ERSIAS Phase IIb EDAS Revascularization for Symptomatic Intracranial Atherosclerotic Steno occlusive Disease Phase IIb Clinical Trial - PROJECT SUMMARY This is a UG3/UH3 application for a Phase IIb prospective, multicenter, randomized, controlled clinical trial (RCT) for the evaluation of encephaloduroarteriosynangiosis (EDAS), a form of low-pressure, indirect bypass for the treatment of patients with symptomatic intracranial atherosclerotic disease (ICAD). ICAD accounts for 10% of all strokes in the US, more than 20% around the world, and has the highest rates of stroke recurrence (37% in high-risk patients, despite intensive medical management [IMM]). Previous RCTs that tested other interventions for ICAD, including angioplasty/stenting (SAMMPRIS, VISSIT, CASSISS) and high-pressure direct bypass (EC-IC Bypass and COSS), failed to show long-term net benefit over IMM due to high periprocedural rates of stroke and death (12%- 15% within 30 days). However, the EC-IC Bypass and COSS trials reduced major strokes after the periprocedural period (7% vs 13.0% and 6.6% vs. 20.7%, respectively), results that indicate that a perfusion-enhancing surgical strategy that could keep low perioperative risk would be a beneficial intervention. In this proposal, we focus on such a surgical technique. EDAS is a well-established, low-pressure, indirect bypass with reduced perioperative risk. EDAS has shown benefits in adult and pediatric patients with other steno-occlusive disorders like moyamoya disease (MMD). Although there is no RCT comparing EDAS with direct bypass in MMD, there is sufficient evidence to support its low procedural risk and Class 2a recommendations from the AHA Guidelines for either technique in managing adult MMD patients. There is growing evidence of EDAS benefits on cerebral hemodynamics, stroke prevention, and cognitive outcomes, and also evidence of earlier revascularization than previously thought, over days to weeks after EDAS. EDAS has several advantages over direct high-pressure bypass being less technically demanding, not requiring temporary occlusion of intracranial vessels, avoiding high-pressure retrograde flow and in situ thrombosis, and preventing post-intervention hyperperfusion syndrome. It also has advantages over angioplasty/stenting, avoiding crossing the diseased arterial segments with wires and catheters, and preventing artery- to-artery embolisms. Based on this rationale and with support from the NINDS-NIH, we successfully completed pilot and intermediate studies of EDAS in ICAD, showing clinical benefit. The ERSIAS-PC (phase IIa) trial met the threshold set by the NINDS for advancement to the next phase and provided evidence of safety, feasibility, and strong signals of the efficacy of EDAS+IMM. The 2021 Guideline for Stroke Prevention of the AHA and the 2022 American Academy of Neurology Intracranial Atherosclerosis Advisory unequivocally indicate the imperative need toadvanceRCTs to compare EDAS with medical management, like the one we are presenting. ERSIAS has been prepared jointly with the NIH-StrokeNet to be a phase IIb trial that will recruit 170 patients with TIA or non-severely disabling (mRS 0-3) ischemic stroke within 30 days of enrollment to be randomized (1:1) to EDAS+IMM or IMM alone from the beginning of the study. All patients will receive IMM from enrollment, and those randomized to surgery will have the intervention performed no later than 7 days after randomization. The study will determine whether, in a multicenter trial, EDAS+IMM is superior to IMM alone in preventing the composite of periprocedural stroke and death plus long-term recurrent ipsilateral ischemic stroke in patients with symptomatic, high-risk ICAD over an average period of 2.5 years.
