Vasodilator and Exercise Study for DMD (VASO-REx)

Phase 2

Recruiting

• Conditions: Duchenne Muscular Dystrophy; Muscular Dystrophy; Vasodilation; Exercise; DMD; Duchenne Disease; Muscular Dystrophy in Children
• Interventions: Drug: Placebo; Drug: Tadalafil; Other: Exercise Training

• Registration Number: NCT06290713
• Lead Sponsor: University of Florida

Brief Summary

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.

Detailed Description

Duchenne muscular dystrophy (DMD) is characterized by rapid muscle deterioration, mitochondrial and vascular impairments, resulting in premature loss of ambulation and mortality. Disease-modifying therapeutics are emerging and although they are expected to improve muscle function and daily activity in boys with DMD, most are not designed to correct the vascular impairment. This impairment is due to the lack of restoration of neuronal nitric oxide synthase signaling, which is crucial for vasodilation during and after exercise. The investigators believe limitations in study design were responsible for the lack of efficacy. Therefore, this study combines tadalafil with aerobic exercise to necessitate increased blood flow and activate the drug.

This Exploratory Clinical Trial will assess two potential adjuvant therapies for ambulatory boys with DMD (6 years and older): 1) aerobic exercise training and 2) tadalafil, an FDA-approved vasodilator drug. Preclinical and clinical data, including recent findings from the principal investigator's lab, support the use of these strategies and their potential to benefit muscle perfusion, fatigue, and quality of life.

The study will first test for drug responsiveness (increase in muscle oxygenation) after a single dose. Drug-responsive boys with DMD will be randomized to a 6-month intervention of daily tadalafil or placebo, combined with structured cycle exercise training. Participants will receive exercise-related equipment for use at home and be monitored by the research team via video. The study will quantify the intervention's impact on vascular impairment, muscle pathophysiology (inflammation, fat accumulation, mitochondrial dysfunction), exertional fatigue, and cycling performance.

Our findings are expected to yield:

1. Criteria to identify DMD patients most likely to benefit from tadalafil as adjuvant therapy.

2. Evidence of a powerful synergy between drug impact and exercise training in DMD.

Study Timeline

• Study First Submitted: 2024-02-09
• Study First Submitted QC: 2024-03-01
• Study First Posted: 2024-03-04
• Status Verified: 2024-06
• Study Start: 2024-06-05
• Last Update Submitted: 2024-06-21
• Last Update Posted: 2024-06-25
• Primary Completion: 2026-11
• Study Completion: 2026-11

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Male
• Target Recruitment: 50

Inclusion Criteria

• Diagnosis of DMD confirmed by genetic report
• Minimum entry age of 6.0 years old
• Ambulatory
• On stable glucocorticoid regimen (for > 3 months)

Exclusion Criteria

• 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
• Contraindications to phosphodiesterase 5 inhibitors (use of nitrates, alpha-adrenergic blockers, other phosphodiesterase 5 inhibitors) or other medications known to modulate blood flow or muscle metabolism
• Participation in currently approved FDA trials or other investigational clinical trials during the period of the study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tadalafil and Exercise Arm	Exercise Training	Participants receive tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).
Placebo and Exercise Arm	Exercise Training	Participants receive a tadalafil placebo tablet matching the tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).
Placebo and Exercise Arm	Placebo	Participants receive a tadalafil placebo tablet matching the tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).
Tadalafil and Exercise Arm	Tadalafil	Participants receive tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).

Primary Outcome Measures

Name	Time	Method
Cycling time to fatigue	Baseline and 6 month follow-up visits of Aim 2.	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.
Vascular responsiveness after muscle contraction to a single dose of tadalafil.	up to 4 weeks after the completion of Visits 1 and 2 of Aim 1.	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.

Secondary Outcome Measures

Name	Time	Method
Quadriceps muscle Fat Fraction	Aim 1 and Aim 2 (baseline and 6 month follow-up)	This outcome serves as a measure of disease severity. This measure is a sensitive and reproducible biomarker of DMD muscle pathology.
The 100-meter timed test (100m)	Through study completion, an average of 3 years.	The 100m is a fixed distance test of maximal performance and will be completed according to published guidelines.
cardiopulmonary exercise testing (CPET) - Minute Ventilation (VE)	Through study completion, an average of 3 years.	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.
cardiopulmonary exercise testing (CPET) - Ventilatory Equivalent for Oxygen (VE/VO2)	Through study completion, an average of 3 years.	Ventilatory Equivalent for Oxygen (VE/VO2): This ratio compares ventilation to oxygen uptake, calculated throughout the CPET. It indicates the efficiency of oxygen utilization during exercise and potential respiratory limitations.; Respiratory efficiency: VE and VE/VO2 assess how well the body utilizes oxygen during exercise, revealing potential respiratory limitations.
cardiopulmonary exercise testing (CPET) - Gas Exchange Threshold (GET)	Through study completion, an average of 3 years.	Gas Exchange Threshold (GET): This point during exercise marks the transition from predominantly aerobic to anaerobic metabolism, identified through changes in blood lactate levels and other CPET parameters. Analyzing GET helps assess exercise tolerance and potential for improvement.; Exercise tolerance and fatigue: GET and W at AT pinpoint the intensity at which fatigue and performance decline become significant, offering insights into exercise limitations and potential for improvement.
the North Star Ambulatory Assessment (NSAA)	Through study completion, an average of 3 years.	The North Star Ambulatory Assessment (NSAA) is a 17-item rating scale that is used to measure physical function and motor abilities in ambulatory boys with DMD and is increasingly being used in clinical trials as an overall measure of physical function.
The 4-stair climb	Through study completion, an average of 3 years.	The time to ascend 4-stairs is a strength-measure. The patient is instructed to climb four standard steps (six inches in height each) with two handrails as fast as safely possible, using the rails if needed.
PROMIS parent proxy for physical activity	Through study completion, an average of 3 years.	Questionnaire used to measure patient's parent-reported outcomes of intervention impact.
PROMIS pediatric physical activity	Through study completion, an average of 3 years.	Questionnaire used to measure patient's parent-reported outcomes of intervention impact.
Metabolic recovery	Through study completion, an average of 3 years.	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)	Through study completion, an average of 3 years.	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.
The Physical activity questionnaire (PAQ-C)	Through study completion, an average of 3 years.	The PAQ-C is a self-administered, 7-day recall instrument developed to assess general levels of physical activity throughout the elementary school year for students in grades 4 to 8 and approximately 8 to 14 years, with high validity. Although reliability is considered to be moderate, other physical activity questionnaires are less reliable. Results will be correlated with indices of disease severity and tadalafil responsiveness.
Neurology Quality of Life (NeuroQoL) pediatric lower extremity function	Through study completion, an average of 3 years.	Questionnaire used to measure patient-reported outcomes of intervention impact.
Patient Reported Outcomes Measurement Information System (PROMIS) pediatric fatigue	Through study completion, an average of 3 years.	Questionnaire used to measure patient-reported outcomes of intervention impact.
cardiopulmonary exercise testing (CPET) - Workload at Anaerobic Threshold (W at AT)	Through study completion, an average of 3 years.	Workload at Anaerobic Threshold (W at AT): This measure, derived from the CPET, quantifies the power output at which anaerobic metabolism significantly contributes to energy production. It reflects exercise intensity at which fatigue and performance decline become prominent.; Exercise tolerance and fatigue: GET and W at AT pinpoint the intensity at which fatigue and performance decline become significant, offering insights into exercise limitations and potential for improvement.
Physical Activity Monitoring - Time in Low-Level Activity	Through study completion, an average of 3 years.	Measurement: Total time spent in low-intensity physical activity per day, as defined by Actigraph criteria.
Physical Activity Monitoring - Time in High-Level Activity	Through study completion, an average of 3 years.	Measurement: Total time spent in high-intensity physical activity per day, as defined by Actigraph criteria.
Pulmonary function testing - vital capacity (FVC)	Through study completion, an average of 3 years.	Measurement: FVC, measured using a standard spirometer according to American Thoracic Society guidelines. This is the maximum amount of air an individual can forcefully exhale after a full inhalation.; Significance: FVC reflects the total lung capacity and is a key indicator of overall lung volume and function. It can help identify restrictive lung diseases, where lung volume is limited, and track respiratory health changes over time.
Physical Activity Monitoring - Daily Step Rate	Through study completion, an average of 3 years.	Measurement: Total number of steps taken per day, assessed using the Actigraph activity monitor.
Pulmonary function testing - forced expiratory volume in 1 second (FEV1)	Through study completion, an average of 3 years.	Measurement: FEV1, measured using a standard spirometer according to American Thoracic Society guidelines. This is the amount of air forcefully exhaled in the first second of a maximal exhalation after a full inhalation.; Significance: FEV1 reflects the efficiency of airflow from the lungs and is sensitive to obstructive lung diseases, like asthma and Chronic Obstructive Pulmonary Disease (COPD), where airflow is impaired.
Physical Activity Monitoring - Time in Moderate-Level Activity	Through study completion, an average of 3 years.	Measurement: Total time spent in moderate-intensity physical activity per day, as defined by Actigraph criteria.

Trial Locations

Locations (1)

University of Florida Clinical and Translational Research Building; 🇺🇸 Gainesville, Florida, United States