Methods to Improve Clinical Trials for A-T

项目摘要/摘要 共济失调毛细血管扩张症(A-T)是一种常染色体隐性遗传性疾病，以小脑为特征 变性、免疫缺陷、肺部疾病和癌症易感性。A-T是复杂的 在表现形式和严重性方面高度可变，但导致其 变异性还没有完全被理解。1995年，A-T临床中心在北京成立 约翰霍普金斯医院(JHH)；它的目标是收集自然历史数据并提供多种 对患有A-T的人进行纪律治疗这项提议的长期目标是优化 通过创建一种将A-T患者分为严重组和 为A-T创建经过验证的功能评定表这项工作将利用数据和资源 A-T临床中心的。这项提案的目的是更好地定义A-T疾病的严重性 制定详细、明确的日常生活活动功能评定量表。 我们的中心假设是：A.房性心动过速的临床特征的开始和频率聚集在 一种允许将患者分配到严重组(例如，重度、中度或轻度)的方法 B.A-T特定功能分级量表将记录疾病严重程度的变化，这些变化包括 对房颤患者有意义 这些假设将通过以下具体目标进行检验：1.A-T的分层 使用遗传型、表型和实验室标记的严重程度。有必要更好地 在A-T中定义超出当前技术水平的严重性组。A-T病的分层 严重程度将利用大量和多样化的JHH A-T患者队列，并将实现 通过识别预测或定义疾病严重程度的各种标记。2. 编制A-T的有效功能评定量表。经过验证的功能评级 A-T的比例不存在。来自A-T儿童项目家庭咨询的意见 理事会和世界卫生组织(世卫组织)顾问，我们的比额表将把 世界卫生组织开发的功能量表框架，并将根据A-TNEST进行验证 (A-T特定神经病学量表)、临床检查和PEDS-QL™。 这个项目的预期结果是一个量化模型，它将提供一个简单和 A-T中确定疾病严重程度的客观方法，以及将对其进行有意义评级的量表 功能严重程度的变化。这些结果将直接影响赞助商和调查人员 希望在临床试验中评估治疗干预措施的有效性 变数很大的疾病。

PROJECT SUMMARY / ABSTRACT Ataxia Telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, pulmonary disease and cancer susceptibility. A-T is complex and highly variable in terms of presentation and severity, but the factors responsible for its variability are not completely understood. In 1995, an A-T Clinical Center was established at Johns Hopkins Hospital (JHH); its goal is to collect natural history data and provide multi- disciplinary care for people with A-T. The long term goals of this proposal are to optimize clinical trials for A-T by creating a system for classifying A-T patients into severity groups and creating a validated functional rating scale for A-T. This work will leverage the data and resources of the A-T Clinical Center. This proposal’s objectives are to better define A-T disease severity and develop a detailed and definitive functional rating scale for activities of daily living. Our central hypotheses are that: a. the onset and frequency of A-T’s clinical features cluster in a way that allows assignment of patients into severity groups (e.g. severe, moderate, or mild) and b. an A-T specific functional rating scale will capture changes in disease severity that are meaningful to patients with A-T. These hypotheses will be tested through the following Specific Aims: 1. Stratification of A-T Severity using Genotypic, Phenotypic and Laboratory markers. There is a need to better define severity groups in A-T beyond the current state of the art. Stratification of A-T disease severity will utilize the large and diverse JHH cohort of patients with A-T and will be achieved through the identification of a variety of markers that predict or define disease severity. 2. Development of a Validated Functional Rating Scale for A-T. A validated functional rating scale for A-T does not exist. With input from the A-T Children’s Project Family Advisory Council and a World Health Organization (WHO) consultant, our scale will integrate the functional scale framework developed by the WHO and will be validated against the A-TNEST (an A-T-specific neurologic scale), clinical exams and the PEDS-QL™. The expected outcomes of this project are a quantitative model that will provide a simple and objective way to determine disease severity in A-T, and a scale that will rate meaningful changes in functional severity. These outcomes will directly impact sponsors and investigators wishing to gauge the efficacy of treatment interventions in clinical trials for this complex and highly variable disease.