Novel approaches to analysis of the North Star Ambulatory Assessment (NSAA) in Duchenne muscular dystrophy (DMD): Observations from a phase 2 trial.

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

Evaluating longitudinal therapy effects via the North Star Ambulatory Assessment.

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

A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial.

BACKGROUND: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. METHOD: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. RESULTS: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. CONCLUSION: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

The Direct Cost of Managing a Rare Disease: Assessing Medical and Pharmacy Costs Associated with Duchenne Muscular Dystrophy in the United States.

BACKGROUND: A Duchenne muscular dystrophy (DMD) cohort was identified using a claims-based algorithm to estimate health care utilization and costs for commercially insured DMD patients in the United States. Previous analyses have used broad diagnosis codes that include a range of muscular dystrophy types as a proxy to estimate the burden of DMD. OBJECTIVE: To estimate DMD-associated resource utilization and costs in a sample of patients identified via a claims-based algorithm using diagnosis codes, pharmacy prescriptions, and procedure codes unique to DMD management based on DMD clinical milestones. METHODS: DMD patients were selected from a commercially insured claims database (2000-2009). Patients with claims suggestive of a non-DMD diagnosis or who were aged 30 years or older were excluded. Each DMD patient was matched by age, gender, and region to controls without DMD in a 1:10 ratio (DMD patients n = 75; controls n = 750). All-cause health care resource utilization, including emergency department, inpatient, outpatient, and physician office visits, and all-cause health care costs were examined over a minimum 1-year period. Costs were computed as total health-plan and patient-paid amounts of adjudicated medical claims (in annualized U.S. dollars). RESULTS: The average age of the DMD cohort was 13 years. Patients in the DMD cohort had a 10-fold increase in health care costs compared with controls ($23,005 vs. $2,277, P < 0.001). Health care costs were significantly higher for the DMD cohort across age strata and, in particular, for DMD patients aged 14-29 years ($40,132 vs. $2,746, P < 0.001). CONCLUSIONS: In the United States, resource use and medical costs of DMD are substantial and increase with age. DISCLOSURES: Funding for this study (GHO-10-4441) was provided by GlaxoSmithKline (GSK). Optum was contracted by GSK to conduct the study. Thayer was an employee of Optum Health Economics and Outcomes Research at the time of this study and was not compensated for her participation as an author of this manuscript. Bell is an employee and shareholder of GSK. McDonald has been a consultant for GSK, Sarepta, PTC Therapeutics, Biomarin, and Catabasis on clinical trials regarding Duchenne muscular dystrophy clinical trial design, endpoint selection, and data analysis; Mitobridge for drug development; and Eli Lilly as part of a steering committee for clinical trials. Study concept and design were contributed primarily by Bell, along with Thayer and McDonald. Thayer collected the data, and data interpretation was performed by Thayer and Bell, along with McDonald. The manuscript was written by Thayer and Bell, along with McDonald, and revised by all the authors.

Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network.

Therapeutic trials in Duchenne Muscular Dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley III Scales of Infant and Toddler Development (Bayley III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n = 24; 1.9 ± 0.7 years) were assessed. The mean Bayley III motor composite score was low (82.8 ± 8; p ≤ .0001) (normal = 100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p ≤ .0001). The mean cognitive comprehensive (p=.0002), receptive language (p ≤ .0001), and expressive language (p = .0001) were also low compared to normal children. Age was negatively associated with Bayley III gross motor (r = -0.44; p = .02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n = 18 boys; 2.2 ± 0.4 years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley III.

Management of pulmonary complications in neuromuscular disease.

Restrictive lung disease occurs commonly in patients with neuromuscular disease. The earliest sign of respiratory compromise in the patient with neuromuscular disease is nocturnal hypoventilation, which progresses over time to include daytime hypoventilation and eventually the need for full-time mechanical ventilation. Pulmonary function testing should be done during regular follow-up visits to identify the need for assistive respiratory equipment and initiate early noninvasive ventilation. Initiation of noninvasive ventilation can improve quality of life and prolong survival in patients with neuromuscular disease.

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.

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

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

Challenges in drug development for muscle disease: a stakeholders' meeting.

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

Use of step activity monitoring for continuous physical activity assessment in boys with Duchenne muscular dystrophy.

OBJECTIVES: To evaluate the StepWatch Activity Monitor (SAM) as a quantitative measure of community ambulation, to investigate activity patterns and heart rate of ambulatory boys with Duchenne muscular dystrophy (DMD), and to correlate the step activity with measures of body composition and strength. DESIGN: Case-control study. SETTING: General community and laboratory. PARTICIPANTS: Sixteen ambulatory boys with DMD and 20 male controls (age range, 5-13 y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Laboratory determinations of body composition, knee extension strength, and minute-by-minute step rate and heart rate during 3 days of community activity. RESULTS: During the 3 days of activity, DMD subjects, when compared with controls, (1) had significantly more inactive minutes (1096+/-90 min/d vs 1028+/-85 min/d), (2) took significantly fewer steps and spent fewer minutes at moderate (66+/-31 min/d vs 94+/-30 min/d) and high step rates (43+/-30 min/d vs 72+/-38 min/d), (3) had higher resting heart rate (110+/-12 beats/min vs 94+/-7 beats/min) and lower increase in heart rate with increased step rate, and (4) had lower maximum heart rates (164+/-24 beats/min vs 208+/-16 beats/min). Percentage of body fat and knee extension strength correlated with total step activity in the DMD group but not in the control group. CONCLUSIONS: Step-rate monitoring with the SAM provides useful outcome measures with which to evaluate the activity of ambulatory boys with DMD. Their heart rate did not increase with activity to the same degree as observed in the control group.

Altered body composition affects resting energy expenditure and interpretation of body mass index in children with spinal cord injury.

BACKGROUND: Individuals with spinal cord injury (SCI) typically undergo changes in their body composition (reduction in lean body mass and an increase in fat mass) that can lead to secondary complications associated with diminished physical activity and obesity. METHODS: This study used dual energy X-ray absorptiometry (DXA) to estimate the total lean tissue mass (LTM), total body fat, and total bone mineral content (BMC) to assess the relationship between body mass index (BMI), body composition, and resting metabolic rate (RMR) in a group of children with SCI who were matched with able-bodied controls for age and sex. Body composition and RMR were measured in 18 boys and 9 girls (10-21 years of age) who had a SCI in the previous 1 to 3 years and in 27 age- and sex-matched controls. RESULTS: Children with SCI had significantly lower mean LTM than control subjects (37.6 +/- 9.6 kg and 46.7 +/- 9.2 kg, respectively; P < 0.001) and higher percent body fat (26.4 +/- 7.9% and 20.2 +/- 8.5%, respectively; P < 0.02) as measured by DXA, despite their reduced BMI (18.9 +/- 3.8 kg/m2 and 21.2 +/- 2.9 kg/m2, respectively; P < 0.01). Children with SCI had lower RMR than the controls subjects (1213 +/- 334 kJ/d and 1511 +/- 257 kJ/d, respectively), but there was no difference in RMR when adjusted for LTM. CONCLUSION: Children with SCI have lower RMRs that are associated with their reduced LTM. The reduction in LTM and RMR may predispose children with SCI to relative gains in body fat. BMI significantly underestimates body fat in children with SCI.