Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function.

OBJECTIVE: To study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD). METHODS: An open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity. RESULTS: Oral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy. CONCLUSIONS: Daily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.

Psychometric properties of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy: a Rasch analysis.

PURPOSE: To explore the psychometric properties of the full 22-item English (UK and US) version of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy. MATERIALS AND METHODS: Caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States, recruited through the TREAT-NMD network, completed the Zarit Caregiver Burden Interview online. The psychometric properties of the Zarit Caregiver Burden Interview were examined using Rasch analysis. RESULTS: A total of 475 caregivers completed the Zarit Caregiver Burden Interview. Model misfit was identified for 9 of 22 items (mean item fit residual 0.061, SD: 2.736) and 13 of 22 items displayed disordered thresholds. The overall item-trait interaction chi-square value was 499 (198 degrees of freedom, p < 0.001). The mean person fit residual was estimated at -0.213 (SD: 1.235). The Person Separation Index and Cronbach's α were estimated at 0.902 and 0.914, respectively. Item dependency was low and we found no significant differential item functioning by country or sex. CONCLUSION: Our Rasch analysis shows that the Zarit Caregiver Burden Interview fails to fully operationalize a quantitative conceptualization of caregiver burden among caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States. Further research is needed to understand the psychometric properties of the Zarit Caregiver Burden Interview in other populations and settings. Implications for Rehabilitation Duchenne muscular dystrophy is a terminal disease characterized by progressive muscle degeneration resulting in substantial disability and a significant burden on family caregivers. The Zarit Caregiver Burden Interview is one of the most widely applied measures of caregiver burden. Our Rasch analysis suggests that the Zarit Caregiver Burden Interview is not fit for purpose to measure burden in UK and US caregivers to patients with Duchenne muscular dystrophy. Clinicians and decision-makers should interpret Zarit Caregiver Burden Interview data from these populations with caution.

Neurology Care, Diagnostics, and Emerging Therapies of the Patient With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy is the most common form of childhood muscular dystrophy. A mutation in the DMD gene disrupts dystrophin (protein) production, causing damage to muscle integrity, weakness, loss of ambulation, and cardiopulmonary compromise by the second decade of life. Life expectancy has improved from mid-teenage years to mid-20s with the use of glucocorticoids and beyond the third decade with ventilator support and multidisciplinary care. However, Duchenne muscular dystrophy is associated with comorbidities and is a fatal disease. Glucocorticoids prolong ambulation, but their side effects are significant. Emerging investigational therapies have surfaced over the past decade and have rapidly been tested in clinical trials. Gene-specific strategies include nonsense readthrough, exon skipping, gene editing, utrophin modulation, and gene replacement. Other mechanisms include muscle regeneration, antioxidants, and antifibrosis and anti-inflammatory pathways. With potential therapies emerging, early diagnosis is needed to initiate treatment early enough to minimize morbidity and mortality. Newborn screening can be used to significantly improve early diagnosis, especially for gene-specific therapeutics.

Psychometric analysis of the pediatric quality of life inventory 3.0 neuromuscular module administered to patients with duchenne muscular dystrophy: A rasch analysis.

INTRODUCTION: Our objective in this study was to assess the psychometric properties of the English (UK and USA) version of the Pediatric Quality of Life Inventory 3.0 Neuromuscular Module (PedsQL NMM) administered to patients with Duchenne muscular dystrophy (DMD). METHODS: Patients with DMD from the UK and the US completed the PedsQL NMM online. The psychometric properties of the instrument were examined using Rasch analysis. RESULTS: A total of 278 patients completed the PedsQL NMM. Model misfit was identified for 6 of 25 items (item fit residual: mean 0.162, standard deviation [SD] 2.333), 22 of 25 items displayed disordered thresholds, and item dependency was high. The mean person fit residual was estimated at -0.183 (SD 1.475). The Person Separation Index and Cronbach's α were estimated at 0.904 and 0.915, respectively. DISCUSSION: The English version of the PedsQL NMM may not be a valid measure of health-related quality of life in patients with DMD. Muscle Nerve 58: 367-373, 2018.

Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan.

Improvements in the function, quality of life, and longevity of patients with Duchenne muscular dystrophy (DMD) have been achieved through a multidisciplinary approach to management across a range of health-care specialties. In part 3 of this update of the DMD care considerations, we focus on primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Many primary care and emergency medicine clinicians are inexperienced at managing the complications of DMD. We provide a guide to the acute and chronic medical conditions that these first-line providers are likely to encounter. With prolonged survival, individuals with DMD face a unique set of challenges related to psychosocial issues and transitions of care. We discuss assessments and interventions that are designed to improve mental health and independence, functionality, and quality of life in critical domains of living, including health care, education, employment, interpersonal relationships, and intimacy.

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management.

Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.

Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management.

A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of Duchenne muscular dystrophy (DMD). Contemporary care has been shaped by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients' duration and quality of life. In part 2 of this update of the DMD care considerations, we present the latest recommendations for respiratory, cardiac, bone health and osteoporosis, and orthopaedic and surgical management for boys and men with DMD. Additionally, we provide guidance on cardiac management for female carriers of a disease-causing mutation. The new care considerations acknowledge the effects of long-term glucocorticoid use on the natural history of DMD, and the need for care guidance across the lifespan as patients live longer. The management of DMD looks set to change substantially as new genetic and molecular therapies become available.

Economic Evaluation in Duchenne Muscular Dystrophy: Model Frameworks for Cost-Effectiveness Analysis.

BACKGROUND: Several treatments are on the horizon for Duchenne muscular dystrophy (DMD), a terminal orphan disease. In many jurisdictions, decisions regarding pricing and reimbursement of these health technologies comprise evidence of value for money. OBJECTIVE: The objective of this study was to develop a cost-effectiveness model based on the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT), a new rating scale created specifically to measure disease progression in clinical practice and trials and model DMD in economic evaluations, and compare it with two alternative model structures. METHODS: We constructed three Markov cohort state-transition models to evaluate the cost-effectiveness of a hypothetical intervention for DMD versus standard of care in a UK setting. Model I was based on the DMDSAT, model II on stages of disease as defined in the DMD clinical care guidelines and model III on patients' ventilation status. The conceptual model structures were formulated in collaboration with three DMD experts. RESULTS: All three models were judged to have good validity with regards to the appropriateness of the choice of modelling technique, conceptual representation of the disease, model input data and model outcomes. Across frameworks, lifetime direct medical costs with standard of care ranged between £217,510 and £284,640, total costs between £624,240 and £713,840, and total number of quality-adjusted life-years between 5.96 and 7.17. CONCLUSIONS: We present a first version of a model for the economic evaluation of treatments for DMD based on the DMDSAT, as well as two alternative frameworks encompassing conventional staging of disease progression. Our findings should be helpful to inform health technology assessments and health economic programmes of future treatments for DMD.

Quantifying the burden of caregiving in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a rare pediatric neuromuscular disease associated with progressive muscle degeneration and extensive care needs. Our objective was to estimate the caregiver burden associated with DMD. We made cross-sectional assessments of caregiver health-related quality of life (HRQL) and burden using the EuroQol EQ-5D, a Visual Analogue Scale (VAS), the SF-12 Health Survey, and the Zarit Caregiver Burden Interview (ZBI) administered online. Results were stratified by disease stage (early/late ambulatory/non-ambulatory) and caregivers' rating of patients' health and mental status. In total, caregivers to 770 patients participated. Mean EQ-5D utility ranged between 0.85 (95 % CI 0.82-0.88) and 0.77 (0.74-0.80) across ambulatory classes and 0.88 (0.85-0.90) and 0.57 (0.39-0.74) across caregivers' rating of patients' health and mental status. Mean VAS score was 0.74 (0.73-0.75), mean SF-12 Mental Health Component Summary score 44 (43-45), and mean ZBI score 29 (28-30). Anxiety and depression, recorded in up to 70 % of caregivers depending on patients' health and mental status, was significantly associated with annual household cost burden (>$5000 vs. <$1000, odds ratio 1.76, 95 % CI 1.18-2.63) and hours of leisure time devoted to informal care per week (25-50 vs. <25 h 2.01, 1.37-2.94; >50 vs. <25 h 3.35, 2.32-4.83) (p < 0.007). We show that caring for a person with DMD can be associated with a substantial burden and impaired HRQL. Our findings suggest that caregivers to patients with DMD should be screened for depression and emphasize the need for a holistic approach to family mental health in the context of chronic childhood disease.

Health-related quality of life in patients with Duchenne muscular dystrophy: a multinational, cross-sectional study.

AIM: To estimate health-related quality of life (HRQOL) in patients with Duchenne muscular dystrophy (DMD). METHOD: HRQOL was assessed using the Health Utilities Index Questionnaire (HUI) and the Pediatric Quality of Life Inventory (PedsQL) neuromuscular module version 3.0 online. Results were stratified by disease stage (early/late ambulatory/non-ambulatory) and caregivers' perceptions of patients' health and mental status. RESULTS: A total of 770 patient-caregiver pairs (173 German, 122 Italian, 191 UK, and 284 USA) participated. Most caregivers (>84%) perceived their patients as happy/somewhat happy and in excellent/very good/good health, irrespective of current ambulatory class. In contrast, mean patient utility (reflecting public preferences: 0, dead; 1, perfect health) deteriorated with disease course, from 0.75 in early ambulatory males to 0.15 in the most severely affected patients. Mean patient PedsQL scores (0-100, higher score indicating better HRQOL) decreased from 80 to 57 across ambulatory classes. INTERPRETATION: HRQOL in DMD, measured through public preferences, is substantially impaired in relation to the general population and significantly associated with disease progression. Still, most patients are perceived as happy and in good health by their caregivers, indicating that influential domains of HRQOL remain intact through the disease progression. Our findings emphasize the challenges in measuring HRQOL in a rare, progressive childhood condition such as DMD.

Development and psychometric analysis of the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT).

The objective of this study was to describe the development and initial psychometric analysis of the UK English version of the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT), a patient-reported outcome (PRO) scale designed to measure functional ability in patients with Duchenne muscular dystrophy (DMD). Item selection was made by neuromuscular specialists and a Rasch analysis was performed to understand the psychometric properties of the DMDSAT. Instrument scores were also linked to cost of illness and health-related quality of life data. The administered version, completed by 186 UK patient-caregivers pairs, included eight items in four domains: Arm function, Mobility, Transfers, and Ventilation status. These items together successfully operationalized functional ability in DMD, with excellent targeting and reliability (Person Separation Index: 0.95; Cronbach's α: 0.93), stable item locations, and good fit to the Rasch model (mean person/item fit residual: -0.21/-0.44, SD: 0.32/1.28). Estimated item difficulty was in excellent agreement with clinical opinion (Spearman's ρ: 0.95) and instrument scores mapped well onto health economic outcomes. We show that the DMDSAT is a PRO instrument fit for purpose to measure functional ability in ambulant and non-ambulant patients with DMD. Rasch analysis augments clinical expertise in the development of robust rating scales.

Compliance to Care Guidelines for Duchenne Muscular Dystrophy.

BACKGROUND: International care guidelines for Duchenne muscular dystrophy (DMD) were published in 2010, but compliance in clinical practice is unknown. OBJECTIVE: The objective of our study was to compare real-world DMD care in Germany, Italy, the UK, and the US with the clinical recommendations. METHODS: DMD patients from Germany, Italy, the UK, and the US were identified through Translational Research in Europe - Assessment & Treatment of Neuromuscular Diseases (TREAT-NMD) registries and invited with a caregiver to complete a questionnaire with questions regarding DMD-related healthcare. Estimates of care were stratified by disease stage (early/late ambulatory/non-ambulatory) and compared against the care guidelines. RESULTS: A total of 770 patients (173 German, 122 Italian, 191 UK, and 284 US) completed the questionnaire. Poor compliance to guidelines of routine follow-up by neuromuscular, cardiac, and respiratory specialists, physiotherapy, and access to medical devices and aids were observed in all countries. Less than 27% (209 of 770) of patients met all absolute recommendations, ranging from 9% (11 of 122) in Italy to 37% (70 of 191) in the UK, and from 49% (76 of 155) in the early ambulatory class to 16% (33 of 205) in the late non-ambulatory class. CONCLUSIONS: We show that the medical management of DMD varies substantially between Germany, Italy, the UK, and the US. Experience of real-world DMD care appears to be in poor agreement with the DMD clinical guidelines and increased compliance is urgently needed to improve treatment outcomes and enable patients to lead fulfilling, independent lives into adulthood.

Adult care for Duchenne muscular dystrophy in the UK.

Survival in Duchenne muscular dystrophy (DMD) has increased in recent years due to iterative improvements in care. We describe the results of the CARE-NMD survey of care practices for adults with DMD in the UK in light of international consensus care guidelines. We also compare the UK experience of adult care with the care available to pediatric patients and adults in other European countries (Germany, Denmark, Bulgaria, Czech Republic, Hungary, and Poland). UK adults experience less comprehensive care compared to children in their access to specialized clinics, frequency of cardiac and respiratory assessments, and access to professional physiotherapy. Access to the latter is especially poor when compared to other European adult cohorts. Although the total number of nights in hospital (planned and unplanned admissions) is lower among UK adults than elsewhere in Western Europe, social inclusion lags behind other Western European countries. We observe that attendance at specialized clinic is associated with more frequent cardiac and respiratory assessments among adults, in line with international best practice. Attendance at such clinics in the UK, though comparable to other countries, is still far from universal. With an increasing adult population living with DMD, and cardiac and respiratory failure the leading causes of death in this population, we suggest the need for an urgent improvement in adult access to specialized clinics and to consistent, comprehensive best practice care.

The burden of Duchenne muscular dystrophy: an international, cross-sectional study.

OBJECTIVE: The objective of this study was to estimate the total cost of illness and economic burden of Duchenne muscular dystrophy (DMD). METHODS: Patients with DMD from Germany, Italy, United Kingdom, and United States were identified through Translational Research in Europe-Assessment & Treatment of Neuromuscular Diseases registries and invited to complete a questionnaire online together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate costs of DMD from the perspective of society and caregiver households. RESULTS: A total of 770 patients (173 German, 122 Italian, 191 from the United Kingdom, and 284 from the United States) completed the questionnaire. Mean per-patient annual direct cost of illness was estimated at between $23,920 and $54,270 (2012 international dollars), 7 to 16 times higher than the mean per-capita health expenditure in these countries. Indirect and informal care costs were substantial, each constituting between 18% and 43% of total costs. The total societal burden was estimated at between $80,120 and $120,910 per patient and annum, and increased markedly with disease progression. The corresponding household burden was estimated at between $58,440 and $71,900. CONCLUSIONS: We show that DMD is associated with a substantial economic burden. Our results underscore the many different costs accompanying a rare condition such as DMD and the considerable economic burden carried by affected families. Our description of the previously unknown economic context of a rare disease serves as important intelligence input to health policy evaluations of intervention programs and novel therapies, financial support schemes for patients and their families, and the design of future cost studies.

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.

The respiratory management of patients with duchenne muscular dystrophy: a DMD care considerations working group specialty article.

In 2001, the Muscular Dystrophy Community Assistance, Research and Education Amendments (MD-CARE Act) was enacted, which directed federal agencies to coordinate the development of treatments and cures for muscular dystrophy. As part of the mandate, the Centers for Disease Control and Prevention (CDC) initiated surveillance and educational activities, which included supporting development of care considerations for Duchenne muscular dystrophy (DMD) utilizing the RAND/UCLA Appropriateness Method (RAM). This document represents the consensus recommendations of the project's 10-member Respiratory Panel and includes advice on necessary equipment, procedures and diagnostics; and a structured approach to the assessment and management of the respiratory complications of DMD via assessment of symptoms of hypoventilation and identification of specific thresholds of forced vital capacity, peak cough flow and maximum expiratory pressure. The document includes a set of Figures adaptable as "pocket guides" to aid clinicians. This article is an expansion of the respiratory component of the multi-specialty article originally appearing in Lancet Neurology, comprising respiratory recommendations from the CDC Care Considerations project.

Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care.

Optimum management of Duchenne muscular dystrophy (DMD) requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address the primary and secondary aspects of the disorder. Implementing comprehensive management strategies can favourably alter the natural history of the disease and improve function, quality of life, and longevity. Standardised care can also facilitate planning for multicentre trials and help with the identification of areas in which care can be improved. Here, we present a comprehensive set of DMD care recommendations for management of rehabilitation, orthopaedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, as well as general surgical and emergency-room precautions. Together with part 1 of this Review, which focuses on diagnosis, pharmacological treatment, and psychosocial care, these recommendations allow diagnosis and management to occur in a coordinated multidisciplinary fashion.