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.

这项研究计划的目的是开发安全有效的遗传性神经疾病治疗方法。过去一年中的具体研究成果包括：(1)继续进行运动治疗脊髓和延髓性肌萎缩症(SBMA)的随机对照试验；(2)继续进行骨骼和心脏成像评估的方案，并进行Duchenne肌营养不良症(DMD)的寡核苷酸治疗试验。 SBMA是一种X连锁的成人起病运动神经元病。我们即将完成一项研究，以检验运动对SBMA患者的安全性和有效性。我们的目标是招募80名患有基因确认的SBMA的男性。这是一项随机、评估者盲法试验，每组有25名受试者参加。在知情同意后，受试者接受初步的医疗和身体评估，然后在NIH为期两天的门诊就诊期间进行一系列神经学测试和血液检查。受试者提供血液工作，以分析荷尔蒙水平和评估任何潜在的肌肉损伤。在访问的第二天，受试者被随机分组，并分别作为研究和对照组的一部分，教授一系列功能性或伸展练习。在对NIH进行基线访问后，在整个研究过程中通过电话联系和包括视频记录在内的其他措施对受试者进行监测，以监测他们的进展和遵守情况。受试者在12周结束时返回NIH，在此期间重复进行身体和实验室测试。使用的主要结果测量工具是成人肌病评估工具。次要结果测量是QMA、计时起跑测试、生活质量测量(SF-36v2)、不良事件问卷、计算机化的平衡动态姿势图评估、运动努力的加速计测量和渐进式身高坐立测试。一些可能受运动影响的探索性生物标志物正在评估中，包括胰岛素样生长因子-1(IGF-1)、IGF结合蛋白3、睾酮、生长激素和肌酸激酶。贝克抑郁问卷测试也被用来确定受试者的情绪是否受到锻炼的影响。 DMD是最常见的遗传性致命儿童疾病。反义寡核苷酸诱导的外显子跳跃是治疗DMD的一种有前景的治疗策略，目前正在进行临床试验。磁共振成像(MRI)和超声成像方法对营养不良肌肉的关键过程，如水肿和脂肪渗透非常敏感，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在评估寡核苷酸GSK2402968对患有DMD的儿童的影响方面的潜力。主要目的是评估接受GSK2402968或安慰剂治疗的DMD儿童的骨骼肌结构MRI测量的纵向变化，这些测量反映了腿部脂肪和浮肿。我们已经登记了9名患有DMD的门诊男孩。他们招募了20名与年龄范围匹配的健康志愿者/对照组男孩，以获得成像研究的比较数据。这项在美国国立卫生研究院进行的关于骨骼肌、心脏和横隔膜成像的前瞻性研究提供给参加2期、双盲、探索性平行组、安慰剂对照临床研究的受试者，受试者患有由GSK2402968诱导的51号外显子跳跃导致的DMD突变。在母研究的筛查阶段，受试者与一名家庭成员一起前往NIH进行核磁共振和超声评估，此外，如果随机，则在母研究的以下时间点进行评估：12周，在盲法治疗期间的24周；最后，在完成24周的治疗后阶段(48周)。如果没有随机，受试者在父母研究的筛选阶段进行一次性评估。还从健康男孩那里获得了数据进行比较，以便探索患有DMD的非卧床男孩的MRI和超声检查的具体病理指标。这项研究的主要结果是在接受GSK2402968或安慰剂治疗的DMD男孩中，MRI检测到的腿部骨骼肌脂肪与基线相比的变化。次级结果测量包括在接受GSK2402968或安慰剂治疗的DMD男孩在12、24和48周时下列结果测量的变化：通过骨骼肌MRI T1成像评估相对肌肉脂肪/水，通过T2成像评估肌肉浮肿，以及通过心脏MRI测量心功能和心肌脂肪和浮肿。探索性结果测量包括通过扩散磁共振评估的肌肉水分扩散率的变化；运动对选定的腿部肌肉MRI测量的影响；监测骨骼肌体积、回声和僵硬变化的肌肉超声；以及对横隔膜运动的MRI评估。