| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Medical condition in which the heart is not pumping as well as it should be. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019279 |
| E.1.2 | Term | Heart failure |
| E.1.2 | System Organ Class | 100000004849 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the superiority of finerenone to placebo in reducing the rate of the composite CV endpoint. |
|
| E.2.2 | Secondary objectives of the trial |
1. To determine superiority of finerenone to placebo for each secondary endpoint.
2. To assess the safety and tolerability of finerenone. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant (male or female) must be aged 40 years and older, at the time of signing the informed consent.
2. Diagnosis of heart failure with NYHA class II–IV, ambulatory or hospitalized primarily for heart failure.
3. On diuretics treatment for at least 30 days prior to randomization
4. Documented LVEF of ≥40% measured by any modality within the last 12 months.
5. Structural heart abnormalities based on any local imaging measurement within the last 12 months, defined by at least one of the following findings: LAD ≥3.8cm, LAA ≥20cm2, LAVI >30 mL/m2, LVMI ≥115 g/m2 (♂)/ 95 g/m2 (♀), septal thickness or posterior wall thickness ≥1.1 cm
6. NT-proBNP ≥300 pg/mL (BNP ≥ 100 pg/mL) in SR and patient does not have an ongoing diagnosis of paroxysmal atrial fibrillation or NT-proBNP ≥900pg/mL (BNP ≥ 300 pg/mL) in AF (or if atrial fibrillation status unknown or if patient has an ongoing diagnosis of paroxysmal
atrial fibrillation) obtained at the following time:
- Within 90 days prior to randomization if patient had been hospitalized for HF requiring initiation or change in HF therapy or if patient had an urgent visit for HF requiring intravenous (IV) diuretic therapy, both within 90 days prior to randomization
OR
- Within 30 days prior to randomization if patient has not been hospitalized for HF nor had an urgent HF visit within the past 90 days.
7. Women of childbearing potential can only be included in the study if a pregnancy test is negative at screening and baseline and if they agree to use adequate contraception which is consistent with local regulations regarding the methods for contraception for those participating in clinical trials.
8. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. |
|
| E.4 | Principal exclusion criteria |
1. eGFR <25 mL/min/1.73 m² at either screening or randomization visit.
2. Serum/plasma potassium >5.0 mmol/L at either screening or randomization visit.
3. Acute inflammatory heart disease, e.g. acute myocarditis, within 90 days prior to randomization
4. Myocardial infarction or any event which could have reduced the ejection fraction within 90 days prior to randomization
5. Coronary artery bypass graft surgery in the 90 days prior to randomization
6. Percutaneous coronary intervention in the 30 days prior to randomization
7. Stroke or transient ischemic cerebral attack within 90 days prior to randomization
8. Probable alternative cause of participants’ HF symptoms that in the opinion of the investigator primarily accounts for patient’s dyspnea such as significant pulmonary disease, anemia or obesity. Specifically, patients with the below are excluded:
- Severe pulmonary disease requiring home oxygen, or chronic oral steroid therapy
- History of primary pulmonary arterial hypertension
- Hemoglobin <10 g/dl *
- Valvular heart disease considered by the investigator to be clinically significant
- BMI >50 kg/m2 at screening
9. SBP ≥160 mmHg if not on treatment with ≥3 blood pressure lowering medications or ≥180 mmHg irrespective of treatments, on 2 consecutive measurements at least 2-minute apart, at screening or at randomization
10. Life-threatening or uncontrolled arrhythmias at screening and/or randomization including but not limited to sustained ventricular tachycardia and atrial fibrillation, or atrial flutter with resting ventricular rate >110 bpm
11. Symptomatic hypotension with mean systolic blood pressure <90 mmHg at screening or at randomization
12. Any primary cause of HF scheduled for surgery, e.g. valve disease such as severe aortic stenosis or severe mitral regurgitation by the time of screening or randomization
13. History of peripartum cardiomyopathy, chemotherapy induced cardiomyopathy, viral myocarditis, right heart failure in absence of left-sided structural disease, pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative
cardiomyopathy including amyloidosis
14. Presence of left ventricular assist device by the time of screening or randomization
15. History of hyperkalemia or acute renal failure during MRA treatment for >7 consecutive days, leading to permanent discontinuation of the MRA treatment
16. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotrophin urine or serum test
17. Known hypersensitivity to the study intervention (active substance or excipients)
18. Hepatic insufficiency classified as Child-Pugh C at screening or randomization
19. Addison’s disease
20. Requirement of any 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) within 24 hours prior to randomization
21. Participants who require treatment with more than one ACEI, ARB or angiotensin-receptor neprilysin inhibitor (ARNI), or two simultaneously at randomization
22. Continuous (at least 90 days) treatment with an MRA (e.g. spironolactone, eplerenone, canrenone, esaxerenone) within 12 months prior to screening. Last intake at least 30 days before randomization. Treatment with MRA should not be interrupted with the purpose of enrollment into the study
23. Concomitant treatment with any renin inhibitor or potassium-sparing diuretic that cannot be stopped prior to randomization and for the duration of the treatment period
24. Concomitant systemic therapy with potent CYP3A4 inhibitors or inducers (e.g.itraconazole, ritonavir, indinavir, cobicistat, clarithromycin) or the moderate or potent CYP3A4
inducers, that cannot be discontinued 7 days prior to randomization and for the duration of the treatment period.
25. Any other condition or therapy, which would make the participant unsuitable for this study and will not allow participation for the full planned study period (e.g. active malignancy or other condition limiting life expectancy to less than 12 months)
26. Previous assignment to treatment during this study
27. Participation in another interventional clinical study (e.g. Phase 1 to 3 clinical studies) or treatment with another investigational medicinal product within 30 days prior to randomization
28. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site)
*Assessment of relevant laboratory parameters is only required if there
is a clinical suspicion of anemia (as an alternative cause of HF
symptoms) or hepatic insufficiency. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the composite of Cardiovascular (CV) death and total (first and recurrent) HF
events (HHF or urgent HF visit) in HF patients (New York Heart Association [NYHA] class II–IV) and LVEF ≥40%. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Time to total (first and recurrent) HF events
2. Improvement in NYHA class from Baseline to Month 12
3.Change from baseline to Month 6, 9 and 12 in Total Symptom Score (TSS) from KCCQ.
4. Time to first occurrence of composite renal endpoint: sustained decrease in eGFR ≥50% relative to baseline over at least 4 weeks, or sustained eGFR decline <15ml/min/1.73m2 or initiation of dialysis or renal transplantation.
5. Time to all-cause mortality |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to end of study (i.e. up to 42 months)
2. Up to 12 month after start of treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarkers and Quality of Life |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 346 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Colombia |
| Hong Kong |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| New Zealand |
| Taiwan |
| United States |
| Austria |
| Finland |
| Latvia |
| Lithuania |
| Poland |
| Bulgaria |
| Netherlands |
| Romania |
| Spain |
| Czechia |
| Germany |
| Greece |
| Italy |
| Denmark |
| Hungary |
| Portugal |
| Russian Federation |
| Slovakia |
| Turkey |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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