Objective: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). Methods:A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months.Results: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. Conclusions:Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. Classification of evidence:This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period. Neurology Duchenne muscular dystrophy (DMD) is a progressive muscle disorder due to mutations in the dystrophin gene.1,2 Current treatments can slow disease progression, prolonging ambulation, and improving quality of life and survival. [3][4][5] Corticosteroid treatment for DMD 6-12 is recommended by an American Academy of Neurology practice parameter.13 Furthermore, a recently published standard of care review emphasized the benefit of corticosteroids for DMD.14,15 In a large DMD natural history study currently run by the Cooperative International Neuromuscular Research Group (CINRG), 85% of participants are steroid-treated. 16,17 We hypothesized that weekend prednisone dosing would provide equally effective treatment for DMD as standard daily dosing. Furthermore, corticosteroids might be more widely used in DMD if a dosing regimen had fewer side effects, including less weight gain, less effect on linear Editorial, page 416Podcast Scan this code with your smartphone to access this feature CME Scan this code with your smartphone to access this feature
Introduction Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD). Methods A cross-sectional analysis of clinical data from a multi-institutional, international CINRG DMD Natural History Study of 340 DMD patients aged 2 to 28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%. Results 231 participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47/174), and it was significantly associated with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P>0.68). In patients with cardiomyopathy, 57 % (27/47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15/127) of patients without cardiomyopathy. Discussion Echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort.
Objective: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD). Methods:This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (ϳ20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test.Results: A total of 64 boys with DMD with a mean age of 9.9 Ϯ 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p ϭ 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs. Conclusion:The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period. Classification of evidence:This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.
Early clinical trials of therapies to treat Duchenne muscular dystrophy (DMD), a fatal genetic X-linked pediatric disease, have been designed based on the limited understanding of natural disease progression and variability in clinical measures over different stages of the continuum of the disease. The objective was to inform the design of DMD clinical trials by developing a disease progression modelbased clinical trial simulation (CTS) platform based on measures commonly used in DMD trials. Data were integrated from past studies through the Duchenne Regulatory Science Consortium founded by the Critical Path Institute (15 clinical trials and studies, 1505 subjects, 27,252 observations). Using a nonlinear mixedeffects modeling approach, longitudinal dynamics of five measures were modeled (NorthStar Ambulatory Assessment, forced vital capacity, and the velocities of the following three timed functional tests: time to stand from supine, time to climb 4 stairs, and 10 meter walk-run time). The models were validated on external data sets and captured longitudinal changes in the five measures well, including both early disease when function improves as a result of growth and development and the decline in function in later stages. The models can be used in the CTS platform to perform trial simulations to optimize the selection of inclusion/ exclusion criteria, selection of measures, and other trial parameters. The data sets and models have been reviewed by the US Food and Drug Administration and the European Medicines Agency; have been accepted into the Fit-for-Purpose and Qualification for Novel Methodologies pathways, respectively; and will be submitted for potential endorsement by both agencies.
Objective To perform an open label, pilot study of an orally administered liquid formulation of immediate release pentoxifylline (PTX) to patients with Duchenne muscular dystrophy (DMD). Treatment efficacy, safety and tolerability were assessed. Methods The tolerability and safety of PTX, measures of muscle strength and function were evaluated during 12 months of treatment with PTX. Results Seventeen boys with DMD, between 4 and 8 years, were enrolled at one of 5 Cooperative International Neuromuscular Research Group (CINRG) centers. Only 9 were able to complete the 12 month PTX treatment phase; the primary reasons for discontinuation were adverse events. Intolerable gastrointestinal side effects were experienced by 65% of participants. Two participants experienced severe leukopenia that resolved with medication withdrawal. Conclusions Open-label treatment with liquid formulation of immediate release PTX resulted in a high level of adverse event in boys with DMD. Poor tolerability of this PTX formulation precluded adequate assessment of efficacy.
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