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: 9335097
• 负责人: Jeffrey Statland
• 金额: $ 51.21万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335097
• 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; Genes; Genetic; Goals; Human; Human Resources; Individual; Industry; Inflammation; International; Intervention; Light; Longitudinal Studies; Manuals; Measures; Methodology; Molecular; Motor; Muscle; Muscular Atrophy; Muscular Dystrophies; Myography; Myotonic Dystrophy; Neuromuscular Diseases; Outcome; Outcome Assessment; Outcome Measure; Participant; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Prevalence; Privatization; Process; Prospective Studies; RNA; Readiness; Reporting; Research; Research Infrastructure; 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; Trees; United States; Validity and Reliability; Work; burden of illness; cohort; design; disability; drug development; effective therapy; electric impedance; experience; falls; functional outcomes; functional status; gain of function; inclusion criteria; knock-down; meetings; novel; pre-clinical; programs; prospective; 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.

本研究的总体目的是促进面部肩胛肱肌营养不良的药物开发