Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

Sponsor

University of Florida (Other)

Overall Status

Recruiting

CT.gov ID

NCT01484678

Collaborator

Oregon Health and Science University (Other), Children's Hospital of Philadelphia (Other), Shriners Hospitals for Children (Other), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)

550

Enrollment

Locations

Anticipated Duration (Months)

183.3

Patients Per Site

3.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Duchenne Muscular Dystrophy Becker Muscular Dystrophy

Detailed 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 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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

550 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Magnetic Resonance Imaging and Biomarkers for Muscular Dystrophy

Actual Study Start Date :

Sep 1, 2020

Anticipated Primary Completion Date :

Aug 1, 2025

Anticipated Study Completion Date :

Aug 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Age Matched Controls 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 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 This group will include ambulatory and non-ambulatory men with Becker Muscular Dystrophy ranging from 18-62 years old. * Recruiting

Outcome Measures

Primary Outcome Measures

Change from baseline in intramuscular lipid up to 3-10 years [Change in baseline 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 from baseline in muscle T2 up to 3 months in DMD [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 substudy requires its own Primary and Secondary Outcome measures.
Correlation between MR measures of intramuscular lipid, functional endpoints and histological markers. [Through study completion, an average of 1 year]
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.

Secondary Outcome Measures

Change from baseline in muscle T2 up to 5-10 years [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 [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 [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 substudy requires its own Primary and Secondary Outcome measures.

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years to 62 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

Inclusion Criteria for boys with DMD:

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:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Gainesville	Florida	United States	32610
2	Oregon Health and Science University	Portland	Oregon	United States	97239
3	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

University of Florida
Oregon Health and Science University
Children's Hospital of Philadelphia
Shriners Hospitals for Children
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

Principal Investigator: William Rooney, PhD, Oregan Health and Science University
Principal Investigator: H. Lee Sweeney, PhD, University of Florida
Principal Investigator: Krista Vandenborne, PhD, University of Florida