Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

Study Overview
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Brief Summary
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The purpose of this research study is to determine the potential of magnetic resonance imaging, spectroscopy, and whole body imaging to monitor disease progression and to serve as an objective outcome measure for clinical trials in Muscular Dystrophy (MD). The investigators will compare the muscles of ambulatory or non-ambulatory boys/men with DMD with muscles of healthy individuals of the same age and monitor disease progression in those with DMD over a 5-10 year period. The amount of muscle damage and fat that the investigators measure will also be related to performance in daily activities, such as walking and the loss of muscle strength. In a small group of subjects the investigators will also assess the effect of corticosteroid drugs on the muscle measurements. Additionally, the investigators will map the progression of Becker MD following adults with this rare disease. The primary objective is to conduct a multi-centered study to validate the potential of non-invasive magnetic resonance imaging and magnetic resonance spectroscopy to monitor disease progression and to serve as a noninvasive surrogate outcome measure for clinical trials in DMD and BMD. The secondary objective is to characterize the progressive involvement of the lower extremity, upper extremity, trunk/respiratory muscles in boys/men with DMD and BMD guiding clinical trials.

Detailed Description
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The overall objective of this proposal is to validate the potential of noninvasive magnetic resonance imaging (MRI) and spectroscopy (MRS) to monitor disease progression and to serve as an outcome measure for clinical trials in muscular dystrophies. Duchenne muscular dystrophy (DMD) is one of the most devastating genetically linked neuromuscular diseases and is characterized by the absence of dystrophin, resulting in progressive muscle weakness, loss of walking ability and premature death. Despite the poor prognosis therapeutic interventions have been lacking, and outcome measures for clinical trials have been limited to measures of muscle function, quality of life, serum biomarkers of muscle breakdown and invasive muscle biopsies. Closely related to DMD, Becker muscular dystrophy (BMD) has also been largely neglected in therapeutic development, due to its heterogeneity, small patient population, lack of outcome measures and uncertainty surrounding the patterns of disease progression, which may be mutation-dependent. Additional quantitative outcome measures that are noninvasive and sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials in both forms of muscular dystrophy. As such, this project targets the development and validation of magnetic resonance as a noninvasive biomarker of disease progression in muscular dystrophy. Using a multi-site research design this study will characterize the intramuscular lipid content, cellular muscle damage and contractile area in the lower and/or upper extremity muscles of 200 ambulatory or non-ambulatory boys/men with DMD, 105 ambulatory or non-ambulatory men with BMD, and 110 healthy age matched boys/men using a combination of sophisticated MRI and MRS technologies. The trunk and respiratory muscles will be characterized in a subgroup of subjects (80 DMD, 20 BMD and 10 controls). In order to assess the sensitivity of each MR measure individually as well as composite MR measures (combination of muscles) to disease progression, all boys/men with DMD or BMD will be re-evaluated in yearly or 6 month intervals. The predictive outcome value of MRI/MRS will be further evaluated by determining the relationship between changes in MR measures and loss in muscle strength and/or functional ability. Using MRI/MRS we will also examine the effect of initiating corticosteroid treatment on skeletal muscle characteristics and composition. Examination of muscles in BMD patients will allow us to increase our understanding of how much dystrophin is needed to protect the muscle. To this end we will specifically examine the relationship between the MR phenotype (e.g. fast or slow increases in fat fraction) and dystrophin mutations, dystrophin expression and other histological markers. Finally, to ensure the rigor of this study we will examine the day-day reproducibility, inter MR system reproducibility and inter-validate the MR measures using localized MRS (golden standard). We anticipate that the MR techniques developed and validated in this study will be suitable for clinical trials in a wide range of muscular dystrophies and other neuromuscular diseases. In addition, MR characterization may serve as a powerful tool to further advance our understanding of the pathogenesis of muscular dystrophy and help guide the design of future trials.

Official Title
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Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy, Becker Muscular Dystrophy

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for boys with DMD: 1. Ambulatory and non-ambulatory males (ages 5-30 at baseline testing) previously diagnosed with DMD based on: clinical features with onset of symptoms before age five elevated serum creatine kinase level or absence of dystrophin expression, as determined by immunostain or western blot (<2%) and/or DNA confirmation of a dystrophin mutation *Subjects will not be excluded based on corticosteroid treatment or other clinical trials Inclusion Criteria for adults with Becker MD: Ambulatory males (ages 18-62) without disease or injury to the lower extremities Specific recruitment of a subset of individuals with deletion mutations in the dystrophin gene involving either exon 51 or exon 45. Inclusion Criteria for age matched controls for Becker MD subjects: 1. Ambulatory males (ages 18-62) without disease or injury to the lower and/or upper extremities will be eligible to participate in this study Exclusion Criteria: Males with a contraindication to an MR examination Males with unstable medical problems Males who are not able to cooperate during testing Males with a secondary condition that may impact muscle metabolism, muscle function or functional ability (i.e. cerebral palsy, endocrine disorders, mitochondrial disease) Daytime ventilation Implantable Cardioverter Defibrillator- (ICD) or pace maker Healthy boys/men who participate in competitive sports specific training in excess of 8 hours per week

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 62 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Age Matched Controls<br>Age matched non-affected (non-DMD) boys * This arm is full Age matched non-affected men, matched for men with Becker MD *Recruiting | |
| Boys/Men with DMD<br>This group will include ambulatory and non-ambulatory boys/men with Duchenne Muscular Dystrophy ranging from 5-30 years old. *Recruiting | |
| Adults with Becker MD<br>This group will include ambulatory and non-ambulatory men with Becker Muscular Dystrophy ranging from 18-62 years old. * Recruiting | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in intramuscular lipid up to 3-10 years | In BMD and DMD, the from baseline in intramuscular lipid of upper/ lower extremity and trunk/respiratory muscles, as well as composite measures. MR measures of intramuscular lipid will be measured in yearly intervals for a period up to 3-10 years. | Change in baseline up to 3-10 years | 
| Change from baseline in muscle T2 up to 3 months in DMD | In a subgroup of subjects the effect of corticosteroids on muscle T2 will be measured at 3 and 6 months. Muscle T2 is a noninvasive marker of muscle damage/inflammation and will be measured using MR. This substudy requires its own Primary and Secondary Outcome measures. | Change in baseline up to 3 months | 
| Correlation between MR measures of intramuscular lipid, functional endpoints and histological markers. | In both BMD and DMD, the correlation between MR measures and functional endpoints will be determined, as well as the ability of MR measures to predict future change and loss in function. | Through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in muscle T2 up to 5-10 years | Muscle T2 will be measured in the lower extremity and/or upper extremity muscles using MR at yearly intervals up to 5-10 years. We will report the change for each year interval. | Change in baseline up to 5-10 years | 
| Change from baseline in muscle contractile area up to 5-10 years | Muscle contractile area will be measured in the lower extremity and/or upper extremity muscles using MR at yearly intervals up to 5 years. We will report the change for each year interval. | change in baseline up to 5-10 years | 
| Change from baseline in muscle T2 at 6 months | In a subgroup of subjects the effect of corticosteroids on muscle T2 will be measured at 3 and 6 months. Muscle T2 is a noninvasive marker of muscle damage/inflammation and will be measured using MR. This substudy requires its own Primary and Secondary Outcome measures. | Change in baseline up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Magnetic Resonance Spectroscopy, Magnetic Resonance Imaging, Muscle