Intracranial Atherosclerosis, Intracranial Arterial Stenosis, Ischemic Stroke
Conditions
Keywords
EDAS, encephaloduroarteriosynangiosis, indirect revascularization, intracranial atherosclerotic disease, intensive medical management
Brief summary
ERSIAS IIb is a multicenter randomized controlled trial, with a Phase IIb design, to find out whether encephaloduroarteriosynangiosis (EDAS), a type of indirect surgical revascularization of the brain, added to intensive medical management, lowers the rate of recurrent stroke and death compared with intensive medical management alone. The trial enrolls 170 adults who have had a recent ischemic stroke or transient ischemic attack caused by intracranial atherosclerotic disease, with a narrowing or blockage of at least 70% of the intracranial internal carotid artery or the middle cerebral artery and reduced blood flow in the territory of that artery. Participants are assigned at random, in equal numbers, to EDAS plus intensive medical management or to intensive medical management alone, and are followed for 18 to 54 months.
Interventions
EDAS is a form of indirect revascularization for cerebral arterial steno-occlusive disorders. The superficial temporal artery (STA) is dissected from the scalp, while maintaining its proximal and terminal connections to the external carotid artery and the skin tissues. The STA is then rerouted under the skull and placed in close proximity to the cortical branches of the middle cerebral artery without a direct anastomosis. EDAS is performed no later than 7 days after randomization.
Medical management administered to both study arms following current and updated standard-of-care parameters, with guidance and oversight from the trial's Medical Management Core. Antiplatelet treatment with aspirin for the entire follow-up and dual antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor for up to 90 days after randomization; management of the primary risk factors targeting systolic blood pressure \<140 mmHg and LDL \<70 mg/dL; management of the secondary risk factors (diabetes, non-HDL cholesterol, smoking, weight, physical activity) with the assistance of a lifestyle modification program. The management protocol may be modified during the trial to reflect the most up-to-date, evidence-based practices; changes apply to participants in both groups.
Sponsors
Cedars-Sinai Medical Center
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Treatment assignment is open. Possible endpoint events are adjudicated centrally by a committee blinded to treatment assignment, and cognitive testing is administered by personnel blinded to treatment assignment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Borderzone or superficial territorial ischemic stroke, or cortical TIA, within 30 days before enrollment, attributed to 70% to 100% atherosclerotic stenosis/occlusion of the intracranial ICA or the MCA (M1 or dominant/co-dominant M2). The eligible borderzone strokes are cortical (external) borderzone infarcts, located between the anterior and middle cerebral artery territories or between the middle and posterior cerebral artery territories; internal borderzone infarcts are not included. A cortical TIA is defined as transient cortical dysfunction evidenced by either visual field defects, spatial neglect, disorder of language, memory, or orientation. The corresponding cerebral artery atherosclerosis may be diagnosed by CTA, contrast-enhanced MRI, or catheter angiography. 2. Evidence of perfusion impairment (minimum: TMax delay ≥ 6 sec, vol ≥ 5 cc) in CTP or perfusion MRI. 3. Functional status better than severely disabled (mRS score 0-3). 4. Age ≥18 years and ≤90 years. If the patient is 18 to 49 years of age, at least 1 of the following should be present: * Insulin-dependent diabetes for at least 15 years. * At least 2 of the following atherosclerotic risk factors: SBP ≥130 mmHg or on antihypertensive therapy; dyslipidemia (LDL \>130 mg/dL, HDL \<40 mg/dL, fasting triglycerides \>150 mg/dL, or on lipid-lowering therapy); smoking; non-insulin-dependent diabetes or insulin-dependent diabetes less than 15 years in duration; family history of any of the following: myocardial infarction, coronary artery bypass, coronary artery angioplasty or stenting, stroke, carotid endarterectomy or stenting, peripheral vascular surgery in parent or sibling who was \<55 years of age for men or \<65 years of age for women at the time of the event. * History of any of the following: myocardial infarction, coronary artery bypass, coronary angioplasty or stenting, carotid endarterectomy or stenting, or peripheral vascular surgery for atherosclerotic disease. * Any stenosis/occlusion 50% to 100% of an extracranial carotid or vertebral artery, another intracranial artery, subclavian artery, coronary artery, iliac or femoral artery, other lower or upper extremity artery, mesenteric artery, or renal artery that was documented by non-invasive vascular imaging or catheter angiography and is considered atherosclerotic. * Aortic arch atheroma documented by non-invasive vascular imaging or catheter angiography. * Any aortic aneurysm documented by non-invasive vascular imaging or catheter angiography that is considered atherosclerotic. 5. Negative pregnancy test in a female who has had any menses 18 months prior to enrollment. 6. Patient willing and able to return for all follow-up visits required by the protocol. 7. Patient is available by telephone. 8. Patient understands the purpose and requirements of the trial, can make himself/herself understood, and has provided informed consent.
Exclusion criteria
1. CT or MRI evidence of an isolated perforator stroke as qualifying event, defined by the Imaging Core based on established templates of cerebral vascular territories. 2. Angioplasty, stenting, or endarterectomy of an ipsilateral extracranial carotid artery within 90 days prior to enrollment or planned within 90 days following enrollment. 3. Stenting of the qualifying intracranial artery at any time, including a stent placed during an endovascular attempt for the qualifying event. Thrombectomy or angioplasty without stent placement is not an exclusion; eligibility is determined on imaging obtained after the procedure. 4. Intracranial tumor or intracranial vascular malformation. 5. TIAs of increased frequency, duration, or severity, or ischemic stroke within 7 days prior to enrollment. 6. Infarct with hemorrhagic transformation within 30 days prior to enrollment. 7. Infarct with hemorrhagic transformation of parenchymatous hematoma type-2 within 90 days prior to enrollment. 8. History of primary intracerebral (parenchymal) hemorrhage. 9. Any other intracranial hemorrhage (subarachnoid, subdural, epidural) within 90 days prior to enrollment. 10. Any untreated chronic subdural hematoma greater than 5 mm in thickness. 11. Intracranial stenosis due to non-atherosclerotic etiologies: evidence of arterial dissection; moyamoya disease; any known vasculitic disease; herpes zoster, varicella zoster or other viral vasculopathy; neurosyphilis; any other intracranial infection; any intracranial stenosis associated with cerebrospinal fluid (CSF) pleocytosis; radiation-induced vasculopathy; fibromuscular dysplasia; sickle cell disease; neurofibromatosis; reversible cerebral vasoconstriction syndrome; postpartum angiopathy; suspected vasospastic process; suspected recanalized embolus. 12. Unequivocal cardiac sources of embolism as stroke etiology, including chronic or paroxysmal atrial fibrillation, symptomatic ventricular arrhythmias, severe or symptomatic aortic or mitral stenosis, mechanical valve, endocarditis, intracardiac clot or vegetation. 13. Myocardial infarction within 1 month prior to enrollment. 14. Unstable or severe angina. 15. Ejection fraction less than 40%. 16. Known allergy or contraindication to general anesthesia. 17. Known allergy to aspirin. 18. Known life-threatening allergy to contrast dye. 19. Active peptic ulcer disease, major systemic hemorrhage within 30 days, active bleeding diathesis, platelets \<100,000/mL, hematocrit \<30%, international normalized ratio \>1.5, clotting factor abnormality that increases the risk of bleeding. 20. Current alcohol or substance abuse within 1 month from enrollment. 21. Uncontrolled severe hypertension (SBP \>180 mmHg or diastolic blood pressure \>115 mmHg). 22. Severe liver impairment (AST or ALT \>3× normal, cirrhosis) that may prevent the use of statins. 23. Severe renal impairment (creatinine \>3.0 mg/dL or on dialysis). 24. Other major surgery planned in the next 90 days after enrollment that may require suspension of antiplatelet therapy. 25. Dementia or a psychiatric problem that prevents the patient from reliably following an outpatient program. 26. Co-morbid conditions that may limit survival to less than 3 years. 27. Pregnancy or of childbearing potential and unwilling to use contraception for the duration of the dual antiplatelet treatment period of the trial. 28. Active enrollment in another therapeutic trial that would conflict with this trial. 29. Evidence of active untreated systemic or serious infections (i.e., pneumonia, complicated urinary infection). 30. Body mass index (BMI) ≥40 kg/m2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of any stroke or death within 30 days of randomization, or ischemic stroke in the territory of the qualifying artery thereafter | From randomization through the end of follow-up (minimum 18 months, maximum 54 months, mean 30 months) | The composite of any stroke (ischemic or hemorrhagic) or death within 30 days of randomization plus recurrent ischemic stroke in the territory of the qualifying artery thereafter during full follow-up. Possible events are centrally adjudicated; the outcome measure is the centrally adjudicated, blinded event, not the site-determined event. Cumulative event rates in the two groups are compared by Kaplan-Meier estimates at 2.5 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with a disabling or disability-worsening stroke, or a fatal stroke | From randomization through the end of follow-up (minimum 18 months, maximum 54 months, mean 30 months) | The composite of 1) any disabling/disability-worsening stroke (ischemic or hemorrhagic) or fatal stroke within 30 days after randomization and 2) any disabling/disability-worsening or fatal ischemic stroke in the territory of the qualifying artery through the end of follow-up. For patients non-disabled (modified Rankin Scale \[mRS\] 0-1) at trial entry: recurrent stroke yielding mRS 2 to 6. For patients already disabled (mRS 2-3) at trial entry: recurrent stroke yielding an mRS value 1 or more levels worse than baseline. Centrally adjudicated, blinded. |
| Change from baseline in the Montreal Cognitive Assessment (MoCA) score | Baseline and 12, 24, 36 and 48 months after randomization | Change from baseline in the MoCA score. Scores on the MoCA range from 0 to 30; higher values represent a better outcome. |
| Change from baseline in cognitive function measured with the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) | Baseline and 12, 24, 36 and 48 months after randomization | Change from baseline in cognitive function measured with the NIHTB-CB. |
| Number of participants who die from any cause | From randomization through the end of follow-up (minimum 18 months, maximum 54 months, mean 30 months) | Number of participants who die from any cause, by group. |
| Number of participants with a procedure-related serious adverse event | From randomization through the end of follow-up (minimum 18 months, maximum 54 months, mean 30 months) | Number of participants with serious adverse events designated as procedure-related by the trial's Procedural Serious Adverse Event Designation Committee. |
| Number of participants with any serious adverse event | From randomization through the end of follow-up (minimum 18 months, maximum 54 months, mean 30 months) | Number of participants with any serious adverse event, by group. |
Contacts
PRINCIPAL_INVESTIGATORNestor R. Gonzalez, MD, MSCR
Cedars-Sinai Medical Center
PRINCIPAL_INVESTIGATORJeffrey L. Saver, MD
University of California, Los Angeles
Outcome results
None listed