Effect of Modulating the nNOS System on Cardiac, Muscular and Cognitive Function in Becker Muscular Dystrophy Patients

• Difference in change from baseline to 4 week placebo/sildenafil treatment in handgrip test with concomitant ultrasound measurement of flow in the brachial artery [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Primary outcome for substudy 1
  
  
• Difference in changes from baseline to 4 week placebo/sildenafil treatment in resting cardiac end-diastolic volume measured by MRI [ Time Frame: Baseline and 4 week treatment ] [ Designated as safety issue: No ]
  Primary outcome for substudy 2
  
  
• Difference in changes from baseline to 4 week placebo/sildenafil treatment in cerebrovascular reactivity to CO2 inhalation and finger stimulation measured by BOLD fMRI [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Primary outcome for substudy 3
  
  
• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in Cognitive function measured by Cambridge Neuropsychological Test Automated Battery (CANTAB) [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Primay outcome for substudy 3
  
  

• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in 6 minutes walk test [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Substudy 1
  
  
• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in max test, measured by O2 uptake during maximal exercise on bike [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Substudy 1
  
  
• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in Quality of life by SF36 [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Substudy 1
  
  
• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in resting cardiac function measured by cardiac MRI [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Substudy 2. Evaluation of resting cardiac ejection fraction and end-systolic volume.
  
  
• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in cardiac function during hand grip exercise measured by cardiac MRI [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Substudy 2. Cardiac volumes and ejection fraction during 1 minute repeated maximal force hand exercise will be measured.
  
  
• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in cerebrovascular reactivity and blood flow [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Substudy 3. fMRI BOLD evaluation of visual stimulation, MRI angiography for arterial diameter, arterial spin labeling for evaluation of cerebral blood flow and blood volumen.
  
  
• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in basic activity and metabolites of the brain [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Substudy 3.Resting state network by fMRI and metabolites in brain regions by MRI spectroskopy.
  
  
• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in cognitive function measured by paper and pen test battery [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Substudy 3. A paper and pen cognitive test battery will be applied, including Trail making A and B, Addenbrooke's Cognitive Examination, Symbol DIgital MOdality tests
  
  
• Difference in changes from baseline to 4 weeks treatment placebo/sildenafil in plasma levels of signalling molecules [ Time Frame: Baseline and 4 weeks treatment ] [ Designated as safety issue: No ]
  Substudy 3. From blood samples taken at baseline, 4 and 10 weeks, analysis of several signalling molecules relevant for cardiac and cerebrovascular function will be performed.
  
  

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.