Beta-blOckers discoNtinuation in patients presenting heart FaIlure with REcovered left ventricular ejection fraction

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

11 Feb 2025 → ongoing

Decision date (initial)

2024-06-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Programme Hospitalier de Recherche Clinique - PHRC 2023 (French Ministry of Health)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To demonstrate the non-inferiority of Βeta-Blockers therapy discontinuation in patients with HF and recovered LVEF (stratified on ischemic vs non-ischemic origin) in terms of HF relapse and adverse cardiovascular outcomes as compared to the continuation of Beta-Blockers.

Secondary objectives 4

1. To assess the non-inferiority of Βeta-blockers therapy discontinuation in patients with HF and recovered LVEF (stratified on ischemic vs non-ischemic origin) in terms of safety endpoints
2. To assess the tolerability of Βeta-blockers therapy discontinuation
3. To assess patients’ compliance to HF therapies
4. To identify clinical, imaging or biological predictors of HF relapse or cardiovascular outcomes

Conditions and MedDRA coding

Heart failure

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Age ≥ 18 years-old
2. Established diagnosis of HF for more than 12 months, from an ischemic or a non-ischemic origin
3. 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.
4. 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)
5. No or mild symptoms of HF (defined as NYHA functional class I or II)
6. No heart failure-related hospital admission within the last six months
7. 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
8. 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.
9. With or without ICD
10. Ability to provide written informed consent to participate to the study
11. Patient affiliated to Social Security

Exclusion criteria 16

1. Atrial, supra-ventricular, or ventricular arrhythmias, in the last 12 months and/or requiring beta-blockers according to investigator
2. Uncontrolled arterial hypertension according to investigator decision
3. Symptomatic angina or evidence of infra-clinic myocardial ischemia requiring beta-blockers according to investigator decision
4. Cardiac resynchronization therapy
5. 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
6. History of severe outcomes at beta-blockers interruption: HF relapse, occurrence of arrythmias
7. Severe valvulopathy, restrictive, infiltrative or hypertrophic cardiomyopathy, constrictive pericarditis, or acute myocarditis within 3 months prior to inclusion visit
8. Planned coronary, carotid, or peripheral artery revascularization known at the day of inclusion
9. Chronic renal failure with eGFR <20mL/Min per 1.73m² (CKD-Epi) at inclusion
10. Hepatic insufficiency classified as Child-Pugh B or C at the inclusion Visit
11. Any past solid organ transplantation or planned organ transplantation within 12 months
12. Any condition other than HF that could limit survival to less than one year
13. Pregnancy or breastfeeding women or women of childbearing potential without adequate contraceptive method
14. Current participation in another interventional trial
15. Patient under legal protection (protection of the court, or in curatorship or guardianship).
16. Any disorder, unwillingness or inability, which in investigator’s opinion, might jeopardize the patient’s safety or compliance with the protocol

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 25

1. 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
2. All-cause Death
3. 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
4. All-cause cardiovascular death
5. Additional analyses of HF relapse: Number of patients with reduction in LVEF by more than 10% (absolute value) and to less than 50%.
6. 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
7. Additional analyses of HF relapse: Number of patients hospitalized for worsening HF
8. Number of patients needing loop diuretics for congestive symptoms, during hospitalization and/or in out-of-hospital settings
9. Changes in NYHA Class
10. Absolute values of NT-pro-BNP concentrations at the different visits
11. Proportion of patients with changes in NT-proBNP concentrations to more than 400 ng/L
12. Number of patients needing beta-blocker re-introduction in the experimental group or beta-blocker discontinuation in the control group
13. Occurrence of arrhythmic events (any types, i.e., supra-ventricular and/or ventricular arrhythmias & requiring hospitalization or not) in all participants
14. Occurrence of infra-clinic supra-ventricular and/or ventricular arrhythmias in patients implanted with ICD before participating the study
15. Quality of life (QoL) evaluated by the auto-questionnaire (EQ5D)
16. Quality of life with heart failure, evaluated by the auto-questionnaire KCCQ-12 filled by the patients himself
17. Anxiety: questionnaire HADS (Hospital Anxiety and Depression Scale)
18. Evaluation of Side effects: Absolute values of heart rate at the different visits and relative change as compared to baseline values (first year)
19. Evaluation of Side effects: Questionnaire on the Presence of Blury Vision
20. Evaluation of Side effects: Sensation of cold hands and feet
21. Evaluation of Side effects: Insomnia
22. Occurrence of Palpitations
23. Syncope / Dizziness requiring a consultation
24. Evaluation of compliance to therapies by self-questionnaire
25. Exercice capacity by 6M walk test (in participating centers)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

1 Avenue Claude Vellefaux

City

Paris

Postcode

75010

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Jean-Sébastien HULOT

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Jean-Sébastien HULOT

Locations

1 EU/EEA country · 39 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications