Dataset Information

Delayed onset of ambulation in boys with Duchenne muscular dystrophy: Potential use as an endpoint in clinical trials.

ABSTRACT: Individuals with Duchenne muscular dystrophy (DMD) often exhibit delayed motor and cognitive development, including delayed onset of ambulation. Data on age when loss of independent ambulation occurs are well established for DMD; however, age at onset of walking has not been well described. We hypothesize that an effective medication given in early infancy would advance the age when walking is achieved so that it is closer to age-matched norms, and that this discrete event could serve as the primary outcome measure in a clinical trial. This study examined three data sets, Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet); Dutch Natural History Survey (DNHS); and Parent Project Muscular Dystrophy (PPMD). The distribution of onset of ambulation in DMD (mean?±?SD) and median age, in months, at the onset of ambulation was 17.3 (±5.5) and 16.0 in MD STARnet, 21.8 (±7.1) and 20.0 in DNHS, and 16.1 (±4.4) and 15 in PPMD. Age of ambulation in these data sets were all significantly later (P?<0.001) than the corresponding age for typically developing boys, 12.1 (±1.8). A hypothetical clinical trial study design and power analyses are presented based on these data.

SUBMITTER: Gissy JJ

PROVIDER: S-EPMC5628390 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Delayed onset of ambulation in boys with Duchenne muscular dystrophy: Potential use as an endpoint in clinical trials.

Gissy Jacob J JJ Johnson Teresa T Fox Deborah J DJ Kumar Anil A Ciafaloni Emma E van Essen Anthonie J AJ Peay Holly L HL Martin Ann A Lucas Ann A Finkel Richard S RS

Neuromuscular disorders : NMD 20170721 10

Individuals with Duchenne muscular dystrophy (DMD) often exhibit delayed motor and cognitive development, including delayed onset of ambulation. Data on age when loss of independent ambulation occurs are well established for DMD; however, age at onset of walking has not been well described. We hypothesize that an effective medication given in early infancy would advance the age when walking is achieved so that it is closer to age-matched norms, and that this discrete event could serve as the pri ...[more]

PMID: 28739181

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Project description:BackgroundDuchenne muscular dystrophy (DMD) exhibits substantial variability in rates of disease progression and response to treatment. This has hindered treatment development and complicated interpretation of drug effects in clinical trials.ObjectiveWe hypothesized that a multivariate combination of early-age clinical outcome measurements can explain differential disease progression.MethodsData on boys with DMD (ages 4-<10 years), both treated with steroidal anti-inflammatories and untreated, were obtained from CINRG Duchenne Natural History Study (n = 209) and vamorolone VBP15-002/003/LTE (n = 46) studies. Velocities from three timed function tests (TFTs; stand from supine, run/walk 10 meters, and climb 4 stairs) were simultaneously modeled in a longitudinal latent class analysis.ResultsThree classes of differentially progressing early age DMD motor trajectories were identified. Quicker decline/progression was associated with lower baseline TFT velocities, earlier loss of ability to finish a TFT, and lower predicted velocities. Earlier substantial steroid exposure was associated with greater TFT velocities while the moderate progression class was observed to have the largest difference in performance between boys treated early with steroids vs. not. Sample size calculations with the class showing the largest treatment response showed a large reduction in required sample size as compared to using summaries from all participants. Gene mutations were also investigated in post-hoc analyses, with mutations near the beginning of the DMD gene (Dp427 absent and Dp140/Dp71 present) found to be enriched in the slowest progressing class.ConclusionsThis study provides insight into the variation in DMD progression through a latent class analysis. Our findings show class-related trajectories of motor outcomes and pharmacological response to corticosteroids, and suggest that enrichment strategies and/or subgroup analyses could be considered further in design of therapeutic interventions in DMD.

Dataset Information

Delayed onset of ambulation in boys with Duchenne muscular dystrophy: Potential use as an endpoint in clinical trials.

Publications

Delayed onset of ambulation in boys with Duchenne muscular dystrophy: Potential use as an endpoint in clinical trials.

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