Observing the Clinical Course of Duchenne Muscular Dystrophy in Medicaid Real-World Healthcare Data.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a rare, severe progressive neuromuscular disease. Health insurance claims allow characterization of population-level real-world outcomes, based on observed healthcare resource use. An analysis of data specific to those with Medicaid insurance is presently unavailable. The objective was to describe the real-world clinical course of DMD based on claims data from Medicaid-insured individuals in the USA. METHODS: Individuals with DMD were identified from the MarketScan Multi-State Medicaid datasets (2013-2018). Diagnosis and procedure codes from healthcare claims were used to characterize the occurrence of DMD-relevant clinical observations; categories were scoliosis, cardiovascular-related, respiratory and severe respiratory-related, and neurologic/neuropsychiatric. Age-restricted analyses were conducted to focus on the ages at which DMD-relevant clinical observations were more likely to be captured, and to better understand the impact of both age and follow-up time. RESULTS: Of 2007 patients with DMD identified, median (interquartile range) age at index was 14 (9-20) years, and median follow-up was 3.1 (1.6-4.7) years. Neurologic and neuropsychiatric observations were most frequently identified, among 49.3% of the cohort; followed by cardiovascular (48.5%), respiratory (38.1%), scoliosis (36.3%), and severe respiratory (25.0%). Prevalence estimates for each category were higher when analyzed within age-restricted subgroups; and increased as follow-up time increased. CONCLUSIONS: This study is the first to use diagnosis and procedure codes from real-world Medicaid claims to document the clinical course in DMD. Findings were consistent with previously published estimates from commercially insured populations and clinical registries; and contribute to the expanding body of real-world evidence around clinical progression of patients with DMD.

"You Take This Day by Day, Come What May": A Qualitative Study of the Psychosocial Impacts of Living with Duchenne Muscular Dystrophy.

INTRODUCTION: Studies have reported health-related quality-of-life impacts of Duchenne muscular dystrophy (DMD); however, further research is needed to understand how those with DMD experience their condition and how psychosocial impacts evolve over time in response to disease progression. This qualitative study explores the social and emotional implications of key transitions, challenges and adaptations throughout the disease course from the perspective of patients and family caregivers. METHODS: Semi-structured interviews were conducted with men and boys with DMD, and/or their caregivers, in the USA. Thematic analysis was used to examine patterns in data collected across the interviews. RESULTS: Nineteen participants were included. Three major themes were identified: (1) barriers to participation are multifaceted; (2) an emotional journey shaped by 'inevitable progression;' (3) family provides critical tangible and emotional support. This study illustrates that psychosocial impacts of DMD are shaped by knowledge of the condition's natural history alongside other factors including the extent of social barriers, personal growth and adaptation, and family support. CONCLUSIONS: Findings provide insight into the strength and resilience with which individuals and their families respond to daily challenges and major clinical milestones and highlight the relative importance of loss of upper limb function as a transition in DMD affecting health-related quality-of-life.

Comparing Preferences for Disease Profiles: A Discrete Choice Experiment from a US Societal Perspective.

OBJECTIVES: There is increasing interest in expanding the elements of value to be considered when making health policy decisions. To help inform value frameworks, this study quantified preferences for disease attributes in a general public sample and examined which combination of attributes (disease profiles) are considered most important for research and treatment. METHODS: A discrete choice experiment (DCE) was conducted in a US general population sample, recruited through online consumer panels. Respondents were asked to select one of a set of health conditions they believed to be most important, characterized by attributes defined by a previous qualitative study: onset age; cause of disease; life expectancy; caregiver requirement; symptom burden (characterized by the Health Utilities Index with varying levels of ambulation independence, dexterity limitations, and degree of pain and discomfort); and disease prevalence. A fractional factorial DCE design was implemented using R, and 60 choice sets were generated (separated into blocks of 10 per participant). Data were analyzed using a mixed-logit regression model, and results used to assess the likelihood of preferring disease profiles. Based on individual attribute preferences, overall preferences for disease profiles, including a profile aligned with Duchenne muscular dystrophy (DMD), were compared. RESULTS: Fifty-two percent of respondents (n = 537) were female, and 70.6% were aged 18-54 years. Attributes considered most important were those related to life expectancy (odds ratio [OR], 95% confidence interval [CI] 1.88 [1.56-2.27] for a 50% reduction in remaining life expectancy vs no impact), and symptom burden (OR [95% CI] 1.84 [1.47-2.31] for severe vs mild burden). Greater importance was also found for pediatric onset, caregiver requirement, and diseases affecting more people. As an example of disease profile preferences, a DMD-like pediatric inherited disease with 50% reduction in life expectancy, extensive caregiver requirement, severe symptom burden, and 1:5000 prevalence had 2.37-fold higher odds of being selected as important versus an equivalent disease with adult onset and no life expectancy reduction. CONCLUSIONS: Of disease attributes included in this DCE, respondents valued higher prevalence of disease, life expectancy and symptom burden as most important for prioritizing research and treatment. Based on expressed attribute preferences, a case study of an inherited pediatric disease involving substantial reductions to length and quality of life and requiring caregiver support has relatively high odds of being identified as important compared to diseases reflecting differing attribute profiles. These findings can help inform expansions of value frameworks by identifying important attributes from the societal perspective.

A qualitative study to understand the Duchenne muscular dystrophy experience from the parent/patient perspective.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, severe, fatal neuromuscular disease characterized by progressive atrophy and muscle weakness, resulting in loss of ambulation, decreased upper body function, and impaired cardiorespiratory function. This study aimed to generate qualitative evidence to describe the primary symptoms and impacts of DMD in ambulatory and non-ambulatory patients as reported by patient/caregiver dyads. Information was also gathered on expectations for future DMD treatments. METHODS: Forty-six dyads (caregiver and patients with DMD aged 4 to 22 years) participated in 60-min semi-structured video interviews. Interview transcripts were analyzed using thematic analysis. Differences in experiences with DMD by ambulation status were examined. RESULTS: Mean ages of ambulatory (n = 28) and non-ambulatory participants (n = 18) were 8.7 and 11.3 years, respectively, with an average age of diagnosis of 3.7 years (SD = 2.3). The primary symptoms reported by both groups were lack of strength (ambulatory: n = 28, 100.0%; non-ambulatory: n = 17, 94.4%) and fatigue (ambulatory: n = 24, 85.7%; non-ambulatory: n = 14, 77.8%). Physical function was the domain that was most impacted by DMD, with participants describing progressive decline of physical function due to loss of physical strength as the primary defining feature of the disease across all stages of ambulatory ability. For those who maintained ambulatory ability at the time of the interview, physical function impacts described impaired mobility (e.g., climbing stairs: n = 16, 57.1%; running: n = 13, 46.4%), impaired upper body function, in particular fine motor skills like holding a pen/pencil or buttoning clothes (n = 17, 60.7%), problem with transfers (e.g., getting off the floor: n = 10, 35.7%), and activities of daily living (ADLs; n = 15, 53.6%). For non-ambulatory participants, the functional impacts most frequently described were problems with transfers (e.g., getting in/out of bed: n = 13, 72.2%; getting in/out of chair or position in bed: both n = 10, 55.6%), impaired upper body function (reaching: n = 14, 77.8%), and ADLs (n = 15, 83.3%). Meaningful treatment goals differed by ambulatory status; for ambulatory participants, goals included maintaining current functioning (n = 20, 71.4%), improving muscle strength (n = 7, 25.9%), and reducing fatigue (n = 6, 22.2%). For non-ambulatory participants, these included increased upper body strength (n = 8, 42.1%) and greater independence in ADLs (n = 6, 31.6%). A preliminary conceptual model was developed to illustrate the primary symptoms and physical function impacts of DMD and capture their relationship to disease progression. CONCLUSION: This study contributes to the limited qualitative literature by characterizing impacts of physical limitations and symptoms of DMD on disease progression and thus providing insights into the lived experience with DMD. Differences in treatment goals were also identified based on ambulatory status. Taken together, these findings can help inform patient-centered measurement strategies for evaluating outcomes in DMD clinical research.

Estimating health state utilities in Duchenne muscular dystrophy using the health utilities index and EQ-5D-5L.

BACKGROUND: The progression of Duchenne muscular dystrophy (DMD) is characterized by loss of ambulation, respiratory insufficiency, cardiomyopathy, and early mortality. DMD profoundly impacts health-related quality-of-life (HRQoL). However, few health state utility data exist; published utilities tend to be derived from small samples for a limited number of health states and are often based on caregiver-reported patient health status. This study estimated utility values for varied clinical and functional health states in DMD, based on patient-reported health status. METHODS: Individuals with DMD in the US aged 12-40 years completed the EQ-5D (5-level) and Health Utilities Index (HUI) preference-based instruments. Based on responses to a clinical questionnaire, participants self-classified into functional health states according to level of lower and upper limb function, use of respiratory support, and presence of cardiomyopathy. Mean [standard deviation (SD)] utility and EQ-5D visual analogue scale (VAS) scores were estimated according to health state; and median (interquartile range) attribute levels calculated to understand which domains of health are most severely affected in DMD. RESULTS: Of 63 males with DMD, mean (SD) age was 19.8 (6.1) years and 11 (17.5%) were ambulatory. Mean (SD) utility values were 0.92 (0.08; HUI2), 0.84 (0.20; HUI3), and 0.84 (0.13; EQ-5D) for ambulatory patients without cardiomyopathy (n = 10). For non-ambulatory patients with moderately impaired upper limb function, night and daytime ventilation without cardiomyopathy, mean (SD) utilities were 0.49 (0.07) for the HUI2, 0.16 (0.15) for the HUI3 and 025 (0.14) for the EQ-5D. Mean (SD) VAS scores for the same health states were 91 (9) and 83 (21), respectively. In addition to impairments in mobility/ambulation, and self-care, attributes like usual activities and pain also showed notable effects of DMD. CONCLUSIONS: In DMD, although a relationship between disease progression and HRQoL is observed, there is large variability in utility within functional health states, and across instruments. Utility values for less severe non-ambulatory health states described by level of upper limb function are novel. These utility values, derived based on direct patient feedback rather than from caregiver report, are relevant to individuals of varying functional statuses and augment scarce DMD-specific utility data.

Patterns of Clinical Progression Among Patients With Autosomal Recessive Limb-Girdle Muscular Dystrophy: A Systematic Review.

OBJECTIVES: As the clinical course of autosomal recessive limb-girdle muscular dystrophy (LGMDR) is highly variable, this study characterized the frequency of loss of ambulation (LOA) among patients by subtype (LGMDR1, LGMDR2, LGMDR3-6, LGMDR9, LGMDR12) and progression to cardiac and respiratory involvement among those with and without LOA. METHODS: Systematic literature review. RESULTS: From 2929 abstracts screened, 418 patients were identified with ambulatory status data (LOA: 265 [63.4%]). Cardiac and/or respiratory function was reported for 142 patients (34.0%; all with LOA). Among these, respiratory involvement was most frequent in LGMDR3-6 (74.1%; mean [SD] age 23.9 [11.0] years) and cardiac in LGMDR9 (73.3%; mean [SD] age 23.7 [17.7] years). Involvement was less common in patients without LOA except in LGMDR9 (71.4% respiratory and 52.4% cardiac). CONCLUSIONS: This study described the co-occurrence of LOA, cardiac, and respiratory involvement in LGMDR and provides greater understanding of the clinical progression of LGMDR.

Paving the way for future gene therapies: A case study of scientific spillover from delandistrogene moxeparvovec.

Gene therapies have potential to improve outcomes of severe diseases after only a single administration. Novel therapies are continually being developed using knowledge gained from prior successes, a concept known as scientific spillover. Gene therapy advancement requires extensive development at each stage: preclinical work to create and evaluate vehicles for delivery of the therapy, design of clinical development programs, and establishment of a large-scale manufacturing process. Pioneering gene therapies are generating spillover as investigators confront myriad issues specific to this treatment modality. These include frameworks for construct engineering, dose evaluation, patient selection, outcome assessment, and safety monitoring. Consequently, the benefits of these therapies extend beyond offering knowledge for treating any one disease to establishing new platforms and paradigms that will accelerate advancement of future gene therapies. This impact is even more profound in rare diseases, where developing therapies in isolation may not be possible. This review describes some instances of scientific spillover in healthcare, and specifically gene therapy, using delandistrogene moxeparvovec (SRP-9001), a gene therapy recently approved by the US Food and Drug Administration for the treatment of ambulatory pediatric patients aged 4-5 years with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene, as a case study.

Exploring the relationship between North Star Ambulatory Assessment and Health Utilities Index scores in Duchenne muscular dystrophy.

BACKGROUND: The North Star Ambulatory Assessment (NSAA) documents motor performance in ambulatory individuals with Duchenne muscular dystrophy (DMD). Health Utilities Index (HUI) scores, reflecting preferences for health-related quality-of-life (HRQoL) implications of health states, are commonly estimated within trials. This study sought to characterize the relationship between the NSAA score and utility in DMD. METHODS: Family members serving as proxy respondents for placebo-treated ambulatory individuals with DMD (NCT01254019; BioMarin Pharmaceuticals Inc) completed the HUI and the NSAA (score range, 0-34). Mean change over time on these measures was estimated, and the correlation between changes in NSAA score and a) HUI utility; b) HUI3 ambulation and HUI2 mobility attribute scores, over 48 weeks was calculated. RESULTS: Baseline mean (range) age was 8.0 years (5-16; n = 61) and mean (standard deviation [SD]) scores were 0.87 (0.13; HUI2), 0.82 (0.19; HUI3), and 21.0 (8.1; NSAA). Mean (SD) change over 48 weeks was -0.05 (0.14; HUI2), -0.06 (0.19; HUI3), and -2.9 (4.7; NSAA). Weak positive correlations were observed between baseline NSAA score and HUI utility (HUI2: r = 0.29; HUI3: r = 0.17) and for change over 48 weeks (HUI2: r = 0.16; HUI3: r = 0.15). Stronger correlations were observed between change in NSAA score and the HUI3 ambulation (r = 0.41) and HUI2 mobility (r = 0.41) attributes. CONCLUSIONS: Among ambulatory individuals with DMD, NSAA score is weakly correlated with HUI utility, suggesting that motor performance alone does not fully explain HRQoL. Stronger relationships were observed between HUI ambulation and mobility attributes, and NSAA. Although unidimensional measures like the NSAA are informative for documenting disease-specific health impacts, they may not correlate well with measures of overall health status; requiring use in conjunction with other patient-reported and preference-based outcomes.

Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States.

Background: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene therapy that may delay progression of Duchenne muscular dystrophy (DMD), a severe, rare neuromuscular disease caused by DMD gene mutations. Early cost-effectiveness analyses are important to help contextualize the value of gene therapies for reimbursement decision making. Objective: To determine the potential value of delandistrogene moxeparvovec using a cost-effectiveness analysis. Study design: A simulation calculated lifetime costs and equal value of life years gained (evLYG). Inputs included extrapolated clinical trial results and published utilities/costs. As a market price for delandistrogene moxeparvovec has not been established, threshold analyses established maximum treatment costs as they align with value, including varying willingness-to-pay up to $500,000, accounting for severity/rarity. Setting: USA, healthcare system perspective Patients: Boys with DMD Intervention: Delandistrogene moxeparvovec plus standard of care (SoC; corticosteroids) versus SoC alone Main outcome measure: Maximum treatment costs at a given willingness-to-pay threshold Results: Delandistrogene moxeparvovec added 10.30 discounted (26.40 undiscounted) evLYs. The maximum treatment cost was approximately $5 M, assuming $500,000/evLYG. Varying the benefit discount rate to account for the single administration increased the estimated value to #$5M, assuming $500,000/evLYG. Conclusion: In this early economic model, delandistrogene moxeparvovec increases evLYs versus SoC and begins to inform its potential value from a healthcare perspective.

Assessing the impact of single or short-term administration on a therapy's cost-effectiveness: a hypothetical disease-agnostic model.

AIMS: Assessing the value of single or short-term therapies (SSTs) within traditional cost-effectiveness analyses (CEAs) has been a topic of discussion as the number of SSTs increases, particularly regarding the effect of discounting on valuation. To quantify the impact of discounting in economic evaluations, a CEA of a hypothetical SST and equivalent chronic therapy was conducted using standard methods. MATERIALS AND METHODS: A lifetime Markov model was developed for a hypothetical chronic, progressive disease that could be treated with an SST, chronic therapy, or no novel treatment, termed standard of care (SoC). Incremental cost-effectiveness ratios (ICERs) with quality-adjusted life years (QALYs) comparing SST vs. SoC and an equivalent chronic therapy vs. SoC were assessed from a payer perspective. Both treatments had equal benefits and undiscounted lifetime costs; 3% discounting was applied to costs/benefits in the base case, and the impact of discounting was assessed. RESULTS: In the base case example, both the SST and equivalent chronic therapy vs. SoC had ICERs of $86,000/QALY without discounting. With 3% discounting, the ICER for the SST increased by 116% ($186,000/QALY) while the ICER for the chronic therapy increased by 10% ($95,000/QALY) despite equal clinical benefit. In scenario analyses, the ICER of the SST was consistently higher than the equivalent chronic therapy across a range of assumptions/inputs. Varying the cost/benefit discount rates had a greater impact on the SST. Differences in the ICERs between the therapies increased with increasing life expectancy/time horizon. LIMITATIONS: The simple model structure may not be reflective of acute or more complex diseases. Also, the scenario of perfect equivalency in efficacy and lifetime costs is hypothetical. CONCLUSIONS: This quantitative assessment showed the extent to which SST CEAs are highly sensitive to discounting, resulting in worse value assessments for SSTs than equivalent chronic therapies.

Characterizing the Occurrence of Key Clinical Milestones in Duchenne Muscular Dystrophy in the United States Using Real-World Data.

BACKGROUND: Data on the clinical course of Duchenne muscular dystrophy (DMD) exist from well-characterized clinical cohorts but estimates from real-world populations are fewer. OBJECTIVE: The objective was to estimate the prevalence of key clinical milestones by age, among real-world commercially-insured DMD patients in the United States. METHODS: MarketScan claims (2013-2018) were used to identify males with DMD. The percentages with wheelchair use or experiencing scoliosis, neurologic/neuropsychiatric involvement, cardiomyopathy, and respiratory involvement were tabulated; as were the median (interquartile range [IQR]) ages at first observed occurrence within the claims data. RESULTS: Among DMD patients (n = 1,964), the median (IQR) baseline age was 15 (9-21) years, and median follow-up was 1.7 years. Wheelchair use was observed in 55% of those aged 8 to 13 years at cohort entry; scoliosis, among 38% of those 8 to 10 and 52% of those 11 to 13 years; neurologic/neuropsychiatric involvement, among 41-43% of those 8 to 13 years; respiratory involvement, among 45% of those 14 to 19 years; and cardiomyopathy, among 68% of those 14 to 16 and 58% of those 17 to 19 years. CONCLUSIONS: The prevalence of key clinical milestones across ages was broadly consistent with published findings. Variability in estimates reflect clinical heterogeneity; these contemporary estimates from real-world data help characterize clinical outcomes in DMD.

QALYs and ambulatory status: societal preferences for healthcare decision making.

BACKGROUND: This research aimed to review the theoretical and methodological aspects of the quality-adjusted life year (QALY) which give rise to potential for bias against certain patient populations, including those with problems with walking or an inability to walk (ambulatory disabilities), when health technology assessment decisions rely on QALY gain to show cost-effectiveness. Societal preferences for treating ambulatory versus non-ambulatory patients were also investigated. METHODS: We reviewed published literature to identify information on theoretical underpinnings of the QALY, measurement of utilities for QALY assessment, and empirical evidence of societal preferences for the treatment of ambulatory and non-ambulatory patients. RESULTS AND DISCUSSION: Health states which represent mobility impairment and the inability to walk receive low valuation from general public preferences. Non-ambulatory patients, for example those with advanced neuromuscular disease, have lower utilities determined by standardized preference-based measurement (PBM) tools. Any treatment that increases survival but could not restore ambulation would result in lower lifetime QALY gains for non-ambulatory versus ambulatory patients. Treatments could therefore potentially be deemed less cost-effective, or not cost-effective at all for this patient population.Empirical research indicates a societal preference for equal treatment of patients regardless of ambulatory status. The main limitation of our review was the non-systematic approach to evidence search and review, however, given the broad scope of content required to meet the aims of the review, we believe that the targeted approach was appropriate. The evidence presented in this article highlights the need for alternatives to strict QALY-based approaches to prevent avoidable health inequities when determining cost-effectiveness of healthcare interventions for non-ambulatory populations against fixed cost-effectiveness thresholds. An alternative metric, the Equal Value of Life Years Gained (evLYG), has been proposed as a supplementary measure for use alongside the QALY for its potential to alleviate bias against disabled patient populations during the assessment of healthcare treatments.

Factors associated with the health-related quality of life among people with Duchenne muscular dystrophy: a study using the Health Utilities Index (HUI).

BACKGROUND: Data on health state utility in Duchenne muscular dystrophy (DMD) are few. This study estimated mean utility values by age, ambulatory status and over time, and investigated which aspects of health-related quality-of-life (HRQoL) are most strongly associated with utility in DMD. METHODS: Data from placebo-treated ambulant boys with DMD with exon 51 skip amenable mutations, (NCT01254019), were included. Ambulatory function assessments were conducted at baseline and every 12 weeks for the trial duration. Family member proxies completed the Health Utility Index (HUI) at baseline, 24 and 48 weeks; and HUI3 and HUI2 utility values were summarized. Changes in HUI attribute level over time, and predictors of changes in utility, were explored. RESULTS: Sixty-one boys (mean [range] age of 8.0 [5-16] years) were included in the analysis. Mean baseline utilities were 0.82 (HUI3) and 0.87 (HUI2); and utilities were 0.35 (HUI3) and 0.55 (HUI2) after loss of ambulation (LOA, where applicable). Over the follow-up period mean utility declined more among the older versus younger boys. Pain accounted for the highest proportion of variability (42%) in change in HUI3 utility from baseline to week 48, while for HUI2, self-care (39%) did. After LOA, change in ambulation levels explained 88% of the decline in mean HUI3 utility and change in mobility levels explained 66% of the decline in mean HUI2 utility. CONCLUSIONS: Utility values among this sample were higher than previously published estimates. In younger boys utility remained relatively stable, but older boys and those losing ambulation experienced important declines over follow-up.

Progression to Loss of Ambulation Among Patients with Autosomal Recessive Limb-girdle Muscular Dystrophy: A Systematic Review.

BackgroundThe impact of age at autosomal recessive limb girdle muscular dystrophy (LGMDR) onset on progression to loss of ambulation (LOA) has not been well established, particularly by subtype. OBJECTIVES: To describe the characteristics of patients with adult-, late childhood-, and early childhood-onset LGMDR by subtype and characterize the frequency and timing of LOA. METHODS: A systematic review was conducted in MEDLINE, Embase and the Cochrane library. Frequency and timing of LOA in patients with LGMDR1, LGMDR2/Miyoshi myopathy (MM), LGMDR3-6, LGMDR9, and LGMDR12 were synthesized from published data. RESULTS: In 195 studies, 695 (43.4%) patients had adult-, 532 (33.2%) had late childhood-, and 376 (23.5%) had early childhood-onset of disease across subtypes among those with a reported age at onset (n = 1,603); distribution of age at onset varied between subtypes. Among patients with LOA (n = 228), adult-onset disease was uncommon in LGMDR3-6 (14%) and frequent in LGMDR2/MM (42%); LGMDR3-6 cases with LOA primarily had early childhood-onset (74%). Mean (standard deviation [SD]) time to LOA varied between subtypes and was shortest for patients with early childhood-onset LGMDR9 (12.0 [4.9] years, n = 19) and LGMDR3-6 (12.3 [10.7], n = 56) and longest for those with late childhood-onset LGMDR2/MM (21.4 [11.5], n = 36). CONCLUSIONS: This review illustrated that patients with early childhood-onset disease tend to have faster progression to LOA than those with late childhood- or adult-onset disease, particularly in LGMDR9. These findings provide a greater understanding of progression to LOA by LGMDR subtype, which may help inform clinical trial design and provide a basis for natural history studies.

Interplay of disability, caregiver impact, and out-of-pocket expenditures in Duchenne muscular dystrophy: a cohort study.

BACKGROUND: Providing caregiving support to people with Duchenne muscular dystrophy (DMD) is challenging, beginning in early childhood, and continuing through the progression of multidimensional disability. This study addressed the interplay between caregiver impact, out-of-pocket expenditures, and DMD disability. To examine these interconnections, we investigated the association between caregiver impact domains and out-of-pocket expenditures; and the presence of clusters in caregivers on the basis of DMD-related disability domains in the patients for whom they provided caregiving support. METHODS: This web-based study recruited 566 DMD caregivers (140 males, 426 females; mean age 41.6 years, SD 8.8, range 21-72), examining caregiver impact using the DMD Caregiver Impact Measure, PROMIS-derived parent-proxy (PPP) measures of their child's disability, and items tapping out-of-pocket expenditures related to home and vehicle accommodations and assistive devices. T-tests compared caregiver impact scores by out-of-pocket expenditures incurred. Latent Profile Analyses (LPA) were conducted to generate impact profiles related to child's disability as reported by caregiver proxies. RESULTS: Higher out-of-pocket expenditures were generally associated with worse impact on the subscales, but several expenditures (e.g., kitchen, bathroom, scooter) were associated with lower impact. LPA indicated that the four-group solution provided the best relative fit and yielded good profile separation (entropy = 0.91). Caregivers with lowest impact reported the highest mobility, cognitive, and upper extremity functioning of their DMD care recipients, whereas the highest caregiver impact was driven by their care recipient's negative affect and fatigue. The upper-middle impact group showed great variability in proxy-disability domains, whereas the lower-middle group had similar levels of disability across domains. Profiles were represented across all child ages. CONCLUSION: Out-of-pocket expenditures were often associated with worse caregiver impact, but some associated with milder impact (i.e., bathroom or kitchen modification, investing in a ceiling lift or medical scooter). While their son's level of disability and age were related to impact on the DMD caregiver, the domains giving rise to highest caregiver impact were not the most visible aspects of disability, such as mobility, but rather negative affect and fatigue. Other contextual attributes are likely implicated, and will be addressed in the companion paper.

Societal perspectives on disease and treatment attributes characterizing rare diseases: a qualitative study from the United States.

PURPOSE: Under a societal perspective, disease and treatment attributes that the general public deem important should be considered within value frameworks. The objective was to investigate how members of the general public value attributes beyond health gains and healthcare system expenditures; and better understand their perspectives regarding the importance of attributes typically characterizing rare genetic diseases like Duchenne muscular dystrophy (DMD). METHODS: Qualitative interviews were conducted to elicit feedback on the importance of disease and treatment attributes from general public participants from three US cities. Participants ranked attributes (scale, 1-10) in terms of importance for future research, reported their rationale for ranking, and provided feedback specific to rare diseases. Interview transcripts were coded using NVivo for thematic analysis. RESULTS: The 33 participants (median age, 51 years; 48.5% male) ranked disease severity (mean [median] ranking, 8.7 [9.0]), treatment availability (8.7 [9.0]), and impact on life expectancy (8.4 [9.0]), as most important. The impact on the family, need for equity, and intrinsic value of life were frequently provided rationales. While rare disease as an attribute received a relatively low ranking (6.1 [7.0]), 88% of participants prioritized disease profiles including attributes of severity, health related quality of life (HRQoL) impact, limited lifespan and young age at onset. CONCLUSION: Attributes including disease severity, impact on life expectancy and HRQoL, and treatment availability were all highly important to members of the general public. These findings support the growing evidence regarding the importance of expanding value assessments to include attributes considered important from a societal perspective.

The impact of genotype on outcomes in individuals with Duchenne muscular dystrophy: A systematic review.

Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness, loss of ambulation (LOA), and early mortality. In this review we have synthesized published data on the clinical course of DMD by genotype. Using a systematic search implemented in Medline and Embase, 53 articles were identified that describe the clinical course of DMD, with pathogenic variants categorizable by exon skip or stop-codon readthrough amenability and outcomes presented by age. Outcomes described included those related to ambulatory, cardiac, pulmonary, or cognitive function. Estimates of the mean (95% confidence interval) age at LOA ranged from 9.1 (8.7-9.6) years among 90 patients amenable to skipping exon 53 to 11.5 (9.5-13.5) years among three patients amenable to skipping exon 8. Although function worsened with age, the impact of genotype was less clear for other outcomes (eg, forced vital capacity and left ventricular ejection fraction). Understanding the distribution of pathogenic variants is important for studies in DMD, as this research suggests major differences in the natural history of disease. In addition, specific details of the use of key medications, including corticosteroids, antisense oligonucleotides, and cardiac medications, should be reported.

Measuring Duchenne muscular dystrophy impact: development of a proxy-reported measure derived from PROMIS item banks.

BACKGROUND: Person-reported outcomes measurement development for rare diseases has lagged behind that of more common diseases. In studies of caregivers of patients with rare diseases, one relies on proxy report to characterize this disability. It is important to measure the child's disability accurately and comprehensively because it affects caregiver burden. We aimed to create a condition-specific caregiver proxy-report measure for Duchenne Muscular Dystrophy (DMD) in order to understand the impact of DMD on the caregiver. Drawing on relevant item banks from the Patient-Reported Outcome Measurement Information System (PROMIS), we sought to confirm their reliability and validity in the target sample of DMD caregivers. METHODS: This web-based study recruited DMD caregivers via Rare Patient Voice, patient-advocacy groups, and word of mouth. Recruitment was stratified by age of the caregiver's child with DMD, which broadly represents stages of DMD progression: 2-7, 8-12, 13-17, and > 18. Telephone interviews with DMD parent-caregivers pretested possible measures for content validity. The web-based study utilized an algorithm to categorize respondents' ambulatory status for tailored administration of PROMIS Parent-Proxy items as well as some new items developed based on caregiver interviews. Item response theory analyses were implemented. RESULTS: The study sample included 521 DMD caregivers representing equally the four age strata. The proxy-report measure included the following domains: fatigue impact, strength impact, cognitive function, upper extremity function, positive affect, negative affect, sleep-device symptoms, and mobility. The first five domains had strong psychometric characteristics (unidimensionality; acceptable model fit; strong standardized factor loadings; high marginal reliability). Negative Affect, covering anger, anxiety, depressive symptoms, and psychological stress, fit a bifactor model with good model fit, high marginal reliability, and strong factor loadings. The Sleep-device symptoms domain was not unidimensional, and the mobility domain did not have a simple structure due to residual correlations among items at opposite end of the mobility-disability continuum. These two domain scores were retained as clinimetric indices (i.e., uncalibrated scales), to achieve the overall goal of having a content-valid DMD-specific measure across all stages of disease severity. CONCLUSIONS: The present study derived a DMD-specific proxy-report measure from PROMIS item banks and supplemental items that could potentially be utilized in caregiver research across all stages of the care recipient's DMD. Future research will focus on assessing the responsiveness and validity of the measure over time and its comparison to DMD patient self-report.

Characterizing the quality-of-life impact of Duchenne muscular dystrophy on caregivers: a case-control investigation.

BACKGROUND: This study examined the impact of Duchenne muscular dystrophy (DMD) on family-member caregivers in terms of quality of life, life stress, and indirect costs, as compared to a stratified comparison group of parents of similar-age children without DMD. METHODS: A web-based survey included DMD caregivers and a nationally representative comparison group of parents of children without DMD stratified by Child Age Group. Outcomes included quality of life, resilience, caregiver impact, stressful life events, financial strain, out-of-pocket expenditures, work productivity and unrealized ambitions. General linear models assessed the main effect of Caregiver Group and the interaction of Caregiver Group with Child-Age-Group, after adjusting for demographic covariates. RESULTS: Compared to parents without a DMD child, DMD Caregivers reported better physical health but worse mental health, positive affect/well-being, environmental mastery, difficulty paying bills, and more hours missed from work. Providing caregiving support for DMD teenagers was the most challenging. DMD caregivers curtailed their educational and professional ambitions, and modified their homes to accommodate the disability associated with DMD. Their non-DMD children had to make sacrifices as well. Nonetheless, in resilience and life stress, DMD caregivers were comparable to the comparison group, and showed consistent levels of positive emotions across the age of their DMD child. CONCLUSION: DMD caregivers fared worse on most outcomes and faced more hurdles in work life. They face constraints and hidden costs that impact their health and financial well-being. Caregivers of teenagers with DMD reported higher impact. Nonetheless, parents of DMD children of all ages maintained notable resilience and positivity.

Characterizing demographics, comorbidities, and costs of care among populations with Duchenne muscular dystrophy with Medicaid and commercial coverage.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe X-linked progressive neurodegenerative disease characterized by loss of ambulation, cardiomyopathy, respiratory insufficiency, and early mortality. Few data are available that describe the direct medical costs among patients with DMD in the United States. OBJECTIVE: To characterize the demographics, comorbidity burden, and direct monthly costs of care among patients with DMD with Medicaid and with commercial insurance coverage. METHODS: IBM MarketScan Commercial and Multi-State Medicaid claims (2013-2018) were used to identify males aged 30 years or under with diagnostic codes for muscular dystrophy or DMD; additional exclusion criteria were applied to identify those with probable DMD. Baseline characteristics and comorbidities were tabulated. The frequency of health care resource use and median (interquartile range [IQR]) monthly costs (in 2018 USD) were estimated from those with at least 12 months of continuous follow-up. RESULTS: Median (IQR) baseline ages were similar between the Medicaid (14 [9-20] years; n = 2,007) and commercial (15 [9-21] years; n = 1,964) DMD cohorts. The frequency of comorbidities over the period was slightly higher with those on Medicaid. The median duration of follow-up was 3.1 years among members of the Medicaid DMD cohort and 1.7 years among the commercial DMD cohort. Median monthly resource use was generally higher among the Medicaid DMD cohort; nonetheless, median (IQR) monthly costs were similar at $1,735 ($367-$5,281) for the Medicaid DMD cohort vs $1,883 ($657-$6,796) for the commercial DMD cohort. CONCLUSIONS: The demographic characteristics and median direct medical costs were similar between patients with commercial vs Medicaid coverage, even though patients with Medicaid coverage had higher resource use. Despite challenges in definitively identifying DMD patients using claims data, these findings help characterize contemporary DMD populations in the United States and the related direct economic burden to the payer. DISCLOSURES: This study was funded by Sarepta Therapeutics, Inc. Klimchak and Gooch are employees of Sarepta Therapeutics Inc. Szabo, Qian, and Popoff are employees of Broadstreet HEOR, which received funds from Sarepta Therapeutics, Inc., for work on this study. Iannaccone has received research funding or consulting fees from Avexis, Biogen, Fibrogen, Mallinkrodt, Regeneron, Sarepta Therapeutics, Inc., Scholar Rock, PTC Therapeutics, Pfizer, MDA, CureSMA, NIH, Genentech-Roche, and BCBS. Publication of the study results was not contingent on the sponsor's approval or censorship of the manuscript. Information from this study was presented, in part, at the AMCP Virtual Annual Meeting, April 21-24, 2020.