Clinical Research in ALS & Related Disorders for Therapeutic Development (CReATe) - Project Core #1

项目摘要/摘要 CREATE联盟的项目#1试图解决以下两个具体挑战： 肌萎缩侧索硬化症及相关疾病。第一个挑战是ALS和ALS的病因和表型的异质性 相关的障碍。不同病因的含义是治疗方法，特别是那些 以上游生物学机制为目标，需要针对具有共同病因和/或共同病原体的患者亚群 生物学。表型的异质性(例如疾病进展或存活率)使对 在自然变异的“噪音”中治疗“信号”。在即将到来的临床试验中 针对特定的患者亚群(例如SOD1和C9ORF72 ALS和SPAST HSP)，迫切需要 定量定义了肌萎缩侧索硬化症和相关疾病最常见的遗传形式的自然历史。这 需要估计最常用的变化率的平均值和人与人之间的变化率 结果指标(如ALSFRS-R、SVC、SPRS)。同时，我们将使用基于锚点的方法来估计 从患者的角度来看，在这些功能测量中，最小的临床重要变化。这个 然而，表型的异质性超出了运动领域，越来越多的人认识到 认知和行为功能障碍是这类障碍的常见表现。因此，我们将， 也描述了认知和行为功能障碍的纵向过程，主要依赖于 爱丁堡认知和行为肌萎缩侧索硬化症屏幕(ECAS)和创造认知行为电池 (C2B2)以及我们将开发的年龄和教育调整后的规范数据。第二个挑战，我们将 地址是患者参与研究的总体比率较低。具体地说，我们将(A)使用ALS推出 Epic电子健康记录中的工具包，以更好地捕获研究过程中的高质量数据 惩戒病人护理；(B)扩大举措，使远程收集结果数据的能力使用移动设备 基于智能手机的技术和家庭使用的肺活量测量设备；以及(C)探索针对ALS的实用程序 患者报告结果(PRO)旨在捕获患者及其 关心对他们来说最重要的事情。这些目标的成功实现预计将产生较低的 评估对患者重要和临床相关的结果的负担方法。

Project Summary / Abstract Project #1 of the CReATe Consortium seeks to address two specific challenges to therapy development for ALS and related disorders. The first challenge is the etiological and phenotypic heterogeneity of ALS and related disorders. The implication of diverse etiology is that therapeutic approaches, especially those that target upstream biological mechanisms, need to be targeted to subsets of patients with shared etiology and/or biology. Heterogeneity of phenotype (e.g. rates of disease progression or survival) complicates discernment of therapeutic ‘signal’ amidst the ‘noise’ of natural variation. With an imminent future of clinical trials that will target specific subsets of patients (e.g. SOD1 and C9ORF72 ALS and SPAST HSP), there is an urgency to quantitative define the natural history of the most common genetic forms of ALS and related disorders. This entails estimating the mean and person-to-person variation in rates of change of the most commonly used outcome measures (e.g. ALSFRS-R, SVC, SPRS). In parallel, we will use anchor-based methods to estimate the minimum clinically important change, from the patient perspective, in these functional measures. The heterogeneity of phenotype, however, extends beyond the motor domain, with increasing recognition that cognitive and behavioral dysfunction are common manifestations of this group of disorders. We will, therefore, also characterize the longitudinal course of cognitive and behavioral dysfunction, relying primarily on the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and the CReATe Cognitive Behavioral Battery (C2B2) and age- and education-adjusted normative data that we will develop. The second challenge we will address is the low overall rate of patient participation in research. Specifically, we will (a) roll out use the ALS Toolkit in the Epic electronic health record to better capture research quality data in the course of multi- disciplinary patient care; (b) expand initiatives to empower remote collection of outcome data using both mobile smartphone-based technology and home use spirometry devices; and (c) explore the utility of an ALS-specific patient reported outcome (PRO) that has been designed to capture the perspective of patients and their caregivers about what matters most to them. Successful completion of these aims is expected to yield low- burden approaches to assessing outcomes that are important to patients and that are clinically relevant.