PHOspholamban RElated CArdiomyopathy STudy - Intervention
- Conditions
- Phospholamban R14del Mutation-related Cardiomyopathy
- Interventions
- Registration Number
- NCT01857856
- Lead Sponsor
- M.p. van den Berg, MD, PhD, professor in Cardiology
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 84
- Phospholamban (PLN) R14del mutation carriers
- Age ≥30 and ≤ 65 years
- New York Heart Association functional class ≤ 1
- LV ejection fraction ≥.45 (measured with MRI)
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Eplerenone Eplerenone Eplerenone (Inspra, 50 mg for 3 years once daily) oral, film-coated tablet 50 mg for 3 years once daily
- Primary Outcome Measures
Name Time Method (Change in) cardiovascular death, including sudden death, likely due to arrhythmogenic cardiomyopathy yearly at 0,1,2 and 3 years, and possibly in between at referral Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI three years LV ejection fraction, absolute decrease >5%, as measured by MRI three years RV ejection fraction, absolute decrease >5%, as measured by MRI three years Change in QRS voltage, decrease >25% (ECG) 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 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) yearly at 0, 1, 2 and 3 years Right ventricular (RV) enddiastolic volume, increase >10%, as measured by MRI three years late gadolinium enhancement, absolute increase >5%, as measured by MRI three years Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing) yearly at 0, 1, 2 and 3 years
- Secondary Outcome Measures
Name Time Method 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 conduction intervals (PR-interval, QRS-duration) on 12-lead ECG and signal averaged-ECG yearly at 0,1, 2 and 3 years Change in biomarkers 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
Trial Locations
- Locations (4)
Antonius ziekenhuis Sneek
🇳🇱Sneek, Friesland, Netherlands
UMCG
🇳🇱Groningen, Netherlands
UMCU
🇳🇱Utrecht, Netherlands
AMC
🇳🇱Amsterdam, North-Holland, Netherlands