Duchenne Muscular Dystrophy
Conditions
Keywords
Duchenne, muscular dystrophy, tadalafil, sildenafil, muscle ischemia, exercise
Brief summary
This study, supported by Parent Project Muscular Dystrophy, will determine if tadalafil or sildenafil can improve muscle blood flow during exercise in boys with Duchenne muscular dystrophy.
Detailed description
Duchenne muscular dystrophy (DMD) is a rare, progressive and fatal muscle disease affecting boys and accounts for 80% of muscular dystrophy cases. Tadalafil and sildenafil are medications approved by the FDA for the treatment of erectile dysfunction and pulmonary hypertension. This class of medication improves muscle blood flow in a mouse model of muscular dystrophy, but their benefit to boys with DMD is unknown. The purpose of this study is to 1) determine if tadalafil or sildenafil can improve muscle blood flow during exercise in boys with DMD; and 2) to inform the design of a subsequent, randomized, multi-center trial with clinical endpoints. The investigators will enroll boys with DMD between the ages of 7 and 15 years who are ambulatory and without clinical heart failure. Participants will undergo 6 visits over the course of 5 weeks. The initial visit will include a medical history, physical exam, echocardiogram, and blood draw to determine eligibility for the study. Boys will be given a Holter monitor (a heart monitor) to wear for 48 hours to observe any irregular heartbeats or abnormalities. Eligible boys will be randomized to one of the two study drugs: tadalafil or sildenafil. The boys will take a low dose (0.25mg/kg) of the study drug for the first 2 days and an intermediate dose (0.5mg/kg) for the subsequent 5 days. Then, boys will take a higher dose (1.0mg/kg) of the study drug for 1 week. Tadalafil will be taken once daily and sildenafil will be taken four times daily. Study visits will occur 2 times at baseline, 2 times during the medication, and 1 time after washout of the medication. For these visits, boys will undergo an arm blood flow and hand grip exercise protocol. In this procedure, blood flow and oxygen delivery to the forearm muscles will be measured (noninvasively) before and during application of lower body negative pressure at rest and during handgrip exercise. Lower body negative pressure stimulates the blood flow changes that normally occur when a person sits up after lying down. During these visits, boys will complete a quality of life questionnaire, echocardiogram, and 6-minute walk tests. At home, boys will wear an accelerometer to measure physical activity and a Holter monitor to check for irregular heartbeats. For boys who wish to continue with the study, there will be an option to cross-over and complete study visits with the drug they did not originally receive.
Interventions
DRUGTadalafil
Escalating dose (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg; once daily) over 2 weeks
DRUGSildenafil
Escalating dose (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg; four times daily) over 2 weeks
Sponsors
Parent Project Muscular Dystrophy
Cedars-Sinai Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
7 Years to 15 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of DMD confirmed by muscle biopsy or DNA analysis 2. Age 7-15y 3. Ambulatory 4. No clinical evidence of heart failure
Exclusion criteria
1. Hypertension, diabetes, or heart failure by standard clinical criteria 2. Elevated BNP level (\>100 pg/ml) 3. LVEF \< 50% 4. Wheelchair bound 5. Cardiac rhythm disorder, specifically: rhythm other than sinus, SVT, atrial fibrillation, ventricular tachycardia 6. Continuous ventilatory support 7. Liver disease 8. Renal impairment 9. Contraindications to tadalafil or sildenafil (use of nitrates, alpha-blockers, CYP3A inhibitors, amlodipine, or other PDE5A inhibitors)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional muscle ischemia | For 5 study visits | Measured by the decrease in muscle tissue oxygenation (near infrared spectroscopy) and blood flow (Doppler ultrasound) evoked by reflex sympathetic activation in exercising forearm muscle. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Function | For 5 study visits | Echocardiogram |
| EKG Monitoring | 5 times over about 6 weeks | 48 hour Holter monitoring |
| 6 Minute Walk Test | For 5 study visits | — |
| Physical Activity | 5 times over about 6-weeks | Assessed by accelerometers |
| Quality of Life | For 5 study visits | PedsQL inventory |
Countries
United States
Outcome results
None listed