PHOspholamban RElated CArdiomyopathy STudy - Intervention (i-PHORECAST)

M.p. van den Berg, MD, PhD, professor in Cardiology

Status and phase

Completed

Phase 3

Conditions

Phospholamban R14del Mutation-related Cardiomyopathy

Treatments

Drug: Eplerenone

Study type

Interventional

Funder types

Other

Identifiers

NCT01857856

2013-001067-23 (EudraCT Number)

TCC2012007

Details and patient eligibility

About

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.

Full 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.

Enrollment

84 patients

Sex

All

Ages

30 to 65 years old

Volunteers

No Healthy Volunteers

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