Vasodilator and Exercise Study for DMD (VASO-REx)

University of Florida

Status and phase: Enrolling; Phase 2

Conditions: DMD; Duchenne Disease; Muscular Dystrophy in Children; Vasodilation; Muscular Dystrophy; Exercise; Duchenne Muscular Dystrophy

Treatments: Drug: Placebo; Other: Exercise Training; Drug: Tadalafil

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT06290713

IRB202301491

PRO00050023 (Other Identifier)

1R21AR079755-01 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 50 estimated patients

Sex: Male

Ages: 6+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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50 participants in 2 patient groups, including a placebo group

Tadalafil and Exercise Arm

Experimental group

Description:

Participants receive tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).

Treatment:

Other: Exercise Training

Drug: Tadalafil

Placebo and Exercise Arm

Placebo Comparator group

Description:

Participants receive a tadalafil placebo tablet matching the tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).

Treatment:

Other: Exercise Training

Drug: Placebo