Studies Of Hereditary Neurological Disease: Clinical Trials

遗传性神经系统疾病的研究：临床试验

• 批准号: 8746816
• 负责人: Kenneth Fischbeck
• 金额: $ 92.23万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8746816
• 关键词: Adult; Adverse event; Affect; Age; Antisense Oligonucleotides; Beck depression inventory; Biological Markers; Blinded; Blood; Blood Tests; Cardiac; Childhood; Clinical Research; Clinical Trials; Controlled Study; Creatine Kinase; Data; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Double-Blind Method; Duchenne muscular dystrophy; Dutasteride; Edema; Educational process of instructing; Enrollment; Equilibrium; Evaluation; Exercise; Exons; Family member; Fatty acid glycerol esters; Friedreich Ataxia; Goals; Height; Hormonal; Image; Infiltration; Informed Consent; Inherited; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Laboratories; Leg; Link; Lower Extremity; Magnetic Resonance Imaging; Measurement; Measures; Medical; Monitor; Moods; Motion; Motor Neuron Disease; Muscle; Mutation; Myocardial; Myocardium; Myopathy; Neurologic; Oligonucleotides; Outcome Measure; Outpatients; Parents; Pathology; Patients; Phase; Placebo Control; Placebos; Process; Prospective Studies; Protocols documentation; Quality of life; Questionnaires; Randomized; Randomized Controlled Trials; Recruitment Activity; Relative (related person); Research; Respiratory Diaphragm; Safety; Series; Skeletal Muscle; Somatotropin; Stretching; Telephone; Testing; Testosterone; Therapeutic; Time; Travel; Ultrasonography; United States National Institutes of Health; Video Recording; Visit; Water; Work; arm; boys; comparative; computerized; effective therapy; exon skipping; healthy volunteer; idebenone; imaging modality; men; nervous system disorder; primary outcome; programs; response; safety testing; screening; secondary outcome; skeletal; spinal and bulbar muscular atrophy; tool; treatment duration

The purpose of this research program is to develop safe and effective treatments for hereditary neurological disorders. Specific research accomplishments in the past year include the following: (1) continuation of a randomized, controlled trial of exercise in spinal and bulbar muscular atrophy (SBMA), (2) continuation of a protocol for evaluation of skeletal and cardiac imaging with a trial of oligonucleotide therapy in Duchenne muscular dystrophy (DMD). SBMA is an X-linked, adult onset motor neuron disease. We are nearing completion of a study to examine the safety and efficacy of exercise in SBMA patients. We aim to enroll 80 men with genetically confirmed SBMA. This is a randomized, evaluator blinded, trial with 25 subjects in each exercise arm. Following informed consent, the subjects undergo initial medical and physical evaluations followed by a series of neurological tests and blood work over a two-day outpatient visit at the NIH. The subjects provide blood work for analysis of hormonal levels and assessment of any potential muscle damage. On the second day of their visit, the subjects are randomized and taught a series of either functional or stretching exercises that they engage in as part of the study and control arms, respectively. Following the baseline visit to NIH, the subjects are monitored throughout the study with telephone contacts and other measures including video recording to monitor their progress and compliance. The subjects return to the NIH at the end of a 12 week period at which time the physical and laboratory testing is repeated. The primary outcome measure used is the Adult Myopathy Assessment Tool . Secondary outcome measures are QMA, the Timed Up and Go test, a quality of life measure (SF-36v2), adverse event questionnaires, a Computerized Dynamic Posturography assessment of balance, accelerometer measurements of exercise effort, and progressive height sit-to-stand testing. Several exploratory biomarkers that may be affected by exercise are being evaluated, including insulin-like growth factor-1 (IGF-1), IGF binding protein 3, testosterone, growth hormone, and creatine kinase. Beck Depression Inventory testing is also being used to determine if the subjects mood is affected by exercise. DMD is the most frequent inherited fatal childhood disease. Antisense oligonucleotide-induced exon skipping is a promising therapeutic strategy for DMD that is currently being explored in clinical trials. Magnetic resonance imaging (MRI) and ultrasound imaging methods are sensitive to key processes in dystrophic muscle such as edema and fat infiltration and therefore could serve as a biomarker of disease progression and therapeutic response. We are completing a study protocol to explore the potential of these imaging biomarkers for assessing the effects of the oligonucleotide GSK2402968 in ambulatory boys with DMD. The primary objective is to assess longitudinal changes in skeletal muscle structural MRI measures reflecting fat and edema in the lower extremities in ambulatory boys with DMD receiving GSK2402968 or placebo. We have enrolled 9 ambulatory boys with DMD. 20 healthy volunteer/control boys matched for the age-range have been recruited to obtain comparative data for the imaging studies. This prospective study of skeletal muscle, cardiac, and diaphragm imaging at the NIH was offered to subjects participating in a phase 2, double blind, exploratory parallel-group, placebo-controlled clinical study in ambulatory subjects with DMD resulting from a mutation that can be corrected by exon 51 skipping induced by GSK2402968. Subjects traveled with a family member to the NIH for MRI and ultrasound assessments during the screening phase of the parent study and additionally, if randomized, then at the following time points in the parent study: at 12 weeks, and 24 weeks during the blinded treatment period; and finally, after completion of 24 weekpost-treatment phase (at 48 weeks). If not randomized, the subjects had a one-time evaluation during the screening phase of the parent study. Data has also been obtained from healthy boys for comparisons to allow exploration of MRI and ultrasound measures specific to pathology in the ambulatory boys with DMD. The primary outcome measure for the study is MRI-detected change in skeletal muscle fat in the lower extremities from baseline in boys with DMD receiving GSK2402968 or placebo. Secondary outcome measures include changes in the following outcome measures at 12, 24, and 48 weeks from baseline in boys with DMD receiving GSK2402968 or placebo: relative muscle fat/water assessed by skeletal muscle MRI T1 imaging, muscle edema assessed by T2 imaging, and cardiac function and myocardial fat and edema as measured by cardiac MRI. Exploratory outcome measures include changes in muscle water diffusivity as assessed by diffusion MRI; the effects of exercise on selected MRI measures in leg muscles, muscle ultrasound to monitor changes in skeletal muscle volume, echogenicity, and stiffness; and MRI assessment of diaphragm motion.

该研究计划的目的是为遗传神经系统疾病开发安全有效的治疗方法。过去一年中的具体研究成就包括：（1）继续进行脊柱和鳞茎肌肉萎缩（SBMA）运动的随机对照试验，（SBMA），（2）继续评估骨骼和心脏成像的方案，并通过对Duchenne Muscular Muscular Muscular Mescular Dymtrophy（DMD）的寡核苷酸疗法进行评估。 SBMA是一种X连锁的成人发作运动神经元疾病。我们正在完成一项研究，以检查SBMA患者运动的安全性和功效。我们的目标是注册80名具有遗传确认的SBMA的男性。这是一个随机，评估者盲目的试验，每个运动臂中有25名受试者。知情同意后，受试者接受了初步的医学和身体评估，然后在NIH进行两天的门诊访问中进行了一系列神经系统检查和血液检查。受试者提供血液工作，以分析激素水平和评估任何潜在的肌肉损害。在访问的第二天，受试者是随机的，并分别在研究和控制臂中进行了一系列功能或伸展运动。在对NIH的基线访问之后，在整个研究中，通过电话联系和其他措施（包括视频记录）监视了受试者，以监控其进度和合规性。受试者在12周结束时返回NIH，然后重复进行物理和实验室测试。使用的主要结果指标是成人肌病评估工具。次要结果度量是QMA，定时和进行测试，生活质量度量（SF-36V2），不良事件问卷，计算机化的动态式姿势评估平衡评估，锻炼努力的加速度计测量以及逐步的高度现场站立测试。正在评估可能受运动影响的几种探索性生物标志物，包括胰岛素样生长因子1（IGF-1），IGF结合蛋白3，睾丸激素，生长激素和肌酸激酶。贝克抑郁量库存测试还用于确定受试者的情绪是否受运动影响。 DMD是最常见的致命儿童疾病。反义寡核苷酸引起的外显子跳过是DMD的有前途的治疗策略，目前正在临床试验中探索。磁共振成像（MRI）和超声成像方法对营养不良肌肉（例如水肿和脂肪浸润）的关键过程敏感，因此可以作为疾病进展和治疗反应的生物标志物。我们正在完成一项研究方案，以探索这些成像生物标志物评估寡核苷酸GSK2402968对DMD的非卧床男孩的影响。主要目的是评估反映DMD接受GSK2402968或安慰剂的骨骼肌结构MRI测量的纵向变化。我们已经招募了9个具有DMD的门诊男孩。已招募了20名健康志愿者/对照男孩的年龄段男孩，以获取成像研究的比较数据。 NIH的骨骼肌，心脏和隔膜成像的前瞻性研究是为参与2阶段的2阶段的受试者提供的。受试者与家人一起前往NIH进行MRI和在父母研究的筛查阶段进行MRI和超声评估，此外，如果随机分组，则在父母研究的以下时间点：在盲人治疗期间的12周和24周；最后，在完成24周柱处理阶段（在48周内）之后。如果不是随机的，则受试者在父母研究的筛查阶段进行一次性评估。还从健康的男孩那里获得了数据，以进行比较，以探索MRI和DMD卧床男孩中特定于病理学的超声措施。该研究的主要结局指标是下肢骨骼肌脂肪的MRI检测变化与DMD接受GSK2402968或安慰剂的男孩的基线变化。次要结局措施包括从基线的12、24和48周的下列结果度量的变化，DMD接受GSK2402968或安慰剂：通过骨架肌肉MRI T1成像评估的相对肌肉脂肪/水，由T2成像和心脏功能和心肌效果评估的肌肉进行肌肉进行，并通过T2成像和心脏质量衡量。探索性结果指标包括通过扩散MRI评估的肌肉水扩散率的变化；运动对腿部肌肉中选定的MRI测量的影响，肌肉超声检查以监测骨骼肌体积的变化，回声和僵硬；和MRI评估膜片运动。