Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD

为解决 FSHD 药物开发障碍做好临床试验准备

• 批准号: 10204130
• 负责人: Jeffrey Statland
• 金额: $ 40.56万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204130
• 关键词: Address; Adult; Advocacy; Affect; Age; Antisense Oligonucleotides; Antisense RNA; Biological Markers; Characteristics; Clinical; Clinical Trials; Communities; Consensus; Cross-Sectional Studies; D4Z4; Data; Disease; Disease Progression; Drug Design; Drug Industry; Duchenne muscular dystrophy; Educational workshop; Eligibility Determination; Epigenetic Process; Facioscapulohumeral Muscular Dystrophy; Fibrosis; Future; Gender; Gene Silencing; Genetic; Goals; Human; Human Resources; Individual; Industry; Inflammation; Infrastructure; International; Intervention; Light; Longitudinal Studies; Manuals; Measures; Methodology; Molecular; Motor; Muscle; Muscular Atrophy; Muscular Dystrophies; Myography; Myotonic Dystrophy; Neuromuscular Diseases; Outcome; Outcome Measure; Participant; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Prevalence; Privatization; Process; Prospective Studies; RNA; Reporting; Research; Research Personnel; Residual state; Sample Size; Severity of illness; Site; Skeletal Muscle; Societies; Spinal Muscular Atrophy; Statistical Methods; Subgroup; Techniques; Testing; Therapeutic Trials; Time; Training; United States; Validity and Reliability; Work; burden of illness; clinical outcome assessment; clinical trial readiness; cohort; design; disability; drug development; early detection biomarkers; early phase clinical trial; effective therapy; electric impedance; experience; falls; first-in-human; functional outcomes; functional status; gain of function; inclusion criteria; knock-down; meetings; novel; pre-clinical; programs; prospective; regression trees; targeted treatment; tool

The overall aim of this study is to hasten drug development for facioscapulohumeral muscular dystrophy (FSHD). Recent breakthroughs in FSHD research have identified the primary disease mechanism as the aberrant expression of a normally silenced gene, DUX4, resulting in a toxic gain-of-function. This disease mechanism is particularly amenable to knock-down of DUX4 using epigenetic strategies or RNA therapies, as well as to other interventions targeting the downstream effects of DUX4 expression. There are many drug companies actively working towards disease-targeted therapies, and two clinical trials either under way now, or planned to start in early Fall 2016. However, meetings with industry, advocacy groups, and FSHD researchers have identified several gaps in our clinical trial arsenal, and clinical trial planning as a major goal for the community. Consequently, there is an urgent need to establish the tools necessary for the conduct of currently planned and expected therapeutic trials in FSHD. To this end we propose to develop two novel clinical outcome assessments (COA), a composite functional outcome measure (FSH-COM) and skeletal muscle biomarker, electrical impedance myography (EIM). In addition there is broad consensus a better understanding of the relationship of genetic and demographic features to disease progression will be necessary for enumerating eligibility criteria. The specific aims are to: 1. Determine the multi-site validity of the COAs, 2. Compare the responsiveness of new COAs to other FSHD outcomes and determine the minimal clinically meaningful changes, and 3. establish FSHD cohort characteristics useful for determining clinical trial eligibility criteria. To achieve these aims, a multicenter, prospective, 18 months study of 150 subjects is proposed. FSHD is the second most common form of adult muscular dystrophy with an estimated prevalence of 1:15,000, and there are currently no effective treatments. Hastening drug development will have significant impact on approximately 21,000 affected individuals in the United States. Other than manual muscle testing and quantitative myometry, there are no validated outcome measures used consistently in clinical trials in FSHD. This proposal will develop novel outcome measures for use in both early phase studies (EIM) and in late phase registration studies (FSH-COM), and will determine genetic or demographic predictors of progression important for defining key eligibility criteria. The process of FDA qualification for both COAs has already been initiated. An established FSHD clinical trial research network, supported by the major FSHD advocacy group, with experienced clinicians and clinical evaluators will be utilized to conduct the study. Data and statistical support will leverage existing clinical trial infrastructure through the Muscle Study Group. It is expected that the study will validate both COAs for use in future FSHD clinical trials. Moreover, the study will provide FSHD cohort characteristics that will be valuable for establishing eligibility criteria for future clinical trials. The data from this study will be made available for any investigator or company pursuing treatments for patients with FSHD.

这项研究的总体目标是加速面肩肩部肌营养不良症的药物开发。 (FSHD)。最近在FSHD研究方面的突破确定了FSHD的主要发病机制为 正常沉默的基因DUX4的异常表达，导致有毒的功能获得。这种病 机制特别适合于使用表观遗传策略或RNA疗法击倒DUX4，如 以及针对DUX4表达的下游效应的其他干预。有很多种药 积极致力于疾病靶向治疗的公司，以及正在进行的两项临床试验，或者 计划于2016年初秋开工。然而，与行业、倡导团体和FSHD研究人员的会议 已经确定了我们的临床试验武器库中的几个缺口，并将临床试验规划作为 社区。因此，迫切需要建立必要的工具来开展目前的工作 FSHD中计划和预期的治疗试验。为此，我们建议开发两种新的临床 结果评估(COA)、综合功能结果测量(FSH-COM)和骨骼肌 生物标记物，电阻抗肌图(EIM)。此外，还有广泛的共识和更好的理解 基因和人口特征与疾病进展的关系将是必要的 列举资格标准。具体目的是：1.确定COA的多站点效度；2.确定COA的多站点有效性。 比较新COA与其他FSHD结果的反应性，并确定临床上最低限度的 有意义的改变，以及3.建立有助于确定临床试验资格的FSHD队列特征 标准。为了实现这些目标，提出了一项多中心、前瞻性、为期18个月的研究，涉及150名受试者。 FSHD是第二种最常见的成人肌营养不良症，估计患病率为1：15,000， 目前还没有有效的治疗方法。加快药物开发将对 在美国大约有21,000名受影响的人。除了手动肌肉测试和 定量肌力测量，在FSHD的临床试验中没有一致使用的有效结果测量方法。 这一建议将开发新的成果衡量标准，用于早期研究(EIM)和后期研究 登记研究(FSH-COM)，并将确定遗传或人口统计学预测进展的重要因素 用于定义关键资格标准。FDA对这两种COA的资格认证程序已经启动。 在主要FSHD倡导团体的支持下，建立了FSHD临床试验研究网络， 经验丰富的临床医生和临床评估师将被用于进行这项研究。数据和统计支持 将通过肌肉研究小组利用现有的临床试验基础设施。预计这项研究 将在未来的FSHD临床试验中验证这两种COA的使用情况。此外，这项研究将提供FSHD队列 这些特征将对建立未来临床试验的资格标准很有价值。来自这里的数据 这项研究将向任何寻求治疗FSHD患者的研究人员或公司提供。