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

Rigshospitalet

Status and phase

Completed

Phase 2

Conditions

Becker Muscular Dystrophy

Treatments

Drug: Placebo

Drug: Sildenafil

Study type

Interventional

Funder types

Other

Identifiers

NCT01350154

RHGLBMD

Details and patient eligibility

About

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.

Full 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.

Enrollment

17 patients

Sex

Male

Ages

18 to 80 years old

Volunteers

No Healthy Volunteers

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