Outcome reliability in non-ambulatory boys/men with Duchenne muscular dystrophy.
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ABSTRACT:
SUBMITTER: Connolly AM
PROVIDER: S-EPMC4305351 | biostudies-other | 2015 Apr
REPOSITORIES: biostudies-other
Publications
Outcome reliability in non-ambulatory boys/men with Duchenne muscular dystrophy.
Connolly Anne M AM Malkus Elizabeth C EC Mendell Jerry R JR Flanigan Kevin M KM Miller J Philip JP Schierbecker Jeanine R JR Siener Catherine A CA Golumbek Paul T PT Zaidman Craig M CM Mcdonald Craig M CM Johnson Linda L Nicorici Alina A Karachunski Peter I PI Day John W JW Kelecic Jason M JM Lowes Linda P LP Alfano Lindsay N LN Darras Basil T BT Kang Peter B PB Quigley Janet J Pasternak Amy E AE Florence Julaine M JM
Muscle & nerve 20150211 4
<h4>Introduction</h4>Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non-ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial.<h4>Methods</h4>Non-ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured.<h4>Results</h4>Forced vit ...[more]
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Project description:The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (±3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers.
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Project description:BackgroundDuchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations of this disease include progressive muscle weakness, gait dysfunction, and motor impairment, leading to a loss of ambulation by the age of 13 years. Molecular diagnosis is the standard diagnostic tool for DMD. This study aimed to investigate disease progression and genetic patterns in Iranian ambulant boys and to find the correlation between genotypes and motor function phenotypes.MethodsThis study was performed on 152 DMD patients. Clinical history, including the disease phenotype, steroid therapy, and the North Star Ambulatory Assessment (NSAA) score, was taken for all the patients. Molecular diagnoses were confirmed by multiplex ligation-dependent probe amplification and next-generation sequencing tests.ResultsA total of 152 Iranian DMD patients were examined in this study. The mean age at the time of disease onset was 4.04 ± 2.00 years, and the mean age at diagnosis was 5.05 ± 2.08 years. The mean age of ambulation loss was 10.9 years. Contracture was reported in 38.9% of cases. In terms of age, the mean total NSAA score showed a peak at 4 years of age, with a mean NSAA score of 24. Annual changes in the NSAA score were determined for all cases, based on the mutation type and exon site. Deletion mutation was found in 79.1% of cases, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon deletion was exon 44 (5.3%), and the most common multiexon deletions were attributed to exons 45-50 and exons 45-52 (4.6%). The results did not indicate any correlation between the mutation type and age at the time of disease onset, loss of ambulation age, and wheelchair dependence; however, a significant association was found between contracture and mutation type. The results showed a significant difference in the NSAA score between the deletion and nonsense groups at the age of 3 years (P = 0.04). No significant correlation was found between the phenotype and exon site. Overall, 91.1% of the study population had a history of corticosteroid use, and 54.1% showed compliance with rehabilitation therapy.ConclusionThis study demonstrated the phenotypes and mutational features of Iranian DMD boys and provided information regarding the natural motor history of the disease, disease progression, diagnosis, and status of DMD management in Iran. The present findings can promote the development of clinical trials and future advanced molecular therapies in Iran.
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Project description:BackgroundDuchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years.ObjectiveEvaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls.MethodsEteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change.ResultsFVC% p annual change was greater for CINRG DNHS Exon 51 controls (- 6.00) versus patients in studies 201/202, study 204, and study 301 (- 2.19, P < 0.001; - 3.66, P 0.004; and - 3.79, P 0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (- 5.67) and All CINRG DNHS (- 5.56) cohorts (P < 0.05, all comparisons).ConclusionsSignificant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.
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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.
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