Factors Associated With Early Motor Function Trajectories in DMD After Glucocorticoid Initiation
Post Hoc Analysis of the FOR-DMD Trial
Abstract
Background and Objectives
Clinical trials in Duchenne muscular dystrophy (DMD) require 3–6 months of stable glucocorticoids, and the primary outcome is explored at 48–52 weeks. The factors that influence the clinical outcome assessment (COA) trajectories soon after glucocorticoid initiation are relevant for the design and analysis of clinical trials of novel drugs. We describe early COA trajectories, associated factors, and the time from glucocorticoid initiation to COA peak.
Methods
This was a prospective 18-month analysis of the Finding the Optimum Corticosteroid Regimen for Duchenne Muscular Dystrophy study. Four COAs were investigated: rise from supine velocity (RFV), 10-meter walk/run velocity (10MWRV), North Star Ambulatory Assessment (NSAA) total score, and 6-minute walk test distance (6MWT). The relationships of baseline age (4–5 vs 6–7 years), COA baseline performance, genotype, and glucocorticoid regimen (daily vs intermittent) with the COA trajectories were evaluated using linear mixed-effects models.
Results
One hundred ninety-six glucocorticoid-naïve boys with DMD aged 4–7 years were enrolled. The mean age at baseline was 5.9 ± 1.0 years, 66% (n = 130) were on daily regimens, 55% (n = 107) showed a 6MWT distance >330 metres; 41% (n = 78) showed RFV >0.2 rise/s; 76% (n = 149) showed 10MWRV >0.142 10m/s, and 41.0% (n = 79) showed NSAA total score >22 points. Mean COA trajectories differed by age at glucocorticoid initiation (p < 0.01 for RFV, 10MWRV, and NSAA; p < 0.05 for 6MWT) and regimen (p < 0.01 for RFV, 10MWRV, and NSAA). Boys younger than 6 years reached their peak performance 12–18 months after glucocorticoid initiation. Boys aged 6 years or older on a daily regimen peaked between months 9 and 12 and those on an intermittent regimen by 9 months. The baseline COA performance was associated with the NSAA (p < 0.01) and the 6MWT trajectory in boys younger than 6 years on a daily regimen (p < 0.01). Differences in the mean trajectories by genotype were not significant.
Discussion
Glucocorticoid regimen, age, duration of glucocorticoid exposure, and baseline COA performance need to be considered in the design and analysis of clinical trials in young boys with DMD.
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Information & Authors
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© 2024 American Academy of Neurology.
Publication History
Received: October 3, 2023
Accepted: January 5, 2024
Published online: May 6, 2024
Published in issue: May 28, 2024
Disclosure
M. Schiava received a grant from UK Duchenne through Newcastle University; J. Broomfield received funding from Duchenne UK, through the University of Leicester and through consultancy; K.R. Abrams reports no disclosures related to this project; M.P. McDermott reports grants from NIH, PTC Therapeutics during the conduct of the study; W.B. Martens reports no disclosures related to this project; S.J. Gregory, reports no disclosures related to this project; A.G. Mayhew has participated in SAB meetings for Summit, PTC, and Biogen and performs consultancy work (training physiotherapists for trial in DMD) for Roche, Pfizer, PTC, Summit, Sarepta, Santhera, Italfarmaco, Amicus, Biogen, and Avexis; C.M. McDonald reports no disclosures related to this project; R.C. Griggs reports grants from NIH, Muscular Dystrophy Association, and Patient Project for Muscular Dystrophy Support and other from PTC and Sarepta pharmaceuticals during the conduct of the study; M. Guglieri participates in advisory boards for PTC Therapeutics, Capricor, Pfizer, and NS Pharma. She has research collaborations with ReveraGen. She is or has been principal investigator for clinical trials with Roche, Italfarmaco, Santhera, ReveraGen, Summit, Pfizer, and PTC Therapeutics. Go to Neurology.org/N for full disclosures.
Study Funding
No funding was received toward this work. The FOR DMD study was funded by grants NS061799 and NS061795 from the National Institute of Neurologic Diseases and Stroke (NINDS). Additional funding was provided by the Muscular Dystrophy Association, Parent Project for Muscular Dystrophy, PTC Therapeutics, Sarepta Therapeutics, and Santhera Pharmaceuticals. None of the FOR DMD study funders had any input into the collection, management, analysis, and interpretation of the data.
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Cited By
- Association between age at loss of ambulation and cardiac function in adults with Duchenne muscular dystrophy, Neuromuscular Disorders, 46, (105276), (2025).https://doi.org/10.1016/j.nmd.2025.105276
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