Digital Measures of Physical Activity, Gait and Balance in CMT (Project 3)

摘要：腓骨肌萎缩症（CMT）是一个遗传性周围神经病家族。CMT是 其特征在于进行性虚弱、不平衡、感觉丧失和步态异常。多重有希望 候选疗法将在5年内准备好进行人体临床试验。我们在遗传性神经病 罕见病临床研究网络联盟（INC RDCRN）定义了CMT1A的自然史 这项研究在其他CMT亚型中继续进行。INC RDCRN还领导了多个， CMT儿童和成人的临床结局评估和患者报告结局指标。 CMT患者认为步态和平衡障碍严重影响他们的生活质量，因此 积极影响这些功能的治疗干预可能是有意义的。为筹备 在CMT的临床试验中，必须紧急填补试验准备方面的一些关键空白，包括准确了解 不同类型CMT患者的真实的体力活动以及疾病进展对 体力活动。早期试验也需要步态和平衡功能障碍的敏感生物标志物， 检测疗效信号。INC网站使用3D运动分析实验室进行的研究表明， 包括步态速度和步幅长度的步态参数对CMT患者的变化高度敏感。 然而，3D运动分析实验室对于多中心试验是不可行的。可穿戴技术包括 活动监测器和惯性传感器易于应用，适用于测量身体活动、步态和平衡 在涉及儿童和成人的多中心研究中。临床研究项目3，“可穿戴传感器测量 CMT中的体力活动、步态和平衡”，解决了临床试验准备的这些差距。这样做的目的是 项目包括：（1）通过测量CMT患者的习惯性身体活动来表征CMT中的真实的世界功能。 儿童和成人最常见的基因亚型。(2)验证步态的“数字生物标志物”， 通过评估可穿戴传感器的可靠性和对变化的响应性来平衡CMT中的缺陷。博士 J. Burns（U.悉尼）和K博士。Eichinger（U.罗切斯特）将共同领导这项研究。伯恩斯医生，帕雷森医生，和维医生 Ounpuu在CMT的定量步态分析方面有丰富的经验。艾兴格博士，T。Estilow博士 Ramdharry在评估CMT中的身体活动，流动性和平衡方面具有专业知识。Shy博士（INC RDCRN） PI，U。爱荷华州），赖利（网站PI，美国。伦敦学院）、谢勒（研究中心PI，U.宾夕法尼亚州）、百胜（儿童医院 的费城）、Ascadi（康涅狄格州儿童医院）和Herrmann（临床团队Liason，研究中心PI，U. 罗切斯特）在CMT的临床方面和结局指标开发方面具有丰富的经验。本研究 汇集了一个领导小组的CMT调查谁有长期的合作历史，并应产生 将对CMT中进行早期和晚期临床试验产生重大影响的结局指标， 目前还没有改善疾病的治疗方法。

SUMMARY: Charcot-Marie-Tooth disease (CMT) is a family of inherited peripheral neuropathies. CMT is characterized by progressive weakness, imbalance, sensory loss, and gait abnormalities. Multiple promising candidate therapies will be ready for human clinical trials within 5 years. We in the Inherited Neuropathies Consortium Rare Disease Clinical Research Network (INC RDCRN) have defined the natural history of CMT1A and this research continues in other CMT subtypes. The INC RDCRN has also led development of multiple, clinical outcome assessments and patient-reported outcome measures for children and adults with CMT. Individuals with CMT identify impairments in gait and balance as highly impacting their quality of life and therefore therapeutic interventions that positively impact these functions are likely to be meaningful. In preparation for clinical trials in CMT, some critical gaps in trial readiness must be urgently filled including precise knowledge of real world physical activity in individuals with different types of CMT and the effect of disease progression on physical activity. Sensitive biomarkers of gait and balance dysfunction are also needed for early phase trials to detect signals of therapeutic effect. Research at INC sites using 3D motion analysis laboratories suggests that gait parameters, including gait speed and stride length, are highly responsive to change in individuals with CMT. 3D motion analysis laboratories are however not viable for multicenter trials. Wearable technology including activity monitors and inertial sensors is easily applied and suitable to measure physical activity, gait and balance in multicenter studies involving children and adults. Clinical Research Project 3, “Wearable Sensor Measures for Physical Activity, Gait and Balance in CMT”, addresses these gaps of clinical trial readiness. The aims of this project include: (1) Characterization of real world function in CMT by measuring habitual physical activity of children and adults with the most common genetic subtypes. (2) Validation of “digital biomarkers” of gait and balance deficits in CMT by assessment of the reliability and responsiveness to change of wearable sensors. Dr. J. Burns (U. Sydney) and Dr. K. Eichinger (U. Rochester) will co-lead this study. Drs. Burns, Pareyson, and V. Ounpuu have extensive experience in quantitative gait analysis in CMT. Dr. Eichinger, T. Estilow and Dr. Ramdharry have expertise in assessing physical activity, mobility and balance in CMT. Drs. Shy (INC RDCRN PI, U. Iowa), Reilly (site PI, U. College of London), Scherer (site PI, U. Pennsylvania), Yum (Children’s Hospital of Philadelphia), Ascadi (Connecticut Children’s Hospital) and Herrmann (Clinical Team Liason, site PI, U. Rochester) have vast experience in clinical aspects and outcome measure development in CMT. This study brings together a leading group of CMT investigators who have a long history of collaboration, and should yield outcome measures that will have a high impact on conducting early and late phase clinical trials in CMT for which no disease-modifying therapy is yet available.