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

Primary Purpose

Dilated Cardiomyopathy

Status

Terminated

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

perindopril

placebo

About this trial

This is an interventional treatment trial for Dilated Cardiomyopathy focused on measuring dilated cardiomyopathy, heart failure, genetics, mutation carrier, ACE treatment, preclinical

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept 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

Sites / Locations

Skejby University Hospital SUH, Aarhus Universit Hospital
Pitié Salpêtrière Hospital
University of Heidelberg UKLHD
Academic Hospital IRCCS Foundation Policlinico San Matteo (OSM)
Academisch Medisch Centrum AMC and InterUniversity Institute AMC/ICIN
Health in Code SL (SME) - Hospital Marítimo de Oza.
The Heart Hospital, University College London NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

perindopril

placebo

Arm Description

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

Outcomes

Primary Outcome Measures

Change in left ventricle diameter / volume / ejection fraction

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

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

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)

Occurence of DCM on Echocardiography: EF< 45% and LVEDD>112% (ref Mahon, 2005)

Deterioration of other Echocardiographic parameters

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

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

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

Clinical end-point (statistical power is known to be sufficient): All cause death cardiovascular death (Safety end-point: no excess of)

Full Information

NCT ID

NCT01583114

First Posted

April 11, 2012

Last Updated

February 23, 2016

Sponsor

Institut National de la Santé Et de la Recherche Médicale, France

1. Study Identification

Unique Protocol Identification Number

NCT01583114

Brief Title

PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors

Acronym

PRECARDIA

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 Type

Interventional

2. Study Status

Record Verification Date

February 2016

Overall Recruitment Status

Terminated

Why Stopped

recruitement problem

Study Start Date

December 2011 (undefined)

Primary Completion Date

January 2014 (Actual)

Study Completion Date

January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Institut National de la Santé Et de la Recherche Médicale, France

4. Oversight

Data Monitoring Committee

Yes

5. 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.

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Dilated Cardiomyopathy

Keywords

dilated cardiomyopathy, heart failure, genetics, mutation carrier, ACE treatment, preclinical

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

perindopril

Arm Type

Experimental

Arm Title

placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

perindopril

Other Intervention Name(s)

Coversyl

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

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).

Primary Outcome Measure Information:

Title

Change in left ventricle diameter / volume / ejection fraction

Description

Time Frame

baseline,12 months, 24 months and 36 months after inclusion

Secondary Outcome Measure Information:

Title

Echocardiographic deterioration of LVEDD or Ejection fraction

Description

Time Frame

at baseline and at 24 months and 36 months after inclusion

Title

MRI - deterioration of LVEDVol or Ejection fraction

Description

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)

Time Frame

at baseline and at 36 months after inclusion

Title

Occurence of DCM (Echo: EF< 45% and LVEDD>112%, ref Mahon, 2005)

Description

Occurence of DCM on Echocardiography: EF< 45% and LVEDD>112% (ref Mahon, 2005)

Time Frame

baseline, 12 months, 24 months and 36 months after inclusion

Title

Deterioration of other Echocardiographic parameters

Description

Time Frame

at baseline, at 12 months, 24 months and 36 months after inclusion

Title

Deterioration of hormonal biomarkers in serum

Description

Time Frame

at baseline, at 18 months and 36 months after inclusion

Title

Clinical end-point

Description

Clinical end-point (statistical power is known to be sufficient): Symptoms: Dyspnoea (NYHA stage 1 to 4) Hospitalisation (not planed) for heart failure

Time Frame

at each visit (inclusion, at 2 weeks, 3 months, 6 months, then every 6 months to 36 months after inclusion)

Title

Clinical end-point: death

Description

Clinical end-point (statistical power is known to be sufficient): All cause death cardiovascular death (Safety end-point: no excess of)

Time Frame

at each visit (inclusion, at 2 weeks, 3 months, 6 months, then every 6 months to 36 months after inclusion)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

PHILIPPE CHARRON

Organizational Affiliation

PITIE SALPETRIERE HOSPITAL, PARIS, FRANCE

Official's Role

Principal Investigator

Facility Information:

Facility Name

Skejby University Hospital SUH, Aarhus Universit Hospital

City

Aarhus

ZIP/Postal Code

8200

Country

Denmark

Facility Name

Pitié Salpêtrière Hospital

City

Paris

ZIP/Postal Code

75013

Country

France

Facility Name

University of Heidelberg UKLHD

City

Heidelberg

ZIP/Postal Code

69120

Country

Germany

Facility Name

Academic Hospital IRCCS Foundation Policlinico San Matteo (OSM)

City

Pavia

ZIP/Postal Code

27100

Country

Italy

Facility Name

Academisch Medisch Centrum AMC and InterUniversity Institute AMC/ICIN

City

Amsterdam

ZIP/Postal Code

1105 AZ

Country

Netherlands

Facility Name

Health in Code SL (SME) - Hospital Marítimo de Oza.

City

A Coruña

ZIP/Postal Code

15006

Country

Spain

Facility Name

The Heart Hospital, University College London NHS Foundation Trust

City

London

ZIP/Postal Code

W1G 8PH

Country

United Kingdom

12. IPD Sharing Statement

Links:

URL

http://www.inheritanceproject.eu

Description

Precardia study is part of global european project INHERITANCE

Learn more about this trial

PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors

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