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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Does Modulation of the nNOS System in Patients With Muscular Dystrophy and Defect nNOS Signalling Affect Cardiac, Muscular or Cognitive Function?

Brief 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 Summary:

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.

Sponsor: Rigshospitalet, Denmark

Current Primary Outcome:

• 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 ]
  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 ]
  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 ]
  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 ]
  Primay outcome for substudy 3

Original Primary Outcome:

• Change from baseline in handgrip test with concomitant ultrasound measurement of flow in the brachial artery at 4 weeks sildenafil or placebo treatment [ Time Frame: Measured at baseline, after 4 and 10 weeks ]
  Primary outcome for substudy 1
• Changes from baseline in resting cardiac end-diastolic volume measured by MRI at 4 weeks sildenafil or placebo treatment. [ Time Frame: Measured at baseline, after 4 and 10 weeks ]
  Primary outcome for substudy 2
• Changes from baseline in cerebrovascular reactivity to CO2 inhalation and finger movements measured by BOLD fMRI at 4 weeks sildenafil or placebo treatment [ Time Frame: Measured at baseline, 4 and 10 weeks ]
  Primary outcome for substudy 3
• Changes from baseline in Cognitive function measured by Cambridge Neuropsychological Test Automated Battery (CANTAB) at 4 weeks sildenafil or placebo treatment [ Time Frame: Measured at baseline, 4 and 10 weeks ]
  Primay outcome for substudy 3

Current Secondary Outcome:

• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in 6 minutes walk test [ Time Frame: Baseline and 4 weeks treatment ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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.

Original Secondary Outcome:

• Changes from baseline in 6 minutes walk test at 4 weeks sildenafil or placebo treatment [ Time Frame: baseline, 4 and 10 weeks ]
  Substudy 1
• Changes from baseline in max test, measured by O2 uptake during maximal exercise on bike at 4 weeks sildenafil or placebo treatment [ Time Frame: baseline, 4 and 6 weeks ]
  Substudy 1
• Changes from baseline in Quality of life by SF36 at 4 weeks sildenafil or placebo treatment [ Time Frame: Baseline, 4 and 10 weeks ]
  Substudy 1
• Changes from baseline in resting cardiac function measured by cardiac MRI at 4 weeks sildenafil or placebo treatment [ Time Frame: Baseline, 4 and 10 weeks ]
  Substudy 2. Evaluation of resting cardiac ejection fraction and end-systolic volume.
• Changes from baseline in cardiac function during hand grip exercise measured by cardiac MRI at 4 weeks sildenafil or placebo treatment [ Time Frame: Baseline, 4 and 10 weeks ]
  Substudy 2. Cardiac volumes and ejection fraction during 1 minute repeated maximal force hand exercise will be measured.
• Changes from baseline in cerebrovascular reactivity and blood flow at 4 weeks sildenafil or placebo treatment [ Time Frame: Baseline, 4 and 10 weeks ]
  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.
• Changes from baseline in basic activity and metabolites of the brain at 4 weeks sildenafil or placebo treatment [ Time Frame: Baseline, 4 and 10 weeks ]
  Substudy 3.Resting state network by fMRI and metabolites in brain regions by MRI spectroskopy.
• Changes from baseline in cognitive function measured by paper and pen test battery at 4 weeks sildenafil or placebo treatment [ Time Frame: Baseline, 4 and 10 weeks ]
  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
• Changes from baseline in plasma levels of signalling molecules at 4 weeks sildenafil or placebo treatment [ Time Frame: Baseline, 4 and 10 weeks ]
  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.

Information By: Rigshospitalet, Denmark

Dates:
Date Received: May 4, 2011
Date Started: November 2011
Date Completion:
Last Updated: April 9, 2013
Last Verified: April 2013