Rabbia Michael, Guridi Ormazabal Maitea, Staunton Hannah, Veenstra Klaas, Eggenspieler Damien, Annoussamy Mélanie, Servais Laurent, Strijbos Paul
Genentech Inc., 1 DNA Way, South San Francisco, CA, USA.
F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland.
J Neuromuscul Dis. 2024;11(3):701-714. doi: 10.3233/JND-230188.
Stride Velocity 95th Centile (SV95C) is the first wearable device-derived clinical outcome assessment (COA) to receive European Medicines Agency (EMA) qualification as a primary endpoint in ambulant patients with Duchenne muscular dystrophy (DMD) aged ≥4 years.
To compare SV95C-in its first-ever clinical trial application as a secondary endpoint-with established motor function COAs used in the trial (Four-Stair Climb [4SC] velocity, North Star Ambulatory Assessment [NSAA], and Six-Minute Walk Distance [6MWD]).
SV95C was a secondary endpoint in a subset (n = 47) of participants in the SPITFIRE/WN40227 trial of taldefgrobep alfa, which was discontinued due to lack of clinical benefit. Participants in the ≤48-week SV95C sub-study were 6-11 years old and received corticosteroids for ≥6 months pre-treatment. Pearson correlations were used to compare SV95C with the other COAs. Responsiveness and changes over time were respectively assessed via standardized response means (SRMs) based on absolute changes and mixed models for repeated measures.
SV95C change at Week 24 was -0.07 m/s, with limited variability (standard deviation: 0.16, n = 27). The SRM for SV95C indicated moderate responsiveness to clinical change at the earliest timepoint (Week 12, n = 46), while those of the other COAs did not indicate moderate responsiveness until Week 36 (6MWD, n = 33) or Week 48 (4SC velocity, n = 20; NSAA total score, n = 20). Baseline correlations between SV95C and other COAs were strong (r = 0.611-0.695). Correlations between SV95C change from baseline to Week 48 and changes in other COAs were moderate to strong (r = 0.443-0.678).∥.
Overall, SV95C demonstrated sensitivity to ambulatory decline over short intervals, low variability, and correlation with established COAs. Although the negative trial precluded demonstration of SV95C's sensitivity to drug effect, these findings support the continued use of SV95C in DMD clinical trials.
步速第95百分位数（SV95C）是首个获得欧洲药品管理局（EMA）资格认定、可作为≥4岁杜氏肌营养不良症（DMD）门诊患者主要终点的可穿戴设备衍生临床结局评估（COA）。
在其作为次要终点的首次临床试验应用中，将SV95C与该试验中使用的既定运动功能COA（四阶梯攀爬[4SC]速度、北极星门诊评估[NSAA]和六分钟步行距离[6MWD]）进行比较。
SV95C是taldefgrobep alfa的SPITFIRE/WN40227试验中一个亚组（n = 47）参与者的次要终点，该试验因缺乏临床获益而提前终止。≤48周SV95C子研究的参与者年龄为6至11岁，在治疗前接受皮质类固醇治疗≥6个月。采用Pearson相关性分析比较SV95C与其他COA。分别基于绝对变化的标准化反应均值（SRM）和重复测量的混合模型评估反应性和随时间的变化。
第24周时SV95C的变化为-0.07m/s，变异性有限（标准差：0.16，n = 27）。SV95C的SRM表明在最早时间点（第12周，n = 46）对临床变化有中度反应性，而其他COA直到第36周（6MWD，n = 33）或第48周（4SC速度，n = 20；NSAA总分，n = 20）才显示出中度反应性。SV95C与其他COA之间的基线相关性很强（r = 0.611 - 0.695）。从基线到第48周SV95C的变化与其他COA变化之间的相关性为中度至强（r = 0.443 - 0.678）。
总体而言，SV95C在短时间内显示出对步行能力下降的敏感性、低变异性以及与既定COA的相关性。尽管该阴性试验无法证明SV95C对药物效应的敏感性，但这些发现支持在DMD临床试验中继续使用SV95C。
