Double Push Acoustic Radiation Force (DP ARF) Ultrasound for Monitoring Degeneration in Duchenne Muscular Dystrophy
Condition: Muscular Dystrophy, Duchenne
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne
Study type: Observational

Summary: 
      This is a pilot clinical trial to assess the ability of a new ultrasound-based imaging
      method, Double-Push Acoustic Radiation Force (DP ARF) ultrasound, to monitor the progression
      of Duchenne muscular dystrophy. The hypothesis being tested is that DP ARF ultrasound
      delineates changes in muscle composition and function in individual dystrophic muscles, from
      early through late stages of disease development, that correlate to time to loss of
      ambulation in patient volunteers.
    

Detailed description: 
      Double Push Acoustic Radiation Force (DP ARF) imaging will be performed in 3 cohorts of up to
      10 boys with DMD and in age-matched boys with no known neuromuscular disorders.

      The first DMD cohort will enroll at age 5-6, the second at age 7-8, and the third at age
      9-10. The rectus femoris (RF), cranial sartorius (CS), gastrocnemius (GAST), and lateral
      deltoid (DT) muscles will be targeted for their known phenotypic variation in response to
      dystrophin deficiency. The RF undergoes early necrosis and fatty deposition, the CS is
      thought to be relatively spared, and the GAST seems to undergo true hypertrophy. The DT,
      which undergoes hypertrophy like the GAST, will also be examined to determine if the impact
      of dystrophin deficiency varies between upper and lower limbs. All boys will be imaged 3
      times annually for 4 years. In addition to DP ARF imaging every 4 mos, the boys will undergo
      standard quantitative muscle testing (QMT) and timed function tests (TFT) of time to
      standing, 6-minute walk, and 30-feet walk. Age at loss of ambulation will also be recorded
      for each boy. Boys with DMD generally loose ambulation by age 10, so we expect that the 20
      boys in the 7-11 and 9-13 aged cohorts will lose ambulation over the course of this study.
      The 10 boys in the 5-9 aged cohort will likely not lose ambulation during the study. Because
      the primary objective of this clinical investigation is to evaluate the potential of DP ARF
      imaging as a relevant surrogate for monitoring disease progression and response to therapies,
      the focus of the study will be on correlating DP ARF results to change in functional
      degeneration and time to loss of ambulation.

      There are two experimental components to this study beyond what is standard practice for DMD
      patients: 1) DP ARF ultrasound imaging of the rectus femoris (RF), cranial sartorius (CS),
      gastrocnemius (GAST), and lateral deltoid (DT) muscles and 2) standard quantitative muscle
      testing (QMT) and timed function tests (TFTs) of time to standing, 6-minute walk, and 30-feet
      walk repeated every four months (three times annually) throughout the four-year duration of
      the study.

      This study will commence with DP ARF ultrasound imaging in the Clinical Neurophysiology
      Laboratory during the patient volunteer's first regularly scheduled research visit. Patient
      volunteers are expected to be outpatients. However, if a patient volunteer is an inpatient,
      DP ARF ultrasound imaging may be performed at the patient volunteer's hospital bedside.
      Immediately following DP ARF examination, the patient volunteer will undergo QMT and TFTs in
      the Physical Therapy Department. QMT and TFT will be conducted by trained physical
      therapists. DP ARF ultrasound imaging, QMT and TFT will be repeated as described above at
      each of the patient volunteers' twelve regularly scheduled research visits over the four-year
      study duration. Whenever possible, we will schedule research visits to coincide with other
      clinical visits to UNC. The patients' parents or caregivers will be compensated $50 per visit
      to defray the costs of travel to UNC, parking and lunch.

      DP ARF will also be performed in 30 boys ages 5-14 with no known neuromuscular disorders.
      Imaging will be performed as described for the boys with DMD. The DP ARF results obtained in
      boys with no known neuromuscular disorders will be compared to those obtained in boys with
      neuromuscular disorders to serve as a control for changes in muscle mechanical property to
      occur with normal muscle growth and development.

      DP ARF ultrasound is a noninvasive diagnostic imaging technology performed using commercially
      available clinical ultrasound imaging equipment - the Siemens Acuson Antares imaging system
      equipped for research purposes and VF10-5 or VF7-3 linear array transducers (Siemens Medical
      Solutions, USA Inc. Ultrasound Division). DP ARF imaging will be carried out by a
      professional sonographer, faculty and/or graduate student research assistants in the UNC-CH
      Joint Department of Biomedical Engineering. The sonographer will acquire DP ARF ultrasound
      data with matched B-Mode (for anatomical reference) in the right RF, CS, GAST, and DT muscles
      of patient volunteers. Patient volunteers will be asked to lie on an examination table in the
      Clinical Neurophysiology Clinic (outpatients) or to remain in their hospital beds
      (inpatients). The head of the exam table/bed may be raised to an approximate 45 degree angle
      to best visualize the muscles of interest with ultrasound imaging.

      Once the patient volunteer is positioned, ultrasound gel will be applied to the patient
      volunteer's skin surface above the muscles of interest. The ultrasound imaging transducer
      will then be placed on top of the gel. Once the first muscle of interest is located, DP ARF
      ultrasound imaging will begin. We will orient the transducer to acquire ultrasound data
      transverse to the muscle fibers in the middle of the muscle length-wise, with three repeated
      acquisitions. We will then rotate our transducer 90 degrees to orient the imaging plane
      parallel to the muscle fibers. The previously imaged cross-section will be positioned in the
      approximate middle of the imaging field of view, with three repeated acquisitions. Muscle
      fiber orientation will be approximate, as surmised from anatomy. The DP ARF axial focal depth
      will be directed to the center of the muscle, approximately 20 - 30 mm.

      The length of time for DP ARF data collection in each muscle is estimated to be less than 10
      minutes. Once DP ARF imaging is completed on one muscle, DP ARF imaging will be performed on
      the other muscles of interest. Once all 4 muscles (RF, CS, GAST and DT) are imaged, the study
      procedure will be completed for the DP ARF imaging portion of the study.

      For the second part of the study, beginning shortly (less than 4 hours) after DP ARF imaging
      is completed, the patient volunteer will undergo clinically standard quantitative muscle
      testing (QMT) of maximum voluntary isometric contraction (MVIC) in the right RF, CS, GAST and
      DT. The patient volunteer will also undergo clinically standard timed function tests (TFTs)
      of (1) time to rise from supine to standing, (2) distance walked in six minutes and (3) time
      to walk 30 feet.

      Patient volunteers' participation will end once both study parts one (DP ARF ultrasound
      imaging) and two (QMT and TFT) are completed twelve times over 4 years. Therefore, there will
      be regularly scheduled follow-up visits required of the patient volunteers every four months.
      The patient volunteer is asked to assent and his parents are asked to permit their son to
      undergo (1) DP ARF ultrasound imaging of his right RF, CS, GAST and DT muscles, and (2) QMT
      and TFTs of time to standing, 6-minute walk, and 30-feet walk. No additional procedures or
      requirements are proposed. Every other aspect of the patient volunteers' care for DMD will be
      carried out in the normal standard of care as clinically indicated.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        The study population will include patient volunteers with Duchenne muscular dystrophy
        (DMD). Thirty volunteers (boys with DMD, enrolling at ages 5 (n=10), 7 (n=10), or 9 (n=10))
        having clinical diagnosis of DMD with clinical onset by age 5 will be considered for
        enrollment.
      
Keywords: Muscular Dystrophy, Duchenne; Ultrasound; Imaging; Acoustic Radiation Force; Double Push