Muntoni Francesco, Signorovitch James, Goemans Nathalie, Manzur Adnan Y, Done Nicolae, Sajeev Gautam, Li Jiayang, Akbarnejad Hanane, Sharma Aarushi, Ward Susan J, Niks Erik H, Servais Laurant, Mercuri Eugenio, Guglieri Michela, Straub Volker, de Groot Imelda, Ridout Deborah, McDonald Craig
Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, United Kingdom.
Analysis Group, Boston, Massachusetts, United States of America.
PLoS One. 2025 Jun 27;20(6):e0325736. doi: 10.1371/journal.pone.0325736. eCollection 2025.
The North Star Ambulatory Assessment (NSAA) is a widely used functional endpoint in drug development for ambulatory patients with Duchenne muscular dystrophy (DMD). Accurately predicting NSAA total score trajectories is important for designing randomized trials for novel therapies in DMD and for contextualizing outcomes, especially over longer-term follow-up (>18 months) when placebo-controlled studies are infeasible. We developed a prognostic model for NSAA total score trajectories over at most 5 years of follow-up for patients with DMD aged 4 to <16 years who were initially ambulatory and receiving corticosteroids but no other disease-modifying therapies. The model was based on longitudinal data from four natural history databases: UZ Leuven, PRO-DMD-01 (provided by CureDuchenne), the North Star Clinical Network, and iMDEX. Candidate predictors included age, height, weight, body mass index, steroid type and regime, NSAA total score, rise from floor velocity, and 10-meter walk/run velocity, as well as DMD genotype class, index year, and data source. Among N = 416 patients at baseline, mean age was 8.2 years, mean NSAA total score was 24, and 61% were receiving prednisone and 39% deflazacort, with the majority having been treated with daily corticosteroid regimens (69%) relative to other regimens (31%). Patients had an average of four NSAA assessments post-baseline during a median follow-up of 2.6 years (inter-quartile range 1.9 to 3.6 years). The best-fitting model in the full study sample explained 39% of the variation in NSAA total score changes, with prediction errors of ±3.6, 5.1, 5.9, 7.5, 9.5 NSAA units during follow-up years 1-5, respectively. The most important predictors were baseline age, NSAA, rise from floor velocity, and 10-meter walk/run velocity. In conclusion, trajectories of ambulatory motor function in DMD, as measured by the NSAA total score, can be well-predicted using readily available baseline characteristics. We discuss applications of these predictions to DMD drug development.
北极星动态评估（NSAA）是杜氏肌营养不良症（DMD）门诊患者药物研发中广泛使用的功能终点指标。准确预测NSAA总分轨迹对于设计DMD新型疗法的随机试验以及对结果进行背景分析非常重要，尤其是在安慰剂对照研究不可行的长期随访（>18个月）中。我们为年龄在4至<16岁、最初能够行走且正在接受皮质类固醇治疗但未接受其他疾病改善疗法的DMD患者，开发了一个在最多5年随访期内预测NSAA总分轨迹的预后模型。该模型基于来自四个自然史数据库的纵向数据：鲁汶大学医院（UZ Leuven）、PRO-DMD-01（由杜氏肌营养不良症治愈协会提供）、北极星临床网络和iMDEX。候选预测因素包括年龄、身高、体重、体重指数、类固醇类型和治疗方案、NSAA总分、从地面站起速度、10米步行/跑步速度，以及DMD基因型类别、索引年份和数据源。在基线时的N = 416名患者中，平均年龄为8.2岁，平均NSAA总分是24分，61%的患者接受泼尼松治疗，39%的患者接受地夫可特治疗，相对于其他治疗方案（31%），大多数患者接受每日皮质类固醇治疗方案（69%）。患者在基线后平均进行了四次NSAA评估，中位随访时间为2.6年（四分位间距为1.9至3.6年）。全研究样本中拟合度最佳的模型解释了NSAA总分变化中39%的变异，在随访的第1 - 5年中，预测误差分别为±3.6、5.1、5.9、7.5、9.5个NSAA单位。最重要的预测因素是基线年龄、NSAA、从地面站起速度和10米步行/跑步速度。总之，使用易于获得的基线特征可以很好地预测以NSAA总分衡量的DMD门诊运动功能轨迹。我们讨论了这些预测在DMD药物研发中的应用。
