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

Becker Muscular Dystrophy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01350154
• Other study ID #: RHGLBMD
• Status: Completed
• Phase: Phase 2
• First received: May 4, 2011
• Last updated: April 9, 2013
• Start date: November 2011
• Est. completion date: April 2013

Study information

• Verified date: April 2013
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: The Regional Committee on Biomedical Research EthicsDenmark: Danish Medicines Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: April 2013
• Est. primary completion date: April 2013
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Becker Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Drug:
• Sildenafil
20 mg in gelatine capsules, oral, three times daily
• Placebo
Lactose monohydrate oral in gelatine capsules, 3 times daily

Locations

Country	Name	City	State
Denmark	Neuromuscular Clinic and Research Unit, Dept. Neurology, Rigshospitalet,	Copenhagen

Sponsors (2)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Glostrup University Hospital, Copenhagen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in change from baseline to 4 week placebo/sildenafil treatment in handgrip test with concomitant ultrasound measurement of flow in the brachial artery	Primary outcome for substudy 1	Baseline and 4 weeks treatment	No
Primary	Difference in changes from baseline to 4 week placebo/sildenafil treatment in resting cardiac end-diastolic volume measured by MRI	Primary outcome for substudy 2	Baseline and 4 week treatment	No
Primary	Difference in changes from baseline to 4 week placebo/sildenafil treatment in cerebrovascular reactivity to CO2 inhalation and finger stimulation measured by BOLD fMRI	Primary outcome for substudy 3	Baseline and 4 weeks treatment	No
Primary	Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in Cognitive function measured by Cambridge Neuropsychological Test Automated Battery (CANTAB)	Primay outcome for substudy 3	Baseline and 4 weeks treatment	No
Secondary	Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in 6 minutes walk test	Substudy 1	Baseline and 4 weeks treatment	No
Secondary	Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in max test, measured by O2 uptake during maximal exercise on bike	Substudy 1	Baseline and 4 weeks treatment	No
Secondary	Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in Quality of life by SF36	Substudy 1	Baseline and 4 weeks treatment	No
Secondary	Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in resting cardiac function measured by cardiac MRI	Substudy 2. Evaluation of resting cardiac ejection fraction and end-systolic volume.	Baseline and 4 weeks treatment	No
Secondary	Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in cardiac function during hand grip exercise measured by cardiac MRI	Substudy 2. Cardiac volumes and ejection fraction during 1 minute repeated maximal force hand exercise will be measured.	Baseline and 4 weeks treatment	No
Secondary	Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in cerebrovascular reactivity and blood flow	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.	Baseline and 4 weeks treatment	No
Secondary	Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in basic activity and metabolites of the brain	Substudy 3.Resting state network by fMRI and metabolites in brain regions by MRI spectroskopy.	Baseline and 4 weeks treatment	No
Secondary	Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in cognitive function measured by paper and pen test battery	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	Baseline and 4 weeks treatment	No
Secondary	Difference in changes from baseline to 4 weeks treatment placebo/sildenafil in plasma levels of signalling molecules	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.	Baseline and 4 weeks treatment	No