Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial

阿托伐他汀治疗伴有症状性出血的海绵状血管瘤探索性概念验证 (AT CASH EPOC) 试验

基本信息

批准号：
9750236
负责人：
ISSAM A AWAD
金额：
$ 78.62万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750236
关键词：
Accounting Adult Adverse event American Baltimore Biological Biological Markers Blood Vessels Brain Brain Stem Cavernous Hemangioma Cerebrum Chicago Chronic Clinical Clinical Research Coenzyme A Collaborations Communities Data Deposition Development Disease Dose Double-Blind Method Drug usage Enrollment Event Futility Genotype Goals Hemorrhage Human Imaging Techniques Infrastructure Intention Intervention Iron Lesion Leukocytes Link Literature Magnetic Resonance Imaging Measures Mediating Morbidity - disease rate Naturopathic Doctor Neurologic Operative Surgical Procedures Outcome Outcome Measure Oxidoreductase Patients Perfusion Peripheral Permeability Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Phosphotransferases Placebos Predisposition Protocols documentation Randomized Readiness Registries Research Research Personnel Resected Risk Role Sample Size Signal Transduction Simvastatin Somatic Mutation Specific qualifier value Specimen Stroke Subgroup Tail Techniques Testing Therapeutic Therapeutic Effect Therapeutic Trials Vascular Permeabilities atorvastatin base biomarker validation capsule contrast enhanced cost disability fasudil follow-up functional outcomes human disease human subject in vivo inhibitor/antagonist irradiation mouse model novel novel marker peripheral blood phase I trial pleiotropism pre-clinical preclinical study prevent primary outcome prospective randomized trial secondary analysis side effect statistics therapeutic development treatment effect trial design

项目摘要

Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial PROJECT SUMMARY More than a million Americans harbor a cerebral cavernous angioma (CA). Of particular concern is the exceptionally high bleeding risk in the fewer than 200,000 cases who have suffered a recent symptomatic hemorrhage, and the high cost and morbidity of stroke and potential surgical interventions in this setting. It would be desirable to develop a drug that stabilizes the hemorrhagic CA lesion and lessen the burden of re- bleeding. A decade of research has identified RhoA kinase (ROCK) activation as a signaling aberration mediating vascular hyper-permeability and bleeding in CAs. ROCK inhibition therapy has been shown to blunt of CA lesion development and hemorrhage in mouse models recapitulating the human disease. A similarly robust therapeutic benefit was recently documented with the hydroxy-methylglutaryl-coenzyme-A reductase inhibitor atorvastatin, and a demonstrably weaker effect by lower potency simvastatin. Atorvastatin, in wide clinical use, achieves ROCK inhibition pleiotropic effect in humans, at approved and well tolerated doses. The Chicago team has implemented and validated novel magnetic resonance imaging techniques in CA patients, reflecting lesional hemorrhage (quantitative susceptibility mapping, QSM) and vascular permeability (dynamic contrast enhanced quantitative perfusion, DCEQP), and linked these measures to clinical hemorrhage in human subjects. These discoveries have motivated a prospective, randomized, double-blinded, placebo- controlled, Phase I-IIa exploratory proof of concept trial assessing the effects of atorvastatin, at doses shown to cause ROCK inhibition, on CA lesions that have recently bled. The primary objective shall evaluate whether the treatment produces a difference in lesional iron deposition (QSM biomarker activity) compared to placebo. Secondary aims shall assess the drug effects on a second biomarker (DCEQP vascular permeability), link drug treatment to ROCK activity in peripheral leukocytes, examine signal effects on clinical outcomes and adverse events, and query pre-specified subgroups. Accounting for all causes of potential attrition and missing data, the study is powered to test the primary hypothesis by enrolling 80 subjects (40 each in placebo and atorvastatin groups). Subjects will be followed for 2 years, with plans for futility analysis and adaptive change in sample size based on observed biomarker effects at midpoint of the trial. This is the first therapeutic trial focused on stabilizing a CA that had recently bled, using mechanistically targeted vascular permeability therapy with the goal of lessening re-bleeding. It will answer the urgent call by the clinical and patient community to assess objectively and scientifically whether the widely available (and in some ways seductive) statins may have a role in CA therapy. A team of investigators and consultants and a robust trial readiness infrastructure have been assembled to maximize the rigor of the proposed study and insure its successful execution. Implications of positive and negative trial results are presented, and corollary go-no-go propositions, within the scope of a broader therapeutic development roadmap. This trial has received U.S. F.D.A. IND Exemption #126840.

阿托伐他汀治疗海绵状血管瘤伴症状性出血探索性概念验证 (AT CASH EPOC) 试验项目概要超过一百万美国人患有脑海绵状血管瘤 (CA)。特别值得关注的是最近出现症状的病例少于 200,000 例，出血风险极高出血、中风的高成本和发病率以及在这种情况下可能进行的手术干预。它需要开发一种药物来稳定出血性 CA 病变并减轻再治疗的负担流血。十年的研究已确定 RhoA 激酶 (ROCK) 激活是一种信号传导异常介导 CA 中的血管高渗透性和出血。 ROCK 抑制疗法已被证明可以削弱重演人类疾病的小鼠模型中 CA 病变发展和出血的研究。一个类似的最近记录了羟甲基戊二酰辅酶 A 还原酶的强大治疗效果抑制剂阿托伐他汀，而效力较低的辛伐他汀的作用明显较弱。阿托伐他汀，广泛临床使用，以批准且耐受性良好的剂量，在人体中实现 ROCK 抑制多效性。这芝加哥团队在 CA 患者中实施并验证了新型磁共振成像技术，反映病灶出血（定量磁敏图，QSM）和血管通透性（动态对比增强定量灌注（DCEQP），并将这些措施与临床出血联系起来人类受试者。这些发现激发了一项前瞻性、随机、双盲、安慰剂研究受控的 I-IIa 期探索性概念验证试验，评估阿托伐他汀的效果，剂量显示对最近出血的 CA 病变产生 ROCK 抑制。主要目标应评估是否与安慰剂相比，该治疗在病变铁沉积（QSM 生物标志物活性）方面产生差异。次要目标应评估药物对第二个生物标志物（DCEQP 血管通透性）的影响，链接药物治疗外周白细胞中的 ROCK 活性，检查对临床结果和不良反应的信号影响事件，并查询预先指定的子组。考虑到潜在损耗和数据缺失的所有原因，该研究通过招募 80 名受试者（安慰剂组和阿托伐他汀组各 40 名）来检验主要假设组）。受试者将被跟踪两年，并计划对样本进行无效分析和适应性改变大小基于试验中点观察到的生物标志物效应。这是第一个治疗试验，重点关注使用机械靶向血管通透性治疗来稳定最近出血的 CA 减少再出血的目标。它将响应临床和患者社区评估的紧急呼吁客观而科学地广泛使用（并且在某些方面具有吸引力）的他汀类药物是否可能发挥作用在CA治疗中。一支由研究人员和顾问组成的团队以及强大的试验准备基础设施已经建立聚集在一起以最大限度地提高拟议研究的严谨性并确保其成功执行。的影响提出积极和消极的试验结果，以及推论的继续或不继续的主张，在范围内更广泛的治疗发展路线图。该试验已获得美国FDA批准。 IND 豁免#126840。