Consistency of changes in %-predicted forced vital capacity between real-world data and trial placebo arms in ambulatory Duchenne muscular dystrophy


Translational Research

Poster Number: 320


James Signorovitch PhD, Analysis Group, Inc., Nathalie Goemans, MD, PhD, University Hospitals Leuven, Craig McDonald, MD, University of California, Davis, Francesco Muntoni, MD, UCL Institute of Child Health and Great Ormond Street Hospital for Children, Gautam Sajeev, ScD, Analysis Group Inc., Nicolae Done, PhD, Analysis Group, Inc., Adnan Manzur, FRCPCH, Dubowitz Neuromuscular Centre, Brenda Wong, MD, University of Massachusetts Medical School, Cuixia Tian, MD, CCHMC, Eugenio Mercuri, MD, PhD, Department of Paediatric Neurology and Nemo Clinical Centre, Catholic University, Chujun He, Analysis Group, Inc., Danielle Peterson, Analysis Group, Inc., Hana Akbarnejad, Analysis Group, Inc., Susan Ward, PhD, cTAP

Use of real-world and natural history data (RWD/NHD) as external controls for pulmonary outcomes is of interest for drug development in ambulatory Duchenne muscular dystrophy (DMD). However, differences across patient populations and RWD/NHD settings raise appropriate concerns about risk of bias. To assess this risk, we compared change in pulmonary function, as measured by percent-predicted forced vital capacity (FVC%p) between RWD/NHD sources and trial placebo arms in ambulatory boys with DMD. RWD/NHD data came from PRO-DMD-01, UZ Leuven, the North Star UK Clinical Network and Cincinnati Children’s Hospital Medical Center. Placebo arm data came from phase 3 trials of tadalafil and drisapersen, and one phase 2 trial of drisapersen. PRO-DMD-01 and drisapersen trial data were provided by CureDuchenne. Change in FVC%p over 48-week intervals was studied in ambulatory, steroid-treated boys aged ≥5 years with baseline FVC%p > 50%. Primary analyses included 409 48-week intervals (263 patients) from RWD/NHD, and 161 intervals (161 patients) from placebo arms. At baseline, average ages in these groups were 9.5 and 8.8 years, respectively, and averages for FVC%p were 97.2% and 103.6%. Mean 48-week change in FVC%p was 2.9% greater in in RWD/NHD vs. placebo arms (95% confidence interval [CI]: -1.0%, 6.7%; p=0.14) in unadjusted analyses. After adjusting for baseline status (age, FVC%p, steroid type, height, weight, body mass index, North Star Ambulatory Assessment total score, and 10-meter walk run and rise from supine velocities) the difference in FVC%p between RWD/NHD and placebo arms decreased to -0.1% (95% CI: -3.6, 3.5; p=0.97). Similarly high consistency was observed in sensitivity analyses adjusting for fewer baseline characteristics. These findings are encouraging for use of external controls for FVC%p outcomes in this population. Additional research is needed to assess consistency of FVC%p over longer-time frames, and among older and non-ambulatory boys.