P.66 Predicting trajectories of ambulatory function in Duchenne muscular dystrophy (DMD)

Abstract

The North Star Ambulatory Assessment (NSAA) is a widely used endpoint in DMD clinical trials. Accurately predicting NSAA trajectories is important for understanding effects of novel therapies, via creation of individualized controls for treated patients, especially over longer-term (> 18 month) follow-up, when placebo controls are infeasible. We used longitudinal data for boys with DMD aged 4-10 years and starting with NSAA >12 at baseline to develop prognostic models for trajectories of NSAA total score for up to 4 years of follow-up. Data were drawn from four natural history databases: UZ Leuven, PRO-DMD-01 (provided by CureDuchenne), the North Star Clinical Network, and iMDEX. NSAA trajectories were fit using mixed effects models with age, steroid use, height, weight, and ambulatory function as baseline predictors. Among N=261 boys, mean age at baseline was 6.8 years, mean NSAA score was 25.6; 53% were receiving prednisone, 23% deflazacort, and 24% no steroid. Almost all initiated steroids within the first year of follow-up. The average patient had 6 post-baseline NSAA assessments over 2-4 years of follow-up. Predictors of greater decline in NSAA identified in the training sample (N=208) included older age, longer rise-from-floor times, higher NSAA (more room to decline), greater height, and greater body mass index. The best-fitting model explained 27% of variation in post-baseline NSAA with average prediction errors of ±5.6 units in a held-out sample (N=53). Bias in mean change in NSAA due to missing data was small (0.2, 0.8 and 1.1 units at years 1, 3 and 4 post-baseline, respectively) and in the direction of better-than-actual outcomes in natural history, which would bias against treatment in comparison to long-term natural history controls. Trajectories of ambulatory function in DMD can be well-predicted using baseline characteristics. Extension of this model to include older boys, and additional validation in larger samples is warranted.