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JNNP Online First, published on March 2, 2015 as 10.1136/jnnp-2014-309405 Neuromuscular

RESEARCH PAPER

The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials Valeria Ricotti,1,3 Deborah A Ridout,2,3 Marika Pane,4 Marion Main,1,3 Anna Mayhew,5 Eugenio Mercuri,1,4 Adnan Y Manzur,1,3 Francesco Muntoni,1,3 on behalf of UK NorthStar Clinical Network 1

Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK 2 Department of Population, Policy and Practice Programme, UCL Institute of Child Health, London, UK 3 Great Ormond Street Hospital, London, UK 4 Department of Paediatric Neurology, Catholic University, Rome, Italy 5 Institute of Human Genetics, Newcastle, UK Correspondence to Professor Francesco Muntoni, Dubowitz Neuromuscular Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; [email protected] Received 3 September 2014 Revised 2 January 2015 Accepted 25 January 2015

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 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).

Ricotti V, et al. J Neurol Neurosurg Psychiatry 2015;0:1–7. doi:10.1136/jnnp-2014-309405

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Neuromuscular NSAA in young boys with DMD Prior to 7 years of age, young DMD boys improve their motor function, with an overall gain of 4.0 linearised units/year (95% CI 2.2 to 5.8 p

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

With the emergence of experimental therapies for Duchenne muscular dystrophy (DMD), it is fundamental to understand the natural history of this disord...
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