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PHOspholamban RElated CArdiomyopathy STudy - Intervention (i-PHORECAST)

Primary Purpose

Phospholamban R14del Mutation-related Cardiomyopathy

Status

Completed

Phase

Phase 3

Locations

Netherlands

Study Type

Interventional

Intervention

Eplerenone

About this trial

This is an interventional treatment trial for Phospholamban R14del Mutation-related Cardiomyopathy focused on measuring Phospholamban, cardiomyopathy, Eplerenone, presymptomatic

Eligibility Criteria

30 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Antonius ziekenhuis Sneek
AMC
UMCG
UMCU

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Active Comparator

Arm Label

No treatment

Eplerenone

Arm Description

no medical treatment

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

Outcomes

Primary Outcome Measures

Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI

LV ejection fraction, absolute decrease >5%, as measured by MRI

Right ventricular (RV) enddiastolic volume, increase >10%, as measured by MRI

RV ejection fraction, absolute decrease >5%, as measured by MRI

late gadolinium enhancement, absolute increase >5%, as measured by MRI

Change in ventricular premature complexes, increase >100% in combination with absolute number >1000/24 hrs (Holter monitoring)

Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing)

Change in QRS voltage, decrease >25% (ECG)

Change in symptoms/signs of heart failure and/or arrhythmias necessitating treatment according to the attending physician and likely due to arrhythmogenic cardiomyopathy

(Change in) cardiovascular death, including sudden death, likely due to arrhythmogenic cardiomyopathy

Secondary Outcome Measures

Change in biomarkers

Change in QRS-axis on 12-lead ECG

Change in conduction intervals (PR-interval, QRS-duration) on 12-lead ECG and signal averaged-ECG

Change in STT-segment on 12-lead ECG

Development of global or regional dysfunction and structural alterations on MRI

(Change in) Diagnosis of ARVC (according to task force criteria)

(Change in) Diagnosis of DCM

Change in occurrence of sustained ventricular tachycardia or ventricular fibrillation

(Change in) hospitalization for a cardiovascular reason

Full Information

NCT ID

NCT01857856

First Posted

May 8, 2013

Last Updated

October 15, 2021

Sponsor

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

Collaborators

University Medical Center Groningen, The Interuniversity Cardiology Institute of the Netherlands, ZonMw: The Netherlands Organisation for Health Research and Development, Netherlands: CVON, CardioVascular Research Netherlands

1. Study Identification

Unique Protocol Identification Number

NCT01857856

Brief Title

PHOspholamban RElated CArdiomyopathy STudy - Intervention

Acronym

i-PHORECAST

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Completed

Study Start Date

May 2013 (undefined)

Primary Completion Date

October 2021 (Actual)

Study Completion Date

October 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

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

Collaborators

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Phospholamban R14del Mutation-related Cardiomyopathy

Keywords

Phospholamban, cardiomyopathy, Eplerenone, presymptomatic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

84 (Actual)

8. Arms, Groups, and Interventions

Arm Title

No treatment

Arm Type

No Intervention

Arm Description

no medical treatment

Arm Title

Eplerenone

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Eplerenone

Other Intervention Name(s)

Inspra

Intervention Description

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

Primary Outcome Measure Information:

Title

Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI

Time Frame

three years

Title

LV ejection fraction, absolute decrease >5%, as measured by MRI

Time Frame

three years

Title

Right ventricular (RV) enddiastolic volume, increase >10%, as measured by MRI

Time Frame

three years

Title

RV ejection fraction, absolute decrease >5%, as measured by MRI

Time Frame

three years

Title

late gadolinium enhancement, absolute increase >5%, as measured by MRI

Time Frame

three years

Title

Change in ventricular premature complexes, increase >100% in combination with absolute number >1000/24 hrs (Holter monitoring)

Time Frame

yearly at 0, 1, 2 and 3 years

Title

Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing)

Time Frame

yearly at 0, 1, 2 and 3 years

Title

Change in QRS voltage, decrease >25% (ECG)

Time Frame

yearly at 0,1,2 and 3 years

Title

Change in symptoms/signs of heart failure and/or arrhythmias necessitating treatment according to the attending physician and likely due to arrhythmogenic cardiomyopathy

Time Frame

yearly at 0,1,2 and 3 years, and possibly in between at referral

Title

(Change in) cardiovascular death, including sudden death, likely due to arrhythmogenic cardiomyopathy

Time Frame

yearly at 0,1,2 and 3 years, and possibly in between at referral

Secondary Outcome Measure Information:

Title

Change in biomarkers

Time Frame

yearly at 0, 1, 2 and 3 years

Title

Change in QRS-axis on 12-lead ECG

Time Frame

yearly at 0,1, 2 and 3 years

Title

Change in conduction intervals (PR-interval, QRS-duration) on 12-lead ECG and signal averaged-ECG

Time Frame

yearly at 0,1, 2 and 3 years

Title

Change in STT-segment on 12-lead ECG

Time Frame

yearly at 0,1, 2 and 3 years

Title

Development of global or regional dysfunction and structural alterations on MRI

Time Frame

three years

Title

(Change in) Diagnosis of ARVC (according to task force criteria)

Time Frame

yearly at 0,1,2 and 3 years, and possibly in between at referral

Title

(Change in) Diagnosis of DCM

Time Frame

yearly at 0,1,2 and 3 years, and possibly in between at referral

Title

Change in occurrence of sustained ventricular tachycardia or ventricular fibrillation

Time Frame

yearly at 0,1,2 and 3 years, and possibly in between at referral

Title

(Change in) hospitalization for a cardiovascular reason

Time Frame

yearly at 0,1,2 and 3 years, and possibly in between at referral

10. Eligibility

Sex

All

Minimum Age & Unit of Time

30 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Maarten van den Berg, MD PhD

Organizational Affiliation

UMCG, Department of Cardiology

Official's Role

Principal Investigator

Facility Information:

Facility Name

Antonius ziekenhuis Sneek

City

Sneek

State/Province

Friesland

ZIP/Postal Code

8600BA

Country

Netherlands

Facility Name

AMC

City

Amsterdam

State/Province

North-Holland

ZIP/Postal Code

1105 AZ

Country

Netherlands

Facility Name

UMCG

City

Groningen

ZIP/Postal Code

9700RB

Country

Netherlands

Facility Name

UMCU

City

Utrecht

ZIP/Postal Code

3584 CX

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

22820313

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.

Results Reference

background

PubMed Identifier

24909667

Citation

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.

Results Reference

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PubMed Identifier

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Citation

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.

Results Reference

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PubMed Identifier

26970417

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.

Results Reference

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PubMed Identifier

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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.

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PubMed Identifier

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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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Citation

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.

Results Reference

derived

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