Search

This study examined functional trajectories of subjects during the transition phase between ambulatory and non-ambulatory Duchenne muscular dystrophy (DMD) to inform clinical trial designs for new therapeutics. Ambulatory, pulmonary, and upper limb function leading up to loss of ambulation (LoA) and non-ambulatory measures following LoA were quantified; time ordering of pulmonary and upper limb milestones relative to LoA were determined; and the 10-second time threshold for 10-meter walk/run (10MWR) as a marker of approaching LOA was explored. Included in this analysis were 51 subjects aged between 7 and 18 years who experienced LoA during follow-up in the PRO-DMD-01 natural history study. Mean age at LoA was 12.7 (7.1–18.6) years. Mean annual rates of decline in forced vital capacity (FVC) <80%-predicted and performance of upper limb (PUL) 1.2 total score were smaller before than after LoA, but not significantly (FVC %-predicted: 5.6% vs. 10.1%, p = 0.21; PUL 1.2 total score: 2.3 vs. 3.8 units, p = 0.20). More than half of patients experienced clinically significant deficits in FVC %-predicted and PUL 1.2 before experiencing LoA. Among subjects with baseline 10MWR >10 s, those with <1 year to LoA had similar mean ages but significantly worse mean ambulatory function at baseline compared to those with ≥1 year to LoA. Enriching DMD clinical trials for patients with declining pulmonary or upper limb function is achievable without restricting enrollment to non-ambulatory patients. The sequencing of LoA and initial deficits in pulmonary and upper limb function varied across patients and highlights the potential for composite outcomes or multi-outcome trial designs to assess disease-modifying therapies more comprehensively. [ABSTRACT FROM AUTHOR]

Background: Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy.Methods: In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 108 CDCs) or placebo intravenously every 3 months for a total of four infusions. Clinicians, caregivers, patients, and clinical operations personnel were fully masked to treatment groups. The primary outcome was the change in mid-level elbow Performance of Upper Limb version 1.2 (PUL 1.2) score at 12 months, assessed in the intention-to-treat population. Safety was assessed in all individuals who received an investigational product. This trial is registered with ClinicalTrials.gov, NCT03406780.Findings: Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7-59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred.Interpretation: CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy.Funding: Capricor Therapeutics. [ABSTRACT FROM AUTHOR]

Introduction/Aims: In comparative studies, treatment effects are typically evaluated at a specific time point. When data are collected periodically, an alternative, clinically meaningful approach could be used to assess the totality of treatment effects. We applied a well‐developed analytical procedure for evaluating longitudinal treatment effects using North Star Ambulatory Assessment (NSAA) data for illustration. Methods: The NSAA comprises 17 scorable items/outcomes that measure changes in motor function. Using NSAA data from the published ataluren phase 3, randomized, placebo‐controlled trial (NCT01826487), cumulative counts of failures to perform each item (transition from 2/1 [able/impaired] to 0 [unable]) were collected at specified time points for each patient over 48 wk. Treatment group‐wise mean cumulative item failure count curves were constructed, comparing ataluren versus placebo and deflazacort versus prednisone/prednisolone among placebo‐treated patients. The steeper the curve, the worse the outcome. A clinically meaningful summary of the between‐group difference was provided for each comparison. Results: The curve was uniformly steeper for placebo than ataluren after 16 wk and for prednisone/prednisolone than deflazacort after 8 wk. The two curves in each comparison continued to diverge thereafter, indicating sustained treatment benefits over time. Using a unique analytical approach, cumulative failure rates were reduced, on average, by 27% for ataluren versus placebo (rate ratio, 0.73; 95% confidence interval [CI], 0.55–0.97; p =.027) and 28% for deflazacort versus prednisone/prednisolone (rate ratio, 0.72; 95% CI, 0.53–0.96; p =.028). Discussion: Unlike fixed‐time analyses, this analytical approach enabled demonstration of cumulative, longitudinal treatment effects over time using repeatedly measured NSAA observations. [ABSTRACT FROM AUTHOR]

Introduction: We conducted an open-label study to examine the effects of the flavonoid (-)-epicatechin in seven ambulatory adult patients with Becker muscular dystrophy (BMD).Methods: Seven participants received (-)-epicatechin 50 mg twice per day for 8 weeks. Pre- and postprocedures included biceps brachii biopsy to assess muscle structure and growth-relevant endpoints by western blotting, mitochondria volume measurement, and cristae abundance by electron microscopy, graded exercise testing, and muscle strength and function tests.Results: Western blotting showed significantly increased levels of enzymes modulating cellular bioenergetics (liver kinase B1 and 5'-adenosine monophosphate-activated protein kinase). Peroxisome proliferator-activated receptor gamma coactivator-1alpha, a transcriptional coactivator of genes involved in mitochondrial biogenesis and cristae-associated mitofilin levels, increased as did cristae abundance. Muscle and plasma follistatin increased significantly while myostatin decreased. Markers of skeletal muscle regeneration myogenin, myogenic regulatory factor-5, myoblast determination protein 1, myocyte enhancer factor-2, and structure-associated proteins, including dysferlin, utrophin, and intracellular creatine kinase, also increased. Exercise testing demonstrated decreased heart rate, maximal oxygen consumption per kilogram, and plasma lactate levels at defined workloads. Tissue saturation index improved in resting and postexercise states.Discussion: (-)-Epicatechin, an exercise mimetic, appears to have short-term positive effects on tissue biomarkers indicative of mitochondrial biogenesis and muscle regeneration, and produced improvements in graded exercise testing parameters in patients with BMD. [ABSTRACT FROM AUTHOR]

Introduction: In this study we characterized disease progression over 48 weeks among boys receiving deflazacort vs prednisone/prednisolone placebo arm treatment in two recent Duchenne muscular dystrophy (DMD) clinical trials.Methods: Ambulatory boys with DMD receiving placebo in the phase 3 ataluren (N = 115) and tadalafil (N = 116) trials were included. The trials required at least 6 months of prior corticosteroid use and stable baseline dosing. Associations between corticosteroid use and 48-week changes in ambulatory function were estimated using mixed models. Adjusted differences between corticosteroid groups were pooled in a meta-analysis.Results: In the meta-analysis, deflazacort-treated patients vs prednisone/prednisolone-treated patients experienced, on average, lower declines of 28.3 meters on 6-minute walk distance (95% confidence interval [CI], 5.7, 50.9; 2.9 seconds on rise from supine [95% CI, 0.9, 4.9 seconds]; 2.3 seconds on 4-stair climb [95% CI, 0.5, 4.1 seconds]; and 2.9 [95% CI, 0.1, 5.8] points on the North Star Ambulatory Assessment linearized score).Discussion: Deflazacort-treated patients experienced significantly lower functional decline over 48 weeks. [ABSTRACT FROM AUTHOR]

Highlights • Natural history changes in pulmonary function tests across time in Duchenne muscular dystrophy. • Treatment with glucocorticoids (steroids) > 1 year was compared to steroid naïve treatment. • Steroid treatment slowed the rate of pulmonary decline as measured by FVC%p in 7–9.9 year olds; • Steroid treatment resulted in higher peak absolute FVC and PEFr values with later onset of decline. • Time to FVC < 1 liter was delayed by steroid treatment; FVC < 1 liter increased risk of death 4-fold. Abstract We describe changes in pulmonary function measures across time in Duchenne muscular dystrophy patients treated with glucocorticoids (GCs) > 1 year compared to GC naïve patients in the Cooperative International Research Group Duchenne Natural History Study, a multicenter prospective cohort study. 397 participants underwent 2799 pulmonary function assessments over a period up to 10 years. Fifty-three GC naïve participants (< 1 month exposure) were compared to 322 subjects with > 1 year cumulative GC treatment. Forced vital capacity (FVC), peak expiratory flow rate (PEFr), maximal inspiratory and expiratory pressures were performed and calculated as a percent predicted (%p). GC treatment slowed the rate of pulmonary decline as measured by FVC%p, in patients aged 7–9.9 years. GC treatment slowed 12 and 24-month progression of percent predicted spirometry to a greater degree in those with baseline FVC%p from < 80–34%. GC treatment resulted in higher peak absolute FVC and PEFr values with later onset of decline. Progression to an absolute FVC < 1 liter was delayed by GC treatment. Patients who reached a FVC below 1 L were 4.1 times more likely to die (p = 0.017). Long-term glucocorticoid treatment slows pulmonary disease progression in Duchenne dystrophy throughout the lifespan. [ABSTRACT FROM AUTHOR]

Abstract: Objective: This double‐blind, randomized, placebo‐controlled Phase 2 study (NCT01462292) assessed the 24‐week efficacy, safety, tolerability, and pharmacokinetics of two different subcutaneous drisapersen doses, and the 24‐week off‐dose persistent effect, in ambulant Duchenne muscular dystrophy (DMD) patients. Methods: Male DMD patients (≥5 years; time to rise from floor ≤15 s) were randomized to drisapersen 3 mg/kg/week, 6 mg/kg/week or placebo. The primary efficacy endpoint was change from baseline in 6‐minute walking distance (6MWD) at week 24. Secondary endpoints included changes in timed function tests, muscle strength, and pulmonary function tests. Results: Fifty‐one patients were randomized to placebo (N = 16), drisapersen 3 mg/kg/week (N = 17) or 6 mg/kg/week (N = 18). All but 2 patients had baseline rise from floor time <7 s. This study was exploratory and not prospectively powered; however, a difference in mean 6MWD versus placebo in favor of drisapersen 6 mg/kg/week was observed at week 24 (27.1 m; P = 0.069) and maintained 24 weeks off‐treatment (27.9 m; P = 0.177). The 3 mg/kg/week group showed no statistically significant difference in mean 6MWD versus placebo. For some secondary endpoints, a more positive response in favor of drisapersen 6 mg/kg/week compared to placebo was shown. Drisapersen had a long half‐life with steady state reached after approximately 36 weeks. Most common adverse events in both drisapersen groups were related to injection site reactions and subclinical proteinuria. Interpretation: Drisapersen 6 mg/kg/week for 24 weeks resulted in a treatment benefit in 6MWD, largely maintained 24 weeks off‐treatment. This study provided insights for further studies to optimize dosage regimen. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy.Methods: For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832.Findings: 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501).Interpretation: In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death.Funding: US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD.Methods: We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs ≥9 years), duration of previous corticosteroid use (6 months to <12 months vs ≥12 months), and baseline 6MWD (<350 m vs ≥350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487.Findings: Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47·7 m (SE 9·3) for ataluren-treated patients and -60·7 m (9·3) for placebo-treated patients (difference 13·0 m [SE 10·4], 95% CI -7·4 to 33·4; p=0·213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7·7 m (SE 24·1, 95% CI -54·9 to 39·5; p=0·749) in the group with a 6MWD of less than 300 m, 42·9 m (15·9, 11·8-74·0; p=0·007) in the group with a 6MWD of 300 m or more to less than 400 m, and -9·5 m (17·2, -43·2 to 24·2; p=0·580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment.Interpretation: Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint.Funding: PTC Therapeutics. [ABSTRACT FROM AUTHOR]

In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10–18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated “by patient” (HR 0.33, p = 0.0187) and for “all BAEs” (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics. [ABSTRACT FROM AUTHOR]

Objective: Delandistrogene moxeparvovec is approved in the USA for the treatment of ambulatory patients (4–5 years) with Duchenne muscular dystrophy. ENDEAVOR (SRP‐9001‐103; NCT04626674) is a single‐arm, open‐label study to evaluate delandistrogene moxeparvovec micro‐dystrophin expression, safety, and functional outcomes following administration of commercial process delandistrogene moxeparvovec. Methods: In cohort 1 of ENDEAVOR (N = 20), eligible ambulatory males, aged ≥4 to <8 years, received a single intravenous infusion of delandistrogene moxeparvovec (1.33 × 1014 vg/kg). The primary endpoint was change from baseline (CFBL) to week 12 in delandistrogene moxeparvovec micro‐dystrophin by western blot. Additional endpoints evaluated included: safety; vector genome copies; CFBL to week 12 in muscle fiber‐localized micro‐dystrophin by immunofluorescence; and functional assessments, including North Star Ambulatory Assessment, with comparison with a propensity score‐weighted external natural history control. Results: The 1‐year safety profile of commercial process delandistrogene moxeparvovec in ENDEAVOR was consistent with safety data reported in other delandistrogene moxeparvovec trials (NCT03375164 and NCT03769116). Delandistrogene moxeparvovec micro‐dystrophin expression was robust, with sarcolemmal localization at week 12; mean (SD) CFBL in western blot, 54.2% (42.6); p < 0.0001. At 1 year, patients demonstrated stabilized or improved North Star Ambulatory Assessment total scores; mean (SD) CFBL, +4.0 (3.5). Treatment versus a propensity score‐weighted external natural history control demonstrated a statistically significant difference in least squares mean (standard error) CFBL in North Star Ambulatory Assessment, +3.2 (0.6) points; p < 0.0001. Interpretation: Results confirm efficient transduction of muscle by delandistrogene moxeparvovec. One‐year post‐treatment, delandistrogene moxeparvovec was well tolerated, and demonstrated stabilized or improved motor function, suggesting a clinical benefit for patients with Duchenne muscular dystrophy. ANN NEUROL 2023;94:955–968 [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data ( N = 57) provided insight into the natural history of the 6-minute walk test (6MWT) and other endpoints. Methods: Evaluations performed every 6 weeks included the 6-minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry. Results: Baseline age (≥7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (Δ6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1 of 42 (2.3%) subjects able to stand from supine lost ambulation. Conclusion: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials. Muscle Nerve 48: 343-356, 2013 [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate-determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357-368, 2013 [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Duchenne muscular dystrophy (DMD) is caused by a genetic defect resulting in absent dystrophin, yet children are able to walk when small and young but lose this ability as they grow. The mdx mouse has absent dystrophin yet does not exhibit significant disability. Methods Allometric modeling of linearly increasing load per muscle fiber and stress on the sarcolemma with growth and exponential decline associated with loss of muscle fibers correlated with case studies and animal models of DMD. Results Smaller species or breeds are predictably less affected than large as follows: mdx mice < small golden retriever muscular dystrophy (GRMD) dogs < large GRMD dogs < humans. Case reports of combined growth hormone and dystrophin deficiency show a relatively benign course of disease. Conclusions Future therapeutic trials in DMD might include specific growth inhibitors in combination with standard of care treatments to delay the clinical onset and reduce the severity of disease and disability. Muscle Nerve 48: 336-342, 2013 [ABSTRACT FROM AUTHOR]

Unlabelled: Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials.Methods: The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2-28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/health-related quality-of-life instruments.Results: Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years).Conclusions: Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics. [ABSTRACT FROM AUTHOR]

ABSTRACT Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials. Methods The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2-28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/health-related quality-of-life instruments. Results Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years). Conclusions Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics. Muscle Nerve, 2013 [ABSTRACT FROM AUTHOR]

Children with spinal cord injury (SCI) are at risk for the same health related complications experienced by adults with SCI; however, children are likely at increased risk due to the young age at which the injury was sustained. Common health related complications impact the cardiovascular, respiratory, and musculoskeletal systems, increasing the risk of cardiovascular disease, metabolic syndrome, and fractures, as well as impacting the ability to complete everyday tasks. The available literature shows that children and adults with SCI have a high prevalence of metabolic syndrome and decreased muscle mass, resting energy expenditure, peak oxygen consumption, and bone mineral density. Exercise may have an impact on these complications, thus increasing overall health and fitness. Some literature is available on the effects of exercise for adults with SCI, but few studies have examined these effects for children. Pediatric and adult studies have shown some positive effects on muscle mass, resting energy expenditure, peak oxygen consumption, and bone mineral density. However, more research is needed to develop optimal exercise programs that adequately address long-term health in children who have a long lifetime ahead. [ABSTRACT FROM AUTHOR]

Children with spinal cord injury (SCI) are at risk for the same health related complications experienced by adults with SCI; however, children are likely at increased risk due to the young age at which the injury was sustained. Common health related complications impact the cardiovascular, respiratory, and musculoskeletal systems, increasing the risk of cardiovascular disease, metabolic syndrome, and fractures, as well as impacting the ability to complete everyday tasks. The available literature shows that children and adults with SCI have a high prevalence of metabolic syndrome and decreased muscle mass, resting energy expenditure, peak oxygen consumption, and bone mineral density. Exercise may have an impact on these complications, thus increasing overall health and fitness. Some literature is available on the effects of exercise for adults with SCI, but few studies have examined these effects for children. Pediatric and adult studies have shown some positive effects on muscle mass, resting energy expenditure, peak oxygen consumption, and bone mineral density. However, more research is needed to develop optimal exercise programs that adequately address long-term health in children who have a long lifetime ahead. [ABSTRACT FROM AUTHOR]

In this study we used the 6-minute walk distance (6MWD) to characterize ambulation over time in Duchenne/Becker muscular dystrophy (DBMD). The 6MWD was assessed in 18 boys with DBMD and 22 healthy boys, ages 4-12 years, over mean [range] intervals of 58 [39-87] and 69 [52-113] weeks, respectively. Height and weight increased similarly in both groups. At 52 weeks, 6MWD decreased in 12 of 18 (67%) DBMD subjects (overall mean [range]: 357 [125-481] to 300 [0-510] meters; Δ −57 meters, −15.9%), but increased in 14 of 22 (64%) healthy subjects (overall mean [range]: 623 [479-754] to 636 [547-717] meters; Δ +13 meters, +2.1%). Two DBMD subjects lost ambulation. Changes in 6MWD depended on stride length and age; improvements usually occurred by 7-8 years of age; older DBMD subjects worsened, whereas older healthy subjects were stable. The 6MWD changes at 1 year confirm the validity of this endpoint and emphasize that preserving ambulation must remain a major goal of DBMD therapy. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

In Duchenne muscular dystrophy, data directly linking changes in clinical outcome measures to patient-perceived well-being are lacking. This study evaluated the relationship between clinical outcome measures used in clinical trials of ambulatory Duchenne muscular dystrophy (Vignos functional grade, quantitative knee extension strength, timed functional performance measures, and gait velocity) and 2 health-related quality of life measures—the Pediatric Outcomes Data Collection Instrument and Pediatric Quality of Life Inventory—in 52 ambulatory Duchenne muscular dystrophy subjects and 36 controls. Those with the disease showed significant decrements in parent proxy-reported health-related quality of life measures versus controls across all domains. The Pediatric Outcomes Data Collection Instrument transfers/basic mobility and sports/ physical function and the Pediatric Quality of Life Inventory physical functioning domains had significant associations with age (and hence disease progression) and traditional clinical outcome measures employed in clinical trials of ambulatory boys with Duchenne muscular dystrophy. Selected domains of the Pediatric Outcomes Data Collection Instrument and generic Pediatric Quality of Life Inventory are potential patient-reported outcome measures for clinical trials in ambulatory individuals with the disease. [ABSTRACT FROM PUBLISHER]

Walking abnormalities are prominent in Duchenne muscular dystrophy (DMD). We modified the 6-minute walk test (6MWT) for use as an outcome measure in patients with DMD and evaluated its performance in 21 ambulatory boys with DMD and 34 healthy boys, ages 4 to 12 years. Boys with DMD were tested twice, ∼1 week apart; controls were tested once. The groups had similar age, height, and weight. All tests were completed. Boys who fell recovered rapidly from falls without injury. Mean ± SD [range] 6-minute walk distance (6MWD) was lower in boys with DMD than in controls (366 ± 83 [125-481] m vs. 621 ± 68 [479-754] m; P < 0.0001; unpaired t-test). Test-retest correlation for boys with DMD was high ( r = 0.91). Stride length ( R2 = 0.89; P < 0.0001) was the major determinant of 6MWD for both boys with DMD and controls. A modified 6MWT is feasible and safe, documents disease-related limitations on ambulation, is reproducible, and offers a new outcome measure for DMD natural history and therapeutic trials. Muscle Nerve, 2010 [ABSTRACT FROM AUTHOR]

Project HERCULES has developed a natural history model (NHM) of disease progression in Duchenne muscular dystrophy (DMD) that comprises eight ordered health states (two ambulatory states, one transfer state indicating increased caregiver burden in which patients cannot walk/run 10m or rise from floor but can still support their own weight, and five non-ambulatory states). The current study used data from nine sources (clinical trial placebo arms, one real-world dataset, and three natural history datasets) to further characterize patients with DMD according to these health states. The study included 1,173 patients across 5,306‬ visits. Patients were on average older and exhibited worse ambulatory, pulmonary, upper limb, and cardiac functions with each successive health state. Mean±SE ages increased monotonically across health states, starting with 8.47±0.07 for early ambulatory, 10.86±0.13 for late ambulatory, 11.65±0.35 for transfer state, and ranging from 13.17±0.32 to 16.84±0.37 for the non-ambulatory states. North Star Ambulatory Assessment (NSAA) total score, which measures motor function and ranges from 34 (best) to 0 (worst), was 23.7 (interquartile range [IQR]: 20–30) for early ambulatory patients, 12.7 (IQR: 9–16) for late ambulatory patients, and 3.9 (IQR: 2–5) for transfer patients. Pulmonary function as measured by mean±SE of forced vital capacity percent predicted (FVC%p) was 94.5±0.8 for early ambulatory, 89.1±1.4 for late ambulatory, and 80.2±2.8 for transfer states, and decreased from 77.2±1.7 to 20.6±1.6 across the five non-ambulatory health states. In summary, these findings further characterize health states and their interpretation in economic modeling and decision-making in DMD management. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether the longitudinal progression of decline in left ventricular ejection fraction (LVEF) in Duchenne muscular dystrophy (DMD) patients is moderated by ADRB1 genotype and whether the efficacy of ß-blocker therapy is influenced by genotype status. About 147 DMD patients (6-34 years.) were analyzed with a focus on β1 adrenergic receptor (ADRB1) genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients and Arg389 patients. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for ß-blocker use. Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (~12 years). However, there was no difference between genotype groups in the progression of decline in LVEF. There was a significant effect of ß-blocker use on longitudinal LVEF, wherein patients on ß-blockers had systematically lower LVEF when compared to patients not on ß-blockers. However, the effect of ß-blocker therapy on LVEF was not affected by ADRB1 genotype. The current study did not demonstrate an influence of patient ADRB1 genotype on longitudinal LVEF in our cohort. Despite previous literature suggesting a positive influence of ß-blocker use on cardiac function in DMD patients and of an ADRB1 genotypic difference in responsiveness to ß-blocker use, we did not observe this in our cohort. Interestingly, our cohort did not demonstrate a positive influence of ß-blocker use on LVEF measures. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Eteplirsen, approved in the US for patients with Duchenne muscular dystrophy (DMD) with exon 51 skip‐amenable variants, is associated with attenuated ambulatory/pulmonary decline versus DMD natural history (NH). We report overall survival in a US cohort receiving eteplirsen and contextualize these outcomes versus DMD NH. Methods: US patients with DMD receiving eteplirsen were followed through a patient support program, with data collected on ages at eteplirsen initiation and death/end of follow‐up. Individual DMD NH data were extracted by digitizing Kaplan–Meier (KM) curves from published systematic and targeted literature reviews. Overall survival age was analyzed using KM curves and contextualized with DMD NH survival curves; subanalyses considered age groups and duration of eteplirsen exposure. Overall survival time from treatment initiation was also evaluated. Results: A total of 579 eteplirsen‐treated patients were included. During a total follow‐up of 2119 person‐years, median survival age was 32.8 years. DMD NH survival curves extracted from four publications (follow‐up for 1224 DMD NH controls) showed overall pooled median survival age of 27.4 years. Eteplirsen‐treated patients had significantly longer survival from treatment initiation versus age‐matched controls (age‐adjusted hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.44–0.98; p <.05). Longer treatment exposure was associated with improved survival (HR, 0.15; 95% CI, 0.05–0.41; p <.001). Comparisons using different DMD NH cohorts to address common risks of bias yielded consistent findings. Discussion: Data suggest eteplirsen may prolong survival in patients with DMD across a wide age range. As more data become available, the impact of eteplirsen on survival will be further elucidated. [ABSTRACT FROM AUTHOR]

• Gly16 patients had lower FVC%p values compared with the Arg16 patients. • The Gly16 polymorphism may be detrimental to respiratory function in DMD patients. • The variability of respiratory interventions may confound these results. • ADRB2 genotyping should be considered in the clinical management of DMD patients. • These findings are preliminary in nature and replication studies are needed. The progression of decline in forced vital capacity as percent predicated (FVC%p) is a strong indicator of worsening prognosis in patients with Duchenne muscular dystrophy (DMD). Evidence suggests that ß 2 adrenergic (ADRB2) receptors may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function. The purpose of this study was to determine the influence of ADRB2 genotype on longitudinal measures of FVC%p as a function of age in DMD patients. Data from the CINRG Duchenne Natural History Study including 169 DMD patients (5–25 yrs) were analyzed. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of FVC%p across patient ages between genotype groups after controlling for patient demographics, corticosteroid-use, and ambulatory status. Both genotype groups displayed a progressive, maturational decline in FVC%p. Notwithstanding this decline, patients expressing the Gly16 polymorphism demonstrated systematically lower FVC%p values at any given age compared with patients expressing the Arg16 polymorphism (P < 0.01). Therefore, expressing the Gly16 polymorphism may prove detrimental to respiratory function in DMD patients. These data suggest maybe ADRB2 genotyping should be considered in the clinical management of DMD patients. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether the longitudinal progression of decline in left ventricular ejection fraction (LVEF) in Duchenne muscular dystrophy (DMD) patients is moderated by ADRB1 genotype and whether the efficacy of β-blocker therapy is influenced by genotype status. About 147 DMD patients (6-34 years.) were analyzed with a focus on β1 adrenergic receptor (ADRB1) genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients and Arg389 patients. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for β-blocker use. Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (~12 years). However, there was no difference tbetween genotype groups in the progression of decline in LVEF. There was a significant effect of β-blocker use on longitudinal LVEF, wherein patients on β-blockers had systematically lower LVEF when compared to patients not on β-blockers. However, the effect of β-blocker therapy on LVEF was not affected by ADRB1 genotype. The current study did not demonstrate an influence of patient ADRB1 genotype on longitudinal LVEF in our cohort. Despite previous literature suggesting a positive influence of β-blocker use on cardiac function in DMD patients and of an ADRB1 genotypic difference in responsiveness to β-blocker use, we did not observe this in our cohort. Interestingly, our cohort did not demonstrate a positive influence of β-blocker use on LVEF measures. [ABSTRACT FROM AUTHOR]

Delandistrogene moxeparvovec is a gene transfer therapy approved in the United States, United Arab Emirates, and Qatar for the treatment of ambulatory patients aged four through five years with a confirmed Duchenne muscular dystrophy (DMD)-causing mutation in the DMD gene. This therapy was developed to address the underlying cause of DMD through targeted skeletal, respiratory, and cardiac muscle expression of delandistrogene moxeparvovec micro-dystrophin, an engineered, functional dystrophin protein. Drawing on clinical trial experience from Study 101 (NCT03375164), Study 102 (NCT03769116), and ENDEAVOR (Study 103; NCT04626674), we outline practical considerations for delandistrogene moxeparvovec treatment. Before infusion, the following are recommended: (1) screen for anti-adeno-associated virus rhesus isolate serotype 74 total binding antibody titers <1:400; (2) assess liver function, platelet count, and troponin-I; (3) ensure patients are up to date with vaccinations and avoid vaccine coadministration with infusion; (4) administer additional corticosteroids starting one day preinfusion (for patients already on corticosteroids); and (5) postpone dosing patients with any infection or acute liver disease until event resolution. Postinfusion, the following are recommended: (1) monitor liver function weekly (three months postinfusion) and, if indicated, continue until results are unremarkable; (2) monitor troponin-I levels weekly (first month postinfusion, continuing if indicated); (3) obtain platelet counts weekly (two weeks postinfusion), continuing if indicated; and (4) maintain the corticosteroid regimen for at least 60 days postinfusion, unless earlier tapering is indicated. Although the clinical safety profile of delandistrogene moxeparvovec has been consistent, monitorable, and manageable, these practical considerations may mitigate potential risks in a real-world clinical practice setting. [ABSTRACT FROM AUTHOR]

Estimation of temporospatial clinical features of gait (CFs), such as step count and length, step duration, step frequency, gait speed, and distance traveled, is an important component of community-based mobility evaluation using wearable accelerometers. However, accurate unsupervised computerized measurement of CFs of individuals with Duchenne muscular dystrophy (DMD) who have progressive loss of ambulatory mobility is difficult due to differences in patterns and magnitudes of acceleration across their range of attainable gait velocities. This paper proposes a novel calibration method. It aims to detect steps, estimate stride lengths, and determine travel distance. The approach involves a combination of clinical observation, machine-learning-based step detection, and regression-based stride length prediction. The method demonstrates high accuracy in children with DMD and typically developing controls (TDs) regardless of the participant's level of ability. Fifteen children with DMD and fifteen TDs underwent supervised clinical testing across a range of gait speeds using 10 m or 25 m run/walk (10 MRW, 25 MRW), 100 m run/walk (100 MRW), 6-min walk (6 MWT), and free-walk (FW) evaluations while wearing a mobile-phone-based accelerometer at the waist near the body's center of mass. Following calibration by a trained clinical evaluator, CFs were extracted from the accelerometer data using a multi-step machine-learning-based process and the results were compared to ground-truth observation data. Model predictions vs. observed values for step counts, distance traveled, and step length showed a strong correlation (Pearson's r = −0.9929 to 0.9986, p < 0.0001). The estimates demonstrated a mean (SD) percentage error of 1.49% (7.04%) for step counts, 1.18% (9.91%) for distance traveled, and 0.37% (7.52%) for step length compared to ground-truth observations for the combined 6 MWT, 100 MRW, and FW tasks. Our study findings indicate that a single waist-worn accelerometer calibrated to an individual's stride characteristics using our methods accurately measures CFs and estimates travel distances across a common range of gait speeds in both DMD and TD peers. [ABSTRACT FROM AUTHOR]

Differences in gait patterns of children with Duchenne muscular dystrophy (DMD) and typically developing (TD) peers are visible to the eye, but quantifications of those differences outside of the gait laboratory have been elusive. In this work, we measured vertical, mediolateral, and anteroposterior acceleration using a waist-worn iPhone accelerometer during ambulation across a typical range of velocities. Fifteen TD and fifteen DMD children from 3 to 16 years of age underwent eight walking/running activities, including five 25 m walk/run speed-calibration tests at a slow walk to running speeds (SC-L1 to SC-L5), a 6-min walk test (6MWT), a 100 m fast walk/jog/run (100MRW), and a free walk (FW). For clinical anchoring purposes, participants completed a Northstar Ambulatory Assessment (NSAA). We extracted temporospatial gait clinical features (CFs) and applied multiple machine learning (ML) approaches to differentiate between DMD and TD children using extracted temporospatial gait CFs and raw data. Extracted temporospatial gait CFs showed reduced step length and a greater mediolateral component of total power (TP) consistent with shorter strides and Trendelenberg-like gait commonly observed in DMD. ML approaches using temporospatial gait CFs and raw data varied in effectiveness at differentiating between DMD and TD controls at different speeds, with an accuracy of up to 100%. We demonstrate that by using ML with accelerometer data from a consumer-grade smartphone, we can capture DMD-associated gait characteristics in toddlers to teens. [ABSTRACT FROM AUTHOR]

Objective: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS). Methods: Patients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression. Results: As of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan–Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone. Conclusion: Long-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015. [ABSTRACT FROM AUTHOR]

Introduction/aims: Pulmonary decline is a major issue in patients with Duchenne muscular dystrophy (DMD). Eteplirsen is a United States-approved treatment for patients with DMD and exon 51 skip-amenable mutations. Previous analyses have shown that eteplirsen is associated with a statistically significant attenuation of pulmonary decline. In this study we evaluate the effect of eteplirsen treatment from newly available data sources on pulmonary function over time in patients with DMD.Methods: We used a post hoc pooled analysis to compare the percentage of predicted forced vital capacity (FVC%p) and projected time with pulmonary function milestones in patients with DMD and exon 51 skip-amenable mutations receiving eteplirsen (Studies 204 and 301) or standard of care (SoC; Cooperative International Neuromuscular Research Group Duchenne Natural History Study). A mixed model for repeated-measures framework was applied to evaluate the impact of eteplirsen.Results: An average annual rate of FVC%p decline for eteplirsen-treated patients was estimated to be 3.47%, a statistically significant attenuation from the 5.95% rate of decline estimated in SoC patients (P = .0001). Using linear extrapolations of the model-estimated decline in FVC%p, the attenuation in FVC%p decline for eteplirsen-treated patients corresponded to a delay of 5.72 years in time to needing continuous ventilation, 3.31 years in time to needing nighttime ventilation, and 2.11 years in time to needing a cough assist device compared with SoC patients.Discussion: The attenuation of FVC%p decline suggests that eteplirsen-treated patients had statistically significant and clinically meaningful attenuations in pulmonary decline compared with SoC patients. [ABSTRACT FROM AUTHOR]

Introduction: The North Star Ambulatory Assessment (NSAA) tool is a key instrument for measuring clinical outcomes in patients with Duchenne muscular dystrophy (DMD). To gain a better understanding of the longitudinal utility of the NSAA, we evaluated NSAA data from a phase II trial of 120 patients with DMD treated with domagrozumab or placebo. Methods: The NSAA exploratory analyses included assessment of individual skills gained/lost, total skills gained/lost, cumulative loss of function, and the impact of transient loss of function due to a temporary disability on NSAA total score (temporary zero score). Results: There was no significant difference in the total number of NSAA skills gained (mean 1.41 and 1.04, respectively; p = 0.3314) or lost (3.90 vs. 5.0; p = 0.0998) between domagrozumab- vs. placebo-treated patients at week 49. However, domagrozumab-treated patients were less likely to lose the ability to perform a NSAA item (hazard ratio 0.80, 95% confidence interval [CI]: 0.65–0.98, p = 0.029) over 48-weeks vs. placebo-treated patients. When temporary zero scores were changed to "not obtainable" (8 values from 7 patients), domagrozumab-treated patients scored higher on the NSAA total score versus placebo-treated patients (difference at week 49: 2.0, 95% CI: 0.1–3.9, p = 0.0359). Conclusions: These exploratory analyses reveal additional approaches to interpreting the NSAA data beyond just change in NSAA total score. These observations also highlight the importance of reporting items as "not obtainable" for a patient with a temporary/transient physical disability that impacts their ability to perform the NSAA test. ClinicalTrials.gov identifier: NCT02310763. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (n = 120 aged 6 to < 16 years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD. Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014. [ABSTRACT FROM AUTHOR]

Current treatment benefits for patients with muscle disease are limited, but progress in legislative and scientific initiatives have set the stage for the development of new therapies. The MD-CARE Act (Public Law 107-84), which allocates federal resources to muscular dystrophy, was approved by Congress and signed into law by the President of the United States in 2001. This has shifted the emphasis toward translational research. To facilitate a push toward therapy for muscle disorders, the Muscular Dystrophy Association (MDA) sponsored a meeting with representatives from industry, the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and other government agencies and academia. Each contributed in different ways. The FDA helped define the necessary data to support investigational new drug (IND) applications including the design of proof-of-principle studies, outcome measures for clinical trials, and the pathway for developing surrogate measures for fast-tracking promising new drugs. The NIH, other government agencies, and the MDA described potential funding sources for translational research. Industry delineated a complementary role with academia, and academic investigators elucidated the current strengths and weaknesses of available clinical endpoints. The meeting provided a format for communication for diverse disciplines that usually have no common meeting ground, helping to lay the foundation for bringing products to market in a timely fashion. Muscle Nerve, 2006 [ABSTRACT FROM AUTHOR]

Introduction: Duchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens. Methods: A list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists' responses were collected using a modified Delphi approach. Results: Among corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid. Discussion: The options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects. [ABSTRACT FROM AUTHOR]

We performed an observational, natural history study of males with in-frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). A prospective natural history study collected longitudinal medical, strength, and timed function assessments. Eighty-three participants with genetically confirmed BMD were enrolled (age range 5.6-75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in-frame deletions that corresponded to an out-of-frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. A prospective natural history cohort with in-frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has resulted in the reorganization of health-care settings affecting clinical care delivery to patients with Duchenne and Becker muscular dystrophy (DBMD) as well as other inherited muscular dystrophies. The magnitude of the impact of this public health emergency on the care of patients with DBMD is unclear as they are suspected of having an increased risk for severe manifestations of COVID-19. In this article, the authors discuss their consensus recommendations pertaining to care of these patients during the pandemic. We address issues surrounding corticosteroid and exon-skipping treatments, cardiac medications, hydroxychloroquine use, emergency/respiratory care, rehabilitation management, and the conduct of clinical trials. We highlight the importance of collaborative treatment decisions between the patient, family, and health-care provider, considering any geographic or institution-specific policies and precautions for COVID-19. We advocate for continuing multidisciplinary care for these patients using telehealth. [ABSTRACT FROM AUTHOR]

• Domagrozumab at 5, 20, and 40 mg/kg was generally safe and well tolerated. • Primary endpoint of mean change from baseline in 4SC time at week 49 was not met. • Efficacy measures did not support a significant treatment effect with domagrozumab. • Nonsignificant increase in muscle volume was observed with domagrozumab vs placebo. We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (–7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619 [ABSTRACT FROM AUTHOR]

Limb contractures are debilitating complications associated with various muscle and nervous system disorders. This report summarizes presentations at a conference at the Shirley Ryan AbilityLab in Chicago, Illinois, on April 19-20, 2018, involving researchers and physicians from diverse disciplines who convened to discuss current clinical and preclinical understanding of contractures in Duchenne muscular dystrophy, stroke, cerebral palsy, and other conditions. Presenters described changes in muscle architecture, activation, extracellular matrix, satellite cells, and muscle fiber sarcomeric structure that accompany or predispose muscles to contracture. Participants identified ongoing and future research directions that may lead to understanding of the intersecting factors that trigger contractures. These include additional studies of changes in muscle, tendon, joint, and neuronal tissues during contracture development with imaging, molecular, and physiologic approaches. Participants identified the requirement for improved biomarkers and outcome measures to identify patients likely to develop contractures and to accurately measure efficacy of treatments currently available and under development. [ABSTRACT FROM AUTHOR]

• Respiratory disease continues to be major cause of morbidity and mortality in DMD. • Cohort study with DMD patients treated with idebenone for up to six years. • Respiratory function evolution with/without idebenone in same patients assessed. • Annual rate of decline in FVC%p was reduced by approximately 50%. • Long-term data confirm disease modifying treatment effect of idebenone. Decline in respiratory function in patients with DMD starts during early teenage years and leads to early morbidity and mortality. Published evidence of efficacy for idebenone on respiratory function outcomes is currently limited to 12 months of follow-up time. Here we report data collected as retrospective cohort study (SYROS) from 18 DMD patients not using glucocorticoids who were treated with idebenone (900 mg/day) under Expanded Access Programs (EAPs). The objective was to assess the long-term respiratory function evolution for periods On-Idebenone compared to periods Off-Idebenone in the same patients. The mean idebenone exposure in the EAPs was 4.2 (range 2.4–6.1) years. The primary endpoint was the annual change in forced vital capacity percent of predicted (FVC%p) compared between Off-Idebenone and On-Idebenone periods. The annual rate of decline in FVC%p was reduced by approximately 50% from −7.4% (95% CI: −9.1, −5.8) for the Off-Idebenone periods to −3.8% (95% CI: −4.8, −2.8) for the On-Idebenone periods (N = 11). Similarly, annual change in peak expiratory flow percent of predicted (PEF%p) was −5.9% (95% CI: −8.0, −3.9) for the Off-Idebenone periods (N = 9) and reduced to −1.9% (95% CI: −3.2, −0.7) for the On-Idebenone periods during the EAPs. The reduced rates of decline in FVC%p and PEF%p were maintained for several years with possible beneficial effects on the rate of bronchopulmonary adverse events, time to 10% decline in FVC%p and risk of hospitalization due to respiratory cause. These long-term data provide Class IV evidence to further support the disease modifying treatment effect of idebenone previously observed in randomized, controlled trials. [ABSTRACT FROM AUTHOR]

• The reachable workspace detects slowly progressive upper extremity change in FSHD. • Decline rates are more pronounced if subjects were challenged with wrist weights. • The reachable workspace is superior to existing scaled assessments over time. • The reachable workspace is useful for stratification for clinical trials. Facioscapulohumeral Dystrophy (FSHD) results in slowly progressive strength impairment, especially the upper extremities. Recent discoveries regarding pathophysiology have led to exciting novel therapeutic strategies. To further facilitate drug development, improved FSHD outcome measures that are functionally-relevant and sensitive to longitudinal change will be critical. Recently, a motion sensor (Kinect)-based upper extremity outcome called 'reachable workspace' that provides a quantitative reconstruction of an individual's reachability was developed. In this study, changes in reachable workspace were tracked upwards for five-years in 18 FSHD subjects. Results show -1.63 %/year decline in total reachable workspace (p = 0.144); with most notable decline in the above-the-shoulder level quadrants (upper-lateral Q3: -9.5 %/year, p < 0.001 and upper-medial Q1: -6.8 %/ year, p = 0.063) with no significant changes in the lower quadrants (Q2, Q4). Reachable workspace declined more significantly if the subjects were challenged with 500 g wrist weights: total reachable workspace: -1.82 %/year, p = 0.039; Q1: -7.20 %/year, p = 0.041; Q3: -8.09 %/year, p = 0.001. Importantly, reachable workspace outcome was also able to distinguish subgroups in FSHD: mildly- and severely-affected with essentially unchanging reachability over years, and moderately-affected who demonstrate the most detectable changes longitudinally. The study demonstrates utility for measuring declines in upper quadrant reachability, and provides enrichment/stratification of FSHD populations most likely to show treatment effects in clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Glucocorticosteroids (GC) are effective in slowing weakness in boys with Duchenne muscular dystrophy (DMD). Methods: This is a multisite, 1‐year, open‐label trial of twice‐weekly prednisolone (5 mg/kg/dose) in infants/young boys (0.4–2.4 years) with DMD. We compared changes in Bayley III Scales of Infant Development (Bayley‐III) with untreated boys followed for 1 year (historical control cohort [HCC]). Twenty‐three of 25 participants completed the study. Results: Treated boys gained an average of 0.5 points on the Bayley‐III gross motor scaled score (GMSS) compared with the HCC who, on average, declined 1.3 points (P = 0.03). All boys maintained linear growth, and none developed Cushingoid features. Excessive weight gain occurred in 13 of 23 (56%) boys. Discussion: This study provides evidence that twice‐weekly GC is well tolerated in infants and young boys with DMD and improves GMSS. Excessive weight gain is a potential risk. Longer follow‐up is required to determine whether early GC initiation is feasible in most infants/boys with DMD. Muscle Nerve 59:650–657, 2019 See editorial on pages 638–639 in this issue. [ABSTRACT FROM AUTHOR]

Introduction: ACT DMD was a 48-week trial of ataluren for nonsense mutation Duchenne muscular dystrophy (nmDMD). Patients received corticosteroids for ≥6 months at entry and stable regimens throughout study. This post hoc analysis compares efficacy and safety for deflazacort and prednisone/prednisolone in the placebo arm.Methods: Patients received deflazacort (n = 53) or prednisone/prednisolone (n = 61). Endpoints included change from baseline in 6-minute walk distance (6MWD), timed function tests, estimated age at loss of ambulation (extrapolated from 6MWD).Results: Mean changes in 6MWD were -39.0 m (deflazacort; 95% confidence limit [CL], -68.85, -9.17) and -70.6 m (prednisone/prednisolone; 95% CL, -97.16, -44.02). Mean changes in 4-stair climb were 3.79 s (deflazacort; 95% CL, 1.54, 6.03) and 6.67 s (prednisone/prednisolone; 95% CL, 4.69, 8.64).Conclusions: This analysis, limited by its post hoc nature, suggests greater preservation of 6MWD and 4-stair climb with deflazacort vs. prednisone/prednisolone. A head-to-head comparison will better define these differences. Muscle Nerve 58: 639-645, 2018. [ABSTRACT FROM AUTHOR]