Evaluation of the Efficacy and Safety of Finerenone and Empagliflozin Combination Therapy in Hospitalized Heart Failure Patients
- Trial ID
- 2023-508874-27-00
- Protocol
- 202303CPC
- Sponsor
- Colorado Prevention Center
Trial statistics
Objectives
The primary objective of the study is to evaluate whether a strategy of early, intensive combination therapy with **finerenone** and an SGLT2 inhibitor provides superior clinical outcomes compared to the local standard of care in patients hospitalized with heart failure. The clinical outcomes are defined as a hierarchical composite of all-cause mortality, heart failure events, and a ≥5 point difference in change from baseline for the Kansas City Cardiomyopathy Questionnaire – Total Symptom Score (KCCQ-TSS). This is clinically relevant as it aims to improve survival rates and quality of life in patients with heart failure, a condition associated with high morbidity and mortality.
Secondary objectives include determining whether early, intensive combination therapy with finerenone and an SGLT2 inhibitor can:
- Reduce all-cause mortality and total heart failure events, both first and recurrent.
- Improve KCCQ-TSS at 6 months.
- Reduce heart failure events at 90 days.
Participants
The clinical trial involves a total of **1350 participants** diagnosed with a **heart condition**. The study population includes both male and female subjects, aged **18 years and older**, who are either currently hospitalized or have been recently discharged with a primary diagnosis of heart failure. Participants were selected based on specific inclusion criteria, such as the presence of heart failure signs and symptoms at the time of hospital admission, and elevated levels of N-terminal pro B-type natriuretic peptide (NTproBNP) or B-type natriuretic peptide (BNP). The trial population is characterized by a diverse range of individuals, including those considered vulnerable. Lifestyle factors such as diet and physical activity are not specified, but participants must have received at least one intravenous dose of a loop diuretic during their index hospitalization. Women of childbearing potential are required to have a negative pregnancy test and agree to use adequate contraception throughout the study. The selection process ensures that participants meet stabilization criteria, including maintaining a systolic blood pressure of at least 100 mmHg and no recent use of intravenous vasodilators or inotropic drugs.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of a combination therapy involving **finerenone** and an SGLT2 inhibitor in patients hospitalized with heart failure. This is a phase 3, randomized, double-blind, controlled study. The trial aims to determine whether early, intensive combination therapy provides superior clinical outcomes compared to the local standard of care. The primary endpoint is a hierarchical composite of all-cause mortality, heart failure events, and a change from baseline in the Kansas City Cardiomyopathy Questionnaire – Total Symptom Score (KCCQ-TSS) by at least 5 points. Secondary endpoints include the mean change in KCCQ-TSS from baseline to 6 months, time to first occurrence of all-cause mortality or heart failure event, and total heart failure events from baseline to 90 days.
The trial is expected to commence recruitment on January 31, 2025, and conclude by January 31, 2026. Participants will be involved in the study for a maximum treatment period of 6 months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. Inclusion criteria require participants to be at least 18 years old, currently hospitalized or recently discharged with a primary diagnosis of heart failure, and to meet specific clinical stabilization criteria. Women of childbearing potential must have a negative pregnancy test and agree to use adequate contraception.
Participants may be withdrawn from the study if they do not adhere to the protocol, experience adverse events that necessitate discontinuation, or if they withdraw consent. The study drugs, **empagliflozin** and **finerenone**, are administered orally in the form of film-coated tablets. The trial is not classified as low intervention, as it investigates the efficacy and safety of already authorized medicinal products in a new indication. The trial is conducted in compliance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants.
Treatment
The clinical trial involves the administration of **Jardiance** 10 mg film-coated tablets, which contain the active substance **empagliflozin**. This medication is provided in the form of film-coated tablets and is administered orally. The maximum daily dose is 10 mg, with a total maximum dose of 1800 mg over a treatment period of up to 6 months. The medication is produced by Boehringer Ingelheim International GmbH and is classified under the ATC code A10BK03. The chemical origin of the active substance is confirmed, and the product is not a paediatric formulation.
Another experimental treatment in the trial is **Finerenone**, which is also provided in the form of film-coated tablets. The active substance, **finerenone**, is of chemical origin and is manufactured by Bayer AG. The trial includes different dosing regimens for finerenone: a maximum daily dose of 10 mg, 20 mg, and 40 mg, with corresponding total maximum doses of 1800 mg, 3600 mg, and 7200 mg, respectively, over a 6-month treatment period. The administration route is oral, and the product is not intended for paediatric use. The sponsor product code for finerenone is BAY 94-8862.
The trial does not specify the use of a placebo or comparator treatment, and the focus is on the combination therapy of finerenone and an SGLT2 inhibitor, such as empagliflozin, to assess their efficacy and safety in patients hospitalized with heart failure. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
Efficacy in the clinical trial titled "COmbiNed eFfIcacy and safety of an eaRly, intensive MAnagement sTrategy with fInerenOne and SGLT2 iNhibitor in patients hospitalized with Heart Failure (CONFIRMATION-HF)" will be assessed using a hierarchical composite endpoint. The primary endpoint includes the following parameters: time to all-cause mortality, number of total heart failure (HF) events, time to first HF event, and a change from baseline in the Kansas City Cardiomyopathy Questionnaire – Total Symptom Score (KCCQ-TSS) of 5 points or greater. This will be evaluated using the win-ratio method.
Secondary endpoints will assess treatment group differences in the mean change from baseline to 6 months in KCCQ-TSS, time to first occurrence of all-cause mortality or HF event (hospitalization for HF or urgent visit due to HF), and total (first and recurrent) HF events from baseline to 90 days. The efficacy parameters will be collected and analyzed at specified timepoints, including baseline, 6 months, and 90 days, using validated scales and methods appropriate for the endpoints described.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥18 years or legal age of majority if >18 years in the participant’s country of residence.
- Current hospitalization or recently discharged with a primary diagnosis of acute HF.
- Heart failure signs and symptoms at the time of hospital admission, including: a. Symptoms (at least one of the following): persistent dyspnea at rest or with minimal exertion worse than baseline or new or worsening orthopnea, and; b. Signs of fluid overload (at least one of the following): congestion on chest X-ray, rales on chest auscultation, clinically relevant edema caused by HF (as judged by the investigator), elevated jugular venous pressure.
- Elevated N-terminal pro B-type natriuretic peptide (NTproBNP) ≥500 pg/mL or B-type natriuretic peptide (BNP) ≥125 pg/mL according to the local lab for patients in sinus rhythm; or elevated NTproBNP ≥1500 pg/mL or BNP ≥375 pg/mL for patients with atrial fibrillation (AF), measured during the current hospitalization, in the 72 hours prior to hospital admission, or during the XY post-discharge. (Note: for patients treated with an angiotensin receptor neprilysin inhibitor [ARNI] in the previous 4 weeks prior to randomization, NTproBNP values should be used where available.)
- Fulfillment of the following stabilization criteria (if randomized during hospitalization): a. Systolic BP ≥100 mmHg and no symptoms of hypotension in the 6 hours prior to randomization. b. No increase in intravenous diuretic dose for 6 hours prior to randomization. c. No intravenous vasodilators, including nitrates, within the last 6 hours prior to randomization. d. No intravenous inotropic drugs or mechanical circulatory support for 24 hours prior to randomization.
- Treatment during the index hospitalization with at least 1 intravenous dose of a loop diuretic (e.g., furosemide, torsemide, bumetanide).
- Women of childbearing potential can only be included in the study if a pregnancy test is negative at screening and if they agree to use effective contraception which is consistent with local regulations regarding the methods for contraception for the duration of the study.
- Provide written informed consent.
Exclusion Criteria
- Diagnosis of type 1 diabetes or prior history of diabetic ketoacidosis.
- Documented prior history of severe hyperkalemia (potassium ≥6.0 mmol/L and/or resulting in hospitalization or Emergency Department visit) in the setting of MRA use.
- Currently on or planned for long-term therapy with non-steroidal MRA (finerenone, esaxerenone, apararenone, balcinrenone), steroidal MRA (spironolactone, eplerenone, canrenone), or SGLT2i. Potential participants should not have MRA or SGLT2i stopped for the purpose of enrollment into the study. Patients with recent MRA exposure should not be randomized or receive study treatment until 7 days from the last dose to allow adequate washout.
- eGFR <30 mL/min/1.73m² and/or potassium >5.0 mmol/L at screening.
- Acute MI due to plaque rupture, coronary revascularization, valve replacement/repair, or implantation of a cardiac resynchronization therapy device within 30 days prior to randomization. (Note: pacemakers or implantable cardioverter defibrillators without resynchronization function are allowed.)
- Prior heart transplant or listed for heart transplant with expectation to receive a transplant during the course of this trial (according to investigator judgement) or currently using or plan for mechanical circulatory support, e.g., left ventricular assist device, intra-aortic balloon pump, or patients on mechanical ventilation or patients with planned outpatient inotropic support.
- Hemodynamically significant (severe) uncorrected primary cardiac valvular disease considered by the investigator to be the primary cause of HF. (Note: secondary mitral regurgitation or tricuspid regurgitation due to dilated cardiomyopathy is not excluded unless planned for surgery or intervention during the course of the study.)
- Cardiomyopathy due to known acute inflammatory heart disease (e.g., acute myocarditis within 90 days prior to randomization), infiltrative diseases (e.g., amyloidosis), accumulation diseases (e.g., haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with reversible causes (e.g., stress cardiomyopathy), known hypertrophic obstructive cardiomyopathy, complex (according to investigator`s judgement) congenital heart disease, or known pericardial constriction.
- Probable alternative cause of participant’s HF symptoms that, in the opinion of the investigator, primarily accounts for patient’s symptoms; specifically, patients with severe pulmonary disease requiring home oxygen or chronic oral steroid therapy, primary pulmonary arterial hypertension at screening.
- Concomitant systemic therapy with potent cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors (e.g., itraconazole, ritonavir, indinavir, cobicistat, clarithromycin), or moderate CYP3A4 inducers (e.g., efavirenz, phenobarbital), or potent CYP3A4 inducers (e.g., carbamazepine, phenytoin, St. John’s Wort) that cannot be discontinued 7 days prior to randomization and for the duration of the treatment period. (Note: a list of excluded CYP3A4 inhibitors and inducers is provided in Appendix D.) Concomitant treatment with renin inhibitor, more than one angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or ARNI, or with a potassium-sparing diuretic that cannot be stopped prior to randomization and for the duration of the treatment period.
- Known hypersensitivity to finerenone or empagliflozin (active substance or excipients).
- Any other condition or therapy (e.g., breastfeeding, cardiogenic shock, clinically overt severe hepatic insufficiency [Child Pugh C], Addison’s disease, or other severe condition as per investigator’s judgment such as disease with <1 year life expectancy) which would make the participant unsuitable for this study and not allow participation for the full planned study period.
- Concurrent participation in another interventional clinical study using an investigational agent (e.g., not approved for any indication) within 30 days or 5 half-lives of the other study intervention, whichever is longer, prior to randomization.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 31 Jan 2025 | 150 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BAY 94-8862 | Test | FILM-COATED TABLET | ORAL | 20 | 6 | PRD1624191 |
Finerenone | Test | FILM COATED TABLET | ORAL | 10 | 6 | PRD9408175 |
Jardiance 10 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 10 | 6 | PRD1594865 |
Finerenone | Test | FILM COATED TABLET | ORAL | 40 | 6 | PRD9408174 |