Studying Skeletal Muscle, Heart, and Diaphragm Imaging in Boys With Duchenne Muscular Dystrophy
Condition: Muscular Dystrophy; Muscular Disease
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Diseases
Study type: Observational

Summary: 
      Background:

      - Duchenne muscular dystrophy (DMD) is a disease in which the muscles are unable to make the
      protein dystrophin. Without this protein, the muscles become gradually weaker. A new medicine
      called GSK2402968 is being tested to see if it can help prevent or slow down this loss of
      muscle strength. In this study, boys with DMD and healthy volunteers will have different
      types of imaging studies to see which ones provide the best images of the muscles. This
      information will help researchers use these imaging techniques to test the safety and
      effectiveness of GSK2402968 and other agents.

      Objectives:

      - To test magnetic resonance imaging and ultrasound techniques that can detect changes in
      muscles of boys with DMD.

      Eligibility:

        -  Boys who have DMD and are in the GSK2402968 drug test study.

        -  Healthy boys of the same age as the above study participants.

      Design:

        -  Participants will be screened with a medical history and physical exam.

        -  Healthy volunteers will have one 2-hour visit with three tests. Magnetic resonance
           imaging (MRI) scans of the skeletal muscles and heart and diaphragm muscles will be
           carried out. Muscle ultrasound imaging of leg and arm muscles will also be done.
           Participants should not perform heavy physical activity like school sports or long walks
           during the week before the visit.

        -  Participants in the GSK2402968 study will have the same series of tests as the healthy
           volunteers. The tests will be given during the study screening phase. They will be
           repeated after 3 months and 6 months of receiving the study agent (GSK2402968 or
           placebo) and at 6 months after stopping the GSK study.
    

Detailed description: 
      Objective:

      Duchenne muscular dystrophy (DMD) is the most frequent inherited fatal childhood disease.
      Antisense oligonucleotide (AON)-induced exon skipping is a promising therapeutic strategy for
      DMD that is currently being explored in clinical trials. Magnetic resonance imaging (MRI) and
      ultrasound imaging methods are sensitive to key processes in dystrophic muscle such as edema
      and fat infiltration and therefore could serve as a biomarker of disease progression and
      therapeutic response. Our objective is to explore the potential of these imaging biomarkers
      for GSK2402968 (AON) effects in ambulatory boys with DMD. The primary objective is to assess
      longitudinal changes in skeletal muscle structural MRI measures reflecting fat and edema in
      the lower extremities in ambulatory boys with DMD receiving GSK2402968 or placebo

      Study Population:

      We aim to enroll up to 65 ambulatory boys with DMD. Healthy volunteer/control boys (up to 25)
      matched for the age-range will be recruited to obtain pilot data for imaging studies.

      Design:

      This prospective study of skeletal muscle, cardiac, and diaphragm imaging at the NIH will be
      offered to all subjects participating in a phase 2, double blind, exploratory parallel-group,
      placebo-controlled clinical study in ambulatory subjects with DMD resulting from a mutation
      that can be corrected by exon 51 skipping induced by GSK2402968 (parent study; DMD114876).
      Subjects will travel with a family member to the NIH for MRI and ultrasound assessments
      during the screening phase of the parent study or up to 3 weeks after randomization and
      additionally at the following time points in the parent study: at 12 weeks ( 3 weeks), and 24
      weeks ( 3 weeks) during the blinded treatment period; and finally, after completion of 24
      week post-treatment phase (at 48 weeks 4 weeks). If not randomized, the subjects will have a
      one-time evaluation during the screening phase of the parent study. Pilot data also will be
      obtained from healthy boys (matched for the age-range) for comparisons to allow exploration
      of MRI and ultrasound measures specific to pathology in the ambulatory boys with DMD.
      Subjects will not be treated with GSK2402968 or any other experimental drug at the NIH. There
      are no follow-up or termination procedures for this study.

      Outcome Measures:

      Primary Outcome Measure: MRI changes in skeletal muscle percent fat in the lower extremities
      using T1w GRE Dixon method at 24 weeks from baseline in the parent study in ambulatory boys
      with DMD receiving GSK2402968 or placebo. Secondary outcome measures: Differences in the
      following outcome measures between healthy boys and ambulatory boys with DMD at baseline; and
      changes in these measures over time in the parent study at 12 weeks, 24 weeks, and 48 weeks
      from baseline in ambulatory boys with DMD receiving GSK2402968 or placebo: 1. Skeletal muscle
      MRI: relative muscle fat/water quantified by T1w GRE Dixon imaging method in skeletal
      muscles; Muscle edema assessed by T2 imaging; Muscle fat/water content and edema additionally
      quantified by IDEAL-CPMG method; and 2. Cardiac MRI: Cardiac function (ejection fraction/ LV
      function) assessed by SSFP Cine MRI and manual planimetry of LV volumes and mass at end
      systole and end diastole; Myocardial fat content assessed by Multiecho Dixon Fat /Water
      Separation method; Myocardial edema assessed by T2 quantification; Myocardial T1 assessed by
      MOLLI (modified Look-Locker Inversion recovery).

      Exploratory Outcome Measures: MRI changes in muscle architecture and water diffusivity will
      be assessed by Diffusion EPI MRI. If well tolerated, then we will use a portable device
      (Ankle IntelliStretch device, RehabTek) to study the effects of exercise on selected MRI
      measures in leg muscles. Muscle ultrasound will be used to monitor changes in skeletal muscle
      volume, echogenicity and stiffness. Dynamic breathing MRI will be performed to measure
      diaphragm motion during free breathing and voluntary maximal inspiration and exhalation.
    

Keywords: Ultrasonography; Muscular Dystrophy; Neuromuscular Disease; Oligonucleotide; Magnetic Resonance Imaging (MRI); Duchenne Muscular Dystrophy; DND