Tadalafil and Sildenafil for Duchenne Muscular Dystrophy

Sponsor

Cedars-Sinai Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT01359670

Collaborator

Parent Project Muscular Dystrophy (Other)

Enrollment

Location

Arms

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Duchenne Muscular Dystrophy	Drug: Tadalafil Drug: Sildenafil	Early Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Functional Muscle Ischemia and PDE5A Inhibition in Duchenne Muscular Dystrophy

Study Start Date :

May 1, 2011

Actual Primary Completion Date :

May 1, 2013

Actual Study Completion Date :

May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tadalafil	Drug: Tadalafil Escalating dose (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg; once daily) over 2 weeks Other Names: Cialis Adcirca
Experimental: Sildenafil	Drug: Sildenafil Escalating dose (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg; four times daily) over 2 weeks Other Names: Viagra Revatio

Arm

Intervention/Treatment

Experimental: Tadalafil

Drug: Tadalafil

Escalating dose (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg; once daily) over 2 weeks

Other Names:

Cialis

Adcirca

Experimental: Sildenafil

Drug: Sildenafil

Escalating dose (0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg; four times daily) over 2 weeks

Other Names:

Viagra

Revatio

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

7 Years to 15 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of DMD confirmed by muscle biopsy or DNA analysis
Age 7-15y
Ambulatory
No clinical evidence of heart failure

Exclusion Criteria:

Hypertension, diabetes, or heart failure by standard clinical criteria
Elevated BNP level (>100 pg/ml)
LVEF < 50%
Wheelchair bound
Cardiac rhythm disorder, specifically: rhythm other than sinus, SVT, atrial fibrillation, ventricular tachycardia
Continuous ventilatory support
Liver disease
Renal impairment
Contraindications to tadalafil or sildenafil (use of nitrates, alpha-blockers, CYP3A inhibitors, amlodipine, or other PDE5A inhibitors)