The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials.
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.
Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK Great Ormond Street Hospital, London, UK.
Valeria
V
Ricotti
Department of Population, Policy and Practice Programme, UCL Institute of Child Health, London, UK Great Ormond Street Hospital, London, UK.
Deborah A
DA
Ridout
Department of Paediatric Neurology, Catholic University, Rome, Italy.
Marika
M
Pane
Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK Great Ormond Street Hospital, London, UK.
Marion
M
Main
Institute of Human Genetics, Newcastle, UK.
Anna
A
Mayhew
Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK Department of Paediatric Neurology, Catholic University, Rome, Italy.
Eugenio
E
Mercuri
Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK Great Ormond Street Hospital, London, UK.
Adnan Y
AY
Manzur
Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK Great Ormond Street Hospital, London, UK.
Francesco
F
Muntoni
D000293:Adolescent; D017668:Age of Onset; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002648:Child; D002986:Clinical Trials as Topic / Q000592:standards*; D015331:Cohort Studies; D018450:Disease Progression; D042241:Early Diagnosis; D005091:Exons; D005500:Follow-Up Studies; D017353:Gene Deletion; D005838:Genotype; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007558:Italy; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics; D012107:Research Design; D006113:United Kingdom; D016138:Walking; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids
MUSCULAR DYSTROPHY; NEUROMUSCULAR