P.14 Analysis of the longitudinal CINRG Becker natural history study dataset

Abstract

The phenotype of Becker muscular dystrophy (BMD) varies from Duchenne-like severity (loss of ambulation in second decade) to much milder disease with ambulation retained into adulthood. We performed a prospective, natural history study (BNHS) of males with in-frame dystrophin deletions causing BMD to better characterize the clinical course. Analysis of the longitudinal dataset offers the opportunity to develop robust outcomes crucial to clinical treatment trials. The BNHS followed 83 ambulatory and non-ambulatory males with BMD aged 5.5 to 75.5 years at enrolment for up to three years with annual assessments. Baseline characteristics of these participants have been published. In this post-baseline analysis, we studied binned repeated cross-sectional clinical outcome data, shift-based analyses of NSAA, longitudinal mixed-effect modeling of clinical outcomes, and survival analysis of time to stand. Analyses were stratified by age (<18 or ≥18 years old). In this dataset, we found that the most common deletion mutations were deletion of dystrophin exons 45-47 or exons 45-48. In those <18 years, the NSAA showed a ceiling effect not observed with other outcomes. In longitudinal modeling of percentage predicted FVC, 3 timed function tests, 6-minute walk distance, and NSAA, age was found to be significantly associated with outcome performance in adulthood but not in those <18 years. Mutation status (del 45-47, 45-48, vs. others) was significantly associated with some outcomes. The median age at which it took 10 seconds or longer to stand was estimated as 51 years (95% CI: 45 years, infinity) by time to event analysis. In conclusion, while the sample size was small, our data demonstrated variable progression of different outcomes based on age groups, and mutation groups, and found that disease progression seems to largely manifest in adulthood for BMD. Our study has clinical trial design implications for enrolment criteria, efficacy determination, and sample size calculations.