Eichinger Katy, Sowden Janet E, Burns Joshua, McDermott Michael P, Krischer Jeffrey, Thornton John, Pareyson Davide, Scherer Steven S, Shy Michael E, Reilly Mary M, Herrmann David N
Department of Neurology, University of Rochester, Rochester, NY, United States.
Faculty of Medicine and Health and Children's Hospital at Westmead, The University of Sydney School of Health Sciences, Sydney, NSW, Australia.
Front Neurol. 2022 Jun 27;13:930435. doi: 10.3389/fneur.2022.930435. eCollection 2022.
With therapeutic trials on the horizon for Charcot-Marie-Tooth type 1A (CMT1A), reliable, valid, and responsive clinical outcome assessments and biomarkers are essential. Accelerate Clinical Trials in CMT (ACT-CMT) is an international study designed to address important gaps in CMT1A clinical trial readiness including the lack of a validated, responsive functional outcome measure for adults, and a lack of validated biomarkers for multicenter application in clinical trials in CMT1A. The primary aims of ACT-CMT include validation of the Charcot-Marie-Tooth Functional Outcome Measure, magnetic resonance imaging of intramuscular fat accumulation as a lower limb motor biomarker, and reflectance confocal microscopy of Meissner corpuscle sensory receptor density, a sensory biomarker. Initial studies have indicated that these measures are feasible, reliable and valid. A large prospective, multi-site study is necessary to fully validate and examine the responsiveness of these outcome measures in relation to existing outcomes for use in future clinical trials involving individuals with CMT1A. Two hundred 15 adults with CMT1A are being recruited to participate in this prospective, international, multi-center study. Serial assessments, up to 3 years, are performed and include the CMT-FOM, CMT Exam Score-Rasch, Overall Neuropathy Limitations Scale, CMT-Health Index, as well as nerve conduction studies, and magnetic resonance imaging and Meissner corpuscle biomarkers. Correlations using baseline data will be examined for validity. Longitudinal analyses will document the changes in function, intramuscular fat accumulation, Meissner corpuscle sensory receptor density. Lastly, we will use anchor-based and other statistical methods to determine the minimally clinically important change for these clinical outcome assessments and biomarkers in CMT1A. Reliable, and responsive clinical outcome assessments of function and disease progression biomarkers are urgently needed for application in early and late phase clinical trials in CMT1A. The ACT-CMT study protocol will address this need through the prospective, longitudinal, multicenter examination in unprecedented detail of novel and existing clinical outcome assessments and motor and sensory biomarkers, and enhance international clinical trial infrastructure, training and preparedness for future therapeutic trials in CMT and related neuropathies.
随着1A型遗传性运动感觉神经病（CMT1A）治疗试验的开展，可靠、有效且具有反应性的临床结局评估和生物标志物至关重要。CMT加速临床试验（ACT-CMT）是一项国际研究，旨在填补CMT1A临床试验准备工作中的重要空白，包括缺乏针对成人的经过验证的、具有反应性的功能结局测量方法，以及缺乏可用于CMT1A临床试验多中心应用的经过验证的生物标志物。ACT-CMT的主要目标包括验证遗传性运动感觉神经病功能结局测量方法、将肌肉内脂肪堆积的磁共振成像作为下肢运动生物标志物，以及将迈斯纳小体感觉受体密度的反射共聚焦显微镜检查作为一种感觉生物标志物。初步研究表明这些测量方法是可行、可靠且有效的。有必要开展一项大型前瞻性多中心研究，以全面验证并检验这些结局测量方法相对于现有结局的反应性，以便在未来涉及CMT1A患者的临床试验中使用。目前正在招募215名成年CMT1A患者参与这项前瞻性、国际性、多中心研究。将进行长达3年的系列评估，包括CMT功能结局测量、CMT检查评分-拉什、总体神经病变限制量表、CMT健康指数，以及神经传导研究、磁共振成像和迈斯纳小体生物标志物。将使用基线数据进行相关性分析以验证有效性。纵向分析将记录功能、肌肉内脂肪堆积、迈斯纳小体感觉受体密度的变化。最后，我们将使用基于锚定的方法和其他统计方法来确定这些CMT1A临床结局评估和生物标志物的最小临床重要变化。在CMT1A的早期和晚期临床试验中，迫切需要可靠且具有反应性的功能和疾病进展生物标志物的临床结局评估。ACT-CMT研究方案将通过以前所未有的详细程度对新的和现有的临床结局评估以及运动和感觉生物标志物进行前瞻性、纵向、多中心检查来满足这一需求，并加强国际临床试验基础设施、培训以及为未来CMT及相关神经病变的治疗试验做好准备。
