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

This study has been completed.
Sponsor:
Collaborator:
Glostrup University Hospital, Copenhagen
Information provided by (Responsible Party):
Christina Kruuse, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier:
NCT01350154
First received: May 4, 2011
Last updated: April 9, 2013
Last verified: April 2013
  Purpose

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.


Condition Intervention Phase
Becker Muscular Dystrophy
Drug: Sildenafil
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Does Modulation of the nNOS System in Patients With Muscular Dystrophy and Defect nNOS Signalling Affect Cardiac, Muscular or Cognitive Function?

Resource links provided by NLM:


Further study details as provided by Rigshospitalet, Denmark:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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.


Enrollment: 17
Study Start Date: November 2011
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sildenafil (Revation) 20 mg
This arm will receive sildenafil for 4 weeks followed by 2 weeks washout and 4 weeks placebo.
Drug: Sildenafil
20 mg in gelatine capsules, oral, three times daily
Other Name: Placebo
Experimental: Placebo
This arm will receive placebo for 4 weeks followed by 2 weeks washout and 4 weeks sildenafil
Drug: Placebo
Lactose monohydrate oral in gelatine capsules, 3 times daily
Other Name: Sildenafil (Revatio)

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Muscular dystrophy with known deficiency in nNOS
  • Reduced cardiac function (<50%) and/or reduced muscular function (MRC<4+)
  • Stable dosing (> 3 month)of cardiovascular medication
  • Signed informed consent

Exclusion Criteria:

  • Recent (< 6 month) cerebral or cardiac stroke
  • Use of nitrate containing compounds, alpha receptor blocking agents or potent CUP3A4 inhibitors.
  • Intolerance or allergy to sildenafil, or intake of drugs not compatible with sildenafil intake
  • Overuse of drugs or alcohol
  • inclusion in other trials of experimental medication within last 30 days
  • known epilepsy
  • reduced liver function (ASAT >500U/l in 2 repeated measurements when corrected for increase in creatinkinase levels.
  • non-arteriitis anterior ischemic optic neuropathy (NAION) with reduced vision
  • contraindications for MRI scan (metal implants, claustrophobia)
  • hypotension (<90 mmHg systolic at baseline)
  • conditions, medical or psychosocial which makes the subject inclusion inadvisable
  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: NCT01350154

Locations
Denmark
Neuromuscular Clinic and Research Unit, Dept. Neurology, Rigshospitalet,
Copenhagen, Denmark, 2100
Sponsors and Collaborators
Rigshospitalet, Denmark
Glostrup University Hospital, Copenhagen
Investigators
Study Chair: John Vissing, MD, DMSci Neuromuscular Clinic and Research Unit, Dept. Neurology, Rigshospitalet
  More Information

No publications provided

Responsible Party: Christina Kruuse, Senior Registrar, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT01350154     History of Changes
Other Study ID Numbers: RHGLBMD
Study First Received: May 4, 2011
Last Updated: April 9, 2013
Health Authority: Denmark: The Regional Committee on Biomedical Research Ethics
Denmark: Danish Medicines Agency

Keywords provided by Rigshospitalet, Denmark:
clinical trial
sildenafil
revatio
muscular dystrophy
adult
nNOS

Additional relevant MeSH terms:
Muscular Dystrophy, Duchenne
Muscular Dystrophies
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
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 August 21, 2014