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: 10404673
• 负责人: ISSAM A AWAD
• 金额: $ 76.45万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404673
• 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; Placebo Control; Placebos; Predisposition; Protocols documentation; Randomized; 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; irradiation; mouse model; multi-site trial; 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; trial readiness

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 项目总结 100多万美国人患有脑海绵状血管瘤(CA)。特别值得关注的是 最近出现症状的不到200,000例患者的出血风险极高 出血，以及中风的高成本和高发病率，以及在这种情况下可能的手术干预。它 开发一种稳定出血性CA病变并减轻再出血负担的药物是可取的 在流血。十年的研究发现，RhoA激酶(ROCK)的激活是一种信号异常 介导血管高通透性和血管出血。摇滚抑制疗法已被证明是钝化的 在总结人类疾病的小鼠模型中CA病变发展和出血的研究。A类似的 最近，羟甲基戊二酰辅酶-A还原酶有很强的治疗效果 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，宽幅 临床使用，在批准和耐受性良好的剂量下，在人体内实现岩石抑制多效性作用。这个 芝加哥研究小组在CA患者中实施并验证了新的磁共振成像技术， 反映皮损出血(定量敏感性图谱，QSM)和血管通透性(动态 对比剂增强定量灌注(DCEQP)，并将这些措施与临床出血联系起来 人类受试者。这些发现激发了一种前瞻性的、随机的、双盲的安慰剂-- 评估阿托伐他汀疗效的I-IIa期对照探索性概念验证试验，剂量显示为 对最近出血的CA皮损造成摇滚抑制。主要目标应评估是否 与安慰剂相比，这种治疗在皮损铁沉积(QSM生物标记物活性)方面产生了不同。 二级AIMS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 治疗外周血白细胞的ROCK活性，检查信号对临床结果和不良反应的影响 事件，并查询预先指定的子组。考虑到潜在的磨损和丢失数据的所有原因， 这项研究通过招募80名受试者(安慰剂和阿托伐他汀各40名)来检验主要假设 组)。受试者将被跟踪两年，并计划在样本中进行无效性分析和适应性变化 大小基于在试验中点观察到的生物标记物效应。这是第一个专注于 稳定最近出血的CA，使用机械靶向血管渗透疗法 减少再出血的目标。它将响应临床和患者社区的紧急呼叫，以评估 客观和科学地说，广泛使用的(在某些方面具有诱惑力的)他汀类药物是否可能起到作用 在CA治疗中。一支由调查人员和顾问组成的团队以及强大的审判准备基础设施 进行整合，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 给出了肯定的和否定的试验结果，以及推论的去不去的主张，在 更广泛的治疗发展路线图。这项试验获得了美国食品和药物管理局IND豁免#126840。