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Updated: Aug 12, 2025
Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy
Published on: January 12, 2019
DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications
Francesco Muntoni1, James Signorovitch2, Gautam Sajeev1
1From the Dubowitz Neuromuscular Centre (F.M., M.C., A.Y.M.), NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, and Great Ormond Street Hospital Trust, United Kingdom; Analysis Group, Inc. (J.S., G.S., H.L., M.J., I.D.), Boston; The Collaborative Trajectory Analysis Project (J.S., S.J.W.), Cambridge, MA; Department of Physical Medicine and Rehabilitation, and Pediatrics (C.M.), University of California, Davis, Sacramento; Child Neurology (N.G.), University Hospitals Leuven, Belgium; Department of Neurology (E.H.N.), Leiden University Medical Centre, the Netherlands; Department of Pediatrics (B.W.), University of Massachusetts Medical School, Worcester; MDUK Oxford Neuromuscular Center (L.S.), Department of Paediatrics, University of Oxford, United Kingdom and Neuromuscular Center of Liège (L.S.), Division of Paediatrics, CHU and University of Liège, Belgium; John Walton Muscular Dystrophy Research Centre (V.S., M.G.), Newcastle University and Newcastle Hospitals NHS Foundation Trust, United Kingdom; Department of Rehabilitation (I.J.M.d.G.), Donders Centre of Neuroscience, Radboud University Nijmegen Medical Center, the Netherlands; Cincinnati Children's Hospital Medical Center (C.T.), and College of Medicine (C.T.), University of Cincinnati, OH; Department of Pediatric Neurology (E.M.), Fondazione Policlinico Gemelli IRCCS, Catholic University, Rome, Italy; and Department of Human Genetics (A.A.-R.), Leiden University Medical Center, the Netherlands.
Background And Objectives:
Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients with untreated patients with the same DMD genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials.
Methods:
More than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children's Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-m walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors.
Results:
The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors.
Discussion:
These findings suggest the viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multigenotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in this study.
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