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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