Project 2

项目2

基本信息

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
项目类别：
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

项目摘要

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 了解FTLD的生物学的改进，再加上毒品的革命性进步开发，创造了可以改变导致基本生物学机制的新化合物 ftld。 FTLD最常见于基础tau（FTLD-TAU）或TAR DNA结合蛋白 43（FTLD-TDP）脑神经病理学和许多正在进入临床试验的新疗法的目标或其他这些分子病理。这为设计临床试验带来了一个重大挑战：如何测量这些新分子靶向疗法在临床异质性症状学中的影响 FTLD人群。该项目的第一个目标是开发新的临床工具和替代端点测量异质FTLD临床人群的疾病进展。第二个目标是发展在临床试验入学时对患者进行分层的方法，以定义更可预测的人群变化率或对特定治疗策略的反应。我们将开发优化的临床成像以及有症状的FTLD临床试验的生物标志物终点，其中可能包括多个临床和遗传具有单个分子病理学的变体（称为篮子试验设计），或者可以在患者中部署具有常见的表型（标准平行设计），以提高检测治疗效果的功率。纵向临床，成像和流体生物标志物数据将在多中心临床试验中收集代表FTLD的完整临床光谱，包括零星FTLD（n = 600）和有症状的F-FTLD （n = 167）来自ARTFL LEFFTDS纵向额颞叶变性（Allftd）联盟，这构成了将支持北部FTLD临床试验招聘的核心中心组美国。我们还将通过使用每种患者的基线特征可以预测哪些措施会随着时间的流逝而下降，并特别重视最大化该患者最有意义的临床意义。具体目的是：（1）确定最好的临床和基于MRI的终点，以测量参加患者的“篮设计”临床试验的效率根据预测的潜在蛋白质病理学，（2）结合的开发试验富集策略多个基线特征可以预测FTLD的临床变化，（3）将注射作为一种有症状的FTLD中潜在的晚期治疗靶标。