7.1.1 Inclusion criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Provide electronic or written informed consent, either personally or through a legally authorized representative (LAR), as permitted by local regulations
2. Age ≥18 years or legal age of majority if >18 years in the participant’s country of
residence
3. Symptomatic HFrEF (must meet all criteria)
• NYHA class II – IV symptoms at screening and randomization
• Most recent ejection fraction <40% by imaging (e.g., echocardiogram, cardiac MRI, nuclear scan) within 12 months prior to screening
• Qualifying natriuretic peptide level: Most recent local laboratory value within 14 daysof 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.
NTproBNP, pg/mL BNP, pg/mL
No current atrial fibrillation
No HHF within last 3 months ≥700, ≥175
HHF within last 3 months ≥500, ≥125
Current atrial fibrillation (regardless of history of HHF) ≥1000, ≥250
NTproBNP N-terminal pro B-type natriuretic peptide, BNP B-type
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 <30mL/min/1.73m2) or considered ineligible for treatment with sMRA .
• Intolerance is defined as at least one episode of hyperkalemia, or an episode of worsening kidney function, or an episode of sexual side effects or hypotension, each leading to drug interruption or discontinuation.
• Ineligibility is in the opinion of the treating physician and/or investigator.
5. Persons of childbearing potential1can 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 contraception for the duration of the study natriuretic peptide

7.1.2 Exclusion criteria
Participants are excluded from the study if any of the following criteria apply:
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
2. 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
3. eGFR <25 mL/min/1.73m² and / or potassium >5.0 mmol/L at screening (most recent value within 14 days of randomization if acutely hospitalized or discharged within the last 10 days; within 30 days of randomization if no recent hospitalization). Note: eGFR
and potassium should be repeated prior to randomization if renin-angiotensin system antagonist started or dose increased since most recent prior measurement
4. Acute MI, coronary revascularization, valve replacement/repair, or implantation of a cardiac resynchronization therapy device within 30 days prior to randomization or planned (note: pacemakers or implantable cardioverter defibrillators without
resynchronization function are allowed)
5. 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 participants on mechanical ventilation or participants with planned outpatient inotropic support
6. Hemodynamically significant (severe) uncorrected primary cardiac valvular disease considered by the investigator to be the primary cause of heart failure (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)
7. Symptomatic bradycardia or second- or third-degree heart block without a pacemaker
8. 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
9. Probable alternative cause of participant’s HF symptoms that, in the opinion of the investigator, primarily accounts for patient’s symptoms; specifically, participants with severe pulmonary disease requiring home oxygen or chronic oral steroid therapy, primary pulmonary arterial hypertension at screening
10. 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 and allowed CYP3A4 inhibitors and inducers is provided in Appendix D).
11. Known hypersensitivity to the IP (active substance or excipients)
12. Any other condition or therapy (e.g., breastfeeding, cardiogenic shock, clinically overt severe hepatic insufficiency [Child Pugh C], Addison’s disease, malignancy 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
13. Concurrent or previous participation in another interventional clinical study using an investigational agent (e.g., not approved for any indication) within 30 days prior to randomization.

• Cardiology

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