Heart Failure
Conditions
Keywords
Heart Failure with Preserved Ejection Fraction,, Mineralocorticoid receptor antagonist (MRA)
Brief summary
The purpose of this study is to evaluate the effect of finerenone compared to placebo (a tablet without active substance) in the reduction of cardiovascular death (generally meaning death due to disease of the heart or blood vessels) and total Heart Failure (HF) events, including HF hospitalization and urgent visits for HF(generally meaning a hospital stay or urgent presentation to a healthcare unit due to worsening symptoms of heart failure) in patients suffering from HF with an ejection fraction greater than or equal to 40%. Researchers will also collect information on how much the heart disease has impact on patient's lives, change of kidney function, and how well finerenone treatment is tolerated. The study plans to enroll 6000 male and female patients of the age of 40 years and above suffering from heart failure with ejection fraction greater than or equal to 40%. Participants will take the study product as oral tablet with a dose between 0 (Placebo) 40 mg once daily. Study duration will be up to 43 months.
Interventions
For participants with an eGFR ≤60 mL/min/1.73 m\^2: Starting dose is 10 mg OD and maximum dose 20 mg OD. For participants with an eGFR \>60 mL/min/1.73 m\^2: Starting dose is 20 mg OD and maximum dose 40 mg OD. Finerenone is administered orally as immediate release tablets.
OTHERPlacebo
Placebo tablets matching BAY94-8862 are administered orally.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant (male or female) must be aged 40 years and older. * Diagnosis of heart failure with New York Heart Association(NYHA) class II-IV, ambulatory or hospitalized primarily for heart failure. * On diuretic treatment for at least 30 days prior to randomization. * Documented left ventricular ejection fraction (LVEF) of ≥40% measured by any modality within the last 12 months. * Structural heart abnormalities based on any local imaging measurement within the last 12 months, defined by at least one of the following findings: left atrial diameter (LAD) ≥3.8cm, left atrial area (LAA) ≥20cm2, left atrial volume index (LAVI) \>30 mL/m2, left ventricular mass index (LVMI) ≥115 g/m2 (♂)/ 95 g/m2 (♀), septal thickness or posterior wall thickness ≥1.1 cm * n-terminal prohormone B-type natriuretic peptide (NT-proBNP) ≥300 pg/mL (BNP ≥100 pg/mL) in sinus rhythm and patient does not have an ongoing diagnosis of paroxysmal atrial fibrillation or NT-proBNP ≥900 pg/mL (BNP ≥300 pg/mL) in atrial fibrillation (or if atrial fibrillation status is unknown or if patient has an ongoing diagnosis of paroxysmal atrial fibrillation) for participants obtained at the following time: * Within 90 days prior to randomization if patient had been hospitalized for heart failure (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. * 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.
Exclusion criteria
* Estimated glomerular filtration rate (eGFR) \<25 mL/min/1.73 m² at either screening or randomization visit. * Serum/plasma potassium \>5.0 mmol/L at either screening or randomization visit. * Acute inflammatory heart disease, e.g. acute myocarditis, within 90 days prior to randomization * Myocardial infarction or any event which could have reduced the ejection fraction within 90 days prior to randomization * Coronary artery bypass graft surgery in the 90 days prior to randomization * Percutaneous coronary intervention in the 30 days prior to randomization * Stroke or transient ischemic cerebral attack within 90 days prior to randomization * 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, Body Mass Index (BMI) \>50 kg/m2 at screening * Systolic blood pressure(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. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of the Composite Endpoint of Cardiovascular Death and Total (First and Recurrent) Heart Failure Events | From randomization up until the end of study, with an average study duration of 32 months | Number of composite endpoint events of cardiovascular death and total (first and recurrent) heart failure (HF) events (hospitalization for heart failure or urgent HF visit) in HF patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Total (First and Recurrent) Heart Failure Events | From randomization up until the end of study, with an average study duration of 32 months | Number of total (first and recurrent) heart failure events. |
| Change From Baseline in Total Symptom Score (TSS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) | From baseline to Month 6, 9 and 12 | The Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) is ranged from 0 to 100. A higher score (closer to 100) reflects fewer symptoms, indicating better heart failure symptom status. For the change from baseline the combined and averaged result across the entire time frame is reported. |
| Proportion of Participants Who Showed Improvement in NHYA Class | from baseline to Month 12 | The New York Heart Association (NYHA) Functional Classification is a simple scale that classifies patients with heart failure based on the severity of their symptoms and how those symptoms affect their physical activity, which ranges from Class I to Class IV, a lower class number is indicative of a better condition. A patient was considered as having improved in NYHA class, if the NYHA class at Month 12 is at least one category improved compared to the baseline visit. |
| First Occurrence of Renal Composite Events | From randomization up to end of study visit, with an average study duration of 32 months | Number of participants with renal composite events encompassing the components sustained decrease in eGFR ≥50% relative to baseline over at least 4 weeks, sustained eGFR decline to \<15 mL/min/1.73 m2 over at least 4 weeks, initiation of chronic dialysis and renal transplantation. |
| Occurence of All-cause Mortality (Full Analysis Set) | From randomization until end of study, with an average of 32 months | Number of participants with death due to any cause were reported as descriptive result. Number of participants with outcome death reported here includes deaths occurred after randomization until the end of the study visit. Deaths after end of study visit are not included in this table. |
Countries
Argentina, Australia, Austria, Brazil, Bulgaria, Canada, China, Colombia, Czechia, Denmark, Finland, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Japan, Latvia, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Poland, Portugal, Romania, Russia, Slovakia, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at multiple centers in 37 countries/regions between 14-Sep-2020 (first participant first visit) and 14-Jun-2024 (last participant last visit).
Pre-assignment details
Of the 7463 screened participants, 1447 were screening failures, 6016 were randomized. Of the 3011 participants randomized into the finerenone group and the 3005 into the placebo group, 8 and 7 participants respectively were prospectively excluded from analysis due to major Good Clinical Practice (GCP) violations.
Participants by arm
| Arm | Count |
|---|---|
| Finerenone (BAY94-8862) Participants received finerenone 10 mg, 20 mg or 40 mg once daily. | 3,003 |
| Placebo Participants received matching placebo once daily. | 2,998 |
| Total | 6,001 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 5 |
| Overall Study | major GCP violations | 8 | 7 |
| Overall Study | Withdrawal by Subject | 6 | 7 |
Baseline characteristics
| Characteristic | Placebo | Finerenone (BAY94-8862) | Total |
|---|---|---|---|
| Age, Continuous | 72.04 Years STANDARD_DEVIATION 9.69 | 71.94 Years STANDARD_DEVIATION 9.6 | 71.99 Years STANDARD_DEVIATION 9.65 |
| Baseline LVEF | 52.49 percentage of ejection fraction STANDARD_DEVIATION 7.81 | 52.64 percentage of ejection fraction STANDARD_DEVIATION 7.82 | 52.56 percentage of ejection fraction STANDARD_DEVIATION 7.81 |
| NYHA class missing | 0 Participants | 1 Participants | 1 Participants |
| NYHA class NYHA class II | 2065 Participants | 2081 Participants | 4146 Participants |
| NYHA class NYHA class III | 910 Participants | 903 Participants | 1813 Participants |
| NYHA class NYHA class IV | 23 Participants | 18 Participants | 41 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 74 Participants | 75 Participants | 149 Participants |
| Race (NIH/OMB) Asian | 499 Participants | 497 Participants | 996 Participants |
| Race (NIH/OMB) Black or African American | 39 Participants | 49 Participants | 88 Participants |
| Race (NIH/OMB) More than one race | 8 Participants | 7 Participants | 15 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 8 Participants | 17 Participants |
| Race (NIH/OMB) White | 2369 Participants | 2366 Participants | 4735 Participants |
| Sex: Female, Male Female | 1377 Participants | 1355 Participants | 2732 Participants |
| Sex: Female, Male Male | 1621 Participants | 1648 Participants | 3269 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 494 / 2,993 | 528 / 2,993 | 3 / 15 |
| other Total, other adverse events | 1,317 / 2,993 | 1,228 / 2,993 | 0 / 15 |
| serious Total, serious adverse events | 1,157 / 2,993 | 1,213 / 2,993 | 0 / 15 |
Outcome results
Primary
Occurrence of the Composite Endpoint of Cardiovascular Death and Total (First and Recurrent) Heart Failure Events
Number of composite endpoint events of cardiovascular death and total (first and recurrent) heart failure (HF) events (hospitalization for heart failure or urgent HF visit) in HF patients.
Time frame: From randomization up until the end of study, with an average study duration of 32 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Finerenone (BAY94-8862) | Occurrence of the Composite Endpoint of Cardiovascular Death and Total (First and Recurrent) Heart Failure Events | 1083 events |
| Placebo | Occurrence of the Composite Endpoint of Cardiovascular Death and Total (First and Recurrent) Heart Failure Events | 1283 events |
Comparison: Rate Ratio (Finerenone/Placebo)p-value: 0.007295% CI: [0.74, 0.95]stratified Andersen-Gill model
Primary
Occurrence of the Composite Endpoint of Cardiovascular Death and Total (First and Recurrent) Heart Failure Events
Number of participants with composite endpoint events of cardiovascular death and total (first and recurrent) heart failure (HF) events (hospitalization for heart failure or urgent HF visit) in HF patients.
Time frame: From randomization up until the end of study, with an average study duration of 32 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Finerenone (BAY94-8862) | Occurrence of the Composite Endpoint of Cardiovascular Death and Total (First and Recurrent) Heart Failure Events | 624 Participants |
| Placebo | Occurrence of the Composite Endpoint of Cardiovascular Death and Total (First and Recurrent) Heart Failure Events | 719 Participants |
Secondary
Change From Baseline in Total Symptom Score (TSS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ)
The Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) is ranged from 0 to 100. A higher score (closer to 100) reflects fewer symptoms, indicating better heart failure symptom status. For the change from baseline the combined and averaged result across the entire time frame is reported.
Time frame: From baseline to Month 6, 9 and 12
Population: Full analysis set with available KCCQ measurements
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Finerenone (BAY94-8862) | Change From Baseline in Total Symptom Score (TSS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) | 7.99 score on scale |
| Placebo | Change From Baseline in Total Symptom Score (TSS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) | 6.43 score on scale |
Comparison: Difference in LS Meanp-value: <0.000195% CI: [0.79, 2.34]Mixed Models Analysis
Secondary
First Occurrence of Renal Composite Events
Number of participants with renal composite events encompassing the components sustained decrease in eGFR ≥50% relative to baseline over at least 4 weeks, sustained eGFR decline to \<15 mL/min/1.73 m2 over at least 4 weeks, initiation of chronic dialysis and renal transplantation.
Time frame: From randomization up to end of study visit, with an average study duration of 32 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Finerenone (BAY94-8862) | First Occurrence of Renal Composite Events | 75 Participants |
| Placebo | First Occurrence of Renal Composite Events | 55 Participants |
Comparison: Cause-specific Hazard Ratiop-value: 0.107195% CI: [0.94, 1.89]Stratified log-rank test
Secondary
Occurence of All-cause Mortality (Full Analysis Set)
Number of participants with death due to any cause were reported as descriptive result. Number of participants with outcome death reported here includes deaths occurred after randomization until the end of the study visit. Deaths after end of study visit are not included in this table.
Time frame: From randomization until end of study, with an average of 32 months
Population: Full analysis set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Finerenone (BAY94-8862) | Occurence of All-cause Mortality (Full Analysis Set) | 491 Participants |
| Placebo | Occurence of All-cause Mortality (Full Analysis Set) | 522 Participants |
Comparison: Hazard Ratiop-value: 0.279495% CI: [0.83, 1.06]stratified log-rank
Secondary
Occurrence of Total (First and Recurrent) Heart Failure Events
Number of participants with total (first and recurrent) heart failure events.
Time frame: From randomization up until the end of study, with an average study duration of 32 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Finerenone (BAY94-8862) | Occurrence of Total (First and Recurrent) Heart Failure Events | 479 Participants |
| Placebo | Occurrence of Total (First and Recurrent) Heart Failure Events | 573 Participants |
Secondary
Occurrence of Total (First and Recurrent) Heart Failure Events
Number of total (first and recurrent) heart failure events.
Time frame: From randomization up until the end of study, with an average study duration of 32 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Finerenone (BAY94-8862) | Occurrence of Total (First and Recurrent) Heart Failure Events | 842 events |
| Placebo | Occurrence of Total (First and Recurrent) Heart Failure Events | 1024 events |
Comparison: Rate Ratio (Finerenone/Placebo)p-value: 0.006295% CI: [0.71, 0.94]Stratified Andersen-Gill model
Secondary
Proportion of Participants Who Showed Improvement in NHYA Class
The New York Heart Association (NYHA) Functional Classification is a simple scale that classifies patients with heart failure based on the severity of their symptoms and how those symptoms affect their physical activity, which ranges from Class I to Class IV, a lower class number is indicative of a better condition. A patient was considered as having improved in NYHA class, if the NYHA class at Month 12 is at least one category improved compared to the baseline visit.
Time frame: from baseline to Month 12
Population: Full analysis set with available NYHA measurement at baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Finerenone (BAY94-8862) | Proportion of Participants Who Showed Improvement in NHYA Class | 0.179 Estimated proportion |
| Placebo | Proportion of Participants Who Showed Improvement in NHYA Class | 0.178 Estimated proportion |
Comparison: Odds ratio (finerenone /placebo)p-value: 0.929595% CI: [0.88, 1.15]Regression, Logistic