Tadalafil and Sildenafil for Duchenne Muscular Dystrophy

Early Phase 1

Completed

• Conditions: Duchenne Muscular Dystrophy
• Interventions: Drug: Tadalafil; Drug: Sildenafil

• Registration Number: NCT01359670
• Lead Sponsor: Cedars-Sinai Medical Center

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.

Study Timeline

• Study Start: 2011-05
• Study First Submitted: 2011-05-23
• Study First Submitted QC: 2011-05-24
• Study First Posted: 2011-05-25
• Primary Completion: 2013-05
• Study Completion: 2013-05
• Status Verified: 2018-04
• Last Update Submitted: 2020-01-10
• Last Update Posted: 2020-01-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 30

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Tadalafil	Tadalafil	-
Sildenafil	Sildenafil	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

Cedars-Sinai Medical Center; 🇺🇸 Los Angeles, California, United States