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Phospholamban R14del Mutation-related CardiomyopathyPhase 3i-PHORECASTNCT01857856

PHOspholamban RElated CArdiomyopathy STudy - Intervention

A Phase 3 study testing Eplerenone in people with Phospholamban R14del Mutation-related Cardiomyopathy, run by M.p. van den Berg, MD, PhD, professor in Cardiology at 4 sites in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 30 to 65 years
What is being tested?
Eplerenone
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
84 participants
Where
4 sitesNetherlands
Study dates
May 2013to Oct 2021
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Phospholamban (PLN) R14del mutation carriers
  • Age ≥30 and ≤ 65 years
  • New York Heart Association functional class ≤ 1
  • LV ejection fraction ≥.45 (measured with MRI)

Who cannot join

  • 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
Show all 21Show fewer
  • 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

Trial locations and contacts

4 sites in 1 country.

Netherlands4 sites

  • AMC

    Amsterdam, North Holland, 1105 AZ

  • UMCG

    Groningen, 9700RB

  • Antonius ziekenhuis Sneek

    Sneek, Provincie Friesland, 8600BA

  • UMCU

    Utrecht, 3584 CX

Other trials in Netherlands

About this study

Official title: 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.

Read the 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.

Being tested
Eplerenone
Keywords
Phospholamban, cardiomyopathy, Eplerenone, presymptomatic
Medical subject headings
Cardiomyopathies

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EplerenoneDrug

    Also called Inspra

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

Study groups in NCT01857856
Study groupRoleWhat they receive
No treatmentNo interventionno medical treatment
EplerenoneActive comparatorEplerenone (Inspra, 50 mg for 3 years once daily) oral, film-coated tablet 50 mg for 3 years once daily
Receives: Drug: Eplerenone

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: three years

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

    Measured: three years

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

    Measured: three years

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

    Measured: three years

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

    Measured: three years

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

    Measured: yearly at 0, 1, 2 and 3 years

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

    Measured: yearly at 0, 1, 2 and 3 years

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

    Measured: yearly at 0,1,2 and 3 years

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

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

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

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

Secondary outcomes (9)

  1. Change in biomarkers

    Measured: yearly at 0, 1, 2 and 3 years

  2. Change in QRS-axis on 12-lead ECG

    Measured: yearly at 0,1, 2 and 3 years

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

    Measured: yearly at 0,1, 2 and 3 years

  4. Change in STT-segment on 12-lead ECG

    Measured: yearly at 0,1, 2 and 3 years

  5. Development of global or regional dysfunction and structural alterations on MRI

    Measured: three years

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

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

  7. (Change in) Diagnosis of DCM

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

  8. Change in occurrence of sustained ventricular tachycardia or ventricular fibrillation

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

  9. (Change in) hospitalization for a cardiovascular reason

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 May 2013 (estimated)
  2. Study startMay 2013
  3. Primary completionOct 2021
  4. Study completionOct 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
84 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01857856
Sponsor's protocol ID
TCC2012007
Other IDs
2013-001067-23
Acronym
i-PHORECAST
Status last verified
Oct 2021
First submitted
8 May 2013
Last updated
18 Oct 2021
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 22820313

  • 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.

    PubMed 24909667

  • 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.

    PubMed 29635323

  • 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.

    PubMed 26970417

  • 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.

    PubMed 28759816

  • 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.

    PubMed 30763825

  • 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.

    PubMed 34143416

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Eplerenone in people with Phospholamban R14del Mutation-related Cardiomyopathy, run by M.p. van den Berg, MD, PhD, professor in Cardiology at 4 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Left ventricular (LV) enddiastolic volume, increase >10%, as measured by MRI (time frame: three years). The study lists 10 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01857856, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Oct 2021.

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