P.2.9 The 6-min walk test and other endpoints in Duchenne MD: Multi center longitudinal natural history observations over 48weeks

Abstract

Duchenne muscular dystrophy (DMD) subjects >5years with nonsense mutations were followed for 48weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (<i>N</i>=57) provide insight into the natural history of the 6-min walk test (6MWT) and other endpoints. Eligibility criteria included nonsense-mediated severe dystrophinopathy, males⩾5years, and ambulatory (defined as ability to walk >75m on the 6MWT). A total of 57 males (70% of whom were treated with glucocorticoids) were randomized to orally receive placebo treatment and followed for 48weeks. Evaluations performed every 6weeks included the 6-min walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry. Natural history (placebo treated) data on 57 males over 48eeks showed decline in mean scores and mean change scores from baseline in 6MWD, increase in time to climb 4 stairs and time to run/walk 10m, and increase in EEI. Quantitative strength remained fairly stable over 48weeks. Baseline age (⩾7years), 6MWD, and selected TFT performance, are strong predictors of decline in ambulation (Δ 6MWD) and time to 10% worsening in 6MWD. Baseline 6MWD was also predictive of weeks to loss of ambulation. A baseline 6MWD of <350m was associated with greater functional decline and loss of ambulation was only seen in those with baseline 6MWD <325m. Only 1/42 (2.3%) of subjects able to stand from supine lost ambulation. A 30m change from mean 6MWD places patients at a level of ambulatory function where they will experience increased risk of disease progression and loss of ambulation. Findings confirm the clinical meaningfulness of the 6MWD—the most accepted primary clinical endpoint in ambulatory DMD trials.