Phase 2 Clinical Trial of Sildenafil for Cardiac Dysfunction in Duchenne Muscular Dystrophy and Becker Muscular Dystrophy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Change in Cardiac Left Ventricular End-systolic Volume (LVESV) by Cardiac Magnetic Resonance (CMR) Imaging.
研究概览
简要总结
This study, supported by Charley's Fund, Inc., is being done to determine if the drug Revatio®(also known as Sildenafil), as compared to placebo (an inactive substance that looks like the study drug, but contains no medication), improves heart function in people with Duchenne Muscular Dystrophy and Becker Muscular Dystrophy (DBMD).
In people with DBMD, dystrophin is not present or lacking in heart and muscle. This is associated with abnormalities in an enzyme called "neuronal nitric oxide synthase" or nNOS, and leads to decreases in "cyclic GMP," which is necessary for proper function of those muscles. Revatio blocks an enzyme called phosphodiesterase 5 (PDE5), and helps to restore the normal amounts of cyclic GMP. The purpose of this research is to determine if Revatio is safe for people with DBMD and if it can improve heart function.
Hypothesis : PDE5 inhibition, with the use of Revatio, will improve cardiac function in patients with DBMD.
详细描述
This clinical trial is focused on cardiovascular disease due to dystrophin deficiency. Dystrophin is normally localized to the muscle cell membrane where it interacts with a complex of proteins including neuronal nitric oxide synthase (nNOS). DMD gene mutations lead to the loss of dystrophin and to mislocalization and reduced activity of nNOS, consequently reducing cyclic guanosine monophosphate (cGMP) and the activity of its downstream effector, protein kinase G. Our group and others have shown that inhibition of phosphodiesterase 5 (PDE5) leads to favorable cardiac remodeling and improved vascular tone in animal models of heart failure.
This will be a phase 2, randomized, double-blind, placebo-controlled single center study for 6 months followed by open-label period of 6 months in which all enrolled subjects receive Revatio (a PDE5 inhibitor). A single dose of Revatio (20 mg three times daily) will be tested based on the safety and efficacy of that dose for treatment of pulmonary hypertension.
The primary endpoint will be the change in cardiac left ventricular end-systolic volume (LVESV) as determined by cardiac MRI after 6 months of Revatio compared to baseline. A 10% change in LVESV will be considered significant. This degree of improvement has generally been observed in cardiac therapies that improve survival such as ACE inhibitors, beta blockers, and cardiac resynchronization. The change from baseline in LVESV after 6 months of Revatio will be compared to the change in LVESV over 6 months with placebo. The study will extend for an additional 6 months of open-label Revatio to provide data on 6 months versus 12 months of Revatio treatment. Additional secondary endpoints will include differences in systolic and diastolic LV function by MRI, differences in LV mass and fibrosis by MRI, brachial flow-mediated vasodilation (peripheral endothelial function), and targeted exploratory assessment of differences in skeletal muscle function using forced vital capacity (FVC) and pincher and grip testing. Safety will be assessed by differences in the frequency and grade of adverse events
The study is taking place at the Kennedy Krieger Institute/Johns Hopkins Medical Institutions in Baltimore, MD. The trial requires out-patient visits over a 12-month period. Travel funds, through a grant from Ryan's Quest, are available.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •DBMD as determined by either a skeletal muscle biopsy demonstrating absence or lack of dystrophin, and/or genetic testing showing a mutation in the dystrophin gene predictive of DBMD, as well as a consistent physical examination
- •Male gender
- •Age greater than or equal to 18 years
- •Cardiac dysfunction with ejection fraction less than or equal to 50% as determined by echocardiogram, cardiac MRI, or multi-gated acquisition (MUGA) scan
- •On a stable dose of ACE-inhibitor or angiotensin receptor blocker (ARB) for at least 3 months; beta-adrenergic receptor blockers and glucocorticosteroids are not required but if used, a stable dose for at least 3 months is required.
- •Ability of the subject or legal guardian to provide informed consent
- •Ability to adhere with study follow-up
- •Willingness to abstain from food and alcohol for 8 hours prior to FMD
排除标准
- •Use of nitrates or alpha-adrenergic receptor blockers
- •Known intolerance or allergy to sildenafil, or a history of any severe allergic or anaphylactic reactions
- •Any medical or psychosocial condition, which, in the view of the study investigator, makes study participation inadvisable
- •Known hereditary retinal disorder such as retinitis pigmentosa
- •History of priapism or conditions that may predispose to priapism such as sickle cell anemia, multiple myeloma, or leukemia
- •Bleeding disorders
- •Active tobacco use
- •Chronic atrial fibrillation or frequent arrhythmia that would result in an irregular pulse
- •Factors that would preclude obtaining an MRI study - (e.g. implantable pacemaker or cardioverter-defibrillator; body habitus cannot fit into scanner)
- •Systolic blood pressure (SBP) less than 85 mmHg at baseline evaluation
- •Chronic kidney disease stages 4 and 5: GFR< 30 mL/min/1.73 m2 as determined by serum cystatin C level and the equation eGFRcys = 76.7 x (serum cystatin C-1.18)
- •Current use of sildenafil.
研究组 & 干预措施
Placebo
This arm will receive placebo (sugar pill) for 6 months and Revatio (sildenafil) for 6 months. During the first 6 months, the subject and investigator will be blinded to treatment. The second 6 months, will be open label treatment with Revatio.
干预措施: Sildenafil (Drug)
Revatio (sildenafil)
This arm will receive Revatio (sildenafil) for 12 months. During the first 6 months, the subject and investigator will be blinded to treatment. The second 6 months, will be open label treatment with Revatio.
干预措施: Sildenafil (Drug)
结局指标
主要结局
Change in Cardiac Left Ventricular End-systolic Volume (LVESV) by Cardiac Magnetic Resonance (CMR) Imaging.
时间窗: 6 months compared to baseline
To determine whether a 6 month trial of oral sildenafil compared to placebo improves cardiac contractile function in DBMD as determined by a \> 10% decline in end-systolic volume as detected by CMR.
次要结局
- Change in Forced Vital Capacity (FVC) by Pulmonary Function Testing(6 months and 12 months)
- Ejection Fraction(6 months)
- Change in Cardiac Systolic and Diastolic Function by CMR(6 months and 12 months)
- Change in Cardiac Mass(6 months and 12 months)
- Change in Skeletal Muscle Strength(6 months and 12 months)
研究者
Kathryn Wagner
Associate Professor of Neurology, Johns Hopkins University School of Medicine
Hugo W. Moser Research Institute at Kennedy Krieger, Inc.