Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study.

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.

Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy.

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

Reachable workspace and performance of upper limb (PUL) in duchenne muscular dystrophy.

INTRODUCTION: The Kinect-based reachable workspace relative surface area (RSA) is compared with the performance of upper limb (PUL) assessment in Duchenne muscular dystrophy (DMD). METHODS: 29 individuals with DMD (ages: 7-23; Brooke: 1-5) underwent both Kinect-based reachable workspace RSA and PUL assessments. RSAs were also collected from 24 age-matched controls. Total and quadrant RSAs were compared with the PUL total, shoulder-, middle-, and distal-dimension scores. RESULTS: The total reachable workspace RSA correlated well with the total PUL score (Spearman ρ = -0.602; P < 0.001), and with each of the PUL dimensional scores: shoulder (ρ = -0.624; P < 0.001), middle (ρ = -0.564; P = 0.001), and distal (ρ = -0.630; P < 0.001). With quadrant RSA, reachability in a particular quadrant was closely associated with respective PUL dimensional-level function (lateral-upper quadrant for shoulder-, lateral-upper/lower quadrants for middle-, and lateral-lower quadrant for distal-level function). CONCLUSIONS: This study demonstrates concurrent validity of the reachable workspace outcome measure (RSA) with the DMD-specific upper extremity outcome measure (PUL).

Reachable workspace reflects dynamometer-measured upper extremity strength in facioscapulohumeral muscular dystrophy.

INTRODUCTION: It is not known whether a reduction in reachable workspace closely reflects loss of upper extremity strength in facioscapulohumeral muscular dystrophy (FSHD). In this study we aimed to determine the relationship between reachable workspace and quantitative upper extremity strength measures. METHODS: Maximal voluntary isometric contraction (MVIC) testing of bilateral elbow flexion and shoulder abduction by hand-held dynamometry was performed on 26 FSHD and 27 control subjects. In addition, Kinect sensor-based 3D reachable workspace relative surface areas (RSAs) were obtained. Loading (500-g weight) effects on reachable workspace were also evaluated. RESULTS: Quantitative upper extremity strength (MVIC of elbow flexion and shoulder abduction) correlated with Kinect-acquired reachable workspace RSA (R = 0.477 for FSHD, P = 0.0003; R = 0.675 for the combined study cohort, P < 0.0001). Progressive reduction in RSA reflected worsening MVIC measures. Loading impacted the moderately weak individuals the most with additional reductions in RSA. CONCLUSIONS: Reachable workspace outcome measure is reflective of upper extremity strength impairment in FSHD.

Upper extremity 3-dimensional reachable workspace analysis in dystrophinopathy using Kinect.

INTRODUCTION: An innovative upper extremity 3-dimensional (3D) reachable workspace outcome measure acquired using the Kinect sensor is applied toward Duchenne/Becker muscular dystrophy (DMD/BMD). The validity, sensitivity, and clinical meaningfulness of this novel outcome measure are examined. METHODS: Upper extremity function assessment (Brooke scale and NeuroQOL questionnaire) and Kinect-based reachable workspace analyses were conducted in 43 individuals with dystrophinopathy (30 DMD and 13 BMD, aged 7-60 years) and 46 controls (aged 6-68 years). RESULTS: The reachable workspace measure reliably captured a wide range of upper extremity impairments encountered in both pediatric and adult, as well as ambulatory and non-ambulatory individuals with dystrophinopathy. Reduced reachable workspaces were noted for the dystrophinopathy cohort compared with controls, and they correlated with Brooke grades. In addition, progressive reduction in reachable workspace correlated directly with worsening ability to perform activities of daily living, as self-reported on the NeuroQOL. CONCLUSION: This study demonstrates the utility and potential of the novel sensor-acquired reachable workspace outcome measure in dystrophinopathy.

Reachable workspace in facioscapulohumeral muscular dystrophy (FSHD) by Kinect.

INTRODUCTION: A depth-ranging sensor (Kinect) based upper extremity motion analysis system was applied to determine the spectrum of reachable workspace encountered in facioscapulohumeral muscular dystrophy (FSHD). METHODS: Reachable workspaces were obtained from 22 individuals with FSHD and 24 age- and height-matched healthy controls. To allow comparison, total and quadrant reachable workspace relative surface areas (RSAs) were obtained by normalizing the acquired reachable workspace by each individual's arm length. RESULTS: Significantly contracted reachable workspace and reduced RSAs were noted for the FSHD cohort compared with controls (0.473 ± 0.188 vs. 0.747 ± 0.082; P < 0.0001). With worsening upper extremity function as categorized by the FSHD evaluation subscale II + III, the upper quadrant RSAs decreased progressively, while the lower quadrant RSAs were relatively preserved. There were no side-to-side differences in reachable workspace based on hand-dominance. CONCLUSIONS: This study demonstrates the feasibility and potential of using an innovative Kinect-based reachable workspace outcome measure in FSHD.

Ataluren treatment of patients with nonsense mutation dystrophinopathy.

INTRODUCTION: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. METHODS: Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. RESULTS: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. CONCLUSIONS: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.

Upper extremity reachable workspace evaluation with Kinect.

We propose a novel low-cost method for quantitative assessment of upper extremity workspace envelope using Microsoft Kinect camera. In clinical environment there are currently no practical and cost-effective methods available to provide arm-function evaluation in three-dimensional space. In this paper we examine the accuracy of the proposed technique for workspace estimation using Kinect in comparison with a motion capture system. The experimental results show that the developed system is capable of capturing the workspace with sufficient accuracy and robustness.

The relationship between regional body composition and quantitative strength in facioscapulohumeral muscular dystrophy (FSHD).

This study determines in facioscapulohumeral muscular dystrophy (FSHD) and able-bodied controls (1) the regional body composition and (2) the correlation between regional lean tissue mass and the corresponding regional strength. This is a cross-sectional, criterion standard, case-control study at a university based neuromuscular disease clinic. A dual-energy X-ray absorptiometry (DEXA) scanner was used to obtain regional body composition measurements in 14 FSHD and anthropometrically matched control pairs. A dynamometer determined peak isometric strength for the elbow and knee. Compared to controls, FSHD subjects showed increased regional fat tissue mass (p < 0.001-0.017), decreased regional lean tissue mass (p < 0.001-0.010), and decreased strength (p < 0.001-0.020). There was a correlation between quantitative strength and lean tissue mass for both FSHD and controls (r = 0.791-0.906; p < 0.001). FSHD subjects have higher regional fat tissue mass and lower regional lean tissue mass despite similar BMI and anthropometrics. Regional lean tissue mass correlates with strength.

Pain in persons with postpolio syndrome: frequency, intensity, and impact.

OBJECTIVE: To describe the frequency, intensity, and impact of pain in persons with postpoliomyelitis syndrome (PPS). DESIGN: Retrospective, cross-sectional survey. SETTING: Community-based survey. PARTICIPANTS: Convenience sample of people with PPS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Overall intensity and duration of pain, pain sites, pain interference, pain treatments, and relief provided by pain treatments. RESULTS: A total of 91% (n=57) of the study participants (N=63) reported pain. The most frequently reported pain sites were the shoulders, lower back, legs, and hips. Participants reported pain intensity to be the greatest in the knees, legs, wrists, lower back, and head. Pain interfered most with sleep and with activities requiring a high level of musculoskeletal involvement. Respondents also reported pain problems that were more severe than those of the general population and than those of a sample of people with multiple sclerosis. Many treatments had been tried previously for pain, but continued use of treatments was reported by relatively few participants at the time of the survey. CONCLUSIONS: The findings indicate that pain is a persistent and common problem in persons with PPS, highlighting the need for effective and accessible pain treatments for this population.

Chronic pain in persons with myotonic dystrophy and facioscapulohumeral dystrophy.

OBJECTIVE: To determine the nature and scope of pain in working-aged adults with myotonic muscular dystrophy (MMD) and facioscapulohumeral muscular dystrophy (FSHD). DESIGN: Retrospective, cross-sectional survey. SETTING: Community-based survey. PARTICIPANTS: Convenience sample of subjects with MMD and FSHD. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Overall intensity and duration of pain, pain inference, pain sites, pain treatments, and relief provided by pain treatments. RESULTS: More subjects with FSHD (82%) than with MMD (64%) reported pain. The most frequently reported pain sites for both diagnostic groups were lower back (66% MMD, 74% FSHD) and legs (60% MMD, 72% FSHD). Significant differences in pain intensity were found between the diagnostic groups in the hands, legs, knees, ankles, and feet, with patients with MMD reporting greater pain intensity at these sites than patients with FSHD. Age was related to the onset of pain (participants reporting pain were younger than those not reporting pain in the FSHD sample), but pain severity was not significantly associated with age in those reporting pain. Respondents with both diagnoses that reported mobility limitations and used assistive devices (eg, wheelchair, cane) reported more pain severity than those with mobility limitations who did not use assistive devices, who, in turn, reported more pain severity than respondents who reported no mobility limitations at all. The treatments that were reported to provide the greatest pain relief were not necessarily those that were the most frequently tried or still used. CONCLUSIONS: The findings indicate that pain is a more common problem in persons with FSHD than in persons with MMD, although it is common in both populations. In addition, these pain problems are chronic, underscoring the need to identify and provide effective pain treatments for patients with these neuromuscular diseases.

Longitudinal pulmonary function testing outcome measures in Duchenne muscular dystrophy: Long-term natural history with and without glucocorticoids.

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.

Aerobic fitness and upper extremity strength in patients aged 11 to 21 years with spinal cord dysfunction as compared to ideal weight and overweight controls.

OBJECTIVE: To determine whether the aerobic fitness, upper extremity strength, and body composition in groups of adolescents with mobility impairment due to thoracic and upper lumbar spinal cord injury (SCI) or spina bifida (SB) are significantly different from those in groups of adolescents without mobility impairment who are of normal weight (CTRL) or overweight (OW). SUBJECTS: One hundred fifteen total subjects were evaluated including 59 female (19 SB, 9 SCI, 17 OW, and 14 CTRL) and 56 male (18 SB, 10 SCI, 8 OW, and 20 CTRL) participants aged 11 to 21 years. METHODS: Aerobic fitness was assessed using a ramp protocol with a magnetically braked arm ergometer. Heart rate and oxygen uptake (VO2) were recorded. Peak isokinetic upper arm and shoulder strength values were determined with a dynamometer. Body composition was estimated using dual energy x-ray absorptiometry (DEXA). Male and female subjects were categorized as overweight if their percent body fat by DEXA exceeded 25% and 30%, respectively. Results were analyzed with an ANOVA using the Bonferroni correction. Significance was accepted at P < 0.05. RESULTS: The percent body fat of both the male and female SB and SCI subjects was significantly higher than CTRL but was not different than OW. In general, the shoulder extension and flexion strength in both the SB and SCI males and females was significantly lower than that of the CTRL and OW. The SCI and SB subjects had significantly reduced aerobic capacity (VO2/kg) compared to the CTRL subjects but were not different than the OW subjects. During the maximal exercise test, the SB and SCI subjects reached exhaustion at significantly lower workloads than the CTRL and OW subjects. CONCLUSIONS: Patients age 11 to 21 years with SB and SCI had reduced aerobic capacity that was associated with being overweight and having reduced upper extremity strength. These data suggest that interventions to increase strength and fitness and to manage weight should be recommended in this population.

Body composition and resting energy expenditure in patients aged 11 to 21 years with spinal cord dysfunction compared to controls: comparisons and relationships among the groups.

OBJECTIVES: To compare body composition in patients aged 11 to 21 years with spinal dysfunction due to spinal cord injury (SCI) and spina bifida (SB) vs. able-bodied control (CTRL) and able-bodied overweight (OW) groups and to examine the relationships between resting energy expenditure (REE) and total lean mass (TLM) in the SCI, SB, CTRL, and OW groups. METHODS: Two hundred fifteen subjects, including 85 CTRL, 31 OW, 33 SCI, and 66 SB, were evaluated. Body composition was estimated by dual energy x-ray absorptiometry (DXA). Measurements included height, weight, total lean mass (TLM), fat tissue mass (FTM), body mass index (BMI), BMI percentile (BMI%tile), and % fat. Resting energy measurements were obtained in fasting subjects with an open-circuit indirect calorimeter. RESULTS: There were gender differences in height, weight, BMI, TLM, fat mass, % fat, and REE. The REE in the SCI and SB groups was significantly different from that in the CTRL and OW groups, but no significant difference was found between the SCI and SB groups. The SB group had significantly higher REE/TLM ratios than did the other groups. The % fat was significantly higher in the SB and OW groups as compared to the CTRL and SCI groups. TLM was significantly higher in CTRL and OW groups as compared to SCI and SB groups, with the lowest TLM found in the SB group. CONCLUSION: Patients aged 11 to 21 years with SB or SCI have significant lean tissue mass deficits by DXA as compared to able-bodied CTRL and OW groups, with the greatest deficits in total lean mass measured in SB. The absolute REE values were significantly reduced in both SCI and SB groups in association with their lean tissue deficits. Interestingly, REE/TLM ratios were remarkably constant in the CTRL, OW, and SCI groups but significantly elevated in the SB group. One would expect an even greater degree of adiposity in the SB group if their REE/TLM ratios were not elevated relative to those without congenital paralysis.

Impact of spinal cord dysfunction and obesity on the health-related quality of life of children and adolescents.

OBJECTIVES: The objectives of this study were: (1) to compare the health-related quality of life (HRQOL) of children and adolescents with mobility impairments due to spinal cord injury (SCI) and spina bifida (SB) to the HRQOL of children and adolescent controls without mobility impairments (CTRL); and (2) to examine the impact of of obesity on the HRQOL of these subjects. METHODS: The Pediatric Quality of Life Inventory (PedsQL) was administered to 42 SB, 71 SCI and 60 able-bodied subjects who were 8-20 years of age. Subjects were categorized as obese if their BMI exceeded the 95th percentile for age. Twenty-one CTRL, 26 SB and 26 SCI subjects were obese. RESULTS: The SCI and SB subjects had significantly lower subscores than the control subjects on the physical (p < 0.001), emotional (p < .01), social (p < .001), and school (p < .001) domains of the PedsQL. The obese (CTRL) group had lower subscores on the physical (p < 0.001), social (p < 0.001), and psychosocial (p < 0.001) domains of the PedsQL as compared to the non-obese CTRL group, while there were no significant differences in subscores from the emotional and school domains. In contrast to the subjects without mobility impairment, there were no significant differences between the sub-scores of the obese and non-obese subjects with spinal cord dysfunction secondary to SCI or SB. The mean total PedsQL score of the non-obese control group (87.7 +/- 2.1) was significantly higher than the obese control group (75.2 +/- 3.4, p < 0.02), which in turn was significantly higher than the SCI group (63.7 +/- 2.2, p < 0.02), and the SB group (63.0 +/- 2.2, p < 0.02). CONCLUSION: Patients with SCI and SB have significantly lower HRQOL than children and adolescents without mobility impairments. Whereas obesity significantly reduces the quality of life scores of adolescents without mobility impairments, it has no significant incremental effect on subjects with SCI or SB.

Behavioral intervention, exercise, and nutrition education to improve health and fitness (BENEfit) in adolescents with mobility impairment due to spinal cord dysfunction.

BACKGROUND/OBJECTIVE: Determine the effects of a nutrition education and exercise intervention on the health and fitness of adolescents with mobility impairment due to spinal cord dysfunction from myelomeningocele and spinal cord injury. Subjects participated in a 16-week intervention consisting of a behavioral approach to lifestyle change, exercise, and nutrition education to improve fitness (BENEfit) program. Participants were given a schedule of aerobic and strengthening exercises and attended nutrition education and behavior modification sessions every other week along with their parent(s). SUBJECTS: Twenty adolescents (aged 11-18 years, mean 15.4 +/- 2.2 years) with spinal cord dysfunction. METHODS: Subjects were tested immediately prior to starting and upon completion of the program. Aerobic fitness was measured using a ramp protocol with an arm ergometer. Heart rate and oxygen uptake were measured. Values at anaerobic threshold and maximum oxygen uptake were recorded. Peak isokinetic arm and shoulder strength were determined with a dynamometer. Body composition was estimated with dual-energy x-ray absorptiometry. Serum chemistry included measures of cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. RESULTS: Fourteen individuals completed all testing sessions. There was no significant overall change in weight, body mass index, body mass index z-scores, or serum chemistry. Overall, there was a significant increase in whole body lean tissue without a concomitant increase in whole body fat. Fitness measures revealed a significant increase in maximum power output, work efficiency as measured by the amount of power output produced aerobically, and resting oxygen uptake. Strength measurements revealed a significant increase in shoulder extension strength and a trend towards increased shoulder flexion strength. There were no significant changes in high-density lipoprotein, low-density lipoprotein, total cholesterol, or triglycerides. CONCLUSIONS: The BENEfit program shows promise as a method for improving the health and fitness of adolescents with mobility impairments who are at high risk for obesity and obesity-related health conditions.

Metabolic syndrome in adolescents with spinal cord dysfunction.

OBJECTIVE: The purpose of this study was to determine the prevalence of components of the metabolic syndrome in adolescents with spinal cord injury (SCI) and spina bifida (SB), and their associations with obesity in subjects with and without SCI and SB. METHODS: Fifty-four subjects (20 SCI and 34 SB) age 11 to 20 years with mobility impairments from lower extremity paraparesis were recruited from a hospital-based clinic. Sixty able-bodied subjects who were oversampled for obesity served as controls (CTRL). Subjects were categorized as obese if their percent trunk fat measured by dual x-ray absorptiometry (DXA) was > 30.0% for males and > 35.0% for females. Ten SCI, 24 SB, and 19 CTRL subjects were classified as obese. Fasting serum samples were collected to determine serum glucose, insulin, and lipid concentrations. Metabolic syndrome was defined as having > or =3 of the following components: (a) obesity; (b) high-density lipoprotein (HDL) <45 mg/dL for males; <50 mg/dL for females; (c) triglycerides 2100 mg/dL; (d) systolic or diastolic blood pressure > or =95th percentile for age/ height/gender, and (e) insulin resistance determined by either fasting serum glucose 100-125 mg/dL; fasting insulin > or =20 microU /mL; or homeostasis model assessment of insulin resistance > or = 4.0. RESULTS: Metabolic syndrome was identified in 32.4% of the SB group and 55% of the SCI group. Metabolic syndrome occurred at a significantly higher frequency in obese subjects (SB = 45.8%, SCI = 100%, CTRL = 63.2%) than nonobese subjects (SB = 0%, SCI = 10%, CTRL = 2.4%). CONCLUSIONS: The prevalence of metabolic syndrome in adolescents with SB/SCI is quite high, particularly in obese individuals. These findings have important implications due to the known risks of cardiovascular diseases and diabetes mellitus associated with metabolic syndrome in adults, particularly those with spinal cord dysfunction.

Duchenne Regulatory Science Consortium Meeting on Disease Progression Modeling for Duchenne Muscular Dystrophy.

INTRODUCTION: The Duchenne Regulatory Science Consortium (D-RSC) was established to develop tools to accelerate drug development for DMD.  The resulting tools are anticipated to meet validity requirements outlined by qualification/endorsement pathways at both the U.S. Food and Drug Administration (FDA) and European Medicines Administration (EMA), and will be made available to the drug development community. The initial goals of the consortium include the development of a disease progression model, with the goal of creating a model that would be used to forecast changes in clinically meaningful endpoints, which would inform clinical trial protocol development and data analysis.  Methods: In April of 2016 the consortium and other experts met to formulate plans for the development of the model.  Conclusions: Here we report the results of the meeting, and discussion as to the form of the model that we plan to move forward to develop, after input from the regulatory authorities.

Measuring quality of life in muscular dystrophy.

OBJECTIVES: The objectives of this study were to develop a conceptual model of quality of life (QOL) in muscular dystrophies (MDs) and review existing QOL measures for use in the MD population. METHODS: Our model for QOL among individuals with MD was developed based on a modified Delphi process, literature review, and input from patients and patient advocacy organizations. Scales that have been used to measure QOL among patients with MD were identified through a literature review and evaluated using the COSMIN (Consensus-Based Standards for the Selection of Health Measurement Instruments) checklist. RESULTS: The Comprehensive Model of QOL in MD (CMQM) captures 3 broad domains of QOL (physical, psychological, and social), includes factors influencing self-reported QOL (disease-related factors, support/resources, and expectations/aspirations), and places these concepts within the context of the life course. The literature review identified 15 QOL scales (9 adult and 6 pediatric) that have been applied to patients with MD. Very few studies reported reliability data, and none included data on responsiveness of the measures to change in disease progression, a necessary psychometric property for measures included in treatment and intervention studies. No scales captured all QOL domains identified in the CMQM model. CONCLUSIONS: Additional scale development research is needed to enhance assessment of QOL for individuals with MD. Item banking and computerized adaptive assessment would be particularly beneficial by allowing the scale to be tailored to each individual, thereby minimizing respondent burden.

Assessment of pain and health-related quality of life in slowly progressive neuromuscular disease.

Few studies have examined the effect of pain on the quality of life of individuals with slowly progressive neuromuscular disease (NMD). The purpose of this study was to determine the frequency and extent to which subjects with slowly progressive NMD report pain and the association between pain and health-related quality of life in persons with NMD. The study design was a descriptive, nonexperimental survey. Of a total of 1,432 subjects with slowly progressive NMDs recruited from a university-based NMD clinic and the membership rosters of worldwide NMD support organizations, 859 agreed to participate. The primary measurement tool used was the Medical Outcomes Study SF-36 health survey. Our results indicated that, with the exception of adult spinal muscular atrophy (SMA), the frequency and severity of pain reported in slowly progressive NMDs was significantly greater than levels of pain reported by the general US population and was comparable to pain reported by subjects with osteoarthritis and chronic low back pain. There was a significant correlation between increased pain and lower levels of general health, vitality, social function, and physical role. Pain was moderately associated with increased fatigue, inability to cope adequately with stress, and sleep disturbance. In conclusion, with the exception of adult SMA, the frequency and severity of pain reported in slowly progressive NMDs was significant.