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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.

沙氏玛丽牙病（CMT）是一种罕见的遗传性周围神经病变家族。CMT1A占所有CMT的50%，由17号染色体内1.4 mB的重复引起，导致外周髓鞘蛋白22 kD （PMP22）过表达。CMT1A的特征是进行性无力、失衡、感觉丧失和步态异常。多种有希望的候选疗法将在3- 5年内准备好进行人体临床试验，包括反义寡核苷酸疗法，可以降低PMP22的表达并纠正啮齿动物模型的表型。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CMT儿童（CMTPedS）的临床结果评估、患者报告的结果和功能量表，显示了CMT1A的反应性。对于CMT1A试验，一些关键的缺口必须尽快填补，包括验证的成人功能结果测量（FDA指南将功能确定为药物批准的关键临床终点），以及验证的疾病进展生物标志物。这项名为“加速CMT临床试验（ACTCMT）”的研究，通过利用INC RDCRN的专业知识和多中心基础设施，对成人CMT1A患者的功能结果（CMT- fom）以及运动和感觉生物标志物进行多中心验证，解决了这些关键空白。本U01提案的目的包括：(1)验证CMT-FOM作为成人CMT1A患者的反应性结果测量。CMT-FOM具有很高的患者相关性，因为它结合了患者对哪些功能限制会产生影响的观点。(2)验证定量三点Dixon MRI肌内脂肪积累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)验证一种无创无痛的方法来测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。Dr. D. Herrmann （U. Rochester）将担任总PI。Herrmann博士开发了CMT-FOM，并将与M. Shy博士（INC董事；U. Iowa）和J. Burns博士（U. Sydney；开发了CMTPedS）共同领导AIM 1。Herrmann博士率先在周围神经病变中使用迈斯纳小体的非侵入性成像，并将领导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 2；他们率先使用肌肉MRI作为CMT1A的生物标志物。Drs。S. Scherer（宾夕法尼亚大学）和D. Pareyson（米兰C. Besta神经学研究所）领导大型CMT诊所，在评估CMT1A患者方面拥有丰富的经验。这项研究汇集了一组具有长期成功合作历史的CMT研究人员，并且应该产生一个经过验证的CMT- fom和生物标志物，这将具有很高的影响，因为这将加速CMT1A的早期和晚期临床试验，目前还没有疾病改善治疗方法。