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

Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy: a phase 2 trial of domagrozumab

Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (n = 120 aged 6 to < 16 years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD.Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014

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

Health Care Use of Cardiac Specialty Care in Children With Muscular Dystrophy in the United States

Background Duchenne and Becker muscular dystrophy are progressive disorders associated with cardiac mortality. Guidelines recommend routine surveillance; we assess cardiac resource use and identify gaps in care delivery. Methods and Results Male patients, aged 1 to 18 years, with Duchenne and Becker muscular dystrophy between January 2013 and December 2017 were identified in the IBM MarketScan Research Database. The cohort was divided into 80% for angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers was observed in 13.6% (419/3083) of total person years among patients in the 10 to 18 years group. Conclusions Children 10 to 18 years of age have higher rates of cardiac resource use compared with those <10 years of age. However, rates in both age groups fall short of guidelines. Opportunities exist to identify barriers to resource use and optimize cardiac care for patients with Duchenne and Becker muscular dystrophy

Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy: a phase 2 trial of domagrozumab.

Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (n = 120 aged 6 to &lt; 16&nbsp;years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD.Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014

A comprehensive study of skeletal muscle imaging in FHL1-related reducing body myopathy

Objective: FHL1-related reducing body myopathy is an ultra-rare, X-linked dominant myopathy. In this cross-sectional study, we characterize skeletal muscle ultrasound, muscle MRI, and cardiac MRI findings in FHL1-related reducing body myopathy patients. Methods: Seventeen patients (11 male, mean age 35.4, range 12- 76 years) from nine independent families with FHL1-related reducing body myopathy underwent clinical evaluation, muscle ultrasound (n = 11/17), and lower extremity muscle MRI (n = 14/17), including Dixon MRI (n = 6/17). Muscle ultrasound echogenicity was graded using a modified Heckmatt scale. T1 and STIR axial images of the lower extremity muscles were evaluated for pattern and distribution of abnormalities. Quantitative analysis of intramuscular fat fraction was performed using the Dixon MRI images. Cardiac studies included electrocardiogram (n = 15/17), echocardiogram (n = 17/17), and cardiac MRI (n = 6/17). Cardiac muscle function, T1 maps, T2-weighted black blood images, and late gadolinium enhancement patterns were analyzed. Results: Muscle ultrasound showed a distinct pattern of increased echointensity in skeletal muscles with a nonuniform, multifocal, and "geographical" distribution, selectively involving the deeper fascicles of muscles such as biceps and tibialis anterior. Lower extremity muscle MRI showed relative sparing of gluteus maximus, rectus femoris, gracilis, and lateral gastrocnemius muscles and an asymmetric and multifocal, "geographical" pattern of T1 hyperintensity within affected muscles. Cardiac studies revealed mild and nonspecific abnormalities on electrocardiogram and echocardiogram with unremarkable cardiac MRI studies. Interpretation: Skeletal muscle ultrasound and muscle MRI reflect the multifocal aggregate formation in muscle in FHL1-related reducing body myopathy and are practical and informative tools that can aid in diagnosis and monitoring of disease progression.Peer reviewe

Medical management of muscle weakness in Duchenne muscular dystrophy.

IntroductionDuchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens.MethodsA list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists' responses were collected using a modified Delphi approach.ResultsAmong corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid.DiscussionThe options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects

MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated serum creatine kinase

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds with biallelic variants in MLIP, which encodes the muscular lamin A/C-interacting protein, MLIP. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. The biallelic truncating variants were predicted to result in disruption of the nuclear localizing signal of MLIP. Additionally, reduced overall RNA expression levels of the predominant MLIP isoform were observed in patients' skeletal muscle. Collectively, our data increase the understanding of the genetic landscape of rhabdomyolysis to now include MLIP as a novel disease gene in humans and solidifies MLIP's role in normal and diseased skeletal muscle homeostasis

A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy

Objective: To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD). Methods: Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg-1·d-1, tadalafil 0.6 mg·kg-1·d-1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome. Results: Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state. Conclusions: Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age. Clinicaltrialsgov identifier: NCT01865084. Classification of evidence: This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy