Methods to Improve Clinical Trials for A-T

项目总结/摘要 共济失调毛细血管扩张症（Ataxia Telangiectasia，A-T）是一种常染色体隐性遗传性疾病， 变性、免疫缺陷、肺病和癌症易感性。T是复杂的 并且在表现和严重程度方面高度可变，但导致其 可变性并不完全被理解。1995年，A-T临床中心成立， 约翰霍普金斯医院（JHH）;其目标是收集自然史数据，并提供多方面的信息。 对患有AT的人进行纪律性治疗。该提案的长期目标是优化 通过创建一个将A-T患者分类为严重程度组的系统， 为A-T创建经验证的功能评定量表。这项工作将利用数据和资源 A-T临床中心该提案的目标是更好地定义A-T疾病的严重程度 并为日常生活活动制定详细和明确的功能评定量表。 我们的主要假设是：a。A-T临床特征的发作和频率集中在 允许将患者分配到严重程度组（例如重度、中度或轻度）的方法，以及 B. A-T特异性功能评定量表将捕捉疾病严重程度的变化， 对A-T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分层 使用基因型、表型和实验室标志物的严重程度。需要更好地 定义A-T的严重程度组，超出当前最先进的水平。A-T疾病的分层 严重程度将利用大量不同的JHH A-T患者队列， 通过识别各种预测或定义疾病严重程度的标志物。2. A-T功能评定量表的研制经过验证的功能评级 A-T的比例不存在。根据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，我们的规模将整合 由WHO开发的功能量表框架，并将根据A-TNEST进行验证 (an A-T特异性神经系统量表）、临床检查和PEDS-QL™。 该项目的预期成果是一个量化模型，将提供一个简单的， 确定A-T中疾病严重程度的客观方法，以及一个有意义的评分量表 功能严重度的变化。这些结果将直接影响申办者和研究者 希望在临床试验中评估治疗干预对这种复杂和 高度可变的疾病。

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.