Fragile X Clinic and Reseach Cooperative Consortium Agreement: component C

Fragile X 诊所和研究合作联盟协议：C 部分

• 批准号: 9131959
• 负责人: Elizabeth Mara Berry-Kravis
• 金额: $ 9.99万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9131959
• 关键词: Fragile; Clinic; Reseach; Cooperative; Consortium

 DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder with an estimated frequency of about 1:4000-5000, affecting all racial and ethnic groups worldwide. Enormous progress in basic and translational FXS research has identified many neuronal targets and allowed early clinical trials of new treatments targeted to the underlying disease. A number of these agents have shown signal for benefit in open-label and early phase trials, but it has been challenging to meet primary behavioral outcomes in larger phase 2b and 3 trials, due to multiple complex issues including dosing age of subjects, length of treatment, placebo effects, and primary outcome off target for drug effect. A significant problem has been poor availability of biomarkers and well-validated cognitive and other objective outcome measures that do not rely on parent report. Further, very long-term treatment over years, a time frame over which placebo controls are not possible, will be necessary to show changes in the trajectory of disease. In order to know whether the disease trajectory has been changed, it will be CRITICAL to have detailed longitudinal phenotyping including cognitive, adaptive, language, motor, behavioral, social, and quality of life on a large cohort of individuals with FXS, in order to define the naturl history of the disease for future comparison in long-term intervention studies. The FORWARD longitudinal database tracks health, behavior and social issues including 3 standardized measures of behavior and social function in a large cohort of individuals with FXS but lacks good consistent cognitive and adaptive data. Given the infrastructure already present, the FORWARD project is the only currently plausible place to collect the necessary detailed longitudinal phenotyping. Thus, through this application, focused on both enhanced measurement and participation, we plan to collaborate with the other Component C FXS clinics to enhance the cohort size in which we will collect a comprehensive core battery of outcome measures yearly for a minimum of 3 years to begin to define the longitudinal trajectory of all aspects of the FXS phenotype (Aim 1). Additionally at our site alone we will collect pilot data longitudinally for two new outcome measures that address two areas of need in the field (Aim 2): objective direct measures of CNS function (auditory event-related potentials), and sensitive direct measures of communication function in very young and non-verbal individuals with FXS (Communication Complexity Scale). Finally, we will implement plans to improve our collection of this data from adults with FXS and from racial and ethnic groups according to the population percentages from the state of Illinois (Aim 3). Analysis plans for the data collected in this projet will be reviewed and modified by experts in FXS outcomes research and CDC partners. Results of analyses resulting from the data collection in this application will be disseminated to all stakeholders including the FXCRC, NFXF, FXS Community Support Network groups, FXS families, other researchers and CDC project partners.

 描述（由申请人提供）：脆性 X 综合征 (FXS) 是智力障碍和自闭症谱系障碍的最常见遗传原因，估计频率约为 1:4000-5000，影响全世界所有种族和民族。基础和转化 FXS 研究的巨大进展已经确定了许多神经元靶点，并允许针对潜在疾病的新疗法进行早期临床试验。其中许多药物已在开放标签和早期试验中显示出有益的信号，但由于多种复杂的问题，包括受试者的给药年龄、治疗时长、安慰剂效应和药物效果偏离目标的主要结果，在更大规模的 2b 期和 3 期试验中满足主要行为结果一直具有挑战性。一个重要的问题是生物标志物和经过充分验证的认知和其他客观结果测量的可用性较差，这些测量不依赖于家长的报告。此外，需要进行多年的长期治疗，在这段时间内无法进行安慰剂对照，才能显示疾病轨迹的变化。为了了解疾病轨迹是否发生了改变，对一大群 FXS 患者进行详细的纵向表型分析（包括认知、适应性、语言、运动、行为、社交和生活质量）至关重要，以便定义疾病的自然史，以便将来在长期干预研究中进行比较。 FORWARD 纵向数据库跟踪一大群 FXS 患者的健康、行为和社会问题，包括 3 项标准化行为和社会功能测量，但缺乏良好一致的认知和适应性数据。鉴于现有的基础设施，FORWARD 项目是目前唯一可能收集必要的详细纵向表型分析的地方。因此，通过此应用程序，重点关注增强的测量和参与，我们计划与其他组件 C FXS 诊所合作，以扩大队列规模，我们将在至少 3 年内每年收集全面的核心结果测量组，以开始定义 FXS 表型所有方面的纵向轨迹（目标 1）。此外，仅在我们的站点，我们将纵向收集两项新结果测量的试点数据，这些测量解决了该领域的两个需求领域（目标 2）：中枢神经系统功能（听觉事件相关电位）的客观直接测量，以及具有 FXS（沟通复杂性量表）的非常年轻和非语言个体的沟通功能的敏感直接测量。最后，我们将实施计划，根据伊利诺伊州的人口百分比，改进 FXS 成人以及种族和族裔群体的数据收集（目标 3）。该项目中收集的数据的分析计划将由 FXS 结果研究专家和 CDC 合作伙伴进行审查和修改。本应用程序中数据收集的分析结果将分发给所有利益相关者，包括 FXCRC、NFXF、FXS 社区支持网络团体、FXS 家庭、其他研究人员和 CDC 项目合作伙伴。