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

• 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
• 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

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.

对症状出血的海绵状血管瘤的阿托伐他汀治疗 探索性概念证明（现金EPOC）试验 项目摘要 超过一百万的美国人拥有脑海绵状血管瘤（CA）。特别关注的是 在遭受最近有症状的少于200,000例病例中，出血风险异常高。 在这种情况下，出血，中风和潜在手术干预的高成本和发病率。它 希望开发一种稳定出血性病变并减轻重新负担的药物 流血。十年的研究已将RhoA激酶（岩石）激活确定为信号畸变 CAS中介导血管过度过度和出血。岩石抑制疗法已显示出钝性 小鼠模型中的CA病变发展和出血的概括。类似的 最近用羟基 - 甲基戊二酰辅酶-A还原酶记录了鲁棒的治疗益处 抑制剂阿托伐他汀，较低的辛伐他汀的效应明显弱。 atorvastatin，宽 临床用途，以批准且耐受性良好的剂量达到人类的岩石抑制多效性效应。这 芝加哥团队已在CA患者中实施并验证了新型的磁共振成像技术， 反映病变出血（定量敏感性映射，QSM）和血管通透性（动态 对比增强了定量灌注，DCEQP），并将这些措施与临床出血联系在一起 人类主题。这些发现激发了一个前瞻性，随机，双盲的安慰剂 - 受控的，I-IIA期探索性概念验证试验评估Atorvastatin的影响，以剂量显示 引起岩石抑制作用，对最近流血的CA病变。主要目标应评估是否 与安慰剂相比，该处理的病变铁沉积（QSM生物标志物活性）的差异。 次要目的应评估对第二个生物标志物（DCEQP血管通透性）的药物影响，Link Drug 对周围白细胞中岩石活性的治疗，检查信号对临床结果的影响和不良 事件和查询预先指定的子组。考虑了潜在流失和丢失数据的所有原因， 研究有能力通过注册80名受试者（每个安慰剂和阿托伐他汀）来检验主要假设 组）。受试者将遵循2年，并计划进行徒劳分析和样本自适应变化 根据在试验中点观察到的生物标志物效应的大小。这是首次关注的治疗试验 使用机械靶向的血管通透性疗法稳定最近流血的CA 减少再出血的目标。它将回答临床和患者社区的紧急呼吁以评估 客观和科学上可用的（在某些方面诱人）他汀类药物是否有角色 在CA疗法中。一个调查人员和顾问团队以及强大的试验准备基础设施已经 组装以最大程度地提高拟议研究的严格性并确保其成功执行。含义 提出了积极和负面试验结果，并在a的范围内提出了推论的命题。 更广泛的治疗开发路线图。该试验已获得美国F.D.A.豁免＃126840。