Duchenne Muscular Dystrophy
Conditions
Keywords
therapy, treatment strategy, vasodilator, exercise
Brief summary
This project will assess the vascular responsiveness in leg muscles of boys with Duchenne muscular dystrophy (DMD) to one single dose of tadalafil, a common vasodilator drug, using non-invasive techniques (MRI or Doppler ultrasound) and exercise testing. These findings will provide proof of concept for a subsequent intervention study to demonstrate efficacy of longer-term tadalafil to counter sympathetic vasoconstriction and slow disease progression in DMD. It will also inform whether a group of patients do not respond to the drug.
Detailed description
This project will target up to 25 ambulatory boys with DMD aged 7-13 years. Because the vascular impact of tadalafil is immediate, we will confirm that the drug target is valid target in lower extremities by assessing the change in post-exercise microvascular perfusion using Blood Oxygen Level-Dependent (BOLD) MRI or change in post-exercise hyperemia using Doppler ultrasonography. We will also assess the functional impact of the drug through exercise testing. Patients will be randomized to undergo the above-mentioned assessments with or without the study drug on two separate visits. Time function tests, MRI-based fat fraction and inflammation measurements will also be obtained in all patients, thus characterizing disease severity and provide a sampling of information on whether a subset of patients do not respond to the drug. This information may be used to inform future trials as to the appropriate target population for PDE5i as well as account for potential failures in a previously published phase 3 clinical trial.
Interventions
DRUGTadalafil
Patient will be randomized to one dose of 0.6 mg/kg tadalafill on one of two study visits. On both visits, assessments (MRI, exercise testing, clinical function) will be performed 3 hours after time of dosing.
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Pre/post single dose tadalafil
Eligibility
Sex/Gender
MALE
Age
7 Years to 13 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of DMD confirmed by 1) clinical history with features before the age of five, 2) physical examination, 3) elevated serum creatine kinase level and 4) absence of dystrophin expression, as determined by immunostaining or Western blot (\<2%) and/or DNA confirmation of dystrophin mutation. * Minimum entry age of 7.0 years * Ambulatory
Exclusion criteria
* Older than 13.0 years of age * Contraindication to an MR examination (e.g. aneurysm clip, severe claustrophobia, magnetic implants) * Presence of unstable medical problems * Presence of a secondary condition that impacts muscle function or muscle metabolism (e.g. myasthenia gravis, endocrine disorder, mitochondrial disease) * Contraindications to Tadalafil (use of nitrates, alpha-adrenergic blockers, other PDE5A inhibitors)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in post-contractile BOLD response after tadalafil dosing | MRI will be done 3 hours after dosing/no-dosing on two separate study visits | MRI technique to measure microvascular function in skeletal muscle |
| Change in post-exercise hyperemia after tadalafil dosing | Doppler ultrasound will be done 3 hours after dosing/no-dosing on two separate study visits | Doppler ultrasound will be used to measure blood flow |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in submaximal exercise capacity after tadalafil dosing | Cycle testing will be done 4 hours after dosing/no-dosing on two separate study visits | incremental cardiopulmonary exercise testing on cycle ergometer will be performed to measure heart rate and parameters of exercise performance. |
Countries
United States
Outcome results
None listed