PHOspholamban RElated CArdiomyopathy STudy - Intervention

NCT01857856 | Completed Phase 3 DMC

• 2 other identifiers: TCC20120072013-001067-23
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 4

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.

Conditions

Phospholamban R14del Mutation-related Cardiomyopathy

Keywords

Phospholamban; cardiomyopathy; Eplerenone; presymptomatic

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (9)

• 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

Study Arms (2)

No treatment

NO INTERVENTION

no medical treatment

Eplerenone

ACTIVE COMPARATOR

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

Drug: Eplerenone

Interventions

Eplerenone DRUG

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

Also known as: Inspra

Eplerenone

Eligibility Criteria

• Age: 30 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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)

Sponsors & Collaborators

• M.p. van den Berg, MD, PhD, professor in Cardiology: lead
• University Medical Center Groningen: collaborator
• The Interuniversity Cardiology Institute of the Netherlands: collaborator
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Netherlands: CVON, CardioVascular Research Netherlands: collaborator

Study Sites (4)

AMC

Amsterdam, North Holland, 1105 AZ, Netherlands

Location

Antonius ziekenhuis Sneek

Sneek, Provincie Friesland, 8600BA, Netherlands

Location

UMCG

Groningen, 9700RB, Netherlands

Location

UMCU

Utrecht, 3584 CX, Netherlands

Location

Related Publications (7)

• 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.

  PMID: 22820313 BACKGROUND

• 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.

  PMID: 24909667 BACKGROUND

• 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.

  PMID: 29635323 BACKGROUND

• 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.

  PMID: 26970417 BACKGROUND

• 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.

  PMID: 28759816 BACKGROUND

• 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.

  PMID: 30763825 BACKGROUND

• 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.

  PMID: 34143416 DERIVED

MeSH Terms

Conditions

Cardiomyopathies

Interventions

Eplerenone

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Maarten van den Berg, MD PhD

  UMCG, Department of Cardiology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD PhD

Study Record Dates

• First Submitted: May 8, 2013
• First Posted: May 20, 2013
• Study Start: May 1, 2013
• Primary Completion: October 1, 2021
• Study Completion: October 1, 2021
• Last Updated: October 18, 2021

Record last verified: 2021-10

Locations

NL (4)