Accelerate Clinical Trials in CMT (ACTCMT) Study

加速 CMT (ACTCMT) 研究的临床试验

• 批准号: 10348706
• 负责人: DAVID N HERRMANN
• 金额: $ 125.86万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348706
• 关键词: 21 year old; Address; Adult; Affect; Ankle; Antisense Oligonucleotide Therapy; Biological Markers; Burn injury; Charcot-Marie-Tooth Disease; Child; Childhood; Chromosome 17; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; 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 of activation protein; 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; cohort; college; density; design; dexterity; disability; early phase clinical trial; early phase trial; effective therapy; effectiveness outcome; 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

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.

Charcot Marie牙齿疾病（CMT）是一个罕见遗传性周围神经病的家族。 CMT1A占所有CMT的50％，是由17号染色​​体内1.4 MB复制引起的，导致外周髓髓蛋白蛋白22 kD的过表达（PMP22）。 CMT1A的特征是进行性弱点，失衡，感觉丧失和步态异常。多种承诺候选疗法将在3至5年内为人类临床试验做好准备，包括降低PMP22表达并纠正啮齿动物模型的表型的反义寡核苷酸疗法。我们在遗传的神经病联盟中，稀有疾病临床研究网络（INC RDCRN）定义了CMT1A的自然史，并进行了临床结局评估，患者报告的结果以及CMT儿童（CMTPEDS）的功能量表，显示CMT1A中的反应性。对于CMT1A试验，必须紧急填补结局指标中的一些关键差距，包括对成年人进行验证的功能结果指标（FDA指导鉴定为药物批准的关键临床终点）以及经过验证的，疾病产生的生物标志物。这项研究“加速了CMT（ACTCMT）的临床试验”，通过利用INC RDCRN的专业知识和多中心基础结构来解决这些关键差距，以对CMT1A的成人进行功能结果（CMT-FOM）的多中心验证（CMT-FOM）以及运动和感觉生物标志物。该U01提案的目的包括以下内容：（1）验证CMT-FOM作为CMT1A成人成人的响应结果指标。 CMT-FOM具有很高的患者相关性，因为它包含了患者的观点，其功能限制具有影响。 （2）验证肌内脂肪积累的定量三分dixon MRI，作为在早期CMT1A试验中使用的脚落下和残疾的关键腿部肌肉中疾病进展的生物标志物。 （3）确定皮肤中Meissner小体（一种重要的感觉受体）密度的非侵入性和痛苦方法的验证，作为CMT1A试验的感觉生物标志物。 D. Herrmann博士（U. Rochester）将担任总体PI。 Herrmann博士开发了CMT-FOM，并将与M. Shy（Inc董事；爱荷华州）和J. Burns博士（U. Sydney; Sepente the CMTPeds）共同领导AIM 1。 Herrmann博士率先在周围神经病中使用了Meissner Corduscles的非侵入性成像，并将领导AIM3。M.Reilly博士和J. Thornton博士（物理学家），都来自大学。伦敦学院将领导AIM 2；他们率先将肌肉MRI用作CMT1A的生物标志物。博士。 S. Scherer（U. Penn）和D. Pareyson（C. Besta神经学研究所，米兰）领导大型CMT诊所，并在评估CMT1A患者方面具有丰富的经验。这项研究汇集了一群领先的CMT研究人员，他们的合作历史悠久，并且应该产生经过验证的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仍无法使用疾病改良治疗。