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.

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.

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.

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.

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.

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.

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 6-Minute Walk Test and Person-Reported Outcomes in Boys with Duchenne Muscular Dystrophy and Typically Developing Controls: Longitudinal Comparisons and Clinically-Meaningful Changes Over One Year.

INTRODUCTION: Data is currently lacking anchoring a 30-meter longitudinal change in walking ability by 6-minute walk test (6MWT) in Duchenne muscular dystrophy as a minimal clinically important difference and "clinically meaningful" person-reported outcomes (PROs) at differing levels of ambulatory ability. METHODS: We describe correlation between measures, 1-year change in measures, and correlation of 1-year changes between measures for the six-minute walk test (6MWT), 10-meter run/walk velocity, PedsQL and POSNA Pediatric Outcomes Data Collection Instrument (PODCI) in 24 4-12 year old. ambulatory DMD and 36 typical controls, and determine if minimal clinically important differences (MCID) of PROs contribute to different estimates of 6-minute walk distance (6MWD) change at differing levels of ability. RESULTS: PedsQL total and physical function and PODCI global, transfer/mobility and sports/physical function PROs demonstrated significant differences between DMD and controls (p<0.00001). In DMD, 6MWD and 10-meter run/walk velocity were correlated with PODCI domain scores, with the transfer/mobility scale showing the strongest relationship (r=0.79 and r=0.76). In DMD, 6MWD distance and 10-meter run/walk velocity weakly correlated with PedsQL domain scores. In DMD, 6MWD, 10-meter run/walk velocity, and PODCI global and transfer and basic mobility demonstrated significant one-year change and exceeded the amount of change representing MCID. In DMD, 6MWD change highly correlated with change in PODCI global and PODCI transfer/mobility scores (r=0.76 and r=0.93). PODCI global and PODCI transfer/mobility scales provided the best estimates of 6MWT performance. A "meaningful" 4.5 point change in a low PODCI transfer / basic mobility score of 30 to 34.5 was associated with a 5.6m 6MWD change from 150.3 to 155.9m. At PODCI levels closer to normative levels for healthy controls, the change in 6MWD distance associated with a "meaningful" change in PODCI scores was almost 46m. DISCUSSION: At lower levels of function, smaller increases in 6MWD result in meaningful change in quality of life (QoL) instrument scores. At higher levels of function, larger increases may be necessary to achieve the same QoL change score.

Development and application of stereo camera-based upper extremity workspace evaluation in patients with neuromuscular diseases.

BACKGROUND: The concept of reachable workspace is closely tied to upper limb joint range of motion and functional capability. Currently, no practical and cost-effective methods are available in clinical and research settings to provide arm-function evaluation using an individual's three-dimensional (3D) reachable workspace. A method to intuitively display and effectively analyze reachable workspace would not only complement traditional upper limb functional assessments, but also provide an innovative approach to quantify and monitor upper limb function. METHODOLOGY/PRINCIPAL FINDINGS: A simple stereo camera-based reachable workspace acquisition system combined with customized 3D workspace analysis algorithm was developed and compared against a sub-millimeter motion capture system. The stereo camera-based system was robust, with minimal loss of data points, and with the average hand trajectory error of about 40 mm, which resulted to ~5% error of the total arm distance. As a proof-of-concept, a pilot study was undertaken with healthy individuals (n = 20) and a select group of patients with various neuromuscular diseases and varying degrees of shoulder girdle weakness (n = 9). The workspace envelope surface areas generated from the 3D hand trajectory captured by the stereo camera were compared. Normalization of acquired reachable workspace surface areas to the surface area of the unit hemi-sphere allowed comparison between subjects. The healthy group's relative surface areas were 0.618±0.09 and 0.552±0.092 (right and left), while the surface areas for the individuals with neuromuscular diseases ranged from 0.03 and 0.09 (the most severely affected individual) to 0.62 and 0.50 (very mildly affected individual). Neuromuscular patients with severe arm weakness demonstrated movement largely limited to the ipsilateral lower quadrant of their reachable workspace. CONCLUSIONS/SIGNIFICANCE: The findings indicate that the proposed stereo camera-based reachable workspace analysis system is capable of distinguishing individuals with varying degrees of proximal upper limb functional impairments.

Percent-predicted 6-minute walk distance in duchenne muscular dystrophy to account for maturational influences.

We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter.

Regional and whole-body dual-energy X-ray absorptiometry to guide treatment and monitor disease progression in neuromuscular disease.

Dual-energy x-ray absorptiometry (DEXA) is a safe, noninvasive, inexpensive tool for managing patients with neuromuscular diseases. Regional and whole-body DEXA can be used to guide clinical treatments, such as determining body composition to guide nutritional recommendations, as well as to monitor disease progression by assessing regional and whole-body lean tissue mass. DEXA can also be used as an outcome measure for clinical trials.

Aging with muscular dystrophy: pathophysiology and clinical management.

Major advances in the fields of medical science and physiology, molecular genetics, biomedical engineering, and computer science have provided individuals with muscular dystrophy (MD) with more functional equipment, allowing better strategies for improvement of quality of life. These advances have also allowed a significant number of these patients to live much longer. As progress continues to change management, it also changes patients' expectations. A comprehensive medical and rehabilitative approach to management of aging MD patients can often fulfill expectations and help them enjoy an enhanced quality of life.

New clinical end points in rehabilitation medicine: tools for measuring quality of life.

Traditional clinical end points in rehabilitation medicine have centered on objective measures of human performance, including quantitative muscle strength testing, functional independence measurements (FIM), and timed motor performance (TMP). However, it is now increasingly recognized that health-related quality of life (HRQoL) is a valid clinical end point. Health-related quality of life is a broad concept involving an individual's physical health, psychological state, personal beliefs, and interpersonal and social support relationships. The goals for this article are to show the value of performing HRQoL measurements and briefly describe methods used to assess quality of life (QoL).

Impact of biopsychosocial factors on chronic pain in persons with myotonic and facioscapulohumeral muscular dystrophy.

To assess the role of biopsychosocial factors in patients with type 1 myotonic and facioscapulohumeral muscular dystrophy (MMD1/FSHD) with chronic pain. Associations between psychosocial factors were found to be important in other samples of persons with pain and both psychological functioning and pain interference in a sample of patients suffering from MMD/FSHD. Prospective, multiple group, survey study of 182 patients with confirmed MMD1 and FSHD. Participants completed surveys assessing pain interference and psychological functioning, as well as psychosocial, demographic, and injury-related variables. Analyses indicated that greater catastrophizing was associated with increased pain interference and poorer psychological functioning, pain attitudes were significantly related to both pain interference and psychological functioning, and coping responses were significantly related only to pain interference. In addition, greater perceived social support was associated with better psychological functioning. The results support the use of studying pain in persons with MMD/FSHD from a biopsychosocial perspective, and the importance of identifying psychosocial factors that may play a role in the adjustment to and response to pain secondary to MMD/FSHD.

Assessment of regional body composition with dual-energy X-ray absorptiometry in Duchenne muscular dystrophy: correlation of regional lean mass and quantitative strength.

The purpose of this study was to assess regional body composition and its correlation with regional strength in Duchenne muscular dystrophy (DMD) subjects and able-bodied controls. Regional dual-energy X-ray absorptiometry (DEXA) measurements and isometric strength were obtained for 23 DMD subjects and 23 control subjects. DMD subjects showed a decreased regional lean mass (P < 0.001). The correlation between regional strength and regional lean mass was stronger for controls than for DMD subjects. DMD subjects had decreased regional lean mass, increased regional fat mass, and decreased strength. Muscle Nerve 39: 647-651, 2009.