Development of a model-based clinical trial simulation platform to optimize the design of clinical trials for Duchenne muscular dystrophy

Abstract

Early clinical trials of therapies to treat Duchenne muscular dystrophy (DMD), a fatal genetic X-linked pediatric disease, have been designed based on the limited understanding of natural disease progression and variability in clinical measures over different stages of the continuum of the disease. The objective was to inform the design of DMD clinical trials by developing a disease progression model-based clinical trial simulation (CTS) platform based on measures commonly used in DMD trials. Data were integrated from past studies through the Duchenne Regulatory Science Consortium founded by the Critical Path Institute (15 clinical trials and studies, 1505 subjects, 27,252 observations). Using a nonlinear mixed-effects modeling approach, longitudinal dynamics of five measures were modeled (NorthStar Ambulatory Assessment, forced vital capacity, and the velocities of the following three timed functional tests: time to stand from supine, time to climb 4 stairs, and 10 meter walk-run time). The models were validated on external data sets and captured longitudinal changes in the five measures well, including both early disease when function improves as a result of growth and development and the decline in function in later stages. The models can be used in the CTS platform to perform trial simulations to optimize the selection of inclusion/exclusion criteria, selection of measures, and other trial parameters. The data sets and models have been reviewed by the US Food and Drug Administration and the European Medicines Agency; have been accepted into the Fit-for-Purpose and Qualification for Novel Methodologies pathways, respectively; and will be submitted for potential endorsement by both agencies.

FIGURE 1

Overall model development and validation strategy. DMD, Duchenne muscular dystrophy; FVC, forced vital capacity; NSAA, North Star Ambulatory Assessment

FIGURE 2

Visual predictive check for final models of all five measures. The visual predictive check plots show the median (dashed black line) and the 5th and 95th percentiles (lower and upper dashed lines, respectively) of the observed data. The blue shaded areas indicate the 90% CIs of the model prediction of the median, and the green shaded areas show 90% CIs of the model prediction for the 5th and 95th percentiles. The solid lines—blue for the median and green for the 5th and 95th percentiles—represent the model prediction. Black dots represent the observed data. CI, confidence interval; FVC, forced vital capacity; NSAA, North Star Ambulatory Assessment

FIGURE 3

Predicted covariate effects on mean time‐course of measures versus age. FVC, forced vital capacity; NSAA, North Star Ambulatory Assessment