Project 2

项目2

• 批准号: 10208710
• 负责人: ADAM L. BOXER
• 金额: $ 37.64万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10208710
• 关键词: Atrophic; Autoimmunity; Behavioral; Biological; Biological Markers; Biology; Brain; C9ORF72; Characteristics; Clinical; Clinical Trials; Clinical Trials Design; Data; Disease; Disease Progression; Enrollment; Frontotemporal Lobar Degenerations; Future; Genes; Goals; Gold; Image; Immunologic Markers; Impaired cognition; Impairment; Individual; Inflammation; Lead; Light; Link; Liquid substance; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Medical Genetics; Methods; Multi-Institutional Clinical Trial; Mutation; North America; Outcome; Outcome Measure; Participant; Pathology; Patient Selection; Patients; Pattern; Phenotype; Plasma; Population; Proteins; Risk; Safety; Sample Size; Severity of illness; Surrogate Endpoint; Syndrome; Testing; Therapeutic; Time; base; behavioral variant frontotemporal dementia; clinical predictors; clinical trial enrollment; design; drug development; genetic variant; imaging biomarker; immune activation; improved; molecular pathology; molecular targeted therapies; motor disorder; multimodality; neurofilament; neuropathology; patient population; patient stratification; polygenic risk score; protein TDP-43; rate of change; recruit; response; tau Proteins; therapeutic target; tool; treatment effect; trial design

ABSTRACT – ARTFL LEFFTDS Longitudinal FTLD: Project 2 Improvements in understanding the biology of FTLD, combined with revolutionary advancements in drug development, have created new compounds that can alter the fundamental biological mechanisms that cause FTLD. FTLD is most commonly associated with either underlying tau (FTLD-tau) or TAR DNA binding protein 43 (FTLD-TDP) brain neuropathology and many new treatments that are now entering clinical trials target one or the other of these molecular pathologies. This creates a major challenge for designing clinical trials: how to measure the effects of these new molecularly-targeted therapies in clinically heterogeneous, symptomatic FTLD populations. The first goal of this project is to develop new clinical tools and surrogate endpoints that can measure disease progression in heterogeneous FTLD clinical populations. The second goal is to develop methods to stratify patients at the time of clinical trial enrollment to define populations with more predictable rates of change or responses to specific therapeutic strategies. We will develop optimized clinical, imaging and biomarker endpoints for symptomatic FTLD clinical trials that could include multiple clinical and genetic variants with a single molecular pathology (referred to as a basket trial design) or could be deployed in patients with a common phenotype (standard parallel design) to improve power to detect treatment effects. Longitudinal clinical, imaging and fluid biomarker data will be collected in a multicenter clinical trial-ready population representing the full clinical spectrum of FTLD, including both sporadic FTLD (n=600) and symptomatic f-FTLD (n=167) from the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) consortium, which constitutes the core group of centers that will support recruitment for FTLD clinical trials in North America. We will also examine the impact of developing personalized outcomes in a trial by using each patient's baseline characteristics to predict which measures will decline over time, with a particular emphasis on maximizing what is most clinically meaningful to that patient. The specific aims are to: (1) identify the best clinical and MRI-based endpoints to measure efficacy in “basket design” clinical trials that enroll patients according to predicted underlying protein pathology, (2) develop trial enrichment strategies that combine multiple baseline characteristics to predict clinical change in FTLD, and (3) investigate inflammation as a potential late stage therapeutic target in symptomatic FTLD.

摘要 – ARTFL LEFFTDS 纵向 FTLD：项目 2 提高对 FTLD 生物学的理解，结合药物的革命性进步 开发，创造了新的化合物，可以改变引起的基本生物机制 FTLD。 FTLD 最常与基础 tau (FTLD-tau) 或 TAR DNA 结合蛋白相关 43 (FTLD-TDP) 脑神经病理学和许多目前进入临床试验的新疗法都针对其中一个目标 或其他这些分子病理学。这给临床试验设计带来了重大挑战：如何 测量这些新的分子靶向疗法在临床异质性、症状性患者中的效果 FTLD 人群。该项目的首要目标是开发新的临床工具和替代终点 测量异质 FTLD 临床人群的疾病进展。第二个目标是发展 在临床试验入组时对患者进行分层的方法，以确定具有更可预测性的人群 对特定治疗策略的变化率或反应率。我们将开发优化的临床、影像 有症状 FTLD 临床试验的生物标志物终点，可能包括多种临床和遗传 具有单一分子病理学的变体（称为篮子试验设计）或可以部署在患者身上 具有共同的表型（标准平行设计），以提高检测治疗效果的能力。纵向 临床、影像和液体生物标志物数据将在多中心临床试验准备人群中收集 代表 FTLD 的完整临床谱，包括散发性 FTLD (n=600) 和症状性 f-FTLD (n=167) 来自 ARTFL LEFFTDS 纵向额颞叶变性 (ALLFTD) 联盟， 该中心构成了核心中心组，将支持北方 FTLD 临床试验的招募 美国。我们还将通过使用每种方法来检查在试验中开发个性化结果的影响 患者的基线特征，以预测哪些指标会随着时间的推移而下降，特别强调 最大化对患者最有临床意义的东西。具体目标是：（1）确定最佳 临床和基于 MRI 的终点，用于衡量招募患者的“篮子设计”临床试验的疗效 根据预测的基础蛋白质病理学，(2) 开发结合以下内容的试验富集策略： 多个基线特征来预测 FTLD 的临床变化，以及 (3) 研究炎症作为 有症状 FTLD 的潜在晚期治疗靶点。