Pfizer Inc, Cambridge, MA, USA.
Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
J Neurol. 2022 Aug;269(8):4421-4435. doi: 10.1007/s00415-022-11084-0. Epub 2022 Apr 8.
Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (n = 120 aged 6 to < 16 years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD.Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014.
杜氏肌营养不良症（DMD）是一种进行性神经肌肉疾病，由 DMD 基因突变引起，导致功能性肌营养不良蛋白缺失。在此，我们报告了定量磁共振成像（MRI）测量在多中心 2 期、随机、安慰剂对照临床试验中的应用，该试验评估了肌生成抑制素抑制剂 domagrozumab 在 DMD （n=120 名 6 至<16 岁的能走动的男孩）中的作用。根据方案，在基线和第 17、33、49 和 97 周时，对大腿进行 MRI 扫描以测量肌肉体积、肌肉体积指数（MVI）、脂肪分数和 T2 弛豫时间。这些定量 MRI 测量似乎是评估疾病进展的敏感和客观的生物标志物，随着时间的推移，肌肉体积、MVI 和 T2 映射测量值发生了显著变化。为了进一步探索定量 MRI 测量作为生物标志物在该队列中报告长期功能变化的效用，进行了回归分析，结果表明肌肉体积、MVI、T2 映射测量值和脂肪分数与 4 级台阶攀登时间和北星门诊评估功能评分的长期变化显著相关。最后，MVI、肌肉束脂肪分数和瘦肌肉脂肪分数的基线较差测量值是在 2 年监测期间丧失行走能力的显著危险因素。这些分析表明，MRI 可以成为临床试验中的一种有价值的工具，并可能有助于预测 DMD 的未来功能变化。试验注册：ClinicalTrials.gov 标识符，NCT02310763；2014 年 12 月注册。
