The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials

Abstract

Objective: With the emergence of experimental therapies for Duchenne muscular dystrophy (DMD), it is fundamental to understand the natural history of this disorder to properly design clinical trials. The aims of this study were to assess the effects produced on motor function by different DMD genotypes and early initiation of glucocorticoids.

Methods: Through the NorthStar Network, standardised clinical data including the NorthStar Ambulatory Assessment score (NSAA) on 513 ambulant UK boys with DMD were analysed from 2004 to 2012. For the analysis of the genetic subpopulation, we also included data from 172 Italian boys with DMD. NSAA raw scores were converted into linear scores.

Results: On the linearised NSAA, we observed an average decline of 8 units/year (4 units on raw NSAA analysis) after age 7. The median age at loss of ambulation (LOA) was 13 years (95% CI 12.1 to 13.5); 2 years prior to LOA, the estimated mean linearised NSAA score was 42/100 (13/34 raw scale). Starting glucocorticoids between 3 and 5 years conferred an additional gain in motor function of 3 units/year (1.3 raw units) up to age 7. When analysing the effect of genotype in the UK and Italian cumulative cohorts, individuals with deletions amenable to exons 44 and 46 skipping declined at a slower rate over 2 years (9 units (4 raw units), p<0.001), while 53 and 51 skippable deletions showed a faster decline of 14 (4.5; p<0.001) and 5 linearised units (2.4 NSAA units; p=0.02), respectively.

Conclusions: Our study provides a novel insight on the current natural history of DMD, which will be instrumental for the design of future clinical trials.

Keywords: MUSCULAR DYSTROPHY; NEUROMUSCULAR.

Figure 1

Genotype breakdown of individuals registered in the UK NorthStar Clinical database. Genetic information was available for 442 UK boys registered in the NorthStar database.

Figure 2

Linearised NorthStar Ambulatory Assessment (NSAA) slope of decline in boys > 7 years of age. With an average linearised NSAA score of 73.4 (95% CI 70.3 to 76.5) at age 7 (raw NSAA: 27.4, 95% CI 26.1 to 28.6), the overall slope coefficient was −7.8 (95% CI −8.8 to −6.9; raw NSAA: −3.7, 95% CI −4.1 to −3.3), meaning that our Duchenne muscular dystrophy (DMD) population on average lost 8 linearised NSAA units for each year, after age 7. At 8 years of age, the mean linearised NSAA was 65.5 (95% CI 62.7 to 68.4; 23.7, 95% CI 22.6 to 24.8), while at 10 years of age it was estimated to be about 49.7 units (95% CI 46.8 to 52.8; 16.3, 95% CI 15.1 to 17.5). The mean linearised NSAA score was 42 units and 34 units 24 and 12 months before losing ambulation (equivalent to 13 and 9 raw scores, respectively).

Figure 3

NorthStar Ambulatory Assessment (NSAA) in boys with Duchenne muscular dystrophy (DMD) <7 years of age. The interaction coefficient between 78 boys with DMD who started daily or intermittent glucocorticoid (GC) before the age of 5 with 163 boys who started steroids between ages 5 and 6.5 years was −2.7 (95% CI −6.8 to 1.3, p=0.2; raw NSAA: −1.3, 95% CI −3.0 to 0.3), p=0.1 favouring early starters. By age 7, the mean total NSAA was 73.8 (95% CI 67.5 to 80.1) in early starters and 68.7 (95% CI 64.1 to 73.4) in late starters (p<0.01; raw NSAA: (27.0, 95% CI 24.6 to 29.4 in early starters and 25.1, 95% CI 23.2 to 26.9 in late starters).

Figure 4

Mean (95% CI) linearised NorthStar Ambulatory Assessment (NSAA) total score mean (A) and change from baseline (B) for skippable genotypes at 12 and 24 months. The overall slope of decline over 24 months is described in boys with Duchenne muscular dystrophy (DMD) >5 years of age, with a minimum NSAA of 52/100 (raw NSAA: 17/34), and at least 3 months on glucocorticoids at baseline. (For illustration purposes only, the plots are shifted to avoid overlap of the 95% CI bars).