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To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD).
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.
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.
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.
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.
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.3–5 Corticosteroid treatment for DMD6–12 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 growth, and fewer behavior problems, while retaining equal effectiveness. In a prior pilot study of 20 boys with DMD, the weekend treatment (10 mg/kg/wk divided over 2 days) produced fewer side effects while retaining the benefits that were observed with daily prednisone.18 The current randomized, blind study was designed to compare the standard daily dose of prednisone (0.75 mg/kg/d) with the weekend dose that was tested in the pilot study (10 mg/kg/wk divided over 2 days) for boys with DMD age 4 to 10 years.
This was a multicenter, international, prospective, 12-month, randomized, double-blind, placebo-controlled, equivalence study enrolled by 12 institutions of the CINRG network.
The study was approved by the Institutional Review Board at each institution. Written informed consent and assent were obtained from all participants’ parents or caregivers. The trial was registered at the NIH Web site (ClinicalTrials.gov: NCT00110669).
Ambulant, steroid-naive boys with a confirmed diagnosis of DMD, age 4 to 10 years, were included. Other inclusion criteria comprised evidence of muscle weakness by clinical or functional assessment and the ability to provide a reproducible unilateral quantitative muscle testing (QMT) biceps score within 15% of the first assessment.
Exclusion criteria were female DMD carrier status, use of carnitine, other aminoacids, creatine, glutamine, coenzyme Q10, or any herbal supplements within 3 months prior to enrollment, significant concomitant illness including cardiomyopathy, positive response to purified protein derivative, and either no prior exposure to chickenpox or no varicella immunization.
Participants were randomized into 2 groups: daily dose group, daily prednisone 0.75 mg/kg/d plus placebo on Saturday and Sunday; and weekend dose group, weekend prednisone 5 mg/kg on Saturday and 5 mg/kg on Sunday, plus a daily placebo. Capsules containing prednisone, rounded to the nearest 2.5 mg, or inert filer were obtained from Franck’s Pharmacy (Ocala, FL). The CINRG central pharmacy dispensed the study drug. Compliance was monitored at each visit by pill counts and review of medication diaries. Concomitant medications allowed during the study included vitamin D, calcium, ranitidine, and Tums. Participants were advised to follow a high-protein, low-carbohydrate, low-fat diet.
Prednisone/placebo dose was reduced for 1) an increase in body mass index (BMI) (kg/m2) greater than 10% over 3 months; 2) a fasting blood sugar greater than 100 mg/dL after dietary modification; 3) an increase in diastolic blood pressure greater than 10 mm Hg over upper limit of normal for age; 4) an increase in systolic blood pressure greater than15 mm Hg since last visit, after 1 month of low sodium diet; and 5) otherwise nonmanageable side-effects.
The study’s 2 primary efficacy endpoints were upper and lower extremity muscle strength as measured by the QMT scores (the summation of maximal isometric voluntary contraction force of both flexors and extensors of elbow and knee). All evaluators performing testing were certified for interrater reliability by standard CINRG protocol.19,20 Secondary efficacy endpoints included individual QMT scores, grip strength, manual muscle testing (MMT) score (modified Medical Research Council scale), timed function tests (time to run/walk 10 meters, time to climb 4 standard steps, and time to get up from supine position on the floor), the modified Brooke and Vignos scales, and pulmonary function tests (PFTs) that comprised percent predicted forced vital capacity (FVC % predicted), percent predicted forced expiratory volume in 1 second (FEV1 % predicted), maximal voluntary ventilation (MVV), and maximum inspiratory pressure (MIP).21,22 PFTs were performed only by participants who were at least 6 years old at baseline.
The primary safety endpoint was change in BMI. Secondary safety endpoints included weight, height, blood pressure, cataracts, lumbar spine Z score, measured by dual-energy x-ray absorptiometry (DEXA), and behavior, assessed by the Child Behavior Check List (CBCL).23 Syndrome subscales in the CBCL are T scores standardized such that values over 70 are clinically significant.
A total of 8 visits took place at the following timepoints: 2 screening visits, month 1, 3, 6, 9, 12, and post study visit (within 1 week of the month 12 visit). At each visit, participants completed assessments, safety laboratory panels, physical and neurologic examination, and adverse event review. The DEXA and ophthalmology assessments were only completed at baseline and month 12 visits. Recruitment took place over 3 years beginning November 2003; the last participant completed the study in November 2007.
Eligible participants were randomized by the CINRG Coordinating Center within site and equal-sized age stratum (4–6 years, 7–10 years) using a random permuted block randomization scheme (block sizes 2 and 4).
Averages of results from the 2 screening visits and the 2 12-month visits were used to assess primary outcome. Baseline characteristics for efficacy and safety outcomes were summarized using means and standard deviations and compared between the 2 groups using 2-way analysis of variance (ANOVA) with treatment as one factor and age stratum as the second factor.
In order to test the primary hypothesis of efficacy equivalence, an observed cases analysis was employed. The equivalence limit was defined using the baseline data and choosing an equivalence limit of approximately 1 SD or less of the baseline distribution for muscle strength tests and percent predicted PFTs. For MMT score the equivalence limit was defined as one point on the 10-point scale for each of 34 muscles tested. This resulted in an equivalence width of ±2 pounds for the muscle strength tests, ±17 points of the MMT score, and ±10% on the percent predicted PFTs. For each endpoint, the observed difference from baseline (+SD) and the 95% confidence limits of the differences in changes between treatments were calculated. If the difference in the magnitude of the changes from baseline between the 2 treatment groups was small (close to zero), this implied the treatments were equivalent. Two one-sided t tests were done to test whether the difference of changes was higher than the lower bound of equivalence and lower than the higher bound of equivalence simultaneously. If both p values were less than or equal to 0.025, this implied that equivalence was established between treatments. Timed function tests had skewed distributions; therefore, in order to analyze the equivalence of change from baseline to 12 months for timed function tests, a log transformation of the data was performed, and the boundaries of equivalence defined as ±0.4 log seconds. If a participant could not perform the timed test at 12 months due to disease progression, we imputed a value of 30 seconds for the 10-meter walk, 45 seconds for the 4-step climb, and 45 seconds for supine to stand.
An additional analysis was performed on the group of participants who both completed the study and in whom there were no dose reductions.
The hypothesis that the weekend dosing regimen would cause fewer side effects than the daily dosing regimen was tested using 2-way ANOVA. The main treatment effect was assessed comparing type of treatment (weekend vs daily) and, secondarily, treatment by age group interaction. In addition, exploratory analyses examine repeated BMI measurements over time for each participant using linear mixed effects models.24 Frequency, body system, severity, and relationship to drug of adverse events were assessed using the National Cancer Institute’s (NCI) Common Toxicity Criteria.25
Twelve institutions screened 77 participants of whom 64 were eligible and randomized (figure 1). Baseline characteristics are provided in table 1. The mean age of all screened participants was 7.1 years and the median age was 6.9 years. The mean age of all randomized participants was 7.3 years and the median age was 7.2 years. Thirty-four (53%) of the participants were Caucasian, 3 (5%) were African American, 12 (19%) were Asian, and 15 (23%) were from other races. CBCL T scores of aggressive behavior and externalizing were the only significant differences at baseline and were not believed to be clinically meaningful; thus, the randomization procedure was successful.
For the primary efficacy outcomes for muscle strength of QMT arm score and QMT leg score, equivalence between the 2 groups was met with both groups showing improved strength (table 2). Secondary muscle strength outcomes for QMT elbow flexors also showed equivalence, and QMT elbow extensors showed borderline equivalence. Equivalence was not met for secondary muscle strength outcomes MMT, QMT grip, and QMT knee tests. Timed tests for 10-meter walk, 4-step climb, and supine to stand were equivalent between the 2 groups.
Two other secondary efficacy outcomes, FVC and FEV1, did not show equivalence between the 2 groups (table 2).
The side effect profiles of the 2 groups were virtually identical at 12 months with no significant differences in the assessments of anthropometrics, vital signs, DEXA, and CBCL (table 3). Importantly, there was no significant difference in the primary safety endpoint, BMI, comparing daily with weekend dosing at 12 months.
There were 6 prednisone dose reductions in 5 participants in the study. In the daily group, 3 participants had dose reductions because of BMI increase and one participant because of behavior problems. In the weekend group, one participant had 2 dose reductions, one for BMI increase and one for cushingoid features.
BMI changes were also analyzed within each age stratum over time and using the piecewise linear mixed effects model, allowing for a change in slope of BMI at 3 months of treatment within treatment and age groups (figure 2). Although these analyses did not achieve statistical significance, for participants 4–6 years old, we observed a numeric difference toward a larger increase in BMI on the daily dose compared to the weekend dose during the first 3 months of treatment. In the 7- to 10-year-old participants, there was a visual numeric difference, which while not significant, suggested a greater increase in BMI on the daily dose.
Although there was no significant difference between the 2 groups for height measured at 12 months (table 3), there was a significant increase in linear growth over 12 months in the weekend group compared to the daily group (mean change in daily dose group of 4.1 cm and in the weekend dose group of 6.6 cm, p =0.002).
There was no significant difference in the lumbar Z score between the weekend and daily groups at 12 months of treatment (table 3). However, there was a significant difference for change in lumbar Z score from baseline to 12 months favoring the weekend dosing (Z score change of −0.30 in the daily dose and of +0.26 in the weekend dose group, p =0.001).
Adverse events were assessed using the NCI Common Toxicity Criteria25 and analyzed descriptively recognizing limitations of sample size. There were 6 events in each group assigned grade 3 or 4. Five of 6 events in the weekend group and 4 of 6 events in the daily group were progression of weakness and considered not related to study drug. There was one severe case of flu and fever in the weekend group. There was one participant with acute appendicitis and one participant with a scalp laceration in the daily group. Overall, there were no significant differences in number or grade of adverse events between the 2 groups.
One participant in each group discontinued from the study prior to or at the first return visit (month 1) because of an adverse event. In the daily group, the participant with appendicitis discontinued and in the weekend group, one participant discontinued due to severe vomiting. Overall, 6 participants withdrew before the end of the study (4 in the weekend group and 2 in the daily group). An additional analysis excluded the 5 participants with dose reductions. Results remained substantially the same (data not shown).
Following the original demonstration of efficacy of prednisone for DMD by the Clinical Investigation of Duchenne Dystrophy group,28 several randomized, controlled trials refined daily dosing of prednisone for DMD.8,12 A further study did not support efficacy of alternate day dosing.29 A pilot study and a randomized, controlled, crossover trial (sample size 17) demonstrated efficacy of prednisone dosing limited to the first 10 days of the month.30,31 A pilot study of weekend prednisone dosing demonstrating beneficial effects on strength preservation, but fewer side effects than daily prednisone, provided the rationale for the current randomized, controlled study.18
The current study demonstrated that weekend dosing of prednisone for DMD was equivalent to daily dosing over 12 months based on the study-defined, primary efficacy outcome of quantitative leg and arm muscle strength and no significant difference in the primary safety outcome of BMI. This randomized, controlled study adds to the body of evidence supporting the use of corticosteroid treatment for DMD and expands the clinical dosing options for prednisone treatment of DMD.12
The current study also examined secondary efficacy outcomes comprising strength assessments by MMT and QMT of several individual muscle groups and demonstrated equivalence of QMT elbow flexor scores between the 2 groups. QMT elbow extensor, MMT, QMT grip score, and QMT knee scores did not meet equivalence. PFT results demonstrated variability and achieved equivalence for MVV and MIP, but not for FVC % predicted and FEV1 % predicted.
The most common adverse effect of corticosteroid use in patients with DMD is weight gain, which increases the mechanical load on weakening muscles and likely contributes to cessation of ambulation.32 BMI was above the 50th percentile for the mean age of our population at baseline.33 This finding alone suggests that caloric intake monitoring is important for patients with DMD. In this study we showed that the primary safety outcome measure, BMI, was not significantly different between the daily and weekend dosing groups at 12 months. Although the study was not powered to establish patterns of BMI change, different effects on BMI emerged from age group subanalysis. Numeric, but not statistically significant, differences observed in figure 2 suggested that older participants with DMD (7–10 years) had a greater increase in BMI than younger participants (4–6 years) with both dose regimens, although more so with the daily dose regimen, possibly due in part to decreased physical activity. Furthermore, the temporal pattern of weight gain in the younger participants (4–6 years) appeared different between the daily and weekend dosing groups, with earlier and greater weight gain with the daily dosing group.
Weekend prednisone dosing was associated with significantly greater linear growth than daily dosing. Although patients with DMD have a normal length and weight at birth,34 delayed growth starts during the first years of life and median height of patients with DMD is slightly less than the 50th percentile before age 10 years. By age 18 years, median height is less than the 5th percentile.35
Osteopenia is common in children with neuromuscular disorders, who have an increased incidence of pathologic fractures.32,36 During 12 months of treatment, weekend and daily prednisone dosing were each associated with small changes in lumbar spine Z score, thus alleviating a common concern that corticosteroid treatment in patients with DMD increases the risk of osteoporosis. Increases in muscle strength and activity induced by prednisone treatment may stabilize bone density, as supported by the current study and postulated previously.32,37–40 However, a longer study would be required to adequately assess the effects of corticosteroid use on bone metabolism and fracture risk. Furthermore, we did not assess femoral bone density, which has been shown to be abnormal even in younger ambulant boys with DMD and to correlate with increased risk of lower extremity fractures.39
Corticosteroid-induced behavior changes, including hyperactivity, depression, or psychosis, are commonly accepted symptoms in patients with DMD that may limit treatment.15 In our study we found no clinically significant baseline behavioral abnormalities. Both daily and weekend prednisone dosing resulted in similar CBCL scores after 12 months of treatment with neither group showing worsening of behavior on therapy. No participants discontinued the study because of behavioral adverse effects although one participant on daily dosing had a dose reduction due to behavioral problems.
A limitation of this study was the 12-month duration of treatment. However, most study participants transitioned into a large multicenter observational study of DMD that will provide long-term follow-up to further inform treatment decisions.
Overall, this randomized, blind placebo-controlled study demonstrated equivalent efficacy of weekend prednisone dosing for DMD as standard daily dosing. Although there was no significant difference in the primary safety outcome of BMI between the groups, there appeared to be significant increases in linear growth and bone mineral density favored by the weekend dose regimen. Most importantly, the finding of equivalently effective but different dosing regimens with similar safety profiles provides clinicians treating patients with DMD with alternative therapeutic options that may aid some families to adjust to corticosteroid treatment, which is of proven benefit for prolonging ambulation in DMD.
Editorial, page 416
Dr. Escolar: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, study supervision, obtaining funding. L.P. Hache: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis, study supervision, study monitoring and grant reports. Dr. Clemens: drafting/revising the manuscript, analysis or interpretation of data. Dr. Cnaan: drafting/revising the manuscript, analysis or interpretation of data, statistical analysis. Dr. McDonald: drafting/revising the manuscript, analysis or interpretation of data, contribution of vital reagents/tools/patients, acquisition of data, study supervision. Dr. Viswanathan: analysis or interpretation of data, acquisition of data, study supervision. Dr. Kornberg: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data, study supervision. Dr. Bertorini: drafting/revising the manuscript, acquisition of data. Dr. Nevo: drafting/revising the manuscript, study concept or design, acquisition of data. Dr. Lotze: drafting/revising the manuscript, acquisition of data, study supervision. Dr. Pestronk: drafting/revising the manuscript, study concept or design, study supervision. Dr. Ryan: study concept or design, analysis or interpretation of data, acquisition of data, study supervision. Dr. Monasterio: study concept or design, acquisition of data. Dr. Day: study concept or design, contribution of vital reagents/tools/patients, acquisition of data. A. Zimmerman: drafting/revising the manuscript, study concept or design, acquisition of data, study supervision. A. Arrieta: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data, statistical analysis, study supervision. E. Henricson: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, study supervision, obtaining funding. J. Mayhew: study concept or design, acquisition of data, study supervision. Dr. Florence: study concept or design, acquisition of data, study supervision. F. Hu: analysis or interpretation of data, statistical analysis. Dr. Connolly: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, study supervision.
Ted Abresch, MS (University of California at Davis, site coinvestigator); Masanori Igarashi, MD (University of Tennessee at Memphis, site coinvestigator); Kathryn North, MD (Children’s Hospital at Westmead, site coinvestigator); Hoda Abdel-Hamid, MD (Children’s Hospital of Pittsburgh of UPMC, site coinvestigator); and Jean Teasley, MD (Children’s Hospital, Richmond, site coinvestigator).
Contributors: Michelle Cregan (University of California at Davis, site study coordinator); Linda Johnson and Elizabeth Pine (University of California at Davis, site clinical evaluators); Sarah Kaminski (Children’s National Medical Center, site study coordinator); Marisa Bartczak, Tina Duong, and Katherine Parker (Children’s National Medical Center, site clinical evaluators); Vijay Anand and Sivaprakasam Chidambaranathan (Sundaram Medical Foundation, site study coordinators); Suresh Kumar (Sundaram Medical Foundation, site clinical evaluator); Kate Carroll, Katy de Valle, Jill Bicknell, and Rachel Kennedy (Royal Children’s Hospital, site study coordinators and clinical evaluators); Hani Rashed (University of Tennessee at Memphis, site study coordinator); Judy Clifft and Ann Coleman (University of Tennessee at Memphis, site clinical evaluators); Debbie Yaffe (Hadassah University Hospital, site study coordinator); Elana Weisband (Hadassah University Hospital, site clinical evaluator); Karen Jones (Texas Children’s Hospital, site study coordinator); Anjali Gupta (Texas Children’s Hospital, site clinical evaluator); Charlie Wulf and Renee Renna (Washington University, site study coordinator); Betsy Malkus and Catherine Siener (Washington University, site clinical evaluators); Kristy Rose (Children’s Hospital at Westmead, site study coordinator and clinical evaluator); Karen Karnavas and Kara Paulukonis (Children’s Hospital of Pittsburgh of UPMC, site clinical evaluators); Barbara Grillo (Children’s Hospital, Richmond, site study coordinator); Susan Blair (Children’s Hospital, Richmond, site clinical evaluator); Susan Rolandelli (University of Minnesota, site study coordinator); and Marcia Margolis (University of Minnesota, site clinical evaluator). The authors thank the patients and their families for their participation in the study; the CINRG Data and Safety Monitoring Board Committee; and Jean Mah and Nancy Kuntz for critical review of the manuscript.
Dr. Escolar serves on a scientific advisory board for the NIH/NINDS; serves on the speakers’ bureau for and has received funding for travel and speaker honoraria from Athena Diagnostics, Inc.; serves as a consultant for Acceleron Pharma, HALO therapeutics, AVI Biopharma, Gerson Lheman Group (GLC), and Medacorp; and has received research support from the NIH, the Muscular Dystrophy Association, and the Foundation to Eradicate Duchenne (FED). L.P. Hache serves on the CINRG Executive Committee, CINRG Publication and Outcomes Subcommittees, and Treat-NMD Global Database Oversight Committee; and has received research/salary support from Genzyme Corporation, the US Department of Defense, and the NIH. Dr. Clemens receives/has received research support from Genzyme Corporation, Amicus Therapeutics, Inc., the US Department of Defense, the US Department of Veterans Affairs, and the NIH. Dr. Cnaan serves on scientific advisory boards for the NIH (NIGMS, NIDDK, NCRR) and the FDA; and receives research support from the NIH (NINDS, NCRR), the US Department of Defense, the US Department of Education, and the Gilbert Family Neurofibromatosis Institute. Dr. McDonald serves on scientific advisory boards for PTC Therapeutics, Inc., GlaxoSmithKline, BioMarin Pharmaceutical Inc., and Gilead Sciences, Inc.; and receives research support from PTC Therapeutics, Inc., Insmed Inc., the NIH/NIDRR, the US Department of Education, Shriner’s Hospital for Children, the Muscular Dystrophy Association, and Clinical Research Network in Duchenne Muscular Dystrophy. Dr. Viswanathan reports no disclosures. Dr. Kornberg has received funding for travel from Genzyme Corporation and Biogen Idec; and has received research support from Multiple Sclerosis Research Australia. Dr. Bertorini serves on speakers’ bureaus for and has received funding for travel and speaker honoraria from Teva Pharmaceutical Industries Ltd., EMD Serono, Inc., Pfeiffer Pharmaceuticals Inc., Allergan, Inc., Pfizer Inc, and Athena Diagnostics, Inc.; serves on the editorial board of the Journal of Clinical Neuromuscular Disorders; and receives publishing royalties from editing three books with Elsevier (2002, 2008, 2010). Dr. Nevo served on the CINRG Executive Committee and serves on CINRG Sub-Therapeutic Subcommittee; has served as a consultant for Teva Pharmaceutical Industries Ltd.; holds a provisional patent on the use of glatiramer acetate in muscular dystrophy; and receives research support from AFM, the Israeli Ministry of Health and the Israel Science Foundation. Dr. Lotze serves on a scientific advisory board for Opexa Therapeutics. Dr. Pestronk serves on the scientific advisory board of the Myositis Association; has served on the speakers’ bureau for and received speaker honoraria from Athena Diagnostics, Inc.; holds stock in Johnson & Johnson; is director of the Washington University Neuromuscular Clinical Laboratory which performs antibody testing and muscle and nerve pathology analysis, procedures for which the Washington University Neurology Department bills; may accrue revenue on patents re: TS-HDS antibody, GALOP antibody, GM1 ganglioside antibody, and Sulfatide antibody; has received license fee payments from Athena Diagnostics, Inc. for patents re: antibody testing; and receives/has received research support from Genzyme Corporation, Insmed Inc., Knopp Neurosciences Inc., Prosensa, Isis Pharmaceuticals, Inc., sanofi-aventis, Cytokinetics, Incorporated, the NIH, CINRG Children’s Hospital Washington DC, the Myositis Association, and the Muscular Dystrophy Association. Dr. Ryan serves on a therapeutic advisory committee for Treat-NMD; serves as an Associate Editor for the Journal of Pediatric Neurology and on the editorial board of the Journal of Clinical Neuroscience; and receives research support from PTC Therapeutics, Inc. Dr. Monasterio reports no disclosures. Dr. Day serves on a scientific advisory board for PTC Therapeutics, Inc.; receives research support from Genzyme Corporation, PTC Therapeutics, Inc., the NIH (NIAMS, NINDS), and the Muscular Dystrophy Association; receives royalties for patents on genetic testing for myotonic dystrophy type 2 and spinocerebellar ataxia type 5 that are licensed to Athena Diagnostics; and serves on the MDA Medical Advisory Committee. A. Zimmerman receives salary support from the US Department of Defense and the US Department of Education. A. Arrieta receives salary support from the US Department of Defense, the US Department of Education, the NIH, and the Muscular Dystrophy Association. E. Henricson serves as a consultant for PTC Therapeutics, Inc. and receives salary support from the US Department of Education. J. Mayhew has received funding for travel and speaker honoraria from Genzyme Corporation and serves/has served as a consultant for Genzyme Corporation and Enobia Pharma Inc. Dr. Florence serves on a scientific advisory board for Prosensa; serves on the editorial board of Neuromuscular Disorders; and has serves/has served as a consultant for Prosensa, GlaxoSmithKline, Genzyme Corporation, PTC Therapeutics, Inc., and Acceleron Pharma. F. Hu receives salary support from the US Department of Defense, the US Department of Education, and the NIH/NCRR. Dr. Connolly serves as a Contributing Editor for the Journal of Child Neurology and receives research support from PTC Therapeutics, Inc., the NIH, and the Muscular Dystrophy Association.