PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors (PRECARDIA)
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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|
- Change in left ventricle diameter / volume / ejection fraction [ Time Frame: baseline,12 months, 24 months and 36 months after inclusion ] [ Designated as safety issue: No ]
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).
- Echocardiographic deterioration of LVEDD or Ejection fraction [ Time Frame: at baseline and at 24 months and 36 months after inclusion ] [ Designated as safety issue: No ]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 [ Time Frame: at baseline and at 36 months after inclusion ] [ Designated as safety issue: No ]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) [ Time Frame: baseline, 12 months, 24 months and 36 months after inclusion ] [ Designated as safety issue: No ]Occurence of DCM on Echocardiography: EF< 45% and LVEDD>112% (ref Mahon, 2005)
- Deterioration of other Echocardiographic parameters [ Time Frame: at baseline, at 12 months, 24 months and 36 months after inclusion ] [ Designated as safety issue: No ]
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 [ Time Frame: at baseline, at 18 months and 36 months after inclusion ] [ Designated as safety issue: No ]
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 [ Time Frame: at each visit (inclusion, at 2 weeks, 3 months, 6 months, then every 6 months to 36 months after inclusion) ] [ Designated as safety issue: No ]
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 [ Time Frame: at each visit (inclusion, at 2 weeks, 3 months, 6 months, then every 6 months to 36 months after inclusion) ] [ Designated as safety issue: Yes ]
Clinical end-point (statistical power is known to be sufficient):
- All cause death
- cardiovascular death (Safety end-point: no excess of)
|Study Start Date:||December 2011|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
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 Name: Coversyl
Placebo Comparator: placebo
same form, administration, posology, frequency and duration as perindopril
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).
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
|Skejby University Hospital SUH, Aarhus Universit Hospital||Not yet recruiting|
|Aarhus, Denmark, 8200|
|Contact: Jens Mogensen, MD +45 89496199 firstname.lastname@example.org|
|Principal Investigator: Jens MOGENSEN, MD|
|Pitié Salpêtrière Hospital||Recruiting|
|Paris, France, 75013|
|Contact: Philippe CHARRON, MD-PhD +33 (0)1 42 16 13 47 email@example.com|
|Principal Investigator: Philippe CHARRON, MD-PhD|
|University of Heidelberg UKLHD||Not yet recruiting|
|Heidelberg, Germany, 69120|
|Contact: Hugo KATUS, Pr +49-6221-56-8670 firstname.lastname@example.org|
|Principal Investigator: Hugo KATUS, Pr|
|Academic Hospital IRCCS Foundation Policlinico San Matteo (OSM)||Not yet recruiting|
|Pavia, Italy, 27100|
|Contact: Eloisa ARBUSTINI, Pr +39 0382 501893 email@example.com|
|Principal Investigator: Eloisa ARBUSTINI, Pr|
|Academisch Medisch Centrum AMC and InterUniversity Institute AMC/ICIN||Not yet recruiting|
|Amsterdam, Netherlands, 1105 AZ|
|Contact: Yigal PINTO, MD +31-20-5664927 firstname.lastname@example.org|
|Principal Investigator: Yigal PINTO, MD|
|Health in Code SL (SME) - Hospital Marítimo de Oza.||Not yet recruiting|
|A Coruña, Spain, 15006|
|Contact: Lorenzo MONSERRAT, MD +34 981167000 ext 5929 email@example.com|
|Principal Investigator: Lorenzo MONSERRAT, MD|
|The Heart Hospital, University College London NHS Foundation Trust||Not yet recruiting|
|London, United Kingdom, W1G 8PH|
|Contact: Perry ELLIOTT, MD +44-20-7573 8888 firstname.lastname@example.org|
|Principal Investigator: Perry ELLIOTT, MD|
|Principal Investigator:||PHILIPPE CHARRON||PITIE SALPETRIERE HOSPITAL, PARIS, FRANCE|