Surgical Indirect Revascularization For Symptomatic Intracranial Arterial Stenosis

手术间接血运重建治疗症状性颅内动脉狭窄

• 批准号: 9314670
• 负责人: Nestor Raul Gonzalez
• 金额: $ 11.08万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-13 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314670
• 关键词: Address; Adult; African American; Angioplasty; Atherosclerosis; Award; Blood Vessels; Blood flow; Brain; Bypass; Cerebrum; Cessation of life; Child; Clinical; Clinical Data; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials; Collateral Circulation; Complement; Dedications; Development; Digital Subtraction Angiography; Disease; Distal; Educational process of instructing; Embolism; Endowment; Enrollment; Environment; Evaluation; Evolution; Fellowship; Female; Functional disorder; Futility; Future; Goals; Growth Factor Gene; Health; Hemorrhage; Hyperemia; Incidence; Individual; Institutes; Intracranial Aneurysm; Intracranial Arterial Stenosis; Intracranial Hemorrhages; Investigation; Ischemic Stroke; Journals; Knowledge; Laboratories; Lead; Lesion; Magnetic Resonance Imaging; Measures; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Monitor; Moyamoya Disease; Multicenter Trials; Operative Surgical Procedures; Outcome; Paper; Pathologic Processes; Patient Selection; Patients; Perfusion; Phase; Phase III Clinical Trials; Physiological; Population; Positioning Attribute; Procedures; Process; Publications; Recurrence; Reporting; Research; Research Project Grants; Research Support; Residencies; Resources; Risk; Role; Stem cells; Stenosis; Stents; Stroke; Stroke prevention; Techniques; Testing; Thrombosis; Time; Training; Transient Ischemic Attack; Translational Research; United States; Vascular blood supply; Vasospasm; Work; arm; artery occlusion; base; candidate selection; career; data management; design; experience; high risk; implementation trial; improved; improved outcome; insight; interest; medical schools; neuroimaging; neurosurgery; next generation; non-invasive imaging; novel; operation; phase 3 study; prevent; professor; success; symptom treatment

DESCRIPTION (provided by applicant): Dr. Nestor Gonzalez is an Assistant Professor of Neurosurgery at UCLA, where he holds a full-time Academic In-Residency position. He has a track of excellence in his studies before and during medical school, as well as during residency and fellowship training. His original work has led to the publication of 11 first-author papers in recognized scientific journals including Journal of Neurosurgery, Neurosurgery and Stroke. He has performed contributory studies in patients with intracranial aneurysms, vasospasm, ischemic stroke, and, of relevance for this application, in the use of indirect surgical revascularization (EDAS) in the management of moyamoya disease and intracranial arterial stenosis. Career Goals and Objectives: Dr. Gonzalez long-term career goal is to become a national leader in clinical translational research and clinical trials in Vascular Neurosurgery. Hi immediate goal with this application is to acquire the necessary training, knowledge and hands-on experience to become an independent leading clinical investigator in his field. His clinical expertise needs to be complemented with training in the appropriate methods of clinical research to fulfill that potential. Environment: The research project and the educational activitie planned for Dr. Gonzalez will take place at UCLA. He has support from the UCLA Stroke Center, directed by Dr. Jeff Saver - Dr. Gonzalez' mentor; the UCLA Laboratory of Neuroimaging (LONI), directed by Dr. Arthur Toga; the UCLA Division of Neuroimaging, with Dr. Noriko Salamon as co-mentor, the UCLA Clinical and Translational Science Institute (CTSI) that would provide support with the resources for clinical trial and data management, and the formal educational training for Dr. Gonzalez through the Masters in Clinical Science, directed by Dr. Elashoff - co-mentor for Dr. Gonzalez; and the Department of Neurosurgery, in which Dr. Gonzalez has obtained additional support for his research interest though the Stotter Chair Endowment for 5 years. He will be relieved of a significant portion of his teaching and clinical activities during the K23 award, to allow a dedication of at least 50%. He also has assembled a respected group of External Advisors that include Dr. Mark Chimowirz, Dr. Colin Derdeyn, Dr. Yuko Palesch, Dr. Michael Scott, and Dr. Greg Albers that would guide beyond the mentors' role the design and implementation of the trial he is proposing. Research: Stroke due to intracranial arterial atherosclerosis is a significant medical problem, carrying one of the highest rates of recurrent stroke despite medical therapy, with annual recurrence rates for ischemic stroke reported in the SAMMPRIS Trial as high as 12.2% in the intensive medical therapy arm. The incidence of recurrence stroke can be even higher in some high-risk groups, as high as 25% in African-Americans and females. The goal of the research proposed by Dr. Gonzalez is to advance a new, promising surgical treatment for symptomatic atherosclerotic intracranial stenosis - encephaloduroarteriosynangiosis (EDAS). Compared with direct revascularization operations (bypass), EDAS has the advantages of being less technically demanding, avoiding temporary occlusion of cerebral vessels, and allowing gradual development of collateral circulation where the brain demands it, deterring early hyper perfusion and hemorrhage. There has been no systematic trial exploring the use of EDAS in cases of symptomatic, non-moyamoya intracranial arterial stenosis. Based on his preliminary positive results, he has the long-term objective of demonstrating that EDAS improves the outcome in patients with symptomatic intracranial stenosis compared with aggressive medical therapy. This will require future phase III clinical trials. The present proposal has the purpose of testing in a phase II futility trial the potential of EDAS for further development before proceeding with the design of a definitive clinical trial of EDAS Revascularization in patients with Symptomatic Intracranial Arterial Stenosis (ERSIAS). The present project will be 4-year futility trial to determine if EDAS revascularization combined with aggressive medical therapy warrants further evaluation in a subsequent pivotal trial as an alternative to aggressive medical management alone for preventing the primary endpoint of stroke or death at two years in patients with symptomatic intracranial arterial stenosis (Specific Aim 1). During the investigation he also proposes to systematically evaluate the time course of collateral genesis and perfusion improvement following EDAS. This detailed knowledge on the timing of collateral development on digital subtraction angiography and of improved blood flow on perfusion MRI will provide useful physiologic information to monitor and refine the EDAS procedure and post-procedure management, and provide a better understanding of the intracranial atherosclerotic pathologic process (Specific Aim 2). Dr. Gonzalez plans year 5 of this award to the publication of the trial results, as well as the physiologic, angiographic, and MRI perfusion results on collateral formation, and to the independent planning of a subsequent phase III multicenter trial. The new knowledge generated by this study on understanding the role of collateral circulation in stroke pathophysiology, patient selection, and use of non-invasive imaging will be useful not only for EDAS evaluation but potentially next generation stents and future novel medical therapies, such as use of angiogenic growth factors and/or endothelial stem cells.

描述（由申请人提供）：Dr. Nynthia Gonzalez是加州大学洛杉矶分校神经外科助理教授，在那里他拥有全职学术住院医师职位。他在医学院之前和期间以及在住院医师和奖学金培训期间的学习中都有卓越的表现。他的原创性工作导致在公认的科学期刊上发表了11篇第一作者论文，包括Journal of Neurosurgery，Neurosurgery和Stroke。他在颅内动脉瘤、血管痉挛、缺血性卒中患者中进行了贡献性研究，并与本申请相关，使用间接手术血运重建（EDAS）治疗烟雾病和颅内动脉狭窄。职业目标和目的：Gonzalez博士的长期职业目标是成为血管神经外科临床转化研究和临床试验的全国领导者。这个应用程序的直接目标是获得必要的培训，知识和实践经验，成为一个独立的领先的临床研究者在他的领域。他的临床专业知识需要补充培训，在适当的临床研究方法，以实现这一潜力。环境：为冈萨雷斯博士计划的研究项目和教育活动将在加州大学洛杉矶分校进行。他得到了加州大学洛杉矶分校中风中心的支持，该中心由杰夫·萨弗博士领导，冈萨雷斯博士的导师;加州大学洛杉矶分校神经成像实验室（LONI），由亚瑟托加博士领导;加州大学洛杉矶分校神经影像部门，Noriko Salamon博士担任共同导师，加州大学洛杉矶分校临床和转化科学研究所（CTSI）将为临床试验和数据管理提供资源支持，以及通过临床科学硕士学位为Gonzalez博士提供的正式教育培训，由Elashoff博士指导-Gonzalez博士的共同导师;以及神经外科部门，其中Gonzalez博士通过Stotter Chair Endowment获得了5年的研究兴趣的额外支持。在K23奖期间，他将被免除相当一部分教学和临床活动，以允许至少50%的奉献。他还组建了一个受人尊敬的外部顾问小组，包括Mark Chimoelz博士、Colin Derdeyn博士、Yuko Palesch博士、Michael Scott博士和Greg阿尔伯斯博士，他们将在导师的角色之外指导他所提议的试验的设计和实施。 研究：颅内动脉粥样硬化引起的中风是一个重大的医学问题， SAMMPRIS试验报告的强化药物治疗组缺血性卒中的年复发率高达12.2%，在某些高危人群中复发性卒中的发生率甚至更高，在非裔美国人和女性中高达25%。Gonzalez博士提出的这项研究的目标是推进一种新的、有希望的治疗症状性动脉粥样硬化性颅内狭窄的手术治疗-脑硬脑膜动脉联合血管形成（EDAS）。与直接血运重建手术（旁路）相比，EDAS具有技术要求低，避免脑血管暂时闭塞，并允许大脑需要侧支循环的逐渐发展，防止早期过度灌注和出血的优点。目前还没有系统性试验探索EDAS在症状性非烟雾病颅内动脉狭窄病例中的应用。基于他的初步积极结果，他的长期目标是证明与积极的药物治疗相比，EDAS可以改善症状性颅内狭窄患者的预后。这将需要未来的III期临床试验。本提案的目的是在进行EDAS的设计之前，在II期无效试验中测试EDAS进一步开发的潜力。 EDAS血运重建在症状性颅内动脉狭窄（ERSIAS）患者中的确定性临床试验。本项目将是一项为期4年的无效试验，旨在确定EDAS血运重建联合积极药物治疗是否需要在后续关键试验中进一步评价，作为单独积极药物治疗的替代方案，以预防症状性颅内动脉狭窄患者2年时卒中或死亡的主要终点（具体目标1）。在研究过程中，他还建议系统地评价EDAS后侧支生成和灌注改善的时间过程。关于数字减影血管造影侧支形成时间和灌注MRI血流改善时间的详细知识将为监测和完善EDAS手术和术后管理提供有用的生理信息，并更好地了解颅内动脉粥样硬化病理过程（具体目标2）。Gonzalez博士计划在该奖项的第5年发表试验结果，以及关于侧支形成的生理学、血管造影和MRI灌注结果，并独立计划随后的III期多中心试验。这项研究产生的关于了解侧支循环在中风病理生理学中的作用、患者选择和非侵入性成像的使用的新知识不仅对EDAS评估有用，而且可能对下一代支架和未来新型医学疗法有用，例如使用血管生成生长因子和/或内皮干细胞。