Clinical trial NCT06290713: Vasodilator and Exercise Study for DMD (VASO-REx)
Official title: Vasodilators and Exercise as Adjuvant Therapy for Duchenne Muscular Dystrophy (VASO-REx Study)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Duchenne Muscular Dystrophy
Duchenne Disease
Muscular Dystrophy
Muscular Dystrophy in Children
Vasodilation
Exercise
DMD
Keywords: DMD
Tadalafil
Drug and Exercise Intervention
Treatment Strategy
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
First posted: 2024-03-04
Enrollment: 50
Sex: MALE
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants are assigned to receive interventions based on their completion and results of Aim 1 (responsiveness to study drug). If participants are found to be Tadalafil-responsive after one dose, they will be included in Aim 2 of the study and will be asked to participate in the double-blinded, randomized, placebo-controlled longitudinal medication \& exercise 6-month study program.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Vascular responsiveness after muscle contraction to a single dose of tadalafil.
timeFrame: up to 4 weeks after the completion of Visits 1 and 2 of Aim 1.
measure: Cycling time to fatigue
timeFrame: Baseline and 6 month follow-up visits of Aim 2.
Secondary outcomes:
measure: Quadriceps muscle Fat Fraction
timeFrame: Aim 1 and Aim 2 (baseline and 6 month follow-up)
measure: Metabolic recovery
timeFrame: Through study completion, an average of 3 years.
measure: cardiopulmonary exercise testing (CPET) - Peak aerobic capacity (VO2max)
timeFrame: Through study completion, an average of 3 years.
measure: cardiopulmonary exercise testing (CPET) - Minute Ventilation (VE)
timeFrame: Through study completion, an average of 3 years.
measure: cardiopulmonary exercise testing (CPET) - Ventilatory Equivalent for Oxygen (VE/VO2)
timeFrame: Through study completion, an average of 3 years.
measure: cardiopulmonary exercise testing (CPET) - Gas Exchange Threshold (GET)
timeFrame: Through study completion, an average of 3 years.
measure: cardiopulmonary exercise testing (CPET) - Workload at Anaerobic Threshold (W at AT)
timeFrame: Through study completion, an average of 3 years.
measure: The 100-meter timed test (100m)
timeFrame: Through study completion, an average of 3 years.
measure: the North Star Ambulatory Assessment (NSAA)
timeFrame: Through study completion, an average of 3 years.
measure: The 4-stair climb
timeFrame: Through study completion, an average of 3 years.
measure: The Physical activity questionnaire (PAQ-C)
timeFrame: Through study completion, an average of 3 years.
measure: Pulmonary function testing - vital capacity (FVC)
timeFrame: Through study completion, an average of 3 years.
measure: Pulmonary function testing - forced expiratory volume in 1 second (FEV1)
timeFrame: Through study completion, an average of 3 years.
measure: Neurology Quality of Life (NeuroQoL) pediatric lower extremity function
timeFrame: Through study completion, an average of 3 years.
measure: Patient Reported Outcomes Measurement Information System (PROMIS) pediatric fatigue
timeFrame: Through study completion, an average of 3 years.
measure: PROMIS parent proxy for physical activity
timeFrame: Through study completion, an average of 3 years.
measure: PROMIS pediatric physical activity
timeFrame: Through study completion, an average of 3 years.
measure: Physical Activity Monitoring - Daily Step Rate
timeFrame: Through study completion, an average of 3 years.
measure: Physical Activity Monitoring - Time in Low-Level Activity
timeFrame: Through study completion, an average of 3 years.
measure: Physical Activity Monitoring - Time in Moderate-Level Activity
timeFrame: Through study completion, an average of 3 years.
measure: Physical Activity Monitoring - Time in High-Level Activity
timeFrame: Through study completion, an average of 3 years.
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida Clinical and Translational Research Building
state: Florida
Study officials:
affiliation: University of Florida, College of Medicine, Department of Physiology and Aging
name: Tanja Taivassalo, Ph.D.
role: PRINCIPAL_INVESTIGATOR
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