Accelerate Clinical Trials in CMT (ACTCMT) Study

加速 CMT (ACTCMT) 研究的临床试验

基本信息

批准号：
10576824
负责人：
DAVID N HERRMANN
金额：
$ 105.96万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576824
关键词：
21 year old Acceleration Address Adult Affect Ankle Antisense Oligonucleotide Therapy Biological Markers Burn injury Charcot-Marie-Tooth Disease Child Childhood Chromosomal Duplication Chromosome 17 Clinic Clinical Clinical Research Clinical Trials Clinical Trials Design Collaborations Critical Pathways Data Disease Disease Progression Drug Approval Eligibility Determination Equilibrium FDA approved Family Fatty acid glycerol esters Foot-drop Functional Magnetic Resonance Imaging Functional disorder Future Gait Gait abnormality Goals Grant Hand functions Human Impairment Individual Infrastructure Inherited Intramuscular Iowa Lead Leg London Lower Extremity Magnetic Resonance Imaging Measures Mediator Medical Research Meissners Corpuscle Methods Microscopy Modeling Motor Multicenter Trials Muscle Muscle Weakness Muscular Atrophy Natural History Neurologic Neuropathy Numbness Outcome Outcome Measure PMP22 gene Painless Pathogenesis Patient Outcomes Assessments Patients Peripheral Nerves Peripheral Nervous System Diseases Persons Phase Phenotype Physical Function Preparation Protocols documentation Quality Control Rare Diseases Reading Recording of previous events Research Research Personnel Resources Rodent Model Running Sensory Sensory Receptors Severities Severity of illness Site Skin Speed Therapeutic Effect Time Touch sensation Treatment Effectiveness Treatment Efficacy Upper Extremity Validation biomarker validation clinical outcome assessment clinical trial readiness cohort college density design dexterity disability early phase clinical trial early phase trial effective therapy equilibration disorder experience functional outcomes health related quality of life hereditary neuropathy in vivo innovation instrument magnetic resonance imaging biomarker meetings muscle strength non-invasive imaging overexpression progression marker receptor density research study validation studies

项目摘要

Charcot Marie Tooth disease (CMT) is a family of rare inherited peripheral neuropathies. CMT1A accounts for 50% of all CMT and is caused by a 1.4 mB duplication within chromosome 17 that results in the overexpression of peripheral myelin protein 22 kD (PMP22). CMT1A is characterized by progressive weakness, imbalance, sensory loss, and gait abnormalities. Multiple promising candidate therapies will be ready for human clinical trials within 3- 5 years, including antisense oligonucleotide therapy that decreases PMP22 expression and corrects the phenotype of rodent models. We in the Inherited Neuropathies Consortium Rare Disease Clinical Research Network (INC RDCRN) have defined the natural history of CMT1A, and developed clinical outcome assessments, patient reported outcomes, and a functional scale for children with CMT (CMTPedS), that shows responsiveness in CMT1A. For CMT1A trials, some critical gaps in outcome measures must be urgently filled, including a validated functional outcome measure for adults (the FDA guidance identifies function as a key clinical endpoint for drug approval), and validated, disease-progression biomarkers. This study, “Accelerate Clinical Trials in CMT (ACTCMT)”, addresses these key gaps by leveraging the expertise and multicenter infrastructure of the INC RDCRN to conduct a multicenter validation of a functional outcome (CMT-FOM), and motor and sensory biomarkers in adults with CMT1A. The aims of this U01 proposal include the following: (1) Validation of the CMT-FOM as a responsive outcome measure in adults with CMT1A. The CMT-FOM has high patient relevance, as it incorporates the patient perspective on which functional limitations are impactful. (2) Validation of a quantitative three-point Dixon MRI of intramuscular fat accumulation as a biomarker of disease progression in key leg muscles invoked in foot drop and disability for use in early phase CMT1A trials. (3) Validation of a non-invasive and painless way to determine the density of Meissner corpuscles (an important kind of sensory receptor) in the skin as a sensory biomarker for CMT1A trials. Dr. D. Herrmann (U. Rochester), will serve as overall PI. Dr. Herrmann developed CMT-FOM and will co-lead AIM 1 with Dr. M. Shy (INC Director; U. Iowa) and Dr. J. Burns (U. Sydney; who developed the CMTPedS). Dr. Herrmann pioneered the use of non-invasive imaging of Meissner corpuscles in peripheral neuropathy, and will also lead AIM 3. Dr. M. Reilly and Dr. J. Thornton (physicist), both from the Univ. College of London, will lead AIM 2; they pioneered the use of muscle MRI as a biomarker in CMT1A. Drs. S. Scherer (U. Penn) and D. Pareyson (C. Besta Neurological Inst., Milan) lead large CMT clinics and have considerable experience in evaluating CMT1A patients. This study brings together a leading group of CMT investigators who have a long history of successfully collaborating, and should yield a validated CMT-FOM and biomarkers that will have high impact because this will accelerate early and late phase clinical trials in CMT1A, for which no disease-modifying treatment is yet available.

夏科玛丽图斯病 (CMT) 是一种罕见的遗传性周围神经病，占所有 CMT 的 50%，由 17 号染色体内 1.4 mB 的重复引起，导致外周髓磷脂蛋白 22 kD (PMP22) 过度表达。 CMT1A 的特点是进行性无力、失衡、感觉丧失和步态异常，多种有前景的候选疗法将在 3-5 年内准备好进行人体临床试验。多年来，包括降低 PMP22 表达并纠正啮齿动物模型表型的反义寡核苷酸疗法，我们在遗传性神经病联盟罕见病临床研究网络 (INC RDCRN) 中定义了 CMT1A 的自然史，并开发了临床结果评估、患者报告的结果。以及 CMT 儿童功能量表 (CMTPedS)，该量表显示了 CMT1A 试验的反应性，必须紧急解决结果测量中的一些关键差距。填充，包括针对成人的经过验证的功能结果测量（FDA 指南将功能确定为药物批准的关键临床终点），以及经过验证的疾病进展生物标志物。这项研究“加速 CMT 临床试验（ACTCMT）”解决了这些问题。通过利用 INC RDCRN 的专业知识和多中心基础设施对患有 CMT1A 的成人的功能结果 (CMT-FOM) 以及运动和感觉生物标志物进行多中心验证，弥补了关键差距。提案包括以下内容：(1) 验证 CMT-FOM 作为 CMT1A 成人的反应性结果测量 CMT-FOM 具有较高的患者相关性，因为它纳入了对功能限制有影响的患者观点。肌内脂肪堆积的定量三点 Dixon MRI 作为足下垂和残疾引起的关键腿部肌肉疾病进展的生物标志物，用于早期 CMT1A 试验 (3) 非侵入性验证。 D. Herrmann 博士（U. Rochester）开发了一种无痛方法来确定皮肤中迈斯纳小体（一种重要的感觉受体）的密度，作为 CMT1A 试验的感觉生物标志物。 CMT-FOM 将与 M. Shy 博士（INC 主任；爱荷华州大学）和 J. Burns 博士（美国悉尼大学；CMTPedS 开发者）共同领导 AIM 1。 Herrmann 博士率先使用 Meissner 小体非侵入性成像治疗周围神经病，并且还将领导 AIM 3。来自伦敦大学学院的 M. Reilly 博士和 J. Thornton 博士（物理学家）将领导 AIM 3。领导 AIM 2；他们率先使用肌肉 MRI 作为 CMT1A 的生物标志物。 Inst., Milan) 领导大型 CMT 诊所，在评估 CMT1A 患者方面拥有丰富的经验。这项研究汇集了一个拥有长期成功合作历史的 CMT 研究人员领导小组，应该会产生经过验证的 CMT-FOM 和生物标志物。影响很大，因为这将加速 CMT1A 的早期和晚期临床试验，目前尚无疾病缓解治疗方法。