Effect of Finerenone on Myocardial Fibrosis and Cardiac Function in HFmrEF/HFpEF Patients

A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of Finerenone on Myocardial Fibrosis and Cardiac Structure and Function in Heart Failure Patients With Mildly Reduced or Preserved Ejection Fraction

FINE-FOCUS study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effect of Finerenone versus placebo on myocardial fibrosis and cardiac structure/function as assessed by cardiac magnetic resonance (CMR) in symptomatic heart failure patients with a left ventricular ejection fraction (LVEF) ≥40%. A sub-study will include 18F-FAPI-PET/CT imaging to evaluate the effect of finerenone on myocardial fibrosis.

Heart failure (HF) with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) are common and associated with high morbidity and mortality. A diverse range of pathophysiological mechanisms is involved in HFmrEF/HFpEF, and this heterogeneity has made it challenging to demonstrate a reduction in mortality in trials to date.

Preclinical studies have established myocardial fibrosis as a key pathophysiological driver of heart failure. In patients with HFmrEF/HFpEF, myocardial fibrosis, assessed by cardiovascular magnetic resonance, is associated with mortality and heart failure hospitalization. Finerenone is a non-steroidal mineralocorticoid receptor antagonist and exhibits more potent anti-inflammatory and antifibrotic effects than steroidal mineralocorticoid receptor antagonists in preclinical models.

Specifically targeting the extracellular matrix may represent a novel therapeutic approach for heart failure, the FINE-FOCUS study(A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of Finerenone on Myocardial Fibrosis and Cardiac Structure and Function in Heart Failure Patients with Mildly Reduced or Preserved Ejection Fraction) was designed to test whether finerenone induces regression of myocardial fibrosis in patients with HFmrEF/HFpEF and evidence of myocardial fibrosis.

PET-CT substudy: A subset of eligible patients will be enrolled into a sub-study to evaluate the effect of finerenone on myocardial fibrosis assessed by 18F-FAPI-PET/CT.

Inclusion Criteria:

1. Aged 18 to 80 years (inclusive), any gender.
2. Symptomatic heart failure (NYHA class II-IV).
3. Emergency department visit or hospitalization for HF within the past 3 months, or escalation of intravenous or oral diuretic therapy for worsening HF within the past 3 months.
4. LVEF ≥40% measured by echocardiography or CMR within the past 30 days prior to screening.
5. NT-proBNP ≥300 pg/mL for patients in sinus rhythm; NT-proBNP ≥900 pg/mL for patients with atrial fibrillation.
6. Presence of myocardial fibrosis, defined as ECV ≥27% measured by CMR at baseline.
7. Capable of providing voluntary written informed consent.

Exclusion Criteria:

• 1. eGFR <25 mL/min/1.73 m² at screening or enrollment. 2. Serum potassium concentration ≥5.0 mmol/L at screening or enrollment. 3. Prior confirmed diagnosis of HFrEF. 4. Acute inflammatory heart disease (e.g., acute myocarditis). 5. Acute myocardial infarction or other event likely to have reduced LVEF within 30 days prior to randomization.

  6. Coronary artery bypass grafting within 30 days prior to randomization. 7. Percutaneous coronary intervention within 30 days prior to randomization. 8. History of stroke or transient ischemic attack (TIA) within 90 days prior to randomization.

  9. Conditions where the investigator considers the primary cause of dyspnea (and thus heart failure symptoms) to be severe pulmonary disease, anemia, or obesity. Specific exclusions include: severe pulmonary disease requiring home oxygen therapy or long-term oral steroids; history of primary pulmonary hypertension; hemoglobin <100 g/L; severe valvular heart disease; BMI ≥50 kg/m².

  10. Systolic blood pressure (SBP) >160 mmHg despite combination therapy with 3 antihypertensive drugs, OR SBP >180 mmHg on any treatment measured on (two consecutive occasions at least 2 minutes apart).

  11. Severe malignant ventricular arrhythmia or atrial fibrillation with resting ventricular rate >100 bpm.

  12. Symptomatic hypotension with mean SBP <90 mmHg. 13. Any HF condition requiring surgical intervention (e.g., severe aortic stenosis or mitral regurgitation).

  14. History of peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, viral myocarditis, primary right ventricular cardiomyopathy, constrictive pericarditis, hereditary hypertrophic cardiomyopathy, or infiltrative cardiomyopathy (including amyloidosis).

  15. Contraindications to CMR (e.g., magnetic metal implants, claustrophobia, contrast allergy).

  16. History of hyperkalemia or acute renal failure during prior MRA therapy. 17. Known allergy or severe adverse reaction to finerenone. 18. History of severe hepatic impairment (Child-Pugh C). 19. Requirement for any intravenous inotropic drugs or mechanical support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device) within 24 hours prior to randomization.

  20. Current or prior use (within 4 weeks before screening) of any MRA (e.g., spironolactone, eplerenone, canrenone, esaxerenone).

  21. Use of renin inhibitors or potassium-sparing diuretics prior to randomization that cannot be discontinued.

  22. Severe comorbidities (e.g., malignancy, lymphoma, cirrhosis, HIV-positive) with life expectancy <2 years.

  23. Pregnancy, lactation, or planning pregnancy. Women of childbearing potential must have a negative serum pregnancy test pre-treatment, agree to serum/urine pregnancy tests at study visits (Months 3 and 6), and commit to using highly effective contraception during the study and for 3 months after. Male participants with female partners of childbearing potential must also agree to use highly effective contraception during the study and for 3 months after.

  24. Participation in another clinical trial within 3 months prior to this study.

  25. Any condition, in the investigator's judgment, that would preclude safe study participation or protocol compliance.