Clinical trial NCT01359670: Tadalafil and Sildenafil for Duchenne Muscular Dystrophy
Official title: Functional Muscle Ischemia and PDE5A Inhibition in Duchenne Muscular Dystrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne
muscular dystrophy
tadalafil
sildenafil
muscle ischemia
exercise
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
Collaborators: name: Parent Project Muscular Dystrophy
First posted: 2011-05-25
Enrollment: 30
Sex: MALE
Minimum age (years): 7
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Functional muscle ischemia
timeFrame: For 5 study visits
Secondary outcomes:
measure: Cardiac Function
timeFrame: For 5 study visits
measure: EKG Monitoring
timeFrame: 5 times over about 6 weeks
measure: 6 Minute Walk Test
timeFrame: For 5 study visits
measure: Physical Activity
timeFrame: 5 times over about 6-weeks
measure: Quality of Life
timeFrame: For 5 study visits
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Ronald Victor, MD
role: PRINCIPAL_INVESTIGATOR
References: