PHOspholamban RElated CArdiomyopathy STudy - Intervention (i-PHORECAST)

This study is not yet open for participant recruitment.
Verified May 2013 by University Medical Centre 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 Centre Groningen
ClinicalTrials.gov Identifier:
NCT01857856
First received: May 8, 2013
Last updated: May 15, 2013
Last verified: May 2013
  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 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 Centre 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: September 2013
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: No intervention
no intervention
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
Other Name: Inspra

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PLN R14del mutation carriers
  • Age ≥18 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/kg)
  • 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 strong CYP3A4-inhibitors
  • Concomitant chronic use of NSAIDs
  • 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 Note: presence of late gadolinium enhancement on MRI is not an exclusion criterion
  Contacts and Locations
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 Not yet recruiting
Sneek, Friesland, Netherlands, 8600BA
Principal Investigator: Paul van Haelst, MD PhD         
AMC Not yet recruiting
Amsterdam, North-Holland, Netherlands, 1105 AZ
Principal Investigator: Arthur Wilde, MD PhD         
UMCG Not yet 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 Centre Groningen
ClinicalTrials.gov Identifier: NCT01857856     History of Changes
Other Study ID Numbers: TCC2012007, 2013-001067-23
Study First Received: May 8, 2013
Last Updated: May 15, 2013
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

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

Additional relevant MeSH terms:
Cardiomyopathies
Heart Diseases
Cardiovascular Diseases
Eplerenone
Aldosterone Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 17, 2014