Clinical trial NCT01857856: PHOspholamban RElated CArdiomyopathy STudy - Intervention
Official title: PHOspholamban RElated CArdiomyopathy STudy - Intervention (Efficacy Study of Eplerenone in Presymptomaticphospholamban R14del Carriers)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Phospholamban R14del Mutation-related Cardiomyopathy
Keywords: Phospholamban
cardiomyopathy
Eplerenone
presymptomatic
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: University Medical Center Groningen
name: The Interuniversity Cardiology Institute of the Netherlands
name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Netherlands: CVON, CardioVascular Research Netherlands
First posted: 2013-05-20
Enrollment: 84
Sex: ALL
Minimum age (years): 30
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI
timeFrame: three years
measure: LV ejection fraction, absolute decrease >5%, as measured by MRI
timeFrame: three years
measure: Right ventricular (RV) enddiastolic volume, increase >10%, as measured by MRI
timeFrame: three years
measure: RV ejection fraction, absolute decrease >5%, as measured by MRI
timeFrame: three years
measure: late gadolinium enhancement, absolute increase >5%, as measured by MRI
timeFrame: three years
measure: Change in ventricular premature complexes, increase >100% in combination with absolute number >1000/24 hrs (Holter monitoring)
timeFrame: yearly at 0, 1, 2 and 3 years
measure: Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing)
timeFrame: yearly at 0, 1, 2 and 3 years
measure: Change in QRS voltage, decrease >25% (ECG)
timeFrame: yearly at 0,1,2 and 3 years
measure: Change in symptoms/signs of heart failure and/or arrhythmias necessitating treatment according to the attending physician and likely due to arrhythmogenic cardiomyopathy
timeFrame: yearly at 0,1,2 and 3 years, and possibly in between at referral
measure: (Change in) cardiovascular death, including sudden death, likely due to arrhythmogenic cardiomyopathy
timeFrame: yearly at 0,1,2 and 3 years, and possibly in between at referral
Secondary outcomes:
measure: Change in biomarkers
timeFrame: yearly at 0, 1, 2 and 3 years
measure: Change in QRS-axis on 12-lead ECG
timeFrame: yearly at 0,1, 2 and 3 years
measure: Change in conduction intervals (PR-interval, QRS-duration) on 12-lead ECG and signal averaged-ECG
timeFrame: yearly at 0,1, 2 and 3 years
measure: Change in STT-segment on 12-lead ECG
timeFrame: yearly at 0,1, 2 and 3 years
measure: Development of global or regional dysfunction and structural alterations on MRI
timeFrame: three years
measure: (Change in) Diagnosis of ARVC (according to task force criteria)
timeFrame: yearly at 0,1,2 and 3 years, and possibly in between at referral
measure: (Change in) Diagnosis of DCM
timeFrame: yearly at 0,1,2 and 3 years, and possibly in between at referral
measure: Change in occurrence of sustained ventricular tachycardia or ventricular fibrillation
timeFrame: yearly at 0,1,2 and 3 years, and possibly in between at referral
measure: (Change in) hospitalization for a cardiovascular reason
timeFrame: yearly at 0,1,2 and 3 years, and possibly in between at referral
Other outcomes:
Locations:
city: Sneek
country: Netherlands
facility: Antonius ziekenhuis Sneek
state: Friesland
city: Amsterdam
country: Netherlands
facility: AMC
state: North-Holland
city: Groningen
country: Netherlands
facility: UMCG
city: Utrecht
country: Netherlands
facility: UMCU
Study officials:
affiliation: UMCG, Department of Cardiology
name: Maarten van den Berg, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van der Zwaag PA, van Rijsingen IA, Asimaki A, Jongbloed JD, van Veldhuisen DJ, Wiesfeld AC, Cox MG, van Lochem LT, de Boer RA, Hofstra RM, Christiaans I, van Spaendonck-Zwarts KY, Lekanne dit Deprez RH, Judge DP, Calkins H, Suurmeijer AJ, Hauer RN, Saffitz JE, Wilde AA, van den Berg MP, van Tintelen JP. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail. 2012 Nov;14(11):1199-207. doi: 10.1093/eurjhf/hfs119. Epub 2012 Jul 20.
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citation: Te Rijdt WP, van Tintelen JP, Vink A, van der Wal AC, de Boer RA, van den Berg MP, Suurmeijer AJ. Phospholamban p.Arg14del cardiomyopathy is characterized by phospholamban aggregates, aggresomes, and autophagic degradation. Histopathology. 2016 Oct;69(4):542-50. doi: 10.1111/his.12963. Epub 2016 May 12.
citation: Te Rijdt WP, van der Klooster ZJ, Hoorntje ET, Jongbloed JDH, van der Zwaag PA, Asselbergs FW, Dooijes D, de Boer RA, van Tintelen JP, van den Berg MP, Vink A, Suurmeijer AJH. Phospholamban immunostaining is a highly sensitive and specific method for diagnosing phospholamban p.Arg14del cardiomyopathy. Cardiovasc Pathol. 2017 Sep-Oct;30:23-26. doi: 10.1016/j.carpath.2017.05.004. Epub 2017 May 30.
citation: Te Rijdt WP, Asimaki A, Jongbloed JDH, Hoorntje ET, Lazzarini E, van der Zwaag PA, de Boer RA, van Tintelen JP, Saffitz JE, van den Berg MP, Suurmeijer AJH. Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy. Cardiovasc Pathol. 2019 May-Jun;40:2-6. doi: 10.1016/j.carpath.2018.12.006. Epub 2018 Dec 21.
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