PHOspholamban RElated CArdiomyopathy STudy - Intervention

Study Overview
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Brief Summary
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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
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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.

Official Title
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PHOspholamban RElated CArdiomyopathy STudy - Intervention (Efficacy Study of Eplerenone in Presymptomaticphospholamban R14del Carriers)

Conditions
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Phospholamban R14del Mutation-related Cardiomyopathy

Intervention / Treatment
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* Drug: Eplerenone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phospholamban (PLN) R14del mutation carriers Age ≥30 and ≤ 65 years New York Heart Association functional class ≤ 1 LV ejection fraction ≥.45 (measured with MRI) Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No treatment<br>no medical treatment | |
| Active Comparator: Eplerenone<br>Eplerenone (Inspra, 50 mg for 3 years once daily) oral, film-coated tablet 50 mg for 3 years once daily | Drug: Eplerenone<br>* eplerenone (inspra; pfizer) one tablet (50mg standard dosis; 25mg reduced dosis) per day<br>* Other names: Inspra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Right ventricular (RV) enddiastolic volume, increase >10%, as measured by MRI |  | three years | 
| RV ejection fraction, absolute decrease >5%, as measured by MRI |  | three years | 
| late gadolinium enhancement, absolute increase >5%, as measured by MRI |  | three years | 
| 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 | 
| Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing) |  | yearly at 0, 1, 2 and 3 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) cardiovascular death, including sudden death, likely due to arrhythmogenic cardiomyopathy |  | yearly at 0,1,2 and 3 years, and possibly in between at referral | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in biomarkers |  | yearly at 0, 1, 2 and 3 years | 
| Change in QRS-axis on 12-lead ECG |  | 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 | 
| Change in STT-segment on 12-lead 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) 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) hospitalization for a cardiovascular reason |  | yearly at 0,1,2 and 3 years, and possibly in between at referral | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phospholamban, cardiomyopathy, Eplerenone, presymptomatic