Meaningful changes in motor function in Duchenne muscular dystrophy (DMD): A multi-center study

PLoS ONE, vol. 19, pp. e0304984

Abstract

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.

Authors 19

1. Francesco Muntoni A

   NIHR Great Ormond Street Hospital Biomedical Research Centre · University College London

   Affiliation as printed

   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

2. James Signorovitch corresponding

   Analysis Group (United States)

   Affiliation as printed

   Analysis Group, Inc., Boston, Massachusetts, United States of America

   The collaborative Trajectory Analysis Project, Cambridge, Massachusetts, United States of America

3. Gautam Sajeev

   Analysis Group (United States)

   Affiliation as printed

   Analysis Group, Inc., Boston, Massachusetts, United States of America

4. Nicolae Done

   Analysis Group (United States)

   Affiliation as printed

   Analysis Group, Inc., Boston, Massachusetts, United States of America

5. Zhiwen Yao

   Analysis Group (United States)

   Affiliation as printed

   Analysis Group, Inc., Boston, Massachusetts, United States of America

6. Nathalie Goemans

   Universitair Ziekenhuis Leuven

   Affiliation as printed

   Child Neurology, University Hospitals Leuven, Leuven, Belgium

7. Craig M. McDonald

   University of California, Davis

   Affiliation as printed

   Department of Physical Medicine and Rehabilitation and Pediatrics, University of California, Davis, Sacramento, California, United States of America

8. Eugenio Maria Mercuri

   Agostino Gemelli University Polyclinic · Istituti di Ricovero e Cura a Carattere Scientifico

   Affiliation as printed

   Department of Pediatric Neurology, Fondazione Policlinico Gemelli IRCCS, Catholic University, Rome, Italy

9. Erik Harmen Niks Aachen Department of Neurology, Leiden University Medical Centre

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands

10. Brenda L. Y. Wong

    University of Massachusetts Chan Medical School

    Affiliation as printed

    Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America

11. Krista Vandenborne

    University of Florida

    Affiliation as printed

    Department of Physical Therapy, University of Florida, Gainesville, Florida, United States of America

12. Volker W. Straub

    Newcastle upon Tyne Hospitals NHS Foundation Trust · Newcastle University

    Affiliation as printed

    John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

13. Imelda J. M. de Groot

    Radboud University Nijmegen · Radboud University Medical Center · Donders Centre for Neuroscience

    Affiliation as printed

    Department of Rehabilitation, Donders Centre of Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands

14. Cuixia Tian

    Cincinnati Children's Hospital Medical Center · University of Cincinnati

    Affiliation as printed

    Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio & College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America

15. Adnan Manzur

    NIHR Great Ormond Street Hospital Biomedical Research Centre · University College London

    Affiliation as printed

    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

16. Ibrahima Dieye

    Analysis Group (United States)

    Affiliation as printed

    Analysis Group, Inc., Boston, Massachusetts, United States of America

17. Henry Clifford Lane

    Analysis Group (United States)

    Affiliation as printed

    Analysis Group, Inc., Boston, Massachusetts, United States of America

18. Susan J. Ward
    Affiliation as printed

    The collaborative Trajectory Analysis Project, Cambridge, Massachusetts, United States of America

19. Laurent Servais

    University of Liège · University of Oxford · Centre Hospitalier Universitaire de Liège

    Affiliation as printed

    Department of Paediatrics, MDUK Oxford Neuromuscular Center, University of Oxford, Oxford, United Kingdom

    Neuromuscular Center of Liège, Division of Paediatrics, CHU and University of Liège, Liège, Belgium