What is the efficacy and safety of finerenone in reducing cardiovascular death and heart failure events in patients with heart failure and reduced ejection fraction who are intolerant of or not eligible for steroidal mineralocorticoid receptor antagonists (sMRA)?

Study sites- National Hospital of Sri Lanka, Colombo North Teaching Hospital, Kandy National Hospital, Colombo South Teaching Hospital, Jaffna Teaching Hospital, Negombo District General Hospital.

Randomization- Participants will be randomly assigned to treatment groups (Investigational medicinal product-IMP/placebo) based on a computer-generated randomization schedule prepared before the study by, or under the supervision of, the sponsor statistician or delegate. Randomization will be balanced by using randomly permuted blocks for each site and stratified by country.

Comparator– Matching placebo containing lactose

Intervention - Patients will be randomly allocated (1:1) to receive either one finerenone tablet (dosed at 10 mg, 20 mg, 40 mg depending on kidney function) or one placebo tablet orally each day. In both groups, background heart failure therapy will be maintained as per local guidelines, to reflect real-world practice. The study dose will be adjusted based on the patient’s kidney function and serum/plasma potassium. The starting dose of finerenone or placebo will depend on the local laboratory eGFR value at baseline. The investigator will titrate the dose of study intervention once the participant has been on a stable dose for 30±7 days. Participants who do not tolerate their starting dose may be down-titrated or interrupted at any point during the study, including between scheduled visits if required for safety reasons. Up titration of dose may be performed from Day 30 onward at any scheduled or unscheduled contact. eGFR and serum/plasma potassium will be checked 28±7 days after dose adjustment and at any other time deemed appropriate by the investigator. Patients will be instructed to take one tablet of study medication by mouth at approximately the same time each day, with a glass of water with or without food. Tablets containing 10 mg and 20 mg finerenone will differ in size from 40 mg finerenone tablets, but will be identical in appearance (size, shape, color) to matching placebo tablets. The packaging and labelling will be designed to maintain the blinding of the investigator’s team and the participants. The placebo tablet is active-free tablet and contains lactose.

Intervention Arm:
Drug: Finerenone
Dose:10 mg, 20 mg, or 40 mg once daily (starting dose depends on baseline eGFR: 10 mg for eGFR 25–60 mL/min/1.73 m²; 20 mg for eGFR >60 mL/min/1.73 m²). Dose adjustments are made based on potassium levels and kidney function.
Route: Oral
Duration: Approximately 30 months (mean participant duration).
Frequency: Once daily.

Control Arm Drug: Matching placebo.
Dose Identical in appearance to finerenone tablets (10 mg, 20 mg, or 40 mg).
Route: Oral.
Duration: Same as intervention arm (~30 months).
Frequency: Once daily.

Standard Therapy (Background Treatment) All participants (both intervention and control arms) receive standard care for heart failure with reduced ejection fraction (HFrEF), which may include:

Beta-blockers.
Renin-angiotensin system antagonists (e.g., ACE inhibitors, ARBs, or ARNIs).
Sodium-glucose co-transporter 2 (SGLT2) inhibitors.
Diuretics.
Other guideline-directed therapies, as per local practice.

Blinding

This is a double-blind study. The following groups are blinded:
1. Participants – Unaware of whether they receive finerenone or placebo.
2. Healthcare providers – Investigators and site staff are blinded to treatment assignment.
3. Data collectors – Personnel collecting efficacy/safety data are blinded.
4. Outcome adjudicators – Clinical Endpoint Committee members reviewing events are blinded.
5. Data analysts – Statisticians analyzing results remain blinded until final analysis.

Unblinding will be permitted only in medical emergencies where knowledge of treatment is critical for clinical management. Sponsor safety staff may unblind for expedited reporting of serious adverse events.

Participants will be randomly assigned to treatment groups based on a computer-generated randomization schedule prepared before the study by or under the supervision of the sponsor statistician or delegate. Randomization will be balanced by using randomly permuted blocks for each site and stratified by country.

1. Provide electronic or written informed consent, either personally or through a legally authorized representative

2. Age >18 years or legal age of majority

3. Symptomatic HFrEF according to:

   a. NYHA class II-IV symptoms at screening and randomization.

   b. Ejection fraction <40% by imaging within 12 months prior to screening.

   c. Qualifying natriuretic peptide level: Most recent local laboratory value within 14 days of randomization for patients with recent HHF (discharged within prior 10 days) or within 30 days for patients without recent HHF must meet the qualifying threshold below. If no value is available in the medical record, a local lab value must be obtained. Note: for participants treated with an angiotensin receptor/neprilysin inhibitor (ARNI) in the previous 4 weeks prior to natriuretic peptide measurement, only NTproBNP values should be used

4. Not on sMRA (i.e., spironolactone, eplerenone or canrenone/potassium canrenoate) due to documented history of being either intolerant, contraindicated (e.g., due to eGFR <30 mL/min/1.73m2 ) or considered ineligible for treatment with sMRA .

5. Persons of childbearing potential can only be included in the study if a pregnancy test is negative at screening and if they agree to use adequate contraception which is consistent with local regulations regarding the methods for contraception2 for the duration of the study.

1.Treatment with nsMRA (e.g., finerenone, esaxerenone, apararenone) within 30 days prior to randomization; treatment with any MRA should not be interrupted for the purpose of enrollment into the study.

1. Documented severe hyperkalemia (potassium >6.0 mmol/L) or related hospitalization/Emergency Department visit with MRA use.

2. Low eGFR or high potassium: eGFR <25 mL/min/1.73m² or potassium >5.0 mmol/L at screening.

3. Acute MI, coronary revascularization, valve replacement/repair, or cardiac resynchronization therapy device implantation within 30 days before randomization or planned.

4. Prior heart transplant or listed for heart transplant, or use of mechanical circulatory support (e.g., left ventricular assist device, intra-aortic balloon pump, or participants on mechanical ventilation or participants with planned outpatient inotropic support).

5. Hemodynamically significant uncorrected primary cardiac valvular disease-causing heart failure.

6. Symptomatic bradycardia or second- or third-degree heart block without a pacemaker.

7. Cardiomyopathy due to acute inflammatory heart disease e.g., acute myocarditis within 90 days prior to randomization, infiltrative diseases, accumulation diseases, muscular dystrophies, reversible causes, hypertrophic obstructive cardiomyopathy, complex congenital heart disease, or pericardial constriction.

8. Alternative cause of HF symptoms: Severe pulmonary disease requiring home oxygen or chronic oral steroid therapy, primary pulmonary arterial hypertension.

9. Concomitant systemic therapy with potent CYP3A4 inhibitors or inducers that cannot be discontinued 7 days prior to randomization.

10. Known hypersensitivity to the investigational product (active substance or excipients).

11. Conditions like breastfeeding, cardiogenic shock, severe hepatic insufficiency, Addison’s disease, malignancy, or other severe conditions with <1 year life expectancy.

13 Concurrent or previous participation in another interventional clinical study using an investigational agent