Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

study id #: NCT01484678

condition: Duchenne Muscular Dystrophy

status: recruiting

The purpose of this research study is to determine the potential of magnetic resonance imaging to monitor disease progression and to serve as an objective outcome measure for clinical trials in Duchenne Muscular Dystrophy (DMD). The investigators also hope to learn more about the changes that occur in muscles of the lower leg and arm in boys with DMD.

The investigators will compare the muscles of ambulatory or non-ambulatory boys with DMD with muscles of healthy children of the same age and monitor disease progression in boys 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.

mechanism of action: No pharmaceutical intervention

results: https://clinicaltrials.gov/ct2/show/results/NCT01484678

last updated: January 07, 2019

start date: May 2010

estimated completion: April 2020

size / enrollment: 200

study description:
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 Duchenne muscular dystrophy (DMD). 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 for patients with muscular dystrophy, therapeutic interventions have been lacking, and outcome measures for clinical trials have been limited to measures of muscle function, serum biomarkers of muscle breakdown and invasive muscle biopsies. 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. As such, this proposal 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 examine the intramuscular lipid content, muscle damage/inflammation and contractile area in the lower extremity and/or upper extremity muscles of 200 ambulatory or non-ambulatory boys with DMD and 100 healthy age matched boys using a combination of MRI and MRS technologies. In order to assess the sensitivity of each MR measure to disease progression, all boys with DMD will be reevaluated in yearly or 6 month intervals. In addition, the investigators will correlate changes in MR measures with standard measures of disease progression, such as loss in muscle strength and functional ability. Using MRI/MRS the investigators will also examine the effect of initiating corticosteroid treatment on skeletal muscle characteristics and composition. Finally, the investigators will deposit immortalized fibroblasts from carefully characterized DMD boys participating in this study in established tissue repositories.
The investigators anticipate that the MR techniques developed and validated in this proposal 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.

primary outcomes:

• Change from baseline in intramuscular lipid up to 5-10 years [Time Frame: Change in baseline up to 5-10 years]
  MR measures of intramuscular lipid will be measured in yearly intervals for a period up to 5-10 years.
  
• Change from baseline in muscle T2 up to 3 months [Time Frame: Change in baseline up to 3 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 sub-study requires its own Primary and Secondary Outcome measures.

secondary outcomes:

• Change from baseline in muscle T2 up to 5-10 years [Time Frame: Change in baseline 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 from baseline in muscle contractile area up to 5-10 years [Time Frame: change in baseline 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 from baseline in muscle T2 at 6 months [Time Frame: Change in baseline up to 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 sub-study requires its own Primary and Secondary Outcome measures.

inclusion criteria:
• Ambulatory and non-ambulatory males (ages 5-18) 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
Inclusion Criteria for age matched controls:
• Ambulatory males (ages 5-18) without disease or injury to the lower extremities

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)
• Healthy boys who participate in competitive sports specific training in excess of 8 hours per week. Participation in multiple recreational sports activities is not an exclusion.

sponsor: University of Florida

contacts:
Krista Vandenborne (PhD), 352-273-6100, kvandenb@phhp.ufl.edu;
Claudia Senesac (PhD), 352-273-6453, csenesac@phhp.ufl.edu

investigators: Gihan Tennekoon, MD; William Rooney, PhD; H. Lee Sweeney, PhD; Krista Vandenborne, PhD

locations: United States