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

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 项目摘要 超过一百万的美国人患有脑海绵状血管瘤（CA）。特别令人关切的是 在不到200，000例最近出现症状性出血的病例中，出血风险异常高 出血，以及高成本和中风发病率和潜在的手术干预在这种情况下。它 将需要开发一种药物，其稳定出血性CA病变并减轻再出血的负担。 流血了十年的研究已经将RhoA激酶（ROCK）激活确定为信号畸变 介导CA中的血管通透性过高和出血。ROCK抑制疗法已被证明可以钝化 CA病变的发展和出血的小鼠模型重演人类疾病。类似 最近证实了羟甲基戊二酰辅酶A还原酶的强大治疗益处 抑制剂阿托伐他汀，和较低效力的辛伐他汀明显较弱的作用。阿托伐他汀，广泛 临床应用中，在批准的和良好耐受的剂量下，在人类中实现ROCK抑制多效性效应。的 芝加哥团队已经在CA患者中实施并验证了新的磁共振成像技术， 反映病变出血（定量敏感性绘图，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， 人类实验对象这些发现激发了一项前瞻性、随机、双盲、安慰剂- 对照、I-IIa期探索性概念验证试验，评估阿托伐他汀的作用，剂量显示 在最近流血的的CA病变上引起ROCK抑制。主要目标应评估是否 与安慰剂相比，该治疗产生了损伤铁沉积（QSM生物标志物活性）的差异。 次要目的应评估药物对第二种生物标志物（DCEQP血管通透性）的影响，将药物 治疗外周血白细胞中的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。考虑到所有可能的流失和缺失数据的原因， 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）。将对受试者进行2年随访，并计划进行无效性分析和适应性样本变更 基于在试验中点观察到的生物标志物效应的大小。这是第一个治疗性试验， 稳定最近流血的的CA，使用机械靶向血管通透性治疗， 目的是减少再出血。它将响应临床和患者社区的紧急呼吁， 客观和科学地说，广泛使用的（在某些方面很有吸引力的）他汀类药物是否可能在 在CA治疗中。一个由调查员和咨询人组成的小组以及一个强大的审判准备基础设施已得到 组装以最大限度地提高拟议研究的严谨性并确保其成功执行。影响 积极和消极的试验结果，并推论去不去的主张，范围内的一个 更广泛的治疗开发路线图。本试验已获得美国FDA IND豁免编号126840。

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.