PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors

NCT01583114 | Terminated Phase 3 DMC

• 2 other identifiers: C10-442010-023184-18
• Study Type: interventional
• Target: 6
• Locations: 7 countries
• Sites: 7

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.

Conditions

Dilated Cardiomyopathy

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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).

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

Secondary Outcomes (7)

• Echocardiographic deterioration of LVEDD or Ejection fraction

  at baseline and at 24 months and 36 months after inclusion

• MRI - deterioration of LVEDVol or Ejection fraction

  at baseline and at 36 months after inclusion

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

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

• Deterioration of other Echocardiographic parameters

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

• Deterioration of hormonal biomarkers in serum

  at baseline, at 18 months and 36 months after inclusion

Study Arms (2)

perindopril

EXPERIMENTAL

Drug: perindopril

placebo

PLACEBO COMPARATOR

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

Drug: placebo

Interventions

perindopril DRUG

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).

Also known as: Coversyl

perindopril

placebo DRUG

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).

placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Institut National de la Santé Et de la Recherche Médicale, France: lead

Study Sites (7)

Skejby University Hospital SUH, Aarhus Universit Hospital

Aarhus, 8200, Denmark

Location

Pitié Salpêtrière Hospital

Paris, 75013, France

Location

University of Heidelberg UKLHD

Heidelberg, 69120, Germany

Location

Academic Hospital IRCCS Foundation Policlinico San Matteo (OSM)

Pavia, 27100, Italy

Location

Academisch Medisch Centrum AMC and InterUniversity Institute AMC/ICIN

Amsterdam, 1105 AZ, Netherlands

Location

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

A Coruña, 15006, Spain

Location

The Heart Hospital, University College London NHS Foundation Trust

London, W1G 8PH, United Kingdom

Location

MeSH Terms

Conditions

Cardiomyopathy, Dilated; Heart Failure

Interventions

Perindopril

Condition Hierarchy (Ancestors)

Cardiomegaly; Heart Diseases; Cardiovascular Diseases; Cardiomyopathies; Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• PHILIPPE CHARRON

  PITIE SALPETRIERE HOSPITAL, PARIS, FRANCE

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2012
• First Posted: April 23, 2012
• Study Start: December 1, 2011
• Primary Completion: January 1, 2014
• Study Completion: January 1, 2014
• Last Updated: February 24, 2016

Record last verified: 2016-02

Locations

NL (1); GB (1); DK (1); ES (1); IT (1); DE (1); FR (1)