Vasodilators and Exercise as Adjuvant Therapy for Duchenne Muscular Dystrophy (VASO-REx Study)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Cycling time to fatigue
研究概览
简要总结
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.
详细描述
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:
- Criteria to identify DMD patients most likely to benefit from tadalafil as adjuvant therapy.
- Evidence of a powerful synergy between drug impact and exercise training in DMD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 6 Years 至 —（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of DMD confirmed by genetic report
- •Minimum entry age of 6.0 years old
- •Ambulatory
- •On stable glucocorticoid regimen (for > 3 months)
排除标准
- •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
研究组 & 干预措施
Tadalafil and Exercise Arm
Participants receive tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).
干预措施: Tadalafil (Drug)
Placebo and Exercise Arm
Participants receive a tadalafil placebo tablet matching the tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).
干预措施: Placebo (Drug)
Placebo and Exercise Arm
Participants receive a tadalafil placebo tablet matching the tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).
干预措施: Exercise Training (Other)
Tadalafil and Exercise Arm
Participants receive tadalafil weight-dependent dosage to take daily for 6 months (26 weeks).
干预措施: Exercise Training (Other)
结局指标
主要结局
Cycling time to fatigue
时间窗: 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.
时间窗: 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.
次要结局
- Quadriceps muscle Fat Fraction(Aim 1 and Aim 2 (baseline and 6 month follow-up))
- The 100-meter timed test (100m)(Through study completion, an average of 3 years.)
- cardiopulmonary exercise testing (CPET) - Minute Ventilation (VE)(Through study completion, an average of 3 years.)
- cardiopulmonary exercise testing (CPET) - Ventilatory Equivalent for Oxygen (VE/VO2)(Through study completion, an average of 3 years.)
- cardiopulmonary exercise testing (CPET) - Gas Exchange Threshold (GET)(Through study completion, an average of 3 years.)
- the North Star Ambulatory Assessment (NSAA)(Through study completion, an average of 3 years.)
- The 4-stair climb(Through study completion, an average of 3 years.)
- PROMIS parent proxy for physical activity(Through study completion, an average of 3 years.)
- PROMIS pediatric physical activity(Through study completion, an average of 3 years.)
- Metabolic recovery(Through study completion, an average of 3 years.)
- cardiopulmonary exercise testing (CPET) - Peak aerobic capacity (VO2max)(Through study completion, an average of 3 years.)
- The Physical activity questionnaire (PAQ-C)(Through study completion, an average of 3 years.)
- Neurology Quality of Life (NeuroQoL) pediatric lower extremity function(Through study completion, an average of 3 years.)
- Patient Reported Outcomes Measurement Information System (PROMIS) pediatric fatigue(Through study completion, an average of 3 years.)
- cardiopulmonary exercise testing (CPET) - Workload at Anaerobic Threshold (W at AT)(Through study completion, an average of 3 years.)
- Physical Activity Monitoring - Time in Low-Level Activity(Through study completion, an average of 3 years.)
- Physical Activity Monitoring - Time in High-Level Activity(Through study completion, an average of 3 years.)
- Pulmonary function testing - vital capacity (FVC)(Through study completion, an average of 3 years.)
- Physical Activity Monitoring - Daily Step Rate(Through study completion, an average of 3 years.)
- Pulmonary function testing - forced expiratory volume in 1 second (FEV1)(Through study completion, an average of 3 years.)
- Physical Activity Monitoring - Time in Moderate-Level Activity(Through study completion, an average of 3 years.)