PDE Inhibitors in DMD Study (Acute Dosing Study)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Ron Victor, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier:
NCT01580501
First received: April 17, 2012
Last updated: January 27, 2014
Last verified: January 2014
  Purpose

PDE5A inhibition, which boosts NO-cGMP signaling, will relieve functional muscle ischemia and restore normal blood flow regulation (i.e., functional sympatholysis) during exercise in boys with DMD. The investigators specific aim is to perform an efficient dose-titration study to inform the design of a randomized multicenter trial of PDE5A inhibition for clinical skeletal muscle and cardiac endpoints.


Condition Intervention Phase
Duchenne Muscular Dystrophy
Drug: Tadalafil and Sildenafil
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Functional Muscle Ischemia and PDE5 Inhibition in Duchenne Muscular Dystrophy: Acute Dosing Study

Resource links provided by NLM:


Further study details as provided by Cedars-Sinai Medical Center:

Primary Outcome Measures:
  • Pre vs. post treatment change in functional sympatholysis by NIR for each dose of each drug. [ Designated as safety issue: No ]
    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:
  • Sympatholysis measured by brachial artery Doppler ultrasound [ Designated as safety issue: No ]

Estimated Enrollment: 12
Study Start Date: March 2012
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Tadalafil and Sildenafil
    PDE-5 Inhibitor; Low dosages will be 0.5mg/kg and high dosages will be 1.0mg/kg
    Other Names:
    • Tadalafil/Cialis
    • Sildenafil/Viagra
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 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.

  Eligibility

Ages Eligible for Study:   7 Years to 15 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
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. 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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01580501

Locations
United States, California
Cedars Sinai Medical Center
Los Angeles, California, United States, 90048
Sponsors and Collaborators
Cedars-Sinai Medical Center
  More Information

No publications provided

Responsible Party: Ron Victor, Associate Director of the Hypertension Center, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT01580501     History of Changes
Other Study ID Numbers: PRO 27521
Study First Received: April 17, 2012
Last Updated: January 27, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Muscular Dystrophy, Duchenne
Tadalafil
Muscular Dystrophies
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Sildenafil
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents

ClinicalTrials.gov processed this record on September 16, 2014