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

Official title

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

Overview

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.

Detailed description

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.

Interventions

• Drug Oral finerenone
  Standard heart failure therapy plus oral finerenone eGFR ≤60 mL/min/1.73 m²: Start 10 mg once daily, target 20 mg once daily. eGFR \>60 mL/min/1.73 m²: Start 20 mg once daily, target 40 mg once daily. Dose adjustments are mandated based on serum potassium levels and eGFR changes.
• Drug Placebo
  Standard heart failure therapy plus matching placebo

Primary outcome measures

• Change in CMR-measured extracellular volume (ECV) from baseline to Month 6 (∆ECV = ECV[post-treatment] - ECV[baseline]) [Time frame: 6 months]

Secondary outcome measures (12)

• Change from baseline to 6 months in CMR-measured parameter: left ventricular end-diastolic volume index [Time frame: 6 months]
• Change from baseline to 6 months in CMR-measured parameter: left ventricular end-systolic volume index [Time frame: 6 months]
• Change from baseline to 6 months in CMR-measured parameter: left ventricular mass index [Time frame: 6 months]
• Change from baseline to 6 months in CMR-measured parameter: left ventricular ejection fraction [Time frame: 6 months]
• Change from baseline to 6 months in CMR-measured parameter: left atrial volume index [Time frame: 6 months]
• Change from baseline to 6 months in CMR-measured parameter: left ventricular myocardial strain [Time frame: 6 months]
• Change from baseline to 6 months in echocardiography-measured parameter: tricuspid regurgitation velocity [Time frame: 6 months]
• Change from baseline to 6 months in echocardiography-measured parameter: E/e' ratio [Time frame: 6 months]
• Change in CMR native T1 mapping from baseline to 6 months [Time frame: 6 months]
• Change in LGE mass from baseline to 6 months [Time frame: 6 months]
• Change in LGE percentage of left ventricular mass from baseline to 6 months [Time frame: 6 months]
• Change in Pulmonary artery pressure by echocardiography from baseline to 6 months [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Aged 18 to 80 years (inclusive), any gender.
• Symptomatic heart failure (NYHA class II-IV).
• 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.
• LVEF ≥40% measured by echocardiography or CMR within the past 30 days prior to screening.
• NT-proBNP ≥300 pg/mL for patients in sinus rhythm; NT-proBNP ≥900 pg/mL for patients with atrial fibrillation.
• Presence of myocardial fibrosis, defined as ECV ≥27% measured by CMR at baseline.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sc — Beijing

Publications

• Lewis GA, Dodd S, Clayton D, Bedson E, Eccleson H, Schelbert EB, Naish JH, Jimenez BD, Williams SG, Cunnington C, Ahmed FZ, Cooper A, Rajavarma Viswesvaraiah, Russell S, McDonagh T, Williamson PR, Miller CA. Pirfenidone in heart failure with preserved ejection fraction: a randomized phase 2 trial. Nat Med. 2021 Aug;27(8):1477-1482. doi: 10.1038/s41591-021-01452-0. Epub 2021 Aug 12. PMID 34385704
• Requena-Ibanez JA, Santos-Gallego CG, Rodriguez-Cordero A, Vargas-Delgado AP, Mancini D, Sartori S, Atallah-Lajam F, Giannarelli C, Macaluso F, Lala A, Sanz J, Fuster V, Badimon JJ. Mechanistic Insights of Empagliflozin in Nondiabetic Patients With HFrEF: From the EMPA-TROPISM Study. JACC Heart Fail. 2021 Aug;9(8):578-589. doi: 10.1016/j.jchf.2021.04.014. PMID 34325888
• Mason T, Coelho-Filho OR, Verma S, Chowdhury B, Zuo F, Quan A, Thorpe KE, Bonneau C, Teoh H, Gilbert RE, Leiter LA, Juni P, Zinman B, Jerosch-Herold M, Mazer CD, Yan AT, Connelly KA. Empagliflozin Reduces Myocardial Extracellular Volume in Patients With Type 2 Diabetes and Coronary Artery Disease. JACC Cardiovasc Imaging. 2021 Jun;14(6):1164-1173. doi: 10.1016/j.jcmg.2020.10.017. Epub 2021 Jan 13. PMID 33454272
• Droebner K, Pavkovic M, Grundmann M, Hartmann E, Goea L, Nordlohne J, Klar J, Eitner F, Kolkhof P. Direct Blood Pressure-Independent Anti-Fibrotic Effects by the Selective Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone in Progressive Models of Kidney Fibrosis. Am J Nephrol. 2021;52(7):588-601. doi: 10.1159/000518254. Epub 2021 Aug 30. PMID 34515038
• Luettges K, Bode M, Diemer JN, Schwanbeck J, Wirth EK, Klopfleisch R, Kappert K, Thiele A, Ritter D, Foryst-Ludwig A, Kolkhof P, Wenzel UO, Kintscher U. Finerenone Reduces Renal RORgammat gammadelta T Cells and Protects against Cardiorenal Damage. Am J Nephrol. 2022;53(7):552-564. doi: 10.1159/000524940. Epub 2022 Jun 8. PMID 35675794
• Barton AK, Tzolos E, Bing R, Singh T, Weber W, Schwaiger M, Varasteh Z, Slart RHJA, Newby DE, Dweck MR. Emerging molecular imaging targets and tools for myocardial fibrosis detection. Eur Heart J Cardiovasc Imaging. 2023 Feb 17;24(3):261-275. doi: 10.1093/ehjci/jeac242. PMID 36575058
• Agarwal R, Green JB, Heerspink HJL, Mann JFE, McGill JB, Mottl AK, Rosenstock J, Rossing P, Vaduganathan M, Brinker M, Edfors R, Li N, Scheerer MF, Scott C, Nangaku M; CONFIDENCE Investigators. Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes. N Engl J Med. 2025 Aug 7;393(6):533-543. doi: 10.1056/NEJMoa2410659. Epub 2025 Jun 5. PMID 40470996
• Solomon SD, McMurray JJV, Vaduganathan M, Claggett B, Jhund PS, Desai AS, Henderson AD, Lam CSP, Pitt B, Senni M, Shah SJ, Voors AA, Zannad F, Abidin IZ, Alcocer-Gamba MA, Atherton JJ, Bauersachs J, Chang-Sheng M, Chiang CE, Chioncel O, Chopra V, Comin-Colet J, Filippatos G, Fonseca C, Gajos G, Goland S, Goncalvesova E, Kang S, Katova T, Kosiborod MN, Latkovskis G, Lee AP, Linssen GCM, Llamas-Espe PMID 39225278

Identifiers

NCT: NCT07583173 · 2025-2885

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗