Methods to Improve Clinical Trials for A-T

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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.