Tadalafil and Sildenafil for Duchenne Muscular Dystrophy

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.

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)