PHOspholamban RElated CArdiomyopathy STudy - Intervention (i-PHORECAST)

October 15, 2021 updated by: M.p. van den Berg, MD, PhD, professor in Cardiology

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

84

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Groningen, Netherlands, 9700RB
        • UMCG
      • Utrecht, Netherlands, 3584 CX
        • UMCU
    • Friesland
      • Sneek, Friesland, Netherlands, 8600BA
        • Antonius Ziekenhuis Sneek
    • North-Holland
      • Amsterdam, North-Holland, Netherlands, 1105 AZ
        • AMC

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

28 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: No treatment
no medical treatment
Active Comparator: Eplerenone
Eplerenone (Inspra, 50 mg for 3 years once daily) oral, film-coated tablet 50 mg for 3 years once daily
Drug: Eplerenone
eplerenone (inspra; pfizer) one tablet (50mg standard dosis; 25mg reduced dosis) per day
Other Names:
  • Inspra

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI
Time Frame: three years
three years
LV ejection fraction, absolute decrease >5%, as measured by MRI
Time Frame: three years
three years
Right ventricular (RV) enddiastolic volume, increase >10%, as measured by MRI
Time Frame: three years
three years
RV ejection fraction, absolute decrease >5%, as measured by MRI
Time Frame: three years
three years
late gadolinium enhancement, absolute increase >5%, as measured by MRI
Time Frame: three years
three years
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
yearly at 0, 1, 2 and 3 years
Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing)
Time Frame: yearly at 0, 1, 2 and 3 years
yearly at 0, 1, 2 and 3 years
Change in QRS voltage, decrease >25% (ECG)
Time Frame: yearly at 0,1,2 and 3 years
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
Time Frame: yearly at 0,1,2 and 3 years, and possibly in between at referral
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
Time Frame: yearly at 0,1,2 and 3 years, and possibly in between at referral
yearly at 0,1,2 and 3 years, and possibly in between at referral

Secondary Outcome Measures

Outcome Measure
Time Frame
Change in biomarkers
Time Frame: yearly at 0, 1, 2 and 3 years
yearly at 0, 1, 2 and 3 years
Change in QRS-axis on 12-lead ECG
Time Frame: yearly at 0,1, 2 and 3 years
yearly at 0,1, 2 and 3 years
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
yearly at 0,1, 2 and 3 years
Change in STT-segment on 12-lead ECG
Time Frame: yearly at 0,1, 2 and 3 years
yearly at 0,1, 2 and 3 years
Development of global or regional dysfunction and structural alterations on MRI
Time Frame: three years
three years
(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
yearly at 0,1,2 and 3 years, and possibly in between at referral
(Change in) Diagnosis of DCM
Time Frame: yearly at 0,1,2 and 3 years, and possibly in between at referral
yearly at 0,1,2 and 3 years, and possibly in between at referral
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
yearly at 0,1,2 and 3 years, and possibly in between at referral
(Change in) hospitalization for a cardiovascular reason
Time Frame: yearly at 0,1,2 and 3 years, and possibly in between at referral
yearly at 0,1,2 and 3 years, and possibly in between at referral

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Collaborators

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

Investigators

  • Principal Investigator: Maarten van den Berg, MD PhD, UMCG, Department of Cardiology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2013

Primary Completion (Actual)

October 1, 2021

Study Completion (Actual)

October 1, 2021

Study Registration Dates

First Submitted

May 8, 2013

First Submitted That Met QC Criteria

May 15, 2013

First Posted (Estimate)

May 20, 2013

Study Record Updates

Last Update Posted (Actual)

October 18, 2021

Last Update Submitted That Met QC Criteria

October 15, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TCC2012007
  • 2013-001067-23 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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