PHOspholamban RElated CArdiomyopathy STudy - Intervention

NCT ID: NCT01857856

Last Updated: 2021-10-18

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

84 participants

Study Classification

INTERVENTIONAL

Study Start Date

2013-05-31

Study Completion Date

2021-10-31

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.

Conditions

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Phospholamban R14del Mutation-related Cardiomyopathy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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No treatment

no medical treatment

Group Type NO_INTERVENTION

No interventions assigned to this group

Eplerenone

Eplerenone (Inspra, 50 mg for 3 years once daily) oral, film-coated tablet 50 mg for 3 years once daily

Group Type ACTIVE_COMPARATOR

Eplerenone

Intervention Type DRUG

eplerenone (inspra; pfizer) one tablet (50mg standard dosis; 25mg reduced dosis) per day

Interventions

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Eplerenone

eplerenone (inspra; pfizer) one tablet (50mg standard dosis; 25mg reduced dosis) per day

Intervention Type DRUG

Other Intervention Names

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Inspra

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
Minimum Eligible Age

30 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University Medical Center Groningen

OTHER

Sponsor Role collaborator

The Interuniversity Cardiology Institute of the Netherlands

OTHER_GOV

Sponsor Role collaborator

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role collaborator

Netherlands: CVON, CardioVascular Research Netherlands

UNKNOWN

Sponsor Role collaborator

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

OTHER

Sponsor Role lead

Responsible Party

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

MD PhD

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Maarten van den Berg, MD PhD

Role: PRINCIPAL_INVESTIGATOR

UMCG, Department of Cardiology

Locations

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AMC

Amsterdam, North Holland, Netherlands

Site Status

Antonius ziekenhuis Sneek

Sneek, Provincie Friesland, Netherlands

Site Status

UMCG

Groningen, , Netherlands

Site Status

UMCU

Utrecht, , Netherlands

Site Status

Countries

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Netherlands

References

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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.

Reference Type BACKGROUND
PMID: 22820313 (View on PubMed)

van Rijsingen IA, van der Zwaag PA, Groeneweg JA, Nannenberg EA, Jongbloed JD, Zwinderman AH, Pinto YM, Dit Deprez RH, Post JG, Tan HL, de Boer RA, Hauer RN, Christiaans I, van den Berg MP, van Tintelen JP, Wilde AA. Outcome in phospholamban R14del carriers: results of a large multicentre cohort study. Circ Cardiovasc Genet. 2014 Aug;7(4):455-65. doi: 10.1161/CIRCGENETICS.113.000374. Epub 2014 Jun 8.

Reference Type BACKGROUND
PMID: 24909667 (View on PubMed)

Te Rijdt WP, Ten Sande JN, Gorter TM, van der Zwaag PA, van Rijsingen IA, Boekholdt SM, van Tintelen JP, van Haelst PL, Planken RN, de Boer RA, Suurmeijer AJH, van Veldhuisen DJ, Wilde AAM, Willems TP, van Dessel PFHM, van den Berg MP. Myocardial fibrosis as an early feature in phospholamban p.Arg14del mutation carriers: phenotypic insights from cardiovascular magnetic resonance imaging. Eur Heart J Cardiovasc Imaging. 2019 Jan 1;20(1):92-100. doi: 10.1093/ehjci/jey047.

Reference Type BACKGROUND
PMID: 29635323 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26970417 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 28759816 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 30763825 (View on PubMed)

Te Rijdt WP, Hoorntje ET, de Brouwer R, Oomen A, Amin A, van der Heijden JF, Karper JC, Westenbrink BD, Sillje HHW, Te Riele ASJM, Wiesfeld ACP, van Gelder IC, Willems TP, van der Zwaag PA, van Tintelen JP, Hillege JH, Tan HL, van Veldhuisen DJ, Asselbergs FW, de Boer RA, Wilde AAM, van den Berg MP. Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST). Neth Heart J. 2022 Feb;30(2):84-95. doi: 10.1007/s12471-021-01584-5. Epub 2021 Jun 18.

Reference Type DERIVED
PMID: 34143416 (View on PubMed)

Other Identifiers

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2013-001067-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

TCC2012007

Identifier Type: -

Identifier Source: org_study_id