PDE Inhibitors in DMD Study (Acute Dosing Study)

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 perform an efficient dos-titration study to inform the design of a randomized
multicenter trial of PDE5A inhibition for clinical skeletal muscles and cardiac 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 five visits and one
follow up phone call over a one month period. The initial visit will include a medical
history, physical exam, echocardiogram, and blood draw to determine eligibility for the
study.

Eligible boys will be given two different study drugs: sildenafil and tadalafil. At the
first set of visits, the boys will take a low dose (0.5mg/kg) of the sildenafil for the
first day and a high dose (1.0mg/kg) for the second day. Blood will be drawn at specific
timepoints to obtain drug levels (15 minutes, 30 minutes, 1-, 2-, 4-, and 8-hours post
dosing). The boys will be asked to return approximately one week later for the second set
of visits to take the other study drug, tadalafil. The boys will be take a low dose
(0.5mg/kg) of tadalafil for the first day and a high dose (1.0mg/kg) for the second day.
Again, blood will be drawn at specific timepoints.

All eligible subjects will be given both open-label sildenafil initially and then tadalafil.

There will be five clinic visits (screening visit, two sets of medication visits) and one
follow up phone call. 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 the
medication visits, boys will have a saline lock inserted in a vein in their arm to obtain
blood for study drug levels.

A one week follow-up telephone call will be done to check for any adverse events.

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. non-ambulatory

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 sildenafil (use of nitrates, alpha-blockers, CYP3A inhibitors,
amlodipine, or other PDE5A inhibitors)