PERINDOPRIL TERT-BUTYLAMINE for Heart failure

Stratification factors

• Ischemic vs non-ischemic origin

Inclusion criteria

• {"criterion_text":"- Age ≥ 18 years-old\n- Ability to provide written informed consent to participate to the study\n- Patient affiliated to Social Security\n- Established diagnosis of HF for more than 12 months, from an ischemic or a non-ischemic origin\n- With a documented history of reduced left ventricular ejection fraction (LVEF ≤ 45%), followed by a normalisation of LVEF (≥ 50 % for the last 6 months) assessed by cardiac echography.\n- With a left ventricular end diastolic volume indexed to body surface area (LVEDVi) within the normal range (≤74ml/m2 in men and ≤61 ml/m2 in women)\n- No or mild symptoms of HF (defined as NYHA functional class I or II)\n- No heart failure-related hospital admission within the last six months\n- Currently receiving a beta-blocker indicated for chronic heart failure (i.e., bisoprolol or carvedilol or metoprolol or nebivolol) whatever the dose used, for at least 12 months\n- And receiving the guideline-directed optimal medical therapy for at least 12 months (i.e., maximal tolerated dose of SGLT2i, of RAAS blocker (Angiotensin receptor neprilysin inhibitor OR Angiotensin-converting-enzyme-inhibitors OR Angiotensin II receptors blockers), and of MRA if tolerated). Loop diuretics use is adjusted to congestive signs according to physicians’ decision. No initiation or major adjustment in heart failure therapies should have occurred during the 3 months prior to study inclusion.\n- With or without ICD"}

Exclusion criteria

• {"criterion_text":"- Atrial, supra-ventricular, or ventricular arrhythmias, in the last 12 months and/or requiring beta-blockers according to investigator\n- Hepatic insufficiency classified as Child-Pugh B or C at the inclusion Visit\n- Any past solid organ transplantation or planned organ transplantation within 12 months\n- Any condition other than HF that could limit survival to less than one year\n- Pregnancy or breastfeeding women or women of childbearing potential without adequate contraceptive method\n- Current participation in another interventional trial\n- Patient under legal protection (protection of the court, or in curatorship or guardianship).\n- Any disorder, unwillingness or inability, which in investigator’s opinion, might jeopardize the patient’s safety or compliance with the protocol\n- Uncontrolled arterial hypertension according to investigator decision\n- Symptomatic angina or evidence of infra-clinic myocardial ischemia requiring beta-blockers according to investigator decision\n- Cardiac resynchronization therapy\n- Extra-cardiac conditions requiring beta-blockers (migraine, essential tremor, prevention of bleeding from esophageal varices in patients with liver cirrhosis, adrenergic symptoms of hyperthyroidism…) according to investigator decision\n- History of severe outcomes at beta-blockers interruption: HF relapse, occurrence of arrythmias\n- Severe valvulopathy, restrictive, infiltrative or hypertrophic cardiomyopathy, constrictive pericarditis, or acute myocarditis within 3 months prior to inclusion visit\n- Planned coronary, carotid, or peripheral artery revascularization known at the day of inclusion\n- Chronic renal failure with eGFR <20mL/Min per 1.73m² (CKD-Epi) at inclusion"}

Primary endpoints

• {"endpoint_text":"- The primary endpoint will be evaluated during the follow-up of the patients (1-year minimum follow-up , 4–year-maximum follow-up) and will be the first occurrence of one of the event of the composite endpoint : 1/ HF relapse (at any time during the study): drop in LVEF >10% (expressed as absolute value), relative increase in body surface area-indexed LVEDVi >10%, increase in NT-proBNP >2x and ≥400 ng/L, worsening HF symptoms requiring hospitalization or urgent visits or out-of-hospital therapeut","definition_or_measurement_approach":"Composite outcome assessed during follow-up (min 1 year, max 4 years); HF relapse defined by drop in LVEF >10% (absolute), relative increase in LVEDVi >10%, increase in NT-proBNP >2x and ≥400 ng/L, or worsening HF symptoms requiring hospitalization, urgent visit or out-of-hospital therapeutic intervention. First occurrence of any component counts."}

Secondary endpoints

• {"endpoint_text":"- HF relapse defined by 1/ Reduction in LVEF by more than 10% (absolute value) 2/ A relative increase in LVEDVi by more than 10% 3/ A two-fold rise in baseline NT-pro-BNP concentration and to more than 400 ng/L. 4/ Clinical evidence of heart failure, based on signs and symptoms as adjudicated by the research team. 5/Hospitalization for worsening HF","definition_or_measurement_approach":"Composite definition provided: reduction in LVEF >10% (absolute), relative LVEDVi increase >10%, NT-proBNP rise ≥2x and >400 ng/L, clinical signs/symptoms adjudicated by research team, hospitalization for worsening HF."}
• {"endpoint_text":"- All-cause Death","definition_or_measurement_approach":"Death from any cause."}
• {"endpoint_text":"- All individual reasons for Hospitalisation, as follows: 1/ ACS or need for coronary catheterisation +/- revascularization ; 2/ Recurrent ischemia ; 3/ Supra-ventricular or ventricular arrhythmias ; 4/ Syncope, PM implantation ; 5/ High blood pressure ; 6/ Stroke","definition_or_measurement_approach":"Individual hospitalization reasons captured and categorized as listed (ACS, revascularization, recurrent ischemia, arrhythmias, syncope/PM implantation, hypertension, stroke)."}
• {"endpoint_text":"- All-cause cardiovascular death","definition_or_measurement_approach":"Cardiovascular cause of death as adjudicated."}
• {"endpoint_text":"- Additional analyses of HF relapse: Number of patients with reduction in LVEF by more than 10% (absolute value) and to less than 50%.","definition_or_measurement_approach":"Counts of patients meeting LVEF reduction >10% and absolute LVEF <50%."}
• {"endpoint_text":"- Additional analyses of HF relapse: Number of patients with a relative increase in LVEDVi by more than 10% and to higher than the normal range","definition_or_measurement_approach":"Counts of patients with LVEDVi relative increase >10% and exceeding normal range."}
• {"endpoint_text":"- Additional analyses of HF relapse: Number of patients hospitalized for worsening HF","definition_or_measurement_approach":"Count of hospitalizations for worsening HF."}
• {"endpoint_text":"- Number of patients needing loop diuretics for congestive symptoms, during hospitalization and/or in out-of-hospital settings","definition_or_measurement_approach":"Count of patients requiring loop diuretics for congestive symptoms in-hospital or out-of-hospital."}
• {"endpoint_text":"- Changes in NYHA Class","definition_or_measurement_approach":"NYHA functional class assessed at visits; changes from baseline recorded."}
• {"endpoint_text":"- Absolute values of NT-pro-BNP concentrations at the different visits","definition_or_measurement_approach":"NT-pro-BNP measured at scheduled visits; absolute concentrations recorded."}
• {"endpoint_text":"- Proportion of patients with changes in NT-proBNP concentrations to more than 400 ng/L","definition_or_measurement_approach":"Proportion of patients whose NT-proBNP increases above 400 ng/L."}
• {"endpoint_text":"- Number of patients needing beta-blocker re-introduction in the experimental group or beta-blocker discontinuation in the control group","definition_or_measurement_approach":"Counts of patients requiring re-introduction or discontinuation of beta-blocker therapy."}
• {"endpoint_text":"- Occurrence of arrhythmic events (any types, i.e., supra-ventricular and/or ventricular arrhythmias & requiring hospitalization or not) in all participants","definition_or_measurement_approach":"Recording of any arrhythmic events (supra-ventricular/ventricular), regardless of hospitalization."}
• {"endpoint_text":"- Occurrence of infra-clinic supra-ventricular and/or ventricular arrhythmias in patients implanted with ICD before participating the study","definition_or_measurement_approach":"Detection of infra-clinic arrhythmias via ICD interrogation in patients with pre-existing ICDs."}
• {"endpoint_text":"- Quality of life (QoL) evaluated by the auto-questionnaire (EQ5D)","definition_or_measurement_approach":"EQ-5D self-questionnaire scores collected at visits."}
• {"endpoint_text":"- Quality of life with heart failure, evaluated by the auto-questionnaire KCCQ-12 filled by the patients himself","definition_or_measurement_approach":"KCCQ-12 patient-reported scores collected."}
• {"endpoint_text":"- Anxiety: questionnaire HADS (Hospital Anxiety and Depression Scale)","definition_or_measurement_approach":"HADS questionnaire administered; anxiety subscale scores recorded."}
• {"endpoint_text":"- Evaluation of Side effects: Absolute values of heart rate at the different visits and relative change as compared to baseline values (first year)","definition_or_measurement_approach":"Heart rate measured at visits; absolute and relative change from baseline during first year reported."}
• {"endpoint_text":"- Evaluation of Side effects: Questionnaire on the Presence of Blury Vision","definition_or_measurement_approach":"Patient questionnaire on blurred vision; responses collected."}
• {"endpoint_text":"- Evaluation of Side effects: Sensation of cold hands and feet","definition_or_measurement_approach":"Patient-reported questionnaire on cold extremities."}
• {"endpoint_text":"- Evaluation of Side effects: Insomnia","definition_or_measurement_approach":"Patient-reported insomnia questionnaire responses."}
• {"endpoint_text":"- Occurrence of Palpitations","definition_or_measurement_approach":"Patient-reported palpitations recorded; clinical confirmation where applicable."}
• {"endpoint_text":"- Syncope / Dizziness requiring a consultation","definition_or_measurement_approach":"Events of syncope/dizziness requiring medical consultation recorded."}
• {"endpoint_text":"- Evaluation of compliance to therapies by self-questionnaire","definition_or_measurement_approach":"Self-reported adherence questionnaires collected."}
• {"endpoint_text":"- Exercice capacity by 6M walk test (in participating centers)","definition_or_measurement_approach":"6-minute walk distance measured in centers participating in this assessment."}

France

Earliest CTIS Part Ii Submission Date

05-06-2024

Latest Decision Or Authorization Date

07-04-2026

Processing Time Days

671

Number Of Sites

37

Number Of Participants

1300

Primary sponsor

Full Name

Assistance Publique Hopitaux De Paris

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France