Strength Training in Duchenne Muscular Dystrophy

NCT02421523 | Completed DMC

• 2 other identifiers: IRB201400874-N1R21AR064949-01A1
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

Duchenne muscular dystrophy (DMD) is a debilitating neuromuscular disease that causes muscle breakdown, weakness, and eventual death. Over the last 40 years parents have received little guidance on the potential of exercise as a therapeutic strategy to maintain muscle function. It is well known that high intensity exercise and eccentric contractions can result in muscle damage in dystrophic muscle, yet the absence of muscle loading will conversely result in muscle wasting. Recent research in rodent models and milder forms of muscular dystrophy supports earlier studies that resistance exercise may have beneficial effects for maintenance of muscle mass in dystrophic muscle. However, careful and systematic investigation into the safety and feasibility of resistance exercise is needed to consider its implementation in boys with DMD. The goal of this project is to assess the safety and feasibility of a home based mild to moderate-intensity strengthening exercise program in boys with Duchenne muscular dystrophy (DMD). Evidence from milder forms of muscular dystrophy and mouse models of DMD suggests that strengthening exercise may be beneficial for these children, but this area has not been adequately explored using human subjects. The results of this study should provide information to assist in the development of scientifically based recommendations concerning optimal exercise parameters for patients with DMD.

Conditions

Duchenne Muscular Dystrophy

Keywords

Exercise; Strength training

Outcome Measures

Primary Outcomes (2)

• Change from baseline in T2 weighted MRI of skeletal muscle in leg for Aim 2

  In order to examine the distribution of affected tissue (versus unaffected tissue) across the lower extremity muscles, multi-slice spin-echo images will be acquired from the lower leg and thigh muscles. A pixel-by-pixel T2 map will be created for each slice (minimal 8 slices) by fitting the decay in image signal intensity (SI) to a single exponential (SI=Aexp-TE/T2+B; A=proton density) with respect to echo time (TE). The total affected tissue volume (% of pixels with T2 \>2SD above control) will be recorded for each of the lower extremity muscles. Subsequently, the same T2 weighted spin-echo sequence will be implemented with fat suppression (FS) and T2 FS maps are created. Based on the difference in proton density between the two spin-echo sequences the T2 FS pixels primarily composed of lipid will be eliminated, and the muscle lesion volume (% of unsuppressed pixels with elevated T2 values) will be recorded for each of the lower extremity muscles.

  Change in baseline relative to 1 week, 6 weeks, 12 weeks

• Change in base line in T2 weighted MRI of skeletal muscle in leg for Aim 1

  Magnetic resonance imaging will be performed with a Philips 3.0T whole body scanner. Subjects will be positioned supine in the magnet. Multi-slice (6 axial slices) multi-echo (16 echoes with equal spacing from 20-320 ms) T2-weighted imaging will be performed on the upper leg (thigh). T2 maps of the thigh muscles will be created and mean T2 values of the knee extensor muscle group and flexor muscle group will be measured as well as the proportion of pixels defined as elevated (\>2SD).

  Change in baseline relative to 48 hours after exercise

Secondary Outcomes (6)

• Change from baseline in Spectroscopic Relaxometry for Aim 2

  Change in baseline relative to 1 week, 6 weeks, 12 weeks

• Change from baseline in Spectroscopic Relaxometry for Aim 1

  Change in baseline relative to 48 hours after exercise

• Change from baseline in Creatine Kinase (CK) Levels for Aim 2

  Change in baseline relative to 1 week, 3 weeks, 6 weeks, 9 weeks, 12 weeks

• Change from baseline in Creatine Kinase (CK) Levels for Aim 1

  Change in baseline relative to 48 hours after exercise

• Change from baseline in Pain for Aim 2

  Change in baseline relative to 1 week, 3 weeks, 6 weeks, 9 weeks, 12 weeks

Other Outcomes (2)

• Change from baseline in Strength of knee extensor and knee flexor muscles for Aim 2

  Change in baseline relative to 6 weeks, 12 weeks

• Change from baseline in Stair Climbing for Aim 2

  Change in baseline relative to 6 weeks, 12 weeks

Study Arms (3)

Aim 2 Exercise group

EXPERIMENTAL

The 10 subjects randomized to the experimental group will participate in an isometric exercise strengthening intervention of the knee extensor and knee flexor muscles in both legs with a frequency of \~three times/week for 12 weeks.

Procedure: Aim 2 Exercise group

Aim 2 Control group

ACTIVE COMPARATOR

The 10 subjects randomized to the control group will not participate in any exercise program during the 12 weeks and will be instructed to continue with their normal activities.

Procedure: Aim 2 Control group

Aim 1 Exercise Dosing

EXPERIMENTAL

In order to implement a pilot home exercise intervention, the dose response and safety of this intervention must first be determined. We will enroll 12 boys with DMD for this aim and testing will be performed on the right leg.

Procedure: Aim 1 Exercise Dosing

Interventions

Aim 2 Exercise group PROCEDURE

The experimental group will participate in an isometric exercise strengthening intervention with a frequency of \~three times/week for 12 weeks. Training will include using a custom-built exercise set-up and a live monitoring system for all of the subjects who participate in the experimental group. Progression of the exercise program will only occur after safety assessments at weeks 3, 6, and 9. The safety assessments to occur at baseline, 1 week, 6 weeks, and 12 weeks include T2 MRI, Spectroscopic relaxometry, pain rating scale, and CK levels. The safety assessments to occur at 3 weeks and 9 weeks include the pain rating scale and CK levels. Participants in this group may also be tested for strength assessments (of the knee flexors and extensors) and time to climb 4 stairs.

Aim 2 Exercise group

Aim 1 Exercise Dosing PROCEDURE

The maximal voluntary contraction (MVC) will be determined for each subject. The first four subjects will exercise at an intensity of \~30% of the subject's MVC. Subjects will be asked to perform \~4 sets of 6 reps of knee extension and knee flexion contractions. 48hs after the exercise is completed a safety assessment will be performed for muscle damage. If none has occurred, four additional subjects will perform the exercise at the next level of intensity (\~50% MVC). Similarly, if no damage has occurred at \~50% MVC, four more subjects exercise at \~70% MVC. All safety measures will be performed 48hrs after the exercise has been completed at each of the levels. These safety assessments include T2 MRI, Spectroscopic relaxometry, pain rating scale, and CK levels.

Aim 1 Exercise Dosing

Aim 2 Control group PROCEDURE

This group will receive safety assessments at baseline, 1 week, 6 weeks, and 12 weeks including T2 MRI, Spectroscopic relaxometry, pain rating scale, and CK levels. They will also receive safety assessments at 3 weeks and 9 weeks that will include the pain rating scale and CK levels. Participants in this group may also be tested for strength assessments (of the knee flexors and extensors) and time to climb 4 stairs.

Aim 2 Control group

Eligibility Criteria

• Age: 7 Years - 10 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Diagnosis of DMD confirmed by
• clinical history with features before the age of five
• physical examination
• elevated serum creatine kinase level
• absence of dystrophin expression, as determined by immunostain or Western blot (\<2%) and/or DNA confirmation of dystrophin mutation.
• Age 7 to 10.5 years: a lower age limit of 7 years was selected, since in our experience children younger than 7 years are likely unable to cooperate and comply with all of the exercise measures as needed. An upper age limit of 10.5 years has been set as boys with DMD tend to reach a rapid progression into a late ambulatory phase soon after this age.
• Ambulatory at the time of the first visit, defined as the ability to walk for at least 100 m without an external assistive device and able to climb four stairs.
• Currently using corticosteroids (prednisone or deflazacort) as prescribed by a physician.

You may not qualify if:

• Contraindication to an MR examination (e.g. aneurysm clip, severe claustrophobia, magnetic implants)
• Presence of a condition in control subjects or a secondary condition in boys with DMD that impacts muscle function or muscle metabolism (e.g. myasthenia gravis, endocrine disorder, mitochondrial disease)
• Secondary condition leading to developmental delay or impaired motor control (e.g. cerebral palsy)
• Secondary condition that impacts muscle function or muscle metabolism (e.g. myasthenia gravis, endocrine disorder, mitochondrial disease)
• Unstable medical condition (e.g. uncontrolled seizure disorder)
• Behavioral problems causing an inability to cooperate during testing

Sponsors & Collaborators

• University of Florida: lead
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): collaborator

Study Sites (1)

University of Florida

Gainesville, Florida, 32611, United States

Location

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne; Motor Activity

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Behavior

Study Officials

• Donovan J Lott, PhD, PT

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 15, 2015
• First Posted: April 20, 2015
• Study Start: May 30, 2015
• Primary Completion: February 15, 2018
• Study Completion: October 8, 2018
• Last Updated: March 6, 2019

Record last verified: 2019-03

Locations

US (1)