Clinical trial NCT04435626
Conditions: Heart Failure
Keywords: Heart Failure with Preserved Ejection Fraction, Mineralocorticoid receptor antagonist (MRA)
Sponsor: Bayer
Start date: 2020-09-14; Completion date: 2024-06-14
Enrollment: 6016 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: Adult patients receive BAY94-8862 arm 2: Adult patients receive placebo
Interventions: intervention 1: Finerenone (BAY94-8862) intervention 2: Placebo
Intervention descriptions: intervention 1: 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. intervention 2: Placebo tablets matching BAY94-8862 are administered orally.

Protocol documents:
Prot_000.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
A multicenter, randomized, double-blind, parallel-group, placebo-
controlled study to evaluate the efficacy and safety of finerenone on 
morbidity and mortality in participants with heart failure (NYHA II-
IV) and left ventricular ejection fraction = 40% (LVEF = 40%) 
NCT Number: 
NCT04435626 
Document Date: 
16 May 2022 
 


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Title Page
Protocol Title:
A multicenter, randomized, double-blind, parallel-group, placebo-controlled 
study to evaluate the efficacy and safety of finerenone on morbidity 
and mortality in participants with heart failure (NYHA II-IV) and 
left ventricular ejection fraction ≥40% (LVEF ≥40%)
Protocol Number:
20103
Protocol Version:
3.0
Amendment Number:
2
Amendment Scope:
Global
Compound Number:
Finerenone / BAY 94-8862
Study Phase:
3
Short Title:
Efficacy and safety of finerenone in participants with symptomatic heart failure 
and left ventricular ejection fraction ≥40% (LVEF ≥40%).
Acronym:
FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR 
to placebo in paTientS with Heart Failure)
Sponsor Name:
Non-US: Bayer AG
US territory: Bayer Healthcare Pharmaceuticals Inc
Legal Registered Address: Non-US:
Bayer AG, 51368 Leverkusen, Germany
US territory:
100 Bayer Boulevard, P.O. Box 915, Whippany 
NJ 07981-0915, USA
Regulatory Agency Identifier Number(s): EudraCT 2020-000306-29
Protocol Date: 
16 MAY 2022
The Medical Monitor’s name and contact information will be provided separately. 
Name:
 
Role:
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD
PPD


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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 2
16 MAY 2022
Amendment IND-2
13 JUL 2021
Amendment JPN-2
13 JUL 2021
Amendment CHN-2
23 FEB 2021
Amendment IND-1
21 DEC 2020
Amendment LTU-1
15 DEC 2020
Amendment 1
21 SEP 2020
Amendment USA-1
21 JUL 2020
Amendment SVK-1
03 JUL 2020
Amendment GBR-1
27 MAY 2020
Amendment JPN-1
06 APR 2020
Amendment CHN-1
24 MAR 2020
Original Protocol
05 MAR 2020
Amendment 2 (16 MAY 2022)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
This amendment was made to alter certain efficacy endpoints of the study. In addition, more 
clarity has been provided and inconsistencies were corrected.
Section # 
and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Section 2.1 Study Rationale
Section 3 Objectives and Endpoints
Section 6.6.2 Monitoring of Renal 
Function and Dose Adjustment
Section 9.4.1.2 Secondary Efficacy 
Variables
Change in the percentage decrease 
(from 40% to 50%) of the eGFR 
component of the secondary renal 
composite endpoint.
Based on updated 
finerenone data on 
FIGARO and FIDELIO 
studies.
Section 1.3 Schedule of Activities (SoA)
Section 10.2 Appendix 2: Clinical 
Laboratory Tests
Removal of measurement of SARS-
CoV-2 serology.
To reflect actual moment 
of pandemic. The mass 
vaccination made these 
measurements inaccurate.
Section 1.3 Schedule of Activities (SoA)
Section 6.1 Study Intervention(s) 
Administered
Full unscheduled safety check for 
reasons other than hyperkalemia; 
otherwise only potassium to be 
rechecked
For clarity
Section 1.3 Schedule of Activities (SoA)
Addition of starting point (after last 
intake) for countdown to the PD Visit.
For clarity.
Section 1.3 Schedule of Activities (SoA)
Footnote s was added stating that at 
Visit 4 an additional NT-proBNP
measurement from serum will be 
performed.
To accommodate the 
regulatory need for 
comparing adult 
biomarkers as a reference 
for measurement in the 
pediatric population.
Section 2 Introduction
Section 7.1 Discontinuation of Study 
Intervention
Details of MRA and its effects adjusted.
Addition of maximum permissible 
duration of MRA use.
To reflect current status of 
MRA use.


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Section 1.1 Synopsis
Section 2.1 Study Rationale
Section 3 Objectives and Endpoints
Section 9.4.1.1 Primary Efficacy Variable
Section 9.4.1.2 Secondary Efficacy 
Variables
Section 9.4.1.3 Exploratory Variables
Change in NYHA class from baseline 
was removed from exploratory 
endpoints, and time to total HF events 
and improvement in NYHA class from 
baseline to month 12 as secondary 
endpoints, and included analysis 
methods for these endpoints.
The endpoint was 
elevated to a key 
secondary endpoint given 
its meaningful clinical 
significance.
Section 3 Objectives and Endpoints
Section 9.4.1.3 Exploratory Variables
Change in UACR from baseline, and 
time to first occurrence of the following 
composite endpoint: sustained 
decrease in eGFR ≥57% relative to 
baseline over at least 4 weeks, or 
sustained eGFR decline <15 
ml/min/1.73m2 or initiation of dialysis or 
renal transplantation, were added as 
exploratory endpoints.
These exploratory 
endpoints were added to 
compare with existing data 
from FIGARO and 
FIDELIO.
Section 5.1 Inclusion Criteria
Addition of details on NT-proBNP in 
relation to paroxysmal atrial fibrillation. 
To reflect current 
guidance.
Section 5.2 Exclusion Criteria
It was clarified for Exclusion Criteria 8 
and 18 that the laboratory parameters 
are only needed at screening if there is 
a suspicion of anemia or hepatic
insufficiency.
Recommendation to clarify 
these criteria following 
local inspection in 
Argentina (The National 
Administration of Drugs, 
Foods and Medical 
Devices)
Section 5.2 Exclusion Criteria
Section 6.5 Prior and Concomitant 
Therapy
Use of all moderate CYP3A4 inhibitors
is allowed, whereas use of moderate 
CYP3A4 inducers is prohibited.
To reflect current label 
requirements. In addition, 
current FINEARTS-HF 
blinded interim data 
suggest that the use of 40 
mg is safe in heart failure 
patients and no excess in 
AEs, in particular 
hyperkalemia or 
discontinuations was 
observed so far.
Moreover, analyses of 
FIDELIO-DKD data show 
that serum potassium 
guided dose titration is the 
key factor managing 
serum potassium and 
preventing increased 
hyperkalemia at higher
finerenone exposure 
levels and doses.
An updated list of the most 
common CYP3A4 
inhibitors will be provided 
separately outside of the 
protocol.
Section 5.4 Screen Failures
Re-screening allowed in exceptional 
circumstances (e.g. pandemic-related 
disruption).
To account for logistic 
issues.


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Section 6.5 Prior and Concomitant 
Therapy
- Updated information on existing 
treatment showing mortality or 
morbidity benefit in participants with 
HFpEF.
- Deletion of text on BCRP/OATP.
-Updating to reflect recent 
data from EMPEROR-
Preserved study in 
HFpEF
-To reflect recently 
completed study 
(#21429) findings that 
showed an absence of 
any relevant effect of 
finerenone on 
BCRP/OATP.
- Sentence urging for caution while 
using acetylsalicylic acid at doses 
greater than 500mg a day was 
removed
-Updated in accordance 
with the current label
Section 6.6.1 Monitoring of Blood 
Potassium and Dose Adjustment
Adjustment of description, requiring that 
potassium is retested if a patient was 
down-titrated or if study drug was 
interrupted.
Included for clarity.
Section 6.6.2 Monitoring of Renal
Function and Dose Adjustment
Wording edited: re-test at central 
laboratory after 4 weeks to confirm 
eGFR decrease of either ≥50 % or 
≥57%
50% is in line with the new 
secondary composite 
endpoint. 57% was added 
to compare with existing 
data from FIGARO and
FIDELIO.
Section 7.1 Discontinuation of Study 
Intervention
Telephone consultation permitted, only 
if onsite EOS visit is not feasible.
To ensure the minimum 
required data collection in 
case subject is not able to 
visit the site.
Section 7.1 Discontinuation of Study 
Intervention
Section 7.1.1 Temporary Discontinuation
Addition of conditions allowing the 
resumption of study intervention.
Restart of study 
intervention allowed if 
reason for permanent 
discontinuation changed 
and the investigator 
considers restart in the 
best interest of the 
subject.
Section 8.2.3 Clinical Safety Laboratory 
Assessments
Option to down-titrate in exceptional 
circumstances (e.g. supply issue). 
To ensure continuation of 
treatment as far as 
possible in exceptional 
circumstances.
Section 8.3.6 Disease-Related Events 
and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
Addition of specific conditions of 
disease-related event: worsening of 
renal function.
Included for completeness
Section 8.8 Biomarkers
The biomarkers NT-proBNP and hs-TnT 
will be determined in plasma at the time 
points indicated in SoA for central 
laboratory assessments (Section 1.3).
To allow NT-proBNP to be 
measured in serum.
Section 9.1 Statistical Hypotheses
Analysis of the competing event of non-
CV death and clarification for mean 
cumulative function were included
Included for clarity on 
handling and presentation 
of competing events.
Section 9.4.1.1 Primary Efficacy Variable Included analysis and presentation of 
cumulative incidence function for the 
competing event of non-CV death. 
Clarified that cumulative incidence 
functions will use Aalen-Johansen 
estimates as opposed to Kaplan-Meier.
Clarity on handling and 
presentation of competing 
events
Section 9.4.1.2 Secondary Efficacy 
Variables
For the composite renal endpoint, 
included analysis and presentation of 
cumulative incidence function for the 
competing event of death. Clarified that 
cumulative incidence functions will use 
Aalen-Johansen estimates as opposed 
to Kaplan-Meier.
Clarity on handling and 
presentation of competing 
events


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Section 9.4.1.3 Exploratory Variables
Added Mean rate of change in eGFR as 
measured by total eGFR slope and its 
subcomponents acute and chronic 
slope as an exploratory endpoint, and
included analysis method for this 
endpoint.
New exploratory endpoint 
of eGFR slope was added, 
and detailed slope 
analysis will be based on 
new exploratory endpoint.
Section 9.4.1.3 Exploratory Variables
Updated proposed presentation of 
DAOH
Clarity on handling of 
interim analyses
Section 9.5 Interim Analysis
Added description of how the interim 
analyses will be conducted
Clarity on handling of 
interim analyses
Section 10.4 Appendix 4: Contraceptive 
guidance and collection of pregnancy 
information
WOCBP should use effective 
contraception.
Table including contraceptives during 
the study was included for clarity.
Updated based on the 
current data available for 
finerenone.
In addition, corrections of errors, editorial and administrative changes have been made 
throughout the document that are not listed in this table.


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Table of Contents
Title Page................................................................................................................................... 1
Protocol Amendment Summary of Changes Table............................................................... 2
Table of Tables.......................................................................................................................... 8
Table of Figures........................................................................................................................ 8
1.
Protocol Summary............................................................................................................. 9
1.1
Synopsis ........................................................................................................................... 9
1.2
Schema........................................................................................................................... 11
1.3
Schedule of Activities (SoA) ......................................................................................... 12
2.
Introduction ..................................................................................................................... 16
2.1
Study Rationale.............................................................................................................. 19
2.2
Background.................................................................................................................... 20
2.3
Benefit/Risk Assessment ............................................................................................... 20
3.
Objectives and Endpoints............................................................................................... 22
4.
Study Design .................................................................................................................... 23
4.1
Overall Design ............................................................................................................... 23
4.2
Scientific Rationale for Study Design............................................................................ 26
4.3
Justification for Dose ..................................................................................................... 26
4.4
End of Study Definition................................................................................................. 29
5.
Study Population ............................................................................................................. 30
5.1
Inclusion Criteria ........................................................................................................... 30
5.2
Exclusion Criteria .......................................................................................................... 31
5.3
Lifestyle Considerations ................................................................................................ 33
5.4
Screen Failures............................................................................................................... 33
6.
Study Intervention........................................................................................................... 34
6.1
Study Intervention(s) Administered............................................................................... 34
6.2
Preparation/Handling/Storage/Accountability............................................................... 36
6.3
Measures to Minimize Bias: Randomization and Blinding ........................................... 36
6.4
Study Intervention Compliance ..................................................................................... 37
6.5
Prior and Concomitant Therapy..................................................................................... 37
6.5.1
Rescue Medicine......................................................................................................... 38
6.6
Dose Modification ......................................................................................................... 39
6.6.1
Monitoring of Blood Potassium and Dose Adjustment.............................................. 39
6.6.2
Monitoring of Renal Function and Dose Adjustment ................................................ 40
6.7
Intervention After the End of the Study......................................................................... 40
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 40
7.1
Discontinuation of Study Intervention........................................................................... 40
7.1.1
Temporary Discontinuation........................................................................................ 41
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 42
7.3
Lost to Follow-up........................................................................................................... 42
8.
Study Assessments and Procedures............................................................................... 43
8.1
Efficacy Assessments..................................................................................................... 43


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8.1.1
Kansas City Cardiomyopathy Questionnaire (KCCQ) and Total Symptom Score 
(TSS)........................................................................................................................... 43
8.1.2
EuroQoL (EQ-5D-5L) ................................................................................................ 44
8.1.3
Patient Global Impression of Severity (PGIS) and Change (PGIC)........................... 44
8.1.4
Assessment of NYHA class........................................................................................ 44
8.1.5
NT-proBNP and hs-TnT............................................................................................. 45
8.2
Safety Assessments........................................................................................................ 45
8.2.1
BMI and Weight ......................................................................................................... 45
8.2.2
Vital Signs .................................................................................................................. 45
8.2.3
Clinical Safety Laboratory Assessments .................................................................... 45
8.3
Adverse Events and Serious Adverse Events ................................................................ 47
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 47
8.3.2
Method of Detecting AEs and SAEs .......................................................................... 47
8.3.3
Follow-up of AEs and SAEs....................................................................................... 48
8.3.4
Regulatory Reporting Requirements for SAEs........................................................... 48
8.3.5
Pregnancy ................................................................................................................... 48
8.3.6
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs....................................................................................................................... 48
8.4
Treatment of Overdose................................................................................................... 49
8.5
Pharmacokinetics ........................................................................................................... 49
8.6
Pharmacodynamics ........................................................................................................ 50
8.7
Genetics.......................................................................................................................... 50
8.8
Biomarkers..................................................................................................................... 50
8.9
Immunogenicity Assessments........................................................................................ 51
8.10
Medical Resource Utilization and Health Economics ................................................... 51
9.
Statistical Considerations ............................................................................................... 51
9.1
Statistical Hypotheses .................................................................................................... 51
9.2
Sample Size Determination............................................................................................ 52
9.3
Populations for Analyses ............................................................................................... 53
9.4
Statistical Analyses ........................................................................................................ 53
9.4.1
Efficacy Analyses ....................................................................................................... 54
9.4.1.1
Primary Efficacy Variable....................................................................................... 54
9.4.1.2
Secondary Efficacy Variables ................................................................................. 55
9.4.1.3
Exploratory Variables.............................................................................................. 58
9.4.2
Safety Analyses .......................................................................................................... 60
9.5
Interim Analyses ............................................................................................................ 61
9.6
Data Monitoring Committee (DMC) ............................................................................. 62
10. Supporting Documentation and Operational Considerations .................................... 63
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 63
10.1.1
Regulatory and Ethical Considerations ...................................................................... 63
10.1.2
Financial Disclosure ................................................................................................... 63
10.1.3
Informed Consent Process.......................................................................................... 63
10.1.4
Data Protection ........................................................................................................... 64
10.1.5
Committees Structure ................................................................................................. 64
10.1.6
Dissemination of Clinical Study Data ........................................................................ 64
10.1.7
Data Quality Assurance.............................................................................................. 65
10.1.8
Source Documents...................................................................................................... 66
10.1.9
Study and Site Closure ............................................................................................... 66


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10.1.10 Publication Policy....................................................................................................... 66
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 67
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .............................................................................................. 69
10.3.1
Definition of AE ......................................................................................................... 69
10.3.2
Definition of SAE....................................................................................................... 70
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 71
10.3.4
Reporting of SAEs...................................................................................................... 73
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 74
10.5
Appendix 5: Definitions of Clinical Events................................................................... 77
10.5.1
Heart Failure (HF) Events .......................................................................................... 77
10.5.1.1
Heart Failure Hospitalization (HHF)....................................................................... 77
10.5.1.2
Urgent Heart Failure (HF) Visits............................................................................. 77
10.5.2
Cardiovascular (CV) Death ........................................................................................ 77
10.6
Appendix 6: Country-Specific Requirements................................................................ 78
10.7
Appendix 7: Calculating the Child Pugh score.............................................................. 78
10.8
Appendix 8: Protocol Amendment History ................................................................... 79
10.8.1
Amendment number 1: 21 SEP 2020 ......................................................................... 79
10.9
Appendix 8: Abbreviations............................................................................................ 82
11. References ........................................................................................................................ 85
Table of Tables
Table 6–1 Dosage of Study Intervention for Administration................................................. 35
Table 6–2 Potassium Levels and Guidance for Dose Adjustment ......................................... 39
Table 6–3 Renal Function Evaluation During Study.............................................................. 40
Table 9–1 Power for Assumed Sample Size Scenario and Some Variations......................... 53
Table 9–2 Populations for Analyses....................................................................................... 53
Table 9–3 Power to Exclude Increased Hazard Ratio on All-Cause Mortality Under Different 
Assumed Treatment Effects on CV Death ............................................................ 54
Table 10–1 Protocol-Required Clinical/Safety Laboratory Assessments ................................ 68
Table 10–2 Grading of Severity of Liver Disease, Adapted from (Pugh et al. 1973).............. 78
Table 10–3 Classification Using the Added Score from Table 10–2, Adapted from (Pugh et al. 
1973)...................................................................................................................... 78
Table of Figures
Figure 1–1 Main SoA............................................................................................................... 12
Figure 1–2 Premature Discontinuation SoA............................................................................ 14


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1. Protocol Summary
1.1
Synopsis
Protocol Title: A multicenter, randomized, double-blind, parallel-group, placebo-controlled 
study to evaluate the efficacy and safety of finerenone on morbidity and mortality in 
participants with heart failure (NYHA II-IV) and left ventricular ejection fraction ≥40%
(LVEF ≥40%).
Short Title: Efficacy and safety of finerenone in participants with symptomatic heart failure 
and left ventricular ejection fraction ≥40% (LVEF ≥40%).
Rationale: Study 20103 will be the first large-scale, long-term outcome study investigating 
the efficacy and safety of the non-steroidal mineralocorticoid receptor antagonist (MRA)
finerenone on morbidity and mortality in participants with heart failure (NYHA II-IV) and 
LVEF ≥40%. 
An inappropriate release of aldosterone contributes to target organ damage found in heart 
failure (HF), myocardial infarction, chronic renal failure, and hypertension. The extensive 
expression of the mineralocorticoid receptor (MR) in the cardiovascular (CV) and renal
systems, including myocytes, endothelial cells, vascular smooth muscle cells, and kidney 
mesangial cells, provides further evidence for the role of aldosterone in CV and renal injury.
Blockade of the action of aldosterone and potentially other MR ligands such as cortisol has 
been demonstrated to be of benefit in HF (Pitt et al. 1999, Zannad et al. 2010). Results from a 
short-term Phase 2b study (ARTS-HF Study 14564) reported a trend towards improvement of 
mortality and CV morbidity with finerenone treatment in addition to standard therapy for HF 
(Filippatos et al. 2016); however, long-term conclusive outcome studies examining whether
MRAs can prevent CV events are still lacking in this patient population. Study 20103 will be 
the first study to address these questions in this population.
Objectives and Endpoints:
Objectives
Endpoints
Primary
1.
To demonstrate the 
superiority of finerenone to 
placebo in reducing the 
rate of the composite CV 
endpoint.
Composite primary endpoint:
Cardiovascular (CV) death and total (first and recurrent) heart 
failure (HF) events (hospitalizations for heart failure [HHF] or 
urgent HF visits) in HF patients (New York Heart Association 
[NYHA] class II–IV) and LVEF ≥40%.
Secondary
2.
To determine the 
superiority of finerenone to 
placebo for each 
secondary endpoint
3.
To assess the safety and 
tolerability of finerenone
Secondary endpoints:
Time to total (first and recurrent) HF events
Improvement in NYHA class from Baseline to Month 12
Change from baseline to Month 6, 9 and 12 in Total Symptom 
Score (TSS) of the KCCQ 
Time to first occurrence of composite renal endpoint: sustained 
decrease in estimated glomerular filtration rate (eGFR) ≥50% 
relative to baseline over at least 4 weeks, or sustained eGFR 
decline to <15 ml/min/1.73m2 or initiation of dialysis or renal 
transplantation.
Time to all-cause mortality


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Overall Design: Multicenter, randomized, double-blind, parallel-group, placebo-controlled
Intervention Model: Parallel-group assignment.
Primary Purpose:
Treatment.
Number of Arms:
2
Masking:

Sponsor

Participant 

Care provider 

Investigator 

Outcomes assessor 
Number of Participants: Approximately 6900 participants will be screened to achieve 
approximately 5500 randomly assigned to study intervention.
Intervention Groups and Duration:
Recruitment is expected to last for approximately 24 months. Randomization will take place 
within 2 weeks of screening. Eligible participants will be randomized in a 1:1 ratio to receive 
once daily (OD) treatment with finerenone or placebo. Planned treatment duration is 
approximately 18 to 42 months until expected events are reported. For participants still taking 
study intervention when the end of study is reached, the post-treatment follow-up period will 
last for 30 (+5) days and will end upon completion of the post-treatment (PT) phone call.
The starting dose will depend on the participant’s eGFR level at the Baseline Visit: 
participants with an eGFR ≤60 mL/min/1.73m² will start with 10 mg OD (dose level 1) and 
have a maximum maintenance dose of 20 mg OD (dose level 2), whereas participants with an 
eGFR >60 mL/min/1.73m² will start with 20 mg OD (dose level 2) and have a maximum 
maintenance dose of 40 mg OD (dose level 3). The minimum dose level is 10 mg for all 
participants. Medication intake is OD preferably in the morning.
Provided the participant’s safety is not affected, and if considered appropriate by the 
investigator, the participant should be up-titrated to the next higher dose level ideally after 
4 weeks of treatment, with the goal of keeping the participant on the maximum tolerated dose 
level for as long as possible. At any scheduled or unscheduled visit from Visit 2 (Month 1) 
onwards, up-titration to the next possible higher dose should be based on the level of 
serum/plasma potassium and eGFR. Participants will attend an additional safety visit 
4 weeks 7 days after each up-titration. Down-titration or interruption of study intervention is 
allowed at any time during the study for safety reasons.
Concomitant therapy is best medical care to treat comorbidities at the investigator’s discretion.
Data Monitoring Committee:
Yes.


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1.2
Schema


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1.3
Schedule of Activities (SoA)
The schedule of activities (SoA) is displayed for the study as a whole in Figure 1–1 (‘Main SoA’) and for participants who prematurely 
discontinue the study, minimal assessments will need to be performed as outlined in Figure 1–2 (‘Premature Discontinuation SoA’).
Figure 1–1
Main SoA
Visit Number / Name
Screening a Baseline a
1
2
3
4
5
6
7, 9, 11, 13, 15, 
17, 19, 21 etc.b
8, 12, 16, 20 
etc.
10, 14, 18 etc.
Up-titration,
re-start and
safety check c
PD
Visit d
EOS
Visit e
PT
Visit f
Day (D) / Month (M)
D1
M1
M3
M6
M9
M12
M14 and every 
4 months (i.e. M18, 
M22, M26, M30, 
M34, M38, M42 etc.)
M16 and every 
8 months 
(i.e. M24, M32, 
M40 etc.)
M20 and every 
8 months 
(i.e. M28, M36 
etc.)
Visit window (days)
-
±3 
±3
±6
±6
±6
±7
±7
±7
±7
+5
On-site (O)/Tel. contact ()
O
O
O
O
O
O
O

O
O
O
O
O

Initiation procedures
Informed consent 
X
Demographic data
X
Substance use (alcohol & tobacco)
X
Medical history
X
NYHA class assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
In- and exclusion criteria
X
X
Clinical procedures/ assessments
Weight 
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Waist and hip circumference
X
Vital signs g
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG (local)
X
AE and endpoint assessment 
(renal endpoints require additional 
confirmed creatinine measurement; 
see Table 6–3 for details)
X
X
X
X
X
X
X
X
X
X
X
X
X
Study intervention
Randomization (IxRS)
X
Dispense study intervention
X
X
X
X
X
X
X
X
X r


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Figure 1–1
Main SoA
Visit Number / Name
Screening a Baseline a
1
2
3
4
5
6
7, 9, 11, 13, 15, 
17, 19, 21 etc.b
8, 12, 16, 20 
etc.
10, 14, 18 etc.
Up-titration,
re-start and
safety check c
PD
Visit d
EOS
Visit e
PT
Visit f
Day (D) / Month (M)
D1
M1
M3
M6
M9
M12
M14 and every 
4 months (i.e. M18, 
M22, M26, M30, 
M34, M38, M42 etc.)
M16 and every 
8 months 
(i.e. M24, M32, 
M40 etc.)
M20 and every 
8 months 
(i.e. M28, M36 
etc.)
Visit window (days)
-
±3 
±3
±6
±6
±6
±7
±7
±7
±7
+5
On-site (O)/Tel. contact ()
O
O
O
O
O
O
O

O
O
O
O
O

Provide and review the study 
contact card
X
X
X
Administration of study 
intervention at study site
X
X
Administration of study 
intervention before the visit
X
X
X
X
X
X
Study intervention accountability
X
X
X
X
X
X
X
X
X
X
Local/central laboratory
Local laboratory h
   (potassium and creatinine i)
X j
X j, m
X k
X k
X k
X k
X k
X k
X k
X k
X k
X k
Pregnancy test
X L
X L, m
Central laboratory including 
urinalysis (see Table 10–1)
X m
X
X
X s
X
X
X
X
X
X
Biomarkers NT-proBNP and 
hs-TnT
X m
X
X
Exploratory biomarkers 
X m
X
X
X
Pharmacokinetics
X n
X o
X o
Other study procedures
KCCQ q
X
X
X
X
X
X
X
EQ-5D-5L q
X
X
X
X
X
X
X
PGIC (applicable to selected sites 
only) q
X
X
X
PGIS (applicable to selected sites 
only) q
X
X
X
X
Please note that footnotes to both SoAs can be found below Figure 1–2.


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Figure 1–2 Premature Discontinuation SoA
Visit Number / Name
Premature 
discontinuation p
2
3
4
5
6
7, 9, 11, 13, etc.b
8, 12, 16, 20 etc.
10, 14, 18 etc.
EOS 
Visit e
Day (D) / Month (M)
M1
M3
M6
M9
M12 M14 every 4 months
(i.e. M18, M22 etc.)
M16 every 8 months
(i.e. M24, M32, M40 etc.)
M20 every 8 months
(i.e. M28, M36 etc.)
Visit window (days)
±3 
±3
±6
±6
±6
±7
±7
±7
On-site (O)/Tel. contact ()

O
O

O

O
O
O
Central laboratory (eGFR)
X
X
X

X
X
X
Biomarkers NT-proBNP and hs-TnT
X
X

AE and endpoint assessment 
(renal endpoints require additional confirmed 
creatinine measurement; see Table 6–3 for 
details)
X
X
X
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
X
X
X
KCCQ q
X
X
X
X
EQ-5D-5L q
X
X
X
X
Please note: 

1 month corresponds to 30 days

Study visits should occur as close as possible to the specified time points in the protocol, but time windows are permitted as specified in the SoA

At any scheduled or unscheduled visit, the dose of study intervention may be increased to the next possible higher dose, based on serum/plasma potassium level 
analyzed in the local laboratory and provided the participant was already on a stable dose for 4 weeks 7 days.
Abbreviations: AE = adverse event; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; D = Day; eGFR = estimated glomerular filtration rate; ECG = 
electrocardiogram; EOS = end-of-study; EQ-5D-5L = EuroQoL Group 5-dimension 5-level questionnaire; hs-TnT = high-sensitivity troponin-t; IxRS = interactive voice / web 
response system; med. = medication; KCCQ = Kansas City Cardiomyopathy Questionnaire; M = Month; NT-proBNP = n-terminal prohormone B-type natriuretic peptide; NYHA =
New York Heart Association; O = on-site; PGIC = Patient Global Impression of Change; PGIS = PGI of Severity; PD = premature discontinuation; PT = post-treatment; 
SoA = schedule of activities; Tel. = telephone
a
Randomization has to occur within 2 weeks of the Screening Visit. If the Screening Visit and Visit 1 (Day 1, Baseline) are performed on the same day, procedures listed for 
both visits are to be performed only once.
b
Study visits to be conducted as a clinic visit or a telephone contact visit. These visits will alternate at 4-monthly intervals from Month 12 onwards with participant contact 
being made every 2 months.
c
This visit should be performed for safety check after any up-titration (4 weeks ±7days) and after restart of study intervention following an interruption for >7 consecutive 
days. A full unscheduled safety visit should be performed within an adequate timeframe proposed by the investigator after down-titration for reasons other than 
hyperkalaemia, otherwise only potassium is to be rechecked (refer to Table 6–1)


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d
The PD Visit should take place as soon as possible but within 7 days after the last intake of study intervention. If the PD Visit cannot be performed within the timeframe 
specified, no PD Visit is required. All randomized participants will be followed until the study ends, even if they did not take study intervention or permanently discontinued 
study intervention. 
e
After the study site is notified of end of study decision, an EOS Visit should be scheduled as soon as possible (but within 4 weeks at the latest).
f
For all participants still on treatment with study drug at the EOS Visit, the post-treatment (PT) telephone call () has to be performed 30 days +5 days after the last intake 
of study drug.
g
For vital sign collection, please adhere to instructions in Section 8.2.2.
h
If BNP, NT-proBNP values (related to inclusion criteria) are not available in medical records, use values assessed by local laboratory. 
i
Creatinine will be used to calculate eGFR using CKD-EPI (Horio et al. 2010, Levey et al. 2009)
j
If local laboratory data for potassium and eGFR are available within the last 24 hours, these may be used instead. This also applies when screening and baseline visits are 
not combined.
k
Study participants may have their local laboratory assessments taken up to 3 days prior to the study visit.
L
Female participants of childbearing potential must have a negative serum or urine pregnancy test at screening and baseline. Further serum or urine pregnancy tests should 
be performed in participants of childbearing potential as required by national/institutional regulations (e.g. at every visit). At any time during study participation, additional 
pregnancy testing should be performed upon suspicion of pregnancy.
m
All procedures at Visit 1 are to be performed prior to randomization.
n
One trough sample is to be collected at steady state before study intervention intake at Visit 3 (if not possible e.g. because study intervention was taken at home before the 
visit, the trough sample collection can be postponed to Visit 4 or 5); study intervention is to be administered at the study site at this visit.
o
Sample to be taken during the visit 1.5-10 hours after study intervention intake at home.
p
The procedures/assessments to be performed at the PD Visit are listed in the main SoA (Figure 1–1). After completing the PD Visit, all subsequent visits are to be 
performed according to the Premature Discontinuation SoA (Figure 1–2). Any visits performed prior to the PD Visit do not need to be repeated (e.g. if PD is at Visit 5, there 
is no need to repeat previous visits).
q
Questionnaires are to be completed by the participants before conducting any study procedure. See also Sections 8.1.1, 8.1.2 and 8.1.3 for details.
r
Only if applicable.
s
At Visit 4 an additional NT-proBNP measurement from serum will be performed.


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2. Introduction
Heart failure (HF) is usually a chronic progressive disease characterized by intermittent acute 
exacerbations. The underlying cause is usually a reduction in the ability of the heart to 
contract (systole) and/or fill (diastole) effectively.
HF is a leading cause of CV morbidity and mortality (Chen et al. 2011). Approximately 1-2% 
of the adult population in developed countries has HF, with the prevalence rising to ≥10% 
among persons 70 years of age or older (Mosterd and Hoes 2007). Projections in the US show 
that the prevalence of HF will increase by 46% from 2012 to 2030, resulting in >8 million 
people with HF (1 in every 33) in the US (Heidenreich et al. 2013). Similar results were found 
in selected western European countries (Danielsen et al. 2017).
Epidemiological studies have reported that about 50% of patients with HF have a relatively 
normal or slightly reduced left ventricular ejection fraction (LVEF), in the range of 40% and 
above, also referred to as HF with preserved ejection fraction (HFpEF) (Fonarow et al. 2007, 
Hogg et al. 2004, Owan et al. 2006, Swedberg et al. 1999, Yancy et al. 2006).
HFpEF is caused by a complex interplay of multiple impairments in ventricular diastolic and 
systolic reserve function, heart rate reserve and rhythm, atrial dysfunction, stiffening of the 
ventricles and vasculature, metabolic derangements, coronary microvascular dysfunction with 
impaired vasodilatation, pulmonary hypertension, endothelial dysfunction, and abnormalities 
in the periphery, including skeletal muscle (Borlaug 2014).
The ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure from 
2016 identified patients with LVEF that ranges from 40 to 49% as a separate group and 
introduced a new term ‘HF with mid-range ejection fraction (HFmrEF)’.
When compared with HFrEF patients, patients with HFpEF are predominantly elderly, 
more women are affected and occurrence of comorbidities such as arterial hypertension and 
atrial fibrillation are higher in the HFpEF population whereas the occurrence of coronary 
artery disease was less likely (Bhatia et al. 2006, Fonarow et al. 2007, Martinez-Selles et al. 
2012, Owan et al. 2006, Vaduganathan et al. 2016, Yancy et al. 2006).
As the population ages, the prevalence of diabetes mellitus, obesity and hypertension 
increases, the substrate for developing HF, in particular HFpEF, and its incidence will 
therefore increase dramatically in the coming decades (Owan et al. 2006). With the increased 
longevity in western societies, the enormous public-health problem of HFpEF will continue to 
grow. In this context, data from Get With The Guidelines–Heart Failure (GWTG-HF), a 
very large, nationwide study of HF hospitalization in the US (n >110,000) showed that the 
proportion of patients hospitalized with HF who had HFpEF increased from 33% in 2005 to 
39% in 2010. Within the same time interval, the proportion of HHF due to HFrEF decreased 
from 52% to 47% (Steinberg et al. 2012).
HHF strongly predicts a poor prognosis: in patients with HFpEF the rates of mortality and 
re-admission at 60 to 90 days after discharge are as high as 9.5% and 29.2%, respectively and 
comparable as to the rates in HFrEF, being 9.8% and 29.9%, respectively. In hospital 
mortality was lower in HFpEF patients although the difference was small (Fonarow et al. 
2007, Owan et al. 2006). HHF is the predominant cause of hospitalization in HFpEF patients 
representing a potential target in order to modify prognosis and quality of life.
To date, international guidelines acknowledge a lack of evidence in the management of 
HFpEF patients, as no treatment has yet been shown to reduce morbidity and mortality in 


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patients with HFpEF. Therefore, management is limited to guideline-based optimal treatment 
of comorbidities as arterial hypertension, coronary artery disease and atrial fibrillation; 
diuretics are recommended in order to alleviate congestion symptoms. According to the 
ESC guidelines, management recommendations for patients with HFmrEF are the same as to 
patients with HFpEF (Ponikowski et al. 2016, Yancy et al. 2006). The ACC/AHA focused 
update of the guidelines in 2017 has included a class IIb recommendation for the use of 
aldosterone receptor antagonist in patients with stage C heart failure and LVEF ≥45%,
elevated B-type natriuretic peptide (BNP) levels or HF admission within 1 year, 
eGFR >30 mL/min, creatinine <2.5 mg/dL, potassium <5.0 mEq/L (Yancy et al. 2017).
A series of studies in different CV cell types demonstrated that mineralocorticoid receptor 
(MR) ablation improves cardiac remodeling in experimental models of heart failure providing 
evidence that aldosterone directly mediates cardiac hypertrophy, fibrosis and inflammation via 
MR in the CV system (Fraccarollo et al. 2011, Lother and Hein 2016). In particular, MR in 
vascular cells appears to be crucially involved in the translation of CV risk factors such as 
obesity, diabetes mellitus or age into cardiac disease. Following the hypothesis that those risk 
factors are closely associated with vascular inflammation as a key driver for diastolic 
dysfunction, these findings suggest a potentially beneficial role for MR antagonists in HFpEF.
Spironolactone has been shown to reduce myocardial fibrosis/cardiac extracellular matrix and 
to improve arterial stiffness in animal models (Lacolley et al. 2001). In line with the data from 
pre-clinical studies, a meta-analysis of 11 randomized trials showed that administration of an
MR antagonist (MRA) was associated with an improvement in diastolic function assessed by 
echocardiography, as well as with a reduction in the concentration of circulating cardiac 
biomarkers reflecting the collagen turnover associated with myocardial fibrosis (Pandey et al. 
2015).
Since activation of the MR by aldosterone is known to promote arterial hypertension, 
endothelial dysfunction, left ventricular hypertrophy, and progressive vascular, renal, and 
myocardial fibrosis, all of which may contribute to the development of HFpEF, the Treatment 
of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial 
sought to test the value of spironolactone as a treatment for HFpEF (Desai et al. 2011). 
In this randomized, double-blind trial, 3445 patients with symptomatic heart failure and a left 
ventricular ejection fraction of 45% or more were assigned to receive either spironolactone 
(15 to 45 mg daily) or placebo. The randomization was stratified according to whether the 
patient met the criterion for previous HHF within the last 12 months or natriuretic peptide 
(NP) elevation within 60 days prior to randomization.
Treatment with spironolactone did not significantly reduce the primary composite endpoint 
which was death from CV causes, aborted cardiac arrest, or HHF (Pitt et al. 2014b).
However, there was a beneficial effect of spironolactone observed in the stratum of patients 
enrolled on the basis of elevated baseline B-type natriuretic peptide (BNP) or N-terminal pro-
B-type natriuretic peptide (NT-proBNP) levels. Furthermore, post hoc analysis revealed 
marked regional differences in incidence rates, baseline clinical profiles, adverse events, and 
compliance with study therapies. A ≈4-fold lower incidence rate in the composite endpoint 
was identified between the 1678 patients randomized from Russia and Republic of Georgia 
compared with the 1767 enrolled from the United States, Canada, Brazil, and Argentina (the 
Americas). Also, the proportion of patients enrolled on the basis of elevated natriuretic peptide
levels versus previous hospitalization for HF was higher in the Americas than in patients from 
Russia and Georgia. In the Americas region, spironolactone reduced the incidence of the 


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primary endpoint compared to placebo. In addition, treatment with spironolactone in patients 
being enrolled from the Americas was associated with more frequent hyperkalemia, elevations 
in creatinine, reductions in blood pressure, and less hypokalemia (Pfeffer et al. 2015).
Analysis of the TOPCAT results in the Americas led to the class IIb recommendation added in 
2017 to the ACC/AHA guidelines (Yancy et al. 2017) and gives reason to hope that targeting 
the MR could result in improved clinical outcome in patients with HFpEF. TOPCAT also 
prompted further investigation in 2 additional global Phase 3 randomized, open label clinical 
trials (ClinicalTrials.gov NCT02901184; EudraCT #2017-000697-11) with planned total 
enrollment of 4500 participants evaluating spironolactone in HFpEF.
Molecular pharmacological considerations suggest that the balance between the interstitial, 
anti-remodeling effects, and the renal epithelial, natriuretic, and antikaliuretic effects of 
MR blockade can be modulated by the molecular structure of the pharmacological agent 
(Kolkhof and Borden 2012). There are 3 currently marketed MRAs, spironolactone, 
canrenone, and eplerenone with a steroidal chemical structure, similar to the natural ligands of 
the MR, aldosterone, and cortisol. In addition, the non-steroidal MRA esaxerenone has been 
approved in Japan. The similar structural and physicochemical properties of the steroidal 
MRAs determine the resulting pharmacological action, not only by their mode of binding to 
the MR, but also by their transport and distribution into different tissues and recruitment or 
blockade of tissue selective and ligand-specific co-factors (Kolkhof and Borden 2012). 
Finerenone (BAY 94-8862) is an oral, selective and potent non-steroidal MRA of human MR 
in functional cellular transactivation assays combining in vitro spironolactone’s potency with 
eplerenone’s selectivity (Kolkhof and Borden 2012).
In animal models, finerenone reduced cardiac and renal hypertrophy, plasma prohormone of 
BNP and proteinuria more efficiently than in those treated with the steroidal MRA 
eplerenone, when comparing equi-natriuretic doses. Finerenone’s tissue distribution pattern in 
rats was found to differ from the steroidal MRAs, i.e. spironolactone and eplerenone, which 
showed a higher accumulation of the drug equivalent concentration in kidney than in heart 
tissue, in contrast to finerenone which was found to be equally distributed in both the kidney 
and heart tissue (Kolkhof et al. 2014). The steroidal MRA spironolactone is known to 
interfere with the steroid hormone receptor, which can cause sexual side effects such as 
gynecomastia in men. However, finerenone is a non-steroidal and selective MRA in vitro, 
without any detectable affinity for the related androgen receptor; sexual side effects are 
therefore not expected to occur with finerenone at therapeutic dose levels.
In the safety and tolerability Phase 2 ARTS study (Pitt et al. 2013) finerenone in daily doses 
ranging from 2.5 to 10 mg was tested in comparison to placebo and spironolactone (25-
50 mg) in patients with HFrEF and mild to moderate kidney disfunction. Results showed 
trends towards greater reduction in NT-proBNP levels with finerenone 10 mg compared with 
spironolactone, whereas increases in serum potassium were statistically significantly lower in 
finerenone arms compared to spironolactone. Moreover eGFR decline was smaller and 
incidence of worsening renal function was lower in all finerenone arms compared to 
spironolactone. Adverse events were reported in 79.4% of patients in the spironolactone arm 
and 53.1% in the highest dose finerenone arm which was comparable with the placebo group 
rates (50.8%).
In the dose finding Phase 2b ARTS-HF study in patients with worsening HFrEF and T2D 
and/or chronic kidney disease (CKD) (Filippatos et al. 2016) finerenone showed a decrease in 
NT-proBNP >30% in similar proportion of patients to that of eplerenone. However,


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finerenone starting at the dose of 5-15 mg OD was observed to reduce CV hospitalization and 
death from any cause to a greater extent compared to eplerenone, whereas the finerenone dose 
of 10-20 mg was associated with the lowest rates of the composite clinical endpoint. Rates of 
hyperkalaemia defined as potassium ≥5.6 mmol/L any time post baseline in the finerenone 
dose of 10-20 mg (3.6%) were comparable to those in the eplerenone arm (4.7%).
Details of the results of the clinical and non-clinical development studies conducted with 
finerenone can be found in the Investigator Brochure.
2.1
Study Rationale
Study 20103 will be the first large-scale, long-term outcome study investigating the efficacy 
and safety of the non-steroidal MRA finerenone on morbidity and mortality in participants 
with heart failure (NYHA II-IV) and LVEF ≥40%, in comparison to placebo and in addition 
to standard-of-care therapy for congestion and comorbidities. As there is currently no 
approved therapy for heart failure with mid-range on preserved ejection fraction, placebo 
treatment was selected as comparator for this trial. Secondary endpoints will include time to 
total HF events; improvement in NYHA class from baseline to Month 12; change from 
baseline to Month 6, 9 and 12 in TSS of the KCCQ; time to first occurrence of composite 
renal endpoint: sustained decrease in estimated glomerular filtration rate (eGFR) ≥50% 
relative to baseline over at least 4 weeks, or sustained eGFR decline to <15 ml/min/1.73m2 or 
initiation of dialysis or renal transplantation; time to all-cause mortality; and the safety and 
tolerability of finerenone.
An inappropriate release of aldosterone contributes to target organ damage found in heart 
failure, myocardial infarction, chronic renal failure, and hypertension. The extensive 
expression of the MR in the CV and renal systems, including the heart, endothelial cells, 
vascular smooth muscle cells, and kidney mesangial cells, provides further evidence for the 
role of aldosterone in CV and renal injury.
Blockade of the action of aldosterone and potentially other MR ligands such as cortisol has 
been demonstrated to be of benefit in HF. Results from a short-term Phase 2b study 
(ARTS-HF Study 14564) suggest that treatment with finerenone in addition to standard 
therapy for HF improves mortality and CV morbidity outcomes; however, long-term 
conclusive outcome studies examining whether non-steroidal MRAs can prevent CV events 
are still lacking. Study 20103 will be the first study to address these questions in this 
population.
Finerenone also has the potential to address the unmet medical need in patients with type 2 
diabetes (T2D) and clinical diagnosis of CKD. The Phase 3 program with finerenone in 
patients with T2D and clinical diagnosis of CKD encompasses 2 placebo-controlled, 
large-scale, long-term outcome trials: Study 16244 examines whether finerenone can slow the 
progression of kidney disease and Study 17530 which is examining the effects of finerenone 
on CV outcomes. Both Phase 3 studies have enrolled over 13,000 participants since 2015 and 
are ongoing at the time of writing this protocol.


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2.2
Background
Patients with HF exhibit an over activation of the renin-angiotensin-aldosterone system
(RAAS) and the inappropriate release of aldosterone contributes to target organ damage, 
myocardial infarction, chronic renal failure, and hypertension. The extensive expression of the 
MR in the CV and renal systems, including myocytes, endothelial cells, vascular smooth 
muscle cells, and kidney mesangial cells, provides further evidence for the role of aldosterone 
in CV and renal injury.
Blockade of the action of aldosterone and potentially other MR ligands such as cortisol has 
been demonstrated to be of benefit in HF. Finerenone is a highly selective and potent 
non-steroidal mineralocorticoid receptor antagonist in development for treatment of chronic 
kidney disease in T2D patients as well as in HF.
A detailed description of the chemistry, pharmacology, efficacy, and safety of finerenone is 
provided in the Investigator’s Brochure.
2.3
Benefit/Risk Assessment
In this study participants with heart failure (NYHA class II-IV) after recent HF 
decompensation and/or with elevated natriuretic peptides (BNP or NT-proBNP), will be given 
oral doses of finerenone once daily 10, 20 and 40 mg, depending on baseline eGFR,
or placebo, in addition to standard-of-care therapies for congestion and comorbidities 
(i.e. RAAS inhibitors, beta-blockers, diuretics).
The eligibility criteria for this study 20103 have been chosen to adequately define a study 
population at high risk for worsening heart failure events, while excluding participants who 
may potentially be exposed to particular risks after study intervention administration or might 
benefit for intervention not included in the trial (i.e. amyloidosis, planned heart surgery).
Due to finerenone’s mode of action, hyperkalemia is an important identified risk. However, in 
ARTS-HF (study 14564) the incidence of hyperkalemia was comparable between finerenone 
and eplerenone; and in ARTS (study 14563), all doses of finerenone resulted in 
significantly smaller serum potassium increase compared with spironolactone.
Worsening of renal function has been shown to occur with the steroidal MRAs, 
i.e. spironolactone and eplerenone (Rossignol et al. 2012). However, acute reductions in
eGFR within the first 3 months upon starting RAAS blocking agents i.e. angiotensin-
converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) or MRAs, in 
patients with CHF and/or CKD (Bakris and Weir 2000, Holtkamp et al. 2011) are postulated 
to reflect a hemodynamic response leading to reduced intraglomerular pressure, rather than 
therapy-induced damage to functioning nephrons (i.e. worsening of renal function). These 
changes are typically reversible on treatment withdrawal, and are associated with an 
attenuation of the long-term decline in eGFR (Heerspink et al. 2011).
In ARTS-HF (study 14564), the incidence of a relative decrease in eGFR of ≥30% from 
baseline was comparable between most of the finerenone dose groups (finerenone 2.5-5 mg 
n=8/119 (6.7%), finerenone 5-10 mg n=9/118 (7.6%), 7.5-15 mg n= 6/119 (5%), finerenone 
10-20 mg n=7/130 (5.4%) and finerenone 15-20 mg n=15/120 (12.5%) except 15-20 mg OD) 
and the eplerenone (n=13/143 (9.1%) group (Filippatos et al. 2016) in supplementary material 
Table 10. In ARTS (study 14563), all doses of finerenone resulted in smaller eGFR 
decreases compared with spironolactone.


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Potassium level and renal function will be closely monitored during treatment in this study
(20103). In addition, patients will be included in this study only if serum/plasma potassium is 
≤5.0 mmol/L. To minimize safety risks to the patient, starting doses of study medication will 
be chosen according to baseline renal function, and subsequent dose up-titration will be 
performed on the basis of measured potassium and eGFR values. Stopping rules for temporary 
and permanent discontinuation or dose reduction of study intervention based on potassium 
values will minimize the risk of hyperkalemia. At any time during the study, the investigator 
has the option to also down-titrate the study intervention, depending on serum potassium.
The high risk for CV mortality and morbidity in the population of this study (20103), taken 
together with the improved clinical outcomes seen with finerenone 10-20 mg OD compared 
with eplerenone in ARTS-HF (study 14564), indicate a positive risk-benefit assessment 
supporting the participation of participants in this study.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of finerenone may be found in the current Investigator’s 
Brochure.


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3. Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate the superiority 
of finerenone to placebo in 
reducing the rate of the 
composite CV endpoint.
Composite primary endpoint:
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%.
Secondary
To determine superiority of 
finerenone to placebo for each 
secondary endpoint
To assess the safety and 
tolerability of finerenone
Secondary endpoints:
Time to total (first and recurrent) HF events
Improvement in NYHA class from Baseline to Month 12
Change from baseline to Month 6, 9 and 12 in Total 
Symptom Score (TSS) of the KCCQ 
Time to first occurrence of composite renal endpoint: 
sustained decrease in estimated glomerular filtration rate 
(eGFR) ≥50% relative to baseline over at least 4 weeks, or
sustained eGFR decline to <15 ml/min/1.73m2 or initiation 
of dialysis or renal transplantation.
Time to all-cause mortality
Exploratory
Exploratory endpoints:
Time to first CV hospitalization
Time to first all-cause hospitalization
Total number of CV hospitalizations
Total number of all-cause hospitalizations
Time to first occurrence of the following composite 
endpoint: CV death or non-fatal CV event (i.e. non-fatal 
myocardial infarction, non-fatal stroke, or HHF)
Time to first occurrence of the following composite 
endpoint: sustained decrease in eGFR ≥57% relative to 
baseline over at least 4 weeks, or sustained eGFR decline 
<15 ml/min/1.73m2 or initiation of dialysis or renal 
transplantation
Change in eGFR from baseline
Mean rate of change in eGFR as measured by total eGFR 
slope and its subcomponents acute and chronic slope
Change in UACR from baseline
Days alive and out of hospital
Time to new onset of atrial fibrillation
Change in health-related quality of life summary scores 
from baseline measured by the KCCQ and EQ-5D-5L
An urgent HF visit is defined as an urgent, unscheduled presentation with signs and/or 
symptoms of an acute HF decompensation requiring prompt medical attention and 
intensification of the existing HF treatment or initiation of a new HF treatment (Hicks et al. 
2018). Further details and definitions will be provided in the Outcome/Endpoint Manual and
Clinical Event Committee (CEC) Charter.


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According to the addendum to International Council on Harmonisation (ICH) E9 (ICH_E9 
(R1) 2019), the 5 attributes of the primary estimand are as follows:
a) Population:
As described by inclusion/exclusion criteria given in Section 5
b) Variable:
Number of unfavorable events including CV death and total (first and recurrent) HHF
c) Treatment condition:
Finerenone vs. placebo
d) Intercurrent events: 
There are 3 important intercurrent events to consider: treatment discontinuation, CV 
death and non-CV death. For treatment discontinuation, a treatment policy strategy 
will be applied, i.e. patients will be followed up for events after discontinuing 
treatment and events and follow-up time after discontinuation of treatment will be 
included in the analysis. CV death will be counted as both an outcome event as well as 
a censoring event, so that a combination of a composite and a while-alive strategy is 
used. Non-CV death is assumed to be a censoring event, since the treatment is not 
assumed to have an effect on these events and interest lies in the treatment effect on 
composite events while patients are alive
e) Population-level summary:
Ratio of exposure-weighted composite event rates between finerenone and placebo. 
Exposure-weighted refers to patients being weighted according to their follow-up time 
in determining the rate.
4. Study Design
4.1
Overall Design
Study 20103 is a randomized, double-blind, parallel-group, placebo-controlled, multicenter, 
event-driven Phase 3 study with independently adjudicated clinical outcome assessments. 
The overall study design is displayed as the schema in Section 1.2.
This study will be conducted in patients with HF and LVEF ≥40%.
Participants will be randomized in a 1:1 ratio to either finerenone or placebo. The study is 
designed to be able to show an effect on the primary endpoint with a power of 90% at an 
alpha level of 5%. It is anticipated that 5500 participants will be randomized and 
approximately 6900 will be screened (screening failure rate of approximately 20%). A total of 
approximately 2375 total (first and recurrent) primary composite events are targeted. 
The anticipated duration of the study will be approximately 42 months, with a recruitment period 
of 24 months. However, as an event-driven study, the actual length of the study will depend on the 
observed event rates, the participant recruitment rate, and the length of the recruitment period. 
Enrolment in the trial may be capped based on the proportion of patients in certain LVEF 
categories, in each NYHA class, with/without atrial fibrillation, and by geographic region, 
among other variables, to ensure recruitment of a representative study population.
The randomization will be stratified by country/region and LVEF (<60%, ≥60%). Additional 
details will be described in the Statistical Analysis Plan (SAP).


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Data from this study will be reviewed for efficacy and safety on an ongoing basis by an 
independent Data Monitoring Committee (DMC). A detailed plan for these assessments will 
be provided in the DMC Charter.
A CEC blinded to study treatment assignment will adjudicate all events that could potentially 
fulfill the criteria for the primary and some of the secondary endpoints during the study. 
The CEC Charter will describe the roles and responsibilities of the CEC and define the events to 
be adjudicated and the manner in which they will be adjudicated. 
The SoA in Section 1.3 summarizes the schedule of procedures.
This study will be event-driven, and all randomized participants will remain in the study until 
either (1) an instruction is received from the sponsor after the targeted number of primary 
efficacy events has occurred, or (2) the study is terminated early at the recommendation of the 
DMC. Therefore, all participants, including those who have stopped taking study intervention, 
should be asked to attend all the protocol-specified study visits in order to perform all 
assessments as stipulated in the main SoA (Figure 1–1); for participants who permanently 
discontinued study intervention, minimal assessments (e.g. central lab for eGFR) will need to 
be performed as outlined in the Premature Discontinuation SoA (Figure 1–2). If a participant 
is unable to attend a study visit, every effort should be made to contact the participant by 
telephone or other means (by checking medical and public records) to determine if any 
endpoints were reached at the time the study visits were scheduled for the remaining duration 
of the study. All attempts to retrieve information about the participant should be documented 
in the participant’s records.
Screening
After providing written informed consent, a Screening Visit to confirm the participant’s 
eligibility will take place prior to randomization. The Screening Visit may take place on the 
same day as randomization (Visit 1). Local laboratories will be used to perform the eligibility
assessments (potassium, creatinine/calculated eGFR). NT-proBNP or BNP levels will be 
evaluated as per medical records or collected locally to check eligibility. Please note the
2 distinct thresholds for NT-proBNP or BNP regarding eligibility (see inclusion criterion 6 in 
Section 5.1).
The higher threshold for NT-proBNP or BNP should be used for patients with prior history of 
atrial fibrillation or in case the cardiac rhythm is unknown. If a participant is hospitalized for 
HF, screening procedures and Visit 1 can take place while the participant is still in the hospital. 
Treatment Period
Following a screening period of up to 2 weeks, eligible participants will be randomized in a 
1:1 ratio to either finerenone or placebo. Participants with an eGFR ≤60 mL/min/1.73 m² 
measured at baseline will start with 10 mg OD (dose level 1) with a maximum maintenance 
dose of 20 mg OD (dose level 2), whereas participants with an eGFR >60 mL/min/1.73 m² 
measured at baseline will start with 20 mg OD (dose level 2) with a maximum maintenance 
dose of 40 mg OD (dose level 3).
There will be at least 2 scheduled visits within the first 3 months from randomization, 
Visit 2 will take place after 1 month and Visit 3 will take place 3 months after randomization; 
thereafter, scheduled visits will occur every 3 months until Visit 6 at Month 12. After 1 year
from randomization, telephone contact visits will take place at Month 14 and from then 
onwards every 4 months (i.e. 18 months, 22 months onwards) alternating with on-site visits 
(i.e. 16 months, 20 months, onwards) until the end of the study is reached.


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Up-titration is expected to occur after 4 weeks 7 days of treatment at Visit 2 (Month 1). 
Ideally, each participant will be on the maximum maintenance dose at this point. In the case of 
elevated potassium values, participants will be down-titrated to the next lower dose. 
Down-titrations can be performed at any time after the start of study intervention treatment, at 
any scheduled or unscheduled visit. At any scheduled or unscheduled visit, the dose of study 
intervention may be increased to the next possible higher dose, based on serum/plasma 
potassium level and provided the participant was already on a stable dose for 4 weeks 7 days.
Participants will attend an additional unscheduled safety visit 4 weeks 7 days after each 
up-titration; potassium levels and renal function will be monitored at this safety visit. 
In addition to the protocol-specified visits, participants may be seen at any time throughout 
the study at the discretion of the investigator.
If, in the opinion of the investigator, the participant cannot tolerate the maximum dose level of 
study intervention, the study intervention dose may be reduced to the next lower dose level. 
Provided the participant’s safety is not affected, and if considered appropriate by the 
investigator, the participant should be re-up-titrated to the next higher dose level as soon as 
possible, preferably within 4 weeks, with the goal of keeping the participant on the maximum 
tolerated dose level for as long as possible. If the study intervention is temporarily interrupted, 
it should be re-introduced as soon as medically acceptable in the opinion of the investigator 
without compromising the participant’s safety. See also Sections 6.1 and 7.1.1 for details.
Changes in the study intervention dose, including interruption/premature discontinuation or 
restart of study intervention, must be recorded in the electronic case report form (eCRF).
It is planned that all randomized participants will remain in the study until either:
a.
an instruction is received from the sponsor after the targeted number of 
primary endpoint events have occurred
or
b. the study is terminated early at the recommendation of the independent DMC.
After randomization, study intervention discontinuation does not constitute the participant’s 
withdrawal from the study, and all participants should continue to be followed up according to 
the Premature Discontinuation SoA (Figure 1–2). 
All randomized participants, including any participant who experiences an event 
considered for the pre-specified primary or secondary endpoints, should continue to receive 
double-blinded treatment until the study is completed, provided there are no safety grounds 
for discontinuing treatment.
Post-treatment Follow-up Period
The period between a participant’s last intake of study intervention and last visit in the study 
is referred to as the ‘post-treatment follow-up period’.
In the event of premature discontinuation of study intervention, participants are expected to 
continue to attend all protocol-specified study visits, and are expected to perform all 
scheduled assessments as described in the Premature Discontinuation SoA (Figure 1–2).
Any participant still taking study intervention at the point of end of study will enter the 
post-treatment follow-up period after stopping study intervention at the EOS Visit. 
For these participants, this phase will last 30 +5 days, and will end upon completion of the 
PT Visit (a telephone call visit; see Figure 1–1).


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4.2
Scientific Rationale for Study Design
The inclusion and exclusion criteria allow the selection of an appropriate participant
population and increase the likelihood of producing reliable and reproducible results, while 
guarding against exploitation of vulnerable persons. The proposed criteria are based on 
existing clinical knowledge and feedback from key opinion leaders involved in treatment of
HF (NYHA II-IV).
4.3
Justification for Dose
Finerenone has been investigated with respect to safety, tolerability, pharmacodynamics and 
pharmacokinetics (PK) in 29 Phase 1 clinical pharmacology studies. PK were also investigated 
in all five Phase 2 studies for finerenone (CHF and CKD) with a total of 2017 patients. 
The dose regimen of finerenone has been selected based on the results of the completed 
Phase 2b ARTS-HF and ARTS-DN studies.
The proposed doses for this Phase 3 study are as follows:

For participants with an eGFR ≤60 mL/min/1.73 m2 at baseline, the starting dose is 
10 mg OD. From Visit 2 (Month 1) onwards and if potassium <5.0 mmol/l and 
eGFR decrease is <30%, the starting dose can be up-titrated to 20 mg OD
and

For participants with an eGFR >60 mL/min/1.73 m2 at baseline, the starting dose is 
20 mg OD. From Visit 2 (Month 1) onwards and if potassium is <5.0 mmol/l and 
eGFR decrease is <30%, the starting dose can be up-titrated to 40 mg OD.
Note: eGFR according to local laboratory values.
The following rationale for extrapolation to patients with LVEF ≥40% of this dose regimen
is based on the expected safety profile of finerenone and the applicability of the 
exposure/response model founded on ARTS-HF data.
In the RALES study, the effect of spironolactone versus placebo on the outcome of patients 
with HFrEF was investigated and in the TOPCAT trial, HFpEF patients were treated either 
with spironolactone or placebo. In both studies, changes of serum potassium under 
spironolactone seem to occur in a similar time-dependent manner in HFpEF and HFrEF 
patients (Pfeffer et al. 2015). 
In addition, the dose-response relationship is comparable in these two HF populations with 
potassium increases by 0.37 mmol/L after 3 months of treatment with spironolactone 25 mg in 
RALES and 0.3 mmol/L after 8 months of treatment with spironolactone in an average dose 
of 21.7 mg in TOPCAT.
Regarding effects on renal parameters, the dose-response relationship for spironolactone seen 
in the TOPCAT trial in HFpEF patients and the RALES trial in HFrEF patients was similar 
indicating that differences in LVEF are not expected to have clinically relevant influence on 
eGFR changes from baseline (serum creatinine change of 0.16 mg/dL after 8 months for 
average dose of 21.7 mg in TOPCAT and of 0.10 mg/dL after 3 months for 25 mg 
spironolactone in RALES). 
Overall, the exposure/response relationship for both parameters in HFrEF patients is 
considered to be applicable for extrapolation to HFpEF patients under the assumption that 
baseline characteristics with regards to factors influencing PK such as body weight, and 


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baseline eGFR and baseline potassium levels are similar to that in the ARTS-HF study 
population. Under these conditions, the expected change of serum potassium is 0.1, 0.2 and 
0.2 mmol/L and the expected relative eGFR change from baseline is 2.4, 3.1 and 3.8% for 
10, 20 and 40 mg finerenone respectively in the total HF population. These ranges are 
expected to already represent the worst-case scenario since approximately 79% of the 
ARTS-HF populations are patients with eGFR ≤60 mL/min/1.73 m2.
Rationale for finerenone 10 mg OD as minimal dose:
10 mg OD will be the minimal dose for the overall population. Up-titration will occur based 
on potassium and eGFR values and the investigator will have the option to down-titrate this
finerenone dose based on its tolerability in terms of potassium values. This 2-step up-titration 
is consistent with current clinical practice to initiate treatment at a low dose, and to up-titrate 
the drug only if tolerated in order to avoid adverse effects on potassium and renal parameters.
In ARTS-HF, the 10-20 mg OD finerenone group compared to eplerenone showed a 
meaningful reduction in the exploratory composite endpoint comprising death from any cause, 
CV death, time to first CV hospitalizations and emergency presentation for worsening HF. 
Finerenone 10-20 mg OD showed a similar safety profile as to that of eplerenone with a 
lower incidence of treatment-emergent adverse events and similar rate of hyperkalemia 
(K+ ≥5.6 mmol/L) (Filippatos et al. 2016).
In ARTS-DN, significant reductions in UACR at Day 90 compared to baseline were observed 
for 7.5 mg, 10 mg and 20 mg OD finerenone compared to placebo (Bakris et al. 2015). For the 
10 and 20 mg doses, albuminuria had not returned to values similar to those at baseline 
30 days after completion of treatment with finerenone suggesting a potential long-lasting 
effect of finerenone in structural changes in the kidney.
Rationale for finerenone 20 mg OD as maximal maintenance dose in patients with 
eGFR ≤60 mL/min/1.73 m2:
A retrospective analysis of a national cohort (Einhorn et al. 2009) comprising 2,103,422 
records from 245,808 veterans with at least 1 hospitalization and at least 1 inpatient or 
outpatient serum potassium record during the fiscal year 2005 showed that CKD and 
treatment with blockers of RAAS were the key predictors of hyperkalemia. The risk of 
hyperkalemia is increased with CKD, and its occurrence increases the odds of mortality 
within 1 day of the event.
Furthermore, patients with an age of 65 years or more with comorbid illness have the highest 
mortality when potassium levels rises above 5 mmol/L (Pitt et al. 2014a).
It was demonstrated in a subgroup analysis of the finerenone ARTS-HF study that 
potassium levels >6 mmol/L and eGFR decrease >40% were mainly found in the subgroup 
with eGFR ≤60 mL/min/1.73m2 and UACR >300 mg/g (71% of the total population). Based 
on this data that showed an increase of finerenone concentrations in patients with impaired 
renal function associated with an increased risk of hyperkalaemia and eGFR reduction, it was 
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Rationale for finerenone 40 mg OD as maximal maintenance dose in patients with 
eGFR > 60 mL/min/1.73 m2:
NT-proBNP seems to be predictive for clinical outcome for both HFpEF and HFrEF patients. 
The prognosis of a patient depends on the NT-proBNP level and is similar in both HF 
populations (Kang et al. 2015). However, the responsiveness of this biomarker to MRAs 
seems to differ in patients with HFrEF and HFpEF. NT-proBNP was significantly reduced 
compared to baseline in the eplerenone arm of the EPHESUS study in HFrEF patients
(Zannad et al. 2011) and in the ARTS-HF finerenone study (Filippatos et al. 2016). However, 
the initially observed difference to the placebo arm after 14 months vanished after 26 months 
in the RAAM-pEF study in HFpEF patients (Deswal et al. 2011). Spironolactone treatment 
was also found to decrease serum NT-proBNP levels in HFrEF patients (Ozkara et al. 2007), 
(Pitt et al. 2013). In the TOPCAT trial in HFpEF patients, however, hazard ratios for 
NT-proBNP terciles were reported to be all >1 indicating that spironolactone did not lead to a 
significant NT-proBNP change compared to placebo. Furthermore, a meta-analysis assessing 
MRA treatment in HFpEF patients showed that no reduction of BNP or NT-proBNP was 
observable in overall 5 studies (Chen et al. 2015). The only trial reporting significant changes 
in NT-proBNP in HFpEF patients was the ALDO-DHF study with a relatively stable HF 
population having only few comorbidities due to the study design (Edelmann et al. 2012).
Dose-response relationships for NT-proBNP for either spironolactone or eplerenone in 
HFpEF and HFrEF patients have not been reported so far, which makes it difficult to assess 
whether or not it is possible to bridge exposure/response models for NT-proBNP between 
these populations. 
There are uncertainties associated with the responsiveness of NT-proBNP to MRAs. No 
quantitative prediction as to the changes of NT-proBNP for different finerenone doses were
performed with an exposure/response model built on ARTS-HF data for finerenone in HFrEF 
patients. However, from a qualitative perspective, a linear exposure response from 2.5 mg up 
to 20 mg has been observed in the ARTS-HF trial indicating that NT-proBNP response was 
not saturated at 20 mg. This would suggest the possibility of greater effects on NT-proBNP at 
doses higher than 20 mg.
40 mg OD is the maximum maintenance dose of finerenone in patients with eGFR 
>60 mL/min/1.73 m2. When the expected systemic finerenone exposure in these patients with 
mild renal impairment or normal renal function is compared with observed data in patients 
with moderate renal impairment receiving finerenone 20 mg in ARTS-HF, largely 
overlapping exposures are noted due to the effect of moderate renal impairment on area-under 
the curve (AUC; about 50% increase). These considerations on exposure in patients receiving 
40 mg are complemented by exposure/response (PK/pharmacodynamics) analyses and 
simulations based on data from ARTS-HF. Changes in serum potassium and eGFR from 
baseline following administration of finerenone 40 mg to patients with normal renal function 
or mild renal impairment were also estimated to largely overlap with changes following 
administration of finerenone 20 mg to patients with moderate renal impairment. Generally, the 
drug effect on serum potassium and eGFR is estimated to be rather small even for 40 mg, 
compared to the impact of baseline values of the respective parameters. Based on model 
simulations, the expected change in steady-state serum potassium and eGFR following 
administration of finerenone 10, 20 and 40 mg OD to the HF population is an increase by 
0.1, 0.2 and 0.2 mmol/L and a decrease by 2.4, 3.1 and 3.8%, respectively. 


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The safety of the 40 mg dose in patients with an eGFR >60 mL/min/1.73 m2 will also be 
ensured by the starting dose of 20 mg with escalation to 40 mg only after measuring 
serum potassium and eGFR levels, and the possibility of down-titration. 
Moreover, doses of 40 mg and higher have previously been found to be safe and well tolerated 
in the Phase 1 program in healthy volunteers, where 80 mg was the highest investigated single 
dose and 40 mg OD was the highest studied multiple dose regimen. Finerenone PK were 
linear across the investigated dose range.
In light of the aforementioned aspects, in particular with no reliable surrogate parameter and 
no additional information beyond the results from ARTS-HF and ARTS-DN to be expected, a 
specific dose-finding study in patients with HFpEF was not considered necessary.
Details of the results of the clinical and non-clinical development studies conducted with 
finerenone can be found in the Investigator Brochure.
4.4
End of Study Definition
The end of study treatment period will be announced when the targeted number of 
primary endpoint events has occurred, unless the study is terminated early because of a 
recommendation of the DMC. 
After notification of study end, an EOS Visit should be scheduled as soon as possible (but within 
4 weeks at the latest) for all participants still participating in the study, to determine whether the 
participant had an event for inclusion in the primary or secondary endpoints.
The date on which the final participant performed the EOS visit is defined as the primary 
completion date (see schema in Section 1.2).
Participants still on treatment will stop study intervention treatment at the EOS Visit and must 
perform the PT Visit 30 +5 days after their last dose of study intervention.
Participants no longer taking study intervention must also be contacted as soon as possible 
after issue of the notification of end of study and be asked to attend the EOS Visit. 
For participants who have objected to releasing further information after withdrawing from 
the study, an updated vital status should be obtained by the investigator from publicly 
available data sources, wherever allowed by local regulations. The collection of vital status 
must be obtained within the timelines provided by the sponsor at this time.
The end of the trial as a whole is defined as the date of the last PT Visit of the last participant 
in the trial globally.


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5. Study Population
Patients with a diagnosis of HF, NYHA class II–IV, and documented LVEF of 40%.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1.
Participant must be aged 40 years and older, at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics:
2.
Diagnosis of heart failure with NYHA class II–IV, ambulatory or hospitalized 
primarily for heart failure (if a hospitalized patient cannot be randomized as an 
in-patient, randomization as soon as possible after discharge is encouraged)
3.
On diuretic treatment for at least 30 days prior to randomization
4.
Documented LVEF of ≥40% measured by any modality within the last 12 months, at 
the latest at screening; if several values are available, the most recent one shall be 
reported. If LVEF was not measured in the past 12 months, a new measurement may 
be done at screening
5.
Structural heart abnormalities based on any local imaging measurement within the last 
12 months, latest at screening, defined by at least 1 of the following findings:
o
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 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; see Section 4.1) for 
participants 1 obtained at the following time:
o
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
o
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.
                                                
1
If a participant is being treated with Entresto (sacubitril/valsartan), the NT-proBNP value only (not BNP) 
should be used.


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Sex
7.
Male or female.
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.
Informed Consent
8.
Capable of giving signed informed consent as described in Section 10.1.3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
eGFR <25 mL/min/1.73 m² at either screening or randomization visit. 
NOTE: one reassessment of eGFR is allowed at the screening and randomization visit, 
respectively
2.
Serum/plasma potassium >5.0 mmol/L at either screening or randomization visit. 
NOTE: one reassessment of potassium is allowed at the screening and randomization visit,
respectively
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

Body mass index (BMI) >50 kg/m2 at screening
9.
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 
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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.
* 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.
Prior/Concomitant Therapy
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 cytochrome P450 isoenzyme 3A4 (CYP3A4) 
inhibitors (e.g. itraconazole, ritonavir, indinavir, cobicistat, clarithromycin) or 


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moderate or potent CYP3A4 inducers, that cannot be discontinued 7 days prior to 
randomization and for the duration of the treatment period.
Other Exclusions
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)
29. Known current alcohol and/or illicit drug abuse that may interfere with the 
participant’s safety and/or compliance at the discretion of the investigator
30. Participant is in custody by order of an authority or a court of law.
5.3
Lifestyle Considerations
No restrictions during the study are required other than those specified in ‘Other Exclusions’.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details (including reason), and eligibility criteria.
If a participant is not eligible during the Screening period for this study (20103), the 
participant may be rescreened once at a later time, provided the investigator believes that a 
change in the participant’s condition makes him/her potentially eligible.
If a participant was eligible but could not be randomized due to exceptional logistical reasons 
(e.g. pandemic-related disruption), the participant may be re-screened once.
The following conditions are pre-requisites of re-screening:
1. Before re-screening, new written informed consent must be obtained
2. Allocation of a new participant number 
3. All assessments for the study must be repeated
4. At least 3 months between initial screening and rescreening (except in the event of a 
participant being re-screened for exceptional logistical reasons).


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6. Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
The IxRS will determine the medication numbers for the study site investigator or designee to 
select for the participant.
Eligible participants will receive study intervention at the doses illustrated in Table 6–1, 
dispensed as outlined in the SoA (Section 1.3). The dose of finerenone will depend on the 
eGFR value at the Baseline Visit (determined by the local laboratory): 
1. Participants with an eGFR ≤60 mL/min/1.73m² will start with 10 mg (dose level 1) and 
have a maintenance dose of 20 mg (dose level 2). Dose level 1 is the minimum dose and 
dose level 2 is the maximum permitted dose in this group of patients
2. Participants with an eGFR >60 mL/min/1.73m² will start with 20 mg (dose level 2) and 
have a maintenance dose of 40 mg (dose level 3). Dose level 1 is the minimum dose and 
dose level 3 is the maximum permitted dose in this group of patients.
The investigator is encouraged to up-titrate the dose of study intervention once the participant 
has been on a stable dose for 4 weeks (±7 days), either at the next regular visit or at an 
Up-titration Visit (see Table 6–1). Participants who do not tolerate their starting dose of 
20 mg may be down-titrated at any point during the study, including between-scheduled visits 
if required for safety reasons. These participants may be up-titrated again based on the rules 
provided in Table 6–1. If the participant is already at the minimum dose, the study 
intervention can be interrupted at the investigator’s discretion as detailed in Section 6.6, based 
on blood potassium levels and renal function which will be monitored throughout the study.
Intake of study intervention
Participants will be instructed to take one tablet of study intervention, preferably in the 
morning, at approximately the same time each day. The study intervention should be taken 
with a glass of water, with or without food. 
Note: On the day of the first PK visit (Month 3) the participant should be instructed not to 
take the tablet at home in the morning but to have the PK sample collected first and then to 
take the study intervention at the study site.


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Table 6–1
Dosage of Study Intervention for Administration
eGFR value at the Baseline Visit, 
based on local laboratory results: eGFR 25 to ≤60 mL/min/1.73m²
eGFR >60 mL/min/1.73m²
Participant randomized to group:
Finerenone
Placebo
Finerenone
Placebo
Starting dose:
10 mg finerenone OD
(Dose Level 1)
Placebo OD
20 mg finerenone OD
(Dose Level 2)
Placebo OD
Maintenance dose:
20 mg finerenone OD
(Dose Level 2)
Placebo OD
40 mg finerenone OD
(Dose Level 3)
Placebo OD
Minimum dose after down-titration:
10 mg finerenone OD
Placebo OD
10 mg finerenone OD
Placebo OD
Maximum dose after up-titration:
20 mg finerenone OD
Placebo OD
40 mg finerenone OD
Placebo OD
Study intervention intake
One tablet of study intervention OD,
preferably in the morning at approximately the same time each day.
Note: Study intervention will be administered at home, except on the 
day of the first PK visit when the tablet will be taken at the study site
Missed intake
If discovered within 16 hours after the scheduled time, the participant 
should take one tablet of study intervention as soon as possible
If discovered >16 hours after the scheduled time, this will be 
considered to be a ‘missed’ dose and the participant should wait and 
take the next tablet of study intervention at the usual (scheduled) 
time.
Up-titration of dose
From Visit 2 (Month 1) onwards, 
at any scheduled or unscheduled 
visit
Follow guidance in Table 6–2 and 
Table 6–3
Perform an additional safety visit 
4 weeks 7 days after each titration; 
monitor* potassium and renal function
Must be documented in the eCRF
Finerenone

Up-titrate study intervention to the next possible higher dose based 
on serum/plasma potassium level

eGFR decrease is <30% compared to last scheduled visit.
Placebo

Sham-titrate.
Down-titration of dose
At any scheduled or unscheduled 
visit
Follow guidance in Table 6–2 and 
Table 6–3
Perform an unscheduled safety visit 
within an adequate timeframe 
proposed by the investigator for 
reason other than hyperkalaemia;
monitor* potassium and renal 
function
Must be documented in the eCRF

If potassium ≥5.5, down-titrate to the next lower dose level in a 
step-wise manner (dose level 2 to 1, or dose level 3 to 2) 

If at dose level 1, interrupt study intervention treatment;
study intervention should be re-introduced at dose level 1 as soon 
as the investigator considers it to be medically justified without 
compromising safety

If in the opinion of the investigator, the participant cannot tolerate 
the maximum dose level of study intervention, the study intervention 
dose may be reduced to the next lower dose level.
Abbreviations: eCRF = electronic case report form; eGFR = estimated glomerular filtration rate; OD = once 
daily, PK = pharmacokinetics
* NOTE: Potassium and eGFR according to local laboratory values


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6.2
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit if applicable, for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be kept in a secure environment and stored as per the instructions on the label.
3. The investigator or the head of the institution (where applicable) is responsible for study 
intervention accountability, reconciliation, and record maintenance (i.e. receipt, 
reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Investigator Site File. 
6.3
Measures to Minimize Bias: Randomization and Blinding
Eligible participants will be centrally assigned to randomized study intervention at Visit 1
using an IxRS. The randomization will be stratified by country/region and LVEF (<60%, 
≥60%). Additional details will be described in the SAP.
Treatment allocation will be done according to a computer-generated randomization list 
specified by the sponsor’s responsible statistician and provided by the sponsor’s 
randomization management group. Additional details are documented in the IxRS instruction 
manuals.
Study intervention will be dispensed at the study visits summarized in the SoA. Returned 
study intervention should not be re-dispensed to the participants.
Tablets containing 10 mg and 20 mg finerenone immediate-release (IR) tablets will differ in 
size from 40 mg finerenone IR tablets, but will be identical in appearance (size, shape, color) 
to matching placebo tablets. The packaging and labeling will be designed to maintain the 
blinding of the investigator’s team and the participants. The study data will remain blinded 
until database lock and authorization of data release according to standard operating 
procedures.
In compliance with applicable regulations, in the event of a suspected unexpected serious 
adverse reaction (SUSAR) related to the blinded treatment, the participant’s treatment code 
will usually be unblinded before reporting to the health authorities and ethics committees. For 
further details, see Section 8.3.6. 
Bioanalytical staff will be unblinded according to the corresponding Bayer standard operating 
procedure (SOP). Pharmacometrics staff may also be unblinded according to Bayer SOPs. 
Pharmacokinetic and exposure-response analyses will be performed using population 
approaches (popPK and popPK/PD, e.g. by non-linear mixed effect modeling). Analysis and 
report will be done under a separate cover. This evaluation might be started prior to database 
lock. If this is applicable, appropriate measures will be taken to maintain blinding of the study 
team, e.g. data will be stored separately, and members of the study team will neither have 
access to the randomization list nor to individual data.
The IxRS will be programmed with blind-breaking instructions. In case of an emergency, the 
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assignment is warranted. If the investigator is unavailable, and a treating physician not 
associated with the study requests emergency unblinding, the emergency unblinding requests 
are forwarded to the study specific emergency medical advice 24 hours/7 day service. The 
participant’s safety must always be the first consideration in making such a determination. If a 
participant’s treatment assignment is unblinded, the sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in 
the source documentation and eCRF, as applicable.
6.4
Study Intervention Compliance
To monitor compliance, the investigator will be required to complete a drug dispensing log for 
each participant. The date of dispensing the study intervention to the participant will be 
documented.
Overall compliance with study intervention intake should be between 80% and 120% of the 
scheduled dose at the end of study intervention treatment.
Study intervention will be dispensed according to the schedule provided in the SoA (Section 1.3).
Participants will be instructed to bring all unused study intervention and empty packages at 
every (un)scheduled visit for accountability purposes. Any discrepancies between actual and 
expected amount of returned study medication must be discussed with the participant at the 
time of the visit, and any explanation must be documented in the source documents.
6.5
Prior and Concomitant Therapy
General considerations, Up until recently, there had been no treatment showing unequivocal 
mortality or morbidity benefit in participants with HFpEF and thus, pharmacologic treatments
for HFpEF typically manage symptoms with diuretics being recommended in congested 
participants in order to alleviate symptoms and signs of HF. Recently, in a study in patients 
with HFpEF (Anker et al. 2021), SGLT2 inhibition with empagliflozin demonstrated a lower 
relative risk in the composite of cardiovascular death or hospitalization for heart failure, 
which was mainly related to a lower risk of hospitalization for heart failure with 
empagliflozin.
Arterial hypertension is highly prevalent among patients with HFpEF preceding the 
development of HF and contributing to CV morbidity and mortality by causing substantial CV 
structural and functional abnormalities by activating the RAAS.
To ensure that a relevant contributor to the development of HF and its outcome is well 
controlled, participants with uncontrolled blood pressure will be excluded; the treatment of
comorbidities in particular arterial hypertension will be at the discretion of the investigator.
All concomitant medication until a participant’s last visit will be recorded in the eCRF.
Concomitant therapies not permitted during treatment with study intervention are:

Eplerenone, spironolactone, canrenone, esaxerenone, any renin inhibitor, or 
potassium-sparing diuretic 

More than one of the following: ACEI, ARB, ARNI

Potent CYP3A4 inhibitors, and potent or moderate CYP3A4 inducers.


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Drug interactions to look out for
The following should be used with caution, at the discretion of the investigator on a 
case-by-case basis:

Potassium supplementation

Non-steroidal anti-inflammatory drugs (NSAIDs)

Trimethoprim and trimethoprim / sulfamethoxazole

Any other medication known to raise potassium levels and/or cause deterioration in 
renal function.
The investigator is expected to regularly assess the participant’s potassium levels and/or renal 
parameters (e.g. eGFR, creatinine), especially for those receiving these medications. For 
further details, see the SoA (Section 1.3).
Potassium-lowering agents (e.g. sodium polystyrene sulfonate, calcium polystyrene sulfonate) 
are allowed to be started during treatment with study intervention following their labeled 
indication.
Any use of potassium supplementation and potassium-lowering agents must be documented in 
the eCRF.
A list of the most common CYP3A4 inhibitors and inducers will be provided.
Caution
Concomitant use of finerenone in combination with weak or moderate CYP3A4 inhibitors 
such as: amiodarone, aprepitant, bicalutamide, chloramphenicol, dasatinib, imatinib, lapatinib, 
mifepristone, nilotinib, norfloxacine, tacrolimus, or verapamil increases finerenone exposure. 
Additional serum potassium monitoring should be considered, and make finerenone treatment 
decisions as directed in Table 6–2. More examples of weak or moderate CYP3A4 inhibitors
will be provided separately.
6.5.1
Rescue Medicine
Not applicable.


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6.6
Dose Modification
As described in Sections 6.6.1 and 4.3, the dose of study intervention should be adjusted 
(up-or down-titration) on the basis of potassium and eGFR levels.
6.6.1
Monitoring of Blood Potassium and Dose Adjustment
Guidance for the adjustment of dose after start of study intervention intake based on 
serum/plasma potassium levels is provided in Table 6–2.
Table 6–2
Potassium Levels and Guidance for Dose Adjustment
Serum / plasma 
potassium
(K+ mmol/L)
Action to be taken
First sample:
<5.0
Increase to the next higher dose level (or continue at maximum permitted dose 
level)
5.0 to <5.5
Continue the current dose level
5.5 to <6.0
Down-titrate to the next lower dose if possible; if patient is already on dose level 1, 
interrupt study intervention. K+ should be re-checked within 72 h of initial K+ result 
awareness; follow option a
≥6.0
Interrupt study intervention and K+ should be re-checked within 72 h of initial K+
result awareness; follow option b
Second and subsequent sample:
Option a
<5.5
Continue current dose
≥5.5
Down-titrate to the next lower dose if possible, or interrupt study intervention and 
recheck K+
Option b
<5.5
Restart at dose level 1
≥5.5
Continue to withhold study intervention, further monitoring of K+.
Restart at dose level 1 ONLY if K+ is <5.0 mmol/L
The following aspects have also to be taken into consideration:
1.
If the participant is already on dose level 1 no further decrease is possible after 
interruption, the same dose level should be re-started once serum/plasma potassium 
falls below 5.5 mmol/L. Serum/plasma potassium is to be measured at a safety visit 
4 weeks 7 days after re-starting treatment or dose adjustment.
2.
If the participant is on dose level 1 of study intervention, but hyperkalemia recurs 
soon after a previous event of hyperkalemia leading to interruption of study 
intervention, and there is no explanation for the recurring hyperkalemia event other 
than intake of study intervention, premature and permanent discontinuation of study 
intervention is recommended.
3.
In case of hyperkalemia, it is at the investigator’s discretion to take measures, 
including treatment and monitoring in accordance with local practice standards, 
beyond those reflected in Table 6–2.


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6.6.2
Monitoring of Renal Function and Dose Adjustment
The dose of study intervention can be adjusted at the discretion of the investigator to account 
for renal function following the recommendations displayed in the table below Table 6–3.
Table 6–3
Renal Function Evaluation During Study
eGFR
(mL/min/1.73 m2) at 
any time after 
randomization
Action to be taken
Decrease ≥25% and 
<40% from baseline
1. Check for potential reversible causes:
a. Concomitant medications known to affect renal function (e.g. NSAIDs, 
antibiotics)
b. Adverse event (e.g. urinary infection, urinary retention, dehydration)
2. Address potential reversible causes if considered clinically appropriate
Decrease ≥40% from 
baseline
1. Check for potential reversible causes and address, as above.
2. At the investigator’s discretion, study drug can be down-titrated or 
interrupted as follows:

Further monitor eGFR/creatinine

If eGFR/creatinine has reached acceptable levels (to be determined for 
the individual participant), please re-start study intervention at the 
next lower dose level (or dose level 1 if the participant was already on 
this dose).
3. Re-test at central laboratory after 4 weeks to confirm eGFR decrease of 
≥50% or ≥57%*
Abbreviations: eGFR = estimated glomerular filtration rate; NSAID = non-steroidal anti-inflammatory drug
* Decrease based on central laboratory data. 
6.7
Intervention After the End of the Study
No intervention is planned following the end of the study.
7. Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention 
After randomization, discontinuation of study intervention (for any reason) does not constitute 
the participants’ withdrawal from the study (see also Section 7.2).
Study intervention must be prematurely and permanently discontinued if any of the following 
occurs:

Pregnancy of the participant (see also Section 8.3.5)

The investigator is of the opinion that continuation of treatment with study 
intervention is harmful to the participant’s well-being

The randomization code is broken by the investigator, or other responsible person, 
when knowledge of the participant’s treatment is required

Any investigational drug other than the study intervention is used.

Treatment with an MRA (eplerenone, spironolactone, canrenone, esaxerenone) for a 
period of more than 2 weeks.


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Study intervention may be prematurely and permanently discontinued if any of the following 
occurs:

Any suspected drug-related AE or SAE

If any exclusion criterion applies during treatment

If a significant violation of the protocol occurs, as defined by the sponsor and the 
coordinating investigator.
Participants who prematurely and permanently discontinue study intervention are expected to 
continue in the post-treatment follow-up period and to attend all protocol-specified study 
visits, and should be encouraged to perform all scheduled assessments described in the SoA
for premature discontinuations (Figure 1–2).
Under certain circumstances, should the reason for permanent discontinuation of study 
intervention change, making it no longer applicable and the investigator is of the opinion it is
in the subject’s best interest to restart treatment, study intervention may be restarted on a case-
by-case basis following comprehensive review by the Study Medical Expert.
If a participant no longer on study intervention is unable to attend the clinic for a study visit, 
a telephone consultation may be performed to determine if relevant health events /endpoints 
(e.g. development of CV or renal complications) have occurred. Ideally, a face-to-face visit 
should be performed at least once a year. The End of Study (EOS) visit is expected to be an 
onsite visit and should not be replaced by a telephone consultation unless an onsite visit is not 
feasible. Expected frequency of telephone contacts should be in line with the standard visit 
schedule, and therefore performed every 4 months. Ad hoc additional telephone contacts may 
also be requested (e.g. prior to the interim analysis) and made to the participant themselves or 
to other contact as provided by the patient, e.g. next of kin, primary physician (or local 
equivalent).
Note that study intervention may be temporarily discontinued (i.e. interrupted), as described in 
Section 6.6.
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation 
and follow-up and for any further evaluations that need to be completed.
7.1.1
Temporary Discontinuation 
Resumption of study intervention after temporary interruption
Upon temporary interruption of the study intervention due to hyperkalemia, eGFR decrease, 
(S)AE, outcome events (OE), intolerability or any other reason, intake should be resumed as 
soon as medically acceptable at the discretion of the investigator. There is no defined 
maximum time limit for temporary interruption. In all cases, the reason for study intervention
interruption must be recorded in the eCRF and the participant’s medical records. 
If the study intervention is interrupted for more than 7 days, the re-start should be 
performed at the next lower dose and the investigator should schedule an up-titration visit 
after 4 weeks (± 7 days) in order to monitor potassium levels and renal function (see Table 6–1). 
If a regular visit will be scheduled to take place 4 weeks ± 7 days after up-titration or re-start, 
the monitoring of potassium and renal function is assured and no up-titration visit has to be 
performed in addition. A restart and/or safety check visit is expected only if the investigator is 
aware of a temporary interruption that was initiated by the study participant.


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7.2
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.

At the time of discontinuing from the study, if possible, a premature discontinuation 
visit should be conducted, as shown in the SoA. See SoA (Section 1.3) for data to be 
collected at the time of study discontinuation and check for any further evaluations 
that need to be completed.

The participant may be prematurely and permanently discontinued from the study 
intervention at that time.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent.
General Procedure for Discontinuation/Withdrawal
In all cases, the reason for withdrawal of study intervention and/or of study participation must 
be recorded in the eCRF and in the participant’s medical records.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow-up, every effort should be made to 
contact him/her or a knowledgeable informant (e.g. family doctor, close relative, as 
indicated in the participant’s medical records) by telephone to ask if any of the 
primary, secondary, or other endpoints have been reached at the scheduled visits for 
the remaining duration of the study. Attempts to contact the participant should be 
documented in the participant’s records. If any participant refuses to be contacted by 
telephone (e.g. withdrawal of consent), every effort should be made to obtain vital 
status (alive or dead) information through consultation of public databases, wherever 
allowed by local regulation.

Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up.


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8. Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a participant
enrollment/identification log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g.
blood tests) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA (Section 1.3).

All procedures and assessments should be conducted on the day of the visit (see 
Section 1.3).
8.1
Efficacy Assessments 
All efficacy evaluations will be conducted according to the schedule detailed in the SoA.
The KCCQ and EQ-5D-5L are available in a high number of validated translations. 
Participants should complete each questionnaire alone and prior to the commencement of the 
other study visit procedures. However, participants in whose language a validated translation 
of the KCCQ or EQ-5D-5L is not available will be exempt from completing the questionnaire.
As an exception, in the following limited circumstances, the questionnaires may be narrated 
by someone designated/approved on study, such as a nurse or investigator, and completed 
based on answers given by the participant

if the participant is legally blind or has poor visual acuity (including due to forgotten 
eyeglasses), 

if the participant is illiterate
The reason(s) for any non-completion of the questionnaires are to be recorded.
8.1.1
Kansas City Cardiomyopathy Questionnaire (KCCQ) and 
Total Symptom Score (TSS)
The KCCQ is a patient-reported disease-specific health status measure intended for the 
assessment of HF patients’ perspectives of how their disease impacts their lives (Green et al. 
2000). Patients are asked to recall how their HF impacted their life over a 2-week recall 
period. Response options for the 23 items (questions) are on a 5- to 7-point Likert-type scale 
with varying response options depending on the question. It requires, on average, 4 to 
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The TSS domain of the KCCQ was selected as the secondary endpoint because it is a direct 
measure of the hypothesized improvement of clinical symptoms. HF symptoms are 
subjective in nature and are best reported by the patient. The frequency and burden of 
clinical symptoms of HF in daily life include fatigue (KCCQ items 5 and 6), shortness of 
breath (KCCQ items 7 and 8), paroxysmal nocturnal dyspnea orthopnea (KCCQ item 9) and 
patient peripheral edema/swelling (KCCQ items 3 and 4) and are summarized in the TSS.
In addition to the KCCQ TSS, the KCCQ also measures the impact of patients’ HF or their 
treatment in distinct domains: symptoms (with subscores for frequency and burden), 
physical limitations, quality of life, social limitations, self-efficacy and symptom stability. 
All scores are transformed to a 0-100 scale, with higher scores indicating a better outcome.
The domains of self-efficacy (a measure of patient knowledge of preventing HF 
exacerbations) and symptom stability (a measure of symptom change over the previous 
2 weeks) will not be considered measures of treatment efficacy.
8.1.2
EuroQoL (EQ-5D-5L)
The EuroQol (EQ-5D-5L) is an instrument used to assess the current health status of patients. 
It consists of 5 domains and one visual analogue scale. This instrument assesses self-reported 
health-related quality of life across the domains of mobility, self-care, usual activity, 
pain/discomfort and anxiety/depression of participants with an overall assessment of health 
status with a visual analog scale.
8.1.3
Patient Global Impression of Severity (PGIS) and Change (PGIC)
The PGIS question asks the patient to assess the current severity of their HF symptoms due to 
HF compared to the start of the treatment; “Please choose the response below that best 
describes the severity of your heart failure symptoms (for example, shortness of breath, 
tiredness and swelling) over the past two weeks.” with the following response options: 
much better, better, a little better, the same, a little worse, worse or much worse.
The PGIC question asks the patient to assess the degree of change in their HF symptoms 
compared to the start of the treatment; “Please choose the response below that best describes 
the overall change in your heart failure symptoms (for example, shortness of breath, tiredness 
and swelling) since you started taking the study medication. My heart failure symptoms are:”
with the following response options: no symptoms, mild, moderate, severe or very severe.
The 2 PGI questions will be administered in a sub-population of approximately 1200 patients, 
recruited at selected sites, at baseline (PGIS only) and at Visit 4 (Month 6), Visit 5 (Month 9) 
and Visit 6 (Month 12). They will be used as an anchor to provide an estimate of clinically 
meaningful in the KCCQ TSS. Details of the analysis, to be described in a separate SAP, will be 
conducted on a blinded dataset and reported separately from the CSR.
8.1.4
Assessment of NYHA class
NYHA class will be assessed according to the classification below:

Class I: No limitation of physical activity

Class II: Slight limitation of physical activity in which ordinary physical activity leads
to fatigue, palpitation, dyspnea, or pain from angina; the person is comfortable at rest

Class III: Marked limitation of physical activity in which less-than-ordinary activity
results in fatigue, palpitation, dyspnea, or anginal pain; the person is comfortable at rest


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
Class IV: Inability to carry on any physical activity without discomfort but also
symptoms of heart failure or the anginal syndrome even at rest, with increased
discomfort if any physical activity is undertaken.
8.1.5
NT-proBNP and hs-TnT
NT-proBNP and hs-TnT measurements during the study (including baseline) will be assessed 
by the central laboratory at the timepoints outlined in the SoA (Section 1.3). NT-proBNP or 
BNP measurements for eligibility check will be retrieved from medical records or assessed 
locally at screening.
8.2
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
Safety assessments will include AEs, physical examination findings (if performed), and vital 
signs including heart rate and blood pressure assessment. Safety laboratory tests will include 
blood chemistry, hematology and urinalysis. 
8.2.1
BMI and Weight
Body weight (in indoor clothing without shoes) will be measured at screening and all on-site
scheduled visits, as weight gain can be the first clinical sign for HF. Height in centimeters will 
be assessed at screening visit for calculation of BMI. Hip and waist circumference in 
centimeters will be measured at the screening visit only.
8.2.2
Vital Signs
Vital signs will be assessed at all on-site scheduled visits.
Blood pressure and pulse measurements will be assessed preferably with a completely 
automated device and should be preceded by at least 10 minutes of rest for the participant in 
a quiet setting without distractions (e.g. television, cell phones).
Vital signs (to be taken before blood collection for laboratory tests) will consist of 
2 pulse and 2 consecutive blood pressure measurements, at least 2 minutes apart in sitting 
position. All blood pressure measurements will be recorded on the eCRF.
8.2.3
Clinical Safety Laboratory Assessments
Section 10.2 lists the clinical laboratory tests to be performed and the SoA specifies the 
timing. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
All protocol-required laboratory assessments, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SoA. 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 


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clinically significant by the investigator (e.g. related to SAE or AE or dose modification), then 
the results must be recorded in the eCRF. 
Central Laboratory Assessment
The name and the address for the central laboratory service provider can be found in the 
documentation supplied by the vendor. Only centrally analyzed blood samples will be 
considered for statistical analysis, unless otherwise specified. Details of the collections, 
shipment of samples and reporting of results by the central laboratory will be provided to the 
investigators in the Laboratory Manual. 

Laboratory evaluations (hematology, HbA1c, clinical chemistry, urinalysis parameters,
biomarkers [NT-proBNP and hs-TnT]) are shown in Section 10.2. 

SoA (Section 1.3) for the timing and frequency.
Local Laboratory Assessment
Blood safety samples will be taken from the Screening Visit onwards for analysis at the 
local laboratory.

The following clinical chemistry parameters must be measured and the values 
documented in the eCRF
o
Serum/plasma creatinine (eGFR will be calculated automatically in the eCRF 
using the CKD-EPI formula)
o
Serum/plasma potassium.
From visit 2 (Month 1) onwards, study participants may have their local laboratory 
assessments taken up to 3 days prior to the study visit.
Potassium values should be recorded using a single decimal point (e.g. 4.5 mmol/L or mEq/L).
In the event of hyperkalemia, please see Table 6–2 for guidance.
Up-titration or down-titration of the study intervention will be based on local potassium results 
and must be documented in the eCRF. Down-titration of the study intervention should occur 
primarily for safety reasons but can also be done for exceptional logistical reasons (e.g. study 
intervention supply issue).
Additionally, at screening, BNP or NT-proBNP can be measured if not available from clinical 
medical records.
In women of childbearing potential, a pregnancy test will be performed locally, at screening and 
baseline. Further pregnancy tests should be performed in participants of childbearing potential 
as required by national/institutional regulations (e.g. at every visit). At any time during study 
participation, additional pregnancy testing should be performed upon suspicion of pregnancy.
Both serological and urine tests are acceptable.


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8.3
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Section 10.3.
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative or health care professional not involved in the 
study).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, or AEs considered related to the study intervention or study procedures, 
or those that caused the participant to discontinue the study intervention or the study (see 
Section 7).
8.3.1
Time Period and Frequency for Collecting AE and SAE Information 
All AEs/SAEs will be collected from the start randomization at the time points specified in the 
SoA (Section 1.3).
Medical occurrences that begin before the start of randomization but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section, except those related to study procedure; the latter have to be 
recorded as (S)AEs after informed consent has been obtained.
A surgical procedure that was planned prior to randomization by any physician treating the 
participant should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
Disease-related events and/or disease-related outcome events that are specified in the 
Section 8.3.6 will not be subject to (S)AE documentation. Thus they will not be recorded as 
SAEs on the AE page and will not be sent to the sponsor’s Pharmacovigilance department. 
Instead, these events will be recorded on the Outcome Event pages of the eCRF. 
Consequently, they will neither be unblinded, not reported to regulatory authorities, IECs, or 
investigators even though the event may meet the definition of an SAE, see Section 8.3.6. All 
other SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstances should this exceed 24 hours, as indicated in Section 10.3. The investigator 
will submit any updated safety-relevant SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
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8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in Section 10.3. 
8.3.4
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g. summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.5
Pregnancy
Details of all pregnancies in female and, if indicated, female partners of male participants will 
be collected after the start of study intervention and until the end of the follow-up period.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Section 10.4.
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital
anomalies, ectopic pregnancy) are considered SAEs.
8.3.6
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as AEs or SAEs
The following disease-related events (DREs) are common in participants with heart failure 
and can be serious/life threatening:

Worsening of heart failure, requiring hospitalization or urgent heart failure visit

Worsening of renal function defined as a sustained eGFR decrease of 50% or 
more, or 57% or more compared to baseline; sustained eGFR decline below 
15 mL/min/1.73m²; initiation of dialysis for at least 30 days or renal 
transplantation.

Myocardial infarction


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
Stroke 

New onset of atrial fibrillation or atrial flutter
These events are typically associated with the disease under study, and will not be reported 
according to the standard process for expedited reporting of SAEs even though the event may 
meet the definition of an SAE. In addition, they will neither be unblinded, nor reported to 
regulatory authorities, IECs, or investigators (see also Section 8.3.4 for details). Instead, these 
events will be documented only on the Outcome Event/Heart Failure pages of the eCRF and 
will undergo adjudication by an independent, blinded Clinical Event Committee as outlined in 
the CEC Charter. 
Adverse events leading to death will be documented on the adverse event eCRF page and 
DREs leading to death will be documented on the outcome event eCRF page. All deaths will 
undergo adjudication.
An independent, unblinded DMC will monitor all events during the study and these DREs
will also be analyzed after end of study and documented in the clinical study report. Should 
unexpected safety issues be identified, specific amendments will be implemented.
8.4
Treatment of Overdose
Document the quantity of the excess dose as well as the duration of the overdose in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
In this trial, an overdose is defined as any occasion when the participant has taken (accidentally 
or intentionally) any dose higher than the maximal target dose prescribed in the protocol.
Overdose following administration of study interventions should be treated as clinically 
indicated based on symptoms and signs. There is no specific reversal agent for finerenone and 
the Sponsor does not recommend specific treatment for an overdose.
Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose taken 
with possible suicidal/self-harming intent (see Section 10.3.1).
8.5
Pharmacokinetics
For the investigation of systemic exposure to finerenone and its relationship with treatment
effects, the plasma concentrations of finerenone will be determined at different time points
using a sparse sampling approach in all study participants. The plasma concentration versus 
time data collected on the visits as outlined in SoA (see Section 1.3) will be evaluated 
descriptively, separated by dose and visit. Plots will be prepared by dose and visit of all
individual plasma concentrations vs. actual relative study times (time of sample collection
after time of study intervention administration).
The PK data may also be evaluated using non-linear mixed effect modeling (NONMEM). that 
may include attempts to identify whether the PK of finerenone is influenced by covariates and 
to explore exposure-response relationships. This evaluation, if performed, will be described in
a separate analysis plan and will be reported separately.
At Visit 3 (Month 3), a trough sample for the determination of finerenone plasma
concentrations will be drawn before intake of study intervention. At this visit, study 
intervention will be administered at the study site by study personnel and the exact time of 


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study intervention intake on the day before the visit and on the day of the visit and the exact 
sampling time will be recorded in the eCRF. Ideally, the study personnel should contact the 
participant prior to Visit 3 to remind them not to take the study intervention as usual in the 
morning at home. In case the trough sample cannot be taken (e.g. study intervention was taken 
at home), this may be postponed to Visit 4 or 5.
At Visit 6 (Month 12) and following visits as outlined in SoA (see Section 1.3), one blood 
sample for the determination of finerenone plasma concentrations will be drawn during the 
visit 1.5-10 hours after study intervention intake at home. The participants should be advised 
to take their drug as usual in the morning at home and recall the time of drug intake or note 
the time of drug intake on the contact card. The exact time of study intervention intake and the 
exact sampling times will be recorded in the eCRF.
The PK bioanalysis will be performed under the responsibility of Bayer Pharmaceuticals 
Bioanalytics Laboratory, BAG-PH-RD-RED-PCD-DMPK-PKBA-BA, 42096 Wuppertal, 
Germany.
Details about the collection, processing, storage and shipment of samples will be provided 
separately (e.g. sample handling sheets or laboratory manual).
8.6
Pharmacodynamics
Analysis of the pharmacodynamics parameters (e.g. blood pressure, heart rate, laboratory 
values) will be described in detail in the SAP.
8.7
Genetics
Genetics are not evaluated in this study.
8.8
Biomarkers
The biomarkers NT-proBNP and hs-TnT will be determined at the time points indicated in 
SoA for central laboratory assessments (Section 1.3).
Sample handling and storage - details on the collection, processing, shipment and storage of 
samples will be provided in separate documents (e.g. sample handling sheets or lab manual).
Samples may be stored for a maximum of 15 years (or according to local regulations) 
following the end of the study at a facility selected by the sponsor to enable further analyses. 
Other biomarkers
In addition to the biomarkers described above, other exploratory biomarkers related to e.g. the 
mode of action or the safety of the study intervention and similar drugs may be investigated. 
The same applies to further biomarkers deemed relevant to CV diseases and associated health 
problems. These investigations may include e.g. diagnostic, safety, pharmacodynamic, 
monitoring, or potentially predictive biomarkers. Samples (one serum and one plasma) for 
these analyses will be collected according to the SoA.
The results of biomarker investigations may be reported separately (e.g. in a biomarker 
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8.9
Immunogenicity Assessments
Not applicable.
8.10
Medical Resource Utilization and Health Economics
Additional analysis will be undertaken to assess the impact of treatment on Healthcare 
resource utilization, this may include hospitalization (by cause, frequency and duration), 
urgent heart failure outpatient visits, other treatments, tests and procedures as appropriate.
9. Statistical Considerations 
9.1
Statistical Hypotheses
The primary endpoint is the composite of CV death and total (first and recurrent) HF events 
(HHFs and urgent HF visits). The primary analysis of this endpoint will be performed in the 
full analysis set using the planned treatment group, in line with the intention-to-treat principle.
Participants without an event of the primary composite endpoint at the time of analysis will be 
censored at the date of their last contact or date of non-CV death. 
The primary analysis of the primary composite endpoint will be based on a stratified 
Andersen-Gill model (Andersen 1982) including treatment group as fixed effect and including 
country/region and LVEF (<60%, ≥60%) as stratification factors. Robust standard errors 
(sandwich estimator) will be used to account for correlations of event times within a 
participant. As shown by (Lin et al. 2000), the Andersen-Gill model with robust standard 
errors can be interpreted as a proportional rates model. After the authors of that paper, the 
model is also referred to as the ‘LWYY model’. Let θ be the ratio of rates in the finerenone 
versus placebo group. In order to evaluate whether finerenone is superior to placebo in 
reducing the rate of the composite event of CV death and total HF events the following null 
hypothesis will be tested using the model above (see Section 9.5 for details regarding the 
nominal significance level):
                                                 :  = 1   versus  
:  ≠1,
where a θ <1 represents a treatment benefit of finerenone over placebo.
A point estimate of the rate ratio together with a 95% confidence interval will be presented
alongside the point estimate and hazard ratio for the competing event of non-CV death, 
calculated using a stratified Cox proportional hazards model. Additionally, plots and 
summaries of the mean cumulative function for the primary endpoint (Ghosh and Lin 2000)
and cumulative incidence function for the competing event of non-CV death (Aalen and 
Johansen 1978) will be presented by treatment group. 
In terms of the addendum to ICH E9 (ICH_E9 (R1) 2019), there are 3 important intercurrent 
events to consider: Treatment discontinuation, CV death and non-CV death. For treatment 
discontinuation a treatment policy strategy will be applied, i.e. patients will be followed up for 
events after discontinuing treatment and these events and the follow-up time will be included 
in the analysis. CV death will be counted as both an outcome event as well as a censoring
event, so that a combination of a composite and a while alive strategy is used. It is thus 
assumed that patients could have had further events for HF, if they had not died. This seems 
appropriate, as including into the model that no further HF events can occur after death, for 
example by censoring patients at the end of the study, would induce a bias in favor of a 


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treatment group with more early deaths. Non-CV death is assumed to be a censoring event, 
since the treatment is not assumed to have an effect on these events and interest lies in the 
treatment effect on composite events while patients are alive. The primary analysis method 
has been investigated with extensive simulation studies and it has been confirmed that it keeps 
the alpha level and has good operating characteristics across a range of plausible scenarios.
9.2
Sample Size Determination 
This is an event-driven study. The study is planned to last 42 months in total with a 
recruitment period of 24 months and participants are to be randomized 1:1 to finerenone and 
placebo. The sample size determination is based on a simulation study assuming a joint frailty 
model in order to account for the correlation between HF events and CV death, and to model 
participant heterogeneity with respect to baseline intensities/hazards. That is, given the 
participant-specific gamma distributed frailties, we assume a homogeneous Poisson process 
for HF events and an exponential distribution for the time to CV death. Furthermore, the 
frailty term is assumed to be the same for HF events and CV death.
The placebo rate parameter of the Poisson process and the hazard rate of the exponential 
distribution were first chosen as 0.014 HHFs/month per participant and 0.004 CV 
deaths/month per participant, respectively. These values lead to an observed annualized 
placebo rate of first composite events of 9.0 (events/ 100 participant-years) and an observed 
annualized placebo rate of CV death of 3.5. These observed rates are similar to rates observed 
in the literature, i.e. an annualized rate of first composite event of 9.1 was observed in the 
CHARM-Preserved trial, 8.9 was observed in PARAGON-HF and 8.5 in the BNP stratum of 
the TOPCAT trial. Regarding CV death, an annualized placebo rate of 3.9 per 100 
participant-years was observed in CHARM-Preserved, 3.1 was observed in PARAGON-HF
and 3.9 was also observed in the TOPCAT BNP stratum. Since it is planned to recruit more 
participants with a very recent hospitalization than in previous trials, which would be at a 
higher risk of events, the rate parameters were subsequently increased by 25% for CV death
leading to a rate of 0.005125 CV deaths/ month per participant. For HF events, the rate was 
increased by 30% to 0.0182 HF events /month per participant to also account for the inclusion 
of urgent HF visits, which have not been included in primary endpoint of the former trials.
The additional increase in event rate is in line with the increase reported for PARAGON-HF
(Solomon et al. 2019), Supplementary Appendix). The resulting observed annualized placebo 
rates are then 12.5 for first composite events and 4.6 for CV death. The frailty variance is 
chosen as 5.0, so that the ratio of total composite to first composite events is about 1.8. 
Similar ratios have been observed across a number of heart failure studies (Anker and 
McMurray 2012). Non-CV deaths are simulated as exponentially distributed censoring events 
with a rate of 0.0016 non-CV deaths/month per participant, leading to approximately 70% of 
all deaths being due to CV causes. 
As treatment effects, a hazard ratio for CV death of 0.8 and a rate ratio for heart failure events 
of 0.75 are assumed. With approximately 5500 randomized participants, it is expected to 
observe approximately 1310 first events and approximately 2375 total events leading to a 
power of 90% to show an effect at a two-sided alpha level of 5%. Under these assumptions it 
is expected to observe a 19% decrease in the rate of the primary endpoint for finerenone. An 
annual drug discontinuation rate of 5% is assumed, with finerenone participants having the 
same risk of events as placebo participants after discontinuation and no change in event rate 
for discontinuing placebo participants. Participants discontinuing study intervention are 
expected to remain under observation in the study. Table 9–1 below shows the resulting 


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power under deviations from the assumed treatment effect as well as the power for a time-to-
first composite event analysis. As it would be desirable for a single pivotal trial to obtain a 
higher level of evidence so that the power at an alpha level of 1% is also given.
Table 9–1
Power for Assumed Sample Size Scenario and Some Variations
Sample 
size
Rate ratio HF 
events
Hazard ratio 
CV death
Power 
primary α=5%
Power 
primary α=1%
Power 
Time-to-first 
α=5%
5500
0.75
0.80
90%
74%
74%
0.75
0.90
89%
73%
64%
0.78
0.90
79%
58%
53%
0.72
0.80
95%
86%
82%
Abbreviations: α = alpha; CV = cardiovascular; HF = heart failure
9.3
Populations for Analyses 
For purposes of analysis, the following populations are defined:
Table 9–2
Populations for Analyses
Population
Description
Enrolled
All participants who sign the informed consent form (ICF).
Randomly assigned to study 
intervention
All participants randomly assigned to study intervention.
Safety analysis set (SAF)
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants will 
be analyzed according to the intervention they actually received.
Full analysis set (FAS)
All randomized participants. Participants will be analyzed 
according to the intervention they were randomized to. Only 
potential reasons for exclusion would be a clearly erroneously 
randomization, or major GCP violations, for example, a serious 
suspicion of fraud. 
Pharmacokinetic analysis set 
(PKS)
All finerenone-treated participants (with the exception of 
participants excluded on the grounds of critical GCP violations) 
with at least 1 valid finerenone plasma concentration and 
without validity findings which would interfere with the 
evaluation of the PK data.
Abbreviations: GCP = Good Clinical Practice; PK = pharmacokinetic
9.4
Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.
Summaries and analyses to address the impact of COVID-19 will also be defined in the SAP.


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9.4.1
Efficacy Analyses
9.4.1.1
Primary Efficacy Variable
The primary efficacy variable is the composite endpoint of CV death and/or total (first and 
recurrent) events for HF. See Section 9.1 for a description of the primary analysis.
As part of the primary analysis, a separate estimate of the treatment effect for CV death as one 
of the components of the primary endpoint will be obtained. The second component of total 
HF events will be a secondary endpoint and analyzed as described in section 9.4.1.2. The 
main cause-specific treatment effect estimate for CV death will be derived from a stratified 
Cox proportional hazards model for time to CV death and the main p-value from a stratified 
log-rank test. A cause-specific treatment effect estimate for the competing event of non-CV 
death will also be calculated using a stratified Cox proportional hazards model and presented 
with associated 95% confidence interval. The cumulative incidence functions for time to CV 
death and time to non-CV death will also be calculated using Aalen-Johansen estimates.
Note that the study is not powered to show an effect on CV death alone. While this is the case, 
a sufficient number of deaths are expected so that an excess risk in mortality can be excluded. 
Under the assumptions of the sample size determination, approximately 535 CV deaths and 
approximately 775 all-cause deaths are expected to occur in the study. Even though no formal 
statistical tests for exclusion of an increased risk will be performed, these expected event counts 
would result in a relatively high power to exclude hazard ratios on all-cause mortality (ACM) 
above 1.15 and 1.25. Table 9–3 provides the respective power values under different assumed 
values for the true hazard ratio on CV death and assuming no treatment effect on non-CV 
deaths (HRNonCVD=1.0). Similar to the primary endpoint, a treatment policy strategy is used 
for treatment discontinuation. With exclusion of a certain hazard ratio value it is meant that 
the upper limit of a 95%-confidence interval is below the value.
Table 9–3
Power to Exclude Increased Hazard Ratio on All-Cause Mortality Under 
Different Assumed Treatment Effects on CV Death
True HRCVD
Exclude HRACM >1.15
Exclude HRACM >1.25
0.8
94%
>99%
0.9
78%
97%
1.0
52%
88%
Abbreviations: ACM = all-cause mortality; CV = cardiovascular; CVD = cardiovascular death; 
HR = hazard ratio
As supportive analysis, a stratified Cox proportional hazard regression analysis of time to first 
composite event (CV death or first HF event) will also be performed and a plot of Aalen-
Johansen estimates of the cumulative incidence function will be provided. An additional 
analysis of the primary endpoint will exclude urgent HF visits and consider only CV deaths 
and HHFs as events.
As a sensitivity analysis, the number of primary composite events will also be analyzed using 
a negative binomial regression model including stratification factors and treatment group as 
covariates and log follow-up time as an offset parameter. 
A total-time approach considering times from randomization to the onset of first, second, third 
composite event using a (Prentice et al. 1981, Wei et al. 1981) model will be applied. This 
model enables analysis of the cumulative effect on the primary endpoint from randomization 
(i.e. the effect on second event includes the effect on the first, and the effect on third event 


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includes the effects on the first and second). The corresponding individual hazard ratios with 
95% CIs comparing treatment groups on the first, second, and third event will be presented. In 
addition a conditional gap-time model according to Prentice et al will be applied to obtain 
hazard ratio estimates with 95% CIs for the time from first to second and from second to third 
event (note that this gives a non-randomized comparison). Both models will employ robust 
standard errors and include the stratification factors and treatment group as fixed effects.
Events that could potentially fulfill the criteria for primary efficacy variables during the study
will be evaluated by the CEC. Definitions of individual endpoints (e.g. CV death) will be 
provided in the Endpoint Manual. 
Additional supportive analyses will be considered and will be described in the SAP.
9.4.1.2
Secondary Efficacy Variables
Secondary efficacy variables are the following: 

Time to total (first and recurrent) HF events

Improvement in NYHA class from Baseline to Month 12

Change from baseline to Month 6, 9 and 12 in TSS of the KCCQ 

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 <15 ml/min/1.73m2 or initiation of dialysis or renal 
transplantation.

Time to all-cause mortality.
The secondary hypotheses will be formally tested, and statistical inferences will be made only 
if the primary hypothesis is rejected. The testing strategy of the secondary endpoints is as 
follows:
1. Total HF events will be tested at the same two-sided significance level as the primary 
endpoint (hereafter denoted αp - see Section 9.5 for details regarding the nominal 
significance level)
2. Only if the hypothesis for the secondary endpoint total HF events is rejected, the
NYHA class and KCCQ endpoints will be tested using the Bonferroni-Holm 
procedure, i.e. if at least one of the hypotheses of the two endpoints NYHA class and 
KCCQ can be rejected at the two-sided αp/2 significance level, the remaining of the 
two endpoints will be tested at the two-sided αp significance level.
3. Only if the hypotheses for all previous secondary endpoints are rejected, the composite 
renal endpoint will be tested at the two-sided αp significance level.
As a hard endpoint and objective indicator of benefit-risk, time to all-cause mortality will be 
tested at a full two-sided significance level of 5%, after the rejection of the primary 
hypothesis. The second component of the primary endpoints, CV death, will also be tested at 
the same significance level as the primary endpoint after the primary hypothesis is rejected.
Testing of time-to-all-cause mortality and CV death will thus be done outside of the alpha-
preserving procedure for the primary and other secondary efficacy variables (Total HF events, 
NYHA class, KCCQ, renal composite).


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Time to total HF events will be analyzed with a joint frailty model (Rogers et al. 2016). This 
model gives a treatment effect on total HF events which is adjusted for a potential treatment 
effect on CV death. An effect on CV death might otherwise dilute the effect seen on the 
hospitalizations, i.e., an effective treatment will prevent CV deaths especially in the more 
severely ill participants, which then potentially realize many hospitalizations. The joint frailty 
model will be fitted using the method described in the paper by (Liu and Huang 2008) where 
the unknown baseline hazard for CV death and unknown baseline intensity for HF events are 
approximated by piecewise constant functions. A gamma frailty distribution will be assumed. 
As a sensitivity analysis a joint frailty model with constant hazard and intensity functions will 
be fitted as well. The flexible model can sometimes have convergence issues, should this 
occur, the estimate of HF events treatment effect of the model with the constant baseline 
functions will be considered to be the main estimate. The estimate from the joint frailty model 
for CV death will be considered supportive for the analysis of this component. The main 
analysis for the CV death component is described under the primary efficacy variable in 
section 9.4.1.1. As supportive analysis, a stratified Cox proportional hazard regression 
analysis of time to first HF event will also be performed.
The percentage of participants with improvement in NYHA class from Baseline to Month 12 
will be analyzed with a logistic regression model including factors for treatment group and 
stratification levels. A patient is considered as having improved in NYHA class, if the NYHA 
class at Month 12 (Visit 6) is at least one category improved compared to the baseline visit. A 
composite strategy will be applied to those cases, where no measurement at Visit 6 is 
available, e.g. due to death or lost to follow-up. That means these patients are considered not 
improved in NYHA class. Odds ratio and two-sided 95% confidence intervals will be 
provided for the comparison of finerenone vs. placebo treatment group. In addition, change 
from baseline in NYHA class will be summarized descriptively using shift tables, presented 
by visit and any time post-baseline.
The absolute change from baseline including measurements up to Month 12 of the TSS of the 
KCCQ will be analyzed by a repeated measures mixed model including the factors treatment 
group, baseline, visit, baseline-by-visit interaction, and factors for the stratification levels. 
Differences between the finerenone and the placebo treatment groups will be calculated with 
two-sided 95% confidence intervals. The comparison assumes a common treatment effect 
across month 6, 9 and 12 and will be considered primary. This analysis will investigate the 
effect on the TSS of the KCCQ while patients are alive and irrespective of any permanent 
treatment discontinuation. This means that all observed values will be included in the analysis 
without any specific imputation. A supportive analysis will apply a worst-case imputation for 
death which means that if a patient dies, a worst score of 0 for the TSS will be imputed for all 
subsequent visits after the patient’s death. Treatment effects at Month 6, 9 and 12 will also be 
investigated individually by adding a treatment-by-visit interaction into the model. The 
primary analysis of the secondary time-to first event variables (i.e., composite renal endpoint 
and ACM) will be done with a stratified log-rank test for testing and a stratified Cox 
proportional hazards model for obtaining a point estimate with 95% confidence interval. The 
Cox proportional hazards model will be stratified according to the stratification factors and 
include treatment group as fixed effect. For the composite renal endpoint, the cause-specific 
point estimate with 95% confidence interval for the competing event of death will also be 
presented. Cumulative incidence function plots and summaries (calculated using Aalen-
Johansen estimates) will be produced for the composite renal endpoint and the competing 
event of death. In addition, components of the composite renal endpoint will be analyzed. 
Furthermore, Aalen-Johansen plots will be displayed for the ACM endpoint.


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Only central laboratory measurements before initiation of dialysis or renal transplantation will 
be considered for the definition of the individual eGFR-based components of the renal 
endpoint. At the up-titration, restart and safety check visits, only a local laboratory 
measurement is obtained. These values will be checked for a potential eGFR event and, in 
case of decline, the investigators will be advised to retest eGFR centrally in an unscheduled 
visit; determination of an eGFR event will then be based on this value. Events will be counted 
from the day of randomization until the EoS visit. If an initial decrease in eGFR occurs on the 
EoS visit, there will be another confirmatory measurement taken at least 4 weeks later to 
confirm the initial decrease. The individual components “Sustained decrease of eGFR ≥50% 
from baseline over at least 4 weeks” as well as “Sustained eGFR decline <15 ml/min/1.73m2” 
will be programmatically derived. Only in case the eGFR decrease was confirmed by at least 
one additional eGFR measurement taken at least 4 weeks later, it will be considered as a 
sustained decrease and counted for the renal endpoint. The date used for the analysis will be 
the date of the initial sample exceeding the threshold. In case there was no confirmatory 
assessment, events will only be counted for the renal endpoint when the patient died after the 
initial decrease or the patient went on renal replacement therapy such as dialysis or 
transplantation. If there is an intermediate measurement that does not confirm the initial 
decrease, the event will not be counted for the renal endpoint. 
The other two components of the renal endpoint, i.e. initiation of dialysis or renal 
transplantation, will be adjudicated. To account for events of initiation of dialysis after the last 
eGFR is recorded at a clinic visit, such events will be included in the efficacy analysis of the 
composite renal endpoint if they occur in the period up to one day before the next planned 
clinic visit. Censoring will be applied at next protocol scheduled visit plus 1 month. For a 
death in this period, the date of death will be used as the censoring date. Randomized 
participants without an event of the composite renal endpoint at the time of analysis will be 
censored at the date of their last visit when complete information on all components of the 
composite renal endpoint is available, up to and including the EoS visit (should this visit 
satisfy this rule), or date of death using a time window next protocol scheduled visit plus 
1 month as above if a subsequent clinic visit had been planned.
Additional supportive analyses will be considered and will be described in the SAP. The
following subgroups will be considered in exploratory subgroup analyses for the primary and 
secondary efficacy variables. This will include descriptive statistics and a statistical test for 
interaction.
The randomization will be stratified by country/region and LVEF (<60%, ≥60%). The most 
important subgroups besides stratification factors are given below (with further details and 
subgroups provided in the SAP): 

Baseline serum potassium (≤4.5, >4.5 mmol/L)

eGFR category at baseline (eGFR 25 to <45, 45 to <60, ≥60 mL/min/1.73 m²) 

Atrial fibrillation at baseline ECG (present, absent)

Diabetes mellitus at baseline (present, absent)

HHF (very recent [≤7 days before randomization], recent [>7 days – ≤3 months], 
>3 months - ≤6 months, >6 months - ≤9 months, >9 months - ≤12 months, no index). 


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It is anticipated that in these proposed subgroups for analysis, differences in treatment effects 
may be observed according to the screening or baseline characteristics defined, due in part to 
the differences in the risk of clinical events expected in the different subgroups.
Furthermore, subgroup analysis usually required will be performed, including the following 
subgroups: 

Race 

Sex

Age group.
9.4.1.3
Exploratory Variables

Time to first CV hospitalization

Time to first all-cause hospitalization

Total number of CV hospitalizations

Total number of all-cause hospitalizations

Time to first occurrence of the following composite endpoint: CV death or non-fatal 
CV event (i.e. non-fatal myocardial infarction, non-fatal stroke, or HHF)

Time to first occurrence of the following composite endpoint: sustained decrease in 
eGFR ≥57% relative to baseline over at least 4 weeks, or sustained eGFR decline 
<15 ml/min/1.73m2 or initiation of dialysis or renal transplantation

Change in eGFR from baseline

Mean rate of change in eGFR as measured by total eGFR slope and its subcomponents 
acute and chronic slope

Change in UACR from baseline

Days alive and out of hospital

Time to new onset of atrial fibrillation

Change in health-related quality of life summary scores from baseline measured by 
KCCQ and EQ-5D-5L
Exploratory time-to-event variables will be analyzed using the stratified log-rank test and the 
stratified Cox proportional hazards model. 
The total number of CV hospitalizations will be analyzed using an LWYY model, similarly to 
the primary efficacy endpoint, and will be summarized descriptively by treatment group 
together with the annual rate of CV hospitalizations. These summaries and analyses will be 
repeated for all-cause hospitalizations.
The absolute change of eGFR to baseline at each visit until Visit 10 (Month 24) will be 
analyzed by a mixed model with the factors treatment group, baseline eGFR, visit, 
treatment-by-visit interaction, baseline-by-visit interaction, and factors for the stratification 
levels (region and LVEF). Differences between the finerenone and placebo groups at each 
visit will be calculated, and corresponding two-sided 95% confidence intervals will be 
computed. Change in UACR from baseline will be analyzed in an identical fashion.


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Frequency tables will be generated for the number and percentage of patients with a relative 
decrease in eGFR of ≥25%, ≥30%, ≥40%, ≥50% and ≥57% from baseline. The analysis will 
be performed for each visit and for any time post-baseline.
The rate of change of eGFR will be compared between the finerenone and the placebo group 
by estimating the total eGFR slope using available assessments from baseline to planned end 
of the treatment period. It is assumed that changes in the mean response can be expressed in 
terms of a linear trend, and the treatment effect can be expressed in terms of the difference in 
slope between finerenone and placebo. For the analysis of the total slope, the serial change in 
eGFR will be modeled using a two-slope linear spline mixed-effects model in which a fixed 
change point will be defined to separate acute and chronic eGFR slope at month 3 (section 2.1 
of (Vonesh et al. 2019)). In addition to fixed effects for the treatment, time (continuous) and 
treatment by time interaction, the model will include fixed effects for the stratification factors
and random effects for the intercept, acute slope (baseline to month 3), and chronic slope 
(month 3 to planned end of treatment period). An unstructured covariance will be used to 
model the between-participant errors. Within-participant errors are assumed to be 
homogenous. Linear contrasts will be constructed to estimate the acute, chronic, and total 
slope in eGFR. LS means and differences of the acute, chronic and total eGFR slope for 
finerenone and placebo group will be provided with 95% confidence intervals (and 
corresponding p-values for the differences).
Days alive and out of hospital (DAOH) will be summarized descriptively by treatment group; 
the number and percentage of DAOH with respect to total potential follow-up time will be 
provided alongside the number and percentage of days dead and days in hospital, including 
breakdown into type of death and hospitalization, respectively. These analyses will be 
performed overall and separately by the stratification factors (region and LVEF).
DAOH will be analyzed by an ANCOVA model including potential follow-up time, treatment 
group, and stratification factors as fixed effects.
DAOH will be analyzed once considering the total potential follow-up time and once 
considering only the first year of follow-up.
For the KCCQ, 3 summary scores (symptom frequency score, total symptom score, and 
overall summary score) will be derived. For the KCCQ symptom frequency scores, the 
following will be presented by visit and treatment group: number of observations, number of 
missing values, minimum, first quartile, mean, standard deviation, median, third quartile, and 
maximum, including the changes from baseline.
For the EQ-5D-5L, summary scores will be calculated from the 5 dimensions according to the 
scoring instructions from Europe and the US (refer to the EQ-5D-5L User Guide 
(EuroQoL_Group 2013) and to the EQ-5D Value Sets (Szende et al. 2007). The values and 
the changes from baseline of the summary scores and the EuroQol Group visual analogue 
scale (EQ VAS) will be summarized by treatment group and visit using the same descriptive 
statistics as for the KCCQ.


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9.4.2
Safety Analyses
All safety analyses will be performed on the SAF. 
The following safety procedures and variables will be assessed during the study:

SAEs and AEs leading to discontinuation of treatment with study intervention

Change in body weight from baseline

Change in serum potassium from baseline

Number of participants with hyperkalemia (serum potassium 5.5 mmol/L)

Number of participants with severe hyperkalemia (serum potassium 6.0 mmol/L)

Number of participants with hospitalization for hyperkalemia

Number of participants permanently discontinuing study intervention due to 
hyperkalemia 

Change in vital signs (heart rate, SBP and DBP) from baseline

Change in renal function measured by eGFR (CKD-EPI formula) change from baseline

Number of participants with hospitalization for worsening of renal function

Number of participants permanently discontinuing study intervention due to worsening 
of renal function

Changes in laboratory values from baseline.
An overall summary of all AEs and treatment emergent AEs (TEAEs) will be generated by 
treatment group.
The number and percentage of patients with TEAEs, post-treatment AEs occurring more than 
3 days after last intake of study intervention, treatment-emergent SAEs, treatment-emergent 
study intervention-related AEs, treatment-emergent study intervention-related SAEs, TEAEs 
causing premature and permanent discontinuation of study intervention, treatment-emergent 
non-serious AEs, TEAEs by maximum intensity, drug-related TEAEs by maximum intensity 
will be summarized by treatment group using MedDRA terms grouped by Primary System 
Organ Class and Preferred Term.
The number of patients with treatment-emergent (until 3 days after last study intervention
administration) abnormal laboratory values above or below the normal range will be tabulated 
by the laboratory parameter and treatment group.
Summary statistics including changes from baseline will be calculated by treatment group and 
visit for all quantitative laboratory parameters, i.e. for hematology, clinical chemistry and 
urinalysis. Geometric statistics and ratios to baseline will be presented for urinary albumin-to-
creatinine ratio (UACR), creatinine, and NT-proBNP, instead of arithmetic statistics with 
changes from baseline. For eGFR the relative change will be displayed in addition to the 
absolute change from baseline.
Summary statistics for serum potassium, eGFR, and serum creatinine will also be repeated by
treatment group and visit separately for each level of the stratification factors (region and LVEF).
The following special safety parameters will be further assessed by displaying the number and 
percentage of patients with safety events as described below by treatment group, visit, and for 


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any time on treatment (including unscheduled assessments) and until 3 days after last study 
intervention administration. This will also be performed by stratification factors. The 
summaries will be provided for the number and percentage of patients with:

Absolute value of serum potassium >5.0 mmol/L, 5.5 mmol/L and 6 mmol/L

Relative decrease from baseline in eGFR of ≥25%, ≥30%, ≥40%, ≥50% and ≥57%

Absolute value of eGFR <30 mL/min/1.73 m²

Increase from baseline in serum creatinine >0.3 mg/dL and >0.5 mg/dL.
The percentage of patients with the respective events (non-stratified) at any time on treatment 
(including unscheduled assessments) and until 3 days after last study intervention
administration will be compared between the finerenone and placebo groups by applying 
separate exploratory χ² tests with continuity correction. If the expected number of patients in 
at least 1 cell of the 2x2 contingency table is <5, Fisher’s exact test will be applied instead of 
the ² test. Estimates and two-sided 95% confidence intervals will be provided for each 
treatment group and the treatment differences. Clopper-Pearson confidence intervals will be 
calculated for each treatment group, while for treatment differences the exact unconditional 
confidence limits will be calculated.
9.5
Interim Analyses 
One non-binding interim analysis for futility is planned when approximately 30% of the 
required total number of primary endpoint events have been observed. If the observed rate 
ratio on the primary endpoint is above 0.95, the trial is planned to be stopped for futility. This 
gives a probability of approximately 69% to stop under the null hypothesis (i.e. no treatment 
effect on the composite of HHFs and CV deaths) and leads to a loss in power of less than 1% 
under the alternative hypothesis of the treatment effect assumed for the sample size 
determination. No adjustment for this loss in power will be made.
The futility analysis is considered to be non-binding, the DMC will be asked to also consider 
important secondary efficacy endpoints as well as safety in their assessment. 
In addition, one formal interim analysis for efficacy is planned when approximately 2/3 of the 
required total number of primary endpoint events have been observed.
If the interim analysis shows clear and consistent benefit in the finerenone treatment group, 
the DMC may recommend early study termination. The Haybittle-Peto rule will be used to 
guide the decision regarding early stopping of the study for success: a reduction of 3 standard 
deviations (of the test statistic) in the analysis of the primary efficacy endpoint (two-sided 
p-value <0.0027) at the interim analysis. In addition, a nominal significant effect on CV death 
component should be present (two-sided p-value<0.05) at the interim analysis. Note: The 
criterion for CV death would not be considered to prove formal statistical significance, as it 
does not keep the alpha level. It has been added so that the trial is only stopped at the interim 
if there is at least a certain amount of evidence of a beneficial treatment effect on CV death.
If the study doesn’t stop for overwhelming efficacy at the interim analysis, a small adjustment 
to the alpha level at the final analysis is required to preserve the overall type I error rate of 
5%. For an information fraction of 2/3, the adjusted alpha level of 4.967% applies. If the study 
is not stopped early for success a p-value of p<0.04967 is therefore required at the final 
analysis to achieve formal statistical significance. No alteration to the sample size is done to 


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account for this adjustment in significance level with negligible loss in power under the 
alternative hypothesis.
The sponsor will oversee and discuss with the Steering Committee overall blinded event rates 
to ensure that they are in line with protocol assumptions. If overall event rates are lower than 
expected, consideration will be given to altering the study design, such as increasing the 
sample size or extending the study duration without knowledge of any treatment effect. 
The non-binding futility interim analysis as well as the efficacy interim analysis will be 
conducted such that the ongoing study integrity is maintained. Only the independent statistical 
support group, who is responsible for providing the interim analyses results to the independent 
data monitoring committee (DMC) will be unblinded to the individual treatment group 
assignments. Interim analyses results will not be shared with investigators, participants, or the 
study team who are involved with the conduct of the study, nor will be available for 
submission before the final database lock. An interim analysis SAP will describe the planned 
interim analyses in greater detail.
9.6
Data Monitoring Committee (DMC)
Ongoing safety monitoring during the conduct of the study will be performed by an external 
and independent DMC. An independent statistical analysis center (SAC) will be involved in 
processing unblinded safety data for the DMC. Analysis periods and procedures will be 
defined in an operational charter (DMC charter) filed in the study file. 
Outcome events as defined in Section 8.3.6 will not be reported as AEs or SAEs by the 
investigators; however, they will be collected in the eCRF. The independent DMC will 
periodically review and assess all outcome events as well as safety data from the study for 
imbalances in safety outcomes in an unblinded manner. It is believed that in this way, patient 
safety can continue to be monitored throughout the duration of the trial, and the integrity of 
the study maintained. If unexpected safety issues are identified, specific amendments will be 
implemented based on the recommendation of the DMC.
Following data review, the DMC will provide written recommendations that will be 
transferred to the chairmen of the Steering Committee and Bayer. DMC opinions and 
recommendations will be notified by Bayer as soon as possible to the competent authorities 
and the IECs where they qualify for expedited reporting.


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10.Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines:
-
Applicable ICH Good Clinical Practice (GCP) Guidelines
-
Applicable laws and regulations.

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. Any substantial modification of the protocol 
will be submitted to the competent authorities as substantial amendments for approval, 
in accordance with ICH Good Clinical Practice and national and international 
regulations.

The investigator will be responsible for the following:
-
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
-
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
-
Providing oversight of the conduct of the study at the site and adherence to 
requirements, ICH guidelines, the IRB/IEC, and all other applicable local 
regulations.
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for one year after completion of the study.
10.1.3
Informed Consent Process
The investigator or his/her qualified representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 


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Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC 
or study site.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorized 
representative.
Participants who are rescreened are required to sign a new ICF.
10.1.4
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.5
Committees Structure
Clinical Event Committee (CEC)
The main task of the CEC, which is composed of a panel of experts in cardiology and 
nephrology, is to adjudicate all HHFs, HF equivalents and all deaths. The committee will be 
provided with all relevant documentation related to the event. 
The procedures followed by the committee will be specified in the CEC charter. Adjudication 
results will be the basis for the final analysis.
Data Monitoring Committee (DMC)
Ongoing safety monitoring during the conduct of the study will be performed by an
independent external and unblinded DMC (see Section 9.6). Analysis periods and procedures 
will be defined in the DMC charter and filed in the electronic trial master file. Following data 
review, the DMC will provide written recommendations that will be transferred to Bayer and 
the Steering Committee chair. All other definitions will be provided in the DMC charter.
10.1.6
Dissemination of Clinical Study Data
Result summaries of Bayer's sponsored clinical trials in drug development Phases 2, 3, and 4 
and Phase 1 studies in participants are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the “Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases”. In addition, results of clinical drug 


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trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers 
participant-level clinical trial data, study-level clinical trial data, and protocols from clinical 
trials in participants for medicines and indications approved in the United States (US) and 
European Union (EU) on or after 01 JAN 2014 as necessary for conducting legitimate 
research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g. risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g.
Contract Research Organizations).
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification to 
the sponsor. 


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10.1.8
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

The site must implement processes to ensure availability of all required source 
documentation. A source document checklist (not part of this protocol) will be used at 
the site to identify the source data for key data points collected and the monitor will 
work with the site to complete this. It is the expectation of the sponsor that all data 
have source documentation available at the site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in ICH-GCP guidelines 
E6(R2) § 1.51, 1.52.
10.1.9
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant
and should assure appropriate participant therapy and/or follow-up.
10.1.10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 


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site data. In this case, a coordinating investigator will be designated by mutual 
agreement.

In addition, the sponsor recognizes the right of the investigator to publish the results 
upon completion of the study. However, the investigator, whilst free to utilize study 
data derived from his/her center for scientific purposes, must obtain written consent of 
the sponsor on the intended publication manuscript before its submission. To this end, 
the investigator must send a draft of the publication manuscript to the sponsor within a 
time period specified in the contract.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10–1 will be performed by the central laboratory. 

In addition to samples for the central laboratory, other blood safety samples will be 
taken from the Screening Visit onwards for analysis at the local laboratory. These 
samples will be taken only as long as the participant has not prematurely and 
permanently discontinued study intervention. From visit 2 (Month 1) onwards, study 
participants may have their local laboratory tests taken up to 3 days prior to the study 
visit. 

eGFR (CKD-EPI) (Horio et al. 2010, Levey et al. 2009) must be measured/calculated 
locally for as long as the participant is treated with the study intervention

Up-titration or down-titration of the study intervention will be based on local potassium
and must be documented in the eCRF. Down-titration of the study intervention will 
occur for safety reasons only.

Potassium values should be recorded using a single decimal point (e.g. 4.5 mmol/L or 
mEq/L). In the event of hyperkalemia, please see Section 6.6.1 for guidance on treatment.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy testing. Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.


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Table 10–1
Protocol-Required Clinical/Safety Laboratory Assessments
Parameter
Component
Hematology
White blood cell count (WBC), red blood cell count (RBC), hemoglobin (Hb), 
hematocrit, platelets, mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), 
mean corpuscular volume (MCV), red cell distribution width (RDW)
Clinical chemistry
(full)
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (AP), creatinine kinase (CK), serum creatinine, 
eGFR (CKD-EPI (Horio et al. 2010, Levey et al. 2009), blood urea nitrogen, 
bilirubin (fractionated), sodium, serum potassium
Glycated 
hemoglobin
HbA1c
Urinalysis
Urinary albumin-to-creatinine ratio (UACR)
Biomarkers
N-terminal prohormone B-type natriuretic peptide (NT-proBNP), 
high-sensitivity troponin-t (hs-TnT)
Investigators must document their review of each laboratory safety report.


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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE 
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g. ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE. 

Events related to study-required procedures (e.g. invasive procedures, side effects 
caused by change of concomitant medication to fulfil study eligibility).
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g. endoscopy, appendectomy) that is not required 
by the study protocol as outlined by the SoA: the condition that leads to the 
procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 


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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening

The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.


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10.3.3
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of the AE/SAE CRF pages.

There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


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Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide the sponsor with a copy of any post mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated safety-relevant SAE data to the sponsor 
within 24 hours of receipt of the information.


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10.3.4
Reporting of SAEs
SAE Reporting to the Sponsor via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to the sponsor will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection transmission (see next section) in order to report the event within 24 
hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section).

Contacts for SAE reporting can be found in in the investigator site file.
SAE Reporting to the Sponsor via Paper CRF

Email transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor.

In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the investigator site file.


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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (e.g. mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview.
2. Postmenopausal female.

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
-
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 

Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Guidance:
According to pre-clinical and clinical data, Finerenone does not indicate teratogenicity/ 
fetotoxicity in early pregnancy (please refer to the Investigator’s Brochure for details). Based
on these data, women of child-bearing potential can be included into the trial if reliable 
contraception is used. 
Contraception should be used until 30 days after last intake of study intervention.


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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency Failure rate of < 1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Azoospermic partner (vasectomized or due to a medical cause)
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days.
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Highly Effective Methodsb That Are User Dependent Failure rate of < 1% per year when used consistently 
and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc

oral

intravaginal

transdermal

injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc

oral

injectable
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.)
Effective Methodsd That Are Not Considered Highly Effective Failure rate of ≥1% per year when used 
consistently and correctly.

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action

Male or female condom with or without spermicide

Cervical cap, diaphragm, or sponge with spermicide

A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-
barrier methods)c
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b) Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly.
c.) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
d) Considered effective, but not highly effective – failure rate of ≥1% per year.
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. 
Male condom and female condom should not be used together (due to risk of failure from friction).


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Male participants do not have to use condoms in the study, because there is no indication of 
male-mediated developmental toxicity. Therefore, female partners of male participants are 
also not required to use contraception.
Collection of Pregnancy Information:
Male Participants with Partners who Become Pregnant 

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in this 
study. This applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure.
Female Participants who Become Pregnant 

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant’s pregnancy. 

The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, after 
obtaining the signed informed consent from both parents, unless local law or specific 
circumstances of the respective case allow otherwise, and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 
6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for 
the procedure.
-
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 
-
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such. 

Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 

Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study.


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10.5
Appendix 5: Definitions of Clinical Events
General clinical event definitions are based on Hicks`s criteria (Hicks et al. 2018) of each 
component of the primary composite endpoint and can be found below. Further details of all 
endpoint definitions and its criteria will be provided in the Endpoint Manual and CEC 
Charter.
10.5.1
Heart Failure (HF) Events
HF events include HHF as well as urgent HF visits. All HF events are to be captured on the 
eCRF.
10.5.1.1
Heart Failure Hospitalization (HHF)

An HHF is defined as an event in which the participant is admitted to the hospital with 
a primary diagnosis of HF. The length of stay is at least 24h (or a change in calendar 
date if the hospital admission and discharge times are unavailable). The participant 
exhibits new or worsening symptoms of HF on presentation, has objective evidence of 
new or worsening HF (physical examination findings and/or laboratory criterion) and 
receives initiation or intensification of treatment specifically for HF.
10.5.1.2
Urgent Heart Failure (HF) Visits

An urgent HF visit is defined as an event in which the participant has an urgent, 
unscheduled office/practice or Emergency Room visit for a primary diagnosis of HF, 
but not meeting the criteria for a HHF. The participant is not admitted to the hospital 
and exhibits new or worsening symptoms of HF (physical examination findings and/or 
laboratory criterion) and receives initiation of intravenous diuretic or vasoactive agent 
or mechanical or surgical intervention (see Endpoint Manual for details). Of note, 
significant augmentation of oral diuretic therapy will NOT be enough to fulfill the 
urgent HF visit criteria

General consideration (urgent HF visits): Clinic visits for scheduled administration of 
HF therapies or procedures (e.g. intravenous diuretics, intravenous vasoactive agents 
or mechanical fluid removal) do NOT qualify as non-hospitalized HF events.
10.5.2
Cardiovascular (CV) Death
CV death includes any death resulting from an acute myocardial infarction, sudden cardiac 
death, sudden death, death due to HF, death due to stroke, death due to CV procedures, death 
due to CV hemorrhage, and death due to other CV causes.


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10.6
Appendix 6: Country-Specific Requirements 
Country-specific requirements will be outlined in local amendments.
10.7
Appendix 7: Calculating the Child Pugh score
The severity of liver disease (Table 10–2) will determine the Child Pugh score (Table 10–3).
Table 10–2
Grading of Severity of Liver Disease, Adapted from (Pugh et al. 1973)
Factor
+1
+2
+3
Bilirubin (mg/dL)
<2
2 – 3
>3
Albumin (g/dL)
>3.5
2.8 – 3.5
<2.8
International Normalized 
Ratio
<1.7
1.7 – 2.3
>2.3
Ascites
None
Mild
Moderate / 
Severe
Encephalopathy
None
Grade I - II
Grade III – IV
Table 10–3
Classification Using the Added Score from Table 10–2, Adapted from 
(Pugh et al. 1973)
Child-Pugh Class
A
B
C
Points
5 6
7 – 9
10 15


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10.8
Appendix 8: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment (number 2) 
is located directly before the table of contents (TOC).
Overall Rationale for all Protocol Amendments
Type of Protocol 
Amendment
Numbering/
Identifier
Type of change(s)
Global
Amendment 2
To alter certain efficacy endpoints of the study, add clarity and correct 
inconsistencies. For details, see Protocol Summary of Changes Table on 
page 2 of this document.
Country-specific
IND-2
To comply with Indian regulatory requirements, details and clarity were 
added to unblinding procedures for SUSARs that derive from disease-
related outcome events.
Country-specific
JPN-2
To account for modifications in Amendment 1 while complying with 
Japanese regulatory requirements on reporting of disease-related 
outcome events in Japan (introduced in JPN-1).
Country-specific
CHN-2
To address constraints of SARS-CoV-2 serology testing in China, 
serology test was removed in some sections of the protocol.
Country-specific
IND-1
To comply with Indian regulatory requirements, the protocol was revised 
to require the documentation of all disease-related outcome events in 
India which are to be reported as (S)AEs.
Country-specific
LTU-1
To comply with Lithuanian regulatory requirements, the protocol was 
revised to include the evaluation of LVEF and structural heart 
abnormalities at least within 90 days prior to randomization.
Global
Amendment 1
To address the requests from health authorities, add clarity and correct 
inconsistencies. For details, see Section 10.8.1.
Country-specific
USA-1
To implement the decentralized clinical trial (DCT) model in 10-20% of 
selected study sites in the US. To ensure clear and easy instructions, an 
integrated protocol (instead of a stand-alone amendment) was prepared.
Country-specific
SVK-1
To comply with Slovakian regulatory requirements, additional pregnancy 
testing was required for certain study visits.
Country-specific
GBR-1
To include erythromycin, a moderate CYP3A4 inhibitor, in the list of 
concomitant therapies that are not permitted during treatment with study 
intervention.
Country-specific
JPN-1
To add the use of the Japanese modification of the CKD-EPI equation in 
study sites in Japan, and to comply with Japanese regulatory 
requirements, the protocol was revisesd to require the documentation of 
certain disease-related outcome events in Japan which are to be 
reported as (S)AEs.
Country-specific
CHN-1
To exclude explorative biomarker assessments except for the 
biomarkers NT-proBNP and hs-TnT in patients in China,.
10.8.1
Amendment number 1: 21 SEP 2020
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union
Overall Rationale for the Amendment:
This amendment was made to address the requests from health authorities. In addition, more 
clarity has been provided and inconsistencies were corrected.


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Section # 
and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities (SoA)
8.2.3 Clinical Safety Laboratory 
Assessments
10.2 Appendix 2: Clinical 
Laboratory Tests
SARS-CoV-2 serology to be conducted at 
baseline and then annually was added.
General regulatory guidance 
to collect SARS-CoV-2 data
1.3 Schedule of Activities (SoA)
Clarification of “applicable to selected sites 
only” was added to PGIC and PGIS.
Additional clarification 
needed
1.3 Schedule of Activities (SoA)
8.2.3 Clinical Safety Laboratory 
Assessments
Biomarkers NT-proBNP and hs-TnT added 
as separate line in the SoA as they will be 
assessed less frequently 
To align with schedule of 
trials in similar populations
1.3 Schedule of Activities (SoA)
8.2.3 Clinical Safety Laboratory 
Assessments
10.2 Appendix 2: Clinical 
Laboratory Tests
The time period of local laboratory 
assessments from visit 2 (Month 1) onwards 
was changed to up to 3 days prior to the 
study visit.
To accomodate site 
requests to reduce patient 
burden to wait for lab results 
during the visit
1.3 Schedule of Activities (SoA)
8.5 Pharmacokinetics
The timing of the PK sample to be taken at 
Visit 6 (Month 12) and Month 20 and every 
8 months was changed to 1.5-10 hours 
during the visit after study intervention intake 
at home.
To optimize PK collection 
scheduling based on 
previous experience
1.3 Schedule of Activities (SoA)
8.5 Pharmacokinetics
The possiblity to postpone the PK trough 
sample from Visit 3 to Visit 4 or 5, if e.g. 
participants took study medication at home 
on the day of Visit 3, was added.
To accomodate site 
requests to provide some 
flexibility
5.1 Inclusion Criteria
Inclusion criterion #3 has been reworded: 
On diuretic treatment for at least 30 days 
prior to randomization
To avoid confusion and 
exclude occasional diuretic 
use
5.2 Exclusion criteria
Exclusion criterion #24 was changed to 
include erythromycin to the list of non-
permitted concomitant therapy.
To keep protocol consistent 
with the IB.
6.3 Measures to Minimize Bias: 
Randomization and Blinding
Pharmacokinetic and exposure-response 
analyses were added.
Standard procedure omitted 
by error in the first version
6.5 Prior and Concomitant 
Therapy
Erythromycin was added to the list of 
concomitant treatments not permitted during 
treatment with study intervention.
To keep protocol consistent 
with the IB.
6.5 Prior and Concomitant 
Therapy
Examples of BCRP/OATP substrates were 
deleted.
To avoid confusion. A list of 
BCRP/OATP substrates will 
be provided and updated 
when needed.
7.1 Discontinuation of Study 
Intervention
Initiation of treatment with an MRA was 
changed to a criterion for the premature and 
permanent discontinuation of the study 
intervention.
To be consistent with other 
sections in the protocol 
(Section 6.5) and clarify that 
concomitant use with an 
MRA is prohibited.
8.1 Efficacy Assessments
The possibility for the questionnaires to be 
read to the participant and answers 
completed by a delegated person in limited 
circumstances was added. 
To avoid missing 
questionnaire data.
8.1.3 Patient Global Impression 
of Change (PGIC) and Severity 
(PGIS)
The content of the 2 PGI questionnaires 
were added.
Updated based on feedback 
from regulatory authority
8.3.6 Disease-Related Events 
and/or Disease-Related 
Outcomes Not Qualifying as 
AEs or SAEs
The definition and handling of the disease 
related events were updated.
Section updated as figure 
was leading to confusion.
8.5 Pharmacokinetics
Details on the analyses of the plasma 
concentration versus time data were added.
Details missed by error in 
previous version
9.1 Statistical Hypotheses
9.4.1.2 Secondary Efficacy 
Variables
Details on the significance level were added 
and referred to Section 9.5.
Full details regarding 
adjustment of significance 
level added to Section 9.5 in 
response to ethics 


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Section # 
and Name
Description of Change
Brief Rationale
committee comment
9.3 Populations for Analyses
Definition of the pharmacokinetic analysis 
set (PKS) was added.
Included for completeness
9.4 Statistical Analyses
Stated that the impact of COVID-19 will be 
addressed in the SAP.
Included for completeness
9.4.1.1 Primary Efficacy 
Variable
9.4.1.2 Secondary Efficacy 
Variables
Statement that events to be evaluated by 
the CEC was updated to those could 
potentially fulfill the criteria for primary 
efficacy variables during the study and was 
moved from Section 9.4.1.2 to 9.4.1.1. 
Included for completeness. 
Statement relevant to 
primary efficacy variables 
(not secondary)
9.4.1.2 Secondary Efficacy 
Variables
Details on the significance level for testing 
secondary endpoints and components of the 
primary endpoint were updated.
Updated for clarity – original 
statement that testing will be 
conducted at „full level of 
alpha“ was ambiguous
9.4.1.2 Secondary Efficacy 
Variables
Details on the components of the renal 
endpoint were updated.
Updated based on feedback 
from regulatory agency
9.4.1.2 Secondary Efficacy 
Variables
Details on the subgroups of the 
hospitalizations for heart failure (HHF) were 
updated.
Updated to be consistent 
with data collection in RAVE
9.4.1.3 Exploratory Variables
Details on the analyses of the total number 
of CV hospitalizations, all-cause 
hospitalizations, and the change from 
baseline in NYHA class were added.
Included from the SAP for 
completeness
9.5 Interim Analyses
Details on the futility analyses and the alpha 
level and associated power loss at the final 
analysis if the study doesn’t stop for 
overwhelming efficacy at the interim analysis 
were added. 
Updated based on feedback 
from Ethics Committee
10.1.7 Data Quality Assurance
The length of time for the records and 
documents, including signed ICFs, 
pertaining to the conduct of this study to be 
retained by the investigator was changed to 
15 years after study completion unless local 
regulations or institutional policies require a 
longer retention period.
To align with current 
regulations the duration was 
updated to 15 years
In addition, editorial and administrative changes have been made throughout the document.


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10.9
Appendix 8: Abbreviations
ACC/AHA
American College of Cardiology/American Heart Association
ACEI
angiotensin-converting enzyme inhibitor
ACM
all-cause mortality
AE
adverse event
ALDO-DHF
Aldosterone Receptor Blockade in Diastolic Heart Failure
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AP
alkaline phosphatase
ARB
angiotensin receptor blocker
ARNI
angiotensin receptor neprilysin inhibitor
ARTS
Mineralocorticoid Receptor Antagonist Tolerability Study
ARTS-DN
Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic 
Nephropathy
ARTS-HF
Mineralocorticoid Receptor Antagonist Tolerability Study–Heart Failure
AST
aspartate aminotransferase
AUC
area-under-the-curve
BMI
body mass index
BNP
B-type natriuretic peptide
CEC
Clinical Event Committee
CFR
Code of Federal Regulations
CHARM
Candesartan in Heart Failure Assessment of Reduction in Mortality and 
Morbidity
CHARM-
Preserved
Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality 
and Morbidity
CHF
chronic heart failure
CKD
chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease of 2019
CRF
case report form
CV
cardiovascular
CVD
cardiovascular death
CYP3A4
cytochrome P450 isoenzyme 3A4
DAOH
days alive and out of hospital
DBP
diastolic blood pressure
DMC
Data Monitoring Committee
DREs
Disease related events
ECG
electrocardiogram
eCRF
electronic case report form


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eGFR
estimated glomerular filtration rate
EPHESUS
Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and 
Survival Study
ESC
European Society of Cardiology
EOS
end-of-study (visit)
EQ-5D-5L
EuroQol Group 5-dimension, 5-level questionnaire
EQ VAS
EuroQol visual analogue scale
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
EuroQoL
European Quality of Life (scale)
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice 
GWTG-HF
Get With the Guidelines - Heart Failure
HbA1c
glycated hemoglobin
HF
heart failure
HFmrEF
HF with mid-range EF
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure with reduced EF 
HHF
hospitalization for heart failure
HR
hazard ratio
HRT
hormone replacement therapy
hs-TnT
high-senstivity troponin-t
ICF
informed consent form 
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IR
immediate release
IV
intravenous
IxRS
interactive voice / web response system
KCCQ
Kansas City Cardiomyopathy Questionnaire
LAA
left atrial area
LAD
left atrial diameter
LAVI
left atrial volume index
LVEF
left ventricular ejection fraction
LVMI
left ventricular mass index
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities


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MR
mineralocorticoid receptor
MRA
mineralocorticoid receptor antagonist
NONMEM
non-linear mixed effect modeling
NP
natriuretic peptide
NSAID
non-steroidal anti-inflammatory drug
NT-proBNP
n-terminal prohormone B-type natriuretic peptide
NYHA
New York Heart Association
OD
once daily
PARAGON-HF
Prospective Comparison of ARNI with ARB Global Outcomes in HF with 
Preserved Ejection Fraction
PD
premature discontinuation
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
pharmacokinetics
PKS
pharmacokinetic analysis set
PT
post-treatment (visit)
RAAM-pEF
Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection 
Fraction
RAAS
renin-angiotensin aldosterone system
RALES
Randomized Aldactone Evaluation Study
RAVE
electronic data capturing system
RDW
red cell distribution width
SAE
serious adverse event 
SAF
safety analysis set 
SAP
statistical analysis plan
SBP
systolic blood pressure
SGLT
sodium glucose transport protein
SoA
schedule of activities
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction 
T2D
type 2 diabetes
TEAE
treatment-emergent adverse event
TOPCAT
Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone 
Antagonist Trial
TSS
Total Symptom Score
UACR
urinary albumin-to-creatinine ratio
US(A)
United States (of America)
WOCBP
women of child-bearing potential


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Coll Cardiol. 2006 Jan 03;47(1):76-84.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Colvin MM, et al. 2017 
ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the 
Management of Heart Failure: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines 
and the Heart Failure Society of America. Circulation. 2017 Aug 8;136(6):e137-e61.
Zannad F, McMurray JJ, Drexler H, Krum H, van Veldhuisen DJ, Swedberg K, et al. 
Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval 
Study in Heart Failure (EMPHASIS-HF). Eur J Heart Fail. 2010 Jun;12(6):617-22.
Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone 
in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 
6;364(1):11-21.

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A multicenter, randomized, double-blind, parallel-group, placebo-
controlled study to evaluate the efficacy and safety of finerenone on 
morbidity and mortality in participants with heart failure (NYHA II-
IV) and left ventricular ejection fraction = 40% (LVEF = 40%) 
NCT Number: 
NCT04435626 
Document Date: 
20 Jun 2024 
 


Statistical Analysis Plan 
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Title Page 
 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures 
The approval of the Statistical Analysis Plan is documented in a separate Signature Document. 
 
 
 
A multicenter, randomized, double-blind, parallel-group, placebo-
controlled study to evaluate the efficacy and safety of finerenone on 
morbidity and mortality in participants with heart failure (NYHA II-IV) 
and left ventricular ejection fraction ≥ 40% (LVEF ≥ 40%) 
 
FINEARTS-HF: FINerenone trial to investigate Efficacy and sAfety superioR to placebo 
in paTientS with Heart Failure 
 
Bayer study drug 
Finerenone / BAY 94-8862  
Study purpose: 
Efficacy and safety 
Clinical study 
phase: 
III 
Date: 
20 JUN 2024 
Study No.: 
 
20103 
Version: 
3.0 
Authors: 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended 
solely for the guidance of the clinical investigation. Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Table of Contents 
 
Title Page ................................................................................................................................... 1 
Table of Tables .......................................................................................................................... 3 
Table of Figures ........................................................................................................................ 3 
Abbreviations ............................................................................................................................ 4 
1. Introduction ....................................................................................................................... 6 
2. Study Objectives ................................................................................................................ 6 
3. Study Design ...................................................................................................................... 9 
4. General Statistical Considerations ................................................................................ 12 
4.1 
General Principles .......................................................................................................... 12 
4.2 
Handling of Dropouts .................................................................................................... 14 
4.3 
Handling of Missing Data .............................................................................................. 14 
4.4 
Interim Analyses and Data Monitoring .......................................................................... 15 
4.5 
Data Rules ...................................................................................................................... 16 
4.5.1 
Baseline Values .......................................................................................................... 16 
4.5.2 
Change from Baseline................................................................................................. 17 
4.5.3 
Time Window for Efficacy Events ............................................................................. 17 
4.5.4 
Annual Rate of Recurrent Events ............................................................................... 17 
4.5.5 
Other Data Handling ................................................................................................... 17 
4.5.6 
Subgroup Analyses ..................................................................................................... 18 
4.6 
Blind Review ................................................................................................................. 19 
4.7 
Testing Procedure and Multiplicity Adjustment ............................................................ 19 
5. Analysis Sets ..................................................................................................................... 21 
5.1 
Assignment of Analysis Sets ......................................................................................... 21 
6. Statistical Methodology ................................................................................................... 21 
6.1 
Population Characteristics ............................................................................................. 21 
6.1.1 
Disposition .................................................................................................................. 21 
6.1.2 
Demography and Other Baseline Characteristics ....................................................... 22 
6.1.3 
Medical History .......................................................................................................... 23 
6.1.4 
Concomitant Medications ........................................................................................... 23 
6.1.5 
Treatment and Study Duration, Extent of Exposure and Compliance........................ 25 
6.2 
Efficacy .......................................................................................................................... 26 
6.2.1 
Analysis of Primary Efficacy Variable ....................................................................... 26 
6.2.2 
Analysis of Secondary Efficacy Variables ................................................................. 29 
6.2.3 
Analysis of Further Exploratory Efficacy Variables .................................................. 33 
6.2.4 
Outcome Events Reported by the Investigators.......................................................... 35 
6.3 
Pharmacokinetics/pharmacodynamics ........................................................................... 36 
6.3.1 
Pharmacokinetics ........................................................................................................ 36 
6.3.2 
Pharmacodynamics ..................................................................................................... 36 
6.4 
Safety ............................................................................................................................. 36 
6.4.1 
Adverse Events ........................................................................................................... 36 


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6.4.2 
Laboratory Parameters ................................................................................................ 38 
6.4.3 
Other Additional Safety Variables.............................................................................. 39 
6.5 
COVID-19 and Related Issues ....................................................................................... 39 
6.6 
Regional crisis between Russia and Ukraine and Related Issues .................................. 42 
7. Document history and changes in the planned statistical analysis ............................. 44 
7.1 
Overview of Changes to SAP – from version 1.0 to version 2.0 ................................... 45 
7.2 
Overview of Changes to SAP – from version 2.0 to version 3.0 ................................... 47 
8. References ........................................................................................................................ 48 
9. Appendix .......................................................................................................................... 50 
9.1 
The Kansas City Cardiomyopathy Questionnaire Scoring Instructions ........................ 50 
 
Table of Tables 
Table 6–1: Power to exclude increased HR on ACM under different assumed treatment 
effects on CV death ............................................................................................... 28 
 
Table of Figures 
Figure 2-1: Testing procedure for primary and secondary endpoints ........................................ 8 
Figure 3-1: Study design .......................................................................................................... 10 
 


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Abbreviations 
ACEI 
Angiotensin-converting enzyme inhibitor 
ACM 
All-cause mortality 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
ARB 
Angiotensin receptor blocker 
ARNI 
Angiotensin receptor neprilysin inhibitor 
ATC 
Anatomical therapeutic chemical 
BMI 
Body mass index 
BP 
Blood pressure 
CABG 
Coronary artery bypass graft 
CEC 
Clinical event committee 
CI 
Confidence interval 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CLIPS 
Clinical Pharmacology Standards 
COPD 
Chronic obstructive pulmonary disease 
CSR 
Clinical study report 
CSS 
Clinical Summary Score 
CoV 
Coefficient of Variation 
CV 
Cardiovascular 
CYP3A4 
Cytochrome P450 isoenzyme 3A4 
DAOH 
Days alive and out of hospital 
DBP 
Diastolic blood pressure 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EoS 
End of study 
EQ VAS 
EuroQol Group visual analogue scale 
EQ-5D-5L 
EuroQol Group 5-dimension, 5-level questionnaire 
FAS 
Full analysis set 
GCP 
Good clinical practice 
HF 
Heart failure 
HHF 
Hospitalization for heart failure 
HR 
Hazard ratio 
hs-TNT 
High sensitive troponin T 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ITT 
Intention-to-treat 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LLOQ 
Lower limit of quantification 
LVEF 
Left ventricular ejection fraction 
LWYY 
Lin, Wei, Yang and Ying 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLG 
MedDRA labeling groupings 
MR 
Mineralocorticoid receptor 
MRA 
Mineralocorticoid receptor antagonist 
NT-proBNP 
N-terminal prohormone B-type natriuretic peptide 
NYHA 
New York Heart Association 
OATP 
Organic anion transporting polypeptides 
OD 
Once daily 
OSS 
Overall Summary Score 
PBMQ 
Project-specific Bayer MedDRA Queries 
PCI 
Percutaneous coronary intervention 
PD 
Pharmacodynamic 


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PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic analysis set 
PLS 
Physical Limitation Score 
PT 
Preferred term 
PWP 
Prentice, Williams and Peterson 
RR 
Rate ratio 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SGLT-2 
Sodium-glucose transport proteins-2 
SMQs 
Standardized MedDRA queries 
SOC 
 
System organ class 
SPA 
Special protocol assessment 
TEAE 
Treatment-emergent adverse event 
TIA 
Transitory ischemic attack 
TLFs 
Tables, Listings and Figures 
TSS 
Total Symptom Score 
UACR 
Urinary albumin-to-creatinine ratio 
ULOQ 
Upper limit of quantification 
WHO-DD 
World Health Organization Drug Dictionary 
WLW 
Wei, Lin and Weissfeld 


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1. 
Introduction 
This Statistical Analysis Plan (SAP) is based on the following document: 
Clinical Study Protocol Amendment 20103 dated 26 OCT 2022 
This SAP describes the statistical analysis of the double-blind placebo-controlled study 
treatment phase. An independent data monitoring committee (DMC) will be involved in the 
review of data for safety and efficacy as will be described in the DMC Charter. Blinded 
adjudication of clinical outcomes will be performed by an independent Clinical Event 
Committee (CEC), as will be described in the CEC Charter. 
2. 
Study Objectives 
Please refer to the study protocol for details on finerenone and on heart failure. 
Study 20103 will be the first large-scale, long-term outcome study investigating the efficacy 
and safety of the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone on 
morbidity and mortality in participants with heart failure (New York Heart Association 
[NYHA] class II-IV) and left ventricular ejection fraction ≥40% (LVEF ≥40%), in 
comparison to placebo and in addition to standard-of-care therapy for congestion and 
comorbidities. Primary endpoint includes Cardiovascular (CV) death and total (first and 
recurrent) heart failure (HF) events (hospitalizations for heart failure [HHF] or urgent HF 
visits) in HF patients (NYHA class II–IV) and LVEF ≥40%. Secondary endpoints will 
include: total HF events; improvement in NYHA class from baseline to Month 12; change 
from baseline to Month 6, 9 and 12 in total symptom score (TSS) of the Kansas City 
Cardiomyopathy Questionnaire (KCCQ); time to first occurrence of composite renal endpoint: 
sustained decrease in estimated glomerular filtration rate (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; time to all-cause mortality (ACM); and the safety and tolerability of 
finerenone. 
The Phase III program with finerenone in patients with type 2 diabetes and clinical diagnosis 
of chronic kidney disease (CKD) encompasses 2 placebo-controlled, large-scale, long-term 
outcome trials: FIDELIO-DKD, the first large-scale, long-term outcome trial that examined 
whether finerenone can slow the progression of kidney disease and FIGARO-DKD which is 
examining the effects of finerenone on CV outcomes. The pooled analysis of two 
complementary trials (FIDELITY-DKD) comprising 13026 patients with a broad spectrum of 
CKD and type 2 diabetes provides robust evidence of both cardiovascular and kidney 
protection with finerenone vs. placebo. Across the FIDELITY-DKD population, the relative 
risk reduction was 14% for the composite cardiovascular outcome of cardiovascular death, 
non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure and 23% 
for the composite kidney outcome of kidney failure, a sustained ≥57% decrease in estimated 
glomerular filtration rate from baseline over ≥4 weeks, or renal death. While MRAs are 
indicated for the treatment of patients with chronic symptomatic heart failure with reduced 
ejection fraction, such patients were excluded from the FIDELIO-DKD and FIGARO-DKD 
studies. The FIDELITY-DKD analysis provides evidence that finerenone use in patients with 
CKD and type 2 diabetes, a population at high risk of developing heart failure, significantly 
reduces the risk of developing HHF. In the FIDELITY-DKD analysis, reduction in HHF was 


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the main driver of the cardiovascular benefit with finerenone, with a relative risk reduction of 
22% vs. placebo (p= 0.0030), in a population that excluded patients with chronic symptomatic 
heart failure with reduced ejection fraction at the run-in visit.An inappropriate release of 
aldosterone contributes to target organ damage found in HF, myocardial infarction, chronic 
renal failure, and hypertension. The extensive expression of the mineralocorticoid receptor 
(MR) in the CV and renal systems, including the heart, endothelial cells, vascular smooth 
muscle cells, and kidney mesangial cells, provides further evidence for the role of aldosterone 
in CV and renal injury. 
Blockade of the action of aldosterone and potentially other MR ligands such as cortisol has 
been demonstrated to be of benefit in HF (Pitt et al. 1999, Zannad et al. 2010). Results from a 
short-term Phase IIb study (ARTS-HF Study 14564) suggest that treatment with finerenone in 
addition to standard therapy for HF with LVEF ≤40% improves mortality and CV morbidity 
outcomes; however, long-term outcome conclusive studies examining whether MRAs can 
prevent CV events are still lacking in this patient population. Study 20103 will be the first 
study to address these questions in the HF with LVEF ≥40% population. 
The primary objective of this study is to: 
• Demonstrate the superiority of finerenone to placebo in reducing the rate of CV death 
and total (first and recurrent) HF events (HHF or urgent HF visit) in HF patients 
(NYHA II–IV) and LVEF ≥40%. 
The secondary objectives of this study, irrespective of the testing procedure as defined in 
section 4.7, are to: 
• Determine the superiority of finerenone to placebo with regard to each of the 
following: 
o Reducing the rate of total (first and recurrent) HF events 
o Improvement in NYHA class from Baseline to Month 12 
o Change from baseline to Month 6, 9 and 12 in TSS from KCCQ  
o 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 
o Time to ACM  
• Assess the safety and tolerability of finerenone 
The testing procedure for the primary and secondary endpoints is presented in Figure 2-1, and 
described in detail in Section 4.7. 


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Figure 2-1: Testing procedure for primary and secondary endpoints
In terms of the addendum to International Council for Harmonisation (ICH) E9 (ICH 2019), 
the five attributes of the primary estimand to address the primary objective of the study are as 
follows:
a.
Population: as described by inclusion/exclusion criteria given in Section 5 of the 
protocol
b. Variable: Number of unfavorable events including CV death and total (first and 
recurrent) heart failure events
c.
Treatment condition: Finerenone vs. placebo
d. Intercurrent events: There are three important intercurrent events to consider -
Treatment discontinuation, CV death and non-CV death. For treatment discontinuation 
a treatment policy strategy will be applied, i.e. patients will be followed up for events 
after discontinuing treatment and events and follow-up time after discontinuation of 
treatment will be included in the analysis. CV death will be counted as both an 
outcome event as well as a censoring event, so that a combination of a composite and a 
while alive strategy is used. It is thus assumed that patients could have had further 
events for HF, if they had not died. This seems appropriate, as including into the 
model that no further HF events can occur after death, for example by censoring 
patients at the end of the study, would induce a bias in favor of a treatment group with 
more early deaths. Non-CV death is assumed to be a censoring event, since the 
treatment is not assumed to have an effect on these events and interest lies in the 
treatment effect on composite events while patients are alive. 
e.
Population-level summary: Ratio of exposure-weighted composite event rates between 
finerenone and placebo. Exposure-weighted refers to patients being weighted 
according to their follow-up time in determining the rate.


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A pooled analysis of study 20103 with studies FIDELIO-DKD and FIGARO-DKD will be 
pre-specified and analyses will be described in a separate SAP. Additional analyses for 
specific scientific questions outside of the scope of the clinical study report (CSR) will be pre-
specified in a separate scientific SAP. 
 
3. 
Study Design 
Study 20103 is a randomized, double-blind, parallel-group, placebo-controlled, multicenter, 
event-driven Phase III study with independently adjudicated clinical outcome assessments. This 
study will be conducted in patients with HF and LVEF ≥40%. The overall study design is 
displayed in Figure 3-1. 
Participants will be randomized in a 1:1 ratio to either finerenone or placebo. The study is 
designed to be able to show an effect on the primary endpoint with a power of 90% at an 
alpha level of 5%. It was originally anticipated that 5500 participants will be randomized and 
approximately 6900 will be screened (screening failure rate of approximately 20%). A total of 
approximately 2375 total (first and recurrent) primary composite events are targeted. Due to 
blinded event rates being lower than those assumed in the sample size calculation, the planned 
number of randomized participants was increased to approximately 6000. The target number 
of primary composite events was not changed. 
The anticipated duration of the study will be approximately 42 months, with a recruitment 
period of 24 months. However, as an event-driven study, the actual length of the study will 
depend on the observed event rates, the participant recruitment rate, and the length of the 
recruitment period.  
Enrolment in the trial may be capped based on the proportion of patients in certain LVEF 
categories, in each NYHA class, with/without atrial fibrillation, and by geographic region, 
among other variables, to ensure recruitment of a representative study population. 
The randomization will be stratified by country/region and baseline LVEF (<60%, ≥60%). 
Since all randomized participants (excluding those with critical GCP violations) belong to the 
Full Analysis Set (FAS) on which the efficacy analyses are based, it is important to avoid 
randomization of non-eligible patients into the study. 
The general study design as applied to this study is shown in Figure 3-1. There is a screening 
period, a double-blind treatment period and a safety follow-up period. Patients prematurely 
terminating from the study and up to the primary study completion will be asked to attend 
scheduled visits to collect efficacy data. 


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Figure 3-1: Study design 
 


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Screening Visit 
After providing written informed consent, a Screening Visit to confirm the participant’s 
eligibility will take place prior to randomization. The Screening Visit may take place on the 
same day as randomization (Visit 1).  
Treatment Period 
Following a screening period of up to 2 weeks, eligible participants will be randomized in a 
1:1 ratio to either finerenone or placebo. Participants with an eGFR ≤60 mL/min/1.73 m² 
measured at baseline will start with 10 mg once daily (OD) (dose level 1) with a maximum 
maintenance dose of 20 mg OD (dose level 2), whereas participants with an 
eGFR >60mL/min/1.73 m² measured at baseline will start with 20 mg OD (dose level 2) with 
a maximum maintenance dose of 40 mg OD (dose level 3). 
There will be at least 2 scheduled visits within the first 3 months from randomization: Visit 2 
will take place after 1 month and Visit 3 will take place 3 months after randomization; 
thereafter, scheduled visits will occur every 3 months until Visit 6 at Month 12. After 1 year 
from randomization, telephone contact visits will take place at Month 14 and from then 
onwards every 4 months (i.e. Month 18, Month 22, etc.) alternating with on-site visits (i.e. 
Month 16, Month 20, etc.) until the end of the study is reached.  
Up-titration is expected to occur after 4 weeks  7 days of treatment at Visit 2 (Month 1). 
Ideally, each participant will be on the maximum maintenance dose at this point. In the event of 
elevated potassium values, participants will be down-titrated to the next lower dose. Down-
titrations can be performed at any time after the start of study intervention treatment, at any 
scheduled or unscheduled visit. At any scheduled or unscheduled visit, the dose of study 
intervention may be increased to the next possible higher dose, based on serum/plasma 
potassium level and provided the participant was already on a stable dose for 4 weeks  7 days.  
Participants will attend an additional unscheduled safety visit 4 weeks  7 days after each up-
titration; potassium levels and renal function will be monitored at this safety visit. In addition 
to the protocol-specified visits, participants may be seen at any time throughout the study at 
the discretion of the investigator. 
Any changes in the study intervention dose, including interruption/permanent discontinuation 
or restart of study intervention, must be recorded in the electronic case report form (eCRF). 
It is planned that all randomized participants will remain in the study until either: 
a. an instruction is received from the sponsor after the targeted number of 
primary endpoint events have occurred 
or 
b. the study is terminated prematurely at the recommendation of the independent DMC. 
After randomization, study intervention discontinuation does not constitute the participant’s 
withdrawal from the study, and all participants should continue to be followed up. All 
randomized participants, including any participant who experiences an event considered for 
the pre-specified primary or secondary endpoints, should continue to receive double-blinded 
treatment until the study is completed, provided there are no safety grounds for discontinuing 
treatment. 


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Post-treatment Follow-up Period 
The period between a participant’s last intake of study intervention and last visit in the study 
is referred to as the ‘post-treatment follow-up period’.  
In case of premature discontinuation of study intervention, participants are expected to 
continue to attend all protocol-specified study visits, and are expected to perform all 
scheduled assessments as described in the Premature Discontinuation Schedule of Assessment 
in the protocol. 
Any participant still taking study intervention at the point of end of study will enter the 
post-treatment follow-up period after stopping study intervention at the End of Study (EoS) 
Visit. For these participants, this phase will last 30 (+5) days, and will end upon completion of 
the Post-Treatment Visit (a telephone call visit). 
4. 
General Statistical Considerations 
4.1 
General Principles 
The statistical evaluation will be performed by using the software package SAS release 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA).  
The analysis will be based on the Global Standard Tables (Version 4.0 or higher) and the 
Clinical Pharmacology Standards (CLIPS) (Version 1.2 or higher) where appropriate. 
Compound Standard Tables will be developed. 
The validity of participants for allocation to various analysis sets will be assessed in an 
ongoing manner in blind review meetings and decisions will be documented in the blind 
review reports prior to unblinding.  
A log-normal distribution is assumed for urinary creatinine and albumin, urinary albumin-to-
creatinine ratio (UACR), and N-terminal prohormone B-type natriuretic peptide (NT-
proBNP). For all other metric variables, a normal distribution is assumed. The distributional 
assumptions will be investigated and if necessary, nonparametric methods or transformation 
of the data will be considered.  
All variables will be analyzed by descriptive statistical methods. The number of data 
available, mean, standard deviation (SD), minimum, median, and maximum will be calculated 
for metric data. The geometric mean, SD and coefficient of variation (CoV) will be provided 
instead of the arithmetic mean and SD for the variables where log-normal distributions are 
assumed, as follows: 
𝐶𝑜𝑉= √exp(𝑆𝐷𝑙𝑛
2 ) −1 
𝑆𝐷𝑙𝑛 being the standard deviation of the log-transformed values. Frequency tables will be 
generated for categorical data. 
The laboratory parameter eGFR will be calculated based on the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula (Levey et al., 2009) for all analyses 
specified in this SAP. For patients recruited in Japan, the Japanese formula adjustment will be 
applied (Horio et al., 2010). 
All participants will be analyzed according to the planned treatment group in FAS per the 
intention-to-treat (ITT) principle. All participants will be analyzed according to the actual 
treatment in the Safety Analysis Set (SAF). If a participant receives both treatments due to a 


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bottle error, the treatment actually received for the majority of the time in the study will be 
used in SAF. 
Only adjudicated outcome events will be used for analysis of the primary and secondary 
efficacy variables (except for sustained decrease in eGFR ≥50% relative to baseline over at 
least 4 weeks and sustained eGFR decline <15ml/min/1.73m2 which will be derived from 
central laboratory measurements and not be adjudicated); Section 6.2.4 specifies how 
investigator-reported outcomes for these variables will be summarized. Outcome events for 
exploratory efficacy variables (e.g. non-fatal myocardial infarction, non-fatal stroke, etc.) will 
not be adjudicated. 
The stratified analyses mentioned in this SAP will be conducted in consideration of the 
randomization stratification factors: 
• LVEF: <60%, ≥60% 
• Pooled region for stratified analyses: randomization will be stratified by 
country/region, for the analyses individual countries/regions will be combined into 
pooled regions as follows: 
o Western Europe and Oceania: Australia, Austria, Denmark, Germany, Israel*, 
Netherlands, New Zealand, United Kingdom 
o Southwestern Europe: Italy, Portugal, Spain 
o Central Europe: Czechia, Hungary, Poland, Slovakia 
o Southeastern Europe: Bulgaria, Greece, Romania, Turkey 
o Northeastern Europe: Finland, Latvia, Lithuania, Russia, Ukraine 
o Asia: China, Hong Kong, India, Japan, Malaysia, South Korea, Taiwan 
o North America: Canada, United States of America 
o Latin America: Argentina, Brazil, Colombia, Mexico 
*Although not geographically located in Western Europe or Oceania, Israel has been included 
in this pooled region. 
In case of issues (e.g. model convergence) with using these predefined pooled regions at the 
final analyses, the pooled regions may be further combined. Any such changes will be 
described in the CSR. 
All participants will be analyzed according to their correct stratification category. In case of a 
large number of stratification errors (≥5% of all patients in the FAS), the primary analysis will 
also be repeated based on the stratification category used in the randomization as a sensitivity 
analysis. 
In case a death cannot be clearly adjudicated as CV-related or non-CV related, it will be 
adjudicated as undetermined death. Undetermined deaths will be handled as non-CV deaths 
for the analysis, unless otherwise specified. Where applicable, the combined results of non-
CV deaths and undetermined death will be displayed along with results for the individual 
categories. 


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4.2 
Handling of Dropouts 
A participant who has been randomized and discontinues study participation prematurely for 
any reason, either during study treatment or during post-treatment follow-up, is defined as a 
‘dropout’, even if no study drug has been taken. Dropouts will not be replaced. 
Data from participants who prematurely terminated the study will be used to the maximum 
extent possible. 
The number of participants discontinuing the epochs, together with the primary reason for 
discontinuation, will be summarized as described in Section 6.1.1. 
The number of participants who prematurely discontinue the study and / or study treatment for 
any reason, as well as the reasons for premature discontinuation of study and / or study 
treatment, will be reported. Kaplan-Meier plots for “patients still participating in study” and 
“patients still on study treatment” will be provided. 
All dropouts and participants prematurely discontinuing study treatment will be evaluated 
with respect to  
• baseline characteristics 
• potential differences between the treatment groups in the proportion of participant 
withdrawals or in the timing of withdrawals 
• the reasons for premature discontinuation of study and/or study treatment. 
4.3 
Handling of Missing Data 
All missing or partial data will be presented in the subject data listing as they are recorded on 
the eCRF.  
General Rules 
When appropriate, the following rules will be implemented so as not to exclude participants 
or observations from statistical analyses due to missing or incomplete data. 
Concomitant medications with missing start and stop date but flagged as being ongoing at a 
participant’s final visit will be considered to have started prior to study medication start and 
ended after stopping of study medication. The start and end reference period will be imputed 
as “before” for the medication start and as “during/after” for the medication end. 
In case of partially missing dates for interruptions or permanent stop of study medication 
intake, a ‘worst-case’ approach will be applied to impute the start and end dates of study 
medication intake as the earliest and latest possible dates, i.e.: 
• first month of the year and/or first day of the month for a partially missing start date, 
and 
• last month of the year and/or last day of the month for a partially missing end date. 
If a participant died earlier than the imputed worst study medication end date, the death date 
will be taken as the study medication end date. However, if these imputations lead to a 
temporal overlap between different exposure date records, the imputed dates will be adjusted 
so that no overlap exists and the time on the higher dose is maximized. The date of first 
exposure to treatment is not expected to be missing as the patients are instructed by the 
investigator to take their first dose of study drug directly at Visit 1, but in the very rare case 


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that this date is not recorded, it will be imputed according to the rules outlined above for 
missing start dates, but not earlier than the randomization date.   
When only partial dates are available for clinical events in the efficacy analysis, a median 
imputation rule will be used: 
• For example if the day is missing and the month is July, then day 16 is chosen.  
• If the number of potential values is even, the lower of the 2 middle numbers is taken. 
For example, if the day is missing and the month is June, then day 15 is imputed. The 
same rule applies if the day and month are missing, e.g. if the year is 2017 and the day 
and month are missing, 2nd July is used.  
• In case the range of possible values is further restricted, e.g. because a patient is 
randomized in the month in which the day is missing or the participant died in the 
month in which the day is missing, the median in the restricted set of possible values is 
calculated. For example, if the clinical event occurred in June 2017 and the respective 
patient died on 11th June 2017, 6th June 2017 is imputed as the date of the clinical 
event.  
In case a death date is completely missing, it will be imputed on the basis of the last known 
contact when the participant was still alive and the first known contact when the participant 
was dead (e.g. from the participant health status follow-up page) as the median of these two 
dates. As above, if the number of potential values is even, the lower of the two middle 
numbers is taken. 
In case both a non-fatal clinical event and death have partially missing dates, then death takes 
precedence and will be imputed first according to the rules outlined above. This also applies 
for non-CV death. 
However, given the importance of an accurate determination of the adjudicated event date in 
relation to randomization date for the time to event analysis, we would expect a minimal 
number of such missing dates. 
A worst-case approach will be applied for determining whether an adverse event (AE) with 
partially missing dates is treatment-emergent or not, i.e. if it is possible that the AE start date 
is within a period of study drug intake +3 days (on or after study treatment start date and on or 
before study treatment end date + 3 days) then the AE is considered treatment-emergent. 
If intensity of the AE is missing, the event will be considered as severe. If the drug 
relationship is missing, the event will be considered as being related to the study drug. 
4.4 
Interim Analyses and Data Monitoring 
One non-binding interim analysis for futility is planned when approximately 30% (~710) of 
the required total number of primary endpoint events have been observed. If the observed rate 
ratio (RR) on the primary endpoint is above 0.95, the trial is planned to be stopped for futility. 
This gives a probability of approximately 69% to stop under the null hypothesis (i.e. no 
treatment effect on the composite of HHFs and CV deaths) and leads to a loss in power of less 
than 1% under the alternative hypothesis of the treatment effect assumed for the sample size 
determination. No adjustment for this loss in power will be made. 
The futility analysis given above is considered to be non-binding, the DMC will be asked to 
also consider important secondary efficacy endpoints as well as safety in their assessment.  


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In addition, one formal interim analysis for efficacy is planned when approximately 2/3 
(~1580) of the required total number of primary endpoint events have been observed. 
If the interim analysis shows clear and consistent benefit in the finerenone treatment group, 
the DMC may recommend early study termination. The Haybittle-Peto rule will be used to 
guide the decision regarding early stopping of the study for success: a reduction of 3 standard 
deviations (of the test statistic) in the analysis of the primary efficacy endpoint (two-sided 
p-value <0.0027) at the interim analysis. In addition, a nominal significant effect on the CV 
death component should be present (two-sided p-value<0.05) at the interim analysis. Note: 
The criterion for CV death would not be considered to prove formal statistical significance, as 
it does not keep the alpha level. It has been added so that the trial is only stopped at the 
interim if there is at least a certain amount of evidence of a beneficial treatment effect on CV 
death.  
See Section 4.7 for a detailed description of the testing procedure, including an adjustment of 
the significance level for the interim analysis. 
If the study is stopped early, the primary analysis reported in the CSR will consider all events 
up to the participants’ respective EoS visits as would have been the case if the study had not 
stopped early. A sensitivity analysis will take all events up to the interim analysis datacut date 
into consideration. For this sensitivity analysis, censoring dates after the datacut date will be 
reset to the datacut date. 
A detailed plan for the routine DMC safety analyses and the interim analysis will be covered 
in the DMC charter, the analysis planned to be provided to the DMC will be described in a 
separate SAP with Tables, Listings and Figures (TLFs) attached to the DMC charter. The 
DMC will review the data in an unblinded manner, both for the routine safety tables and the 
interim analysis. There are no predefined stopping conditions for the ongoing safety 
monitoring of this trial. The statistical analysis for the DMC meetings will be performed by an 
independent statistical analysis center. The sponsor will oversee and discuss with the Steering 
Committee overall blinded event rates to ensure that they are in line with protocol 
assumptions. If overall event rates are lower than expected, consideration will be given to 
altering the study design, such as increasing the sample size or extending the study duration 
without knowledge of any treatment effect.  
4.5 
Data Rules 
General data rules are described in this section, further data rules for specific parameters or 
analyses are specified in the respective subsections of Section 6. 
4.5.1 
Baseline Values 
Baseline values will be defined as the last non-missing measurement before or on the day of 
randomization. If the last observation available prior to randomization is the measurement 
from the Screening Visit, this would be used as the baseline value. This also includes 
assessments from a local laboratory, if no assessment from the central laboratory prior to first 
intake of study drug is available. Otherwise baseline will be missing.  
If more than one measurement was planned for a scheduled time point, for example blood 
pressure (BP) measurements and heart rate, the mean value of the last set of measurements per 
time point prior to randomization will be used as the baseline value. In case of repeated 
measurements for pre-treatment visits and Visit 1 (Day 1; baseline), the closest measurement 
prior to the randomization will be used for analysis instead of the scheduled measurements. 


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When the Screening and Baseline visits are performed on the same day for a participant, the 
following assessments (scheduled to be performed at both the Screening and Baseline visits) 
will only be performed once and the data will appear under Screening: 
• NYHA class 
• Vital signs 
• Local lab potassium and creatinine 
• Pregnancy test 
Where necessary, these data will be considered in the derivation of baseline values per the 
rules above.  
4.5.2 
Change from Baseline 
Change from baseline will in general be displayed as absolute change from baseline defined 
as the difference to baseline, i.e.: 
Absolute change = Post baseline value – baseline value. 
Some parameters will be additionally analyzed as relative change defined as 
Relative change = 100 * [(post baseline value – baseline value) / baseline value]. 
For specific analyses, the relative decrease of a variable will be analyzed instead of the 
relative change. The relative decrease is equivalent to the negative of the relative change and 
defined as  
Relative decrease = 100 * [(baseline value – post baseline value) / baseline value]. 
4.5.3 
Time Window for Efficacy Events 
Events for time to first / recurrent analyses (e.g. primary efficacy endpoint) will be counted 
from the day of randomization (planned at Visit 1) onwards until the EoS visit following the 
study termination decision, or until the date of EoS notification + 4 weeks, if the EoS visit has 
not been performed. In the event of premature discontinuation from the study with no 
subsequent follow-up information, events will be counted up to the day of the last visit when 
information on the component is available. 
4.5.4 
Annual Rate of Recurrent Events 
The annual rate of a recurrent event for an individual patient is calculated as: 
Annual rate = (Total number of events) / (Follow-up time (days) / 365.25) 
4.5.5 
Other Data Handling 
Only the data provided by the central laboratory will be used for analysis; values from local 
laboratories will not be used in the statistical analysis unless otherwise specified and will be 
listed only. For example, as described above, local values will be used in the derivation of 
baseline, if no central measurement is available (cf. Section 4.5.1). 
At all visits post-randomization and if not stated otherwise, only the values at scheduled 
measurements will be used for analysis. 
For the derived visit “Any time post baseline” (applicable for efficacy) this will include any 
measurement after randomization, including unscheduled assessments. For the derived visit 


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“Any time on treatment” (applicable for efficacy), only assessments on or after study 
medication start date until 30 days after last study drug administration, including unscheduled 
assessments, will be considered. For safety, “Any time treatment-emergent” will include 
measurements on or after study medication start date until 3 days after last study drug 
administration, including unscheduled assessments. 
For values which are < LLOQ (Lower limit of quantification), half the value of the LLOQ 
will be used for analysis. Differences between two values < LLOQ will be assigned values of 
0. Ratios between two values < LLOQ will be assigned a value of 1. For values which are > 
ULOQ (Upper limit of quantification), the ULOQ will be used for analysis. 
In case of non-normally distributed data, descriptive statistics other than minimum, maximum 
and median will only be calculated if at least 2/3 of the individual data were measured and 
were above the lower limit of quantification. In tables showing descriptive statistics, where 
values below LLOQ are included, these descriptive statistics will be marked.  
4.5.6 
Subgroup Analyses 
Exploratory subgroup analysis will be done for the primary and secondary efficacy variables. 
The subgroup analyses will include subgroups based on the stratification factors. The list of 
key subgroups (in addition to the stratification factors) and other subgroups analyzed is 
specified below. Analysis will include descriptive statistics, graphical display of estimated 
treatment effects with 95% confidence intervals (CIs) in a forest plot and a statistical test for 
interaction. 
Subgroups based on stratification factors  
• Pooled region for subgroup analysis (Western Europe, Oceania and Others; Eastern 
Europe; Asia; North America; Latin America); the subgroup Western Europe, Oceania 
and Others combines the groups Western Europe and Oceania and Southwestern 
Europe from the pooled region for stratified analyses. The subgroup Eastern Europe 
combines the groups Central Europe, Southeastern Europe, and Northeastern Europe 
from the pooled region for stratified analyses.  
• LVEF (<60%, ≥60%) 
Key subgroups 
• Baseline serum potassium value ( 4.5, > 4.5 mmol/L) 
• eGFR category at baseline (eGFR <60, ≥60 mL/min/1.73 m²)  
• Atrial fibrillation at baseline electrocardiogram (ECG) (present, absent)  
• Diabetes Mellitus at baseline (present, absent) 
• Index HF event (very recent (≤ 7 days before randomization), recent (> 7 days – ≤ 3 
months), > 3 months or no index HF event).  
Other subgroups 
• Race (white, black, Asian, other) 
• Sex (male, female) 
• Age ( median vs. > median) 
• Baseline body mass index (BMI) (< 30 vs. ≥30 kg/m2) 


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• Systolic blood pressure (SBP) at baseline ( median vs. > median )  
• Angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB) 
or angiotensin receptor-neprilysin inhibitor (ARNI) use at baseline (yes, no) 
• Treatment with sodium-glucose transport proteins-2 inhibitor (SGLT-2i) (yes, no) 
• NYHA functional class at baseline (II, III/IV) 
• Baseline NT-proBNP (≤ median vs. > median) 
• Baseline UACR (<30 vs. ≥30 mg/g)  
For subgroups split by median, the FAS will be taken as reference population for derivation of 
median.  
Individual country analyses, e.g. for Japan, required for regulatory purposes, will be included 
in a country-specific study SAP.  
4.6 
Blind Review 
The results of the final data assessment will be documented in the final list of important 
deviations, validity findings and assignment to analysis set(s). Any changes to the statistical 
analysis prompted by the results of the review of study data will be documented in an 
amendment and, if applicable, in a supplement to this SAP. 
4.7 
Testing Procedure and Multiplicity Adjustment 
If the interim analysis shows clear and consistent benefit in the finerenone treatment group 
(defined as two-sided p-value <0.0027 for the primary efficacy endpoint and two-sided p-
value <0.05 for the CV death component at the formal interim analysis for efficacy) the DMC 
may recommend early stopping of the study for success (see Section 4.4 for full details). 
If the study is stopped early for success: the final analysis for the primary endpoint will be 
performed at an overall two-sided significance level of 0.0027. Additionally, the secondary 
endpoints of: 
• Total (first and recurrent) HF events 
• Improvement in NYHA class from Baseline to Month 12 
• Change from baseline to Month 6, 9 and 12 in TSS from KCCQ  
• Time to first occurrence of composite renal endpoint 
will be formally tested. The testing strategy of the secondary endpoints is as follows: 
1. Total HF events will be tested at the 0.0027 two-sided significance level. 
2. If the hypothesis of the secondary endpoint total HF events is rejected, the NYHA 
class and KCCQ endpoints will be tested using the Bonferroni-Holm procedure, i.e. if 
at least one of the hypotheses of the two endpoints NYHA class and KCCQ can be 
rejected at the two-sided (0.0027/2) significance level, the remaining of the two 
endpoints will be tested at the 0.0027 significance level. 
3. If the hypotheses for all previous secondary endpoints are rejected, the composite renal 
endpoint will be tested at the 0.0027 significance level. 


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If the test for any endpoint produces a non-significant result, the testing of the remaining 
endpoints further down in the procedure will be performed in an explorative manner only. 
Furthermore, the second component of the primary endpoint (CV deaths) will be tested at the 
0.0027 two-sided significance level outside of the alpha-preserving procedure for the primary 
and other secondary efficacy endpoints (Total HF events, NYHA class, KCCQ, renal 
composite). 
If the study is not stopped early for success: a group sequential design with a single interim 
analysis when 2/3 of the information is available with a stopping rule of two-sided p <0.00270 
would require a small adjustment to the alpha level at the final analysis to maintain the overall 
significance level at 0.05. For an information fraction of 2/3, the adjusted alpha level of 
0.04967 applies. If the study is not stopped early for success a p-value of p<0.04967 is 
therefore required at the final analysis to achieve formal statistical significance.  
If the primary hypothesis is rejected, the secondary endpoints of: 
• Total (first and recurrent) HF events 
• Improvement in NYHA class from Baseline to Month 12 
• Change from baseline to Month 6, 9 and 12 in TSS from KCCQ  
• Time to first occurrence of composite renal endpoint 
will be formally tested with the following test strategy: 
1. Total HF events will be tested at the 0.04967 two-sided significance level. 
2. If the hypothesis of the secondary endpoint total HF events is rejected, the NYHA 
class and KCCQ endpoints will be tested using the Bonferroni-Holm procedure, i.e. if 
at least one of the hypotheses of the two endpoints NYHA class and KCCQ can be 
rejected at the two-sided (0.04967/2) significance level, the remaining of the two 
endpoints will be tested at the 0.04967 significance level. 
3. If the hypotheses for all previous secondary endopints are rejected, the composite renal 
endpoint will be tested at the 0.04967 significance level. 
If the primary hypothesis is not rejected, these tests will be performed in an explorative 
manner only; similarly, if the test for any secondary endpoint produces a non-significant 
result, the testing of the remaining endpoints further down in the procedure will be performed 
in an explorative manner only. 
Furthermore, if the primary hypothesis is rejected then the second component of the primary 
endpoint (CV deaths) will also be tested at the 0.04967 two-sided significance level outside of 
the alpha-preserving procedure for the primary and other secondary efficacy endpoints (total 
HF events, NYHA class, KCCQ, renal composite). 
Regardless of whether the study is stopped early for success: as a hard endpoint and 
objective indicator of benefit-risk, time to ACM will be tested at a two-sided significance 
level of 0.05, after the rejection of the primary hypothesis. Testing of time to ACM will thus 
be done outside of the alpha-preserving procedure for the primary and other secondary 
efficacy variables (total HF events, NYHA class, KCCQ, renal composite).  


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5. 
Analysis Sets 
5.1 
Assignment of Analysis Sets 
Final decisions regarding the assignment of participants to analysis sets will be made during 
the review of study data and documented in the final list of important deviations, validity 
findings and assignment to analysis set(s) (see Section 4.6). 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled 
All participants who sign the informed consent form (ICF) 
Randomly assigned to study 
intervention 
All participants randomly assigned to study intervention 
Full analysis set (FAS) 
All randomized participants. Participants will be analyzed 
according to the intervention they were randomized to. The only 
potential reasons for exclusion would be a clearly erroneously 
randomization, or major good clinical practice (GCP) violations, 
for example, a suspicion of fraud. 
Safety analysis set (SAF) 
All participants in the FAS who take at least 1 dose of study 
intervention. Participants will be analyzed according to the 
intervention they actually received. 
Pharmacokinetic analysis set 
(PKS) 
All finerenone-treated participants (with the exception of 
participants excluded on the grounds of critical GCP violations) 
with at least 1 valid finerenone plasma concentration and 
without validity findings which would interfere with the 
evaluation of the pharmacokinetic (PK) data. 
Listing-only set 
All participants enrolled who were not randomized or were 
excluded from the FAS. Their data is provided as individual 
participant data listings and will not be included in any statistical 
analyses.  
6. 
Statistical Methodology 
6.1 
Population Characteristics 
Population characteristic analyses, except for participant disposition, will be performed for the 
FAS, if not stated otherwise. 
6.1.1 
Disposition 
The number of participants enrolled, randomized and valid for the FAS and SAF will be 
summarized overall and by treatment group, country/region and study site. The number of 
participants discontinuing each epoch, together with the primary reason for discontinuation 
will be presented by treatment group (post-randomization epochs only) and overall in separate 
tables. In addition, the number of participants with important deviations will be presented 


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overall, by country/region for each treatment group, and in total. The frequencies of each 
important deviation and validity finding will be presented by treatment group and in total.  
6.1.2 
Demography and Other Baseline Characteristics 
Demography includes age (continuous and categorized by 40-<65, 65-<75, 75-<85, ≥85), sex, 
race, pooled region (for stratified analysis and for subgroup analysis), body weight 
(continuous and categorized by <60, 60-<90, ≥90 kg), body height, BMI (continuous and 
categorized by <30 vs. ≥30 as well as by <18.5, 18.5 to <25, 25 to <30, 30 to <35, ≥35 
kg/m2), hip and waist circumference and waist-hip ratio, smoking history (never, former, 
current smoker) and alcohol consumption.  
Other baseline characteristics include baseline 
• LVEF (continuous and categorized by <60% vs. ≥60% as well as <50, 50-<60, ≥60%) 
• NYHA Class (II, III, IV)   
• index HF event (randomized during/at HF event, very recent (≤ 7 days from 
randomization), recent (>7 days - ≤ 3 months), >3 months, no index; as well as ≤ 7 
days from randomization, >7 days - ≤ 3 months, >3 months or no index event)  
• type of (latest) index HF event with respective timing (hospitalization for heart failure, 
urgent HF visit, no index event) 
• serum potassium (continuous and categorized by ≤4.5 mmol/L vs. >4.5 mmol/L) 
• eGFR (calculated by CKD-EPI formula, Japanese formula adjustment made for 
participants recruited in Japan; continuous and categorized by <60 vs. ≥60 
mL/min/1.73 m² as well as <45, 45 to <60, 60 to <90, ≥90 mL/min/1.73 m²),  
• serum creatinine (continuous) 
• SBP (continuous and categorized by <90, 90-<130, 130-<160, ≥160 mmHg) 
• diastolic blood pressure [DBP] (continuous) 
• heart rate (continuous) 
• NT-proBNP (continuous) 
• UACR (continuous and categorized by <30 vs. ≥30 as well as <30, 30-<300, ≥300 
mg/g) 
• history of LVEF<40% (yes [improved], no). For participants with a history of LVEF 
<40%, prior LVEF values will be summarized. 
• Atrial fibrillation at baseline per ECG 
• Diabetes Mellitus at baseline 
• ACEI, ARB or ARNI use at baseline 
• SGLT-2i use at baseline. 
All demographic data and baseline characteristics will be tabulated by treatment group and 
overall. The demographic and other baseline characteristics table will also be presented, 
separated by each level of the stratification factors. 


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The non-stratified demographic and other baseline characteristics table will be repeated for 
the SAF if ≥5% of randomized patients do not take at least one dose of study intervention (i.e. 
are in the FAS but not the SAF). 
As stated in Section 4.2, demographics and other baseline characteristics will also be 
presented separately for participants prematurely discontinuing the study and for participants 
permanently discontinuing study treatment.  
6.1.3 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Medical history will be presented for each MedDRA Primary System Organ 
Class (SOC) and Preferred Term (PT) by treatment group and overall in a summary table. 
Additional medical history terms by the following Standard MedDRA Queries (SMQs), 
Project-specific Bayer MedDRA Queries (PBMQs), Bayer MedDRA Labeling Groupings 
(MLGs) or selected PTs will also be presented: 
• Hyperlipidemia (MLG) 
• Hypertension (MLG) 
• Type 2 diabetes mellitus (PT) 
• Atrial fibrillation/flutter (PBMQ) 
• Ischemic Stroke/Transitory Ischemic Attack (TIA) (PBMQ) 
• Myocardial Infarction (MLG) 
• Coronary Artery Disease (PBMQ) 
• Peripheral Arterial Occlusive Disease (PBMQ) 
• Cardiac Failure (MLG) 
• Coronary Artery Bypass Graft (CABG) (PBMQ) 
• Chronic Obstructive Pulmonary Disease (COPD) (PT) 
• Percutaneous coronary intervention (PCI) (PBMQ) 
• COVID-19 (SMQ narrow) 
• Hepatic cirrhosis (PT) 
• Sleep Apnea Syndrome (PT) 
• Chronic Kidney Disease (CKD) (PT) 
The medical history tables will be repeated for SAF. 
6.1.4 
Concomitant Medications 
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). The number of participants who took at least one concomitant medication and 
the number of participants who took at least one medication that started before administration 
of study drug will be presented by treatment group and overall using anatomical therapeutic 
chemical (ATC) classes and subclasses.  


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These tables will be repeated summarizing the number of participants with medications in the 
Standard drug groups of interest. In addition, the number of participants who took at least one 
concomitant medication that started after start of study drug and the number of participants 
who took at least one medication ongoing at baseline (i.e. starting before or on the day of 
randomization and ending at least one day after the day of randomization) will be presented 
by treatment group and overall. Standard drug groups of interest are: 
• ACEIs and ARBs 
• ARNIs 
• Beta-blockers 
• Loop diuretics 
• Thiazide diuretics 
• Digoxin 
• Nitrates 
• Potassium supplements 
• Potassium lowering agents (including binders) 
• Alpha blocking agents 
• Calcium channel blockers 
• Centrally acting antihypertensives 
• Strong, unclassified, moderate, weak cytochrome P450 isoenzyme 3A4 (CYP3A4) 
inhibitors  
• Strong, unclassified, moderate, weak CYP3A4 inducers 
• Aspirin 
• Statins 
• MRAs 
• Organic anion transporting polypeptides (OATP) substrates 
 
Anti-diabetic drugs 
• Insulin and analogues 
• SGLT-2 inhibitors 
• Other anti-diabetic drugs (Dipeptidyl Peptidase 4 inhibitors or Glucagon-like peptide-
1 agonists or Biguanides or Sulfonylureas or Alpha glucosidase inhibitors or 
Metiglinides or Thiazolidinediones.) 
A participant will be counted only once within each ATC class / subclass or Standard drug 
group, respectively. 
A listing will be provided including all medications classified as a strong, unclassified, 
moderate, or weak CYP3A4 inhibitor according to the drug groupings together with the 
respective classification information. 


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For potassium lowering agents, ACEIs, ARBs, diuretics and SGLT-2 inhibitors shift tables for 
changes of use for baseline vs. any time treatment-emergent will be provided. 
The number of participants with MRA use during follow-up will be given by substance.  
6.1.5 
Treatment and Study Duration, Extent of Exposure and Compliance 
The analyses described in this section will be repeated for the SAF if ≥5% of randomized 
patients do not take at least one dose of study intervention (i.e. are in the FAS but not the 
SAF). All tables and figures regarding treatment duration, extent of exposure and compliance 
will be presented by treatment group and overall (unless otherwise stated). 
Treatment duration, defined as time from start of study drug to permanent stop of study drug 
(in months), will be summarized using descriptive statistics by treatment group and overall. 
The total duration in patient-years will be provided. In addition, treatment duration will be 
categorized to ≤ 1 month, 1 – 3 months, >3 – 6 months, >6 – 12 months, and then further six-
monthly intervals, and presented with the corresponding number and percentage of 
participants. Cumulative treatment duration will be categorized to at least one dose, at least 1 
month, at least 3 months, then further 3 monthly intervals. A table will be presented with the 
absolute and relative frequencies of participants still on study medication at each visit. 
Kaplan-Meier plots for “patients still on study treatment” will be provided, as also described 
in Section 4.2. 
The above analyses will be repeated for study duration, from the day of randomization to the 
EoS visit. 
The extent of exposure to study drug (total amount of intake in grams) and the average daily 
dose in mg during treatment will be summarized using descriptive statistics by treatment 
group. The table will be repeated by participants starting on 10 mg and 20 mg, respectively. 
The number and percentage of participants on each dose level (blinded) will be summarized by 
visit and treatment group, overall and differentiated by participants starting on 10 mg or 20 mg. 
The overall titration status, regardless of actual or sham up-titration, will be summarized with 
absolute and relative frequencies per treatment group, overall and differentiated by patients 
starting on 10 mg or 20 mg. In addition, the number of patients with study drug down-titrated 
or temporarily interrupted (dose recorded as 0 mg) as well as associated reason will be 
summarized with absolute and relative frequencies per treatment group, overall and 
differentiated by participants starting on 10 mg and 20 mg, respectively. 
The overall compliance (as a percentage) will be calculated as follows:  
100 * Number of tablets taken / Number of planned tablets. 
The number of planned tablets will be calculated as follows: 
(Days from randomization to last intake of study drug + 1) * Number of planned tablets per 
day. 
For participants who withdraw prematurely from the study drug, compliance will be 
calculated up to the time of last dose. 
The overall compliance will be summarized descriptively by treatment group and overall. In 
addition, percentage compliance will be categorized into three groups, less than 80%, 80 to 
120% and greater than 120%, and the categories will be summarized by treatment group and 
overall. 


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6.2 
Efficacy 
6.2.1 
Analysis of Primary Efficacy Variable 
Events that could potentially fulfill the criteria for primary efficacy variables during the study 
will be evaluated by the CEC. Definitions of individual endpoints (e.g. CV death) will be 
provided in the Endpoint Manual.  
 
6.2.1.1 
Primary Efficacy Variable: Primary Analysis 
The primary Estimand as defined in Section 2 will be used for the primary analysis. The 
primary endpoint is the composite of CV death and total (first and recurrent) HF events (HHF 
or urgent HF visit) in HF patients. The primary analysis of this endpoint will be performed in 
the FAS using the planned treatment group, in line with the ITT principle. 
Participants without an event of the primary composite endpoint at the time of analysis will be 
censored at the date of their last contact or date of non-CV death. 
The number and incidence rate of primary endpoint events and censoring events (i.e. non-CV 
death) will be summarized per treatment group, both overall and per individual event 
category. 95% CIs of the incidence rates will be derived based on a Poisson model with robust 
variance estimator. 
The primary analysis of the primary composite endpoint will be based on a stratified 
Andersen-Gill model (Andersen, 1982) including treatment group as fixed effect and 
including pooled region for stratified analyses and baseline LVEF (<60%, ≥60%) as 
stratification factors. Robust standard errors (sandwich estimator) will be used to account for 
correlations of event times within a participant. As shown by Lin et al. 2000, the Andersen-
Gill model with robust standard errors can be interpreted as a proportional rates model. After 
the authors of the paper, the model is also referred to as Lin, Wei, Yang and Ying (LWYY) 
model. Let θ be the RR for the finerenone versus placebo group. In order to evaluate whether 
finerenone is superior to placebo in reducing the rate of the composite event of CV death and 
total HF events the following null hypothesis will be tested using the model above (see 
Section 4.7 for details regarding the nominal significance level): 
                         𝐻0: 𝜃= 1  versus  𝐻1: 𝜃≠1, 
where θ < 1 represents a treatment benefit of finerenone over placebo. 
A point estimate of the RR together with a 95% CI will be presented alongside the point 
estimate and hazard ratio for the censoring event of non-CV death, calculated using a 
stratified Cox proportional hazards model.  
The primary analysis method has been investigated with extensive simulation studies and it 
has been confirmed that it keeps the alpha level and has good operating characteristics across 
a range of plausible scenarios. A small adjustment will be made to the nominal significance 
level and the critical value at the final analysis to take into account the interim analysis (see 
Section 4.7 for details). No adjustment to the sample size calculation is done for this.  
The SAS code below illustrates the program for the Anderson-Gill model: 
PROC PHREG DATA=primary COVS(aggregate); 
  MODEL (time_start, time_rec)*status(0)=treat/ties=efron rl; 
  ID patid; 


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  STRATA {stratum}; 
RUN; 
 
primary is the input dataset, time_start is the previous event stop time and time_rec 
is the current event stop time, the censoring variable status (0 for censored and 1 for event) 
should take the value 1 if the last event is a CV death and 0 if it is censored for a non-CV 
death or at the end of study for the given patient; patid is the participant ID and treat is 
the treatment group identifier. 
If a participant experiences an HF event and subsequently dies for a cardiovascular reason, 
this will be considered as two separate events for the primary analysis unless the participant 
dies on the same calendar day as the HF event (both events would still be considered for the 
analyses of the separate components). If a participant is hospitalized for HF shortly after an 
urgent HF visit, this will be considered as two separate events for the primary analysis unless 
they occur on the same calendar day. 
Additionally, plots and summaries of the mean cumulative function for the primary endpoint 
(Nelsen-Aalen estimate) will be presented by treatment group.  
 
6.2.1.2 
Primary Efficacy Variable: Sensitivity Analysis 
As a sensitivity analysis, the number of primary composite events will also be analyzed using 
a negative binomial regression model including stratification factors and treatment group as 
covariates and log follow-up time as an offset parameter.  
 
As a sensitivity analysis, plots and summaries of the mean cumulative function for the 
primary endpoint will be derived based on a competing-risk approach (Ghosh and Lin, 2000) 
and cumulative incidence function for the competing event of non-CV death (Aalen and 
Johansen, 1978) will be presented by treatment group. The following SAS Code illustrates the 
program for the mean cumulative function for the primary endpoint: 
PROC PHREG DATA=primary; 
  MODEL (time_start, time_rec)*event(0)= / eventcode=1; 
  STRATA treat; 
  ID patid; 
  BASELINE OUT=mcfdat CIF=cif LOWERCIF=lcif UPPERCIF=ucif /  
      SEED=999; 
RUN; 
 
DATA mcfdat; 
  SET mcfdat; 
  mcf = -log(1-cif) 
  lmcf = -log(1-lcif) 


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  ucif = -log(1-ucif) 
RUN;  
primary is the input dataset, time_start is the previous event stop time and 
time_rec is the current event stop time, the event variable event (0 for censored, 1 for 
primary event, and 2 for competing event) and patid is the participant ID and treat is the 
treatment group identifier. 
 
6.2.1.3 
Primary Efficacy Variable: Supportive Analysis of CV death 
component 
As part of the primary analysis, a separate estimate of the treatment effect for CV death as one 
of the components of the primary endpoint will be obtained. The second component of total 
HF events will be a secondary endpoint and analyzed as described in Section 6.2.2.1.  
The main cause-specific treatment effect estimate for CV death will be derived from a 
stratified Cox proportional hazards model for time to CV death and the main p-value from a 
stratified log-rank test.  A cause-specific treatment effect estimate for the censoring event of 
non-CV death will also be calculated using a stratified Cox proportional hazards model and 
presented with associated 95% confidence interval. The cumulative incidence functions for 
time to CV death and time to non-CV death will also be calculated using Aalen-Johansen 
estimates.  
Note that the study is not powered to show an effect on CV death alone. While this is the case, 
a sufficient number of deaths are expected so that an excess risk in mortality can be excluded. 
Under the assumptions of the sample size determination, approximately 535 CV deaths and 
approximately 775 all-cause deaths are expected to occur in the study. Even though no formal 
statistical tests for exclusion of an increased risk will be performed, these expected event 
counts would result in a relatively high power to exclude increased hazard ratios (HRs) on 
ACM. Table 6–1 provides the respective power values to exclude HRs above 1.15 and 1.25 
under different assumed values for the true HR on CV death and assuming no treatment effect 
on non-CV deaths (HRNonCVD=1.0). Similar to the primary endpoint, a treatment policy 
strategy is used for treatment discontinuation. With exclusion of a certain HR value it is meant 
that the upper limit of a 95% CI is below the value.  
 
Table 6–1: 
Power to exclude increased HR on ACM under different assumed 
treatment effects on CV death 
True HRCVD 
Exclude HRACM>1.15 
Exclude HRACM>1.25 
0.8 
94% 
>99% 
0.9 
78% 
97% 
1.0 
52% 
88% 
 
6.2.1.4 
Primary Efficacy Variable: Supportive Analysis of Time-to first event 
of Composite Endpoint 
As supportive analysis, stratified Cox proportional hazard regression analysis will be 
performed for the time to first composite of HF event or CV death and a plot of Aalen-
Johansen estimates of the cumulative incidence function will be provided.  


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6.2.1.5 
Primary Efficacy Variable: Other Supportive Analyses 
A supportive analysis of the primary endpoint will exclude urgent HF visits and consider only 
CV deaths and HHFs as events. Also, an additional analysis of the primary endpoint will 
restrict CV deaths to HF-related events and thus will consider HF events and CV deaths due 
to HF. These analyses will both be performed for total (first and recurrent) events and for first 
events only. 
A total-time approach considering times from randomization to the onset of first, second, third 
composite event using a Wei, Lin, and Weissfeld (WLW, 1989) model will be applied. This 
model enables analysis of the cumulative effect on the primary endpoint from randomization 
(i.e. the effect on second event includes the effect on the first, and the effect on third event 
includes the effects on the first and second). The corresponding individual HRs with 95% CIs 
comparing treatment groups on the first, second, and third event will be presented.  
In addition, a conditional gap-time model according to Prentice, Williams and Peterson (PWP, 
1981) will be applied to obtain HR estimates with 95% CIs for the time from first to second 
and from second to third event (note that this gives a non-randomized comparison). Both 
models will employ robust standard errors and include the stratification factors and treatment 
group as fixed effects. Both WLW and PWP approaches are known to have limitations and 
hence are strictly only performed as supplemental analyses since they aim at describing 
different aspects of recurrent events.  
An “on-treatment” analysis will be performed, including only events occurring up to 30 days 
after treatment discontinuation. This analysis will be performed in the SAF instead of the 
FAS.  
In addition, table and figure of risk ratios and respective confidence intervals will be provided 
for the primary efficacy endpoint with patients being censored sequentially at each study day 
similar to figure 3 in Packer et al. (2021). The first day where the upper CI of the RR is below 
1 and stays below for the remainder will be marked. 
The primary analysis for the primary endpoint will also be repeated for the “Total HF events 
and ACM” endpoint. 
In addition, the primary analysis will also be repeated where patients are included with only 
up to a maximum of 4 composite events, to examine the impact of patients with a large 
number of events. For this analysis, patients who experienced 4 or more events will be 
censored at the time of their 4th event. 
An additional analysis of the primary endpoint will include a time-dependent covariate for  
SGLT-2 inhibitor use. 
 
6.2.2 
Analysis of Secondary Efficacy Variables 
6.2.2.1 
Secondary Efficacy Variables: Primary Analysis 
Secondary efficacy variables are the following: 
• Total (first and recurrent) HF events 
• Improvement in NYHA class from Baseline to Month 12 
• Change from baseline to Month 6, 9 and 12 in TSS of the KCCQ  


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• 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 
• Time to ACM 
See Section 4.7 for details regarding the testing hierarchy for secondary endpoints and 
nominal significance levels.  
Total HF events will be analyzed in a similar fashion to the primary endpoint, using an 
LWYY model including treatment group as fixed effect and including pooled region for 
stratified analyses and baseline LVEF (<60%, ≥60%) as stratification factors. A treatment 
policy strategy will be applied for treatment discontinuation, i.e., all events and follow-up 
time will be included in the analysis; all-cause death will be a censoring event for a while-
alive approach. 
The percentage of participants with improvement in NYHA class from Baseline to Month 12 
will be analyzed with a logistic regression model including factors for treatment group and 
stratification levels. A patient is considered as having improved in NYHA class, if the NYHA 
class at Month 12 (Visit 6) is at least one category improved compared to the baseline visit. A 
composite strategy will be applied to those cases, where no measurement at Visit 6 is 
available due to stop of treatment prior to Visit 6. That means these patients are considered to 
have not improved in NYHA class. Participants who are still in the treatment period at Visit 6, 
but have NYHA assessment missing, will be imputed by taking the mean of the last available 
measurement prior to Visit 6 and the first measurement thereafter. Participants with no further 
value available after Visit 6 or whose only available information is from EoS visit will be 
imputed as non-responders. Participants with missing baseline value will be excluded from 
the analysis. Odds ratio and two-sided 95% confidence intervals will be provided for the 
comparison of finerenone vs. placebo treatment group. In addition, change from baseline in 
NYHA class will be summarized descriptively using shift tables, presented by visit and any 
time post-baseline. These tables will present the number of participants with the class at a 
certain visit by their respective baseline class. 
The absolute change from baseline including measurements up to Month 12 of the KCCQ 
TSS will be analyzed by a repeated measures mixed model including the factors treatment 
group, baseline, visit, baseline-by-visit interaction, and factors for the stratification levels. For 
each treatment group a separate covariance pattern will be estimated based on an unstructured 
covariance to adjust for within participant variance.  
In case the model does not converge, different covariance patterns will be used, in the 
following order, until convergence is met: separate unstructured covariance patterns, separate 
Toeplitz covariance patterns, separate Autoregressive(1) covariance patterns, and finally 
separate Compound Symmetry covariance patterns will be used. 
Differences between the finerenone and the placebo treatment groups will be calculated with 
two-sided 95% CIs. The comparison assumes a common treatment effect across Month 6, 9 
and 12 and will be considered primary. This analysis will investigate the effect on the KCCQ 
TSS while patients are alive and irrespective of any permanent treatment discontinuation. This 
means that all observed values will be included in the analysis.   
The primary analysis of the secondary time-to first event variables (i.e. composite renal 
endpoint and ACM) will be done with a stratified log-rank test for testing and a stratified Cox 
proportional hazards model for obtaining a point estimate with 95% CIs. The Cox 
proportional hazards model will be stratified according to the stratification factors and include 


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treatment group as fixed effect. For the composite renal endpoint, the cause-specific point 
estimate with 95% confidence interval for the censoring event of death will also be presented. 
Cumulative incidence function plots and summaries (calculated using Aalen-Johansen 
estimates) will be produced for the composite renal endpoint and the censoring event of death. 
In addition, components of the composite renal endpoint will be analyzed. Furthermore, 
Aalen-Johansen plots will be displayed for the ACM endpoint. 
Only central laboratory measurements before initiation of dialysis or renal transplantation will 
be considered for the definition of the individual eGFR-based components of the renal 
endpoint. At the up-titration, restart and safety check visits, only a local laboratory 
measurement is obtained. These values will be checked for a potential eGFR event and, in 
case of decline, the investigators will be advised to retest eGFR centrally in an unscheduled 
visit; determination of an eGFR event will then be based on this value. If an initial decrease in 
eGFR occurs on the EoS visit, there will be another confirmatory measurement taken at least 
4 weeks later to confirm the initial decrease. The individual components “Sustained decrease 
of eGFR ≥ 50% from baseline over at least 4 weeks” as well as “Sustained eGFR decline 
<15ml/min/1.73m2” will be programmatically derived. Only in the event that the eGFR 
decrease was confirmed by at least one additional eGFR measurement taken at least 4 weeks 
later, it will be considered as a sustained decrease and counted for the renal endpoint. The 
confirmatory additional eGFR measurements will typically be taken during an unscheduled 
visit. The date used for the analysis will be the date of the initial sample exceeding the 
threshold. If there was no confirmatory assessment, events will only be counted for the renal 
endpoint when the patient died after the initial decrease or the patient went on renal 
replacement therapy such as dialysis or transplantation prior to their scheduled confirmatory 
assessment. If there is an intermediate measurement that does not confirm the initial decrease, 
the event will not be counted for the renal endpoint.  
eGFR events will be counted from the day of randomization until the EoS visit (or EoS 
notification + 28 days if EoS visit is missing). Participants will be censored at the earliest of 
the date of their last visit when a central eGFR measurement is available or EoS visit date (or 
EoS notification + 28 days if EoS visit is missing). If no post-baseline eGFR measurement is 
available, participants will be censored at day 1 (randomization date). 
The other two components of the renal composite endpoint, i.e. initiation of dialysis or renal 
transplantation, will be adjudicated. To account for events of initiation of dialysis or renal 
transplantation after the last eGFR is recorded at a clinic visit, such events will be included in 
the efficacy analysis of the composite renal endpoint if they occur in the period up to the next 
planned clinic visit (+ 1 month) or EoS visit date (or EoS notification + 28 days if EoS visit is 
missing) or death date or last contact date. If no post-baseline eGFR measurement is available, 
the next planned visit is the date of Visit 2 (Month 1). Censoring will be applied at the  last 
eGFR date (or day 1 if last eGFR date is missing) or at the earliest of EoS visit date (or EoS 
notification + 28 days if EoS visit is missing) or death date or last contact date, if these occur 
earlier than the next eGFR date + 1 month.  
Randomized participants without an event of the composite renal endpoint at the time of 
analysis will be censored at the latest censoring date of their individual components. 
6.2.2.2 
Secondary Efficacy Variables: Sensitivity Analysis 
As a sensitivity analysis for the total HF events endpoint, a joint frailty model (Rogers et al., 
2016) with constant baseline hazard for CV death and constant baseline intensity for HF 
events will be fitted including effects for treatment group, pooled region for stratified analyses 


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and baseline LVEF (<60%, ≥60%). A gamma frailty distribution will be assumed. This model 
gives a treatment effect on total HF events which is adjusted for a potential treatment effect on 
CV death. An effect on CV death might otherwise dilute the effect seen on the 
hospitalizations, i.e. an effective treatment will prevent CV deaths especially in the more 
severely ill participants, which then potentially results in many hospitalizations.  
The joint frailty model can sometimes have convergence issues (Toenges & Jahn-
Eimermacher, 2020); additionally, estimates obtained from the model have sometimes been 
observed as unstable (e.g., large differences with changes in starting values and/or ordering of 
covariates in the model). Should such problems be encountered, a simpler model including 
only treatment group as a fixed effect will be used instead. The joint frailty model additionally 
produces an estimate for CV death; however, this will be considered only supportive for the 
analysis of this component and instead the main analysis for the CV death component is 
described under the primary efficacy variable in Section 6.2.1.2.  
6.2.2.3 
Secondary Efficacy Variables: Supportive Analysis 
As supportive analysis for the total HF events endpoint, stratified Cox proportional hazard 
regression analyses will be performed for the following endpoints and plots of Aalen-
Johansen estimates of the cumulative incidence functions will be provided:  
• Time to first HF event 
• Time to first HHF 
• Time to first urgent HF visit 
The additional analyses of the secondary time-to-first event endpoints will include an “on-
treatment analysis”. For the renal composite endpoint, events will only be counted if they 
occur within 5 months after the last visit with complete information on all components of the 
composite primary endpoint. A 5-month time window is used as visits are 4-monthly and in 
order to allow for late attendance by an additional 1 month. The proportional hazards 
assumption will be investigated by plotting smoothed Schoenfeld residuals. For the renal 
endpoint, a time-to-first event analysis will be done separately for each of the components.  
A supportive analysis of the KCCQ TSS will apply a worst-case imputation for death which 
means that if a patient dies, a worst score of 0 for the TSS will be imputed for all subsequent 
visits after the patient’s death (i.e., composite strategy). Treatment effects at Month 6, 9 and 
12 will also be investigated individually by adding a treatment-by-visit interaction into the 
model. 
A responder analysis for the KCCQ TSS will also be performed, defining patients with an 
increase of ≥5 points from baseline to Month 12 (or, for those with a baseline score of >95, a 
score of >95 at Month 12 without decline from baseline) as a responder. All observed values 
will be included irrespective of any permanent treatment discontinuation. In case of missing 
data, a patient’s last available post-baseline score prior to Month 12 will be used (i.e. while-
alive strategy) unless the patient died before Month 12 in which case they will be imputed as a 
non-responder (i.e. composite strategy). Responder status will be analysed using a logistic 
regression model including treatment, baseline TSS and stratification factors as covariates; the 
odds ratio and associated 95% CI will be reported.  This analysis will be repeated for cut-offs 
of ≥10 points increase from baseline to Month 12 (or maintaining a score of >90 from 
baseline to Month 12 without decrease from baseline) and ≥20 points increase (or maintaining 
a score of >80 without decrease from baseline). These cut-offs correspond to small (≥5), 
moderate (≥10) and large (≥20) clinically meaningful improvements (Spertus et al, 2005). A 


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further analysis will define those responders who do not experience a ≥5 points decrease from 
baseline (or, for those with a baseline score of <5, a score of ≥5 at Month 12). This is 
equivalent to not experiencing a small deterioration. The number and percentage of patients 
who are responders or non-responders per each of the above criteria will be presented at 
Months 6, 9 and 12. This will include a breakdown of the criteria met for response (e.g. 
increase from baseline of ≥5, >95 at baseline and post-baseline visit) or non-response (e.g. 
change from baseline of <5, >95 at baseline and ≤95 at post-baseline visit, missing score at 
post-baseline visit). 
A second responder analysis for the KCCQ TSS will use the thresholds derived from the 
anchor-based analyses with the Patient Global Impression of Severity (PGIS) and Patient 
Global Impression of Change (PGIC) for a clinically meaningful within-patient change in 
KCCQ TSS at month 6, 9 and 12, respectively, which have been performed separately on 
blinded data (cf. Section 6.2.3.1). The derived thresholds are 
• 
Minimally important within-patient improvement: 9.09  
• 
Moderate within-patient improvement: 19.85  
These thresholds will be used for each timepoint.. All observed values will be included 
irrespective of any permanent treatment discontinuation. In case of missing data, a patient’s 
last available post-baseline score prior to Month 6, 9 or 12, respectively, will be used unless 
the patient died before the respective scheduled visit in which case they will be imputed as a 
non-responder. Responder status will be analysed using a logistic regression model at each 
timepoint including treatment, baseline TSS and stratification factors as covariates; the odds 
ratio and associated 95% CI will be reported.   
Empirical cumulative density functions will be plotted for Months 6, 9 and 12, with change 
from baseline in KCCQ TSS (+100 to -100, ordered from greatest possible improvement to 
greatest possible worsening) on the x-axis and proportion of participants achieving this 
change or greater on the y-axis. Separate curves will be presented for each treatment group. 
 
6.2.3 
Analysis of Further Exploratory Efficacy Variables 
Other exploratory efficacy variables will be as follows: 
• Time to first CV hospitalization 
• Total number of CV hospitalizations 
• Time to first all-cause hospitalization 
• Total number of all-cause hospitalizations 
• Time to first occurrence of the following composite endpoint: CV death or non-fatal 
CV event (i.e. non-fatal myocardial infarction, non-fatal stroke, or HHF) 
• Time to first occurrence of the following composite endpoint: sustained decrease in 
eGFR ≥ 57% relative to baseline over at least 4 weeks, or sustained eGFR decline < 15 
ml/min/1.73m2 or initiation of dialysis or renal transplantation 
• Change in eGFR from baseline 
• Mean rate of change in eGFR slope and its subcomponents acute and chronic slope 
• Change in UACR from baseline 


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• Days alive and out of hospital (DAOH) 
• Time to new onset of atrial fibrillation  
• Change in health-related quality of life summary scores from baseline measured by 
KCCQ and EuroQol Group 5-dimension 5-level questionnaire (EQ-5D-5L) 
Exploratory time-to-event variables will be analyzed using the stratified log-rank test and the 
stratified Cox proportional hazards model. Plots of Aalen-Johansen estimates of the 
cumulative incidence function will be provided. 
The total number of CV hospitalizations will be analyzed using an LWYY model, similarly to 
the primary efficacy endpoint, and will be summarized descriptively by treatment group 
together with the annual rate of CV hospitalizations. These summaries and analyses will be 
repeated for all-cause hospitalizations. 
The absolute change from baseline in eGFR at each visit until Visit 10 (Month 24) will be 
analyzed by a repeated measures mixed model with the factors treatment group, baseline 
eGFR, visit, treatment-by-visit interaction, baseline-by-visit interaction, and factors for the 
stratification levels (pooled region for stratified analyses and LVEF). Differences between the 
finerenone and placebo treatment groups at each visit will be calculated, and corresponding 
two-sided 95% CIs will be computed. For each treatment group a separate covariance pattern 
will be estimated based on an unstructured covariance to adjust for the within participant 
variance. Change in logarithmized UACR from baseline will be analyzed in an identical 
fashion. Results will be back-transformed to the original scale so that ratios will be displayed 
in table outputs. 
Frequency tables will be generated for the number and percentage of patients with a relative 
decrease in eGFR of ≥25%, ≥30%, ≥40%, ≥50% and ≥57% from baseline. The analysis will 
be performed for each visit and for any time post-baseline. 
The rate of change of eGFR will be compared between the finerenone and the placebo group 
by estimating the total eGFR slope using available assessments from baseline to planned end 
of the treatment period. It is assumed that changes in the mean response can be expressed in 
terms of a linear trend, and the treatment effect can be expressed in terms of the difference in 
slope between finerenone and placebo. For the analysis of the total slope, the serial change in 
eGFR will be modeled using a two-slope linear spline mixed-effects model in which a fixed 
change point will be defined to separate acute and chronic eGFR slope at Month 3 (Section 
2.1 of Vonesh et al. 2019). In addition to fixed effects for the treatment, time (continuous) and 
treatment by time interaction, the model will include fixed effects for the stratification factors 
and random effects for the intercept, acute slope (baseline to Month 3), and chronic slope 
(Month 3 to planned end of treatment period). An unstructured covariance will be used to 
model the between-participant errors. Within-participant errors are assumed to be 
homogenous. Linear contrasts will be constructed to estimate the acute, chronic, and total 
slope in eGFR. LS means and differences of the acute, chronic and total eGFR slope for 
finerenone and placebo group will be provided with 95% confidence intervals (and 
corresponding p-values for the differences). 
DAOH will be summarized descriptively by treatment group; the number and percentage of 
DAOH with respect to total potential follow-up time will be provided alongside the number 
and percentage of days dead and days in hospital, including breakdown into type of death. 
These analyses will be performed overall and separately by the stratification factors (pooled 
region for stratified analyses and LVEF). 


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DAOH will be analyzed by an ANCOVA model including potential follow-up time, treatment 
group, and stratification factors as fixed effects. Potential follow-up time is defined as the 
time from randomization up to end of study or lost to follow-up or withdrawal date, in case 
the patient did not complete the study. 
DAOH will be analyzed once considering the total potential follow-up time and once 
considering only the first year of follow-up. 
For the KCCQ, 3 further summary scores (physical limitation score [PLS], clinical summary 
score [CSS] and overall summary score [OSS]) will be derived. For the KCCQ PLS, CSS and 
OSS, the absolute change from baseline including measurements up to month 12 of the 
KCCQ TSS will be analyzed by a repeated measures mixed model including the factors 
treatment group, baseline, visit, baseline-by-visit interaction, and factors for the stratification 
levels. Differences between the finerenone and the placebo treatment groups will be 
calculated with two-sided 95% CIs. In addition, descriptive statistics will be presented by visit 
and treatment group: number of observations, number of missing values, minimum, first 
quartile, mean, standard deviation, median, third quartile, and maximum, including the 
changes from baseline. The analyses for TSS are described in Section 6.2.2. 
For the EQ-5D-5L, summary scores will be calculated from the 5 dimensions according to the 
scoring instructions from UK and the US (refer to the EQ-5D-5L User Guide (EuroQoL 
Group 2013) and to the EQ-5D Value Sets (Szende et al. 2007). The values and the changes 
from baseline of the summary scores and the EuroQol Group visual analogue scale (EQ VAS) 
will be summarized by treatment group and visit using the same descriptive statistics as for 
KCCQ.  
6.2.3.1 
Patient Global Impression of Change (PGIC) and Severity (PGIS) 
A sub-population of approximately 1200 participants is being asked the following questions at 
baseline (PGIS only) and at Visit 4 (Month 6), Visit 5 (Month 9) and Visit 6 (Month 12): 
• PGIC: the participant is asked to assess the degree of change in their HF symptoms 
compared to the start of the treatment using the following response options: much 
better, better, a little better, the same, a little worse, worse or much worse 
• PGIS: the patient is asked to assess the current severity of their HF symptoms due to 
HF using the following response options: no symptoms, mild, moderate, severe or 
very severe 
These questions will be used as an anchor to provide an estimate of clinically meaningful 
change in the KCCQ TSS. Details of the analysishave been described in a separate SAP. The 
analysis has been conducted on a blinded dataset and will be reported separately from the 
CSR. 
6.2.4 
Outcome Events Reported by the Investigators 
Outcome events using the investigator-reported terms will be summarized by treatment group, 
using tables analogous to those for aEs. Only adjudicated outcome events will be used for the 
analysis of the primary composite endpoint. Adjudication of the secondary renal endpoint will 
be restricted to cases of initiation of dialysis or renal transplant. No adjudication will be done 
for events only included in an exploratory efficacy endpoint (e.g. non-fatal myocardial 
infarction) and therefore the investigator-reported events will be used in the analysis of those 
endpoints. An overall summary of all outcome events will be generated by treatment group.  


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The number of participants with all outcome events, outcome events from randomization up 
to 30 days after stop of study medication, post-treatment outcome events occurring more than 
30 days after stop of study drug or after the EoS Visit and outcome events by maximum 
intensity will be summarized by treatment group using MedDRA terms grouped by Primary 
SOC and PT. 
The incidence rate of outcome events per 100 patient-years will also be provided by treatment 
group using MedDRA terms grouped by Primary SOC and PT. The time under risk for the 
incidence rates is defined as the time from randomization until the first onset of the event or 
the last date of contact with the participant in case no such event is recorded. 
Outcome events will be summarized separately in the CSR Section 8.2 tables. 
6.3 
Pharmacokinetics/pharmacodynamics 
6.3.1 
Pharmacokinetics 
The finerenone plasma concentration versus time data collected at various study visits will be 
evaluated descriptively, separated by dose and visit. Plots will be prepared of all individual 
plasma concentrations vs. actual relative study times (time of sample collection after time of 
study drug administration). 
Evaluation of the concentration data will be performed using Population Pharmacokinetic 
(PK) methods, followed by PK / Pharmacodynamic (PD) analyses. These analyses will be 
described in a separate Analysis Plan outside of this document and will be reported separately. 
6.3.2 
Pharmacodynamics 
Analysis of the pharmacodynamics parameters (e.g. blood pressure, heart rate, laboratory 
values) will be described in detail in a separate SAP. 
6.4 
Safety 
All analyses on safety and tolerability data will be performed in SAF. 
6.4.1 
Adverse Events 
AEs will be coded using the latest version of MedDRA available prior to database freeze. A 
listing will be provided linking the original investigator terms and the coded terms. AEs will 
be presented grouped by SOCs and PTS. 
AEs that occurred or worsened after the first dose of study drug and up to 3 days after the last 
dose of study drug will be considered as treatment-emergent AEs (TEAEs).  
To comply with local regulatory requirements in Japan and India, certain cardiovascular 
disease-related outcome events will also be documented as (S)AEs in Japan and India. These 
will be included in the outcome event tables (see Section 6.2), and to avoid double-counting 
of such events, they will not be included in the adverse event summary tables or listings. 
Separate listings will be generated for all AEs excluded from the AE analysis due to double 
reporting in Japan and India, respectively. 
An overall summary of all AEs, pre-treatment AEs, post-treatment AEs occurring more than 3 
days after stop of study drug and TEAEs will be generated by treatment group. TEAEs and 
treatment-emergent SAEs will be summarized by subgroups as defined in section 4.5.6. 


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The number of participants with TEAEs, post-treatment AEs occurring more than 3 days after 
stop of study drug, treatment-emergent serious adverse events (SAEs), treatment-emergent 
study drug-related AEs, treatment-emergent study drug-related SAEs, TEAEs and treatment-
emergent SAEs resulting in discontinuation of study drug, treatment-emergent study drug-
related AEs resulting in discontinuation of study drug, treatment-emergent non-serious AEs, 
TEAEs and treatment-emergent SAEs by maximum intensity, drug-related TEAEs by 
maximum intensity, TEAEs and treatment-emergent SAE by worst outcome and drug-related 
TEAEs by worst outcome will be summarized by treatment group using MedDRA terms 
grouped by Primary SOC and PT.  
Hyperkalemia and worsening of renal function are considered events of special safety interest. 
Hyperkalemia will be defined by MLG ‘Hyperkalemia’ and worsening of renal function will 
be defined by 
• List of PTs: ‘Acute kidney injury’, ‘Blood creatinine increased’, ‘Glomerular filtration 
rate decreased’, ‘Postrenal failure’, ‘Prerenal failure’, ‘Renal failure’ and ‘Renal 
impairment’ 
• SMQ ‘Acute renal failure’ (narrow search) 
• SMQ ‘Acute renal failure’ (broad search). 
An overall summary for each definition of worsening of renal function as well as for 
hyperkalemia will provide the number of participants once for all events and once for all 
treatment-emergent events by treatment group. 
In addition, further safety variables listed in Section 9.4.2 of the protocol are: 
- 
Number of participants with hospitalization for hyperkalemia 
- 
Number of participants permanently discontinuing study intervention due to 
hyperkalemia 
- 
Number of participants with hospitalization for worsening of renal function 
- 
Number of participants permanently discontinuing study intervention due to 
worsening of renal function 
These will be summarized for treatment-emergent events by treatment group using frequency 
counts and grouped by Primary SOC and PT. 
Cumulative incidences based on Aalen-Johansen estimates and accounting for mortality as 
competing risk will be provided for the time to first treatment-emergent hyperkalemia event. 
For this analysis, the person-time at risk for a single participant is the number of days from 
first intake of study intervention until the event of interest or until the minimum of (date of 
death, last exposure to treatment + 3 days). Since the number of particpants with 
hospitalization or permanently discontinuing study intervention due to hyperkalemia is very 
low, no cumulative incidences will be displayed for these variables. 
For hyperkalemia AEs, an additional sensitivity analysis will be performed where events are 
defined as treatment-emergent, if the AE started or worsened after the first dose of study drug 
up to 3 days after any temporary or permanent interruption of study drug.  
The incidence of TEAEs and treatment-emergent SAEs per 100 person-years will also be 
provided by treatment group using MedDRA terms grouped by Primary SOC and PT. This 
analysis will consider the first AE per Primary SOC or PT for a participant. Per SOC or PT, 
the incidence per 100 person-years will be derived as 


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100 * (number of participants with TE(S)AE) / (sum of time at risk). 
The time at risk per patient is defined as time from first dose of study drug to last dose of 
study drug + 3 days (treatment-emergent), or death, if earlier, for those patients without a 
respective AE. For patients with AE, it is the time from first dose of study drug to AE start 
date. In case the AE start date is (partially) missing, the earliest possible date will be imputed; 
i.e. first day of a month, first month of a year, restricted to date of first study drug intake.   
In case of events with different intensity within a participant, the maximum reported intensity 
will be used. If intensity is missing, the event will be considered as severe. If the same event 
is reported as both unrelated and related to the study drug within a participant, the event will 
be considered as related to study drug. If the drug relationship is missing, the event will be 
considered as being related to the study drug. Deaths and SAEs will be listed separately. 
Any AEs/SAEs related to study procedure recorded after signing of informed consent but 
prior to randomization will be tabulated separately. 
6.4.2 
Laboratory Parameters 
Generally, only central laboratory measurements will be used for analyses. The only 
exception is for hematology, where a few countries have the possibility to use local labs in 
exceptional circumstances (e.g. logistical challenges due to global pandemic, natural disaster, 
or regional crisis). These local measurements will also be used for the analysis. 
The number of participants with treatment-emergent (after the first dose of study drug and up 
to 3 days after last dose of study drug) abnormal laboratory values above or below the normal 
range will be tabulated by the laboratory parameter and treatment group. 
Summary statistics including changes to baseline will be calculated by treatment group and 
visit for all quantitative laboratory parameters, e.g. for hematology, NT-proBNP, high 
sensitive troponin T (hs-TNT), clinical chemistry and urinalysis. Geometric statistics and 
ratios to baseline will be presented for urinary creatinine, albumin and UACR and NT-
proBNP instead of arithmetic statistics with changes from baseline. For eGFR the relative 
change will be displayed in addition to the absolute change from baseline. Graphical displays 
will be provided for change from baseline and ratio to baseline by visit, respectively. 
Proportion of patients with available and missing measurements will also be displayed. 
Summary statistics for serum potassium, eGFR, NT-proBNP and serum creatinine will also be 
repeated by treatment group and visit separately for each level of the stratification factors. 
The following special safety parameters will be further assessed by displaying the number of 
participants with safety events as described below by treatment group, visit and for any time 
treatment-emergent (including unscheduled assessments) and up to 3 days after last study 
drug administration. This will also be performed by stratification factors. The summaries will 
be performed for the number of participants with: 
• Absolute value of serum potassium >5.0 mmol/L, >5.5 mmol/L (hyperkalemia), >6.0 
mmol/L (severe hyperkalemia) and >7.0 mmol/L 
• Relative decrease from baseline in eGFR of ≥25%, ≥30%, ≥40%, ≥50% and ≥57%, 
also sustained decrease over 4 weeks 
• Absolute value of eGFR < 30 ml/min/1.73m²  
• Increase from baseline in serum creatinine >0.3 mg/dL and >0.5 mg/dL.  


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The percentage of participants with the respective events (non-stratified) at any time post-
baseline (including unscheduled assessments) and within 3 days after last study drug 
administration will be compared between the finerenone and placebo group by applying 
separate explorative χ² tests with continuity correction. If the expected number of participants 
in at least 1 cell of the 2x2 contingency table is <5 (Agresti 2005), Fisher’s exact test will be 
applied instead of the ² test. Estimates and two-sided 95% CIs will be provided for each 
treatment group and the treatment differences. Clopper-Pearson CIs will be calculated for 
each treatment group, while for treatment differences the exact unconditional confidence 
limits will be calculated. 
6.4.3 
Other Additional Safety Variables 
6.4.3.1 
Vital Signs 
At the corresponding visits, 2 BP and 1 pulse measurements of vital signs parameters will be 
taken. Averages of non-missing values of these two BP measurements will be calculated and 
used for the statistical analysis. If only one of the planned measurements is available, this 
value will be used. 
Vital signs values will be summarized by treatment group and visit using descriptive statistics 
including absolute changes from baseline. Changes from baseline will also be displayed 
graphically. The analysis will be repeated for SBP stratified by baseline SBP ≥90 to <130 
mmHg, 130 to <160 mmHg and ≥160 mmHg. 
6.4.3.2 
Weight and BMI 
The values and the changes from baseline will be summarized by treatment group and visit 
using descriptive statistics for weight and BMI.  
 
6.5 
COVID-19 and Related Issues 
It is expected that the COVID-19 pandemic – ongoing at the start of the trial (14-Sep-2020) – 
will have some impact on this trial. Every effort will be made to capture the effect of COVID-
19 on the study conduct. All adjudicated outcome events will additionally be adjudicated for 
relationship to COVID-19 (yes, possibly, no). COVID-19 related study disruptions comprise 
missing visits or procedures, study drug interruptions or permanent discontinuations, AEs 
related to COVID-19, and (other) protocol deviations and will be analysed as follows: 
• All patients affected by study disruption related to the COVID-19 pandemic will be 
listed together with site information and the type of study disruption(s) 
• Number of patients affected, number of missed visits, number and type of protocol 
deviations will be tabulated 
• COVID-19 pandemic related reasons (participant decision, physician decision, or 
logistical reasons) for premature discontinuation of study epochs (e.g., screen failure, 
discontinuation of study drug, etc.) and changes in study treatment (e.g., dose titration, 
interruption, discontinuation, etc.) will be included in the relevant summaries 
• Coded terms for COVID-19 will be included in medical history and adverse event 
summaries 
 


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Supportive analyses to evaluate the impact of the COVID-19 pandemic on the primary 
analysis will be conducted for the primary and secondary efficacy endpoints. 
 
The primary analysis of the primary and secondary endpoints mostly follows the treatment 
policy strategy as described in ICH E9 (ICH 2019), in which participants are analyzed as they 
were intended to be treated and all relevant data are used regardless of any previous 
intercurrent events like COVID-19 infections or study drug interruptions which could have an 
influence on the occurrence of the event of interest. Only the following intercurrent events are 
handled with different approaches: 
 
Endpoint 
Intercurrent events and strategies 
Primary endpoint (CV death 
and total HF events) 
Non-CV death is treated as a censoring event for a while-
alive strategy. Additionally, CV death is counted as both 
an outcome event as well as a censoring event, hence a 
combination of composite and while-alive strategy 
Total HF events 
Non-CV death is treated as a censoring event for a while-
alive strategy. Additionally, the effect on total HF events 
is adjusted for a potential treatment effect on CV death 
Improvement in NYHA class 
from Baseline to Month 12 
A composite strategy is applied when no measurement is 
available at Month 12 (due to death, or other reasons) 
Change from baseline to 
Month 6, 9 and 12 in TSS from 
KCCQ 
All observed values up to death for any cause are 
included, i.e. a while-alive strategy is used 
Time to first occurrence of 
renal composite endpoint 
All-cause death is treated as a censoring event for a 
while-alive strategy. If a participant had a decrease or 
decline in eGFR but died before a confirmatory eGFR 
measurement could be taken, then the event is counted 
for the analysis 
Time to ACM 
Not applicable 
 
This general approach is still considered valid despite the presence of the COVID-19 
pandemic, considering the following factors: 
• COVID-19 related study disruptions are expected to be equally likely to occur in 
either treatment group, therefore not creating bias for the treatment effect 
• Information on most adjudicated endpoint events can still be collected even when 
physical visits cannot take place although incidences or reporting of some adjudicated 
events might change, e.g. as fewer participants might be hospitalized and have a 
higher risk of death 
 
To quantify the impact of the COVID-19 pandemic, the following supplemental analyses will 
be performed: 
• Primary endpoint (CV death and total HF events) 
o To address the hypothetical scenario in which participants did not experience 
any study disruption due to the COVID-19 pandemic, three separate analyses 


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will be conducted using the LWYY model described in Section 6.2.1.1 where 
participants are censored at 
a) Date of permanent discontinuation of study treatment due to COVID-
19 
b) Date of first COVID-19 adverse event (SMQ narrow) 
c) Date of first direct or indirect COVID-19 study disruption 
This analysis will be performed once including all primary efficacy 
events and once excluding those events adjudicated as related to 
COVID-19. For the latter analysis, the affected participants will be 
censored  at the first occurrence of a COVID-19 related event 
Additionally, plots and summaries of the mean cumulative function for the 
primary endpoint (Nelsen-Aalen estimate) will be presented by treatment 
group.  
o To investigate the effect of COVID-19 related study disruption on the results 
of the primary analysis, a time-dependent covariate capturing whether a 
participant is affected by COVID-19 at the respective time together with its 
interaction with treatment group will be included in the LWYY model 
described in Section 6.2.1.1. Separate models will be used for the three 
COVID-19 related categories described above (permanent discontinuation of 
study treatment, AEs, and study disruption). Events occurring before and after 
participants are affected by COVID-19 will also be summarized by treatment 
group 
o Primary efficacy events (CV death and HF events) and the competing event of 
non-CV death will be summarized by treatment group and relationship to 
COVID-19 as adjudicated by the CEC, defined as follows: 
▪ Yes (positive testing, typical clinical trajectory) 
▪ Possibly (inconclusive or absent testing, typical clinical trajectory) 
▪ No (testing negative or not done, not suspected) 
o If ≥5% of the total number of primary efficacy events are adjudicated as “Yes” 
or “Possibly” related to COVID-19, a further analysis using the LWYY model 
will be performed excluding such events; the affected participants will be 
censored at the first occurrence of a COVID-19 related event 
o Primary efficacy events occurring during interruption of study treatment (due 
to COVID-19, or due to other reasons) up to 30 days after any temporary or 
permanent stop of study treatment will be summarized by treatment group 
• Total HF events 
o Summaries of HF events occurring before and after participants are affected by 
COVID-19, and during interruption of study treatment, will be included as part 
of the summaries for the primary endpoint described above 
• Improvement in NYHA class from Baseline to Month 12 
o Reasons for a participant being classified as “not improved” at Month 12 under 
the composite strategy will be summarized, including: 


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▪ NYHA measured at Month 12 and not improved from baseline 
▪ NYHA not measured at Month 12 due to COVID-19 related reason 
▪ NYHA not measured at Month 12 due to other reason 
• Change from baseline to Month 6, 9 and 12 in TSS from KCCQ 
o No additional summaries or analyses are proposed. This endpoint will be 
analyzed by a repeated measures mixed model which is valid under the missing 
at random assumption, and COVID-19 related study disruptions are expected 
to be equally likely to occur in either treatment group and therefore not related 
to study treatment 
• Time to first occurrence of renal composite endpoint 
o Events occurring before and after COVID-19 related study disruption, and 
during study treatment interruptions due to COVID-19 or other reasons, will be 
summarized by treatment group 
• Time to ACM 
o To address the hypothetical scenario in which participants were not affected by 
the COVID-19 pandemic, the stratified log-rank test and stratified Cox 
proportional hazard model as described in Section 6.2.2.1 will be repeated 
excluding any death adjudicated as “Yes” or “Possibly” related to COVID-19; 
these participants will instead be censored at the date of death. Aalen-Johansen 
plots for non-COVID and COVID related deaths will also be displayed 
 
6.6 
Regional crisis between Russia and Ukraine and Related Issues 
During the conduct of the FINEARTS-HF study, the conflict between Russia and the Ukraine 
escalated in February 2022 and, as of finalization of this amendment of the SAP, the regional 
crisis is ongoing in Ukraine. Every effort will be made to capture the effect of this regional 
crisis on study conduct. 
Crisis-related study disruptions comprise missing visits or procedures, study drug 
interruptions or permanent discontinuations, AEs related to the regional crisis, and (other) 
protocol deviations and will be summarized as follows: 
• All patients affected by study disruption related to the regional crisis will be listed 
together with site information and the type of study disruption(s) 
• Number of patients affected, number of missed visits, number and type of protocol 
deviations will be tabulated 
• Crisis -related reasons (participant decision, physician decision, or logistical reasons) 
for premature discontinuation of study epochs (e.g., screen failure, discontinuation of 
study drug, etc.) and changes in the study treatment (e.g., dose titration, interruption or 
discontinuation of study drug, etc.) will be included in the relevant summaries 
• AEs related to the regional crisis will be included in the relevant summaries; if 
possible, these will be identified and highlighted in the CSR 
See Section 6.5 (COVID-19 and Related Issues) or individual analysis sections for a 
description of the intercurrent event strategies for the primary and secondary endpoints. 


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Similarly to the impact of COVID-19, the general approach for these endpoints is still 
considered valid despite the presence of the regional crisis, considering the following factors: 
• Crisis-related study disruptions are expected to be equally likely to occur in either 
treatment group, therefore not creating bias for the treatment effect 
• Information on most adjudicated endpoint events can still be collected even when 
physical visits cannot take place although incidences or reporting of some adjudicated 
events might change 
Despite this, it is recognized that issues arising from the regional crisis (including but not 
limited to missing data, data of compromised quality and crisis-triggered intercurrent events) 
may have a substantial impact on individual data points, patients, sites and/or countries. 
Therefore, the situation will be monitored on an ongoing basis and a final decision will be 
made prior to unblinding as to whether specific data-handling rules are required for individual 
data points, patients, sites and/or countries. This decision will be documented in an SAP 
amendment or – if that is not possible – a note to file, and all rules will be described and 
justified in the CSR. Additional summaries and sensitivity analyses may also be required, and 
these will be reported in the CSR. 
For example, due to substantial impact of the regional crisis on a specific site, a decision may 
be made to censor all study participants from that site at a specific date (e.g. 24-Feb-2022, 
recognized as the date that the conflict escalated).  
Regardless of any decision to implement data-handling rules for data affected by the regional 
crisis, the following supplemental analyses will be performed to quantify the impact of the 
regional crisis: 
 
• Primary endpoint (CV death and total HF events) 
o To address the hypothetical scenario in which Ukraine participants did not 
experience any study disruption due to the regional crisis, two separate 
analyses will be conducted using the LWYY model described in Section 
6.2.1.1 where Ukraine participants are censored at 
a) Date of first direct or indirect crisis-related study disruption (missed 
assessment, missed visit, study drug interruption or permanent 
discontinuation due to the regional crisis) 
b) 24-Feb-2022, recognized as the date that the conflict escalated (date of 
the television broadcast “On conducting a special military operation” 
by Russian president Vladimir Putin) 
Additionally, plots and summaries of the mean cumulative function for the 
primary endpoint (Nelsen-Aalen estimate) will be presented by treatment 
group.  
o To investigate the effect of regional crisis related study disruption on the 
results of the primary analysis, a time-dependent covariate capturing whether a 
Ukraine participant is affected by the regional crisis the respective time 
together with its interaction with treatment group will be included in the 
LWYY model described in Section 6.2.1.1 Separate models will be used for 
the two dates described above. Events occurring before and after participants 


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are affected by the regional crisis will also be summarized by treatment group 
(separately for FAS and for Ukraine participants in the FAS only) 
o Primary efficacy events occurring during interruption of study treatment (due 
to the regional crisis, or due to other reasons) up to 30 days after any temporary 
interruption or permanent discontinuation of study treatment will be 
summarized by treatment group (separately for FAS and for Ukraine 
participants in the FAS only) 
• Total HF events 
o Summaries of HF events occurring before and after participants are affected by 
the regional crisis, and during interruption of study treatment, will be included 
as part of the summaries for the primary endpoint described above 
• Improvement in NYHA class from Baseline to Month 12 
o Reasons for a participant being classified as “not improved” at Month 12 under 
the composite strategy will be summarized, including: 
• NYHA measured at Month 12 and not improved from baseline 
• NYHA not measured at Month 12 due to crisis-related reason 
• NYHA not measured at Month 12 due to other reason 
• Change from baseline to Month 6, 9 and 12 in TSS from KCCQ 
o No additional summaries or analyses are proposed. This endpoint will be 
analyzed by a repeated measures mixed model which is valid under the missing 
at random assumption, and crisis-related study disruptions are expected to be 
equally likely to occur in either treatment group and therefore not related to 
study treatment 
• Time to first occurrence of renal composite endpoint 
o Events occurring before and after crisis-related study disruption, and during 
study treatment interruptions due to regional crisis or other reasons, will be 
summarized by treatment group (separately for FAS and for Ukraine 
participants in the FAS only) 
• Time to ACM 
o Events occurring before and after crisis-related study disruption, and during 
study treatment interruptions due to regional crisis or other reasons, will be 
summarized by treatment group (separately for FAS and for Ukraine 
participants in the FAS only) 
 
7. 
Document history and changes in the planned statistical analysis 
• SAP version 0.4 dated 16 DEC 2019: unsigned draft version for special protocol 
assessment (SPA) submission 
• SAP version 1.0 dated 04 SEP 2020 
• SAP version 2.0 dated 24 FEB 2023 
• SAP version 3.0 dated 20 JUN 2024 
 
 


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7.1 
Overview of Changes to SAP – from version 1.0 to version 2.0 
Description of the finerenone program in DKD is updated.  
Primary and secondary objectives of the trial are moved from Section 3 to Section 2. 
Description of the primary Estimand is moved from Section 6.2.1.1 to Section 2. A figure of 
the testing procedure is included. 
Total (first and recurrent) HF events is elevated from supportive analysis of the primary 
endpoint to a new secondary endpoint. Supportive analyses of the primary endpoint 
concerning only HF events are moved accordingly to become supportive analyses of the new 
secondary endpoint. This is based on changes made to the secondary endpoints in protocol 
V3.0 
Improvement in NYHA class from Baseline to Month 12 is elevated from exploratory 
endpoint to new secondary endpoint. A logistic regression analysis is newly specified for the 
endpoint accordingly in accordance with protocol V3.0. 
The composite renal secondary endpoint is changed to include sustained decrease in eGFR 
≥50% relative to baseline instead of ≥40% in accordance with protocol V3.0. 
Additional separate SAPs are mentioned for specific analyses (pooled analyses, scientific 
SAP). 
Increase in sample size from 5500 randomized to 6000 randomized is described. 
Handling of death adjudicated as undetermined death is clarified for the analyses. 
Clarification of use of local laboratory values for analysis. 
Clarification of definition of on-treatment analysis for efficacy vs. treatment-emergent 
analysis for safety is aligned throughout the document. 
Subgroups are revised (pooled region; baseline eGFR; index HF event; age; BMI; SBP; 
ACEI/ARB/ARNI), additional subgroup is included (Baseline UACR) and some ‘other’ 
subgroups are removed (weight; MRA, beta-blocker, diuretic, anti-diabetics, potassium, 
CYP3A4 or Entresto use; history of CAD; Baseline hs-TNT).  
The testing procedure and multiplicity adjustment is adjusted to reflect the two new secondary 
endpoints in accordance with protocol V3.0. 
Demography and baseline characteristics are revised to ensure consistency with subgroups yet 
keeping baseline characteristics that are not any more used for subgroup analyses. 
Inclusion of additional specific medical history terms (COVID-19, Liver cirrhosis, Sleep 
Apnea Syndrome, Chronic Kidney Disease) and clarification of derivations (via e.g. PT, 
MLG, etc). 
Remove concomitant BCRP substrate use from concomitant medications of interest. 
Additional tables for exposure and titration by starting dose have been specified. 
Analysis strategies for the primary endpoint and secondary endpoints are revised to include 
the handling of censoring events. This concerns the primary endpoint, the supportive analysis 
of CV death, as well as secondary and exploratory time-to event endpoints. 
Summary of incidence rate of primary endpoint events has been included. 
Handling of multiple primary endpoint events (i.e. ‘7-day’ rule) has been revised to a ‘same 
calendar day’ rule. The supportive analysis on the ‘7-day’ rule has been removed accordingly. 


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Ghosh and Lin competing risk approach for the mean cumulative function has been moved to 
sensitivity analysis and respective example SAS Code for the mean cumulative function has 
been included. 
Sensitivity and supportive analyses for the primary efficacy variable have been structured in 
separate sections (Section 6.2.1.2: Sensitivity and Section 6.2.1.3 to Section 6.2.1.5: 
Supportive). For the secondary endpoint of total HF events, a separate section with sensitivity 
analysis is included as well. 
An additional sensitivity analysis with LVEF as continuous variable has been specified for the 
primary efficacy endpoint. 
Further supportive analyses for the primary efficacy endpoint have been included (restriction 
to HF-related CV death; sequential censoring; time-dependent covariate of SGLT2-inhibitor 
use). 
The analysis of the secondary endpoint of total HF events is changed from a joint frailty 
model (as specified in protocol V3.0) to the LWYY model. A joint frailty model with constant 
baseline hazard for CV death and constant baseline intensity for HF events was instead 
included as sensitivity analysis. This change in analysis strategy is based on potential 
convergence issues and unstable estimates of the joint frailty model.  
Additional model specification is included for the repeated measures model of the change in 
KCCQ TSS. 
An additional sensitivity analysis with LVEF as continuous variable has been specified for the 
total HF endpoint. 
Analyses with joint frailty models as supportive analyses of recurrent HHFs and recurrent 
urgent HF events have been removed. 
A responder analysis based on thresholds of the anchor-based analyses with the PGIS/PGIC 
are included for KCCQ TSS. Empirical cumulative density functions are included for change 
from baseline in KCCQ TSS. 
Time to first occurrence of a new composite renal endpoint including sustained decrease in 
eGFR ≥57% relative to baseline, mean rate of change in eGFR slope, and change in UACR 
from baseline are included as new exploratory endpoints and respective analyses of these 
endpoints are specified. 
Additional model specification is included for the repeated measures model of the change in 
eGFR and UACR. 
Exchanging analysis of AEs by SMQs with MLGs. 
Handling of SAE and outcome events for Japan and India have been clarified. 
Inclusion of analyses for hyperkalemia and acute renal failure. 
Clarification of derivation of incidences per 100 person-years. 
Handling of local hematology measurements due to local protocol amendment has been 
clarified. 
Revision of cutoffs for special safety parameters. 
Listing further safety variables in line with protocol. 
Inclusion of further analyses for COVID-19 related issues.  


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Inclusion of analyses due to regional crisis between Russia and Ukraine. 
A new section on document history and changes is included as this is required to document 
respective changes from the first version. 
 
7.2 
Overview of Changes to SAP – from version 2.0 to version 3.0 
Removed reference to older protocol versions. 
Clarification of log-normality assumption for specific parameters added. 
Specification for the derivation of median for subgroup splits included. 
Updated definition of SAF – clarifying excludion of participants with GCP violation. 
Included definition of listing-only participants. 
Removed ‘ethnicity’ from demography as not being collected in the study. Included a further 
category of <90 for SBP categorization, due to respective observed values. 
Updated PT Term from ‘Liver cirrhosis’ to ‘Hepatic cirrhosis’. 
Restricted some analyses on concomitant medications to medications in the standard drug 
groups of interest. 
Separated CYP3A4 inhibitors and inducers.  
Removed analysis of mean daily dose of MRAs due to unclean data. 
Included total treatment duration in patient-years. 
Removed analyses with continuous covariate of baseline LVEF as well as analysis with time 
by treatment interaction for primary and secondary endpoints. 
Updated definition of ‘on-treatment’ in general and for renal composite endpoint specifically. 
Included information on handling time after the forth event for analysis of the first 4 
composite events. 
Included further imputation rules for secondary endpoint ‘Improvement in NYHA class'. 
Rules for usage of covariance patterns in case of non-convergence included for MMRM 
analysis of KCCQ TSS. 
Updated the information on censoring for the renal endpoint and specifically for the different 
components. 
Clarified intercurrent event strategies for KCCQ responder analyses. 
Included thresholds for clinically meaningful change derived from separate anchor analysis. 
Clarified analysis of UACR used log-transformation. 
Removed breakdown of hospitalizations for DAOH. 
Removed MedDRA Labelling Groupings analyses for Adverse events. Included further 
analyses for AEs by SOC and PT. Included analyses of AEs by subgroups. 
The section 6.4.3.3 Further Safety Variables has been integrated into Advere Events Section 
6.4.1 with further details included on the definition of Hyperkalemia and Worsening renal 
function events. 


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Included display of cumulative incidences for TE hyperkalemia events. 
Updated list of lab parameters to be analyzed with geometric statistic (i.e. assuming log-
normal data). Included graphical displays for lab parameters. 
Included graphical displays for vital signs. 
Minor wording updates throughout the document (e.g. changed ‘conflict’ to ‘regional crisis’; 
‘subject’ to ‘participant’) and correction of typos. 
 
8. 
References 
Agresti, A. (2007): An Introduction to Categorical Data Analysis, Chapter 2, Second Edition, 
New York: John Wiley & Sons. 
Andersen, P. K. A. G., R.D (1982). Cox's Regression Model Counting Process: a Large 
Sample Study. Annals of Statistics, 10, 1100-1120. 
EuroQoL_Group T. EQ-5D-5L user guide version 2.0: EuroQoL Group, 2013. 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide_
EQ-5D-5L_v20_October_2013.pdf 
International Council for Harmonization (2019): Addendum on estimands and sensitivity 
analysis in clinical trials to the guideline on statistical principles for clinical trials. ICH E9 
(R1). 
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9. 
Appendix 
9.1 
The Kansas City Cardiomyopathy Questionnaire Scoring Instructions 
There are 10 summary scores within the KCCQ, which are calculated as follows: 
 
1. Physical Limitation 
 
• 
Code responses to each of Questions 1a-f as follows: 
 
Extremely limited = 1 
 
Quite a bit limited = 2 
Moderately limited = 3 
Slightly limited = 4 
Not at all limited = 5 
Limited for other reasons or did not do = <missing value> 
 
• 
If at least three of Questions 1a-f are not 
missing, then compute 
Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) 
– 1]/4 (see footnote at end of this document for explanation of meaning of 
“actually answered”) 
2.  Symptom Stability 
 
• 
Code the response to Question 2 as follows: 
 
Much worse = 1 
 
Slightly worse = 2 
Not changed = 3 
Slightly better = 4 
Much better = 5 
I’ve had no symptoms over the last 2 weeks = 3 
 
• 
If Question 2 is not missing, then compute  
Stability Score = 100*[(Question 2) – 1]/4 
 
3. Symptom Frequency 
 
• 
Code responses to Questions 3, 5, 7 and 9 as follows: 
 
Question 3 
 
Every morning = 1 
3 or more times a week but not every day = 2 
1-2 times a week = 3 


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Less than once a week = 4 
Never over the past 2 weeks = 5 
 
Questions 5 and 7 
 
All of the time = 1 
Several times a day = 2 
At least once a day = 3 
3 or more times a week but not every day = 4 
1-2 times a week = 5 
Less than once a week = 6 
Never over the past 2 weeks = 7 
 
Question 9 
 
Every night = 1 
3 or more times a week but not every day = 2 
1-2 times a week = 3 
Less than once a week = 4 
Never over the past 2 weeks = 5 
 
• 
If at least two of Questions 3, 5, 7 and 9 are not missing, then compute: 
 
S3 = [(Question 3) – 1]/4 
 
S5 = [(Question 5) – 1]/6 
S7 = [(Question 7) – 1]/6 
S9 = [(Question 9) – 1]/4 
 
Symptom Frequency Score = 100*(mean of S3, S5, S7 and S9) 
 
 
4. Symptom Burden 
 
•   Code responses to each of Questions 4, 6 and 8 as follows: 
 
Extremely bothersome = 1 
 
Quite a bit bothersome = 2 
Moderately bothersome = 3 
Slightly bothersome = 4 
Not at all bothersome = 5 
I’ve had no swelling/fatigue/shortness of breath = 5 
 
• 
If at least one of Questions 4, 6 and 8 is not missing, then compute 
 
Symptom Burden Score = 100*[(mean of Questions 4, 6 and 8 actually answered) – 
1]/4 
 
 
5. Total Symptom Score 
 
= mean of the following available summary 
scores: Symptom Frequency Score 
 


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Symptom Burden Score 
 
 
6. Self-Efficacy 
 
•   Code responses to Questions 10 and 11 as follows: 
 
Question 10 
 
Not at all sure = 1 
Not very sure = 2 
Somewhat sure = 3 
Mostly sure = 4 
Completely sure = 5 
 
Question 11 
 
Do not understand at all = 1 
Do not understand very well = 2 
Somewhat understand = 3 
Mostly understand = 4 
Completely understand = 5 
 
• If at least one of Questions 10 and 11 is not missing, then compute Self-Efficacy 
Score = 100*[(mean of Questions 10 and 11 actually answered) – 1]/4 
 
7. Quality of Life 
 
• 
Code responses to Questions 12, 13 and 14 as follows: 
 
Question 12 
 
It has extremely limited my enjoyment of life = 1 
It has limited my enjoyment of life quite a bit = 2 
It has moderately limited my enjoyment of life = 3 
It has slightly limited my enjoyment of life = 4 
It has not limited my enjoyment of life at all = 5 
 
Question 13 
 
Not at all satisfied = 1 
Mostly dissatisfied = 2 
Somewhat satisfied = 3 
Mostly satisfied = 4 
Completely satisfied = 5 
 
Question 14 
 
I felt that way all of the time = 1 
I felt that way most of the time = 2 
I occasionally felt that way = 3 
I rarely felt that way = 4 
I never felt that way = 5 
 
• 
If at least one of Questions 12, 13 and 14 is not missing, then compute 


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Quality of Life Score = 100*[(mean of Questions 12, 13 and 14 actually answered) – 
1]/4 
 
 
8. Social Limitation 
 
• 
Code responses to each of Questions 15a-d as follows: 
 
Severely limited = 1 
 
Limited quite a bit = 2 
Moderately limited = 3 
Slightly limited = 4 
Did not limit at all = 5 
Does not apply or did not do for other reasons = <missing value> 
 
• 
If at least two of Questions 15a-d are not missing, then compute 
 
Social Limitation Score = 100*[(mean of Questions 15a-d actually answered) – 1]/4 
 
 
9. Overall Summary Score 
 
= mean of the following available 
summary scores: Physical 
Limitation Score 
Total Symptom 
Score Quality of 
Life Score Social 
Limitation Score 
 
 
10. Clinical Summary Score 
 
= mean of the following available 
summary scores: Physical 
Limitation Score 
 
Total Symptom Score 
____________________ 
 
Note: references to “means of questions actually answered” imply the following. 
 
Ƅ If there are n questions in a scale, and the participant must answer m to score the 
scale, but the participant answers only n-i, where n-i >= m, calculate the mean of 
those questions as 
(sum of the responses to those n-i 
questions) / (n-i) not 
 
(sum of the responses to those n-i questions) / n