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PHOspholamban RElated CArdiomyopathy STudy - Intervention (i-PHORECAST)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2015 by University Medical Center Groningen
Sponsor:
Collaborators:
Netherlands: TCC, Trial Coordination Center UMCG
The Interuniversity Cardiology Institute of the Netherlands
ZonMw: The Netherlands Organisation for Health Research and Development
Netherlands: CVON, CardioVascular Research Netherlands
Information provided by (Responsible Party):
M.p. van den Berg, MD, PhD, professor in Cardiology, University Medical Center Groningen
ClinicalTrials.gov Identifier:
NCT01857856
First received: May 8, 2013
Last updated: December 1, 2015
Last verified: December 2015
  Purpose
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.

Condition Intervention Phase
Phospholamban R14del Mutation-related Cardiomyopathy
Drug: Eplerenone
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: PHOspholamban RElated CArdiomyopathy STudy - Intervention (Efficacy Study of Eplerenone in Presymptomatic PLN-R14del Carriers)

Resource links provided by NLM:


Further study details as provided by University Medical Center Groningen:

Primary Outcome Measures:
  • LV enddiastolic volume, increase >10%, as measured by MRI [ Time Frame: three years ] [ Designated as safety issue: No ]
  • LV ejection fraction, absolute decrease >5%, as measured by MRI [ Time Frame: three years ] [ Designated as safety issue: No ]
  • RV enddiastolic volume, increase >10%, as measured by MRI [ Time Frame: three years ] [ Designated as safety issue: No ]
  • RV ejection fraction, absolute decrease >5%, as measured by MRI [ Time Frame: three years ] [ Designated as safety issue: No ]
  • late gadolinium enhancement, absolute increase >5%, as measured by MRI [ Time Frame: three years ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing) [ Time Frame: yearly at 0, 1, 2 and 3 years ] [ Designated as safety issue: No ]
  • Change in QRS voltage, decrease >25% (ECG) [ Time Frame: yearly at 0,1,2 and 3 years ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • (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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in biomarkers [ Time Frame: yearly at 0, 1, 2 and 3 years ] [ Designated as safety issue: No ]
  • Change in QRS-axis on 12-lead ECG [ Time Frame: yearly at 0,1, 2 and 3 years ] [ Designated as safety issue: No ]
  • Change in conduction intervals (PR-interval, QRS-duration) on 12-lead ECG and SA-ECG [ Time Frame: yearly at 0,1, 2 and 3 years ] [ Designated as safety issue: No ]
  • Change in STT-segment on 12-lead ECG [ Time Frame: yearly at 0,1, 2 and 3 years ] [ Designated as safety issue: No ]
  • Development of global or regional dysfunction and structural alterations on MRI [ Time Frame: three years ] [ Designated as safety issue: No ]
  • (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 ] [ Designated as safety issue: No ]
  • (Change in) Diagnosis of DCM [ Time Frame: yearly at 0,1,2 and 3 years, and possibly in between at referral ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • (Change in) hospitalization for a cardiovascular reason [ Time Frame: yearly at 0,1,2 and 3 years, and possibly in between at referral ] [ Designated as safety issue: No ]

Estimated Enrollment: 150
Study Start Date: May 2013
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: May 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Inspra

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

Ages Eligible for Study:   30 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 highering/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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01857856

Contacts
Contact: Maarten van den Berg, MD PhD 0031503612355 m.p.van.den.berg@umcg.nl
Contact: Wouter te Rijdt, MD 0031503615385 w.p.te.rijdt@umcg.nl

Locations
Netherlands
Antonius ziekenhuis Sneek Recruiting
Sneek, Friesland, Netherlands, 8600BA
Principal Investigator: Paul van Haelst, MD PhD         
AMC Recruiting
Amsterdam, North-Holland, Netherlands, 1105 AZ
Principal Investigator: Arthur Wilde, MD PhD         
UMCG Recruiting
Groningen, Netherlands, 9700RB
Sub-Investigator: Wouter te Rijdt, MD         
Principal Investigator: Maarten van den Berg, MD PhD         
UMCU Not yet recruiting
Utrecht, Netherlands, 3584 CX
Principal Investigator: Jeroen van der Heijden, MD PhD         
Sponsors and Collaborators
M.p. van den Berg, MD, PhD, professor in Cardiology
Netherlands: TCC, Trial Coordination Center UMCG
The Interuniversity Cardiology Institute of the Netherlands
ZonMw: The Netherlands Organisation for Health Research and Development
Netherlands: CVON, CardioVascular Research Netherlands
Investigators
Principal Investigator: Maarten van den Berg, MD PhD UMCG, Department of Cardiology
  More Information

Publications:
Responsible Party: M.p. van den Berg, MD, PhD, professor in Cardiology, MD PhD, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT01857856     History of Changes
Other Study ID Numbers: TCC2012007  2013-001067-23 
Study First Received: May 8, 2013
Last Updated: December 1, 2015
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by University Medical Center Groningen:
Phospholamban
cardiomyopathy
Eplerenone
presymptomatic

Additional relevant MeSH terms:
Cardiomyopathies
Heart Diseases
Cardiovascular Diseases
Eplerenone
Spironolactone
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents

ClinicalTrials.gov processed this record on September 27, 2016