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

NCT01350154 | Completed Phase 2 DMC

• 1 other identifier: RHGLBMD
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

Becker Muscular Dystrophy

Keywords

clinical trial; sildenafil; revatio; muscular dystrophy; adult; nNOS

Outcome Measures

Primary Outcomes (4)

• 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

• 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

• 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

• 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

Secondary Outcomes (9)

• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in 6 minutes walk test

  Baseline and 4 weeks treatment

• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in max test, measured by O2 uptake during maximal exercise on bike

  Baseline and 4 weeks treatment

• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in Quality of life by SF36

  Baseline and 4 weeks treatment

• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in resting cardiac function measured by cardiac MRI

  Baseline and 4 weeks treatment

• Difference in changes from baseline to 4 weeks placebo/sildenafil treatment in cardiac function during hand grip exercise measured by cardiac MRI

  Baseline and 4 weeks treatment

Study Arms (2)

Sildenafil (Revation) 20 mg

EXPERIMENTAL

This arm will receive sildenafil for 4 weeks followed by 2 weeks washout and 4 weeks placebo.

Drug: Sildenafil

Placebo

EXPERIMENTAL

This arm will receive placebo for 4 weeks followed by 2 weeks washout and 4 weeks sildenafil

Drug: Placebo

Interventions

Sildenafil DRUG

20 mg in gelatine capsules, oral, three times daily

Also known as: Placebo

Sildenafil (Revation) 20 mg

Placebo DRUG

Lactose monohydrate oral in gelatine capsules, 3 times daily

Also known as: Sildenafil (Revatio)

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• Glostrup University Hospital, Copenhagen: collaborator

Study Sites (1)

Neuromuscular Clinic and Research Unit, Dept. Neurology, Rigshospitalet,

Copenhagen, 2100, Denmark

Location

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne; Muscular Dystrophies

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• John Vissing, MD, DMSci

  Neuromuscular Clinic and Research Unit, Dept. Neurology, Rigshospitalet

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Registrar

Study Record Dates

• First Submitted: May 4, 2011
• First Posted: May 9, 2011
• Study Start: November 1, 2011
• Primary Completion: April 1, 2013
• Study Completion: April 1, 2013
• Last Updated: April 10, 2013

Record last verified: 2013-04

Locations

DK (1)