Global Product Development, Pfizer Inc., La Jolla, California, USA.
Global Product Development, Pfizer Inc., Cambridge, Massachusetts, USA.
CPT Pharmacometrics Syst Pharmacol. 2023 Mar;12(3):375-386. doi: 10.1002/psp4.12921. Epub 2023 Feb 14.
Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by decreased or absent dystrophin gene leading to progressive muscle degeneration and weakness in young boys. Disease progression models for the North Star Ambulatory Assessment (NSAA), a functional measurement widely used to assess outcomes in clinical trials, were developed using a longitudinal population modeling approach. The relationship between NSAA total score over time, loss of ambulation, and potential covariates that may influence disease progression were evaluated. Data included individual participant observations from an internal placebo-controlled phase II clinical trial and from the external natural history database for male patients with DMD obtained through the Cooperative International Neuromuscular Research Group (CINRG). A modified indirect response model for NSAA joined to a loss of ambulation (LOA) time-to-event model described the data well. Age was used as the independent variable because ambulatory function is known to vary with age. The NSAA and LOA models were linked using the dissipation rate constant parameter from the NSAA model by including the parameter as a covariate on the hazard equation for LOA. No covariates were identified. The model was then used as a simulation tool to explore various clinical trial design scenarios. This model contributes to the quantitative understanding of disease progression in DMD and may guide model-informed drug development decisions for ongoing and future DMD clinical trials.
杜氏肌营养不良症（DMD）是一种罕见的遗传性疾病，由肌营养不良蛋白基因的减少或缺失引起，导致年轻男孩的肌肉进行性退化和无力。北星门诊评估（NSAA）的疾病进展模型是使用纵向人群建模方法开发的，该模型是一种广泛用于评估临床试验结果的功能测量方法。评估了 NSAA 总分随时间的变化、丧失步行能力以及可能影响疾病进展的潜在协变量之间的关系。数据包括来自内部安慰剂对照 II 期临床试验的个体参与者观察结果，以及通过合作国际神经肌肉研究组（CINRG）从 DMD 男性患者的外部自然史数据库中获得的数据。改良的间接反应模型与 LOA 时间事件模型相结合，很好地描述了 NSAA 的数据。年龄被用作自变量，因为众所周知，步行功能会随年龄而变化。NSAA 和 LOA 模型通过将参数作为 LOA 危险方程的协变量包含在内，使用 NSAA 模型的耗散速率常数参数进行链接。未确定协变量。该模型随后被用作模拟工具来探索各种临床试验设计方案。该模型有助于定量了解 DMD 的疾病进展，并可能为正在进行和未来的 DMD 临床试验中的基于模型的药物开发决策提供指导。
