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PHOspholamban RElated CArdiomyopathy STudy - Intervention (i-PHORECAST)

This study is currently recruiting participants.
Verified October 2016 by M.p. van den Berg, MD, PhD, professor in Cardiology, University Medical Center Groningen
Sponsor:
ClinicalTrials.gov Identifier:
NCT01857856
First Posted: May 20, 2013
Last Update Posted: October 25, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
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
Information provided by (Responsible Party):
M.p. van den Berg, MD, PhD, professor in Cardiology, University Medical Center Groningen
May 8, 2013
May 20, 2013
October 25, 2016
May 2013
January 2020   (Final data collection date for primary outcome measure)
  • LV enddiastolic volume, increase >10%, as measured by MRI [ Time Frame: three years ]
  • LV ejection fraction, absolute decrease >5%, as measured by MRI [ Time Frame: three years ]
  • RV enddiastolic volume, increase >10%, as measured by MRI [ Time Frame: three years ]
  • RV ejection fraction, absolute decrease >5%, as measured by MRI [ Time Frame: three years ]
  • late gadolinium enhancement, absolute increase >5%, as measured by MRI [ Time Frame: 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 ]
  • Change in the occurrence of non-sustained ventricular tachycardia (Holter monitoring, exercise testing) [ Time Frame: 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 ]
  • 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 ]
  • (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 ]
Same as current
Complete list of historical versions of study NCT01857856 on ClinicalTrials.gov Archive Site
  • Change in biomarkers [ Time Frame: 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 ]
  • 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 ]
  • Change in STT-segment on 12-lead ECG [ Time Frame: yearly at 0,1, 2 and 3 years ]
  • Development of global or regional dysfunction and structural alterations on MRI [ Time Frame: 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 ]
  • (Change in) Diagnosis of DCM [ Time Frame: 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 ]
  • (Change in) hospitalization for a cardiovascular reason [ Time Frame: yearly at 0,1,2 and 3 years, and possibly in between at referral ]
Same as current
Not Provided
Not Provided
 
PHOspholamban RElated CArdiomyopathy STudy - Intervention
PHOspholamban RElated CArdiomyopathy STudy - Intervention (Efficacy Study of Eplerenone in Presymptomatic PLN-R14del Carriers)
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.
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.
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Phospholamban R14del Mutation-related Cardiomyopathy
Drug: Eplerenone
eplerenone (inspra; pfizer) one tablet (50mg standard dosis; 25mg reduced dosis) per day
Other Name: Inspra
  • 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
    Intervention: Drug: Eplerenone

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
150
April 2020
January 2020   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
30 Years to 65 Years   (Adult)
No
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
Netherlands
 
 
NCT01857856
TCC2012007
2013-001067-23 ( EudraCT Number )
Yes
Not Provided
Not Provided
M.p. van den Berg, MD, PhD, professor in Cardiology, University Medical Center Groningen
M.p. van den Berg, MD, PhD, professor in Cardiology
  • 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
Principal Investigator: Maarten van den Berg, MD PhD UMCG, Department of Cardiology
University Medical Center Groningen
October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP