The primary objective is to show that eplerenone treatment reduces progression of disease in presymptomatic PLN R14del-carriers
ID
Source
Brief title
Condition
- Other condition
- Myocardial disorders
Synonym
Health condition
genetische aandoeningen: erfelijke cardiomyopathien (late-onset)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is a composite of at least one the following components:
• LV enddiastolic volume, increase >10%
• LV ejection fraction, absolute decrease >5%
• RV enddiastolic volume, increase >10%
• RV ejection fraction, absolute decrease >5%
• late enhancement, absolute increase >5%
(all the above parameters to be assessed with MRI)
• QRS voltage, decrease >25% (ECG, measured in lead I, II and III in mV)
• the occurrence of non-sustained ventricular tachycardia (Holter monitoring,
exercise testing)
• symptoms/signs of heart failure and/or arrhythmias necessitating treatment
according to the attending physician and likely due to arrhythmogenic
cardiomyopathy
• cardiovascular death, including sudden death, likely due to arrhythmogenic
cardiomyopathy
Secondary outcome
• Diagnosis of DCM
• Diagnosis of ARVC (according to task force criteria)
• Development of global or regional dysfunction and structural alterations,
(according to task force criterion)
• All individual components of the primary endpoint
• QRS-axis on 12-lead ECG
• Conduction intervals (PR-interval, QRS-duration) on 12-lead ECG and SA-ECG
• STT-segment changes on 12-lead ECG
• Change in biomarkers
• Occurrence of sustained ventricular tachycardia or ventricular fibrillation
• Hospitalization for a cardiovascular reason
Background summary
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. We 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 objective
The primary objective is to show that eplerenone treatment reduces progression
of disease in presymptomatic PLN R14del-carriers
Study design
Multicenter, prospective, randomized trial with blinded assessment of
endpoints (PROBE design).
Intervention
One group receives once daily a 50 mg tablet of eplerenone and the other group
receives no treatment. Duration of treatment: 3 years.
Study burden and risks
The burden for the study subjects is limited.
All participants are followed according to routine patient care, which includes
baseline assessments (i.e. after identification as PLN R14del-carrier) and
yearly assessments. All these assessments are non-invasive, except for blood
sampling.
Half of the subjects (control group) will not take study medication and they
will receive care as usual. The only additional measurement is blood analysis
(venous puncture) at the start of the study and at the end of the study. The
other half of the study subjects will receive eplerenone 50 mg for 3 years once
daily and they will pay an additional visit to check serum potassium.
Eplerenone is usually very well tolerated and has minimal side-effects. The
most important side-effect is hyperkaliemia but in clinical practice this
occurs only in the setting of concomitant use of other potassium-sparing drugs,
e.g. ACE-inhibitors and renal impairment. The risk associated with eplerenone
is hyperkaliemia but the likelihood of hyperkaliemia in this study group is
very low (given the exclusion criteria). Moreover, serum potassium will be
checked yearly and the dose of eplerenone will be lowered if needed.
On the other hand, the potential benefit of the study is large. If our
hypothesis is confirmed that eplerenone retards disease progression in this
patient group, this will have immediate beneficial consequences for these
subjects. Treatment with eplerenone can be instituted right away in all study
subjects as well as the other presymptomatic PLN R14del-mutation carriers in
the Netherlands and elsewhere.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
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)
•Global or regional RV dysfunction and/or structural alterations (according to
task force criterion 1).
•Ventricular premature complexes >2500 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/1.73m^2)
•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
•Concomitant use of NSAIDs
•Concomitant use of potassium highering/sparing-agents
•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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001067-23-NL |
| ClinicalTrials.gov | NCT01857856 |
| CCMO | NL43771.042.13 |