Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD

这项研究的总体目标是加快面肩肱型肌营养不良症的药物开发 （FSHD）。FSHD研究的最新突破已将主要疾病机制确定为 正常沉默基因DUX 4的异常表达，导致毒性功能获得。这种疾病 这种机制特别适合于使用表观遗传策略或RNA疗法敲低DUX 4， 以及其他针对DUX 4表达的下游效应的干预。有许多药物 公司积极致力于疾病靶向治疗，两项临床试验正在进行中， 计划于2016年秋季初开始。然而，与工业界、倡导团体和FSHD研究人员的会议 我已经确定了我们的临床试验武器库中的几个差距，临床试验规划是我们的主要目标。 社区因此，迫切需要建立必要的工具， 计划和预期的FSHD治疗试验。为此，我们建议开发两种新的临床 结果评估（COA），复合功能结果测量（FSH-COM）和骨骼肌 生物标志物，电阻抗肌描记术（EIM）。此外，各方还达成了广泛共识， 遗传和人口统计学特征与疾病进展的关系将是必要的， 列举资格标准。具体目标是：1.确定COA的多中心有效性，2。 将新COA的反应性与其他FSHD结局进行比较，并确定最小临床 有意义的变化，3。建立用于确定临床试验合格性FSHD队列特征 的搜索.为了实现这些目标，提出了一项150例受试者的多中心、前瞻性、18个月研究。 FSHD是成人肌营养不良症的第二种最常见形式，估计患病率为1：15，000， 并且目前没有有效的治疗方法。加快药物开发将对 美国约有21，000人受影响。除了手动肌肉测试和 定量肌测量，在FSHD的临床试验中没有一致使用的有效结局指标。 该提案将开发新的结局指标，用于早期研究（EIM）和晚期研究。 登记研究（FSH-COM），并将确定重要的进展的遗传或人口统计学预测因素 定义关键的资格标准。FDA对这两份COA的资格审查程序已经启动。 一个成熟的FSHD临床试验研究网络，由主要的FSHD倡导团体支持， 将利用经验丰富的临床医生和临床评价人员进行研究。数据和统计支助 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 将验证这两个COA用于未来的FSHD临床试验。此外，该研究将提供FSHD队列 这些特征对于建立未来临床试验的合格标准很有价值。从这个数据 研究将提供给任何研究者或公司寻求治疗FSHD患者。

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.