PDE Inhibitors in DMD Study (Acute Dosing Study)
Condition: Duchenne Muscular Dystrophy
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

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.
    

Intervention name(s): Tadalafil and Sildenafil
Intervention type(s): Drug
Intervention description(s): PDE-5 Inhibitor; Low dosages will be 0.5mg/kg and high dosages will be 1.0mg/kg
Other intervention name(s): Tadalafil/Cialis; Sildenafil/Viagra
Intervention MeSH terms: Sildenafil Citrate; Tadalafil
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment