Examining two strategies as potential adjuvant therapies for Duchenne muscular dystrophy (DMD); aerobic exercise training (to induce adaptations in skeletal muscle and improve cardiovascular health) and tadalafil, an FDA-approved vasodilator (to optimize blood flow and muscle perfusion which is impaired and often overlooked in DMD). Target: improved muscle function, vascular health, and DMD treatment.
Diagnosis of DMD confirmed by genetic report
Minimum entry age of 6.0 years old
Ambulatory
On stable glucocorticoid regimen (for > 3 months)
Contraindication to a Magnetic resonance Imaging examination (e.g. severe claustrophobia, magnetic implants, unable/unwilling to perform test)
Presence of unstable medical problems, including severe cardiomyopathy, left ventricular ejection fraction <45%, cardiac conduction abnormalities as evidenced on ECG, uncontrolled seizure disorder, uncontrolled hypo or hypertension
Presence of a secondary condition that impacts muscle function or muscle metabolism (e.g., myasthenia gravis, endocrine disorder, mitochondrial disease)
Presence of a secondary condition leading to developmental delay or impaired motor control (e.g., cerebral palsy) or previous history of unprovoked rhabdomyolysis
Parallel
Tadalafil
DrugPatients will be given either the intervention medication or a placebo (double-blinded, randomized trial) and will be asked to take the medication every day for 6 months in conjunction with weekly exercise sessions.
Placebo
DrugPatients will be given either the intervention medication or a placebo (double-blinded, randomized trial) and will be asked to take the medication every day for 6 months in conjunction with weekly exercise sessions.
Exercise Training
Other interventionThe home-based cycling exercise training program is designed to improve muscle strength and endurance. Participants will engage in individualized exercise sessions up to four times per week, lasting up to 40 minutes each. Live video and heart rate monitoring will ensure proper exercise performance and allow for adjustments to the program throughout the study. The participants will receive the exercise equipment for use at home.
Vascular responsiveness after muscle contraction to a single dose of tadalafil.
Responsiveness will be determined by an increase in post-contractile muscle oxygenation using MRI-Blood Oxygen Level Dependent (BOLD) responses after dosing compared to before. Study participants demonstrating an increase (\>50%) in post-contractile BOLD after tadalafil will be enrolled into Aim 2 of this study.
Cycling time to fatigue
The study will assess the impact of tadalafil on exercise performance and fatigue resistance compared to placebo. Participants will undergo a maximal effort cycling test before and after the intervention period. The time it takes for participants to reach exhaustion (TTE) will be recorded as the primary outcome measure. Measurement: Time to exhaustion (TTE) during a maximal effort cycling test on a recumbent, stationary ergometer. This test will quantify fatigue resistance by measuring the duration participants can sustain maximal effort cycling.
Quadriceps muscle Fat Fraction
This outcome serves as a measure of disease severity. This measure is a sensitive and reproducible biomarker of DMD muscle pathology.
Metabolic recovery
The rate of phosphocreatine resynthesis after leg exercise will be quantified and serves as index of skeletal muscle mitochondrial oxidative capacity. (Part of Aim 2 of the study).
cardiopulmonary exercise testing (CPET) - Peak aerobic capacity (VO2max)
Patients will undergo cycling exercise at submaximal and peak workloads to quantify peak aerobic capacity, ventilation. Peak Oxygen Uptake (VO2max): This measure quantifies the maximum amount of oxygen the body can utilize during exercise, assessed through maximal cycling effort in a CPET. It serves as a primary indicator of overall cardiovascular and aerobic fitness. Peak aerobic capacity: VO2max reflects the maximum oxygen utilization capacity, indicating overall cardiovascular fitness.
cardiopulmonary exercise testing (CPET) - Minute Ventilation (VE)
Minute Ventilation (VE): This measure reflects the total volume of air breathed per minute during exercise, assessed throughout the CPET. Evaluating VE at various workloads provides insights into respiratory efficiency and potential limitations during exercise. Respiratory efficiency: VE and VE/VO2 assess how well the body utilizes oxygen during exercise, revealing potential respiratory limitations.
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University of Florida
Lead sponsor
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Collaborator
