Effect of Modulating the nNOS System on Cardiac, Muscular and Cognitive Function in Becker Muscular Dystrophy Patients
Condition: Becker Muscular Dystrophy
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne
Study type: Interventional
Phase: Phase 2

Summary: 
      This study is done to evaluate whether treatment with the drug sildenafil (Revatio®) can
      improve muscular, cardiac, cerebrovascular or cognitive function in patients with Beckers
      muscular dystrophy when compared to placebo (inactive medication). The study is based on the
      recent findings of an improved cardiac function in a mouse model of muscular dystrophy (Adamo
      et al 2010) and the previous findings of changed cognitive function in people with Becker
      dystrophy.

      In muscular dystrophy, the cellular protein, dystrophin is affected. During normal
      conditions, the enzyme neuronal nitric oxide synthase (nNOS), which produce nitric oxide
      (NO), is attached to dystrophin. NO is important in normal vascular function in each of
      muscle, heart and brain by stimulating production of cyclic GMP. However, in muscular
      dystrophy with dystrophin deficiency, nNOS do not have the normal cellular anchor, resulting
      in decreased NO levels and subsequent reduced cyclic GMP production. Sildenafil inhibits
      degradation of cGMP thus prolonging and increasing a cGMP response. Such effects are the
      basis for use of sildenafil in pulmonary hypertension and erectile dysfunction. Current
      hypothesis: Sildenafil restores the cyclic GMP function affected in muscular dystrophy wit
      nNOS deficiency resulting in improved muscle, cardiac, cerebrovascular and cognitive
      function.
    

Detailed description: 
      The current clinical trial including people with Becker's muscular dystrophy and established
      deficiency in muscular content of nNOS protein consist of three sub-studies focusing on each
      of muscle function, cardiac function and brain function. In muscular dystrophy the dystrophin
      cellular complex usually located to muscle cells, is disrupted resulting in a known reduced
      nNOS activity. The reduced nNOS leads to reduced cyclic GMP production. nNOS and cyclic GMP
      are involved in the vascular response in striate muscle, cardiac vessels as well as the
      cerebrovascular response to hypercapnia and regional activation. In muscular dystrophy, the
      is an affected muscular and cardiac function and in some patients a changed cognitive
      function in described. Whether such is related to a reduced nNOS function and subsequent cGMP
      production is not fully understood. Inhibition of cGMP degradation by inhibiting the cGMP
      degrading enzyme phosphodiesterase 5 (PDE5) using PDE5 inhibitors such as sildenafil may
      result in restoration of vascular responses.

      The study is designed as a double blind, randomised, balanced, placebo-controlled cross-over
      study performed during a 10 week treatment period. The patients will receive 4 weeks of
      either sildenafil or placebo with a 2 week washout period in between treatments. The study
      out-come parameters will be performed on two consecutive days at baseline, 4 weeks and 10
      weeks, at two collaborating centers, Rigshospitalet for muscle and cardiac parameters and
      Glostrup Hospital for cerebrovascular and cognitive parameters.

      The primary endpoints relate to each sub-study, assessing and comparing individual changes
      from baseline and during placebo/sildenafil treatment.
    

Intervention name(s): Sildenafil; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 20 mg in gelatine capsules, oral, three times daily; Lactose monohydrate oral in gelatine capsules, 3 times daily
Other intervention name(s): Placebo; Sildenafil (Revatio)
Intervention MeSH terms: Sildenafil Citrate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: clinical trial; sildenafil; revatio; muscular dystrophy; adult; nNOS