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

ALS 临床研究

• 批准号: 10020812
• 负责人: Michael Benatar
• 金额: $ 63.38万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020812
• 关键词: Address; Age; Amyotrophic Lateral Sclerosis; Antisense Oligonucleotides; Behavioral; Biological; Biology; C9ORF72; Caregivers; Cellular Phone; Characteristics; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cognitive; Collection; DNA Sequence Alteration; Data; Development; Devices; Diagnostic; Disease; Disease Progression; Education; Electronic Health Record; Enrollment; Etiology; Forced expiratory volume function; Functional disorder; Funding; Future; Gender; Genetic; Goals; Health; Heterogeneity; Home environment; International; Investigational Therapies; Measures; Methods; Motor; Mutation; Natural History; Noise; Nose; Outcome; Outcome Measure; Patient Care; Patient Outcomes Assessments; Patient Participation; Patient Participation Rates; Patient Self-Report; Patients; Pennsylvania; Performance; Persons; Phenotype; Population; Predictive Factor; Primary Lateral Sclerosis; Progressive Disease; Protocols documentation; Research; Signal Transduction; Signs and Symptoms; Spastic Paraplegia; Spirometry; Structure; Subgroup; Technology; Testing; Therapeutic; Time; Travel; Universities; Variant; Viral Vector; Visit; Vital capacity; arimoclomol; base; clinical research site; clinically relevant; cohort; design; disease heterogeneity; gene therapy; indexing; innovation; longitudinal course; multidisciplinary; outcome forecast; patient subsets; phase II trial; phase III trial; phenotypic data; pressure; rate of change; study population; success; superoxide dismutase 1; therapeutic development; therapy development

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.

项目总结/摘要 CReATe联盟的项目#1旨在解决治疗开发的两个具体挑战， ALS和相关疾病。第一个挑战是ALS的病因学和表型异质性， 相关疾病。不同病因的含义是，治疗方法，特别是那些 靶向上游生物学机制，需要靶向具有共同病因的患者亚群和/或 生物学表型的异质性（例如疾病进展率或生存率）使识别 在自然变化的“噪音”中的治疗“信号”。随着临床试验的即将到来， 针对特定的患者亚群（例如SOD 1和C9 ORF 72 ALS和SPAST HSP），迫切需要 定量定义ALS和相关疾病的最常见遗传形式的自然史。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 结局指标（例如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，这些功能指标的最小临床重要变化。的 然而，表型的异质性超出了运动域，越来越多的人认识到， 认知和行为功能障碍是这类疾病的常见表现。因此，我们将， 还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ALS筛查（ECAS）和CReATe认知行为成套测验 （C2 B2）和年龄和教育调整的规范性数据，我们将开发。第二个挑战是 解决的问题是患者参与研究的总体比例较低。具体而言，我们将（a）推广使用ALS Epic电子健康记录中的工具包，可在多个研究过程中更好地捕获研究质量数据， 学科病人护理;（B）扩大倡议，授权使用移动的 基于智能手机的技术和家用肺活量测定设备;以及（c）探索ALS特异性 患者报告结局（PRO），旨在获取患者及其 照顾者知道什么对他们最重要。成功完成这些目标，预计将产生低- 负担方法，以评估对患者重要且具有临床相关性的结局。