PHOspholamban RElated CArdiomyopathy STudy - Intervention (Efficacy Study of Eplerenone in Presymptomaticphospholamban R14del Carriers)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 84
- 试验地点
- 4
- 主要终点
- Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI
研究概览
简要总结
Phospholamban (PLN) R14del mutation carriers may develop dilated cardiomyopathy (DCM) and/or arrhythmmogenic cardiomyopathy (ACM). Analogous to other inherited cardiomyopathies, the natural course of the disease is age-related ("age-related penetrance"); after a presymptomatic phase of variable length many PLN R14del-carriers progress to overt disease, and are diagnosed with either DCM or ARVC. PLN is a regulator of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) pump in cardiac muscle and thereby important for maintaining Ca2+ homeostasis. Cardiac fibrosis appears to be an early manifestation of disease. The investigators hypothesize that treatment of presymptomatic PLN R14del-carriers with eplerenone, which by virtue of its mineralocorticoid(aldosterone)-blocking properties is a strong antifibrotic agent, reduces disease progression and postpones onset of overt disease.
详细描述
In the Netherlands ≈15% of idiopathic dilated cardiomyopathy (DCM) and ≈10% arrhythmogenic right ventricular cardiomyopathy (ARVC) patients carry a single (founder) mutation in the gene encoding Phospholamban, PLN R14del. Analogous to other inherited cardiomyopathies, the natural course of the disease is age-related ("age-related penetrance"); after a presymptomatic phase of variable length many PLN R14del-carriers progress to overt disease, and are diagnosed with either DCM or ARVC. PLN is a regulator of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) pump in cardiac muscle and thereby important for maintaining Ca2+ homeostasis. Cardiac fibrosis appears to be an early manifestation of disease. The investigators hypothesize that treatment of presymptomatic PLN R14del-carriers with eplerenone, which by virtue of its mineralocorticoid(aldosterone)-blocking properties is a strong antifibrotic agent, reduces disease progression and postpones onset of overt disease.
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
- None
入排标准
- 年龄范围
- 30 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Phospholamban (PLN) R14del mutation carriers
- •Age ≥30 and ≤ 65 years
- •New York Heart Association functional class ≤ 1
- •LV ejection fraction ≥.45 (measured with MRI)
排除标准
- •Palpitations necessitating treatment (at the discretion of the attending physician)
- •A diagnosis of DCM (see appendix 1). Note: regional LV wall motions abnormalities are acceptable.
- •A diagnosis of ARVC (according to the task force criteria, see appendix 2)
- •Global or regional RV dysfunction and/or structural alterations (according to task force criterion 1, see appendix 2).
- •Ventricular premature complexes >1000 during 24hours Holter-monitoring
- •Non-sustained ventricular tachycardia during Holter-monitoring or exercise-testing
- •History of sustained ventricular tachycardia or ventricular fibrillation
- •Hypertension requiring the use of antihypertensive drugs, or when this is anticipated within the coming 3 years
- •Evidence of ischemic heart disease
- •Treatment with cardioactive medication
- •Hyperkaliemia (serum potassium >5.0 mmol/l)
- •Severe renal dysfunction (eGFR <30 ml/min/1.73 m2)
- •Severe hepatic impairment (Child-Pugh class C)
- •Women who are currently pregnant or report a recent pregnancy (last 60 days) or plan on becoming pregnant.
- •Concomitant use of CYP3A4-inhibitors (see appendix 5)
- •Concomitant use of NSAIDs (see appendix 5)
- •Concomitant use of potassium sparing-agents (see appendix 5)
- •Known intolerance or contraindication to aldosterone antagonists
- •Participation in another drug trial in which the last dose of drug was within the past 30 days.
- •Contra-indications for MRI (claustrophobia, metal devices)
- •Subjects unable or unwilling to provide written informed consent
研究组 & 干预措施
Eplerenone
Eplerenone (Inspra, 50 mg for 3 years once daily) oral, film-coated tablet 50 mg for 3 years once daily
干预措施: Eplerenone (Drug)
结局指标
主要结局
Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI
时间窗: three years
LV ejection fraction, absolute decrease >5%, as measured by MRI
时间窗: three years
RV ejection fraction, absolute decrease >5%, as measured by MRI
时间窗: three years
Change in QRS voltage, decrease >25% (ECG)
时间窗: yearly at 0,1,2 and 3 years
Change in symptoms/signs of heart failure and/or arrhythmias necessitating treatment according to the attending physician and likely due to arrhythmogenic cardiomyopathy
时间窗: yearly at 0,1,2 and 3 years, and possibly in between at referral
(Change in) cardiovascular death, including sudden death, likely due to arrhythmogenic cardiomyopathy
时间窗: yearly at 0,1,2 and 3 years, and possibly in between at referral
Change in ventricular premature complexes, increase >100% in combination with absolute number >1000/24 hrs (Holter monitoring)
时间窗: yearly at 0, 1, 2 and 3 years
Right ventricular (RV) enddiastolic volume, increase >10%, as measured by MRI
时间窗: three years
late gadolinium enhancement, absolute increase >5%, as measured by MRI
时间窗: three years
Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing)
时间窗: yearly at 0, 1, 2 and 3 years
次要结局
- Change in QRS-axis on 12-lead ECG(yearly at 0,1, 2 and 3 years)
- Change in STT-segment on 12-lead ECG(yearly at 0,1, 2 and 3 years)
- (Change in) Diagnosis of DCM(yearly at 0,1,2 and 3 years, and possibly in between at referral)
- Change in occurrence of sustained ventricular tachycardia or ventricular fibrillation(yearly at 0,1,2 and 3 years, and possibly in between at referral)
- Change in biomarkers(yearly at 0, 1, 2 and 3 years)
- Change in conduction intervals (PR-interval, QRS-duration) on 12-lead ECG and signal averaged-ECG(yearly at 0,1, 2 and 3 years)
- Development of global or regional dysfunction and structural alterations on MRI(three years)
- (Change in) Diagnosis of ARVC (according to task force criteria)(yearly at 0,1,2 and 3 years, and possibly in between at referral)
- (Change in) hospitalization for a cardiovascular reason(yearly at 0,1,2 and 3 years, and possibly in between at referral)
研究者
M.p. van den Berg, MD, PhD, professor in Cardiology
MD PhD
University Medical Center Groningen