PRECARDIA: PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors

Sponsor

Institut National de la Santé Et de la Recherche Médicale, France (Other)

Overall Status

Terminated

CT.gov ID

NCT01583114

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

0.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicentre European double-blind,randomized and controlled trial with 2 parallel groups (1 study medication, 1 placebo) in order to analyse the impact of ACE inhibitors (ACEi) in subjects who carry a mutation but have not yet developed DCM (dilated cardiomyopathy).

Objective of the trial: Study the impact of ACE inhibitors (ACEi) in subjects who carry a mutation (leading to a genetic form of heart failure) but have not yet developed DCM.

Context. Dilated Cardiomyopathy (DCM) is one of the leading causes of Heart Failure due to systolic dysfunction and at least 30% of DCM are of familial/genetic origin, usually with autosomal dominant inheritance, and underlying genes and mutations are increasingly identified. Familial Dilated Cardiomyopathy (fDCM) is characterized by age-related penetrance (or delayed-onset), that means that the cardiac expression of the disease (echocardiographic abnormalities) is usually absent for a long period and progressively appears with advanced age, usually after 20 years of age

Hypothesis : ACEi may delay or prevent the occurrence of DCM in these subjects (pre-clinical stage).

Expected results: If the hypothesis is confirmed, and as a consequence, the knowledge derived from basic research (genes identification in DCM) will be translated into clinical practice (early identification of subjects at high risk of developing heart failure through predictive genetic testing) with the development of new therapeutic management (early ACEi) that will help to decrease the morbidity and mortality associated with the disease. This will constitute a paradigm of the development of preventive medicine thanks to the development of genetics in the cardiovascular field.

Subjects who are concerned are ≥18 years of age and ≤60 years, carry a mutation responsible for DCM and are at a preclinical stage of the disease. Total duration of treatment (perindopril versus placebo) is 3 years. A total number of 200 participants will be enrolled (100 in each group) in 7 centres.

Condition or Disease	Intervention/Treatment	Phase
Dilated Cardiomyopathy	Drug: perindopril Drug: placebo	Phase 3

Detailed Description

This study is part of a broader research program, "INHERITANCE" (INtegrated HEart Research In TrANslational genetics of dilated Cardiomyopathies in Europe) research project, submitted to EU (FP7 European Union, HEALTH-2009-2.4.2-3: Translation of basic knowledge on inherited cardiomyopathies into clinical practice) and accepted in 2009 (Grant agreement n° 241924, global coordinator: Pr Eloisa Arbustini, Pavia, Italy).

Precardia / clinical trial Principal Investigator: Dr Philippe Charron, Pitié Salpêtrière hospital, France
FP7 Global Inheritance network coordinator: Pr Eloisa Arbustini, Italia

Study Design

Study Type:

Interventional

Actual Enrollment :

6 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Preventive Effect of ACE Inhibitor Perindopril)on the Onset or Progression of Left Ventricular Dysfoction in Subjects at a Preclinical Stage From Families With Dilated Cardiomyopathy

Study Start Date :

Dec 1, 2011

Actual Primary Completion Date :

Jan 1, 2014

Actual Study Completion Date :

Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: perindopril	Drug: perindopril form:1 tablet contained 5 mg of perindopril; posology: 1 intake per day, initiated at a dose of 2.5 mg (1/2 tablet) per day during one week, then 5 mg (1 tablet) per day during two weeks, then 10 mg (2 tablets), or the maximal dose tolerated, until the end of the study (36 months). Other Names: Coversyl
Placebo Comparator: placebo same form, administration, posology, frequency and duration as perindopril	Drug: placebo form:1 tablet contained 5 mg placebo; posology: 1 intake per day, initiated at a dose of 2.5 mg (1/2 tablet) per day during one week, then 5 mg (1 tablet) per day during two weeks, then 10 mg (2 tablets), or the maximal dose tolerated, until the end of the study (36 months).

Arm

Intervention/Treatment

Experimental: perindopril

Drug: perindopril

form:1 tablet contained 5 mg of perindopril; posology: 1 intake per day, initiated at a dose of 2.5 mg (1/2 tablet) per day during one week, then 5 mg (1 tablet) per day during two weeks, then 10 mg (2 tablets), or the maximal dose tolerated, until the end of the study (36 months).

Other Names:

Coversyl

Placebo Comparator: placebo

same form, administration, posology, frequency and duration as perindopril

Drug: placebo

form:1 tablet contained 5 mg placebo; posology: 1 intake per day, initiated at a dose of 2.5 mg (1/2 tablet) per day during one week, then 5 mg (1 tablet) per day during two weeks, then 10 mg (2 tablets), or the maximal dose tolerated, until the end of the study (36 months).

Outcome Measures

Primary Outcome Measures

Change in left ventricle diameter / volume / ejection fraction [baseline,12 months, 24 months and 36 months after inclusion]
Primary composite end point: Occurence of DCM (LV ejection fraction LVEF<45% and LVEDD>112%) or deterioration of LV end-diastolic diameter / volume (occurrence of events defined as "+4% LVEDD/LVEDV") or deterioration of Ejection fraction (occurrence of events defined as "-4% LVEF") All criteria determined either by Echocardiography (primary end-point 1) or by Magnetic resonance imaging (MRI) primary end-point 2).

Secondary Outcome Measures

Echocardiographic deterioration of LVEDD or Ejection fraction [at baseline and at 24 months and 36 months after inclusion]
Echocardiographic deterioration of LVEDD (comparison of average "final LVEDD compared to baseline LVEDD" between arms) or Ejection fraction (comparison of average "final LVEF vs baseline LVEF" between arms)
MRI - deterioration of LVEDVol or Ejection fraction [at baseline and at 36 months after inclusion]
MRI deterioration of LVEDVol (comparison of average "final LVEDVol compared to baseline LVEDVol" between arms) or Ejection fraction (comparison of average "final LVEF vs baseline LVEF" between arms)
Occurence of DCM (Echo: EF< 45% and LVEDD>112%, ref Mahon, 2005) [baseline, 12 months, 24 months and 36 months after inclusion]
Occurence of DCM on Echocardiography: EF< 45% and LVEDD>112% (ref Mahon, 2005)
Deterioration of other Echocardiographic parameters [at baseline, at 12 months, 24 months and 36 months after inclusion]
Deterioration of other Echocardiographic parameters: TDI velocities (average Sa & Ea velocities) at the mitral annulus (lateral and septal), and the E/Ea ratio strain and strain rate (radial, longitudinal, circonferential strain rate in the basal, mid and apical segments) LV volumes (LVED Vol and LVES Vol, Simpson method, 4 cavity incidence)
Deterioration of hormonal biomarkers in serum [at baseline, at 18 months and 36 months after inclusion]
Deterioration of hormonal biomarkers in serum: Natriuretic peptid: BNP and NTproBNP (+/-4% or final versus baseline). Mid-Regional pro-Adrenomedullin (MR-proADM) and Mid-Regional proANP, (+/-4% or final versus baseline).
Clinical end-point [at each visit (inclusion, at 2 weeks, 3 months, 6 months, then every 6 months to 36 months after inclusion)]
Clinical end-point (statistical power is known to be sufficient): Symptoms: Dyspnoea (NYHA stage 1 to 4) Hospitalisation (not planed) for heart failure
Clinical end-point: death [at each visit (inclusion, at 2 weeks, 3 months, 6 months, then every 6 months to 36 months after inclusion)]
Clinical end-point (statistical power is known to be sufficient): All cause death cardiovascular death (Safety end-point: no excess of)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age: ≥18 years and ≤60 years
At least one family member should have a clinical diagnosis of dilated cardiomyopathy (LVEF<45% and LVEDD>112%)and should not be considered as the burn-out phase of another cardiomyopathy (such as HCM, ARVC). LV noncompaction may co-exist with DCM in this patient.NB:in a patient with a mutation in LMNA gene, LVEDD may be normal whereas EF is markedly reduced, so that only a reduced LVEF is mandatory(LVEF<45%).
Carriers of the mutation that has been identified in the family as associated with DCM, and who have received appropriate genetic counselling before and after the announcement of the genetic result. The mutation within the family should be considered as disease-causing.
No obvious DCM as assessed by diagnostic criteria indicated elsewhere on echocardiography (WHO & Mestroni et al. 1999 and Mahon et al. 2005: references 3 and 9): LVEF <45% and enlarged LVEDD (>112% of predicted value according to age,BSA).
Presence of minor LV abnormality:
isolated LVEDD > 112% (Henry Formula)
or reduced systolic dysfunction: 45% < LVEF < 55%, as assessed on echocardiography.
Able to provide informed consent, and signed informed consent.
Able to understand and accept the study constraints
For some European countries (such as France and Spain): participants (by themselves) should have medical health care coverage to be included in a research study

Exclusion Criteria:

Other disease or factor that can cause minor LV abnormalities, such as cardiotoxic treatment or significant blood hypertension (with uncontrolled blood pressure or significant hypertrophy on echocardiography).
Contraindication to ACE inhibitor
Participants who are already treated with ACE inhibitor, sartan or aldosterone receptor antagonists (for various reason such as arterial hypertension) can not be included in this study, unless they have been off these drugs for a period of 6 weeks before inclusion.
Impaired renal function: estimated Glomerular Filtration Rate (eGFR), using MDRD formula, < 60 ml/mn/1.73m2.
Baseline serum potassium >5.5 mmol/L.
Pregnant, parturient or breastfeeding woman or woman of childbearing potential not under effective contraception or planned pregnancy.
Participation in another therapeutic trial in the previous 3 months
Participants treated with lithium
Participant under legal guardianship

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Skejby University Hospital SUH, Aarhus Universit Hospital	Aarhus	Denmark	8200
2	Pitié Salpêtrière Hospital	Paris	France	75013
3	University of Heidelberg UKLHD	Heidelberg	Germany	69120
4	Academic Hospital IRCCS Foundation Policlinico San Matteo (OSM)	Pavia	Italy	27100
5	Academisch Medisch Centrum AMC and InterUniversity Institute AMC/ICIN	Amsterdam	Netherlands	1105 AZ
6	Health in Code SL (SME) - Hospital Marítimo de Oza.	A Coruña	Spain	15006
7	The Heart Hospital, University College London NHS Foundation Trust	London	United Kingdom	W1G 8PH