Abstract

Objective: To explore novel, real-world biotelemetry disease progression markers in patients with amyotrophic lateral sclerosis (ALS) and to compare with clinical gold-standard measures. Methods: This was an exploratory, non-controlled, non-drug 2-phase study comprising a variable length Pilot Phase (n = 5) and a 48-week Core study Phase (n = 25; NCT02447952). Patients with mild or moderate ALS wore biotelemetry sensors for ∼3 days/month at home, measuring physical activity, heart rate variability (HRV), and speech over 48 weeks. These measures were assessed longitudinally in relation to ALS Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC); assessed by telephone [monthly] and clinic visits [every 12 weeks]). Results: Pilot Phase data supported progression into the Core Phase, where a decline in physical activity from baseline followed ALS progression as measured by ALSFRS-R and FVC. Four endpoints showed moderate or strong between-patient correlations with ALSFRS-R total and gross motor domain scores (defined as a correlation coefficient of ≥0.5 or >0.7, respectively): average daytime active; percentage of daytime active; total daytime activity score; total 24-hour activity score. Moderate correlations were observed between speech endpoints and ALSFRS-R bulbar domain scores; HRV data quality was insufficient for reliable assessment. The sensor was generally well tolerated; 6/25 patients reported mostly mild or moderate intensity skin and subcutaneous tissue disorder adverse events. Conclusions: Biotelemetry measures of physical activity in this Pilot Study tracked ALS progression over time, highlighting their potential as endpoints for future clinical trials. A larger, formally powered study is required to further support activity endpoints as novel disease progression markers.

摘要

目的：探索肌萎缩侧索硬化症 (ALS) 患者的新型、真实世界生物遥测疾病进展标志物，并与临床金标准措施进行比较。方法：这是一项探索性、非对照、非药物的两阶段研究，包括一个可变长度的试验阶段（n = 5）和一个 48 周的核心研究阶段（n = 25；NCT02447952）。轻度或中度 ALS 患者每月在家佩戴生物遥测传感器约 3 天，在 48 周内测量身体活动、心率变异性 (HRV) 和言语。这些措施根据肌萎缩侧索硬化功能评定量表修订版 (ALSFRS-R) 评分和用力肺活量 (FVC) 进行纵向评估；通过电话[每月]和门诊[每 12 周]进行评估）。结果：试验阶段数据支持进入核心阶段，其中身体活动从基线开始下降，随后 ALS 进展，如 ALSFRS-R 和 FVC 所测量。四个终点显示患者与 ALSFRS-R 总和粗大运动领域评分（分别定义为≥0.5 或 >0.7 的相关系数）之间存在中度或强相关性：平均日间活动；白天活跃的百分比；日间活动总分；24 小时活动总分。在语音端点和 ALSFRS-R 延髓域分数之间观察到中等相关性；HRV 数据质量不足以进行可靠评估。传感器通常具有良好的耐受性；6/25 名患者报告大多为轻度或中度强度皮肤和皮下组织紊乱不良事件。结论：该试点研究中身体活动的生物遥测测量跟踪了 ALS 随着时间的推移进展，突出了它们作为未来临床试验终点的潜力。需要一项更大规模、正式有力的研究来进一步支持活动终点作为新的疾病进展标志物。