Finerenone and Cardiac Remodeling

Official title

Finerenone and Cardiac Remodeling: A Randomized, Double- Blind, Placebo-Controlled Study to Evaluate The Effects of Finerenone on Ventricular Remodeling

Overview

The goal of this clinical trial is to learn if the drug finerenone (Karendia) can improve heart function in participants who are at risk for heart and kidney disease. The main question it aims to answer is whether adding finerenone to standard-of-care heart failure medical therapies will beneficially alter the heart structure and function of people who have risk factors for heart and kidney complications and whose left side of the heart is enlarged. The researchers will compare finerenone to a placebo (a look-alike substance that contains no drug) to see if finerenone improves heart structure and function. Participants will: * take a finerenone or a placebo tablet once a day for 12 months * have a cardiac magnetic resonance imaging (cMRI; a safe, non-invasive scan to measure heart mass, stiffness and function) test at the beginning of the study and 12 months later * visit the clinic after one, three, six and twelve months to assess overall health and/or perform blood or urine tests

Detailed description

Finerenone is a potent and selective oral non-steroidal mineralocorticoid receptor antagonist that has demonstrated marked cardiovascular benefits in people living with diabetic kidney disease, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction. However, the mechanistic basis of these broad cardiovascular benefits remains unclear.

The FINE-MECH CardioLink-11 trial is a multicentre, prospective, randomized, double-blind trial of finerenone vs placebo in addition to standard-of-care in adults with evidence of left ventricular hypertrophy and cardiorenal risk factors. A total of 156 individuals who provide written informed consent and meet all the inclusion criteria (and none of the exclusion criteria) will be assigned (1:1) to receive either finerenone or placebo QD for 12 months. There will be 6-7 clinic visits. Outcome assessors will be blinded to the investigational product allocation and the time point at which each assessment was completed.

Interventions

• Drug Finerenone
  Participants will be allocated a starting dose of 10 or 20 mg of finerenone (dependent on kidney function) once daily, in addition to standard-of-care. Participants may be up-titrated or down-titrated based on potassium levels or estimated glomerular filtration rate with a minimum dose of 10 mg and maximum dose of 40 mg finerenone
• Drug Placebo
  Participants will be allocated a starting dose of 10 or 20 mg of placebo (dependent on kidney function) once daily, in addition to standard-of-care. Participants may be up-titrated or down-titrated based on potassium levels or estimated glomerular filtration rate with a minimum dose of 10 mg and maximum dose of 40 mg placebo

Primary outcome measures

• Left ventricular mass indexed to baseline body surface area (LVMi) [Time frame: 12 months]

Secondary outcome measures (7)

• Left Ventricular Ejection Fraction (LVEF) [Time frame: 12 months]
• Left Ventricular End-Diastolic Volume indexed to baseline body surface area (LVEDVi) [Time frame: 12 months]
• Left Ventricular End-Systolic Volume indexed to baseline body surface area (LVESVi) [Time frame: 12 months]
• Right Ventricular Ejection Fraction (RVEF) [Time frame: 12 months]
• Right Ventricular End-Diastolic Volume indexed to baseline body surface area (RVEDVi) [Time frame: 12 months]
• Right Ventricular End-Systolic Volume indexed to baseline body surface area (RVESVi) [Time frame: 12 months]
• Left Atrial Volume indexed to baseline body surface area (LAVi) [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Individuals ≥18 years of age who are willing and able to provide signed informed consent
• Evidence of left ventricular (LV) hypertrophy ≤12 months prior to or at screening showing at least one (≥1) of the following:

• Interventricular septal (IVS) thickness by echocardiography: Female ≥1.2 cm or Male ≥1.3 cm
• Posterior wall (PW) thickness by echocardiography: Female ≥1.2 cm or Male ≥1.3 cm
• Left ventricular mass indexed to baseline body surface area (LVMi) by echocardiography: Female >95 g⁄m\^2 or Male >115 g⁄m\^2
• LVMi (with papillary muscles included in the LV blood pool) by cMRI: Female >59 g⁄m\^2 or Male >75 g⁄m\^2
• LVMi (if the papillary muscles are included in the LVM) by cMRI: Female >68 g⁄m\^2 or Male >85 g⁄m\^2
• The presence of at least one (≥1) of the following risk factors:

• History of heart failure with preserved ejection fraction (left ventricular ejection fraction \[LVEF\] ≥50%);
• Type 2 diabetes mellitus;
• Estimated glomerular filtration rate (eGFR) ≥25 and <75 mL/min/1.73 m\^2;
• Urine albumin-creatinine ratio (UACR) >3.39 mg/mmol and <565 mg/mmol;
• Left atrial volume indexed to baseline body surface area (LAVi) >40 mL/m\^2 (by echocardiography and as measured by either the biplane area-length method or Simpson's biplane method);
• IVS ≥1.4 cm;
• PW ≥1.4 cm;
• LVMi ≥125 g⁄m\^2 for males and ≥105 g⁄m\^2 for females (by echocardiography);
• N-terminal pro-B-type natriuretic peptide (NT-proBNP; within past 6 months) ≥150 pg/mL if in sinus rhythm or ≥450 pg/mL if atrial fibrillation is present.
• Females who are of childbearing age can only be included if I. they are postmenopausal (i.e. no menstruation for at least one \[≥1\] year) or have had a surgical procedure ≥6 months at screening that prevents them from becoming pregnant; or II. the result of their pregnancy test at the baseline visit is negative, and they agree to use medically acceptable contraception methods to avoid pregnancy for the duration of the trial and for 1 month after taking the last dose of the assigned investigational product.

Exclusion criteria

• Females who are planning to become pregnant, are breastfeeding or are planning to breastfeed;
• Males who are planning to either father a child or donate sperm for the duration of the trial and for 1 month after taking the last dose of the assigned IP;
• Serum potassium level ≥5 mmol/L at the time of screening;
• eGFR <25 mL/min/1.73 m\^2 at the time of screening or on kidney replacement therapy;
• UACR ≥565 mg/mmol at the time of screening;
• Seated systolic blood pressure <110 mmHg at the time of screening;
• History of pulmonary arterial hypertension;
• Type 1 diabetes mellitus;
• Body mass index ≥40 kg/m\^2;
• Contraindication or inability to undergo MRI;
• Known persistent hypoalbuminemia (≤30 g/L on >1 measurement within last 6 months);
• Currently on a mineralocorticoid receptor antagonist (MRA) or in the opinion of the investigator, an MRA is either clinically indicated or contraindicated (e.g. history of marked hyperkalemia, marked hemodynamic stress, intolerance to MRAs) - individuals who previously experienced gynecomastia with spironolactone may be eligible if they meet all the inclusion criteria and none of the exclusion criteria;
• Requirement of any intravenous (IV) vasodilating drug (e.g. nitrates, nitroprusside), any IV natriuretic peptide (e.g. nesiritide, carperitide), any IV positive inotropic agents, or mechanical support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device) ≤24 hours prior to randomization;
• Concomitant systemic therapy with potent cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors (e.g. itraconazole, ritonavir, indinavir, cobicistat, clarithromycin) or moderate or potent CYP3A4 inducers, that cannot be discontinued 7 days prior to randomization and for the duration of the treatment period;
• History of cardiac device implant (e.g. implantable cardioverter defibrillator/cardiac resynchronization therapy/pacemaker) or planned device implant ≤90 days after screening;
• Hospitalized for heart failure (HF) requiring initiation or change in HF therapy or an urgent visit for HF requiring IV diuretic therapy, either ≤45 days prior to screening;
• LVEF <40% per the most current echocardiogram or MRI;
• Symptomatic bradycardia or second- or third-degree heart block without a pacemaker;
• History of peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, viral myocarditis, right HF in the absence of left-sided structural disease, pericardial constriction, hypertrophic cardiomyopathy, or infiltrative cardiomyopathy including amyloidosis;
• Myocardial infarction ≤45 days of screening;
• Planned or previous cardiac surgery or major non-cardiac surgery ≤45 days of screening;
• Planned or previous percutaneous coronary intervention ≤45 days of screening;
• Stroke or transient ischemic stroke ≤90 days before randomization;
• Severe valvular heart disease;
• Addison's disease;
• Individuals who are heart or kidney transplant recipients or who are (or are expected to be) listed for heart transplant, kidney dialysis or a kidney transplant ≤12 months of screening;
• Any other known condition or therapy which would make the individual unsuitable for this trial (e.g. hepatic insufficiency, liver biomarkers >3X upper limit of normal, chronic pulmonary disease, life threatening arrhythmia, uncontrolled arrhythmia) or not allow participation for the full planned trial duration (e.g. active malignancy ≤24 months of screening or condition limiting life expectancy to <12 months);
• Allergy to finerenone (or its excipients);
• Allergy to gadolinium;
• Participation in an investigational study ≤15 days prior to screening, or during study.

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

Quadruple blind

Primary purpose

Treatment

Study locations

Canada · 3 centers

• Cambride Cardiac Care Centre — Cambridge
• North York Diagnostic and Cardiac Centre — North York
• Diagnostic Assessment Centre — Toronto

Publications

• Wang Y, Zhou R, Lu C, Chen Q, Xu T, Li D. Effects of the Angiotensin-Receptor Neprilysin Inhibitor on Cardiac Reverse Remodeling: Meta-Analysis. J Am Heart Assoc. 2019 Jul 2;8(13):e012272. doi: 10.1161/JAHA.119.012272. Epub 2019 Jun 26. PMID 31240976
• Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, Garcia-Ropero A, Mancini D, Pinney S, Macaluso F, Sartori S, Roque M, Sabatel-Perez F, Rodriguez-Cordero A, Zafar MU, Fergus I, Atallah-Lajam F, Contreras JP, Varley C, Moreno PR, Abascal VM, Lala A, Tamler R, Sanz J, Fuster V, Badimon JJ; EMPA-TROPISM (ATRU-4) Investigators. Randomized Trial of Empagliflozin in Nondiabetic Patients With Hea PMID 33197559
• Kasama S, Toyama T, Sumino H, Matsumoto N, Sato Y, Kumakura H, Takayama Y, Ichikawa S, Suzuki T, Kurabayashi M. Additive effects of spironolactone and candesartan on cardiac sympathetic nerve activity and left ventricular remodeling in patients with congestive heart failure. J Nucl Med. 2007 Dec;48(12):1993-2000. doi: 10.2967/jnumed.107.045427. Epub 2007 Nov 15. PMID 18006623
• Dorr K, Kammerlander A, Lauriero F, Lorenz M, Marculescu R, Beitzke D. Effect of etelcalcetide versus alfacalcidol on left ventricular function and feature-tracking cardiac magnetic resonance imaging in hemodialysis-a post-hoc analysis of a randomized, controlled trial. J Cardiovasc Magn Reson. 2023 Nov 6;25(1):62. doi: 10.1186/s12968-023-00975-4. PMID 37932788
• Everett RJ, Tastet L, Clavel MA, Chin CWL, Capoulade R, Vassiliou VS, Kwiecinski J, Gomez M, van Beek EJR, White AC, Prasad SK, Larose E, Tuck C, Semple S, Newby DE, Pibarot P, Dweck MR. Progression of Hypertrophy and Myocardial Fibrosis in Aortic Stenosis: A Multicenter Cardiac Magnetic Resonance Study. Circ Cardiovasc Imaging. 2018 Jun;11(6):e007451. doi: 10.1161/CIRCIMAGING.117.007451. PMID 29914867
• Biederman RW, Magovern JA, Grant SB, Williams RB, Yamrozik JA, Vido DA, Rathi VK, Rayarao G, Caruppannan K, Doyle M. LV reverse remodeling imparted by aortic valve replacement for severe aortic stenosis; is it durable? A cardiovascular MRI study sponsored by the American Heart Association. J Cardiothorac Surg. 2011 Apr 14;6:53. doi: 10.1186/1749-8090-6-53. PMID 21492429
• Cicoira M, Zanolla L, Rossi A, Golia G, Franceschini L, Brighetti G, Marino P, Zardini P. Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure. J Am Coll Cardiol. 2002 Jul 17;40(2):304-10. doi: 10.1016/s0735-1097(02)01965-4. PMID 12106936
• Kosmala W, Przewlocka-Kosmala M, Szczepanik-Osadnik H, Mysiak A, Marwick TH. Fibrosis and cardiac function in obesity: a randomised controlled trial of aldosterone blockade. Heart. 2013 Mar;99(5):320-6. doi: 10.1136/heartjnl-2012-303329. Epub 2013 Jan 23. PMID 23343682

Identifiers

NCT: NCT07270367 · CL-0011

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗