Tadalafil and Sildenafil for Duchenne Muscular Dystrophy

• ClinicalTrials.gov Identifier: NCT01359670
• Recruitment Status: Completed
• First Posted: May 25, 2011
• Last Update Posted: January 14, 2020
• Sponsor: Cedars-Sinai Medical Center
• Collaborator: Parent Project Muscular Dystrophy
• Information provided by (Responsible Party): Cedars-Sinai Medical Center

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 (Clinical Trial)
• 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 2011
• Actual Primary Completion Date: May 2013
• Actual Study Completion Date: May 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

Outcome Measures

Primary Outcome Measures :

1. Functional muscle ischemia [ Time Frame: 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 :

1. Cardiac Function [ Time Frame: For 5 study visits ]
   Echocardiogram
2. EKG Monitoring [ Time Frame: 5 times over about 6 weeks ]
   48 hour Holter monitoring
3. 6 Minute Walk Test [ Time Frame: For 5 study visits ]
4. Physical Activity [ Time Frame: 5 times over about 6-weeks ]
   Assessed by accelerometers
5. Quality of Life [ Time Frame: For 5 study visits ]
   PedsQL inventory

Eligibility Criteria

• Ages Eligible for Study: 7 Years to 15 Years (Child)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

United States, California

Cedars-Sinai Medical Center

Los Angeles, California, United States, 90048

Sponsors and Collaborators

Cedars-Sinai Medical Center

Parent Project Muscular Dystrophy

Investigators

• Principal Investigator: Ronald Victor, MD; Cedars-Sinai Medical Center

More Information

• Responsible Party: Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT01359670
• Other Study ID Numbers: PPMD
• First Posted: May 25, 2011
• Last Update Posted: January 14, 2020
• Last Verified: April 2018

Keywords provided by Cedars-Sinai Medical Center:

Duchenne; muscular dystrophy; tadalafil; sildenafil; muscle ischemia; exercise

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Sildenafil Citrate; Tadalafil; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Urological Agents