Analysis of the longitudinal CINRG Becker Natural History Study dataset

Topic:

Clinical Trials

Poster Number: 88

Author(s):

Utkarsh Dang, PhD, Carleton University, Heather Gordish-Dressman, PhD, George Washington University, Gabriela Niizawa, BS, Ksenija Gorni, MD, PDMA Neuroscience and Rare Disease, F. Hoffmann-La Roche Ltd, Michela Guglieri, MD, John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne, UK., Anne Connolly, MD, Nationwide Children's Hospital, Matthew Wicklund, MD, Tulio Bertorini, MD, MDA Clinic of Memphis/ Semmes Murphey Clinic, Jean Mah, MD, Mathula Thangarajh, MD, PhD, Virginia Commonwealth University, Edward Smith, MD, Duke University Hospital, Nancy Kuntz, MD, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, USA., Craig McDonald, MD, UC Davis Health, Erik Henricson, PhD, UC Davis, Saila Upadhyayula, MD, Emory + Children's Healthcare of Atlanta, Barry Byrne, MD, PhD, University of Florida, Georgios Manousakis, MD, University of Minnesota, Amy Harper, MD, VCU Health, Susan Iannaccone, MD, UT Southwestern Medical Center, Paula R. Clemens, MD, University of Pittsburgh School of Medicine, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA, CINRG BNHS Investigators

Background: The phenotype of Becker muscular dystrophy (BMD) is extremely variable, ranging from Duchenne-like severity (loss of ambulation in second decade) to much milder disease with ambulation retained well into adulthood. We performed a prospective, natural history study (BNHS) of males with in-frame dystrophin gene mutations causing BMD to better characterize the clinical course and outcomes crucial to rigorous clinical treatment trials.
Objective: To present natural history of clinical outcomes in BMD from a longitudinal dataset.
Approach: The BNHS followed 83 ambulatory and non-ambulatory males with BMD aged 5.5 to 75.5 years at enrollment for up to three years with annual assessments. Baseline characteristics of these participants have been published. In this post-baseline analysis, we studied binned repeated cross-sectional clinical outcome data, shift-based analyses of NSAA, longitudinal mixed-effect modeling of clinical outcomes, and survival analysis of time to stand. Analyses were stratified by age (<18 or ?18 years old).
Results: Deletion exons del 45-47 and 45-48 were most common. In those <18 years, the NSAA showed a ceiling effect not observed with other outcomes. In longitudinal modeling of percentage predicted FVC, 3 timed function tests, 6-minute walk distance, and NSAA, age was found to be significantly associated with outcome performance in adulthood but not in those <18 years. Mutation status (del 45-47, 45-48, vs. others) was significantly associated with some outcomes. The median age at which it took 10 seconds or longer to stand was estimated as 51 years (95% CI: 45 years, infinity) by time to event analysis.
Conclusions: While the sample size was small, our data demonstrated variable progression of different outcomes based on age groups, and mutation groups, and found that disease progression seems to largely manifest in adulthood for BMD. Our study has clinical trial design implications for enrolment criteria, efficacy determination, and sample size calculations.