Humans; Child; Adolescent; Male; Child, Preschool; Walk Test; Minimal Clinically Important Difference; Female; Walking/physiology; Motor Activity/physiology; Muscular Dystrophy, Duchenne/physiopathology; Motor Activity; Muscular Dystrophy, Duchenne; Walking; Multidisciplinary
Abstract :
[en] Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to <18 years and receiving steroids. Minimal clinically important differences (MCIDs) for worsening were also estimated. Estimated MDC thresholds for >80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.
Disciplines :
Pediatrics
Author, co-author :
Muntoni, Francesco; Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, United Kingdom
Signorovitch, James ; Analysis Group, Inc., Boston, Massachusetts, United States of America ; The collaborative Trajectory Analysis Project, Cambridge, Massachusetts, United States of America
Sajeev, Gautam; Analysis Group, Inc., Boston, Massachusetts, United States of America
Done, Nicolae ; Analysis Group, Inc., Boston, Massachusetts, United States of America
Yao, Zhiwen; Analysis Group, Inc., Boston, Massachusetts, United States of America
Goemans, Nathalie; Child Neurology, University Hospitals Leuven, Leuven, Belgium
McDonald, Craig; Department of Physical Medicine and Rehabilitation and Pediatrics, University of California, Davis, Sacramento, California, United States of America
Mercuri, Eugenio; Department of Pediatric Neurology, Fondazione Policlinico Gemelli IRCCS, Catholic University, Rome, Italy
Niks, Erik H ; Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands
Wong, Brenda ; Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
Vandenborne, Krista; Department of Physical Therapy, University of Florida, Gainesville, Florida, United States of America
Straub, Volker ; John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
de Groot, Imelda J M; Department of Rehabilitation, Donders Centre of Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
Tian, Cuixia; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio & College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America
Manzur, Adnan; Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, United Kingdom
Dieye, Ibrahima; Analysis Group, Inc., Boston, Massachusetts, United States of America
Lane, Henry; Analysis Group, Inc., Boston, Massachusetts, United States of America
Ward, Susan J ; The collaborative Trajectory Analysis Project, Cambridge, Massachusetts, United States of America
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques ; Department of Paediatrics, MDUK Oxford Neuromuscular Center, University of Oxford, Oxford, United Kingdom
This study was conducted by the collaborative Trajectory Analysis Project (cTAP), a precompetitive coalition of academic clinicians, drug developers, and patient foundations formed in 2015 to overcome the challenges of high variation in clinical trials in DMD. cTAP has received sponsorship from Astellas (Mitobridge), Avidity Biosciences, BioMarin Pharmaceutical, Bristol
Meyers Squibb, Catabasis, Daiichi Sankyo, Edgewise Therapeutics, Entrada Therapeutics, FibroGen, Italfarmaco SpA, Marathon Pharmaceuticals, NS Pharma, Pfizer, PTC Therapeutics, Roche, Sarepta Therapeutics, Shire,
Solid Biosciences, Summit Therapeutics, Ultragenyx, Vertex Pharmaceuticals, Parent Project Muscular Dystrophy, Charley’s Fund, and
CureDuchenne, a founding patient advocacy partner and provider of initial seed funding to cTAP. Physical function testing at Universitaire Ziekenhuizen Leuven was funded by Fonds
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