10.1161/STROKEAHA.110.588335. Epub 2010 Aug 26. — View Citation

Stead LG, Gilmore RM, Bellolio MF, Jain A, Rabinstein AA, Decker WW, Agarwal D, Brown RD Jr. Cardioembolic but not other stroke subtypes predict mortality independent of stroke severity at presentation. Stroke Res Treat. 2011;2011:281496. doi: 10.4061/2011/281496. Epub 2011 Oct 10. — View Citation

Tang Y, Lu A, Aronow BJ, Sharp FR. Blood genomic responses differ after stroke, seizures, hypoglycemia, and hypoxia: blood genomic fingerprints of disease. Ann Neurol. 2001 Dec;50(6):699-707. — View Citation

Tang Y, Xu H, Du X, Lit L, Walker W, Lu A, Ran R, Gregg JP, Reilly M, Pancioli A, Khoury JC, Sauerbeck LR, Carrozzella JA, Spilker J, Clark J, Wagner KR, Jauch EC, Chang DJ, Verro P, Broderick JP, Sharp FR. Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study. J Cereb Blood Flow Metab. 2006 Aug;26(8):1089-102. Epub 2006 Jan 4. — View Citation

Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991 Aug;22(8):983-8. — View Citation

Xu H, Tang Y, Liu DZ, Ran R, Ander BP, Apperson M, Liu XS, Khoury JC, Gregg JP, Pancioli A, Jauch EC, Wagner KR, Verro P, Broderick JP, Sharp FR. Gene expression in peripheral blood differs after cardioembolic compared with large-vessel atherosclerotic stroke: biomarkers for the etiology of ischemic stroke. J Cereb Blood Flow Metab. 2008 Jul;28(7):1320-8. doi: 10.1038/jcbfm.2008.22. Epub 2008 Apr 2. — View Citation

Zhan X, Jickling GC, Tian Y, Stamova B, Xu H, Ander BP, Turner RJ, Mesias M, Verro P, Bushnell C, Johnston SC, Sharp FR. Transient ischemic attacks characterized by RNA profiles in blood. Neurology. 2011 Nov 8;77(19):1718-24. doi: 10.1212/WNL.0b013e318236eee6. Epub 2011 Oct 12. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Development of point of care testing for ischemic stroke, transient ischemic attack (TIA), and transient neurological events (TNE).	Investigate the ability to translate the primary and secondary objectives into platforms that may be used in acute ischemic stroke evaluation.	Up to 60 days.
Primary	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.
Primary	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	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.
Secondary	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.
Secondary	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.