Conditions: Chronic Kidney Disease
Keywords: CKD Diabetic Kidney Disease Type 2 Diabetes Kidney diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5734
Healthy volunteers: no

Brief summary:
The primary objective of this study was to demonstrate whether, in addition to standard of care, finerenone is superior to placebo in delaying the progression of kidney disease, as measured by the composite endpoint of time to first occurrence of kidney failure, a sustained decrease of estimated glomerular filtration rate (eGFR) ≥40% from baseline over at least 4 weeks, or renal death.

Detailed description:

Arms:
arm 1: Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy arm 2: Participants received matching placebo once daily in addition to standard of care therapy

Interventions: intervention 1: Finerenone (BAY94-8862) intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet; starting dose at 10 mg for subjects with an eGFR between 25 to \< 60 mL/min/1.73m² at the Screening Visit; starting dose at 20 mg for subjects with an eGFR ≥ 60 mL/min/1.73m² at the Screening Visit; dose could be up-titrated from Month 1 onwards or down-titrated at any time during the study; once daily in the morning, until the trial was completed provided there were no safety grounds for discontinuing treatment intervention 2: Matching placebo, oral tablet, once daily in the morning, until the trial was completed provided there were no safety grounds for discontinuing treatment

Protocol document:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
A randomized, double-blind, placebo-controlled, parallel-group, 
multicenter, event-driven Phase III study to investigate the 
efficacy and safety of finerenone, in addition to standard of care, 
on the progression of kidney disease in subjects with type 2 
diabetes mellitus and the clinical diagnosis of diabetic kidney 
disease 
NCT Number: 
NCT02540993 
Document Date: 
26-FEB-2019 
 
 


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Cover page of the integrated protocol
A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-
driven Phase III study to investigate the efficacy and safety of finerenone, in addition 
to standard of care, on the progression of kidney disease in subjects with type 2 
diabetes mellitus and the clinical diagnosis of diabetic kidney disease
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 10 JUN 2015
Amendment 03, (global amendment described in Section 15.1)
forming integrated protocol Version 2.0, dated 02 MAY 2017
Amendment 04, (global amendment, refer to the “Protocol amendment 
summary of changes” section) forming integrated protocol Version 3.0, 
dated 26 FEB 2019
Local amendments not forming part of this integrated global protocol:
Amendment 01, (dated 18 AUG 2015)
(local amendment, valid for Japan only)
Amendment 02, (dated 29 JUL 2016)
(local amendment, valid for Turkey only)


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1.
Title page - amended
Study title
A randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven 
Phase III study to investigate the efficacy and safety of finerenone, in addition to standard of 
care, on the progression of kidney disease in subjects with type 2 diabetes mellitus and the 
clinical diagnosis of diabetic kidney disease
Short title:
Efficacy and safety of finerenone in subjects with type 2 diabetes 
mellitus and the clinical diagnosis of diabetic kidney disease
Acronym:  
FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and 
dIsease prOgression in Diabetic Kidney Disease)
Test drug:
Finerenone / BAY 94-8862
Study purpose:
Efficacy and safety
Clinical study phase:
III
Date:
26 FEB 2019
Registration:
EudraCT: 2015-000990-11
Version no.: 3.0
Sponsor’s study no.:
16244 
Sponsor:
Non- US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer Healthcare Pharmaceuticals Inc.,
100 Bayer Boulevard, P.O. Box 915, Whippany 
NJ 07981-0915, USA
Sponsor’s medical expert:
Study Medical Expert
Bayer S.A.
04779 900 São Paulo, Brazil
Phone no.: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
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) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD
PPD


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Signature of the sponsor's medically responsible person 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
 
Role: 
Global Clinical Leader 
Date: 2 -=f FEB 
PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s investigator site file.


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2.
Synopsis - amended
This section was changed in Amendment 3, see Section 15.1.2.2.
Title
A randomized, double-blind, placebo-controlled, parallel-group, multicenter, 
event-driven Phase III study to investigate the efficacy and safety of finerenone, in 
addition to standard of care, on the progression of kidney disease in subjects with 
type 2 diabetes mellitus and the clinical diagnosis of diabetic kidney disease
Short title
Efficacy and safety of finerenone in subjects with type 2 diabetes mellitus and 
the clinical diagnosis of diabetic kidney disease
Acronym
FIDELIO-DKD
(FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic 
Kidney Disease)
Clinical study phase
III
Study objectives
The primary objective of this study is to:

Demonstrate whether, in addition to standard of care (SoC), 
finerenone is superior to placebo in delaying the progression of 
kidney disease, as measured by the composite endpoint of time to first 
occurrence of kidney failure, a sustained decrease of eGFR ≥ 40% from 
baseline over at least 4 weeks or renal death 
The secondary objectives of this study are to determine whether, in addition 
to SoC, finerenone compared to placebo:

Delays the time to first occurrence of the following composite endpoint: 
cardiovascular (CV) death or non-fatal CV events 
(i.e. non-fatal myocardial infarction, non-fatal stroke, hospitalization for 
heart failure [HF])

Delays the time to all-cause mortality

Delays the time to all-cause hospitalizations

Change in UACR from baseline to Month 4

Delays the time to first occurrence of the following composite endpoint:
onset of kidney failure, a sustained decrease in eGFR of ≥57% from 
baseline over at least 4 weeks or renal death.
Test drugs
Name of active ingredient Finerenone
Doses

10 mg finerenone tablet once daily in the morning OR

20 mg finerenone tablet once daily in the morning
Route of administration
Oral
Duration of treatment
As an event-driven trial, the actual length of the treatment will depend on the 
observed event rate, the patient recruitment rate, and length of the recruitment 
period and will be approximately 3.5 years.


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Reference drug
Name of active ingredient Placebo
Dose

Placebo tablet once daily in the morning
Route of administration
Oral
Duration of treatment
As an event-driven trial, the actual length of the treatment will depend on the 
observed event rate, the patient recruitment rate, and length of the recruitment 
period and will be approximately 3.5 years.
Background treatment
Standard of care (SoC) therapy
Indication
Diabetic kidney disease (DKD)
Diagnosis and main criteria 
for inclusion /exclusion
Key inclusion criteria:
Men or women ≥18 years of age
T2DM as defined by the American Diabetes Association
Diagnosis of DKD with at least one of the following criteria at Run-in and 
Screening visits:
−persistent high albuminuria 1 and presence of diabetic retinopathy
OR
−persistent very high albuminuria 2.
Pretreated for at least 4 weeks prior to the Screening Visit with 
either ACEI or ARB at maximal tolerated labeled dose,  preferably 
without adjustments to dose or choice of agent or other treatment
Serum potassium ≤4.8 mmol/L.
Key exclusion criteria:

Confirmed significant non-diabetic renal disease, including clinically 
relevant renal artery stenosis

Uncontrolled arterial hypertension (ie, mean sitting SBP ≥170 mmHg, 
sitting DBP ≥110 mmHg at run-in visit, or mean sitting SBP ≥160 mmHg, 
sitting DBP ≥100 mmHg at screening)

Clinical diagnosis of chronic HFrEF and persistent symptoms 
(NYHA class II – IV) at run-in visit (class 1A recommendation for MRAs)

Dialysis for acute renal failure within 12 weeks of run-in visit

Renal allograft in place or scheduled within next 12 months

HbA1c > 12%.
Study design
Randomized, double-blind, placebo-controlled, parallel-group, multicenter, 
event-driven
Methodology
Randomized subjects will be treated with finerenone or placebo OD in a 
blinded fashion.  The starting dose of study drug will depend on the subject’s 
eGFR level at the Screening Visit: a lower dose of 10 mg OD if eGFR was 
                                                
1
High albuminuria (previously known as ‘micro-albuminuria’) is defined as 300 mg/g > UACR  ≥ 30mg/g in 2 out of 3 first 
morning void samples.
2
Very high albuminuria (previously known as ‘macro-albuminuria’) is defined as UACR  ≥ 300mg/g in 2 out of 3 first 
morning void samples.


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between 25 to < 60 mL/min/1.73m², or the higher (target) dose of 20 mg OD if 
eGFR was ≥60 mL/min/1.73m².  Study drug may be up-titrated from Visit 2 
(Month1) onwards provided potassium is ≤4.8 mmol/L and eGFR decrease is 
less than 30% below the value last measured.  Down-titration or interruption of 
study drug is permitted at any time during the study for safety reasons.
Type of control
Placebo
Data Monitoring Committee
Yes
Number of subjects
Planned 9600 subjects screened, 4800 subjects randomized to achieve 
approximately 1068 primary efficacy events
Primary variable
Time to first occurrence of the composite endpoint of onset of kidney failure, 
a sustained decrease of eGFR ≥ 40% from baseline over at least 4 weeks,
or renal death
Time point/frame of 
measurement for 
primary variables
Events for inclusion in the primary variable (above) will be counted from the 
day of randomization (Visit 1) onwards until the End-of-Study (EOS) visit 
following the study termination decision.  In the case of premature termination 
from the study with no subsequent follow-up information, events will be 
counted up to the day of premature termination
Plan for statistical analysis
The log-rank test for the difference of the survival function of finerenone 
compared to placebo, stratified by the stratification factors region, type of 
albuminuria and eGFR category will be used, an overall two-sided significance 
level of 5.0% or 3.333% if the CV composite endpoint is not statistically 
significant according to the weighted Bonferoni-Holm procedure, with a small 
adjustment for an interim analysis


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Protocol amendment summary of changes
Amendment 4 (26 FEB 2019)
This amendment is considered to be nonsubstantial 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 because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment:
This amendment summarizes minor changes in the conduct of the study and planned analyses. 
The main change is that the PT Visit will be performed as a telephone contact for all patients 
except those participating in the iohexol clearance sub-study. The PT Visit is to be performed 
within 4 weeks + 5 days after last study drug intake for those patients still on treatment at the 
EOS Visit (Sections 9.1, 9.2.10, and 9.2.11). The rationale for the change is that a telephone 
call is considered adequate to inquire about possible AEs and concomitant medication usage. 
This change neither compromises patient safety nor scientific value. The performance as a 
telephone contact will minimize the burden on patients, sites, and the sponsor. Procedures that 
would require the presence of the patient at the study site have been adapted accordingly. The 
following activities will no longer be performed: physical examination, ECG, recording of 
body weight and vital signs, and laboratory sampling.
All other minor changes with their brief rationale are summarized in the table below.
Table 1
Protocol amendment summary of minor changes
Section number 
and name
Description of change
Brief rationale
10.1 General 
considerations
10.3.2 Treatment 
duration, extent 
of exposure, up-
titration status 
and compliance
Specification of baseline values.
This was added to clarify the handling of 
subjects who did not immediately start 
with study drug treatment at 
randomization, because all analyses 
follow the intent-to-treat principle.
10.1 General 
considerations
10.3.3.2 Primary 
efficacy variable: 
supportive
For on-treatment efficacy 
analyses, the time window after 
last study drug administration is 
increased from 3 to 30 days.
The time window was increased to better 
reflect the more protracted nature of the 
development and diagnosis of clinical 
outcome events of interest in relation to 
treatment exposure.
continued


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Section number 
and name
Description of change
Brief rationale
10.3.4
Provision of more precise 
wording about the type of 
discontinuation.
Considering the nature of the underlying 
disease and the long duration of the 
study, it is the impact of permanent 
discontinuation of the study drug that is of 
particular interest.
10.3.4.1 Adverse 
events
New definition of treatment-
emergent AEs.
The definition of TEAEs was specified to 
account for permitted study drug 
interruptions (i.e. temporary 
discontinuations) which may occur over 
extended periods.
10.3.4.2 Laboratory 
data
Specification regarding 
interruption of study treatment.
This was updated to consider treatment 
interruptions in a similar manner as done 
for the AE presentation.
10.3.3.5.2 
Decrease in 
eGFR
10.3.4.2 Laboratory 
data
Deletion of the following 
analyses:

Absolute value of serum 
potassium >5.0 mmol/L

Relative decrease from 
baseline in eGFR of ≥25%

Increase from baseline in 
serum creatinine >0.3 mg/dL 
and >0.5 mg/dL
Patients remain on study drug treatment
with potassium values up to 5.5 mmol/L. 
Safety specific information will be 
obtained by analyzing the remaining 
thresholds of >5.5 mmol/L (moderate 
hyperkalemia) and >6.0 mmol/L (severe 
hyperkalemia) for serum potassium.
In this long-term trial relative eGFR 
decrease from baseline ≥25% does not 
provide clinically relevant information. The 
same applies to analyses of change in 
serum creatinine, which is already 
incorporated in the currently planned 
analyses of change in eGFR.
Throughout Section 
10 Statistical 
methods and 
determination of 
sample size
More precise wording.
Specifications changed for correctness.
Where applicable
Minor editorial and typographical 
errors, updated information on 
responsible persons.
Unsubstantial changes for correctness.
Abbreviations: AE = adverse event; eGFR = estimated glomerular filtration rate; TEAE = treatment-emergent
adverse event


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Table of contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page - amended.......................................................................................................... 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis - amended............................................................................................................ 5
Protocol amendment summary of changes ............................................................................ 8
Table of contents..................................................................................................................... 10
Table of tables......................................................................................................................... 15
Table of figures....................................................................................................................... 15
List of abbreviations............................................................................................................... 16
3.
Introduction..................................................................................................................... 20
3.1
Background.................................................................................................................... 20
3.2
Rationale of the study .................................................................................................... 24
3.3
Benefit-risk assessment.................................................................................................. 24
4.
Study objectives............................................................................................................... 27
5.
Study design - amended................................................................................................... 28
6.
Study population ............................................................................................................. 32
6.1
Inclusion criteria ............................................................................................................ 33
6.2
Exclusion criteria - amended ......................................................................................... 34
6.3
Justification of selection criteria.................................................................................... 35
6.4
Withdrawal of subjects from study................................................................................ 36
6.4.1
Withdrawal ................................................................................................................. 36
6.4.1.1
Discontinuation of study drug - amended ............................................................... 36
6.4.1.2
Discontinuation of study ......................................................................................... 37
6.4.2
Replacement ............................................................................................................... 37
6.4.2.1
Re-screening - amended.......................................................................................... 38
6.4.2.2
Switch over between studies ................................................................................... 38
6.5
Subject identification ..................................................................................................... 39
7.
Treatment(s) .................................................................................................................... 39
7.1
Treatments to be administered....................................................................................... 39
7.2
Identity of study treatment............................................................................................. 40
7.3
Treatment assignment.................................................................................................... 40
7.4
Dosage and administration - amended........................................................................... 41
7.5
Blinding ......................................................................................................................... 43
7.5.1
Blinding measures ...................................................................................................... 43
7.5.2
Unblinding - amended ................................................................................................ 43
7.5.3
Emergency unblinding by the investigator................................................................. 43


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7.6
Drug logistics and accountability................................................................................... 43
7.7
Treatment compliance.................................................................................................... 44
8.
Non-study therapy........................................................................................................... 44
8.1
Prior and concomitant therapy....................................................................................... 44
8.1.1
General considerations for prior and concomitant therapy ........................................ 44
8.1.2
Medical management.................................................................................................. 46
8.1.3
Control of blood pressure - amended ......................................................................... 47
8.1.4
Use of potassium supplements and lowering agents .................................................. 47
8.2
Post-study therapy.......................................................................................................... 47
9.
Procedures and variables ............................................................................................... 48
9.1
Tabular schedule of evaluations - amended................................................................... 48
9.2
Visit description - amended ........................................................................................... 52
9.2.1
Run-in Visit (4 to 16 weeks prior to the Screening Visit) - amended ........................ 52
9.2.2
Screening Visit (≤2 weeks prior to Visit 1) - amended............................................. 53
9.2.3
Visit 1 (randomization; Day 1 and baseline) - amended ............................................ 53
9.2.4
Visit 2 (Month 1)........................................................................................................ 54
9.2.5
Visit 3 (Month 4) - amended ...................................................................................... 55
9.2.6
Visit 4, 6, 7, 9, etc. (every 4 months; Month 8, 16, 20, 28, etc., excluding yearly 
visits) - amended......................................................................................................... 55
9.2.7
Visit 5, 8, 11, etc. (every 12 months; Month 12, 24, 36, etc) - amended ................... 56
9.2.8
Up-titration Visit (4 weeks ± 7 days after up-titration or restart of study drug and 
for up-titration of study drug) - amended................................................................... 57
9.2.9
Premature Discontinuation (PD) Visit (as soon as possible but within 7 days after 
study drug is permanently discontinued) - amended.................................................. 57
9.2.10
End of study (EOS) visit - amended........................................................................... 58
9.2.11
Post-Treatment (PT) Visit - amended......................................................................... 59
9.3
Population characteristics .............................................................................................. 59
9.3.1
Demographic .............................................................................................................. 59
9.3.2
Medical history - amended ......................................................................................... 60
9.4
Efficacy- amended ......................................................................................................... 60
9.4.1
Primary efficacy variable............................................................................................ 60
9.4.2
Secondary efficacy variables...................................................................................... 60
9.4.3
Other exploratory efficacy variables - amended......................................................... 61
9.5
Pharmacokinetics / pharmacodynamics - amended....................................................... 62
9.6
Safety ............................................................................................................................. 63
9.6.1
Adverse events............................................................................................................ 63
9.6.1.1
Definitions - amended ............................................................................................. 63
9.6.1.2
Classifications for adverse event assessment.......................................................... 64
9.6.1.2.1
Seriousness........................................................................................................... 64
9.6.1.2.2
Intensity................................................................................................................ 65
9.6.1.2.3
Causal relationship............................................................................................... 65
9.6.1.2.4
Action taken with study treatment ....................................................................... 66
9.6.1.2.5
Other specific treatment(s) of adverse events...................................................... 66
9.6.1.2.6
Outcome............................................................................................................... 67


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9.6.1.3
Assessments and documentation of adverse events (AEs) - amended.................... 67
9.6.1.3.1
Event versus outcome .......................................................................................... 68
9.6.1.4
Reporting of serious adverse events (SAEs) - amended ......................................... 68
9.6.1.5
Expected adverse events.......................................................................................... 70
9.6.2
Pregnancies................................................................................................................. 70
9.7
Other procedures and variables...................................................................................... 71
9.7.1
Monitoring of potassium - amended........................................................................... 71
9.7.2
Laboratory assessments.............................................................................................. 72
9.7.2.1
Central laboratory.................................................................................................... 72
9.7.2.2
Local laboratory - amended..................................................................................... 73
9.7.3
Physical examination.................................................................................................. 74
9.7.4
Weight and height....................................................................................................... 74
9.7.5
Measurement of vital signs......................................................................................... 74
9.7.6
Electrocardiogram (ECG) - amended......................................................................... 74
9.7.7
Health-related quality of life (HRQoL) questionnaires.............................................. 74
9.7.8
Planned optional sub-studies ...................................................................................... 75
9.7.8.1
Sub-studies .............................................................................................................. 75
9.7.8.1.1
Echocardiography sub-study - amended.............................................................. 75
9.7.8.1.2
Biomarker sub-study............................................................................................ 78
9.7.8.1.3
Iohexol clearance sub-study - amended............................................................... 78
9.8
Appropriateness of procedures / measurements ............................................................ 79
10. Statistical methods and determination of sample size ................................................. 80
10.1
General considerations................................................................................................... 80
10.2
Analysis sets - amended................................................................................................. 81
10.3
Variables and planned statistical analyses..................................................................... 81
10.3.1
Disposition, baseline, history, demography and medication...................................... 81
10.3.1.1
Disposition - amended............................................................................................. 81
10.3.1.2
Population characteristics........................................................................................ 82
10.3.1.3
Demography and other baseline characteristics - amended .................................... 82
10.3.1.4
Medical history........................................................................................................ 82
10.3.1.5
Concomitant medication ......................................................................................... 82
10.3.2
Treatment duration, extent of exposure, up-titration status and compliance -
amended...................................................................................................................... 83
10.3.3
Efficacy variables ....................................................................................................... 83
10.3.3.1
Primary efficacy variable: primary analysis............................................................ 83
10.3.3.2
Primary efficacy variable: supportive analyses....................................................... 85
10.3.3.3
Secondary efficacy variables: primary analysis...................................................... 85
10.3.3.4
Secondary efficacy variables: supportive analyses ................................................. 86
10.3.3.5
Analysis of other exploratory efficacy variables..................................................... 86
10.3.3.5.1
UACR and albuminuria - amended...................................................................... 86
10.3.3.5.2
Decrease in eGFR ................................................................................................ 87
10.3.3.5.3
Health-related quality of life (HR-QoL).............................................................. 87
10.3.3.5.4
New diagnosis of atrial fibrillation, new diagnosis of heart failure and 
regression of albuminuria .................................................................................... 87


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10.3.3.6
Subgroup analyses................................................................................................... 88
10.3.4
Safety variables........................................................................................................... 88
10.3.4.1
Adverse events ........................................................................................................ 89
10.3.4.2
Laboratory data ....................................................................................................... 89
10.3.4.3
Vital signs................................................................................................................ 90
10.3.4.4
Weight and BMI...................................................................................................... 90
10.3.4.5
Further safety variables ........................................................................................... 90
10.3.5
Missing data / drop outs ............................................................................................. 91
10.4
Determination of sample size - amended....................................................................... 91
10.5
Planned interim analyses - amended.............................................................................. 92
11. Data handling and quality assurance............................................................................ 93
11.1
Data recording................................................................................................................ 93
11.2
Monitoring ..................................................................................................................... 94
11.3
Data processing.............................................................................................................. 94
11.4
Missing data................................................................................................................... 95
11.5
Audit and inspection ...................................................................................................... 96
11.6
Archiving ....................................................................................................................... 96
12. Premature termination of the study.............................................................................. 97
13. Ethical and legal aspects................................................................................................. 97
13.1
Investigator(s) and other study personnel...................................................................... 97
13.1.1
Executive Committee ................................................................................................. 98
13.1.2
Clinical Event Committee (CEC)............................................................................... 98
13.1.3
Data Monitoring Committee (DMC)........................................................................ 100
13.1.4
Steering Committee.................................................................................................. 100
13.2
Funding and financial disclosure ................................................................................. 100
13.3
Ethical and legal conduct of the study......................................................................... 101
13.4
Subject information and consent.................................................................................. 101
13.5
Publication policy and use of data ............................................................................... 103
13.6
Compensation for health damage of subjects / insurance............................................ 103
13.7
Confidentiality ............................................................................................................. 103
14. Reference list.................................................................................................................. 104
15. Protocol amendments.................................................................................................... 108
15.1
Amendment 3............................................................................................................... 108
15.1.1
Overview of changes to the study............................................................................. 108
15.1.2
Changes to the protocol text..................................................................................... 110
15.1.2.1
Section 1 Title page............................................................................................... 111
15.1.2.2
Section 2 Synopsis ................................................................................................ 111
15.1.2.3
Section 5 Study design.......................................................................................... 112
15.1.2.4
Figure 5-1 Overall study design............................................................................ 114
15.1.2.5
Section 6.2 Exclusion criteria................................................................................ 115
15.1.2.6
Section 6.4.1.1 Discontinuation of study drug...................................................... 115
15.1.2.7
Section 6.4.2.1 Re-screening................................................................................. 116


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15.1.2.8
Section 7.4 Dosage and administration................................................................. 116
15.1.2.9
Section 7.5.2 Unblinding....................................................................................... 117
15.1.2.10 Section 8.1.3 Control of blood pressure................................................................ 118
15.1.2.11 Table 9-1 Study 16244: schedule of activities and evaluations ............................ 119
15.1.2.12 Table 9-2 Sub-studies of Study 16244: schedule of procedures ........................... 121
15.1.2.13 Section 9.2 Visit description ................................................................................. 123
15.1.2.14 Section 9.2.1 Run-in Visit (4 to 16 weeks prior to the Screening Visit)............... 123
15.1.2.15 Section 9.2.2 Screening Visit (≤2 weeks prior to Visit 1).................................... 124
15.1.2.16 Section 9.2.3 Visit 1 (randomization; Day 1 and baseline)................................... 124
15.1.2.17 Section 9.2.5 Visit 3 (Month 4)............................................................................. 125
15.1.2.18 Section 9.2.6 Visit 4, 6, 7, 9, etc. (every 4 months; Month 8, 16, 20, 28, etc., 
excluding yearly visits) ......................................................................................... 125
15.1.2.19 Section 9.2.7 Visit 5, 8, 11, etc. (every 12 months; Month 12, 24, 36, etc.)......... 125
15.1.2.20 Section 9.2.8 Up-titration Visit (unscheduled; from 4 weeks ± 7 days post-
titration)................................................................................................................. 126
15.1.2.21 Section 9.2.9 Premature Discontinuation (PD) Visit ............................................ 126
15.1.2.22 Section 9.2.10 End of study (EOS) visit ............................................................... 126
15.1.2.23 Section 9.2.11 Post-Treatment (PT) Visit............................................................. 127
15.1.2.24 Section 9.3.2 Medical history................................................................................ 127
15.1.2.25 Section 9.4 Efficacy .............................................................................................. 127
15.1.2.26 Section 9.4.3 Other exploratory efficacy variables............................................... 127
15.1.2.27 Section 9.5 Pharmacokinetics / pharmacodynamics ............................................. 128
15.1.2.28 Section 9.6.1.1 Definitions.................................................................................... 129
15.1.2.29 Section 9.6.1.3 Assessments and documentation of adverse events (AEs)........... 129
15.1.2.30 Section 9.6.1.4 Reporting of serious adverse events (SAEs)................................ 130
15.1.2.31 Section 9.7.1 Monitoring of blood potassium....................................................... 130
15.1.2.32 Section 9.7.2.2 Local laboratory ........................................................................... 131
15.1.2.33 Section 9.7.6 Electrocardiogram (ECG) ............................................................... 131
15.1.2.34 Section 9.7.8.1.1 Echocardiography sub-study..................................................... 132
15.1.2.35 Section 9.7.8.1.3 Iohexol clearance sub-study...................................................... 132
15.1.2.36 Section 10.2 Analysis sets..................................................................................... 133
15.1.2.37 Section 10.3.1.1 Disposition ................................................................................. 133
15.1.2.38 Section 10.3.1.3 Demography and other baseline characteristics......................... 134
15.1.2.39 Section 10.3.2 Treatment duration, extent of exposure, up-titration status and 
compliance ............................................................................................................ 134
15.1.2.40 Section 10.3.3.5.1 UACR and albuminuria........................................................... 134
15.1.2.41 Section 10.4 Determination of sample size........................................................... 135
15.1.2.42 Section 10.5 Planned interim analyses.................................................................. 136
15.2
Amendment 4............................................................................................................... 136
16. Appendices..................................................................................................................... 137
16.1
Guidance on use of common CYP inhibitors or inducers ........................................... 137
16.2
Calculating the Child Pugh score................................................................................. 138
16.3
HR-QoL questionnaires ............................................................................................... 139


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Table of tables
Table 1
Protocol amendment summary of minor changes ................................................... 8
Table 7–1 Identity of test drug / finerenone and matching placebo....................................... 40
Table 7–2 Dosage of study drug for administration............................................................... 41
Table 8–1 Dose ranges of ACEIs and ARBs for adults ......................................................... 45
Table 9–1 Study 16244: schedule of activities and evaluations - amended........................... 49
Table 9–2 Sub-studies of Study 16244: schedule of procedures – amended ......................... 51
Table 9–3 Blood potassium: guidance for dose adjustment at Visit 2 and subsequent visits 71
Table 9–4 Central laboratory parameters ............................................................................... 73
Table 9–5 Echocardiography sub-study: biomarkers for evaluation...................................... 76
Table 9–6 Echocardiography sub-study: variables for evaluation ......................................... 77
Table 9–7 Biomarker sub-study: variables for evaluation ..................................................... 78
Table 13–1 Endpoint events to be reported to the Clinical Event Committee (CEC).............. 99
Table 16–1 Cytochrome P450: list of concomitant medication ............................................. 137
Table 16–2 Grading of severity of liver disease (adapted from (54)) .................................... 138
Table 16–3 Classification using the added score from Table 16–2 (adapted from (54))....... 138
Table 16–4 KDQOL-36: grouping of items and description.................................................. 139
Table of figures
Figure 3–1 Prognosis of CKD by GFR and albuminuria category (3) .................................... 20
Figure 3–2 Approaches to improving outcomes related to DKD (8) ...................................... 21
Figure 3–3 Mechanisms of cardiac and renal damage induced by aldosterone excess (20).... 22
Figure 5–1 Overall study design - amended ............................................................................ 30
Figure 8–1 Background therapy with RAS blockade .............................................................. 45
Figure 9–1 Medical finding during the study: event versus outcome...................................... 68


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List of abbreviations
AASK
African-American Study of Kidney disease and hypertension
ACEI(s)
angiotensin-converting enzyme inhibitor(s)
AE
adverse event
ANCOVA
analysis of covariance
ALT
alanine aminotransferase
ALTITUDE
Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints 
AP
alkaline phosphatase
ARB(s)
angiotensin receptor blocker(s)
ARTS
MinerAlocorticoid Receptor Antagonist Tolerability Study
ARTS-DN
MinerAlocorticoid Receptor Antagonist Tolerability Study - Diabetic 
Nephropathy
AST
aspartate aminotransferase
AUC
area under the plasma concentration vs. time curve of total (bound and 
unbound) drug from zero to infinity after single (first) dose
BMI
body mass index
BNP
B-type natriuretic peptide
BP
blood pressure
BSA
body surface area
CEC
Clinical Event Committee
Cmax
maximum total (bound and unbound) drug concentration in plasma after 
single dose administration
CK
creatine kinase
CKD
chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRO
contract research organization
CV
Cardiovascular
CVD
cardiovascular disease
CYP
cytochrome P450
CYP3A4
cytochrome P450 isoenzyme 3A4
DBP
diastolic blood pressure
DKD
diabetic kidney disease
DMC
Data Monitoring Committee
DN
diabetic nephropathy
ECG
electrocardiogram 
eCRF
electronic case report form
EED
end expiratory diameter
eGFR
estimated glomerular filtration rate
EOS
End-of-Study (visit)
EQ-5D-5L
EuroQol Group 5-dimension, 5-level questionnaire
ESRD
end-stage renal disease
EU
European Union
EWDT
E-wave deceleration time
FAS
full analysis set


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FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
FU
follow-up
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma glutamyl transpeptidase
GMP
Good Manufacturing Practice
HbA1c
glycated hemoglobin
HDL
high density lipoprotein
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
HFrEF
heart failure with reduced ejection fraction
HOPE
Heart Outcomes Prevention Evaluation
HRQoL
health-related quality of life
hs-CRP
high-sensitivity C-reactive protein
Hs-TnT
high-sensitivity troponin T
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IDNT
Irbesartan Diabetic Nephropathy Trial
IEC
Independent Ethics Committee
IR
immediate release
IRB
Institutional Review Board
IVCD
inferior vena cava diameter
IVSd
inter-ventricular septum diameter
IxRS
Interactive Voice / Web Response System
KDQOL
Kidney Disease Quality of Life
KDIGO
Kidney Disease: Improving Global Outcomes
LA
left atrial
LDH
lactate dehydrogenase
LDL
low density lipoprotein
LOS
listing only set
LVED
left ventricular end-diastolic
LVEDD
left ventricular end-diastolic dimension
LVEDV
left ventricular end-diastolic volume
LVEDVi
left ventricular end-diastolic volume index
LVESV
left ventricular end-systolic volume
LVESVi
left ventricular end-systolic volume index
LVEF
left ventricular ejection fraction
LVM
left ventricular mass
LVMi
left ventricular mass index
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
M.D.
doctor of medicine


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MedDRA
Medical Dictionary for Regulatory Activities
MICRO-HOPE
Microalbuminuria, Cardiovascular, and Renal Outcomes (substudy of the 
HOPE trial)
MR
mineralocorticoid receptor
MRA
mineralocorticoid receptor antagonist
NGAL
neutrophil gelatinase-associated lipocalin
NIDDM
non-insulin dependent diabetes mellitus
NONMEM
non-linear mixed effect modeling
NT-proBNP
N-terminal prohormone B-type natriuretic peptide
NYHA
New York Heart Association
OD
once daily
OPN
osteopontin
PD
premature discontinuation
PGTV
pressure gradient of tricuspid valve
PIIINP
N-terminal pro-peptide of collagen III
PK
pharmacokinetic(s)
PKS
pharmacokinetic analysis set
PP
polypropylene
PPS
per-protocol analysis set
PR
PR interval in ECG
PT
Post-Treatment (visit)
PWd
posterior wall diameter
QA
quality assurance
RA(A)S
renin-angiotensin(-aldosterone) system
RAP
right atrial pressure
RAVE
electronic data capturing system
RBC
red blood cells
RENAAL
Reduction in Endpoints in NIDDM (non-insulin-dependent diabetes 
mellitus) with the Angiotensin II Antagonist Losartan
RWT
relative wall thickness
SAE
serious adverse event
SAF
safety analysis set
SAP
statistical analysis plan
SAS
Statistical Analysis System
SAVOR-TIMI 53 Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with 
Diabetes Mellitus –Thrombolysis in Myocardial Infarction 53
SBP
systolic blood pressure
SD
study drug
SDv
standard deviation
SID
subject identification
SMQ
Standardized MedDRA Queries
SoC
standard of care
sST2
soluble suppression of tumorigenicity 2
SUSAR
suspected, unexpected serious adverse reaction


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T2DM
type 2 diabetes mellitus
TAPSE
tricuspid annular plane systolic excursion
tmax
time to reach Cmax in plasma after single (first) dose
TEAE
treatment-emergent adverse event
TIA
transient ischemic attack
UACR
urinary albumin-to-creatinine ratio
UAE
urinary albumin excretion
US
United States (of America)
VTR
velocity of tricuspid regurgitation
WBC
white blood cells
WHO
World Health Organization


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3.
Introduction
3.1
Background
Diabetic kidney disease (DKD) is the most frequent cause of end-stage renal disease (ESRD) 
in western countries (1). In addition, the risk of cardiovascular (CV) disease and death 
increases in patients with DKD with decreasing glomerular filtration rate (GFR) and 
increasing albuminuria levels (2, 3).
As the type 2 diabetes mellitus (T2DM) population rapidly grows throughout the world within 
the next years (4), and with it the DKD population, there is an increasing need for new 
therapeutic agents that effectively target underlying disease mechanisms and slow or halt the 
progression of kidney disease, whilst also addressing the high CV morbidity and mortality in 
this population.
DKD is a clinical syndrome affecting individuals with diabetes that is characterized by 
albuminuria on at least 2 occasions separated by 3 to 6 months (5). DKD is usually 
accompanied by hypertension, progressive rise in proteinuria, and decline in renal function (3). 
DKD is categorized based on the level of urinary albumin excretion (UAE), either 
high albuminuria (formerly micro-albuminuria, urinary albumin-to-creatinine ratio [UACR] 
30 to < 300 mg/g) or very high albuminuria (formerly macro-albuminuria, UACR ≥ 300 mg/g).
As indicated in Figure 3–1, increased UAE and decreased GFR are both associated with a 
worse prognosis, with an increase in all-cause and CV mortality. Additionally, increased UAE 
and decreased GFR are also risk factors for ESRD, acute kidney injury and progressive CKD, 
independent of each other and of other cardiovascular disease (CVD) risk factors in general as 
well as in high-risk populations (2, 6, 7).
Figure 3–1
Prognosis of CKD by GFR and albuminuria category (3)
Interventions to improve outcomes related to DKD focus on reducing risk (Figure 3–2), 
including counseling on lifestyle modifications (i.e. smoking cessation and dietary 
GFR = glomerular filtration rate.


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modifications to reduce proteinuria and aid in weight loss) and interventions aimed at 
glycemic control, dyslipidemia, and hypertension (8).
Figure 3–2
Approaches to improving outcomes related to DKD (8)
Treatment with renin-angiotensin system (RAS) inhibitors has been of particular interest 
given the ability of these drugs to reduce the rate of progression of renal disease, 
independently and in addition to their antihypertensive effects, as evidenced in the Heart 
Outcomes Prevention Evaluation (HOPE) trial (9), the Reduction of Endpoints in NIDDM 
with the Angiotensin II Antagonist Losartan (RENAAL) trial (10), and the Irbesartan DN 
Trial (IDNT) (11). 
Therefore, angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin-receptor 
blockers (ARBs) can be considered as standard of care (SoC) therapy in patients with DKD 
and are often prescribed to patients with DKD at early stages (8). However, they slow but 
neither halt nor reverse kidney disease progression (12). 
In addition, in placebo controlled studies in patients with early DKD (i.e. patients with high 
albuminuria at baseline), only ACEIs were found to significantly reduce the risk of all-cause 
and CV mortality and morbidity (9). In patients with advanced DKD (i.e. patients with 
decreased kidney function and very high albuminuria at baseline) an impact on overall 
survival has not yet been demonstrated with ARBs (10, 11). ACEIs have not been 
investigated in outcome studies in the advanced DKD population yet. 
Animal studies have shown that aldosterone has an independent role in the development of 
hypertensive kidney disease and vascular injury resulting in myocardial and renal fibrosis 
(Figure 3–3) and its blockade reduces proteinuria (13-16). Long-term RAS blockade with 
ACEIs and ARBs results in incomplete suppression of serum aldosterone levels and is known 
as the ‘aldosterone escape’ phenomenon (17). Exploratory clinical studies in adults have 
shown that in adults with CKD exhibiting the ‘aldosterone escape’ phenomenon, treatment 
with mineralocorticoid-receptor antagonists (MRAs) improves kidney outcomes such as 
proteinuria (18). However, there is also evidence for possible therapeutic utility of 
CVD = cardiovascular disease; ESRD = end-stage renal disease;
RAAS = renin-angiotensin-aldosterone system.


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mineralocorticoid receptor (MR) blockade in conditions of tissue and organ damage with 
normal aldosterone levels (19).
Figure 3–3
Mechanisms of cardiac and renal damage induced by aldosterone 
excess (20)
The results of several short-term studies support the proposal of Shavit et al. that aldosterone 
should be considered a novel therapeutic renal target in CKD patients with the added potential 
‘off-target’ effects on heart and vasculature (21). Nevertheless, large-scale, long-term 
outcome trials examining whether MRAs can slow progression of kidney disease or prevent 
CV events in this population are missing.
Moreover, the use of currently available steroidal MRAs is known to increase the risk of 
hyperkalemia, particularly in patients with T2DM and decreased kidney function (20, 22).
Finerenone (BAY 94-8862) is a next-generation, oral, selective, non-steroidal MRA. In 
animal models, finerenone reduced cardiac and renal hypertrophy, plasma prohormone of 
brain natriuretic peptide (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 (23).  Steroidal MRAs are 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.  These characteristics may translate to a drug 
with a positive benefit-risk ratio in patients with DKD.
In a Phase IIa study, finerenone was studied in individuals with stable HFrEF and mild (eGFR 
60 to < 90 mL/min/1.73 m2) -to-moderate (30–60 mL/min/ 1.73 m2) CKD. In this 


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minerAlocorticoid Receptor Antagonist Tolerability Study (ARTS; IMPACT No. 14563, 
NCT01345656), finerenone doses of 2.5 to 10 mg/day safely reduced albuminuria and doses 
of 5.0–10.0 mg/day reduced plasma natriuretic peptides levels to the same magnitude as 
spironolactone 25–50 mg/day. All doses of finerenone were associated with a statistically 
significantly smaller mean increase in serum potassium concentration and clinically 
significantly smaller decreases in eGFR compared to spironolactone (24). 
The MinerAlocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy 
(ARTS-DN; IMPACT No. 16243; NCT01874431) was a multicentre, randomized, 
double-blind, placebo-controlled, parallel-group, Phase IIb study investigating the safety and 
efficacy of several oral doses of finerenone in patients with T2DM and a clinical diagnosis of 
DKD, based on either high albuminuria (UACR 30 to 299 mg/g) or very high albuminuria 
(UACR 300 to 3000 mg/g), and with an estimated glomerular filtration rate (eGFR) of 
30 mL/min/1.73 m2 or more. Finerenone doses of 1.25 mg up to 20 mg once daily (OD) were 
investigated in 823 randomized patients over 90 days of treatment compared to placebo in 
addition to SoC, including a RAS-inhibitor. Finerenone statistically significantly reduced 
albuminuria by 21 to 38%, compared to placebo, at doses of 7.5 mg to 20 mg OD when added 
to RAS blockade. All doses of finerenone were safe and well-tolerated. Incidences of 
treatment-emergent adverse events (TEAEs) were similar between placebo and all finerenone 
dose groups.
Based on the aforementioned properties and initial results of finerenone in Phase II clinical 
trials, finerenone has the potential to address the unmet medical needs in patients with the 
clinical diagnosis of DKD. When added to SoC therapy including a RAS blocker, 10 or 20mg 
finerenone given OD might demonstrate a reduction of CV mortality and morbidity and also 
delay the progression of renal disease compared to placebo in addition to SoC. 
Further details can be found in the latest available version of the Investigator’s Brochure (IB), 
which contains comprehensive information on the study drug.
In this study (16244), finerenone will be investigated in patients at high risk of progressing to 
kidney failure and at high risk of CV events.  A second study of the Phase III program of 
finerenone in DKD, Study 17530, will investigate finerenone in patients at lower risk of 
progressing to kidney failure but still at a high-risk of developing a first or recurrent CV 
event.  Accordingly, in Study 16244, the primary endpoint will focus on renal outcomes 
whereas in Study 17530, the primary endpoint will focus on CV outcomes.


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3.2
Rationale of the study
Study 16244 will be the first large-scale, long-term outcome trial examining whether the 
non-steroidal MRA finerenone can slow the progression of kidney disease in patients with the 
clinical diagnosis of DKD.  Secondary endpoints will focus on CV outcomes, all-cause 
mortality, all-cause hospitalizations and change in UACR.
The risk for CKD progression and ESRD is elevated in this population of patients with 
advanced DKD, with lower eGFR and higher levels of albuminuria being independent risk 
factors (6).
Together with Study 17530, which will be the first large-scale, long-term outcome trial 
examining whether the non-steroidal MRA finerenone can decrease CV mortality and 
morbidity in patients with the clinical diagnosis of DKD, Study 16244 is part of the Phase III 
trial program to evaluate if finerenone in addition to SoC can reduce the incidence of 
important clinical outcomes in patients with the clinical diagnosis of DKD. 
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 system including the heart, endothelial cells, vascular smooth 
muscle cells and kidney mesangial cells gives 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 different forms of CVD (25-27).  Results from several 
short-term studies show that treatment with MRAs in addition to RAS blockade with an ACEI 
or ARB improves albuminuria; however, long-term outcome trials examining whether MRAs 
can prevent CV events or slow progression of kidney disease in a diabetic or non-diabetic 
CKD population are still lacking. The Phase III program with finerenone in DKD will be the 
first program addressing both questions: Study 16244 will investigate the effects of the 
non-steroidal MRA finerenone on renal outcomes and Study 17530 will investigate the effects 
of finerenone on CV outcomes. 
The actual mechanisms behind the pathological effects of aldosterone in DKD have not yet 
been fully elucidated; however, aldosterone seems to be a key player in the progression of 
kidney disease, and also contributes to the accompanying high CV morbidity and mortality of 
these patients. Potent and selective MR blockade with finerenone may therefore provide 
protection against the burden of CVD and also slow or halt the progression of kidney disease 
in the targeted DKD population. 
3.3
Benefit-risk assessment
Among patients with diabetes, those with kidney disease are consistently observed to have 
substantially elevated mortality rates. Much of this mortality is due to CVD, although non-CV 
mortality is also increased. Albuminuria and eGFR are independently and additively associated 
with increased risks of CV events, CV mortality, and all-cause mortality (28). There is a high 
unmet medical need for treatments that can reduce the extensive burden of CV mortality and 
morbidity and the progression of kidney disease in patients with DKD.


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The population for Study 16244 has been chosen to adequately define a study population at high 
risk of developing renal events.  Meta-analyses have shown that very high albuminuria is 
associated with a 3- to 5-fold increased risk for the development of ESRD compared with those 
with normal levels of albuminuria (29, 30).  Another analysis of > 10000 individuals with T2DM 
have shown that patients with very high albuminuria and an eGFR < 60 mL/min/1.73 m2 had a 
16-fold higher risk for renal events compared to patients with neither of these risk factors (31).  
Patients with very high albuminuria and reduced eGFR have a substantially increased risk of 
subsequent renal events and rapidly progress to ESRD (6).  In patients with high albuminuria, the 
presence of diabetic retinopathy may indicate rapid loss of renal function and thus may be an 
additional predictive prognostic factor for the progression of CKD secondary to diabetes (32).
Therefore, Study 16244 will include a majority of patients with very high albuminuria and an 
eGFR< 60 mL/min/1.73 m2.  However, there are patients with advanced renal disease with 
very high albuminuria and an eGFR up to 75 mL/min/1.73m2 who may also benefit.  Patients 
with high albuminuria and a history of diabetic retinopathy have a higher risk within the 
patient population of high albuminuric patients to progress to ESRD and have therefore also 
been chosen as part of the target population for this study.
The presence of albuminuria in an individual is highly predictive of CV events and 
progression of kidney disease. In ARTS-DN (study 16243) in patients with T2DM and DKD 
treated with finerenone in combination with SoC therapy using a RAS inhibitor, a 
dose-dependent reduction in UACR from baseline to Day 90 was demonstrated.  Statistically 
significant reductions in UACR of 21%, 25%, 33% and 38% at Day 90 compared to baseline 
were observed for the 4 highest doses of finerenone (7.5, 10 mg, 15 mg, and 20 mg od, 
respectively) compared to placebo.  In a post hoc analysis, UACR decreases of ≥ 30% from 
baseline to Day 90 in the placebo, 7.5 mg, 10 mg, 15 mg and 20 mg groups were seen for 
23.9%, 40.2%, 46.0%, 51.3% and 62.5% of subjects, respectively, and UACR decreases of 
≥50% in the same groups were seen for 13.6%, 17.2%, 17.2%, 33.6% and 40.2% of subjects, 
respectively. Post-hoc analyses of randomized clinical trials (33, 34) suggest that a meaningful 
reduction in albuminuria may translate to protection from CV events and declining renal 
function in patients with diabetic and non-diabetic renal disease with albuminuria.  For every 
30% reduction in albuminuria, the risk of ESRD decreased by 23.7% (95% confidence interval, 
11.4% to 34.2%; p=0.001) (33); there was an 18% reduction in CV risk and 27% reduction in 
HF risk for every 50% reduction in albuminuria (34).
Due to finerenone’s mode of action, hyperkalemia is an important identified risk which was 
also identified from previous studies with finerenone. Patients with pre-existing impairment 
of their renal function are likely to have a greater risk of experiencing clinically significant 
hyperkalemia. A greater risk for hyperkalemia may also occur if drugs which raise the 
potassium concentration (e.g. ACEI, ARBs or potassium-sparing diuretics) are used 
concomitantly. 
Worsening of renal function has been shown to occur with the steroidal MRAs, i.e.
spironolactone and eplerenone, as well as RAS blocker in general.
The risk for such adverse events with finerenone is not ruled out.  However, in ARTS-DN, 
the incidence of hyperkalemia was low, and the incidence of eGFR decline ≥30% relative to 


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baseline was similar between placebo and finerenone groups, with no imbalance in reported 
AEs related to the MedDRA primary system organ class ‘Renal and urinary disorders’. In 
ARTS (study 14563), all doses of finerenone resulted in significantly lower potassium 
increase and less eGFR reduction compared to spironolactone.
Thus, potassium levels and renal function will be closely monitored in this study. 
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.  A 2-step up-titration is consistent with 
current clinical practice to initiate treatment with a RAS blocker at a low dose, and 
to up-titrate the drug only if tolerated in order to avoid adverse effects on potassium and renal 
parameters. Stopping rules for temporary and permanent discontinuation or dose reduction of 
study drug 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 drug, depending 
on serum potassium and the progression of the underlying disease.  
All protocol-related procedures, including vital signs measurements, 12-lead electrocardiograms 
(ECGs), echocardiography and blood and urine sampling, are non-invasive or established 
routine assessments in the management of patients with DKD with or without CVD. 
The high risk for progression of kidney disease and fatal and non-fatal CV events in the study 
population of Study 16244, taken together with the beneficial results of MRAs on CVD in 
previous clinical trials and the results of finerenone in the Phase II studies all point towards a 
positive risk-benefit assessment that is in favor of the participation of subjects in this study.


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4.
Study objectives
The primary objective of this study is to:

Demonstrate whether, in addition to standard of care (SoC), finerenone is superior to 
placebo in delaying the progression of kidney disease, as measured by the 
composite endpoint of time to first occurrence of kidney failure, a sustained decrease 
of eGFR ≥ 40% from baseline over at least 4 weeks, or renal death. 
The secondary objectives of this study are to determine whether, in addition to SoC, 
finerenone compared to placebo:

Delays the time to first occurrence of the following composite endpoint:
CV death or non-fatal CV events (i.e. non-fatal myocardial infarction, non-fatal stroke, 
hospitalization for heart failure [HF])

Delays the time to all-cause mortality

Delays the time to all-cause hospitalization 

Change in UACR from baseline to Month 4

Delays the time to first occurrence of the following composite endpoint: onset of 
kidney failure, a sustained decrease of eGFR ≥57% from baseline over at least 
4 weeks, or renal death.


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5.
Study design - amended
This section was changed in Amendment 3, see Section 15.1.2.3.
Design overview
Study 16244 is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, 
event-driven Phase III study. Figure 5–1 displays the overall study design.
Patients from approximately 900 study centers worldwide will be randomized in a 1:1 ratio to 
either finerenone or placebo in addition to SoC therapy. Assuming a screening failure rate of 
approximately 50%, 9600 patients will have to be screened to randomize approximately 
4800 patients. 
The anticipated duration of the study is approximately 4 years: this includes an anticipated 
recruitment period of 2.75 years followed by a study drug treatment period of 1 year after the 
enrolment of the last patient into the trial and a maximum of 4.5 months for the run-in and 
screening period and 1 month for the follow-up period. However, as an event-driven trial, the 
actual length of the trial will depend on the observed event rates, the patient recruitment rate, 
and length of the recruitment period. 
Since all randomized subjects belong to the Full Analysis Set (FAS) on which the efficacy 
analyses are based, it is important to avoid randomization of non-eligible subjects into the study. 
Run-in Period (4 up to 16 weeks)
Subjects with written informed consent who complete the Run-in Visit and meet all
eligibility3 criteria will be enrolled into a mandatory Run-in Period, the purpose of which is to 
ensure that the subject’s SoC therapy including treatment with ACEIs or ARBs is optimized 
and that all inclusion and exclusion criteria are met at the Screening Visit.  The Run-in Period 
will last for a minimum of 4 weeks and a maximum of 16 weeks.
In the absence of documentation of diagnosis of high or very high albuminuria (see Section 3.1
for definition), the subject may still be enrolled into the study as albuminuria will be 
measured at the Run-in Visit; in this case, the Run-in Period must last for a minimum of 
12 weeks and a maximum of 16 weeks.
Screening Period (up to 2 weeks)
At the end of the Run-in Period, a Screening Visit to confirm the subject’s eligibility will take 
place within ≤ 2 weeks prior to the planned randomization. At this visit, it will be assessed 
whether the subject still meets all the inclusion and none of the exclusion criteria.3
For those subjects without a prior documented diagnosis of high or very high albuminuria, the 
Screening Visit must be performed at least 12 weeks after the Run-in Visit, and albuminuria 
should then be re-evaluated. If the subject still suffers from high or very high albuminuria 
                                                
3 Eligibility criteria related to central laboratory evaluation will be assessed once results are available.


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whilst on SoC treatment, and fulfills all other eligibility criteria, she/he can be randomized 
into the study.


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Figure 5–1
Overall study design - amended  


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Treatment Period
Eligible subjects will be randomized to receive once daily (OD) oral doses of finerenone 
(10 mg or 20 mg) or placebo in addition to their SoC therapy.
There will be up to 4 planned visits (including randomization at Visit 1) in the first 4 months; 
thereafter visits will take place every 4 months until the end of the study. Study drug dose can 
be up-titrated from Visit 2 (Month 1) onwards or down-titrated at any point (even between 
scheduled visits); guidance on dose adjustment is provided in Section 7.4. Subjects may be 
seen at any time throughout the study, in addition to scheduled visits, at the discretion of the 
investigator.
It is planned that all randomized subjects will remain in the trial until either: 
a.
the projected number of primary endpoints (see Sections 9.4.1 and 10.4) is reached, or 
b. the trial is terminated prematurely at the recommendation of the independent Data 
Monitoring Committee (DMC) (see Section 13.1.3). 
All randomized subjects, including any subject who experienced a health event considered for 
the pre-specified primary or secondary endpoints, should continue to receive study drug until 
the trial is completed (see definition for end of study below) provided there are no safety 
grounds for discontinuing treatment.
Discontinuation of study drug (for any reason) does not constitute the subject’s withdrawal 
from the study, except if the investigator believes that it is in the best interest of the subject or 
if the subject withdraws consent (see Section 6.4.1 for details).  
Details on procedures that are important to ensure the safety of the individual study subject 
are provided in the relevant sections of this protocol (i.e. medical management, control of 
blood pressure and use of potassium supplements/lowering agents in Section 8.1, and 
monitoring blood potassium in Section 9.7.1). 
Follow-up Period
The period between the subject’s last intake of study drug and last visit in the study is referred 
to as the ‘Follow-up Period’. If a subject withdraws from study drug permanently but does 
not withdraw from the study, this would apply to the period between the Premature 
Discontinuation (PD) Visit, which should take place as soon as possible following permanent 
discontinuation of study drug, and the EOS Visit. In the case where a subject discontinues 
treatment at the EOS Visit, the Follow-up Period applies to the period between the EOS visit 
and PT visit.
All subjects who had withdrawn consent can be followed up for vital status if they do not sign 
the ‘Declaration of Objection’ form. In addition, vital status can be obtained by the 
investigator from publicly available data sources. The collection of vital status must be 
obtained within the timelines provided by Bayer.


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End of study
The end of the study as a whole will be reached as soon as the last visit of the last subject of 
Study 16244 has been reached in all centers in all participating countries (EU and non-EU).
The study will terminate either when:
(1) the targeted number of primary efficacy endpoint events have been positively adjudicated
OR
(2) at a recommendation of the DMC, whichever is earlier.
After notification of study termination, for all subjects still participating in the study, 
an End-of-Study (EOS) Visit should be scheduled as soon as possible (within 4 weeks of 
notification at the latest) to determine whether the subject had an event for inclusion in the 
primary or secondary endpoints.
Subjects who are still on treatment will discontinue study drug treatment at the EOS Visit and 
must perform the Post-Treatment (PT) Visit (4 weeks + 5 days) after their last dose of study 
drug.
The primary completion event for this study is the last visit for the last subject.
The primary completion date for this study according to the FDA Amendment Act is specified 
in a separate document (not part of this study protocol).
6.
Study population
Subjects with T2DM and a clinical diagnosis of DKD treated with the individual maximum 
tolerated labeled dose of either an ACEI or an ARB (but not both), who meet all the inclusion 
criteria and none of the exclusion criteria will be eligible for enrollment in this study. Subjects 
switching over from Study 17530 to this study at the Screening Visit must only meet all the 
inclusion criteria and none of the exclusion criteria at the Screening Visit to be eligible for 
enrollment in this study (16244).


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6.1
Inclusion criteria
Subjects must meet all of the following inclusion criteria to be included in the study:
1. Written informed consent signed before any study-specific procedure
2. Men or women aged 18 years and older. The lower age limit may be higher if legally 
required in the participating country.
3. Women of childbearing potential can only be included in the study if a pregnancy test is 
negative at the Screening Visit and if they agree to use adequate contraception. Adequate 
contraception is defined as any combination of at least 2 effective methods of birth 
control, of which at least one is a physical barrier (e.g. condoms with hormonal 
contraception or implants or combined oral contraceptives, certain intrauterine devices). 
Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate) or 6 months of spontaneous amenorrhea with serum FSH levels 
> 40 mIU/mL [for US only: FSH levels > 40 mIU/mL and estradiol < 20 pg/mL] or have 
had surgical treatment such as bilateral tubal ligation, bilateral ovarectomy, or 
hysterectomy.
4. Subjects with type 2 diabetes mellitus as defined by the American Diabetes Association (35)
5. Subjects with a clinical diagnosis of DKD based on either of the following criteria at the 
Run-in and Screening Visit:

Persistent high albuminuria defined as UACR of 30 mg/g (3.4 mg/mmol) 
but < 300 mg/g (< 33.9 mg/mmol) in 2 out of 3 first morning void samples and 
eGFR 25 but < 60 mL/min/1.73 m2 (CKD-EPI) (36, 37) and presence of 
diabetic retinopathy in the medical history 4
OR

Persistent very high albuminuria defined as UACR of ≥300 mg/g (≥33.9 mg/mmol)
in 2 out of 3 first morning void samples and eGFR ≥25 but < 75 mL/min/1.73 m2
(CKD-EPI) (36, 37) 5
Note: One re-assessment of eGFR and UACR is allowed at the Run-in Visit and the 
Screening Visit. If one of the 3 UACR measurements is missing but the other 
2 are valid, these values can be used to assess subject’s eligibility for this study.
                                                
4
Note: The number of subjects with high albuminuria and presence of diabetic retinopathy in the medical 
history will be capped at approximately 10% of the total population at screening.
5
Note: The number of subjects with eGFR ≥60 to 75 mL/min/1.73m2 and very high albuminuria will be capped 
at approximately 10% of the total population with very high albuminuria at screening.


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6. Prior treatment with ACEIs and ARBs as follows:

For at least 4 weeks prior to the Run-in Visit, subjects should be treated with 
either an ACEI or ARB, or both

Starting with the Run-in Visit, subjects should be treated with only an ACEI or ARB

For at least 4 weeks prior to the Screening Visit, subjects should be treated with the 
maximum tolerated labeled dose (but not below the minimal labeled dose) of only an 
ACEI or an ARB (not both) preferably without any adjustments to dose or choice of 
agent or to any other antihypertensive or antiglycemic treatment (see Section 8.1).
7. Serum potassium ≤4.8 mmol/L at both the Run-in and the Screening Visit 
Note: One re-assessment of potassium is allowed at the Run-in and the Screening Visit.
8. Ability to understand and follow study-related instructions.
6.2
Exclusion criteria - amended
This section was changed in Amendment 3, see Section 15.1.2.5.
Subjects who meet any of the following criteria will be excluded from the study:
Medical and surgical history
1. Known significant non-diabetic renal disease, including clinically relevant renal artery 
stenosis 
2. UACR > 5000 mg/g (> 565 mg/mmol) at the Run-in Visit or Screening Visit
Note: One re-assessment is allowed in case UACR is > 5000 mg/g in one of the three 
urine samples collected at the Run-in Visit and the Screening Visit.
3. HbA1c > 12% (> 108 mmol/mol) at the Run-in Visit or Screening Visit
4. Uncontrolled arterial hypertension with mean sitting systolic blood pressure (SBP) 
170 mmHg or mean sitting diastolic blood pressure (DBP) 110 mmHg at the 
Run-in Visit or mean sitting SBP 160 mmHg or mean sitting DBP 100 mmHg at the 
Screening Visit
5. Mean SBP < 90 mmHg at the Run-in Visit or at the Screening Visit
6. Subjects with a clinical diagnosis of chronic heart failure with reduced ejection fraction 
(HFrEF) and persistent symptoms (New York Heart Association class II - IV) at the 
Run-in Visit (class 1A recommendation for MRAs)
7. Stroke, transient ischemic cerebral attack, acute coronary syndrome, or hospitalization for 
worsening heart failure, in the last 30 days prior to the Screening Visit
8. Dialysis for acute renal failure within 12 weeks prior to the Run-in Visit
9. Renal allograft in place or a scheduled kidney transplant within the next 12 months from 
the Run-in Visit
10. Known hypersensitivity to the study treatment (active substance or excipients)


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11. Addison’s disease
12. Hepatic insufficiency classified as Child-Pugh C (see Section 16.2).
Medication and drug use
13. Concomitant therapy with eplerenone, spironolactone, any renin inhibitor, or 
potassium-sparing diuretic which cannot be discontinued at least 4 weeks prior to the 
Screening Visit
14. Concomitant therapy with both ACEI and ARBs which cannot be discontinued for the 
purpose of the study 
15. Concomitant therapy with potent cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitors or 
inducers (to be stopped at least 7 days before randomization) (see Section 16.1).
Other
16. Any other condition or therapy, which would make the subject 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)
17. Pregnant or breast-feeding or intention to become pregnant during the study
18. Previous assignment to treatment during this study or Study 17530
19. Previous (within 30 days prior to randomization) or concomitant participation in another 
clinical study (i.e. Phase I-III clinical studies) with investigational medicinal product(s), 
except for participation in the Run-in and Screening period of Study 17530 (see also 
details on switch over in Section 6.4.2.2)
20. 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).
6.3
Justification of selection criteria
The selection criteria were chosen to adequately define a DKD study population at high risk 
of progressing with their CKD towards ESRD or developing CV events, and to exclude 
subjects from the study who may potentially be exposed to particular risks after study drug 
administration and subjects with conditions that may have an impact on the aims of the study.


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6.4
Withdrawal of subjects from study
6.4.1
Withdrawal
6.4.1.1
Discontinuation of study drug - amended
This section was changed in Amendment 3, see Section 15.1.2.6.
After randomization, discontinuation of study drug (for any reason) does not constitute the 
subject’s withdrawal from the study (see also Section 6.4.1.2).
Study drug must be permanently discontinued if any of the following occurs:

Pregnancy of the study subject (see also Section 9.6.2)

The investigator is of the opinion that continuation of treatment with study drug is 
harmful to the subject’s well-being

The randomization code is broken by the investigator, or other responsible person, 
when knowledge of the subject’s treatment is required

Any investigational drug other than the study drug is used.
Study drug may be 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.
In general, subjects who permanently discontinue study drug are expected to continue in the 
follow-up period and to attend all protocol-specified study visits, and should be encouraged to 
perform all assessments described in the visit schedule (see Section 9.2).
If a subject no longer on study drug 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. 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 subject themselves or to other contact as provided by the patient, e.g. a next of 
kin, primary physician (or local equivalent).
Note that study drug may be temporarily discontinued (i.e. interrupted), as described in 
Section 7.4.


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6.4.1.2
Discontinuation of study
Subjects must be withdrawn from the study if the following occurs:

At their own request or at the request of their legally acceptable representative. 
At any time during the study and without giving reasons, a subject may decline to 
participate further. The subject will not suffer any disadvantage as a result (see also 
Section 13.4).
Subjects may be withdrawn from the study if either of the following occurs:

If, in the investigator's opinion, continuation of the study would be harmful to the 
subject’s well-being 

At the specific request of the sponsor and in liaison with the investigator.
Should a subject withdraw consent to participate in the study, he/she may either:

Agree to continue releasing information for the study (for details, see Section 9.1),
or

Refuse to allow further release of information.
Depending on the time point of withdrawal: 

A subject who discontinues study participation prematurely for any reason is defined 
as ‘dropout’ if the subject has already been randomized

A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates 
the study before randomization is regarded as a ‘screening failure’.
General procedures
In all cases, the reason for withdrawal of study drug and/or of study participation must be 
recorded in the eCRF and in the subject’s medical records.
As specified in Section 13.4, the subject may object to the generation and processing of 
post-withdrawal data.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.
6.4.2
Replacement
Randomized subjects who withdraw prematurely will not be replaced.
If applicable, a subject who is not eligible at the Run-in or Screening Visit may be re-screened 
at a later time (see Section 6.4.2.1) or switch over to Study 17530 (see Section 6.4.2.2) 
provided the pre-requisites are met.


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6.4.2.1
Re-screening - amended
This section was changed in Amendment 3, see Section 15.1.2.7.
If a subject is not eligible at the Run-in or Screening Visit for either this study (16244) or 
Study 17530, the subject may be re-screened at a later time.
The following conditions are pre-requisites of re-screening:

Before re-screening, new written informed consent must be obtained

Allocation of a new subject identification number 

All assessments for the study must be repeated

A minimum of 3 months between the initial Run-in Visit and re-screening.
A subject may be re-screened only once and after being declared as a screening failure.  
During re-screening, a switch over between studies is allowed (see Section 6.4.2.2).
6.4.2.2
Switch over between studies
DKD is a disease continuum characterized by 2 highly variable parameters, eGFR and UACR. 
The thresholds of these parameters for these studies (16244 and 17530) were chosen in order 
to define a high risk population.  It should be noted these parameters may vary in daily life 
making the patient eligible for one or the other study.  Nevertheless, these variations still reflect 
the disease continuum and do not alter the high risk. The reason for allowing switch over is to 
account for these intrinsic variations.  In addition, it also serves the purpose of reducing the 
burden on the subjects due to not needing to repeat the run-in and screening assessments.  
Subjects are permitted to switch from Study 16244 to Study 17530, or vice versa. 
A switch over from either study is permitted only once and should take place during the 
respective Run-in and Screening periods.
An example is as follows:
If a subject initially enrolled in Study 16244 is found to be not eligible during the Run-in 
or Screening Period of Study 16244, the investigator may consider enrolling this subject 
into Study 17530 if the subject meets the eligibility criteria at run-in or screening for 
Study 17530. Prior to the subject being enrolled in Study 17530, the subject must provide 
written informed consent.
The subject will be transferred to Study 17530 in the IxRS system as outlined in the 
Investigator Guide. The subject will continue with their originally assigned subject 
identification (SID) into Study 17530. Within the SID, the study identifier will indicate 
the subject has switched from Study 16244 to Study 17530 (see Section 6.5). The 
procedures and assessments from the Run-in and/or Screening Visit(s) of Study 16244 do 
not have to be repeated for Study 17530; the data, including laboratory data, will be 
transferred from Study 16244 to Study 17530.

If a subject switches from Study 16244 to Study 17530 in the Run-in period but is found 
not to meet the in- and exclusion criteria of Study 17530 at the end of the Screening Period, 


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this subject is not permitted to switch back into Study 16244 and must be registered as a 
screening failure of study 17530. If this is the case, the subject may still be re-screened for 
either of the studies if he or she fulfills the criteria mentioned in Section 6.4.2.1.
6.5
Subject identification
Upon signing the informed consent form and registering the subject in IxRS, each subject will 
automatically be assigned a unique 9 digit subject identification (SID) number by the IxRS for 
unambiguous identification throughout the study.  The SID number is constructed as follows:
Digits 1 - 2:
Unique country number
Digits 3 - 5:
Study center number, unique within any country
Digit 6:
Study-specific identifier
Digits 7 - 9:
Subject number, unique within any study center of a given country for the study.
7.
Treatment(s)
7.1
Treatments to be administered
Finerenone immediate-release (IR) tablets are light orange film-coated tablets, oval 
(modified oblong), containing 10 mg or 20 mg finerenone (Table 7–1). Matching placebo 
tablets will be supplied.
Following a Screening Visit, eligible subjects will be randomized 1:1 to either finerenone or 
placebo, and study drug will be dispensed according to the visit schedule (see Section 9.1).
The subject will receive the following:

Finerenone
−
10 mg finerenone tablet once daily (OD)
(starting dose for subjects with an eGFR between 25 to < 60 mL/min/1.73m² 
at the Screening Visit) 
−
20 mg finerenone tablet OD
(starting dose for subjects with an eGFR ≥60 mL/min/1.73m² 
at the Screening Visit) 
or

Placebo tablet OD. 
Following randomization of the subject, the IxRS will determine the bottle number for the 
study site investigator or designee to select for the subject. The investigator at the study site is 
to instruct subjects to take 1 tablet OD, preferably in the morning. The first dose of study drug 
should be taken at the site on the same day as Visit 1 (Day 1), preferably in the morning.


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7.2
Identity of study treatment
Details (e.g. composition, formulation) of the study drug are provided in Table 7–1. 
All study drugs will be labeled according to the requirements of local law and legislation. 
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk batch of the ingredients. Lists linking all numbering levels
will be maintained by the sponsor’s clinical supplies quality assurance (QA) group. 
A complete record of batch numbers and expiry dates of all study treatment as well as the 
labels will be maintained in the sponsor’s study file.
Table 7–1
Identity of test drug / finerenone and matching placebo
Sponsor’s substance code
BAY 94-8862
Generic name / brand name
Finerenone
Sponsor’s material
name and number
finerenone TABL 10 MG 450 COAT
finerenone TABL 20 MG 850 COAT
finerenone PLAC TABL 002 COAT
Formulation
Film-coated tablet
Tablet strength
10 mg and 20 mg or placebo
Composition
Active ingredient:
finerenone micronized
Other ingredients:
Cellulose microcrystalline, croscarmellose sodium, hypromellose 
5 cP, lactose monohydrate, magnesium stearate, sodium laurilsulfate, 
talc, titanium dioxide, ferric oxide
Placebo
Cellulose microcrystalline, hypromellose 5 cP, lactose monohydrate, 
magnesium stearate, talc, titanium dioxide, ferric oxide
Type of primary packaging
Plastic bottle high-density polyethylene white opaque closed with screw 
cap polypropylene (PP) / PP white with sealing insert
Marketing Authorization Holder
Not applicable
7.3
Treatment assignment
Eligible subjects will be randomized within ≤2 weeks after the Screening Visit. The 
randomization will be stratified by region (North America, Europe, Asia, Latin America and 
others), type of albuminuria at screening (high or very high albuminuria) and eGFR at 
screening (25 to <45, 45 to <60, ≥60 mL/min/1.73m²). The eGFR will be calculated by the 
Central Laboratory applying the CKD-EPI formula (36).
The number of subjects with eGFR ≥60 to <75 mL/min/1.73 m2 and very high albuminuria 
will be capped at approximately 10% of the total population with very high albuminuria at 
screening. The number of subjects with high albuminuria and presence of diabetic retinopathy 
in the medical history will be capped at approximately 10% of the total population at screening.


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7.4
Dosage and administration - amended
This section was changed in Amendment 3, see Section 15.1.2.8.
As shown in Table 7–2, the starting dose of finerenone will depend on the eGFR value at the 
Screening Visit.
Thus, at randomization, subjects with an eGFR between 25 to < 60 mL/min/1.73m² at the 
Screening Visit (central laboratory results) will be assigned to the lower dose of finerenone 
(10 mg) or placebo in addition to SoC, whilst subjects with an eGFR ≥60 mL/min/1.73m² will 
be assigned to the higher dose of finerenone (20 mg) or placebo in addition to SoC.
Table 7–2
Dosage of study drug for administration
eGFR value at the Screening 
Visit, based on central laboratory 
results:
25 to < 60 mL/min/1.73m²
≥60 mL/min/1.73m²
Subject randomized to group:
Finerenone
Placebo
Finerenone
Placebo
Receives
10 mg finerenone OD 
+ SoC
Placebo OD
+ SoC
20 mg finerenone OD
+ SoC
Placebo OD
+ SoC
Study drug intake
One tablet of SD once daily,
preferably in the morning at approximately the same time each day.
Missed intake
If >8 hours before the next scheduled dose, the subject should take 
one tablet of SD as soon as possible.
If ≤8 hours of the next scheduled dose, the subject should wait and take 
the next tablet of SD at the usual time.
Up-titration of dose
Allowed from Visit 2 (Month 1) 
onwards provided that:
Potassium is ≤4.8 mmol/L a
eGFR decrease is less than 
30% below the value measured 
at the last scheduled visit a
Must be documented in eCRF
20 mg finerenone OD, 
maintain SoC
Sham-titrate, 
maintain SoC
Not applicable
Not applicable
Down-titration of dose
Only for safety reasons (for 
guidance, see Section 9.7.1)
Allowed any time during the study 
(e.g. between scheduled visits)
Must be documented in eCRF
An unscheduled safety visit is 
performed within an adequate  
timeframe proposed by the 
investigator

If at higher dose of SD, down-titrate to lower dose of SD, maintain SoC

If at lower dose of SD, interrupt SD, maintain SoC
Abbreviations:
eGFR = estimated glomerular filtration rate; SD = study drug; SoC = standard of care
a Potassium and eGFR according to local laboratory values
Intake of study drug
Subjects will be instructed to take one tablet of study drug, preferably in the morning, at 
approximately the same time each day. The study drug can be taken with a glass of water, 
with or without food.


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Missed intake of study drug
If the subject misses his/her scheduled daily intake of study drug, he/she should consider the 
following 2 options before continuing study drug intake:
(1) If intake of the missed tablet is discovered >8 hours before the next scheduled dose, the 
subject should take the study drug as soon as possible
(2) If the missed intake is discovered within 8 hours of the next scheduled dose, 
the subject should wait and take the next tablet at the usual time.
Up- and down-titration of study drug
The investigator is encouraged to up-titrate the dose of study drug at any time once the patient 
has been on a stable dose for 4 weeks (± 7 days) (e.g. from Visit 2 onwards for patient starting 
study drug on the lower dose) either at a regular visit or an Up-titration Visit.  Up-titration can 
be performed provided:

the potassium concentration (local laboratory value) is ≤4.8 mmol/L,
AND

eGFR decrease (local laboratory value) is less than 30% below the value measured at 
the last regular visit. 
Subjects who started with or were up-titrated to the target dose (20 mg OD) of the study drug 
but who do not tolerate this dose may be down-titrated at any point during the study, 
including between-scheduled visits if required for safety reasons. These subjects may be 
up-titrated again based on the rules provided above. If the subject is already at the lower dose, 
the study drug can be interrupted at the investigator’s discretion (refer to Section 9.7.1 for 
guidance). If the study drug is interrupted for more than 7 days, the study drug should be re-
started at the lower dose (10 mg OD).
Subsequent to an up-titration or re-start of study drug after interruption of study drug intake
for more than 7 days, the investigator should perform an Up-titration Visit 4 weeks (±7 days) 
after titration or restart, in order to monitor potassium levels and renal function (see
Table 9–1). If a regular study visit will be scheduled to take place 4 weeks (± 7 days) after up-
titration, the monitoring of potassium and renal function is assured and no Up-titration Visit 
has to be performed in addition.  With down-titrations, the unscheduled safety visit may need 
a smaller time window and should be performed at the investigator’s discretion.
At any point during study drug treatment, if blood potassium is found to be elevated, 
study drug treatment should be adjusted according to guidance provided in Section 9.7.1.
Both up- and down-titrations will be at the investigator’s discretion and will depend on the 
general clinical condition of the individual subject. The investigator should attempt to reach 
the maximum (target) dose of study drug as long as safety is not compromised.
All titrations, including the reasons for down-titration or for not dispensing the 20 mg dose, 
must be documented in the eCRF.


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7.5
Blinding
7.5.1
Blinding measures
Finerenone IR tablets (10 mg and 20 mg) and placebo tablets will be identical in appearance 
(size, shape, color). The packaging and labeling will be designed to maintain the blinding of 
the investigator’s team and the subjects. The study data will remain blinded until database 
lock and authorization of data release according to standard operating procedures.
Appropriate measures will be taken to maintain blinding while bioanalysis is ongoing.
7.5.2
Unblinding - amended
This section was changed in Amendment 3, see Section 15.1.2.9.
In compliance with applicable regulations, in the event of a SUSAR (see Section 9.6.1.4) 
related to the blinded treatment, the subject’s treatment code will usually be unblinded before 
reporting to the health authorities and ethic committees.
In order to maintain the integrity of the study, SUSARs will be waived from unblinding and 
expedited safety reporting if it represents one of the pre-specified disease-related efficacy 
endpoints (see also Section 9.6.1.4).
7.5.3
Emergency unblinding by the investigator
In the event of an emergency or any finding that requires unblinding, the investigator may 
break the blind for an individual subject via the IxRS according to the unblinding procedure 
outlined in the Investigator’s Guide. This system allows the investigator, or other responsible 
person, to identify the study drug if there is an emergency, without jeopardizing the 
double-blind integrity of the remainder of the study.
The code can be broken by the investigator, or other responsible person, when knowledge of 
the subject’s treatment is required for the clinical management of the subject. If it becomes 
necessary to know the individual treatment during the study and thus to break the code for 
that subject, the date and reason for unblinding are to be recorded on the relevant eCRF page. 
The investigator is required to promptly document and explain to the sponsor any premature 
unblinding (e.g. unblinding due to a serious adverse event [SAE]) of the study drug), 
and study drug must be discontinued permanently.
7.6
Drug logistics and accountability
All study drugs will be stored at the investigational site in accordance with GCP and GMP 
requirements and the instructions given by the clinical supplies department of the sponsor (or 
its affiliate/CRO), and will be inaccessible to unauthorized personnel. Special storage 
conditions and a complete record of batch numbers and expiry dates can be found in the 
sponsor’s study file; the site-relevant elements of this information will be available in the 
investigator site file. On the day of receipt, the responsible site personnel will confirm receipt of 
study drug via IxRS. The personnel will use the study drug only within the framework of this 
clinical study and in accordance with this protocol. Receipt, distribution, return and destruction 


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(if any) of the study drug must be properly documented according to the sponsor’s agreed and 
specified procedures.
Written instructions on study drug destruction will be made available to affected parties as 
applicable.
7.7
Treatment compliance
To monitor compliance, the investigator will be required to complete a drug dispensing log 
for each subject. The date of dispensing the study drug to the subject will be documented.
Study drug will be dispensed at each scheduled visit starting from Visit 1 (Day 1), as applicable.
Subjects will be instructed to return all of the study drug packaging including unused study 
drug and empty packaging.  Accountability must be performed at each visit (if applicable). 
Any discrepancies between actual and expected amount of returned study medication must be 
discussed with the subject at the time of the visit, and any explanation must be documented in 
the source records.
8.
Non-study therapy
8.1
Prior and concomitant therapy
8.1.1
General considerations for prior and concomitant therapy
Figure 8–1 depicts the conditions of prior therapy on ACEIs and ARBs during the time 
leading up to the Screening Visit.  

For at least 4 weeks prior to the Run-in Visit, all subjects must be treated with  
either an ACEI or ARB, or both

Starting with the Run-in Visit, subjects should be treated with only an ACEI or ARB

For at least 4 weeks prior to the Screening Visit, subjects should be treated with the 
maximum tolerated labeled dose (but not below the minimal labeled dose) of 
only an ACEI or an ARB (not both), preferably without any adjustments to dose or 
choice of agent or to any other antihypertensive or antiglycemic treatment.


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Figure 8–1
Background therapy with RAS blockade
‡
If applicable
*
During the maintenance phase, there should preferably be no adjustments to dose of ACEI or ARB or to any other 
antihypertensive or antiglycemic treatment
The maximum tolerated labeled dose for ACEIs or ARBs should be the highest dose within
the ranges shown in Table 8–1 or according to local labels, as applicable, which the subject 
can safely tolerate. This dose should not be below the minimum labeled dose in order to 
maximize therapeutic benefit of background SoC.
Table 8–1
Dose ranges of ACEIs and ARBs for adults
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Generic name
Dose Range (mg/day)*
Generic name
Dose Range (mg/day)*
Benazepril
20 – 40
Candesartan
16 – 32
Captopril
50 – 450
Eprosartan
400 – 800
Cilazapril
1 – 5
Irbesartan
150 – 300
Enalapril
10 – 40
Losartan
50 – 100
Fosinopril
20 – 80
Olmesartan
20 – 40
Lisinopril
20 – 40
Telmisartan
40 – 80
Moexipril
7.5 – 30
Valsartan
80 – 320
Perindopril
4 – 16
Quinapril
20 – 80
Ramipril
2.5 – 20
Trandolapril
2 – 4
Source: Adapted from Table 28 of reference (38)


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Variations to these recommended dose ranges may exist in local clinical guidelines or labels. 
If the maximum labeled dose cannot be reached, the reason(s) should be documented in the 
eCRF. Antihypertensive therapy for renal and CVD protection will be administered according 
to local guidelines (see also Section 8.1.2 on medical management).
Depending on blood pressure, serum creatinine or eGFR, subjects may need to have their study 
drug dose or the dose of another concomitant medication reduced or discontinued. The dosage 
of SoC therapies should not be reduced in order to solely facilitate maintenance of study drug.
Prior medication that was discontinued to comply with the eligibility criteria of the study 
should also be recorded in the eCRF.
All concomitant medication including therapy for T2DM and DKD until the PT Visit will be 
recorded in the eCRF.
The following therapies are NOT permitted:

Concomitant therapy with eplerenone, spironolactone, any renin inhibitor, or 
potassium-sparing diuretic which cannot be discontinued at least 4 weeks prior to the 
Screening Visit and during study drug treatment

Concomitant therapy with both an ACEI and an ARB during the Run-in and Screening
periods, and during study drug treatment

Concomitant therapy with potent cytochrome P450 isoenzyme 3A4 (CYP3A4) 
inhibitors or inducers must be stopped at least 7 days before randomization and
is not allowed to be started during study drug treatment
A list of the most common medication regarded as potent CYP3A4 inhibitors or inducers is 
provided in Section 16.1.
Caution: Increases in finerenone exposure in combination with the following moderate 
CYP3A4 inhibitors cannot be excluded: amiodarone, aprepitant, bicalutamide, 
chloramphenicol, imatinib, mifepristone, norfloxacine, tacrolimus, verapamil, 
lapatinib, dasatinib, and nilotinib. Caution should also be exercised with 
concomitant use of high-dose acetylsalicylic acid (>500 mg/day), non-steroidal 
anti-inflammatory agents or trimethoprim or trimethoprim / sulfamethoxazole.
8.1.2
Medical management
ACEs and ARBs are considered as SoC therapy in patients with DKD and often prescribed to 
patients with DKD at early stages (8).
It is advisable to follow the recommendations of local guidelines for the management of 
CVD and CKD, the use of statins, anti-platelets and beta-blockers, and for glycemic control.


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8.1.3
Control of blood pressure - amended
This section was changed in Amendment 3, see Section 15.1.2.10.
According to international guidelines, the recommended target blood pressure for subjects 
with T2DM and albuminuria, who are at increased risk of CVD and CKD progression, is 
<130/80 mmHg (39-41). However, this value may vary for the individual subject depending 
on concomitant diseases and well-being.
If blood pressure is considered uncontrolled by the investigator during the study period, 
non-potassium-sparing diuretics may be added as first choice to the treatment regimen if this 
was not already done. Thereafter, the addition of antihypertensive medication can be 
performed according to local guideline recommendations.
All concomitant medication added to the treatment regimen during the course of the study 
must be recorded in the eCRF.
8.1.4
Use of potassium supplements and lowering agents
If needed, potassium supplementation can be prescribed during the course of the study. 
Investigators are advised to monitor potassium carefully at each visit and to adapt the dose of 
any potassium supplementation in accordance with the potassium value measured at each visit 
or discontinue potassium supplementation once the potassium is within the normal range.
Potassium-lowering agents (e.g. sodium polystyrene sulfonate, calcium polystyrene sulfonate) 
are allowed to be started during treatment with study drug.
Any use of potassium supplementation and potassium-lowering agents must be documented 
in the eCRF.
8.2
Post-study therapy
The investigator will decide in consultation with the individual subject if additional treatment 
is required and choose from existing treatment options.
The investigator must provide follow-up medical care for all subjects who complete the study 
or who are prematurely withdrawn from the study, or must refer them for appropriate ongoing 
care as required.


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9.
Procedures and variables
9.1
Tabular schedule of evaluations - amended
This section was changed in Amendment 3, see Section 15.1.2.11 and Section 15.1.2.12.
Table 9–1 depicts the schedule of activities and evaluations for this study (16244).
An overview of the procedures for sub-studies of 16244 is provided in Table 9–2.
All randomized subjects will remain in the study until its termination, either:
(1) after positive adjudication of the targeted number of primary efficacy endpoint events, 
or
(2) at a recommendation of the DMC.
Thus, all subjects, including those who stopped taking study drug, should be asked to attend 
all the protocol-specified study visits in order to perform all assessments as stipulated in the 
visit schedule (Table 9–1).
If any subject refuses to return for the defined assessments or is unable to do so, every effort 
should be made to contact him/her or a knowledgeable informant 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 (see Section 6.4.1.1 for details).  Attempts to contact the 
subject should be documented in the subject’s records. If any subject refuses to be contacted 
by telephone (e.g. the subject withdrew consent to release further information), every effort 
should be made to obtain vital status (alive or dead) information through consultation of 
public databases, wherever allowed by local regulations.


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Table 9–1
Study 16244: schedule of activities and evaluations - amended
Visit 
Run-in
Screening
Visit 
1 
(Baseline)
Visit 
2
Visit 
3
Visit
4, 6, 7, 9,
etc h
Visit
5, 8, 11, 
etc
Up-titration 
Visit j
PD
Visit
EOS
Visit k
PT
Visit m
Day / Month
4 to 16 
weeks pre-
screening
2 weeks
Day
1
Month
1
Month
4
(every 
4 months, 
i.e.
Month 8, 16, 
20, 28, etc)
(every 
12 months, 
i.e. 
Month 12, 
24, 36, etc)
For up-titration/restart 
after interruption, and 
for safety check 
4 weeks ± 7 days after 
any up-titration
(see also footnote j)
As soon as 
possible but 
within 7 days 
after SD is 
permanently 
discontinued
After
study 
termi-
nation
4 weeks 
+ 5 days 
after last 
SD intake 
Informed consent
X
In- and exclusion criteria
X
X
X
Demographic data
X
Smoking status
X
Alcohol consumption
X
Medical history
X
Prior medication
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Drug accountability
X
X
X
X
X
X
X
Study drug dispense
X
X
X
X
X
Study drug administration
X
X
KDQOL-36, EQ-5D-5L
X
X
X
X
Physical examination
X
X
X
X
X
Weight, height,
waist and hip circumference a
X
X
X
X
X
X
X
X
X
X
Vital signs b
X
X
X
X
X
X
X
X
X
X
12-lead ECG (local)
X
X
X
X
X
X
PK blood sample
X n
X o
Full central laboratory
X
X
X
X
X
X
X
X
Limited chemistry (central) 
X
X
Urinalysis (central) c
X
X
X
X
X
X
Safety laboratory (local) d
X
X
X
X
X
X
Endpoint assessment e
X
X
X
X
X
X
X
AE assessment f
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test g
X
X


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Table 9–1
Study 16244: schedule of activities and evaluations - amended
NOTE: 
One month corresponds to 30 days
A time frame of ± 7 days is allowed for Visit 2 (Month 1), and for the Up-titration Visit(s).
A time frame of ± 12 days is allowed for all regular visits from Visit 3 (Month 4) onwards.
Abbreviations: ECG = electrocardiogram; EOS = end of study; EQ-5D-5L = EuroQol Group 5 dimension, 5 level questionnaire; 
KDQOL = Kidney Disease Quality of Life; PD = premature discontinuation; PT = post-treatment; (S)AE = (serious) adverse event; SD = study 
drug
a
Height, waist and hip circumference to be assessed at Run-in Visit only.
b
After resting for at least 5 minutes, 3 measurements to be taken with at least 1-minute interval in a sitting position (all 3 readings within a maximum of 
20 minutes).
c
At Visit 1, first morning void urine samples to be preferably collected on three consecutive days at the subject’s home within 7 days before scheduled visit 
and before any intake of study drug. At the other visits the 3 consecutive samples can be collected ± 7 days from the visit date. 
d
Blood samples (for potassium and creatinine) for measurement in the local laboratory may be obtained up to 72 hours before a scheduled visit. Samples to 
be taken only if the subject is still taking study drug,
e
Categorical renal endpoints, ≥40% or ≥57% decrease in eGFR compared to baseline and an eGFR decrease to less than 15 mL/min/1.73 m2, have to be 
confirmed by at least one additional standardized serum creatinine measurement.  This confirmation should be done at least 4 weeks after the initial 
measurement as an unscheduled assessment.
f
AEs related to study procedures occurring after signing the informed consent as well as all other AEs starting after randomization will be documented on the 
respective eCRF pages.
g
Female subjects of childbearing potential must have a negative serum or urine pregnancy test at screening and yearly thereafter (to be performed at the local 
laboratory). If required by national / institutional regulations, a serum or urine pregnancy test in subjects of childbearing potential should be performed 
more often (e.g. at every visit, see Section 9.7.2).
h
Every 4 months until study termination, excluding the yearly visits (i.e. Visits 5, 8, 11, etc., at Months 12, 24, 36, etc.).
j
The “Up-titration Visit” should be performed for up-titration (at any time after Visit 2), after restart of SD after an interruption for >7 days, and for safety check 
4 weeks ± 7 days after any up-titration.
k
After the study site is notified about study termination, an EOS Visit must be performed for all the subjects as soon as possible and within 4 weeks at the 
latest.
m
For all the subjects still on treatment with study drug at the EOS Visit, the PT Visit has to be performed 4 weeks + 5 days after last intake of study drug and 
will be performed by a telephone contact (except for subjects participating in the iohexol sub-study).
n
A trough PK sample will be drawn before study drug is administered at the study center by study personnel. The exact time of study drug intake on the day 
before the visit and on the day of the visit and the exact sampling time will have to be recorded in the eCRF. If the trough sample was not taken at Visit 3 it 
should be obtained at Visit 4 (see Section 9.5).
o
Study drug will be taken as usual, ideally in the morning at home. One PK sample will be drawn during the visit. The exact time of study drug intake and the 
exact sampling times will have to be recorded in the eCRF.


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Table 9–2
Sub-studies of Study 16244: schedule of procedures – amended
Visit 
Run-in
Screening
Visit 
1 
(Baseline)
Visit 
2
Visit 
3
Visit
4, 6, 7, 9,
etc
Visit
5, 8, 11, etc
Up-titration 
Visit
PD
Visit
EOS
Visit
PT
Visit c
Day / Month
4 to 16 
weeks pre-
screening
2 weeks
Day
1
Month
1
Month
4
(every 
4 months, 
i.e. 
Month 8, 16, 
20, 28, etc)
(every 
12 months, 
i.e. 
Month 12, 24, 
36, etc)
For up-titration/ restart 
after interruption, and 
for safety check 
4 weeks ± 7 days after 
any up-titration
As soon as 
possible but 
within 7 days after 
SD is permanently 
discontinued
After
study 
termi-
nation
4 weeks 
+ 5 days 
after last 
SD intake 
Informed consent a
X
Echocardiography f
X
X
X e
X e
Sampling for biomarkers
X
X
X
X e
X e
Iohexol clearance b
X
X
X d
X d
X e
X e
X
NOTE: 
One month corresponds to 30 days.
A time frame of ± 7 days is allowed for Visit 2 (Month 1).
A time frame of ± 12 days is allowed all regular visits from Visit 3 (Month 4) onwards.
Abbreviations: EOS = end of study; PD = premature discontinuation PK = Pharmacokinetics; PT = post-treatment; SD = study drug
a
Separate informed consent for each sub-study is required. 
b
Sites in Italy only. 
c
For all the subjects still on treatment with study drug at the EOS Visit, the PT Visit has to be performed 4 weeks + 5 days after last intake of study drug. 
d
Every other visit (every 8 months) , i.e. Visit 5, Visit 7, Visit 9, Visit 11, etc.
e
Assessment at the end of the study, either at the PD Visit or the EOS Visit.
f   Time window for the assessment at Visit 1 is -14/+7 days, at other visits +/-30 days. Each time an echocardiography is performed, one blood sample should be 
drawn to assess the echo biomarkers


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9.2
Visit description - amended
This section was changed in Amendment 3, see Section 15.1.2.13.
One month in the study schedule corresponds to 30 days. Although study visits should occur 
as close as possible to the time points specified in the protocol, a time frame of ± 7 days is 
allowed for Visit 2 (Month 1), and for the Up-titration Visit(s).  Starting from Visit 3 (Month 
4), a time frame of ± 12 days is allowed for all regular visits.
All procedures and assessments should preferably be conducted on the day of the visit; 
however, if this is not possible for logistical reasons, the following time windows are allowed:
Blood sampling, ECG and recording of vital signs:

Screening Visit and all the visits starting from Visit 2: Visit date ± 7 days

Run-In, PD and EOS Visit: Visit date ± 3 days
Sub-studies / iohexol and biomarker samples:

all visits starting from Visit 3: Visit date ± 7 days

PD and EOS Visit: Visit date ± 3 days
Sub-study / echocardiography (note that each time an echocardiography is performed, one 
blood sample should be drawn to assess the echo biomarkers):

at Visit 1: Visit date -14 / +7 days

Other visits: Visit date ± 30 days
NOTE:
If applicable, a subject who is not eligible at the Run-in or Screening Visit may be 
re-screened at a later time (see Section 6.4.2.1) or switch over to Study 17530 (see 
Section 6.4.2.2) provided the pre-requisites are met.
9.2.1
Run-in Visit (4 to 16 weeks prior to the Screening Visit) - amended
This section was changed in Amendment 3, see Section 15.1.2.14.
The following procedures and assessments will be performed at the Run-in Visit:

Obtain signed informed consent (may be done earlier).
NOTE: any study-specific procedure can be performed only if written informed 
consent is available

Check inclusion and exclusion criteria (see Sections 6.1 and 6.2)

Collect demographic data, smoking status and alcohol consumption (see Section 9.3.1)

Record medical history (see Section 9.3.2)

Record use of prior and concomitant medication (see Section 8.1)

Perform physical examination (see Section 9.7.3)

Record body weight, height, waist and hip circumference (see Section 9.7.4)


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
Record vital signs (see Section 9.7.5)

Perform 12-lead ECG (see Section 9.7.6)

Take samples (hematology, HbA1c, chemistry and urinalysis) for central laboratory 
evaluations (see Section 9.7.2.1).
Note: If HbA1c cannot be analyzed by the central laboratory due to technical reasons, 
subject can be considered suitable for randomization with one result only (Run-In or 
Screening).

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3)
9.2.2
Screening Visit (≤2 weeks prior to Visit 1) - amended
This section was changed in Amendment 3, see Section 15.1.2.15.
The following procedures and assessments will be performed at the Screening Visit:

Check inclusion and exclusion criteria (see Sections 6.1 and 6.2)

Record use of concomitant medication (see Section 8.1)

Perform physical examination (see Section 9.7.3)

Record body weight (see Section 9.7.4)

Record vital signs (see Section 9.7.5)

Perform 12-lead ECG (see Section 9.7.6)

Take samples (hematology, HbA1c, chemistry, urinalysis) for central laboratory 
evaluations (see Section 9.7.2.1)
Note: If HbA1c cannot be analyzed by the central laboratory due to technical reasons, 
subject can be considered suitable for randomization with one result only (Run-In or 
Screening).

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3)

Perform pregnancy test (see Section 9.6.2).
9.2.3
Visit 1 (randomization; Day 1 and baseline) - amended
This section was changed in Amendment 3, see Section 15.1.2.16.
All measurements on Visit 1 are to be performed on the day of the visit before first study drug 
intake. The following procedures and assessments will be performed at Visit 1:

Instruct the subject on how to complete KDQOL-36 and EQ-5D-5L questionnaires; 
the subject completes the questionnaires (see Section 9.7.7).

Obtain informed consent for sub-studies (see Section 9.7.8.1)

Check inclusion and exclusion criteria (see Sections 6.1 and 6.2)


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
Record use of concomitant medication (see Section 8.1)

Record body weight (see Section 9.7.4)

Record vital signs (see Section 9.7.5)

Perform 12-lead ECG (see Section 9.7.6)

Take samples (hematology, HbA1c, chemistry, urinalysis) for central laboratory 
evaluations (see Section 9.7.2.1)

Take samples (potassium, creatinine) for local safety laboratory evaluations (see 
Section 9.7.2.2)

Optional: if the subject had signed informed consent for the sub-study, obtain 
respective samples for biomarkers (see Section 9.7.8.1.2) and/or iohexol clearance 
(see Section 9.7.8.1.3), perform echocardiography (see Section 9.7.8.1.1)
Note: Time window for the echocardiography at Visit 1 is -14/+7 days. On the day the 
echocardiography is performed, a blood sample should also be drawn to assess the 
echo biomarkers.

Randomization to finerenone or placebo once daily (see Section 7.1)

Dispense the study drug (see Section 7.2)

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3)

First administration of study drug.
9.2.4
Visit 2 (Month 1)
The following procedures and assessments will be performed at Visit 2:

Record use of concomitant medication (see Section 8.1)

Collect unused study drug and perform accountability to assess compliance 
(see Section 7.6)

Dispense the study drug (see Section 7.2)

Record body weight (see Section 9.7.4)

Record vital signs (see Section 9.7.5)

Take samples (limited chemistry) central laboratory evaluations (see Section 9.7.2.1)

Take samples (potassium, creatinine) for local safety laboratory evaluations (see 
Section 9.7.2.2)

Assess if the subject has any endpoint event(s) (see Table 13–1 and Section 9.6.1.3.1) 

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3).


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9.2.5
Visit 3 (Month 4) - amended
This section was changed in Amendment 3, see Section 15.1.2.17.
Ideally, the study personnel should contact the subject prior to Visit 3 to remind them not to 
take the study drug as usual in the morning at home. The following procedures and 
assessments will be performed at Visit 3:

Record use of concomitant medication (see Section 8.1)

Collect unused study drug and perform accountability to assess compliance (see 
Section 7.6)

Dispense the study drug (see Section 7.2)

Record body weight (see Section 9.7.4)

Record vital signs (see Section 9.7.5)

Take samples (hematology, HbA1c, chemistry, urinalysis) for central laboratory 
evaluations (see Section 9.7.2.1)

Take samples (potassium, creatinine) for local safety laboratory evaluations 
(see Section 9.7.2.2)

Obtain pre-dose sample for PK (see Section 9.5)

Administer study drug after PK sample has been obtained (see Section 9.5)

Optional: if the subject had signed informed consent for the sub-study, obtain 
respective samples for biomarkers (see Section 9.7.8.1.2) and/or iohexol clearance 
(see Section 9.7.8.1.3)

Assess if the subject has any endpoint event(s) (see Table 13–1 and Section 9.6.1.3.1) 

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3).
9.2.6
Visit 4, 6, 7, 9, etc. (every 4 months; Month 8, 16, 20, 28, etc., excluding 
yearly visits) - amended
This section was changed in Amendment 3, see Section15.1.2.18.
The following procedures and assessments will be performed at Visit 4, 6, 7, 9, etc.:

Record use of concomitant medication (see Section 8.1)

Collect unused study drug and perform accountability to assess compliance 
(see Section 7.6)

Dispense the study drug (see Section 7.2)

Record body weight (see Section 9.7.4)

Record vital signs (see Section 9.7.5)


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
Take samples (hematology, HbA1c, chemistry) for central laboratory evaluations 
(see Section 9.7.2.1)

Take samples (potassium, creatinine) for local safety laboratory evaluations 
(see Section 9.7.2.2)

Visit 4 only: Obtain pre-dose sample for PK if no PK sample was taken at Visit 3 (see 
Section 9.5)

Optional: if the subject had signed informed consent for the sub-study, obtain samples 
for iohexol clearance (see Section 9.7.8.1.3)
Note: Iohexol clearance should be performed every 8 months only (Visit 7, Visit 9, 
etc.)

Assess if the subject has any endpoint event(s) (see Table 13–1 and Section 9.6.1.3.1) 

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3).
9.2.7
Visit 5, 8, 11, etc. (every 12 months; Month 12, 24, 36, etc) - amended
This section was changed in Amendment 3, see Section 15.1.2.19.
The following procedures and assessments will be performed at Visit 5, 8, 11, etc.:

Subject to complete KDQOL-36 and EQ-5D-5L questionnaires (see Section 9.7.7).

Record use of concomitant medication (see Section 8.1)

Collect unused study drug and perform accountability to assess compliance 
(see Section 7.6)

Dispense the study drug (see Section 7.2)

Perform physical examination (see Section 9.7.3)

Record body weight (see Section 9.7.4)

Record vital signs (see Section 9.7.5)

Perform 12-lead ECG (see Section 9.7.6)

Take samples (hematology, HbA1c, chemistry, urinalysis) for central laboratory
evaluations (see Section 9.7.2.1)

Take samples (potassium, creatinine) for local safety laboratory evaluations 
(see Section 9.7.2.2)

Obtain sample for PK (see Section 9.5)

Optional: if the subject had signed informed consent for the sub-study, obtain samples 
for biomarkers (see Section 9.7.8.1.2), perform echocardiography (see 
Section 9.7.8.1.1)


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
Optional: if the subject had signed informed consent for the sub-study, obtain samples 
for iohexol clearance (see Section 9.7.8.1.3).  
Note: Iohexol clearance should be performed every 8 months only (Visit 5, Visit 11, 
etc.)

Assess if the subject has any endpoint event(s) (see Table 13–1 and Section 9.6.1.3.1) 

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3)

Perform pregnancy test (see Section 9.6.2).
9.2.8
Up-titration Visit (4 weeks ± 7 days after up-titration or restart of 
study drug and for up-titration of study drug) - amended
This section was changed in Amendment 3, see Section 15.1.2.20.
The following procedures and assessments will be performed at the Up-titration Visit (see 
Section 7.4 for details):

Record use of concomitant medication (see Section 8.1)

Collect unused study drug and perform accountability to assess compliance, if 
applicable (see Section 7.6)

Record body weight (see Section 9.7.4)

Record vital signs (see Section 9.7.5)

Take samples (limited chemistry) central laboratory evaluations (see Section 9.7.2.1)

Take samples (potassium, creatinine) for local safety laboratory evaluations 
(see Section 9.7.2.2)

Assess if the subject has any endpoint event(s) (see Table 13–1 and Section 9.6.1.3.1) 

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3).
9.2.9
Premature Discontinuation (PD) Visit (as soon as possible but within 7
days after study drug is permanently discontinued) - amended
The section title was changed in Amendment 3, see Section 15.1.2.21.
If the PD visit cannot be performed within the timeframe specified, no PD visit is required. 
The following procedures and assessments will be performed at the PD Visit:

The subject completes KDQOL-36 and EQ-5D-5L questionnaires (see Section 9.7.7)

Record use of concomitant medication (see Section 8.1)

Collect unused study drug and perform accountability to assess compliance (see 
Section 7.6)


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
Perform physical examination (see Section 9.7.3)

Record body weight (see Section 9.7.4)

Record vital signs (see Section 9.7.5)

Perform 12-lead ECG (see Section 9.7.6)

Take samples (hematology, HbA1c, chemistry) for central laboratory evaluations (see 
Section 9.7.2.1)

Optional: if the subject had signed informed consent for the sub-study, obtain 
respective samples for biomarkers (see Section 9.7.8.1.2) and/or for iohexol clearance 
(see Section 9.7.8.1.3), perform echocardiography (see Section 9.7.8.1.1)

Assess if the subject has any endpoint event(s) (see Table 13–1 and Section 9.6.1.3.1) 

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3).
9.2.10
End of study (EOS) visit - amended
This section was changed in Amendment 3, see Section 15.1.2.22.
The following procedures and assessments will be performed at the EOS Visit:

The subject completes KDQOL-36 and EQ-5D-5L questionnaires (see Section 9.7.7)

Record use of concomitant medication (see Section 8.1)

Collect unused study drug and perform accountability to assess compliance (see 
Section 7.6)

Perform physical examination (see Section 9.7.3)

Record body weight (see Section 9.7.4)

Record vital signs (see Section 9.7.5)

Perform 12-lead ECG (see Section 9.7.6)

Take samples (hematology, HbA1c, chemistry, urinalysis) for central laboratory 
evaluations (see Section 9.7.2.1)

Optional: if the subject had signed informed consent for the sub-study, obtain 
respective samples for biomarkers (see Section 9.7.8.1.2) and/or for iohexol clearance 
(see Section 9.7.8.1.3), perform echocardiography (see Section 9.7.8.1.1)

Assess if the subject has any endpoint event(s) (see Table 13–1 and Section 9.6.1.3.1) 
o
Any eGFR declines that meet endpoint criteria that are identified at the EOS 
Visit, or that cannot be confirmed by the time of the EOS Visit, should be 
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
In exceptional circumstances only, if the subject is unable to attend this visit during 
the given timeframe, the subject (or primary physician/ next of kin) should be 
contacted to obtain survival status. 

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3).
9.2.11
Post-Treatment (PT) Visit - amended
This section was changed in Amendment 3, see Section 15.1.2.23.
For all subjects (except those who participate in the iohexol clearance study) who are still on 
treatment with study drug at the end of study visit, this will be performed by telephone 
contact within 4 weeks + 5 days after last study drug intake. The following will be performed 
at the PT Visit:  

Record use of concomitant medication (see Section 8.1)

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3).
For subjects who signed informed consent for the iohexol clearance sub-study, the PT Visit 
will be performed as an on-site visit with the following procedures and assessments:

Record use of concomitant medication (see Section 8.1)

Obtain samples for iohexol clearance (see Section 9.7.8.1.3)

Record adverse events (see Section 9.6.1), accounting for the rules of assessment and 
documentation (see Section 9.6.1.3).
9.3
Population characteristics
9.3.1
Demographic
The following demographic data will be collected in the eCRF:

Year of birth and age at the Run-in Visit

Ethnic group

Race

Sex

Smoking habits and alcohol consumption.


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9.3.2
Medical history - amended
This section was changed in Amendment 3, see Section 15.1.2.24.
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the investigator:

Pertaining to the study indication or CVD history

Start before randomization

Considered relevant to the study (e.g. CV and metabolic diseases, periodontal disease)

Medical history related to concomitant medication.
Detailed instructions on the differentiation between (1) medical history and (2) adverse events 
can be found in Section 9.6.1.1.
9.4
Efficacy- amended
This section was changed in Amendment 3, see Section 15.1.2.25.
The parameters in Section 9.4.1 (primary), Section 9.4.2 (secondary) and Section 9.4.3
(exploratory) will be used to assess the efficacy of the study drug.
Efficacy endpoints will be evaluated by a Clinical Event Committee (CEC) (see Section 13.1.2).
Kidney failure is defined as either the occurrence of ESRD or an eGFR of less than 15 
mL/min/1.73 m², confirmed by a second measurement at the earliest 4 weeks after the initial 
measurement. ESRD is defined as the initiation of chronic dialysis (haemo- or peritoneal-
dialysis) for at least 90 days or renal transplantation. In addition, the eGFR threshold of 15 
mL/min/1.73 m² is consistent with the definition of kidney failure from KDIGO (Kidney 
Disease: Improving Global Outcomes)(3) and was chosen in order to include an objective 
component to the endpoint because the decision to initiate dialysis therapy or kidney 
transplantation may be affected by factors other than the eGFR. All other definitions of 
individual endpoints (e.g. CV death) will be provided in the Endpoint Manual.
9.4.1
Primary efficacy variable
The primary efficacy variable will be the time to the first occurrence of the composite endpoint
of onset of kidney failure, a sustained decrease of eGFR ≥ 40% from baseline over at least 
4 weeks, or renal death.
9.4.2
Secondary efficacy variables
Secondary efficacy variables will be as follows:

Time to first occurrence of the following composite endpoint:  cardiovascular (CV) 
death or non-fatal CV events (i.e. non-fatal myocardial infarction, non-fatal stroke, or 
hospitalization for HF)

Time to all-cause mortality

Time to all-cause hospitalization


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
Change in UACR from baseline to Month 4

Time to the first occurrence of the following composite endpoint:
onset of kidney failure, a sustained decrease of eGFR ≥ 57% from baseline over at 
least 4 weeks, or renal death.
9.4.3
Other exploratory efficacy variables - amended
This section was changed in Amendment 3, see Section 15.1.2.26.
Other exploratory efficacy variables will be as follows:

Time to onset of ESRD

Time to onset of eGFR decrease of ≥ 40% from baseline sustained over at least 
4 weeks

Time to onset of eGFR decrease of ≥ 57% from baseline sustained over at least 
4 weeks

Time to CV death

Time to first CV hospitalization

Time to first non-fatal CV event
(e.g. myocardial infarction, stroke, hospitalization for HF)

Number of subjects with new diagnosis of atrial fibrillation or atrial flutter

Number of subjects with new diagnosis of HF

Change in UACR from baseline

Change in eGFR from baseline

Regression from very high to high albuminuria and high albuminuria to albuminuria 
accompanied by a decrease in UACR of at least 30% from baseline

Number of subjects with UACR decrease of at least 30% from baseline at any time 
post-baseline

Number of subjects with UACR decrease of at least 50% from baseline at any time 
post-baseline

Change in QoL summary scores measured by the following health-related quality of 
life (HRQoL) questionnaires: Kidney Disease Quality of Life (KDQOL-36) and 
EuroQol Group 5-dimension, 5-level questionnaire (EQ-5D-5L), see Section 9.7.7 for 
details.


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9.5
Pharmacokinetics / pharmacodynamics - amended
This section was changed in Amendment 3, see Section 15.1.2.27.
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 participating subjects.  Details about the collection, 
processing, storage and shipment of samples will be provided separately (Laboratory Manual).
The plasma concentration versus time data of Visit 3 (Month 4) and at subsequent yearly 
visits will be evaluated descriptively, separated by dose. Plots will be prepared of all 
individual plasma concentrations vs. actual relative study times (time of sample collection 
after time of study drug administration). 
The PK data will be evaluated using non-linear mixed effect modeling (NONMEM). In 
addition, attempts will be made to identify whether the PK of finerenone is influenced by 
covariates and to explore exposure-response relationships. This evaluation will be described 
in a separate analysis plan and will be reported separately.
At Visit 3 (Month 4), a trough sample for the determination of finerenone plasma 
concentrations will be drawn before intake of study drug (if the sample could not be obtained 
at Visit 3, it can be drawn at Visit 4). At this visit, study drug will be administered at the study 
center by study personnel and the exact time of study drug 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 subject prior to Visit 3 to remind them not to take the 
study drug as usual in the morning at home.
At each of the yearly visits, one blood sample for the determination of finerenone plasma 
concentrations will be drawn during the visit after intake of study drug at home. The subjects 
should be advised to take their drug as usual in the morning at home and recall the time of 
drug intake. The exact time of study drug intake and the exact sampling times will be 
recorded in the eCRF.
PK sampling is not necessary if the study treatment was temporarily interrupted or 
permanently discontinued at the time of the visit.
The PK bioanalysis will be performed under the responsibility of Bayer Bioanalytics 
Laboratory, Bayer AG, 
, 42096 Wuppertal, Germany. Study 
responsible bioanalytical personnel will remain unblinded during the study.  
PPD


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9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions - amended
This section was changed in Amendment 3, see Section 15.1.2.28.
Definition of adverse event (AE)
An AE is any untoward medical occurrence (i.e. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a patient or clinical 
investigation subject. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
All diagnoses, symptom(s), sign(s) or finding(s) with a start date from randomization 
onwards must be recorded as (S)AEs, except those related to study procedure. The latter have 
to be recorded as (S)AEs after informed consent has been obtained (see also end of this 
section for definition of SAE).
A surgical procedure that was planned prior to randomization by any physician treating the 
subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term 
‘condition’ may include abnormal physical examination findings, symptoms, diseases, 
laboratory or ECG findings:

Conditions that were present before randomization and for which 
no symptoms or treatment are present until randomization are recorded as medical 
history (e.g. seasonal allergy without acute complaints)

Conditions that started before randomization and for which symptoms or treatment are 
present after randomization, at unchanged intensity, are recorded as medical history 
(e.g. allergic pollinosis)

Conditions that started or deteriorated after randomization will be documented as 
(S)AEs

Conditions assessed as related to study procedure (such as invasive procedures 
and adjustment of SoC therapy [see Section 8.1.1 for guidance]) that 
start or deteriorate after signed informed consent must be documented as (S)AEs.


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Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f):
a.
Results in death
b.
Is life-threatening
The term ‘life-threatening’ in the definition refers to an event in which the subject 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
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met:

The admission results in a hospital stay of less than 12 hours

The admission is pre-planned
(e.g. elective or scheduled surgery arranged prior to the first dose of study drug; 
admission is part of the study procedures as described in Section 9.2)

The admission is not associated with an AE
(e.g. social hospitalization for purposes of respite care).
However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 
dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d.
Results in persistent or significant disability / incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.
e.
Is a congenital anomaly / birth defect
f.
Is another serious or important medical event as judged by the investigator.
9.6.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.2.


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9.6.1.2.2
Intensity
The intensity of an AE is classified according to the following categories:
Mild: usually transient in nature and generally not interfering with normal activities
Moderate: sufficiently discomforting to interfere with normal activities
Severe: prevents normal activities.
9.6.1.2.3
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the eCRF.
The assessment is based on the question whether there was a ‘reasonable causal relationship’ 
to the study treatment in question.
Possible answers are ‘yes’ or ‘no’.
An assessment of ‘no’ would include:
1.
The existence of a highly likely alternative explanation, e.g. mechanical bleeding at 
surgical site.
or
2.
Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration.
An assessment of ‘yes’ indicates that that the AE is reasonably associated with the use of the 
study treatment.
Important factors to be considered in assessing the relationship of the AE to study treatment 
include the following:
–
The temporal sequence from drug administration:
The event should occur after the drug is given. The length of time from drug exposure 
to event should be evaluated in the clinical context of the event.
–
Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge):
Subject’s response after de-challenge or re-challenge should be considered in view of 
the usual clinical course of the event in question.
–
Underlying, concomitant, intercurrent diseases:
Each event should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the subject may have.
–
Concomitant medication or treatment:
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them might have caused the event in question.


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–
The pharmacology and pharmacokinetics of the study treatment:
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) 
of the study treatment, coupled with the individual subject’s pharmacodynamics 
should be considered.
–
The assessment is not possible.
Causal relationship to protocol-required procedure(s)
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a ‘reasonable causal relationship’ to 
protocol-required procedure(s). 
Possible answers are ‘yes’ or ‘no’.
9.6.1.2.4
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below as follows:
Drug withdrawn
Drug interrupted
Dose reduced
Dose not changed
Dose increased
Not applicable
Unknown.
9.6.1.2.5
Other specific treatment(s) of adverse events
Specific treatment of AE(s), if given, is to be documented follows:
None
Remedial drug therapy
Other.


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9.6.1.2.6
Outcome
The outcome of the AE is to be documented as follows: 
Recovered/resolved
Recovering/resolving
Recovered/resolved with sequelae
Not recovered/not resolved
Fatal
Unknown.
9.6.1.3
Assessments and documentation of adverse events (AEs) - amended
This section was changed in Amendment 3, see Section 15.1.2.29.
Attention is to be paid to the time of occurrence of AEs at all stages of the examination. Thus, 
the subject should be closely observed by the investigator.
AEs observed, mentioned upon open questioning by a member of the investigator’s team or 
spontaneously reported by the patient will be documented. The observation period for AEs will 
start with randomization and will end with the last visit of follow-up except for AEs related to 
study procedures; the observation period for the latter AEs will start with signed informed 
consent and will end with the last visit of follow-up. In the event of ongoing study-related 
AEs and medically relevant AEs at the end of the study, the investigator is urged to monitor 
the subject and document the outcome on the subject’s source document. After the end of the 
follow-up phase, there is no requirement to actively collect AEs including deaths. The type of 
information that should be assessed and recorded by the investigator for each AE is listed in 
Section 9.6.1.2.
See also Section 9.6.1.1 above for the differentiation between medical history and AEs.
The investigator is responsible for the grading of each category mentioned. An assessment of 
the seriousness of the event will be made by the investigator.  SAEs will be recorded on the 
AE page of the eCRF.
Emerging AEs will be allocated to the period in which they have started, e.g. a symptom 
starting in the treatment period and continuing in the follow-up period without deterioration 
will only be documented for that treatment period.
When assigning its cause, ‘death’ should not be recorded as an AE on the AE page.  
Instead, ‘death’ is the outcome of underlying AE(s).
For all serious adverse events (SAEs), the sponsor has to carry out a separate assessment for 
expectedness, seriousness and causal relationship to study drug.


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9.6.1.3.1
Event versus outcome
The efficacy and pre-defined disease-related outcome events specified in Figure 9–1 will 
not be documented as (S)AEs.  Instead, these events will be documented only on the 
Outcome Event pages of the eCRF. In addition, they will not be reported as SAEs and will 
neither be unblinded, nor reported to regulatory authorities, IECs, or investigators (see also 
Section 9.6.1.4 for details). 
However, they will be collected in the eCRF, monitored by the DMC during the study and 
analyzed in the clinical report after study termination. If unexpected safety issues are 
identified, specific amendments will be implemented.
Figure 9–1
Medical finding during the study: event versus outcome
9.6.1.4
Reporting of serious adverse events (SAEs) - amended
This section was changed in Amendment 3, see Section 15.1.2.30.
The definition of SAEs is provided in Section 9.6.1.1. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.
The pre-defined disease-related efficacy events (see Table 13–1) will not be subject to AE 
documentation and expedited reporting as SAE because they are not unexpected in this study 
population. Thus, they will not be recorded as SAEs on the AE page and will not be sent to 


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Sponsor’s Pharmacovigilance department.  Instead, these events will be recorded on the eCRF 
as outcome events. Consequently, they will neither be unblinded, nor reported to regulatory 
authorities, IECs or investigators. However, they will be collected in the eCRF, evaluated by 
the CEC, monitored by the independent DMC during the study and analyzed in the clinical 
study report after termination of the study. The independent DMC will periodically review 
and assess all safety data for imbalances in safety outcomes. It is believed that in this way, 
patient safety can continue to be monitored throughout the duration of the trial, without 
affecting the integrity of the study.  Should unexpected safety issues be identified, specific 
amendments will be implemented.
All other SAEs that fulfill the seriousness criteria provided in Section 9.6.1.1 must be 
collected on the AE page of the eCRF and reported as SAEs to the Sponsor’s 
Pharmacovigilance department. All SAEs that fulfill SUSAR criteria as defined by the 
ICH E2A Guideline will be reported to the concerned authorities by expedited means (see 
details below).
The investigator is responsible for continuing to follow-up on all SAE reports (whether or not 
the event is related to study drug) until resolution of the event, or until the event is considered 
chronic and/or stable by the investigator and/or other physician who is responsible for the 
subject’s medical care. Follow-up SAE reports will be reported according to the same 
timelines as initial reports, as soon as new significant information becomes available.
Investigator’s notification of the sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, will be summarized in the investigator site file and updated as needed.
The investigator must report immediately (within 24 hours of the investigator’s awareness) 
all SAEs that are not exempted from SAE reporting occurring during the observation period 
defined in Section 9.6.1.3 to the recipient detailed in the instructions for SAE reporting 
included in the Investigator File.
Each SAE must be followed up until resolution or stabilization by submission of updated 
reports to the designated recipient.
SAEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
The efficacy and pre-defined disease-related outcome events as described in Section 9.6.1.3.1
will not be subject to AE documentation. Thus they will neither be unblinded, nor reported to 
regulatory authorities, IECs, or investigators in the event of fulfilling criteria for a SUSAR.
Notification of the IECs / IRBs
Notification of the IECs / IRBs about all relevant events (e.g. SAEs, suspected, unexpected, 
serious adverse reactions [SUSARs]) will be performed by the sponsor and/or by the 
investigator according to all applicable regulations.


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In compliance with applicable regulations, in the event of a SUSAR, the subject’s treatment 
code will usually be unblinded before reporting to the competent authorities, IECs/IRBs. For 
reporting to investigators the treatment blind will be kept.
Notification of the authorities
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations.
Sponsor’s notification of the investigational site
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations.
9.6.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the IB for 
finerenone.
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations.
9.6.2
Pregnancies
Female subjects of childbearing potential must have a negative serum or urine pregnancy test 
at screening and at yearly-intervals during study participation. If required by 
national/institutional regulations, a serological or urine pregnancy test in subjects of 
childbearing potential should be performed more often (e.g. at every visit). 
The investigator must report to the sponsor any pregnancy occurring in a female study subject 
during her participation in this study. The outcome of the pregnancy should be followed up 
carefully, and any outcome of the mother and the child at delivery should be reported.
The child’s health should be followed up until birth.
For a pregnancy in the partner of a male study subject, all efforts should be made to obtain 
similar information on course and outcome of the pregnancy and the health of the child, 
subject to the partner’s consent.
For all reports, the forms provided are to be used. The investigator should submit them within 
the same timelines as an SAE, i.e. within 24 hours of his/her awareness.


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9.7
Other procedures and variables
9.7.1
Monitoring of potassium - amended
This section was changed in Amendment 3, see Section 15.1.2.31.
Hyperkalemia is a frequent event in subjects with DKD progressing to ESRD and one of the 
main risks identified from previous studies with MRAs including finerenone. Potassium will 
be monitored closely during this study, with assessments of potassium concentration 
scheduled at all visits (see Table 9–1 for schedule).
During treatment with study drug, all assessments of potassium, including re-tests, will be 
performed at both local and central laboratories.  Due to sample handling and extended 
transportation time to the central laboratory, falsely elevated serum potassium values in 
centrally (but not locally) analyzed samples have been observed in previous studies with 
finerenone.  Since the value of potassium in the local sample is usually not affected by this 
and results from the local laboratory are available earlier, local samples will be taken not only 
for safety purposes but also for dose adjustments.
Re-checking of potassium values must be done at the latest within 72 hours of the investigator 
being aware of results that need confirmation.  The investigator can perform a re-test at any 
time if they consider it necessary to confirm the potassium concentration of the local or the 
central sample.
Adjustment of dose after start of study drug intake based on blood potassium levels is 
provided in Table 9–3. 
Table 9–3
Blood potassium: guidance for dose adjustment at Visit 2 and 
subsequent visits
Blood potassium (mmol/L)
Action
First sample:
≤4.8
If on lower dose of study drug, up-titrate to higher dose.
If on higher dose of study drug, continue on the same dose.
4.9 to 5.5
Continue on the same dose.
>5.5
Withhold study drug and re-check potassium within 72 hours.
Second and subsequent samples:
≤5.0
Re-start study drug at lower dose.
>5.0
Continue to withhold study drug; continue to monitor potassium and restart 
study drug at the lower dose only if potassium is ≤5.0
NOTE: lower dose = 10 mg once daily; higher dose = 20 mg once daily.


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The following aspects have also to be taken into consideration:

Blood potassium should be measured 4 weeks (± 7 days) after re-starting treatment or 
dose adjustment, especially after up-titration

If central laboratory results for blood potassium differ from local laboratory results to 
such an extent that the investigator is uncomfortable with the dose adjustment guidance 
shown in Table 9–3 , blood sampling may be repeated at the investigator’s discretion

If the subject is already on the lower dose of study drug but hyperkalemia recurs soon 
after a previous event of hyperkalemia with interruption of study drug, and there is 
no explanation for the recurring hyperkalemia event other than intake of study drug, 
permanent discontinuation of study drug is recommended

If blood potassium is > 6.5 mmol/L, an ECG should be obtained

Subjects will maintain their normal diet throughout the study and will not be given any 
specific advice on dietary potassium restrictions.
9.7.2
Laboratory assessments
9.7.2.1
Central laboratory
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 and urinalysis parameters) 
are shown in Table 9–4. Hematology, HbA1c and (full) clinical chemistry are considered as 
‘Full central laboratory’ assessments.
Laboratory evaluations will be performed according to the visit schedule (see Table 9–1). 


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Table 9–4
Central laboratory parameters
Parameter
Component
Hematology
White blood cell count (WBC), red blood cell count (RBC), hemoglobin, 
hematocrit, mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), platelets
Glycated hemoglobin 
(HbA1c)
HbA1c only
Clinical chemistry
(full)
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
alkaline phosphatase (AP), gamma glutamyl transpeptidase (GGT), 
lactate dehydrogenase (LDH), creatine kinase (CK),
cholesterol (high density lipoprotein [HDL], low density lipoprotein [LDL], total),
triglycerides, creatinine, eGFR (CKD-EPI), blood urea nitrogen, uric acid, 
bilirubin, sodium, serum potassium, magnesium, total protein, albumin, 
high-sensitivity C-reactive protein (hs-CRP)
Clinical chemistry
(limited)
Serum creatinine, eGFR (CKD-EPI), sodium, serum potassium
Urinalysis
Urine albumin-to-creatinine ratio (UACR) will be measured in the first morning 
void urine samples collected at the subject’s home on 3 consecutive days
9.7.2.2
Local laboratory - amended
This section was changed in Amendment 3, see Section 15.1.2.32.
In addition to samples for the central laboratory, other blood safety samples will be taken 
from Visit 1 (Day 1; baseline) onwards (see Table 9–1) for analysis at the local laboratory. 
These samples may be obtained up to 72 hours before a scheduled visit.
The following clinical chemistry parameters must be measured for as long as subject is not 
prematurely discontinued from the study drug:

Blood potassium

Blood creatinine (eGFR will be calculated automatically in the eCRF using the 
CKD-EPI formula (36)).
Up-titration of the study drug will be based on local potassium and eGFR values and must be 
documented in the eCRF. Down-titration of the study drug will occur for safety reasons only 
(for guidance, see Section 9.7.1 and Table 7–2).
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 9.7.1 for guidance on treatment.
In women of childbearing potential, a pregnancy test will be performed locally, at the 
Screening Visit and following randomization at yearly visits as long as the subject is not 
permanently discontinued from the study drug (since more than 7 days). However, pregnancy 
tests in subjects of childbearing potential should be performed more frequently (e.g. at every 
visit) if this is required by national / institutional regulations. Both serological and urine tests are 
acceptable.


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9.7.3
Physical examination
Abnormal physical examination findings are recorded either as medical history or as an AE 
(see Section 9.6.1.1).
A complete physical examination will be performed at the Run-In and Screening Visits, at the 
yearly visits and again at the PD and EOS Visits (see Table 9–1).  
9.7.4
Weight and height
Body weight (to the nearest 0.1 kg in indoor clothing without shoes) will be measured at 
all scheduled visits except the PT Visit (see Table 9–1). Height as well as hip and waist 
circumference in centimeters will be only measured at the Run-in Visit.
9.7.5
Measurement of vital signs
Vital signs will be assessed at all scheduled visits except the PT Visit (see Table 9–1). This 
will include blood pressure (BP) and pulse measurements.
BP will be measured by using a standard sphygmomanometer with an appropriate size cuff in 
the sitting position after 5 minutes of rest.
There must be 3 consecutive BP readings with at least a 1-minute interval between each reading
(all 3 readings should be obtained within a maximum of 20 minutes).
The same arm and the appropriate size cuff should be used for measurements at each visit. 
9.7.6
Electrocardiogram (ECG) - amended
This section was changed in Amendment 3, see Section 15.1.2.33.
A standard 12-lead ECG will be performed locally at the Run-In Visit, Screening Visit, at 
Visit 1 (Day 1; baseline), at the yearly visits, and again at the PD and EOS Visits (see Table 
9–1). If there is any clinical indication, unscheduled 12-lead ECGs can be performed at any 
point during the study.
In addition, an ECG should be obtained if potassium >6.5 mmol/L.
The interpretation of the tracing must be made locally by a qualified physician.
The date of the recording must be documented on the ECG section of the eCRF. Each ECG 
tracing should be labeled with the study number, subject number, and date and kept in the 
source documents at the study site.
Clinically significant abnormalities should be reported as AEs or outcome event as appropriate
(e.g. new onset atrial fibrillation) when not already reported in the medical history or in one of 
the previous recordings and in case of worsening of previous findings.
9.7.7
Health-related quality of life (HRQoL) questionnaires
HRQoL questionnaires will be completed by the subject at Visit 1 (Day 1; baseline), the 
yearly visits and at the PD and EOS Visits (see Table 9–1). The following HRQoL 
questionnaires will be used: ▪Kidney Disease Quality of Life (KDQOL-36) and ▪EuroQol 


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Group 5-dimension, 5-level questionnaire (EQ-5D-5L). A general description of these 
questionnaires is provided in Section 16.3.
The subject will be instructed to fill in the questionnaires himself / herself before any other 
procedure of each visit. Subsequently, a member of the site investigator’s team will enter the 
responses into the eCRF.
9.7.8
Planned optional sub-studies
9.7.8.1
Sub-studies
The results of the sub-studies for Study 16244 will not be presented in its main clinical study 
report (CSR) but will be provided as separate reports.
9.7.8.1.1
Echocardiography sub-study - amended
This section was changed in Amendment 3, see Section 15.1.2.34.
At selected centers, approximately 500 subjects per study consenting to participate in 
Studies 16244 and 17530 will be invited to take part in an echocardiography sub-study. 
Subjects will be asked to sign a separate informed consent to participate in this sub-study. 
Diabetes mellitus, hypertension and dyslipidemia are CV risk factors which contribute to the 
CVD continuum and potentially results in a sequence of CV events. The development of HF in 
subjects with DKD is the most common CV complication and imposes significant morbidity 
and mortality (42, 43). Patients with symptomatic HFrEF are excluded from the Phase III 
program of finerenone in DKD. However, before becoming symptomatic, sub-clinical cardiac 
dysfunction and abnormal leftventricular structure including leftventricular hypertrophy can 
be demonstrated in the majority of subjects with moderate CKD. Imaging plays a central role 
in the diagnosis of structural heart disease. Of the various imaging modalities available, for 
reasons of accuracy, availability, safety and cost, echocardiography is the method of choice in 
subjects with suspected or the beginnings of structural heart disease.
In all participating sites, echocardiography will be performed according to a study-specific 
protocol at Visit 1 (Day 1; baseline), at yearly visits and at the end of the study (either at the 
PD Visit or the EOS Visit). If a baseline assessment is not available or analysable, the subject 
will not continue in to undergo echocardiography assessments due to inability to perform a 
comparison against baseline.
Echocardiography examinations, data collection and procedures for central blinded adjudication 
in the echo core laboratory are given in the Echocardiography Manual. In addition, each time an 
echocardiography is performed, one blood sample should be drawn to assess the following 
biomarkers shown in Table 9–5.


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Table 9–5
Echocardiography sub-study: biomarkers for evaluation
Biomarker
Mechanism
Rationale for assessing this biomarker
NT-proBNP
myocardial 
pressure-volume 
overload
NT-proBNP is typically increased in patients with asymptomatic or 
symptomatic left ventricular dysfunction and is associated with coronary 
artery disease and myocardial ischemia.
Galectin-3
(Cardiac) fibroblast / 
cardiomyocyte stress
Gal-3 is barely detectable in cardiomyocytes but cardiac fibroblasts 
express high levels of this protein Serum Gal-3 predicts short-, mid- and 
long-term mortality and HF-associated hospitalization in early and late 
stage HFpEF and HFrEF
sST2
Myocardial stress
In HF, ST2 mRNA and protein are upregulated and protein becomes 
detectable in serum. In severe chronic HF, change in serum sST2 
independently predicts mortality or transplant.
PIIINP 
Tissue remodeling / 
collagen synthesis
PIIINP is produced and secreted into the circulation upon collagen 
synthesis Increased baseline PIIINP levels are associated with increased 
risk of death in CHF patients and decreased in response to 
spironolactone or eplerenone
OPN
Inflammation / tissue 
remodelling
OPN mRNA and protein are hardly detectable in healthy myocardium, but 
becomes detectable upon cardiomyocyte and fibroblast injury. 
Abbreviations: CHF = chronic heart failure;  CRT = cardiac resynchronization therapy;  HFp/rEF = heart failure 
with preserved/reduced ejection fraction; NT-proBNP = N-terminal pro-peptide of brain 
natriuretic peptide; OPN = osteopontin;  PIIINP = N-terminal pro-peptide of collagen III
Local echocardiography examinations will be performed to capture at least all of the variables 
listed in Table 9–6. The recordings of echocardiography examinations will be digitally 
transferred to the vendor / echo core laboratory (ECL) for centralized interpretation and 
reporting. Echocardiography from videotape will be digitized, and analyses will be performed 
on an offline analysis workstation. Quantitative measures on all study echocardiographies will 
be performed by dedicated analysts at the core laboratory, who will be blinded to clinical 
information and randomized treatment assignment. The echocardiography results will not be 
provided to sites. 


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Table 9–6
Echocardiography sub-study: variables for evaluation
Variables
Details
LV structure, 
systolic function 
and geometry

Left ventricular ejection fraction (LVEF %) using modified Simpson’s biplane method

LV end-diastolic volume (LVEDV, ml), LVED volume index (LVEDVi [=LVEDV /body 
surface area (BSA)], mL/m2)

LV end-systolic volume (LVESV, ml), LVES volume index (LVESVi [=LVESV /BSA], 
mL/m2)

LV end-diastolic dimension (LVEDD, cm) and LV end-systolic diameter (LVESD, cm)

LV mass (LVM, g) and LV mass index (LVMi [LVM/BSA], g/m2)

Wall thicknesses, including inter-ventricular septum diameter (IVSd, cm) and LV 
posterior wall diameter (PWd, cm) in diastole

Relative wall thickness (RWT) defined as [2 x PWd] / LVEDD

LV geometry based on RWT and LVMi (normal, concentric remodeling, concentric 
hypertrophy or eccentric hypertrophy)
LV diastolic 
function

Left atrial size (LA diameter, cm; LA area, cm2), LA volume index (LAVi [=LA/BSA], 
mL/m2)

Early diastolic mitral annular velocity (e’, cm/s), using average calculated from:
o
Lateral e’ (early diastolic mitral annular relaxation velocity at lateral border of 
mitral annulus [by Tissue Doppler], cm/s) and
o
Septal e’ (early diastolic mitral annular relaxation velocity at septal border of 
mitral annulus [by Tissue Doppler], cm/s) 

E wave (mitral peak early diastolic transmitral flow velocity, m/s)

A wave (mitral peak late diastolic transmitral flow velocity, m/s) 

Ratio of E/A 

Ratio of E/e’ (using lateral e’, septal e’ and average e’)

E-wave deceleration time (EWDT, ms)
Right heart function

Pulmonary artery systolic pressure estimated by pressure gradient of tricuspid valve 
(PGTV) + estimated right atrial pressure (RAP)
o
PGTV [equivalent to peak RV-to-RA systolic gradient] = 4 x [tricuspid 
regurgitation velocity (VTR, m/s)]2
o
Estimated RAP depends on inferior vena cava diameter (IVCD, mm) and 
its respiratory collapsibility / change with respiration (end expiratory diameter 
[EED] - end inspiratory diameter / EED x 100, %) as well as the ratio of systolic to 
diastolic flow signals in the hepatic veins

Right heart function (using tricuspid annular plane systolic excursion [TAPSE], mm)
Other

Assessment of aortic and mitral valves for stenosis or regurgitation, using color or 
continuous wave Doppler  


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9.7.8.1.2
Biomarker sub-study 
At selected centers, the first approximately 500 subjects per study who consent to participate 
in Studies 16244 and 17530 will be invited to take part in a biomarker sub-study. Subject will 
be asked to sign a separate informed consent to participate in this sub-study.
For participating sites, samples for biomarkers will be drawn at Visit 1 (Day 1; baseline), at 
Visit 3 (Month 4), at yearly visits and at the end of the study (either at the PD Visit or the 
EOS Visit). The selected biomarkers studied are the ones believed to be relevant to the 
pathophysiology of the disease processes of CV and renal disease progression. The 
biomarkers studied are shown in Table 9–7.
Table 9–7
Biomarker sub-study: variables for evaluation
Biomarker
Mechanism
Rationale for assessing this biomarker
NT-proBNP
Cardiomyocyte 
pressure-volume 
overload
NT-proBNP is typically increased in subjects with 
asymptomatic or symptomatic left ventricular dysfunction 
and is associated with coronary artery disease and 
myocardial ischemia.
High sensitivity troponin T 
(hs-TnT)
Cardiomyocyte injury
Cardiac troponin T is independently associated with 
cardiovascular events and mortality in patients with CKD. 
Serum levels of hs-TnT reflect subclinical myocardial 
injury in ambulatory patients.
Cystatin C
Cystatin C level to have an important association with 
mortality across the GFR range
Neutrophil Gelatinase-
Associated Lipocalin 
(NGAL)
Renal tubuluar cells 
injury
Increased NGAL levels are an indicator of progression of 
renal damage in CKD patients even after adjustment for 
eGFR
9.7.8.1.3
Iohexol clearance sub-study - amended
This section was changed in Amendment 3, see Section 15.1.2.35.
At selected centers in Italy, at least 50 subjects per study consenting to participate in 
Studies 16244 and 17530 will be invited to take part in an iohexol clearance sub-study. 
Subjects will be asked to sign a separate informed consent to participate in this sub-study. 
Subjects who are included in this sub-study will have their GFR directly measured by the 
iohexol plasma clearance technique (44).
Iohexol plasma clearance will be assessed at Visit 1 (Day 1, baseline), at Visit 3 (Month 4) 
and thereafter at every other visit (i.e. every 8 months) until the end of the study (either at the 
PD Visit or the EOS Visit) plus an additional assessment at the PT Visit (recovery). The 
Iohexol results will not be provided to the sites. 


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The variables for evaluation in this sub-study are as follows:

Primary variable:
Chronic GFR slope, i.e. the rate of GFR decline from Visit 3 (Month 4) after 
randomization to the end of the treatment period.
As previously addressed in the AASK trial, this approach is needed to address the 
biphasic change in GFR decline that is expected after exposure to the study drug. 
The GFR slope will be determined separately during the first 4 months following 
randomization (acute slope) and after 4 months (chronic slope). The acute and chronic 
phases are differentiated because the study treatment might have acute effects on 
GFR that may differ from its long term effects on disease progression (45, 46)
(an approach approved by the U.S. National Institute of Diabetes and Digestive and 
Kidney Diseases (47)).

Exploratory variable:
o
Change in GFR from Visit 1 (baseline) and at the PT Visit (recovery)
o
Acute GFR changes from baseline to Visit 3 (Month 4)
o
Acute GFR changes from the end of the treatment period until the end of the 
recovery period
o
Correlation analyses between short term GFR changes between Visit 1 (baseline) 
and Visit 3 (Month 4) after randomization, and long term GFR decline (chronic 
slope).
An ANCOVA model will be fitted to the GFR efficacy variables including the factors 
treatment group, the stratification factors (type of albuminuria, eGFR category) and the 
baseline GFR as covariate.  Corresponding two-sided 95% confidence intervals will be 
computed. In addition, correlation analyses between short term GFR changes between 
Visit 1 (baseline) and Visit 3 (Month 4) after randomization, and long term GFR decline 
(chronic slope).
9.8
Appropriateness of procedures / measurements
All parameters and their methods of measurement are standard variables / methods in 
clinical studies and / or clinical practice. They are widely used and generally recognized as 
reliable, accurate and relevant.


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10.
Statistical methods and determination of sample size
10.1
General considerations
Statistical analysis will be performed using SAS; the version used will be specified in the 
statistical analysis plan (SAP).
A log-normal distribution is assumed for serum creatinine and UACR. 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 (SDv), minimum, median, and maximum will be 
calculated for metric data. The geometric mean and SDv will be provided instead of the 
arithmetic mean and SDv for the variables where lognormal distributions are assumed. 
Frequency tables will be generated for categorical data.
Baseline values will be defined as the last non-missing measurement before randomization
(Visit 1). 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, in case that prior to randomization, no assessment from the central 
laboratory is available. Otherwise baseline will be missing. The measurement from the Run-in 
Visit will not be used as a baseline value. If more than one measurement was planned for a 
scheduled time point, for example blood pressure 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.
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 and listed only. 
In the event of repeated measurements for Pre-treatment Visits and the Visit 1 (Day 1; baseline),
the closest measurement prior to randomization will be used for analysis instead of the 
scheduled measurements. At all visits post-randomization and unless stated otherwise, only 
the values at scheduled measurements will be used for analysis.
The derived visit ‘Any time post baseline’ (applicable for efficacy) will include any measurement 
after randomization, including unscheduled assessments. For the derived visit ‘Any time on 
treatment’, only assessments up to 30 days after last study drug administration, including 
unscheduled assessments, will be considered (applicable for efficacy; for safety assessments 
within 3 days after last study drug administration will be considered).
Further details on the statistical analyses will be provided in the SAP that will be approved 
before database release. 


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10.2
Analysis sets - amended
This section was changed in Amendment 3, see Section 15.1.2.36.
Safety analysis set (SAF): 
All randomized subjects who have taken at least 1 dose 
of study drug 
Full analysis set (FAS): 
All randomized subjects 
Per-protocol analysis set (PPS): 
All subjects of the FAS without any validity findings
Pharmacokinetic analysis set (PKS): All finerenone-treated subjects with at least 1 valid 
finerenone plasma concentration and without protocol 
deviation, which would interfere with the evaluation of 
the PK data.
Listing only set (LOS):
All other subjects screened who did not receive any 
dose of study drug or for whom no data after beginning 
of treatment are available will be classified as LOS.  
Their data will be presented in the individual subject 
data listings but will not be included in any statistical 
analysis.
All subjects will be analyzed according to the planned treatment in FAS (the intent-to-treat or 
ITT principle). All subjects will be analyzed according to the actual treatment in SAF and 
PPS. If a subject receives both treatments due to a bottle error, the treatment actually received 
for the majority of the time in the study will be used in SAF and PPS.
The stratum variable type of albuminuria and eGFR category used in the statistical analysis 
will be derived based on the screening UACR and eGFR assessment, respectively. All 
subjects will be analyzed according to their correct stratification category. In the event of 
stratification errors, the primary analysis will also be repeated based on the stratification 
category used in the randomization as a sensitivity analysis. 
10.3
Variables and planned statistical analyses
10.3.1
Disposition, baseline, history, demography and medication
The analyses of disposition, baseline, history and demography are described below:
10.3.1.1
Disposition - amended
This section was changed in Amendment 3, see Section 15.1.2.37.
The number of subjects enrolled, randomized and valid for the SAF, FAS, PPS and PKS will 
be summarized overall and by treatment group, country and investigator. The number of 
subjects discontinuing the treatment and follow-up epochs, together with the primary reason 
for discontinuation will be presented by treatment group and overall in separate tables. In 
addition, the number of subjects with important deviations and validity findings will be 
presented overall, by investigator and country 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.


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10.3.1.2
Population characteristics
Population characteristics analyses, except for subject disposition, will be performed for the 
FAS, if not stated otherwise.
10.3.1.3
Demography and other baseline characteristics - amended
This section was changed in Amendment 3, see Section 15.1.2.38.
Demography includes age, sex, race, ethnicity, region (North America, Europe, Asia, Latin 
America and others), body weight, body height, BMI, hip and waist circumference, smoking 
history (never, former, current smoker) and alcohol consumption. Other baseline 
characteristics include baseline UACR, serum potassium, categories for serum potassium 
(≤4.5 mmol and > 4.5 mmol), eGFR (calculated by CKD-EPI formula), serum creatinine, 
HbA1c, values for vital signs parameters (i.e. systolic blood pressure, diastolic blood pressure 
and heart rate).
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 type of albuminuria, region and eGFR 
category.
The non-stratified demographic and other baseline characteristics table will be repeated for all 
other analysis sets if they differ in sample size from the FAS.
Demographics and other baseline characteristics will be presented for the FAS separately for 
the subjects belonging to PPS or not (only overall, not by treatment group).
10.3.1.4
Medical history
Medical history will be coded using the MedDRA dictionary. Medical history will be 
presented for each MedDRA Primary System Organ Class and Preferred Term by treatment 
group and overall in a summary table. Additional medical history terms by Standardized 
MedDRA Queries (SMQ) will also be presented.
10.3.1.5
Concomitant medication
Concomitant medication will be coded using the WHO Drug Dictionary (WHO-DD). The 
number of subjects who took at least one concomitant medication, the number of subjects 
who took at least one medication that started and ended before administration of study drug 
and the number of subjects who took at least one concomitant medication that started after 
start of study drug will be presented by treatment group and overall using ATC classes and 
subclasses. These tables will be repeated, summarizing the number of subjects with 
medication in the Bayer drug groups of interest (including ACEI, ARBs, beta-blocker, 
diuretics, potassium supplements, potassium lowering agents, alpha blocking agents, calcium 
channel blockers, centrally acting antihypertensives and strong, moderate and weak CYP3A4 
inhibitors and CYP3A4 inducers). A subject will be counted only once within each ATC 
class / subclass or Bayer drug group, respectively.


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A listing will be provided including all medication classified as a weak, moderate or strong 
CYP3A4 inhibitor according to the Bayer drug groupings together with the respective 
classification information.
10.3.2
Treatment duration, extent of exposure, up-titration status and 
compliance - amended
This section was changed in Amendment 3, see Section 15.1.2.39.
The analyses described in this section will be repeated for the SAF and PPS if they differ in 
sample size from the FAS.
Treatment duration (number of months with study drug intake) will be summarized using 
descriptive statistics by treatment group and overall. In addition, treatment duration will be 
categorized and presented with the corresponding number and percentage of subjects by 
treatment group and overall. Further specification of the categories will be provided in the 
SAP.
A table will be presented with the absolute and relative frequencies of subjects still in the 
study at each visit. Kaplan-Meier plots for ‘Time to end of study treatment’ will be provided. 
The extent of exposure to study drug (total amount of intake in grams) will be summarized 
using descriptive statistics by treatment group. 
The up-titration status (yes/no), regardless of actual or sham up-titration, will be summarized 
with absolute and relative frequencies per treatment group for each visit as well as subjects 
never up-titrated, up-titrated once, and up-titrated more than once. Compliance (as a percentage)
will be calculated as follows: 
100 * Number of taken tablets / 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.
All tablets, including the dummy placebo tablets, will be counted. For subjects who withdraw 
prematurely from the study drug, compliance will be calculated up to the time of last dose.
The compliance will be summarized descriptively by treatment group and overall. In addition, 
percent of compliance will be categorized into three groups, <80%, ≥80 to ≤120% and 
>120%, and the categories will be summarized by treatment group and overall.
10.3.3
Efficacy variables
The primary and secondary variables of efficacy are defined in Section 9.4.
10.3.3.1
Primary efficacy variable: primary analysis
The primary analysis of the primary efficacy variable will be performed in FAS.


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Randomized subjects without an event of the primary composite endpoint at the time of 
analysis will be censored at the date of their last visit or date of non-renal death. Subjects 
without information about the primary composite endpoint after baseline will be censored at 
Day 1.
The weighted Bonferroni-Holm procedure will be used for the hierarchical testing of the 
primary and secondary efficacy endpoints. 

If the primary renal composite endpoint achieves statistical significance at a two-sided 
p-value ≤0.03333 (z0.9833 = 2.128), the secondary CV endpoint will be tested at the 
two-sided 0.05 level. 

Alternatively, if the secondary CV endpoint achieves statistical significance at a 
two-sided p-value ≤ 0.01667 (z0.99167 = 2.394), the primary renal composite endpoint 
will be tested at the two-sided 0.05 level.

Only if both the renal and CV endpoints achieve formal statistical significance, 
can further secondary endpoints be tested.
In order to evaluate whether finerenone is superior to placebo in prolonging the time to the 
first event of the primary composite endpoint, the following null hypothesis will be tested 
using the log-rank test at the significance level given above:
H0: Sfinerenone(t) = Splacebo (t) for all time points t ≥ 0
The alternative hypothesis will be:
H1: Sfinerenone (t) > Splacebo (t) for at least one time point t ≥ 0 and 
Sfinerenone (t) ≥Splacebo (t) for all time points t ≥ 0,
where Sfinerenone denotes the ‘survival’ function of the finerenone treatment group and 
Splacebo denotes the ‘survival’ function of the placebo treatment group. ‘Survival’ means 
‘no event of the primary composite endpoint’ in this context. 
The following decision rule to test the null hypothesis will be applied:
According to the size of this study it is justified to assume under H0 a sufficiently close 
approximation of the log-rank test (48) to the normal distribution. If the z-value from the 
log-rank test (for the difference Sfinerenone – Splacebo), stratified by the stratification factors 
(type of albuminuria, region, eGFR category) is larger than the critical quantile from the 
normal distribution (z0.975 = 1.960 or z0.9833 = 2.128), the null hypothesis will be rejected in 
favor of the alternative hypothesis.
The nominal significance levels and the critical values at the final analysis will be adjusted to 
account for the interim analysis, see Section 10.5 for more details.
In order to provide a point estimate of the hazard ratio and a corresponding 
two-sided 95% or 96.67% confidence interval, a stratified Cox proportional regression model 
will be used. Kaplan-Meier curves will be provided for the cumulative proportions of events 
by treatment groups.


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10.3.3.2
Primary efficacy variable: supportive analyses
The primary analysis of the primary efficacy variable will be repeated in the PPS as a 
supportive analysis. Further supportive analyses of the primary efficacy variable will be 
performed in the FAS and PPS.
The absolute and relative frequency of subjects with an event of the primary composite 
endpoint until 6, 12, 18, 24, 30 and 36 months will be displayed overall and by treatment 
group. The number of individual events of the primary composite endpoint until 6, 12, 18, 24, 
30 and 36 months will be displayed overall and by treatment group. Frequencies will be 
calculated for the number of individual events of the primary composite endpoint per subject 
until 6, 12, 18, 24, 30 and 36 months overall and by treatment group.
Kaplan-Meier estimates (the 25th, 50th and 75th percentile) of the time to the first event of the 
primary composite endpoint (including 95% or 96.67% confidence interval), overall 
‘survival’ rates at 6, 12, 18, 24, 30 and 36 months and Kaplan-Meier curves will be presented 
for each treatment group. These analyses will be presented in total and for each level of the 
stratification factors (type of albuminuria, region, eGFR category). 
The censoring mechanism of subjects without an event of the primary composite endpoint at 
the time of analysis is assumed to be non-informative for the primary efficacy analysis. 
Sensitivity analyses will be performed, assessing the impact of potential informative 
censoring of such subjects. These will include the use of different imputation rules for 
considering subjects without an event of the primary composite endpoint as having an event 
or being censored, and will be further outlined in the SAP. 
For the individual events of the primary composite endpoint, the number of events per patient 
year will be presented overall and by treatment group. The frequency of events per patient 
year for a treatment group will be calculated as the number of events observed for a treatment 
group (counting all events, not only the first one) divided by the sum of the days from first 
intake of study drug for all subjects within a treatment group and multiplied by 365.25.
An ‘on-treatment’ analysis will be performed, including only events occurring while taking 
study drug or until 30 days after stop of study drug. This analysis will be performed in the 
FAS.
10.3.3.3
Secondary efficacy variables: primary analysis
The primary analysis of the secondary efficacy variables will be analyzed in FAS.
The testing procedure for the secondary CV composite endpoint is described in 
Section 10.3.3.1. If the null hypothesis of both the primary renal composite endpoint analysis 
and the secondary CV composite endpoint analysis are rejected using the Bonferroni-Holm 
procedure as described in Section 10.3.3.1, the further secondary efficacy variables will be 
tested hierarchically in the order as they are listed in Section 9.4.2, while keeping the 
two-sided significance level of 5.0%. Otherwise, the testing of the secondary efficacy 
variables will be performed in an explorative manner only. 
The primary analysis of the secondary time-to-event endpoints will be analyzed analogously 
to the primary analysis of the primary composite endpoint.


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An ANCOVA model will be fitted to the logarithmized ratios of UACR at Month 4 to UACR 
at baseline including the factors treatment group, the stratification factors (type of 
albuminuria, region, eGFR category) and the logarithmized baseline UACR as covariate.  
Corresponding two-sided 95% confidence intervals will be computed.  This is consistent with
the primary analysis of the Phase II Study 16243.
10.3.3.4
Secondary efficacy variables: supportive analyses
The primary analysis of the secondary efficacy variables will be repeated in the PPS as a 
supportive analysis. Further supportive analyses of the secondary efficacy variables will be 
performed in FAS and PPS.
The supportive analysis of the secondary time-to-event endpoints will be analyzed in the same 
way as that for the primary composite endpoint, UACR at Month 4 will be analyzed using an 
ANCOVA as described above. 
10.3.3.5
Analysis of other exploratory efficacy variables
All other efficacy variables will be analyzed in FAS and PPS in an explorative manner. 
10.3.3.5.1 UACR and albuminuria - amended
This section was changed in Amendment 3, see Section 15.1.2.40.
UACR during the study will be summarized descriptively by treatment group and visit 
including ratios to baseline. These analyses will be performed overall and separated by the 
stratification factors (type of albuminuria, region and eGFR category). 
The log-transformed ratio of UACR to baseline at each visit up to Month 24 will be analyzed 
by a mixed model with the factors treatment group, visit, treatment by visit interaction, 
factors for the stratification levels (type of albuminuria, region and eGFR category), 
log-transformed baseline value as covariate nested within type of albuminuria and 
log-transformed baseline value by visit interaction. Pairwise ratios between the finerenone 
and the placebo treatment group will be calculated and corresponding two-sided 95% 
confidence intervals will be computed.
Frequency tables will be generated for the number of subjects with a relative decrease and 
increase in UACR of ≥30%, ≥40% and ≥50% from baseline UACR. The analysis will be 
performed for each visit and for any time post baseline. The analysis will also be performed 
stratified for each level of the stratification factors (type of albuminuria, region and eGFR 
category).
A shift table will be provided displaying the number of subjects who changed from baseline 
to each visit from very high albuminuria to high albuminuria, from very high albuminuria to 
UACR < 30mg/g, from high albuminuria to UACR < 30mg/g, from high albuminuria to very 
high albuminuria and from UACR < 30mg/g to high and very high albuminuria by treatment 
group and overall. The albuminuria category changes will only be considered as shifts, if they 
are accompanied by a UACR decrease of at least 30% from baseline to each visit.
The additional categorical UACR efficacy variables listed in Section 9.4.3 will be summarized 
for presence or absence of the event using logistic regression with the factors treatment group 


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and stratification levels (type of albuminuria, region and eGFR category). Pairwise differences 
between the finerenone and the placebo treatment group will be calculated and corresponding 
two-sided 95% confidence intervals will be computed.
10.3.3.5.2 Decrease in eGFR
eGFR will be summarized descriptively by treatment group and visit including absolute and 
relative changes to baseline. These analyses will be performed overall and separated by the 
stratification factors (type of albuminuria, region and eGFR category). 
The absolute change of eGFR to baseline at each visit until Month 24 will be analyzed by a 
mixed model with the factors treatment group, visit, treatment by visit interaction, factors for 
the stratification levels (type of albuminuria, region and eGFR category), baseline value as 
covariate nested within eGFR category and baseline by visit interaction. Pairwise differences 
between the finerenone and the placebo treatment group will be calculated and corresponding 
two-sided 95% confidence intervals will be computed.
Frequency tables will be generated for the number of subjects with a relative decrease in 
eGFR of ≥30%, ≥40%, ≥50% and ≥57% from baseline eGFR. The analysis will be performed 
for each visit and for any time post baseline. In addition, for each patient, the annual change 
in eGFR will be calculated by fitting the patient’s eGFR assessments into a linear regression 
model with time as the independent variable. The derived annual change will be analyzed 
using an ANCOVA model including baseline, treatment group and stratification factors as 
fixed-effects.
10.3.3.5.3 Health-related quality of life (HR-QoL)
Domain scores for each of the 5 domains (PCS, MCS, Burden of Kidney Disease, Symptoms / 
Problems, and Effects of Kidney Disease) will be calculated according to the KDQOL scoring 
instruction (http://www.rand.org/health/surveys_tools/kdqol.html [6th September 2013]). The 
KDQOL-36 domain scores will be presented by visit and treatment group by means of 
number of observations, number of missing values, minimum, first quartile, mean, SDv, 
median, third quartile, and maximum, including the changes from baseline. 
Summary scores will be calculated out of the 5 dimensions according to the scoring 
instructions from Europe and the US [refer to the EQ-5D-5L User Guide (49) and to the 
EQ-5D Value Sets (50)]. The values and the changes from baseline of the summary scores 
and the EQ Visual Analogue scale (VAS) will be summarized by treatment group and visit 
using the same descriptive statistics as for KDQOL. 
For details on HR-QoL questionnaires, see Section 16.3.
10.3.3.5.4 New diagnosis of atrial fibrillation, new diagnosis of heart failure and 
regression of albuminuria
These other exploratory efficacy variables will be summarized for presence or absence of the 
event using logistic regression with the factors treatment group and stratification levels (type 
of albuminuria, region and eGFR category). Pairwise differences between the finerenone and 
the placebo treatment group will be calculated and corresponding two-sided 95% confidence 
intervals will be computed.


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10.3.3.6
Subgroup analyses
Exploratory subgroup analyses are planned for the primary efficacy variable, also the 
secondary efficacy variables.  This will include descriptive statistics and a statistical test for 
interaction.
The following subgroups will be considered for exploratory subgroup analyses:

Region (North America, Latin America, Europe, Asia, Others)

eGFR category at screening and baseline (eGFR 25 to < 45, 45 to < 60 and 
≥60 mL/min/1.73m2)

Type of albuminuria at screening and baseline (high albuminuria vs very high 
albuminuria) 

History of CVD (present, absent)

Baseline serum potassium (≤ 4.5 vs. > 4.5 mmol/L)

Systolic blood pressure at baseline (90 to <130 , 130 to <160 and ≥ 160 mmHg).
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

Gender

Age group.
10.3.4
Safety variables
All analyses on safety and tolerability data will be performed in the SAF.
The following safety variables will be assessed during the study:

SAEs and AEs leading to discontinuation of treatment with study drug

Change in body weight

Change in serum potassium from baseline

Number of subjects with hyperkalemia (serum potassium > 5.5 mmol/L)

Number of subjects with severe hyperkalemia (serum potassium > 6.0 mmol/L)

Number of subjects with hospitalization for hyperkalemia

Number of subjects discontinuing study drug permanently due to hyperkalemia

Change in vital signs from baseline


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
Change in renal function measured by eGFR (CKD-EPI) change from baseline

Number of subjects with hospitalization for worsening of renal function

Number of subjects discontinuing study drug permanently due to worsening of 
renal function

Changes in laboratory values.
10.3.4.1
Adverse events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, latest version available prior to data base freeze). A listing will be provided 
linking the original investigator terms and the coded terms. AEs will also be presented 
grouped by SMQs. 
AEs that started or worsened after the first dose of study drug up to 3 days after any 
temporary or permanent interruption of study drug will be considered as treatment emergent 
AEs (TEAEs).
An overall summary of all AEs and TEAEs will be generated by treatment group. 
The number of subjects with TEAEs, post-treatment AEs occurring more than 3 days after 
stop of study drug, treatment-emergent SAEs, treatment-emergent study drug-related AEs, 
treatment-emergent study drug-related SAEs, TEAEs causing permanent discontinuation of 
study drug, treatment-emergent non-serious AEs, non-serious AEs, TEAEs by maximum 
intensity, treatment-emergent SAEs by maximum intensity, drug-related TEAEs by maximum 
intensity, TEAEs by worst outcome and treatment-emergent SAEs by worst outcome will be 
summarized by treatment group using MedDRA terms grouped by Primary System Organ 
Class and Preferred Term. 
In case of events with different intensity within a subject, 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 subject, the event will be 
reported as related to study drug. If the drug relationship is missing, the event will be 
considered as being related to the study drug.
Separate tables summarizing TEAEs, treatment-emergent study drug-related AEs, and SAEs
that occurred in more than 5% of the subjects will be provided.
Deaths, SAEs and AEs leading to permanent study drug discontinuation will be listed 
separately.
10.3.4.2
Laboratory data
The number of subjects with treatment emergent (until 3 days after any temporary or 
permanent interruption 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, HbA1c, clinical chemistry 
and urinalysis. Geometric statistics and ratios to baseline will be presented for creatinine 


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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 (type of 
albuminuria, region and eGFR category). 
The following special safety parameters will be further assessed by displaying the number of 
subjects with safety events as described below by treatment group, visit and for any time on 
treatment (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 subjects with

Absolute value of serum potassium >5.5 mmol/L and >6 mmol/L 

Relative decrease from baseline in eGFR of ≥30%, ≥40%, ≥50% and ≥57%, also 
sustained decrease over 4 weeks

Absolute value of eGFR < 30 mL/min/1.73m² 
The percentage of subjects 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 the placebo treatment group by 
applying separate explorative χ² tests with continuity correction. If the expected number of 
subjects in at least 1 cell of the 2x2 contingency table is <5 (51), 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.
10.3.4.3
Vital signs
At the corresponding visits, 3 measurements of vital signs parameters will be taken in sitting 
position with at least a 1-minute interval between each reading. Averages of 
non-missing values of these three 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. The analysis will be repeated for SBP stratified by 
baseline SBP >90 to <130 mmHg, 130 to <160 mmHg and ≥160 mmHg.
10.3.4.4
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. 
10.3.4.5
Further safety variables
All safety variables are listed at the start of this section.  Not covered in the above sections is 
the presence or absence of events associated with hyperkalemia and renal failure. These will 
be summarized by treatment group using frequency counts.


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10.3.5
Missing data / drop outs
A subject who has been randomized and discontinues study participation prematurely for any 
reason, either from study treatment or from follow-up, is defined as a ‘dropout’, even if 
no study drug has been taken. Dropouts will not be replaced. 
Data from subjects who prematurely terminated the study will be used to the maximum extent 
possible.
All missing or partial data will be presented in the subject data listing as they are recorded on 
the electronic eCRF.
Sensitivity analyses using other imputation methods will be performed for the primary 
endpoint.
For further information on missing data, please refer to Section 11.4.
10.4
Determination of sample size - amended
This section was changed in Amendment 3, see Section 15.1.2.41.
This is an event-driven study. A total of 1068 primary efficacy endpoint events will have a 
minimum 90% power to demonstrate superiority of finerenone to placebo using a logrank test at 
a two-sided significance level of 3.3333%, assuming a 20% relative risk reduction, i.e. a true 
hazard ratio of 0.80 (the hazard ratio that will be observed in the study will be different, i.e. 
closer to 1 due to treatment discontinuations). The study will stop when at least 1068 primary 
efficacy endpoints accrue across both treatment arms.
With an assumed treatment duration of 44 months (duration of recruitment period: 33 months, 
equal recruitment pattern during the accrual period, maximum treatment period of the last 
subject recruited: 11 months), the planned total number of subjects to be randomized is 
estimated to be 4690 subjects, assuming an annual placebo event rate of 12%, a common 
annual lost-to-follow-up rate of 0.7% in both treatment groups, an annual finerenone 
discontinuation rate of 5% and assuming that placebo discontinuation will not change the 
hazard. 4800 subjects are planned to be randomized taking a certain ramp-up during 
recruitment into account. Assuming a screening failure rate of 50%, 9600 subjects are planned 
to be screened. 
Due to the minimal effect of the interim analysis on the overall power of the study, an 
adjustment of sample size would be negligible.
The assumption of the annual placebo event rate of 12% is based on a recent analysis of the 
results from the IDNT and RENAAL trials using alternative endpoints defined by smaller 
declines in eGFR, similar to those proposed in Study 16244. Event rates were obtained from 
the respective studies in the arms where treatment would more closely resemble that in the 
placebo population of study 16244 who will be on standard of care treatment for DKD. 
Annual event rates for the composite renal endpoint range from 11-16% for these studies. The 
planned population of study 16244 will have some differences compared to IDNT and 
RENAAL, with a likely lower median UACR value but comparable mean eGFR. The 
comorbidity of diabetic retinopathy in subjects with high albuminuria may predict a higher 


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rate of renal events. Consequently, the assumed annual placebo event rate of 12% is assumed 
to be appropriate for this Phase III setting (10, 11). 
The calculations of the required total number of events and subjects to be randomized were 
performed using PASS 11 (52).
10.5
Planned interim analyses - amended
This section was changed in Amendment 3, see Section 15.1.2.42.
One formal interim analysis is planned when 2/3 of the required total number of primary 
efficacy endpoint events have been observed. Based on the assumptions from sample size 
determination the interim analysis will take place about 34 months after start of study 
treatment. As an event-driven trial, the actual timing of the interim analysis will depend on the 
observed event rate, the patient recruitment rate, and length of the recruitment period.
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 in the analysis of the primary efficacy endpoint and the secondary CV composite 
endpoint at the interim analysis (two-sided p-value < 0.00270). 
If the decision will be to stop the study early for success, the final primary analyses, both for 
the primary and secondary efficacy endpoints, will be performed at an overall two-sided 
significance level of 0.270%. 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 final p < 0.04967 (p < 0.03283, p < 0.01576) to maintain the overall significance 
level at 5% (3.333%, 1.667%). Consequently, if the decision will be to continue the study 
without stopping early for success, the following testing procedure at the final analysis will 
control the overall familywise error rate at 5% according to Tang and Geller (1999) (53).

If the primary renal composite endpoint achieves statistical significance at a two-sided 
p value ≤ 0.03283 (z0.9836 = 2.134), the secondary CV endpoint will be tested at the 
two sided level of 0.04967 (z0.9752 = 1.963)

Alternatively, if the secondary CV endpoint achieves statistical significance at a two 
sided p value ≤ 0.01576 (z0.9921 = 2.414), the primary renal composite endpoint will be 
tested at the two-sided level of 0.04967 (z0.9752 = 1.963)

Only if both the renal and CV endpoints achieve formal statistical significance, the 
remaining secondary endpoints will be tested hierarchically at a two-sided level of 
0.04967 (z0.9752 = 1.963).
For a lack of efficacy, a non-binding futility approach will be utilized at the time of the 
planned interim analysis. If the conditional probability of rejecting the null hypothesis for the 
primary comparison, given the assumed and current event rates, falls to an unacceptably low 
level (as will be specified in the DMC Charter), the DMC may consider recommending early 
termination of the study.


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The Executive Committee will oversee overall blinded event rates to ensure that they meet 
protocol projections. If overall event rates are lower than expected, consideration will be 
given to altering the trial design, such as increasing the sample size or extending the study 
duration without knowledge of any treatment effect.
11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be a validated electronic data capture system called 
RAVE. Subject data necessary for analysis and reporting will be entered/transmitted into a 
validated database or data system. 
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based EDC software system RAVE, which Bayer has licensed 
from Medidata Solutions Worldwide. RAVE has been validated by Medidata Solutions 
Worldwide and Bayer for use in its clinical studies. RAVE allows for the application of 
software logic to set-up data entry screens and data checks to ensure the completeness and 
accuracy of the data entered by the site personnel. Bayer extensively applies the logic to 
ensure data are complete and reflect the clinical data requirements of the study. Data queries 
resulting from the application of the software logic are resolved by the site personnel. The 
data are stored at a secure host facility maintained by Medidata Solutions Worldwide and 
transferred on a periodic basis to Bayer's internal computer system via a secure Virtual Private 
Network.
All access to the RAVE system is through a password-protected security system that is part of 
the RAVE software. All internal Bayer and external investigator site personnel seeking access 
must go through a thorough RAVE training process before they are granted access to RAVE 
for use in Bayer's clinical studies. Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE System contains a system-generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.
Source documentation
It is the expectation of the sponsor that key data entered into the eCRF has source 
documentation available at the site.
Study-specific data (race and ethnic group) may be entered directly into the CRF, without 
availability of corresponding source documentation.  For all other data, source documentation 
must be available at the site.


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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.
Data recorded from screening failures
Data of ‘only screened subjects’ will be recorded at least as source data, as far as the reason 
for the premature discontinuation is identifiable. At minimum, the following data should be 
recorded in the eCRF:
Demographic information (subject number; year of birth / age; sex; if applicable race / 
ethnicity)
Date of informed consent
Reason for premature discontinuation
Date of last visit.
These data will be transferred to the respective database.
11.2
Monitoring
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate and complete. 

Safety and rights of subjects are being protected

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol)

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
11.3
Data processing
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable sponsor’s/CRO’s standards and data cleaning 
procedures. This is applicable for data recorded on eCRF as well as for data from other 
sources (e.g. IxRS, laboratory, adjudication committees).


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For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
11.4
Missing data 
All efforts will be made to collect complete data for all subjects randomized in this study. 
Subjects will be followed until the end of the study, and all required data will be collected, 
regardless of their compliance with study medication use or visit schedule.
After randomization, study drug discontinuation for any reason does not constitute withdrawal 
from the study and should not lead to the subject being withdrawn from the study. On the 
contrary, even subjects who have stopped taking study drug are expected to attend all the 
protocol specified study visits and will be encouraged to perform all assessments as stipulated 
in the visit schedule.
If it is not possible for a subject who has withdrawn from study drug to attend any visit(s) in 
person, the site staff will keep in touch with the subject by means of phone contact to the 
subject himself/herself, or to a person pre-designated by the subject, in accordance with the 
subject’s study visit schedule. Data will continue to be collected about the subject’s health 
status, including information on developing of renal or CV complications and vital status. 
This information may be provided either by the subject himself/herself, his/her general 
practitioner or a family relative (if allowed in the respective country). Data, such as 
information on survival and potential protocol-specified endpoints, might be also collected 
from a healthcare provider, from public or medical records, or other sources as available 
according to local guidelines and as allowed by local regulations. These data will be collected 
until the study is concluded, even if the subject no longer attends study visits in person, 
unless the subject withdrew consent and did not agree to release further information.
When an event date is not known, the site investigator will be asked to provide a best-estimate 
as to when the event occurred. Even though the exact date of an event is unknown, the 
investigator often has some information that would give an approximate date (e.g. the 
first week of a month, the fall of a year, or the middle of a particular year) or at least the 
date when the subject was last seen or contacted. This information can be meaningfully 
incorporated into the estimated date recorded, as this is likely to be closer to the true date than 
any produced by an uninformed computer algorithm. This estimated date should be the 
middle date within the period that the event is known to have occurred. If the event is known 
to have occurred in the first week of a month, then the date in the middle of that week should 
be recorded as the estimate. If it occurred in the fall of a year, then the middle date in the fall 
is the appropriate estimate. If no information is known, then the date in the middle of the 
plausible time period should be given, based on the last contact with the subject prior to the 
event and the date of contact when information about the event was known.
Data from subjects who prematurely terminate the study will be used to the maximum extent 
possible. All missing or partial data will be presented in the subject data listing as they are 
recorded on the eCRF. Data are collected primarily through an EDC system, which allows 
ongoing data entry and monitoring.


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For those subjects who withdraw consent, sensitivity analyses will be performed to assess the 
impact of potential informative censoring of such subjects. These will include the use of 
different imputation rules for considering subjects without an event of the primary composite 
endpoint as having an event or being censored.
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The investigator should notify the sponsor immediately of any such inspection.
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues. Audits and inspections may occur at any time during or after 
completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution or private practice. Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The investigator/institution notifies the sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership).
The investigator site file is not to be destroyed without the sponsor’s approval.
The contract with the investigator/institution will contain all regulations relevant for the study site.


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12.
Premature termination of the study
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. centers]) at any time, which may be due but not limited to the following reasons: 
If risk-benefit ratio becomes unacceptable owing to, for example,
Safety findings from this study (e.g. SAEs)
Results of any interim analysis
Results of parallel clinical studies
Results of parallel animal studies 
(on e.g. toxicity, teratogenicity, carcinogenicity or reproduction toxicity).
If the study conduct (e.g. recruitment rate; drop-out rate; data quality; protocol compliance) 
does not suggest a proper completion of the trial within a reasonable time frame.
The investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:
Closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing.
All affected institutions (e.g. IEC(s)/IRB(s); competent authority(ies); study center; 
head of study center) must be informed as applicable according to local law.
All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.
In the event of a partial study closure, ongoing subjects must be taken care of in an 
ethical manner.
Details for individual subject's withdrawal can be found in Section 6.4.1.
13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file.
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the site, or an appropriately qualified, trained and delegated 
individual of the investigational site.
The principal investigator of each center must sign the protocol signature page and must 
receive all required external approvals (e.g. health authority, ethics committee, sponsor) 


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before subject recruitment may start at the respective center. Likewise, all amendments to the 
protocol must be signed by the principal investigator and must have received all required 
external approvals before coming into effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor’s study file.
The global sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature pages.
The coordinating investigators for this study are:
ASH Comprehensive Hypertension Center,
The University of Chicago Medicine & Biological Sciences
5841 S. Maryland Avenue; MC 1027, Chicago, IL 60637
and
University of Athens, University Hospital Attikon
Department of Cardiology, Heart Failure Unit
28 Doukissis Plakentias; 11523 Athens; Greece
13.1.1
Executive Committee
The Executive Committee, which consists of external experts in the area of nephrology, 
diabetology and cardiology, will ensure the overarching integrity of the study. 
The Executive Committee will be established for Study 16244 and Study 17530. The 
committee’s responsibilities include the following: 

Review feedback from the independent DMC

Input into the Clinical Event Committee (CEC) charter

Provision of recommendations regarding sub-studies and amendments to the protocol

Contribution to and oversight of publications and communication of study results

Projecting study termination, and other study-related activities as appropriate

Overseeing overall blinded event rates to ensure that they meet protocol projections.
Decisions will be made by consensus; in the absence of consensus, the co-Chairs of the 
Executive Committee will provide their recommendation to the Sponsor for final determination.
13.1.2
Clinical Event Committee (CEC)
A Clinical Event Committee (CEC), blinded to study treatment assignment, will adjudicate all 
events that could potentially fulfill the criteria for the primary, secondary or other endpoints 
during the study. 
PPD
PPD


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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 CEC will judge whether 
an event meets the predetermined definitions. The co-Chairs of the CEC will be members of the 
Executive Committee established for Study 16244 and Study 17530.
All of the endpoint events shown in Table 13–1 will be reported to the CEC.
Table 13–1
Endpoint events to be reported to the Clinical Event Committee (CEC)
●  Kidney failure
●  Decrease of eGFR of ≥40% from baseline, confirmed by at least one additional standardized 
measurement at least 4 weeks after the initial measurement
●  Decrease of eGFR of ≥57% from baseline, confirmed by at least one additional standardized 
measurement at least 4 weeks after the initial measurement
●  Decrease of eGFR to less than 15 mL/min/1.73m², confirmed by at least one additional 
standardized measurement at least 4 weeks after the initial measurement
●  CV and renal death events
●  Non-fatal myocardial infarction
●  Non-fatal stroke
●  Hospitalization for heart failure
●  Other CV hospitalization
●  New onset of atrial fibrillation or atrial flutter
Note:
Other endpoints of interest may be added. These will be specified in the CEC Charter.
The CEC will be responsible for classifying all death and hospitalization events and for 
determining whether pre-specified endpoint criteria were met for CV, renal or other fatal and 
non-fatal events. Sites are instructed to take a conservative approach when reporting 
endpoints; if the investigator suspects an endpoint may have occurred, it is best to report the 
event to the CEC for a final determination.
Reporting guidelines for AEs and SAEs as outlined in Sections 9.6.1.1 and 9.6.1.4 must 
be followed if the event is not a defined endpoint (see Table 13–1).


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13.1.3
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 9.6.1.3.1 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 Executive 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.
13.1.4
Steering Committee 
The Steering Committee will consist of country representative(s) and will be led by the 
Executive Committee. The Steering Committee will be blinded to the study data while the 
trial is ongoing. Their main responsibilities are as follows: 

Provide input to protocol-related issues and protocol amendments that may arise 
during the course of the study

Oversee study progress and provide recommendations to Executive Committee in 
regards to any necessary modifications that may be required in study conduct or study 
monitoring

Transmission of information to individual investigators

Serve as resource for scientific review of sub-studies, publications, presentations
and/or educational material as applicable.
13.2
Funding and financial disclosure
Funding
This study will be funded by its sponsor.
Financial disclosure 
Each investigator (including principal and/or any sub investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements. All relevant documentation will be filed in the 
trial master file.


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13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
Good Clinical Practice (GCP) guidelines and the guiding principles detailed in the 
Declaration of Helsinki. The study will also be carried out in keeping with applicable local 
law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the sponsor. The responsible unit (e.g. IEC/IRB, head 
of the study center/medical institution) must supply to the sponsor, upon request, a list of the 
EC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator or the sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/sponsor approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/sponsor. Any deviations from the protocol must be explained and documented by 
the investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
All relevant information on the study will be summarized in an integrated subject information 
sheet and informed consent form provided by the sponsor or the study center. A sample 
subject information and informed consent form will be provided as a document separate to 
this protocol.
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject / legal representative or proxy consenter (if the subject is 
under legal protection), prior to his/her entry into the study (i.e. before any examinations and 
procedures associated with the selection for the study are performed or any study-specific data 
is recorded on study-specific forms).
The investigator will also mention that written approval of the IRB/IEC has been obtained.


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Each subject / legal representative or proxy consenter will be informed about the following 
aspects of premature withdrawal:

Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 

The subject’s consent covers end-of-study examinations as specified in the visit 
description described in Section 9.2 to be conducted after withdrawal of consent. 

The subject’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan. 

Subject-specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such 
as blood, urine or tissues); these data would also be retained and statistically analyzed 
in accordance with the statistical analysis plan. The subject has the right to object to 
the generation and processing of this post-withdrawal data. For this, he/she needs to 
sign a corresponding declaration of objection; alternatively, the subject’s oral 
objection may be documented in the subject’s source data.
Each subject / legal representative or proxy consenter will have ample time and opportunity to 
ask questions.
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study. Additionally, the 
investigator will personally sign and date the form. The subject / legal representative or proxy 
consenter will receive a copy of the signed and dated form.
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the subject’s note/file of the medical institution.
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed 
consent was obtained prior to these procedures.

If the subject is not capable of providing a signature, a verbal statement of consent can 
also be given in the presence of an impartial witness (independent of the sponsor and 
the investigator). This is to be documented by a signature from the informing 
physician as well as by a signature from the witness.

For adults under legal protection, consent shall be given by the legal guardian(s). The 
consent of an adult under legal protection shall also be requested where such a person 
is able to express his/her own will. His/her refusal or the withdrawal of his/her consent 
may not be disregarded.
The informed consent form and any other written information provided to subjects / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the subject information and / or the 
written informed consent form. The investigator will inform the subject / legal representative 


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or proxy consenter of changes in a timely manner and will ask the subject to confirm his/her 
participation in the study by signing the revised informed consent form. Any revised written 
informed consent form and written information must receive the IEC/IRB`s approval / 
favorable opinion in advance of use.
13.5
Publication policy and use of data
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations. The sponsor is interested in the publication of the 
results of every study it performs. 
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. 
The sponsor will review the manuscript promptly and will discuss its content with the 
investigator to reach a mutually agreeable final manuscript. 
13.6
Compensation for health damage of subjects / insurance
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.
Subject names will not be supplied to the sponsor. Only the subject number will be recorded 
in the eCRF, and if the subject name appears on any other document (e.g. pathologist report), 
it must be obliterated before a copy of the document is supplied to the sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the informed consent process, the subjects will be informed in writing that representatives of 
the sponsor, IEC/IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The investigator will maintain a list to enable subjects to be identified.


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14.
Reference list 
1.
Fernandez Fernandez B, Elewa U, Sanchez-Nino MD, Rojas-Rivera JE, Martin-Cleary 
C, Egido J, et al. 2012 update on diabetic kidney disease: the expanding spectrum, 
novel pathogenic insights and recent clinical trials. Minerva Med. 2012;103(4):219-
34.
2.
Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et 
al. Association of estimated glomerular filtration rate and albuminuria with all-cause 
and cardiovascular mortality in general population cohorts: a collaborative meta-
analysis. Lancet. 2010;375(9731):2073-81.
3.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 
2012 clinical practice guideline for the evaluation and management of chronic kidney 
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Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in 
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Silvestre JS, Robert V, Heymes C, Aupetit-Faisant B, Mouas C, Moalic JM, et al. 
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Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A. Rise in plasma 
concentration of aldosterone during long-term angiotensin II suppression. J 
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Fritsch Neves M, Schiffrin EL. Aldosterone: a risk factor for vascular disease. Curr 
Hypertens Rep. 2003;5(1):59-65.
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Funder JW. Eplerenone: hypertension, heart failure and the importance of 
mineralocorticoid receptor blockade. Future Cardiol. 2006;2(5):535-41.
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Bolignano D, Palmer SC, Navaneethan SD, Strippoli GF. Aldosterone antagonists for 
preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 
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treatment paradigms. Kidney Int. 2012;81(10):955-68.
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Nappi JM, Sieg A. Aldosterone and aldosterone receptor antagonists in patients with 
chronic heart failure. Vasc Health Risk Manag. 2011;7:353-63.
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Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist 
protects from rat cardiorenal injury. J Cardiovasc Pharmacol. 2014;64(1):69-78.
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Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H, et al. Safety 
and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 
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disease population cohorts. Kidney Int. 2011;79(12):1331-40.
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Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, et al. 
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outcomes in diabetes. J Am Soc Nephrol. 2009;20(8):1813-21.
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lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA. 
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hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288(19):2421-
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15. Protocol amendments
15.1
Amendment 3
Amendment 3 is the first global amendment dated 02 MAY 2017.  The following is an 
overview of the changes made to the original Protocol Version 1.0.
15.1.1
Overview of changes to the study
The original protocol for this study was amended for the following reasons:
1) To account for the lower than expected recruitment rate, the duration of study and the 
number of sites required worldwide were increased.
2) To allow re-screening at an earlier stage and even if the reason for initial screen failure 
was an elevated blood potassium value, the re-screening rules were amended.
3) To allow randomization of patients with a recent CVD episode (i.e. those suffering 
from stroke, transient ischemic cerebral attack, acute coronary syndrome or 
hospitalization for worsening heart failure in the last 30 days prior to the Screening 
visit), the respective Exclusion criterion (#7) was modified.
4) In order to allow up-titration of study drug at any time during the study (from Visit 2 
onwards), the instructions for up-titration were modified. Additionally, a requirement 
to specify the reason for not dispensing the 20 mg dose in the eCRF was added.
5) The recommended blood pressure targets after randomization were updated according 
to the most recent literature.
6) The definition of the endpoint “kidney failure” was added.
7) Administrative changes: 
Sponsor name was updated (Bayer AG became the sponsor for ongoing Bayer 
HealthCare AG sponsored studies on 1st July 2016), Sponsor for US territory was 
added, contact details for Sponsor’s medical expert were updated, and terminology 
changes due to updated Operating Instructions (“protocol deviation” was replaced by 
“validity finding”) were made. 
8) To improve clarity and correct typographical errors or inconsistencies. 
Sections affected include:

Section 1 Title page

Section 2 Synopsis

Section 5 Study design

Figure 5-1 Overall study design

Section 6.2 Exclusion criteria

Section 6.4.1.1 Discontinuation of study drug


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
Section 6.4.2.1 Re-screening

Section 7.4 Dosage and administration

Section 7.5.2 Unblinding

Section 8.1.3 Control of blood pressure

Table 9-1 Study 16244: schedule of activities and evaluations

Table 9-2 Sub-studies of Study 16244: schedule of procedures

Section 9.2 Visit description

Section 9.2.1 Run-in Visit (4 to 16 weeks prior to the Screening Visit)

Section 9.2.2 Screening Visit (≤2 weeks prior to Visit 1)

Section 9.2.3 Visit 1 (randomization; Day 1 and baseline)

Section 9.2.5 Visit 3 (Month 4)

Section 9.2.6 Visit 4, 6, 7, 9, etc. (every 4 months; Month 8, 16, 20, 28, etc., excluding 
yearly visits)

Section 9.2.7 Visit 5, 8, 11, etc. (every 12 months; Month 12, 24, 36, etc.

Section 9.2.8 Up-titration Visit (unscheduled; from 4 weeks ± 7 days post-titration)

Section 9.2.9 Premature Discontinuation (PD) Visit

Section 9.2.10 End of study (EOS) visit

Section 9.2.11 Post-Treatment (PT) Visit

Section 9.3.2 Medical history

Section 9.4 Efficacy

Section 9.4.3 Other exploratory efficacy variables

Section 9.5 Pharmacokinetics / pharmacodynamics

Section 9.6.1.1 Definitions

Section 9.6.1.3 Assessments and documentation of adverse events (AEs)

Section 9.6.1.4 Reporting of serious adverse events (SAEs)

Section 9.7.1 Monitoring of blood potassium

Section 9.7.2.2 Local laboratory

Section 9.7.6 Electrocardiogram (ECG)

Section 9.7.8.1.1 Echocardiography sub-study

Section 9.7.8.1.3 Iohexol clearance sub-study

Section 10.2 Analysis sets

Section 10.3.1.1 Disposition

Section 10.3.1.3 Demography and other baseline characteristics

Section 10.3.2 Treatment duration, extent of exposure, up-titration status and 
compliance


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
Section 10.3.3.5.1 UACR and albuminuria

Section 10.4 Determination of sample size

Section 10.5 Planned interim analyses
15.1.2
Changes to the protocol text
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version. As applicable, changes to the protocol text are highlighted as 
follows:
Addition of a whole new portion
Brief identification of the new portion
Removal of a whole portion
Complete display of the removed portion, formatted 
as crossed out
Editing of an existing portion
Comparative presentation of “old text” versus “new 
text”, with “old text” referring to the most recent 
previous protocol version. Deletions are crossed out
in the “old text”. Additions are underlined in the 
“new text”. 
Tables / figures
The term “amended” is added to the caption.
Terminological changes
Brief specification of the terminological change
Thus, in this section, a terminological change (e.g. 
“period” versus “epoch”) is defined only once, 
without displaying “old text” versus “new text” for 
each appearance.
Corrections of typos or omissions are not highlighted in this section.


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15.1.2.1
Section 1 Title page
Old text:
Sponsor:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
Sponsor’s medical expert:
Study Medical Expert
Bayer S.A.
Bayer HealthCare
04779-900  São Paulo, Brazil.
Phone no.: 
New text:
Sponsor:
Non-US territory: Bayer AG, D-51368 Leverkusen, Germany
US territory: Bayer Healthcare Pharmaceuticals Inc.,
100 Bayer Boulevard, P.O. Box 915, Whippany 
NJ 07981-0915, USA
Sponsor’s medical expert:
Study Medical Expert
Bayer AG
Aprather Weg 18a
42113 Wuppertal, Germany
Phone no.: 
15.1.2.2
Section 2 Synopsis
Old text:
Test drugs
Name of active ingredient Finerenone
Doses

10 mg finerenone tablet once daily in the morning OR

20 mg finerenone tablet once daily in the morning
Route of administration
Oral
Duration of treatment
Approximately 3.25 years (i.e. an anticipated 2-year recruitment period plus 
a study drug treatment period of 1.25-year after enrolment of the last patient 
into the trial)
PPD
PPD
PPD
PPD


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Reference drug
Name of active ingredient Placebo
Dose

Placebo tablet once daily in the morning
Route of administration
Oral
Duration of treatment
Approximately 3.25 years (i.e. an anticipated 2-year recruitment period plus a 
study drug treatment period of 1.25-year after enrolment of the last patient 
into the trial)
New text:
Test drugs
Name of active ingredient Finerenone
Doses

10 mg finerenone tablet once daily in the morning OR

20 mg finerenone tablet once daily in the morning
Route of administration
Oral
Duration of treatment
As an event-driven trial, the actual length of the treatment will depend on the 
observed event rate, the patient recruitment rate, and length of the recruitment 
period and will be approximately 3.5 years. 
Reference drug
Name of active ingredient Placebo
Dose

Placebo tablet once daily in the morning
Route of administration
Oral
Duration of treatment
As an event-driven trial, the actual length of the treatment will depend on the 
observed event rate, the patient recruitment rate, and length of the recruitment 
period and will be approximately 3.5 years. 
15.1.2.3
Section 5 Study design
Old text:
[…]
Patients from approximately 650 study centers worldwide will be randomized in a 1:1 ratio to 
either finerenone or placebo in addition to SoC therapy. Assuming a screening failure rate of 
approximately 50%, 9600 patients will have to be screened to randomize approximately 
4800 patients. 
The anticipated duration of the study is approximately 3.25 years: this includes an anticipated 
recruitment period of 2 years followed by a study drug treatment period of 1.25 years after the 
enrolment of the last patient into the trial. However, as an event-driven trial, the actual length 
of the trial will depend on the observed event rates, the patient recruitment rate, and length of 
the recruitment period. 
[…]
Run-in Period (4 up to 16 weeks)


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Subjects with written informed consent who complete the Run-in Visit and meet all eligibility
criteria will be enrolled into a mandatory Run-in Period, the purpose of which is to ensure that 
the subject’s SoC therapy including treatment with ACEIs or ARBs is optimized and that all 
inclusion and exclusion criteria are met at the Screening Visit. 
[…]
Screening Period (up to 2 weeks)
At the end of the Run-in Period, a Screening Visit to confirm the subject’s eligibility will take 
place within ≤ 2 weeks prior to the planned randomization. At this visit, it will be assessed 
whether the subject still meets all the inclusion and none of the exclusion criteria.
[…]
Treatment Period
[…]
There will be up to 4 planned visits (including randomization at Visit 1) in the first 4 months; 
thereafter visits will take place every 4 months until the end of the study. Study drug dose can 
be up-titrated at scheduled visits starting from Visit 2 (Month 1) onwards or down-titrated at 
any point (even between scheduled visits); guidance on dose adjustment is provided in 
Section 7.4. Subjects may be seen at any time throughout the study, in addition to scheduled 
visits, at the discretion of the investigator.
[…]
End of study
[…]
All subjects who had withdrawn consent can be followed up for vital status if they do not sign 
the ‘Declaration of Objection’ form. In addition, vital status can be obtained by the 
investigator from publicly available data sources. The collection of vital status must be 
obtained within the timelines provided by Bayer.
[…]
New text:
[…]
Patients from approximately 900 study centers worldwide will be randomized in a 1:1 ratio to 
either finerenone or placebo in addition to SoC therapy. Assuming a screening failure rate of 
approximately 50%, 9600 patients will have to be screened to randomize approximately 
4800 patients. 
The anticipated duration of the study is approximately 4 years: this includes an anticipated 
recruitment period of 2.75 years followed by a study drug treatment period of 1 year after the 
enrolment of the last patient into the trial and a maximum of 4.5 months for the run-in and 
screening period and 1 month for the follow-up period. However, as an event-driven trial, the 
actual length of the trial will depend on the observed event rates, the patient recruitment rate, 
and length of the recruitment period. 


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[…]
Run-in Period (4 up to 16 weeks)
Subjects with written informed consent who complete the Run-in Visit and meet all 
eligibility3 criteria will be enrolled into a mandatory Run-in Period, the purpose of which is to 
ensure that the subject’s SoC therapy including treatment with ACEIs or ARBs is optimized 
and that all inclusion and exclusion criteria are met at the Screening Visit. 
3 Eligibility criteria related to central laboratory evaluation will be assessed once results are available.
[…]
Screening Period (up to 2 weeks)
At the end of the Run-in Period, a Screening Visit to confirm the subject’s eligibility will take 
place within ≤ 2 weeks prior to the planned randomization. At this visit, it will be assessed 
whether the subject still meets all the inclusion and none of the exclusion criteria.3
3 Eligibility criteria related to central laboratory evaluation will be assessed once results are available.
[…] 
Treatment Period
[…]
There will be up to 4 planned visits (including randomization at Visit 1) in the first 4 months; 
thereafter visits will take place every 4 months until the end of the study. Study drug dose can 
be up-titrated from Visit 2 (Month 1) onwards or down-titrated at any point (even between 
scheduled visits); guidance on dose adjustment is provided in Section 7.4. Subjects may be 
seen at any time throughout the study, in addition to scheduled visits, at the discretion of the 
investigator.
[…]
Follow-up period
All subjects who had withdrawn consent can be followed up for vital status if they do not sign 
the ‘Declaration of Objection’ form. In addition, vital status can be obtained by the 
investigator from publicly available data sources. The collection of vital status must be 
obtained within the timelines provided by Bayer.
[…]
15.1.2.4
Figure 5-1 Overall study design
Old text:
‡
For all subjects who have received SD. Subjects who continued taking study drug until 
the EOS visit and consent to the LTE study will not have to undergo this visit.
New text:
‡
For all subjects still on treatment with SD at the EoS Visit


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15.1.2.5
Section 6.2 Exclusion criteria 
Old text:
2. UACR > 5000 mg/g (> 565 mg/mmol) at the Run-in Visit or Screening Visit
[…]
5. SBP < 90 mmHg at the Run-in Visit or at the Screening Visit
[…]
7. Stroke, transient ischemic cerebral attack, acute coronary syndrome, or hospitalization for 
worsening heart failure, in the last 30 days prior to the Run-in Visit
[…]
18. Previous assignment to treatment during this study or Studies 17530 or 16275
New text:
2. UACR > 5000 mg/g (> 565 mg/mmol) at the Run-in Visit or Screening Visit
Note: One re-assessment is allowed in case UACR is > 5000 mg/g in one of the three 
urine samples collected at the Run-in Visit and the Screening Visit.
[…]
5. Mean SBP < 90 mmHg at the Run-in Visit or at the Screening Visit
[…]
7. Stroke, transient ischemic cerebral attack, acute coronary syndrome, or hospitalization for 
worsening heart failure, in the last 30 days prior to the Screening Visit
[…]
18. Previous assignment to treatment during this study or Study 17530
15.1.2.6
Section 6.4.1.1 Discontinuation of study drug
Old text:

The randomization code is broken for any reason
[…]
If a subject no longer on study drug 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.


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New text:

The randomization code is broken by the investigator, or other responsible person, 
when knowledge of the subject’s treatment is required
[…]
If a subject no longer on study drug 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. 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 
subject themselves, a next of kin or primary physician (or local equivalent).
15.1.2.7
Section 6.4.2.1 Re-screening
Old text:
If a subject is not eligible at the Run-in or Screening Visit for either this study (16244) or 
Study 17530, the subject may be re-screened at a later time provided the investigator believes 
that a change in the subject’s condition will make the subject potentially eligible at a later 
time point.
[…]

A minimum of 6 months between the initial Run-in Visit and re-screening.
Re-screening of the subject is not allowed if elevated blood potassium was the reason for the 
subject’s non eligibility.
A subject may be re-screened only once. During re-screening, a switch over between studies 
is allowed (see Section 6.4.2.2).
New text:
If a subject is not eligible at the Run-in or Screening Visit for either this study (16244) or 
Study 17530, the subject may be re-screened at a later time. 
[…]

A minimum of 3 months between the initial Run-in Visit and re-screening.
A subject may be re-screened only once and after being declared as a screening failure.  
During re-screening, a switch over between studies is allowed (see Section 6.4.2.2).
15.1.2.8
Section 7.4 Dosage and administration
Old text:
Up- and down-titration of study drug


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If a subject started with the lower dose of finerenone, the investigator may up-titrate the dose 
of study drug. Up-titration can be performed at any scheduled visit from Visit 2 (Month 1) 
onwards provided: 
[…]
Subjects who started with or were up-titrated to the target dose (20 mg OD) of the study drug 
but who do not tolerate this dose may be down-titrated at any point during the study, 
including between-scheduled visits if required for safety reasons. These subjects may be 
up-titrated at any scheduled visit based on the rules provided above. […]
Subsequent to any up-titration or re-start of study drug after interruption of study drug intake, 
the investigator should perform an unscheduled visit within 4 weeks (±7 days) of titration or 
restart, in order to monitor potassium levels and renal function. […]
All titrations, including the reasons for down-titration, must be documented in the eCRF.
New text:
Up- and down-titration of study drug
The investigator is encouraged to up-titrate the dose of study drug at any time once the patient 
has been on a stable dose for 4 weeks (± 7 days) (e.g. from Visit 2 onwards for patient starting 
study drug on the lower dose) either at a regular visit or an Up-titration Visit. Up-titration can 
be performed provided:
[…]
Subjects who started with or were up-titrated to the target dose (20 mg OD) of the study drug 
but who do not tolerate this dose may be down-titrated at any point during the study, 
including between-scheduled visits if required for safety reasons. These subjects may be 
up-titrated again based on the rules provided above. […]
Subsequent to an up-titration or re-start of study drug after interruption of study drug intake 
for more than 7 days, the investigator should perform an Up-titration Visit 4 weeks (±7 days) 
after titration or restart, in order to monitor potassium levels and renal function (see Table 9-
1). If a regular study visit will be scheduled to take place 4 weeks 
(± 7 days) after up-titration, the monitoring of potassium and renal function is assured and no 
Up-titration Visit has to be performed in addition. […]
All titrations, including the reasons for down-titration or for not dispensing the 20 mg dose, 
must be documented in the eCRF.
15.1.2.9
Section 7.5.2 Unblinding
Old text:
In compliance with applicable regulations, in the event of a SUSAR (see Section 9.6.1.4) 
related to the blinded treatment, the subject’s treatment code will usually be unblinded before 
reporting to the health authorities, ethic committees and investigators.


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New text:
In compliance with applicable regulations, in the event of a SUSAR (see Section 9.6.1.4) 
related to the blinded treatment, the subject’s treatment code will usually be unblinded before 
reporting to the health authorities and ethic committees.
15.1.2.10 Section 8.1.3 Control of blood pressure
Old text:
According to international guidelines, the target blood pressure for subjects with T2DM is 
<140/90 mmHg (39, 40). […]
New text:
According to international guidelines, the recommended target blood pressure for subjects 
with T2DM and albuminuria, who are at increased risk of CVD and CKD progression, is 
<130/80 mmHg (39-41). […]


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15.1.2.11 Table 9-1 Study 16244: schedule of activities and evaluations
Old text: 
Table 9-1
Study 16244: schedule of activities and evaluations
Visit 
Run-in
Screening
Visit
1 
Visit 
2
Visit 
3
Visit
4, 6, 7, 
9, etc h
Visit
5, 8, 11, 
etc
Up-titration 
visit j
PD
visit
EOS
visit k
PT
visit m
(Baseline)
(every 
4 months)
(every 
12 months)
(from 4 weeks 
± 7 days 
post-titration)
        Day / Month
4 to 16 weeks 
pre-screening
2 weeks
Day
1
Month
1
Month
4
Month
8, 16, 
20, 28, etc
Month
12, 24, 
36, etc
Unscheduled
After SD is 
permanently 
discontinued
After
study 
termination
4 weeks + 5 
days after last 
SD intake 
[…]
NOTE: 
One month corresponds to 30 days
A time frame of ± 7 days is allowed for Visit 2 (Month 1), and for the unscheduled Up-titration Visit(s).
A time frame of ± 12 days is allowed for all regular visits from Visit 3 (Month 4) onwards.
[…]
c
First morning void urine samples to be collected at the subject’s home on 2 consecutive days before scheduled visit and on the day of the visit. At the Run 
in visit, the 3 samples can be collected the 3 days after the visit.
d
Blood samples (for potassium and creatinine) for measurement in the local laboratory.  Samples to be taken only if the subject is still taking study drug.
[…]
f
AEs related to study procedures occurring after signing the informed consent as well as all other AEs starting after the first dose of study drug will be 
documented on the respective eCRF pages.
[…]
j
These procedures also apply for a re-start of study drug after interruption of study drug intake .
m
For all the subjects who have taken any study drug, the PT Visit has to be performed 4 weeks + 5 days after last intake of study drug. 
n
A trough PK sample will be drawn before study drug is administered at the study center by study personnel. The exact time of study drug intake on the day 
before the visit and on the day of the visit and the exact sampling time will have to be recorded in the eCRF.
o
Study drug will be taken as usual in the morning at home. One PK sample will be drawn during the visit. The exact time of study drug intake and the exact 
sampling times will have to be recorded in the eCRF.


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New text:
Table 9-1
Study 16244: schedule of activities and evaluations
Visit 
Run-in
Screening
Visit 
1 
(Baseline)
Visit 
2
Visit 
3
Visit
4, 6, 7, 9,
etc h
Visit
5, 8, 11, 
etc
Up-titration 
Visit j
PD
Visit
EOS
Visit k
PT
Visit m
Day / Month
4 to 16 
weeks pre-
screening
2 weeks
Day
1
Month
1
Month
4
(every 
4 months, 
i.e. 
Month 8, 16, 
20, 28, etc)
(every 
12 months, 
i.e. 
Month 12, 
24, 36, etc)
For up-titration/restart 
after interruption, 
and for safety check 
4 weeks ± 7 days after 
any up-titration 
(see also footnote j)
As soon as 
possible but 
within 7 days 
after SD is 
permanently 
discontinued
After
study 
termi-
nation
4 weeks 
+ 5 days 
after last 
SD intake 
[…]
NOTE: 
One month corresponds to 30 days
A time frame of ± 7 days is allowed for Visit 2 (Month 1), and for the Up-titration Visit(s).
A time frame of ± 12 days is allowed for all regular visits from Visit 3 (Month 4) onwards.
[…]
c
At Visit 1, first morning void urine samples to be preferably collected on three consecutive days at the subject’s home within 7 days before scheduled visit 
and before any intake of study drug. At the other visits the 3 consecutive samples can be collected ± 7 days from the visit date.
d
Blood samples (for potassium and creatinine) for measurement in the local laboratory may be obtained up to 72 hours before a scheduled visit. Samples to 
be taken only if the subject is still taking study drug.
[…]
f
AEs related to study procedures occurring after signing the informed consent as well as all other AEs starting after randomization will be documented on the 
respective eCRF pages.
[…]
j
The “Up-titration Visit” should be performed for up-titration (at any time after Visit 2), after restart of SD after an interruption for >7 days, and for safety check 
4 weeks ± 7days after any up-titration.
m
For all the subjects still on treatment with study drug at the EOS Visit, the PT Visit has to be performed 4 weeks + 5 days after last intake of study drug.
n
A trough PK sample will be drawn before study drug is administered at the study center by study personnel. The exact time of study drug intake on the day 
before the visit and on the day of the visit and the exact sampling time will have to be recorded in the eCRF. If the trough sample was not taken at Visit 3 it 
should be obtained at Visit 4 (see Section 9.5).
o
Study drug will be taken as usual, ideally in the morning at home. One PK sample will be drawn during the visit. The exact time of study drug intake and the 
exact sampling times will have to be recorded in the eCRF.


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15.1.2.12 Table 9-2 Sub-studies of Study 16244: schedule of procedures
Old text: 
Table 9-2
Sub-studies of Study 16244: schedule of procedures
Visit 
Run-in
Screening
Visit
1 
Visit 
2
Visit 
3
Visit
4, 6, 7, 
9, etc
Visit
5, 8, 11, 
etc
Up-titration 
visit
PD
visit
EOS
visit k
PT
visit m
(Baseline)
(every 
4 months)
(every 
12 months)
(from 4 weeks 
± 7 days 
post-titration)
         Day / Month
4 to 16 weeks 
pre-screening
2 weeks
Day
1
Month
1
Month
4
Month
8, 16, 
20, 28 etc
Month
12, 24, 36 etc
Unscheduled
After SD is 
permanently 
discontinued
After
study
termination
4 weeks 
+ 5 days 
after last 
SD intake 
Informed consent a
X
Echocardiography
X
X
X e
X e
Sampling for biomarkers
X
X
X
X e
X e
Iohexol clearance b
X
X
X d
X e
X e
X
[…]
c
For all the subjects who have taken any study drug, the PT Visit has to be performed 4 weeks + 5 days after last intake of study drug. 
d
Every other visit (i.e. every 8 months)
[…]


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New text: 
Table 9-2
Sub-studies of Study 16244: schedule of procedures
Visit 
Run-in
Screening
Visit 
1 
(Baseline)
Visit 
2
Visit 
3
Visit
4, 6, 7, 9,
etc
Visit
5, 8, 11, 
etc
Up-titration visit
PD
visit
EOS
visit
PT
visit c
Day / Month
4 to 16 
weeks pre-
screening
2 weeks
Day
1
Month
1
Month
4
(every 
4 months, 
i.e. 
Month 8, 16, 
20, 28, etc)
(every 
12 months, 
i.e. 
Month 12, 
24, 36, etc)
For up-titration/ 
restart after 
interruption, and for 
safety check 4 weeks 
± 7 days after any 
up-titration
As soon as possible 
but within 7 days after 
SD is permanently 
discontinued
After
study 
termi-
nation
4 weeks 
+ 5 days 
after last 
SD intake 
Informed consent a
X
Echocardiography f
X
X
X e
X e
Sampling for biomarkers
X
X
X
X e
X e
Iohexol clearance b
X
X
X d
X d
X e
X e
X
[…]
c
For all the subjects still on treatment with study drug at the EOS Visit, the PT Visit has to be performed 4 weeks + 5 days after last intake of study drug. 
d
Every other visit (every 8 months) , i.e. Visit 5, Visit 7, Visit 9, Visit 11, etc.
[…]
f   Time window for the assessment at Visit 1 is -14/+7 days, at other visits +/-30 days. Each time an echocardiography is performed, one blood sample should be 
drawn to assess the echo biomarkers


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15.1.2.13 Section 9.2 Visit description
Old text:
One month in the study schedule corresponds to 30 days. Although study visits should occur 
as close as possible to the time points specified in the protocol, a time frame of ± 7 days is 
allowed for Visit 2 (Month 1), and for the unscheduled Up-titration Visit(s).  Starting from 
Visit 3 (Month 4), a time frame of ± 12 days is allowed for all regular visits.
[…]
New text:
One month in the study schedule corresponds to 30 days. Although study visits should occur 
as close as possible to the time points specified in the protocol, a time frame of ± 7 days is 
allowed for Visit 2 (Month 1), and for the Up-titration Visit(s).  Starting from Visit 3 (Month 
4), a time frame of ± 12 days is allowed for all regular visits.
All procedures and assessments should preferably be conducted on the day of the visit; 
however, if this is not possible for logistical reasons, the following time windows are allowed:
Blood sampling, ECG and recording of vital signs:

Screening Visit and all visits starting from Visit 2: Visit date ± 7 days

Run-In, PD and EOS Visit: Visit date ± 3 days
Sub-studies / iohexol and biomarker samples:

all visits starting from Visit 3: Visit date ± 7 days

PD and EOS Visit: Visit date ± 3 days
Sub-study / echocardiography (note that each time an echocardiography is performed, one 
blood sample should be drawn to assess the echo biomarkers):

at Visit 1: Visit date -14 / +7 days

Other visits: Visit date ± 30 days
[…]
15.1.2.14 Section 9.2.1 Run-in Visit (4 to 16 weeks prior to the Screening Visit)
Old text:

Take samples (hematology, HbA1c, chemistry and urinalysis) for central laboratory 
evaluations (see Section 9.7.2.1).
New text:

Take samples (hematology, HbA1c, chemistry, urinalysis) for central laboratory 
evaluations (see Section 9.7.2.1)
Note: If HbA1c cannot be analyzed by the central laboratory due to technical reasons, 


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subject can be considered suitable for randomization with one result only (Run-In or 
Screening).
15.1.2.15 Section 9.2.2 Screening Visit (≤2 weeks prior to Visit 1)
Old text:

Take samples (hematology, HbA1c, chemistry and urinalysis) for central laboratory 
evaluations (see Section 9.7.2.1).
New text:

Take samples (hematology, HbA1c, chemistry, urinalysis) for central laboratory 
evaluations (see Section 9.7.2.1)
Note: If HbA1c cannot be analyzed by the central laboratory due to technical reasons, 
subject can be considered suitable for randomization with one result only (Run-In or 
Screening).
15.1.2.16 Section 9.2.3 Visit 1 (randomization; Day 1 and baseline)
Old text: 
All measurements on Visit 1 are to be performed before first study drug intake. The following 
procedures and assessments will be performed at Visit 1:
[…]

Optional: if the subject had signed informed consent for the sub-study, obtain 
respective samples for biomarkers (see Section 9.7.8.1.2) and/or iohexol clearance 
(see Section 9.7.8.1.3), perform echocardiography (see Section 9.7.8.1.1)
New text:
All measurements on Visit 1 are to be performed on the day of the visit before first study drug 
intake. The following procedures and assessments will be performed at Visit 1:
[…]

Optional: if the subject had signed informed consent for the sub-study, obtain 
respective samples for biomarkers (see Section 9.7.8.1.2) and/or iohexol clearance 
(see Section 9.7.8.1.3), perform echocardiography (see Section 9.7.8.1.1)
Note: Time window for the echocardiography at Visit 1 is -14/+7 days. On the day the 
echocardiography is performed, a blood sample should also be drawn to assess the 
echo biomarkers.


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15.1.2.17 Section 9.2.5 Visit 3 (Month 4)
Old text:

Obtain sample for PK (see Section 9.5)
New text:

Obtain pre-dose sample for PK (see Section 9.5)
15.1.2.18 Section 9.2.6 Visit 4, 6, 7, 9, etc. (every 4 months; Month 8, 16, 20, 28, 
etc., excluding yearly visits)
Old text:

Take samples (potassium, creatinine) for local safety laboratory evaluations (see 
Section 9.7.2.2) 

Optional: if the subject had signed informed consent for the sub-study, obtain samples 
for iohexol clearance (see Section 9.7.8.1.3). 
Note: Iohexol clearance should be performed every 8 months only
New text:

Take samples (potassium, creatinine) for local safety laboratory evaluations (see 
Section 9.7.2.2) 

Visit 4 only: Obtain pre-dose sample for PK if no PK sample was taken at Visit 3 (see 
Section 9.5)

Optional: if the subject had signed informed consent for the sub-study, obtain samples 
for iohexol clearance (see Section 9.7.8.1.3). 
Note: Iohexol clearance should be performed every 8 months only (Visit 7, Visit 9, 
etc.)
15.1.2.19 Section 9.2.7 Visit 5, 8, 11, etc. (every 12 months; Month 12, 24, 36, etc.)
Added text:

Optional: if the subject had signed informed consent for the sub-study, obtain samples 
for iohexol clearance (see Section 9.7.8.1.3).
Note: Iohexol clearance should be performed every 8 months only  (Visit 5, Visit 11, 
etc.)


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15.1.2.20 Section 9.2.8 Up-titration Visit (unscheduled; from 4 weeks ± 7 days
post-titration)
Old text:
9.2.8 Up-titration Visit (unscheduled; from 4 weeks ± 7 days post-titration)
The following procedures and assessments will be performed at the Up-titration Visit. These 
procedures also apply for a re-start of study drug after interruption of study drug intake.

Record use of concomitant medication (see Section 8.1)

Collect unused study drug and perform accountability to assess compliance 
(see Section 7.6)
New text:
9.2.8 Up-titration Visit (4 weeks ± 7 days after up-titration or restart of study drug, and 
for up-titration of study drug)
The following procedures and assessments will be performed at the Up-titration Visit (see 
Section 7.4 for details). 

Record use of concomitant medication (see Section 8.1)

Collect unused study drug and perform accountability to assess compliance, if 
applicable (see Section 7.6)
15.1.2.21 Section 9.2.9 Premature Discontinuation (PD) Visit
Old text:
9.2.9
Premature Discontinuation (PD) Visit
The following procedures and assessments will be performed at the PD Visit:
New text:
9.2.9
Premature Discontinuation (PD) Visit (as soon as possible but within 7 days after 
study drug is permanently discontinued)
If the PD visit cannot be performed within the timeframe specified, no PD visit is required.
The following procedures and assessments will be performed at the PD Visit:
15.1.2.22 Section 9.2.10 End of study (EOS) visit
Added text:

In exceptional circumstances only, if the subject is unable to attend this visit during 
the given timeframe, the subject (or primary physician / next of kin) should be 
contacted to obtain survival status. 


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15.1.2.23 Section 9.2.11 Post-Treatment (PT) Visit
Old text:
The following procedures and assessments will be performed at the PT Visit:
New text:
For all subjects who are still on treatment with study drug at the end of study visit, the 
following procedures and assessments will be performed at the PT Visit:
15.1.2.24 Section 9.3.2 Medical history
Old text:

Start before first dose of study drug
New text:

Start before randomization 
15.1.2.25 Section 9.4 Efficacy
Old text:
Definitions of individual endpoints (e.g. CV death) will be provided in the Endpoint Manual. 
New text:
Kidney failure is defined as either the occurrence of ESRD or an eGFR of less than 15 
mL/min/1.73 m², confirmed by a second measurement at the earliest 4 weeks after the initial 
measurement.  ESRD is defined as the initiation of chronic dialysis (haemo- or peritoneal-
dialysis) for at least 90 days or renal transplantation. In addition, the eGFR threshold of 15 
mL/min/1.73 m² is consistent with the definition of kidney failure from KDIGO (Kidney 
Disease: Improving Global Outcomes)(3) and was chosen in order to include an objective 
component to the endpoint because the decision to initiate dialysis therapy or kidney 
transplantation may be affected by factors other than the eGFR. All other definitions of 
individual endpoints (e.g. CV death) will be provided in the Endpoint Manual. 
15.1.2.26 Section 9.4.3 Other exploratory efficacy variables
Old text:

Time to confirmed decrease of eGFR ≥ 40% from baseline sustained over at least 
4 weeks

Time to confirmed decrease of eGFR ≥ 57% from baseline sustained over at least 
4 weeks
[...]


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
Number of subjects with UACR decrease of more than 30% from baseline at any time 
post-baseline

Number of subjects with UACR decrease of more than 50% from baseline at any time 
post-baseline
New text:

Time to onset of eGFR decrease of ≥ 40% from baseline sustained over at least 
4 weeks

Time to onset of eGFR decrease of ≥ 57% from baseline sustained over at least 
4 weeks
[...]

Number of subjects with UACR decrease of at least 30% from baseline at any time 
post-baseline

Number of subjects with UACR decrease of at least 50% from baseline at any time 
post-baseline
15.1.2.27 Section 9.5 Pharmacokinetics / pharmacodynamics
Old text:
At Visit 3 (Month 4), a trough sample for the determination of finerenone plasma 
concentrations will be drawn before intake of study drug. [...]
The PK bioanalysis will be performed under the responsibility of Bayer HealthCare
Bioanalytics Laboratory, Bayer Pharma AG, 
, 42096 
Wuppertal, Germany.
New text:
At Visit 3 (Month 4), a trough sample for the determination of finerenone plasma 
concentrations will be drawn before intake of study drug (if the sample could not be obtained 
at Visit 3, it can be drawn at Visit 4). [...]
PK sampling is not necessary if the study treatment was temporarily interrupted or 
permanently discontinued at the time of the visit.
The PK bioanalysis will be performed under the responsibility of Bayer Bioanalytics 
Laboratory, Bayer AG, 
, 42096 Wuppertal, Germany. Study 
responsible bioanalytical personnel will remain unblinded during the study.  
PPD
PPD


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15.1.2.28 Section 9.6.1.1 Definitions
Old text:
All diagnoses, symptom(s), sign(s) or finding(s) with a start date after first dose of study drug
must be recorded as (S)AEs, except those related to study procedure. [...]
A surgical procedure that was planned prior to administration of study drug by any physician 
treating the subject should not be recorded as an AE (however, the condition for which the 
surgery is required may be an AE).
[...]

Conditions that were present before first dose of study drug and for which no 
symptoms or treatment are present until administration of study drug are recorded as 
medical history (e.g. seasonal allergy without acute complaints)

Conditions that started before first dose of study drug and for which symptoms or 
treatment are present after first dose of study drug, at unchanged intensity, are 
recorded as medical history (e.g. allergic pollinosis)

Conditions that started or deteriorated after first dose of study drug will be 
documented as (S)Aes
New text:
All diagnoses, symptom(s), sign(s) or finding(s) with a start date from randomization 
onwards must be recorded as (S)AEs, except those related to study procedure. [...]
A surgical procedure that was planned prior to randomization by any physician treating the 
subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
[...]

Conditions that were present before randomization and for which no symptoms or 
treatment are present until randomization are recorded as medical history (e.g. 
seasonal allergy without acute complaints)

Conditions that started before randomization and for which symptoms or treatment are 
present after randomization, at unchanged intensity, are recorded as medical history 
(e.g. allergic pollinosis)

Conditions that started or deteriorated after randomization will be documented as 
(S)AEs
15.1.2.29 Section 9.6.1.3 Assessments and documentation of adverse events (AEs)
Old text:
AEs observed, mentioned upon open questioning by a member of the investigator’s team or 
spontaneously reported by the patient will be documented. The observation period for AEs 


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will start with administration of first dose of study drug and will end with the last visit of 
follow-up except for AEs related to study procedures; the observation period for the latter 
AEs will start with signed informed consent and will end with the last visit of follow-up. 
New text:
AEs observed, mentioned upon open questioning by a member of the investigator’s team or 
spontaneously reported by the patient will be documented. The observation period for AEs 
will start with randomization and will end with the last visit of follow-up except for 
AEs related to study procedures; the observation period for the latter AEs will start with 
signed informed consent and will end with the last visit of follow-up.
15.1.2.30 Section 9.6.1.4 Reporting of serious adverse events (SAEs)
Old text:
In compliance with applicable regulations, in the event of a SUSAR, the subject’s treatment 
code will usually be unblinded before reporting to the competent authorities, IECs/IRBs. For 
reporting to investigators the treatment blind, if possible, will be kept.
New text:
In compliance with applicable regulations, in the event of a SUSAR, the subject’s treatment 
code will usually be unblinded before reporting to the competent authorities, IECs/IRBs. For 
reporting to investigators the treatment blind will be kept.
15.1.2.31 Section 9.7.1 Monitoring of blood potassium
Old text:

Blood potassium should be measured within the first month (4 weeks ± 7 days) after 
re-starting treatment or dose adjustment, especially after up-titration
New text:

Blood potassium should be measured 4 weeks (± 7 days) after re-starting treatment or 
dose adjustment, especially after up-titration


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15.1.2.32
Section 9.7.2.2 Local laboratory
Old text:
In addition to samples for the central laboratory, other blood safety samples will be taken 
from Visit 1 (Day 1; baseline) onwards (see Table 9-1) for analysis at the local laboratory.  
These samples will be taken only while the subject is treated with the study drug.
The following clinical chemistry parameters must be measured for as long as subject is treated 
with the study drug:

Blood potassium

Serum creatinine (eGFR will be calculated automatically in the eCRF using the 
CKD-EPI formula (36)).
[…]
In women of childbearing potential, a pregnancy test will be performed locally, at the 
Screening Visit and following randomization at yearly visits. [...]
New text:
In addition to samples for the central laboratory, other blood safety samples will be taken 
from Visit 1 (Day 1; baseline) onwards (see Table 9-1) for analysis at the local laboratory.  
These samples may be obtained up to 72 hours before a scheduled visit.
The following clinical chemistry parameters must be measured for as long as subject is not 
prematurely discontinued from the study drug:

Blood potassium

Blood creatinine (eGFR will be calculated automatically in the eCRF using the 
CKD-EPI formula (36)).
[…]
In women of childbearing potential, a pregnancy test will be performed locally, at the 
Screening Visit and following randomization at yearly visits as long as the subject is not 
permanently discontinued from the study drug (since more than 7 days). [...]
15.1.2.33 Section 9.7.6 Electrocardiogram (ECG)
Old text:
A standard 12-lead ECG will be performed locally at the Run-In Visit, Screening Visit, at 
Visit 1 (Day 1; baseline), at the yearly visits, and again at the PD, EOS and PT Visits (see 
Table 9-1).
New text:
A standard 12-lead ECG will be performed locally at the Run-In Visit, Screening Visit, at 
Visit 1 (Day 1; baseline), at the yearly visits, and again at the PD, EOS and PT Visits (see 


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Table 9-1). If there is any clinical indication, unscheduled 12-lead ECGs can be performed at 
any point during the study.
15.1.2.34 Section 9.7.8.1.1 Echocardiography sub-study
Old text:
In all participating sites, echocardiography will be performed according to a study-specific 
protocol at Visit 1 (Day 1; baseline), at yearly visits and at the end of the study (either at the 
PD Visit or the EOS Visit). 
Echocardiography examinations, data collection and procedures for central blinded adjudication 
in the echo core laboratory are given in the Echocardiography Manual. Vital signs (i.e. systolic 
and diastolic BP and heart rate) should be measured during echocardiography in addition to 
acquisition of echo data. In addition, each time an echocardiography is performed, one blood 
sample should be drawn to assess the following biomarkers shown in Table 9-5.
[...] Quantitative measures on all study echocardiographies will be performed by dedicated 
analysts at the core laboratory, who will be blinded to clinical information and randomized 
treatment assignment. 
New text:
In all participating sites, echocardiography will be performed according to a study-specific 
protocol at Visit 1 (Day 1; baseline), at yearly visits and at the end of the study (either at the 
PD Visit or the EOS Visit). If a baseline assessment is not available or analysable, the subject 
will not continue to undergo echocardiography assessments due to the inability to perform a 
comparison against baseline.
Echocardiography examinations, data collection and procedures for central blinded adjudication 
in the echo core laboratory are given in the Echocardiography Manual. In addition, each time an 
echocardiography is performed, one blood sample should be drawn to assess the following 
biomarkers shown in Table 9-5.
[...] Quantitative measures on all study echocardiographies will be performed by dedicated 
analysts at the core laboratory, who will be blinded to clinical information and randomized 
treatment assignment. The echocardiography results will not be provided to sites. 
15.1.2.35 Section 9.7.8.1.3 Iohexol clearance sub-study
Old text:
Iohexol plasma clearance will be assessed at Visit 1 (Day 1, baseline), at Visit 3 (Month 4) 
and thereafter at every other visit (i.e. every 8 months) until the end of the study (either at the 
PD Visit or the EOS Visit) plus an additional assessment at the PT Visit (recovery). 


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New text:
Iohexol plasma clearance will be assessed at Visit 1 (Day 1, baseline), at Visit 3 (Month 4) 
and thereafter at every other visit (i.e. every 8 months) until the end of the study (either at the 
PD Visit or the EOS Visit) plus an additional assessment at the PT Visit (recovery). The 
Iohexol results will not be provided to the sites.  
15.1.2.36 Section 10.2 Analysis sets
Old text:
Per-protocol analysis set (PPS): All subjects of the FAS without major protocol deviations
[…]
All subjects will be analyzed according to the planned treatment in FAS (the intent-to-treat or 
ITT principle). All subjects will be analyzed according to the actual treatment in SAF and PPS.
New text:
Per-protocol analysis set (PPS): All subjects of the FAS without any validity findings
[…]
All subjects will be analyzed according to the planned treatment in FAS (the intent-to-treat or 
ITT principle). All subjects will be analyzed according to the actual treatment in SAF and PPS.  
If a subject receives both treatments due to a bottle error, the treatment actually received for 
the majority of the time in the study will be used in SAF and PPS.
15.1.2.37 Section 10.3.1.1 Disposition
Old text:
[...] In addition, the number of subjects with major and minor protocol deviations will be 
presented overall, by investigator and country for each treatment group, and in total. The 
frequencies of each major protocol deviation will be presented by treatment group and in total.
New text:
[...] In addition, the number of subjects with important deviations and validity findings will be 
presented overall, by investigator and country 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.


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15.1.2.38 Section 10.3.1.3 Demography and other baseline characteristics
Old text:
[...] Other baseline characteristics include baseline UACR, serum potassium, categories for 
serum potassium (<4.5 mmol and ≥4.5 mmol), eGFR (calculated by CKD-EPI formula), 
serum creatinine, HbA1c, values for vital signs parameters (i.e. systolic blood pressure, 
diastolic blood pressure and heart rate).
New text:
[...] Other baseline characteristics include baseline UACR, serum potassium, categories for 
serum potassium (≤4.5 mmol and > 4.5 mmol), eGFR (calculated by CKD-EPI formula), 
serum creatinine, HbA1c, values for vital signs parameters (i.e. systolic blood pressure, 
diastolic blood pressure and heart rate).
15.1.2.39 Section 10.3.2 Treatment duration, extent of exposure, up-titration 
status and compliance
Old text:
Treatment duration (number of months with study drug intake, excluding any gaps) will be 
summarized using descriptive statistics by treatment group and overall. [...]
New text:
Treatment duration (number of months with study drug intake) will be summarized using 
descriptive statistics by treatment group and overall. [...]
15.1.2.40 Section 10.3.3.5.1 UACR and albuminuria
Old text:
[...] The albuminuria category changes will only be considered as shifts, if they are 
accompanied by a UACR change of more than 30% from baseline to each visit.
New text:
[...] The albuminuria category changes will only be considered as shifts, if they are 
accompanied by a UACR change of at least 30% from baseline to each visit.


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15.1.2.41 Section 10.4 Determination of sample size
Old text:
This is an event-driven study. A total of 1061 primary efficacy endpoint events will have 
90% power to demonstrate superiority of finerenone to placebo using a logrank test at a two-
sided significance level of 3.3333%, assuming a 20% relative risk reduction, i.e. a true hazard 
ratio of 0.80 (the hazard ratio that will be observed in the study will be different, i.e. closer to 1 
due to treatment discontinuations). The study will stop when at least 1061 primary efficacy 
endpoints accrue across both treatment arms.
With an assumed study duration of 39 months (duration of recruitment period: 24 months, 
equal recruitment pattern during the accrual period, maximum treatment period of the last 
subject recruited: 15 months), the planned total number of subjects to be randomized is 
estimated to be 4701 subjects, assuming an annual placebo event rate of 12%, a common 
annual lost-to-follow-up rate of 0.7% in both treatment groups, an annual finerenone 
discontinuation rate of 5% and assuming that placebo discontinuation will not change the 
hazard. [...]
The assumption of the annual placebo event rate of 12% is based on the results from the 
MICRO-HOPE, RENAAL, IDNT, ALTITUDE and SAVOR-TIMI 53 trials. The latter 2 are 
more recent studies. Event rates were obtained from the respective studies in the arms where 
treatment would more closely resemble that in the placebo population of the CV-DKD study 
who will be on standard of care treatment for DKD. Annual event rates for the composite CV
endpoint range from 7-10% for older studies and 5-6% for more recent studies. As the 
anticipated population of Study 16244 will be more enriched for CV outcomes than 
ALTITUDE and SAVOR-TIMI 53 with regard to the requirement for CV history or CV risk 
factors for subjects with high albuminuria, a likely lower mean eGFR and higher median 
UACR value, the assumed annual placebo event rate of 12% is assumed to be appropriate for 
this Phase III setting.
New text:
This is an event-driven study. A total of 1068 primary efficacy endpoint events will have a 
minimum 90% power to demonstrate superiority of finerenone to placebo using a logrank test at 
a two-sided significance level of 3.3333%, assuming a 20% relative risk reduction, i.e. a true 
hazard ratio of 0.80 (the hazard ratio that will be observed in the study will be different, i.e. 
closer to 1 due to treatment discontinuations). The study will stop when at least 1068 primary 
efficacy endpoints accrue across both treatment arms.
With an assumed treatment duration of 44 months (duration of recruitment period: 33 months, 
equal recruitment pattern during the accrual period, maximum treatment period of the last 
subject recruited: 11 months), the planned total number of subjects to be randomized is 
estimated to be 4690 subjects, assuming an annual placebo event rate of 12%, a common 
annual lost-to-follow-up rate of 0.7% in both treatment groups, an annual finerenone 
discontinuation rate of 5% and assuming that placebo discontinuation will not change the
hazard. [...]


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The assumption of the annual placebo event rate of 12% is based on a recent analysis of the 
results from the IDNT and RENAAL trials using alternative endpoints defined by smaller 
declines in eGFR, similar to those proposed in Study 16244. Event rates were obtained from 
the respective studies in the arms where treatment would more closely resemble that in the 
placebo population of study 16244 who will be on standard of care treatment for DKD. 
Annual event rates for the composite renal endpoint range from 11-16% for these studies. The 
planned population of study 16244 will have some differences compared to IDNT and 
RENAAL, with a likely lower median UACR value but comparable mean eGFR. The 
comorbidity of diabetic retinopathy in subjects with high albuminuria may predict a higher 
rate of renal events. Consequently, the assumed annual placebo event rate of 12% is assumed 
to be appropriate for this Phase III setting
15.1.2.42 Section 10.5 Planned interim analyses
Old text:
One formal interim analysis is planned when 2/3 (707) of the required total number of 
primary efficacy endpoint events have been observed. Based on the assumptions from sample 
size determination the interim analysis will take place about 30 months after study initiation.
New text:
One formal interim analysis is planned when 2/3 of the required total number of primary 
efficacy endpoint events have been observed. Based on the assumptions from sample size 
determination the interim analysis will take place about 34 months after start of study 
treatment. As an event-driven trial, the actual timing of the interim analysis will depend on the 
observed event rate, the patient recruitment rate, and length of the recruitment period.
15.2
Amendment 4
Amendment 4 is presented using a different approach compared with the previous amendment 
to this protocol (Amendment 3, Section 15.1). The rationale for this amendment and all 
affected sections are provided in the “Protocol amendment summary of changes” section 
directly before the “Table of contents” in this document. Changes are made directly in the 
protocol body without annotations. A separate file with tracked changes against the last 
integrated protocol version is available upon request. 


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16.
Appendices
16.1
Guidance on use of common CYP inhibitors or inducers
Table 16–1 lists the most common medication regarded as potent CYP3A4 inhibitors or 
inducers.
Table 16–1
Cytochrome P450: list of concomitant medication
Excluded
Excluded
Allowed
CYP3A4 inducers
CYP3A4 inhibitors
CYP3A4 inhibitors
▪
avasimibe
▪
amprenavir
▪
amiodarone
▪
bosentan
▪
atazanavir and other inhibitors of 
human HIV protease
▪
aprepitant
▪
carbamazepin
▪
boceprevir
▪
bicalutamide
▪
efavirenz
▪
clarithromycin
▪
chloramphenicol
▪
enzalutamide
▪
cobicistat
▪
conivaptan ≤ 20 mg
▪
etravirine
▪
conivaptan > 20 mg
▪
fluconazole ≤ 200 mg
▪
fosphenytoin
▪
crizotinib
▪
imatinib
▪
hypericum perforatum / 
St John's wort
▪
danoprevir
▪
mifepristone
▪
lersivirine
▪
darunavir
▪
norfloxacine
▪
mephenytoin
▪
delavirdine
▪
tacrolimus
▪
methylphenobarbital
▪
diltiazem
▪
verapamil
▪
mitotane
▪
dronedarone
▪
lapatinib
▪
modafinil
▪
elvitegravir
▪
dasatinib
▪
nafcillin
▪
erythromycin
▪
nilotinib
▪
nevirapine
▪
fluconazole > 200 mg
▪
oxcarbazepine
▪
fosamprenavir
▪
phenobarbital
▪
grapefruit
▪
phenytoin
▪
idealisib
▪
primidone
▪
indinavir
▪
rifabutin
▪
itraconazole
▪
rifampicin
▪
ketoconazole
▪
semagacestat
▪
lopinavir
▪
talviraline
▪
miconazole
▪
thioridazine
▪
nefazodone
▪
troglitazone
▪
nelfinavir
▪
vemurafenib
▪
posaconazole
▪
ritonavir
▪
saquinavir
▪
telaprevir
▪
telithromycin
▪
tipranavir
▪
troleandomycin
▪
voriconazole


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16.2
Calculating the Child Pugh score
The severity of liver disease (Table 16–2) will determine the Child Pugh score (Table 16–3).
Table 16–2
Grading of severity of liver disease (adapted from (54))
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 16–3
Classification using the added score from Table 16–2 (adapted from (54))
Child-Pugh Class
A
B
C
Points
5 6
7 – 9
10 15


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16.3
HR-QoL questionnaires
KDQOL-36 is a specific measure of health-related quality of life for CKD that includes 
effects and burden of kidney disease as well as physical and mental health scores. 
Two forms of the KDQOL exist: the KDQOL-SF and the KDQOL-36. Both were developed
by the Kidney Disease Quality of Life Working Group at RAND Corporation. The 
KDQOL-SF is based on the SF-36 with additional questions specific to kidney disease 
concerning symptoms and problems, effects of kidney disease on daily life, burden of 
kidney disease, cognitive function, work status, sexual function, quality of social interaction, 
and sleep (55). It was developed for use with a dialysis patient population but it has also been 
found to be valid and reliable in a kidney transplant patient population (56). Studies using the 
KDQOL revealed that psychological factors, including depression, were a much stronger 
determinant of quality of life than biological measures like dialysis adequacy (57). While the 
KDQOL-SF has 134 questions the shorter form KDQOL-36 consists of 36 questions and 
contains the SF-12. The items of the KDQOL-36 are grouped as shown in Table 16–4.
The EQ-5D-5L was introduced in 2005. The EQ-5D-5L still consists of 2 pages: the 
EQ-5D-5L descriptive system and the EQ Visual Analogue scale (EQ VAS). 
The descriptive system comprises the same 5 dimensions as the EQ- 5D-3L (mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression). However, each dimension 
now has 5 levels: no problems, slight problems, moderate problems, severe problems, and 
extreme problems.
Table 16–4
KDQOL-36: grouping of items and description
Items 1-12:
SF-12
Physical Component Summary (PCS) on physical functioning, role-physical, 
bodily pain, general health; Mental Component Summary (MCS) on 
vitality, social functioning, role-emotional, mental health
Items 13-16:
Burden of Kidney Disease (4)
Interference with daily life, time to deal with kidney disease, frustration, 
feeling like a burden
Items 17-28:
Symptoms / Problems (12)
General health, activity limits, ability to accomplish desired tasks, 
depression/anxiety, energy level, social activities 
Items 29-36:
Effects of Kidney Disease (8)
Impact of fluid & diet limits, ability to work around the house and to travel, 
feeling depending on medical team, stress or worries, sex life, personal 
appearance

SAP_001.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
A randomized, double-blind, placebo-controlled, parallel-group, 
multicenter, event-driven Phase III study to investigate the 
efficacy and safety of finerenone, in addition to standard of care, 
on the progression of kidney disease in subjects with type 2 
diabetes mellitus and the clinical diagnosis of diabetic kidney 
disease 
NCT Number: 
NCT02540993 
Document Date: 
14-FEB-2020 
 
 


Statistical Analysis Plan
Protocol No.: BAY 94-8862/16244
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Statistical Analysis Plan for study 16244 (FIDELIO-DKD) in finerenone
Phase III study in diabetic kidney disease
Bayer study drug
BAY 94-8862 / Finerenone
Study purpose:
Efficacy and safety
Clinical study 
phase:
III
Date:
14 FEB 2020
Study No.:
16244
Version:
4.0
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.
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.
PPD
PPD
PPD


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Table of Contents
Abbreviations............................................................................................................................ 4
1.
Introduction ....................................................................................................................... 6
2.
Study Objectives................................................................................................................ 8
3.
Study Design ...................................................................................................................... 8
4.
General Statistical Considerations ................................................................................ 11
4.1
General Principles.......................................................................................................... 11
4.2
Handling of Dropouts .................................................................................................... 12
4.3
Handling of Missing Data.............................................................................................. 13
4.4
Interim Analyses and Data Monitoring.......................................................................... 14
4.5
Data Rules...................................................................................................................... 15
4.5.1
Baseline values ........................................................................................................... 15
4.5.2
Change from baseline ................................................................................................. 15
4.5.3
Other data handling..................................................................................................... 15
4.5.4
Subgroup analyses ...................................................................................................... 17
4.6
Validity Review ............................................................................................................. 19
4.7
Testing procedure and multiplicity adjustment.............................................................. 19
5.
Analysis Sets..................................................................................................................... 20
5.1
Safety analysis set (SAF)............................................................................................... 20
5.2
Full analysis set (FAS)................................................................................................... 20
5.3
Per-protocol analysis set (PPS)...................................................................................... 20
5.4
Pharmacokinetic analysis set (PKS) .............................................................................. 21
5.5
Listing only set (LOS) ................................................................................................... 21
5.6
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 .......................................................................................................... 22
6.1.4
Prior and Concomitant Medications........................................................................... 23
6.1.5
Treatment duration, extent of exposure and compliance............................................ 24
6.2
Efficacy.......................................................................................................................... 26
6.2.1
Analysis of primary efficacy variable......................................................................... 26
6.2.1.1
Primary efficacy variable: primary analysis............................................................ 26
6.2.1.2
Primary efficacy variable: supportive analysis ....................................................... 27
6.2.2
Analysis of secondary efficacy variables ................................................................... 29
6.2.2.1
Secondary efficacy variables: primary analysis ...................................................... 29
6.2.2.2
Secondary efficacy variables: supportive analysis.................................................. 30
6.2.3
Analysis of other exploratory efficacy variables........................................................ 31
6.2.3.1
Components of primary and secondary composite endpoints................................. 32
6.2.3.2
UACR and albuminuria........................................................................................... 32
6.2.3.3
Decrease in eGFR.................................................................................................... 33
6.2.3.4
Health-related quality of life ................................................................................... 34
6.2.3.5
New diagnosis of atrial fibrillation, new diagnosis of heart failure and regression 
of albuminuria ......................................................................................................... 35


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6.2.3.6
Outcome events reported by the investigators ........................................................ 35
6.3
Pharmacokinetics/pharmacodynamics........................................................................... 35
6.3.1
Pharmacokinetics........................................................................................................ 35
6.3.2
Pharmacodynamics..................................................................................................... 36
6.4
Safety ............................................................................................................................. 36
6.4.1
Adverse events............................................................................................................ 36
6.4.2
Laboratory parameters................................................................................................ 37
6.4.3
Vital Signs .................................................................................................................. 37
6.4.4
Weight and BMI ......................................................................................................... 38
7.
Document history and changes in the planned statistical analysis............................. 38
7.1
Overview of Changes to SAP – from version 1.0 to version 2.0................................... 38
7.2
Overview of Changes to SAP – from version 2.0 to version 3.0................................... 42
7.3
Overview of Changes to SAP – from version 3.0 to version 4.0................................... 43
8.
References ........................................................................................................................ 44
9.
Appendix .......................................................................................................................... 45
9.1
Appendix A  Technical details missing data imputation model for time to event......... 45
9.2
Appendix B  Technical details missing data imputation model for UACR................... 48
9.3
Appendix C  Region grouping ....................................................................................... 50


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Abbreviations
ACEI
Angiotensin-converting-enzyme inhibitor
AE
Adverse event
AP
Asia Pacific
ARB
Angiotensin-receptor blocker
ATC
Anatomical Therapeutic Chemical
BMI
Body mass index
BNP
B-type natriuretic peptide
BOCF
Baseline observation carried forward
CEC
Clinical event committee
CHF
Chronic heart failure
CI
Confidence interval
CKD
Chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CLIPS
Clinical Pharmacology Standards
CSR
Clinical Study Report
CV
Cardiovascular
CV
Coefficient of Variation
CVD
Cardiovascular disease
CYP3A4
Cytochrome P450, Family 3, Subfamily A, Polypeptide 4
DAOH
Days alive and out of hospital
DKD
Diabetic kidney disease
DM
Diabetes mellitus
DMC
Data monitoring committee
DPP-4
Dipeptidyl peptidase 4
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EOS
End-of-study
EQ-5D-5L
EuroQol Group 5 dimension, 5 level
ESRD
End-stage renal disease
FAS
Full analysis set
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GLP-1
Glucagon-like peptide-1
HbA1c
Glycated hemoglobin
HEOR
Health Economics, Outcomes & Reimbursement
HF
Heart failure
HFrEF
Heart failure with reduced ejection fraction
HRQoL
Health-related quality of life
ICH
International Committee on Harmonization
ITT
Intent-to-treat
IxRS
Interactive voice/web response system
KDQOL
Kidney Disease Quality of Life
LLOQ
Lower limit of quantification
LOCF
Last observation carried forward
LOS
Listing only set
LVSD
Left ventricular systolic dysfunction
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MCS
Mental component summary
MMRM
Mixed model repeated measures
MR
Mineralocorticoid receptor
MRA
Mineralocorticoid receptor antagonist
NT-proBNP
N-terminal prohormone B-type natriuretic peptide
NYHA
New York Heart Association
N/A
Not applicable
OD
Once daily


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PCS
Physical component summary
PD
Premature discontinuation
PDD
Protocol deviation document
PK
Pharmacokinetic
PKS
Pharmacokinetic analysis set
PPS
Per-protocol set
PRO
Patient-reported outcome
PT
Post-treatment
RAS
Renin-angiotensin system
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SD
Standard deviation
SF-12
Short form 12
SGLT
Sodium-glucose transport proteins
SMQs
Standardized MedDRA Queries
SoC
Standard of care
T2DM
Type 2 diabetes mellitus
TEAE
Treatment-emergent adverse event
TLF
Tables, Listings and Figures
UACR
Urinary albumin-to-creatinine ratio
UAE
Urinary albumin excretion
ULOQ
Upper limit of quantification
WHO-DD
World Health Organization Drug Dictionary


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1.
Introduction
This is a Statistical Analysis Plan (SAP) for study 16244 (FIDELIO-DKD) in finerenone.
It is based on the following document(s):
Integrated Clinical Study Protocol 16244 (DKD) version 3.0 dated 26 FEB 2019
Amendment 1 (local, Japan), dated 18 AUG 2015
Assessment Criteria Identification Requirement Document for the phase III DKD 
studies 16244 and 17530 version 4.0 dated 27 AUG 2019
DMC Charter version 3.0 dated 11 OCT 2016
CEC Charter version 2.0 dated 23 NOV 2016 
This SAP describes the statistical analysis of the period from informed consent to 
randomization, the double-blind placebo-controlled study treatment and post-treatment 
follow-up phase (expected duration 3 years or more) and the 4 week period up to the post-
treatment visit (if applicable). One formal interim analysis is currently planned. An 
independent data monitoring committee (DMC) will be involved in the review of data for 
safety and efficacy as described in the DMC Charter. Blinded adjudication of clinical 
outcomes will be performed by an independent Clinical Event Committee (CEC), as described 
in the CEC Charter.
Background
Finerenone (BAY 94-8862) is a next-generation, oral, selective, non-steroidal MRA. In 
animal models, finerenone reduced cardiac and renal hypertrophy, plasma prohormone of 
brain natriuretic peptide (BNP) and proteinuria more efficiently than in those treated with the 
steroidal mineralocorticoid receptor antagonist (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. Steroidal MRAs 
are 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. These 
characteristics may translate to a drug with a positive benefit-risk ratio in patients with DKD.
Treatment with renin-angiotensin system (RAS) inhibitors has been of particular interest 
given the ability of these drugs to reduce the rate of progression of renal disease, 
independently and in addition to their antihypertensive effects. Therefore, angiotensin-
converting-enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) can be 
considered as standard of care (SoC) therapy in patients with DKD. During the run-in period 
of the phase III DKD studies, the subject’s SoC therapy including treatment with ACEIs or 
ARBs will be optimized.
Finerenone has been investigated in phase II for two indications that are planned to proceed 
into phase III: diabetic kidney disease (DKD) and chronic heart failure (CHF).


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Study 14563 was a phase IIa study, where finerenone was studied in individuals with stable 
HFrEF and mild (estimated glomerular filtration rate [eGFR] 60 to < 90 mL/min/1.73 m2) -to-
moderate (eGFR 30–60 mL/min/ 1.73 m2) chronic kidney disease (CKD).
Study 16243 was a Phase IIb multicentre, randomized, double blind, placebo-controlled, 
parallel-group study investigating the safety and efficacy of several oral doses of finerenone in 
patients with type 2 diabetes mellitus (T2DM) and a clinical diagnosis of DKD, based on 
either high albuminuria (urinary albumin-to-creatinine ratio [UACR] 30 to 299 mg/g) or very 
high albuminuria (UACR 300 to 3000 mg/g), and with an eGFR of 30 mL/min/1.73 m2 or 
more.
Study 14564 was a Phase IIb randomized, adaptive, double-blind, double-dummy, 
comparator-controlled, parallel-group, multi-center study, that investigated the safety and 
efficacy of finerenone in subjects with worsening CHF and left ventricular systolic 
dysfunction (LVSD) and either T2DM with/without CKD, or moderate CKD alone.
Diabetic kidney disease
DKD is the most frequent cause of end-stage renal disease (ESRD) in western countries. In 
addition, the risk of cardiovascular (CV) disease and death increases in patients with DKD 
with decreasing glomerular filtration rate (GFR) and increasing albuminuria levels.
As the T2DM population rapidly grows throughout the world within the next years, and with 
it the DKD population, there is an increasing need for new therapeutic agents that effectively 
target underlying disease mechanisms and slow or halt the progression of kidney disease, 
whilst also addressing the high CV morbidity and mortality in this population.
DKD is a clinical syndrome affecting individuals with diabetes that is characterized by 
albuminuria on at least 2 occasions separated by 3 to 6 months. DKD is usually accompanied 
by hypertension, progressive rise in proteinuria, and decline in renal function. DKD is 
categorized based on the level of urinary albumin excretion (UAE), either high albuminuria 
(UACR 30 to <300 mg/g) or very high albuminuria (UACR ≥300 mg/g).
Increased UAE and decreased GFR are both associated with a worse prognosis (Figure 1–1), 
with an increase in all-cause and CV mortality. Additionally, increased UAE and decreased 
GFR are also risk factors for ESRD, acute kidney injury and progressive CKD, independent of 
each other and of other cardiovascular disease (CVD) risk factors in general as well as in 
high-risk populations.


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Figure 1–1
Prognosis of CKD by GFR and Albuminuria Categories
In study 16244, finerenone will be investigated in patients at high risk to develop end-stage 
renal disease and will therefore focus on renal endpoints. In study 17530, patients at high risk 
to develop CVD will be enrolled, and here the primary endpoint will be cardiovascular events.
2.
Study Objectives
The primary objective of this study is to:
•
Demonstrate whether, in addition to standard of care (SoC), finerenone is superior to 
placebo in delaying the progression of kidney disease, as measured by the composite 
endpoint of time to first occurrence of kidney failure, a sustained decrease in eGFR of 
≥40% from baseline over at least 4 weeks, or renal death.  
The secondary objectives of this study are to determine whether, in addition to SoC, 
finerenone compared to placebo:
•
Delays the time to first occurrence of the following composite endpoint: 
cardiovascular (CV) mortality and morbidity in subjects with T2DM and the clinical 
diagnosis of DKD 
•
Delays the time to all-cause mortality 
•
Delays the time to all-cause hospitalization
•
Reduces UACR from baseline to Month 4
•
Delays the time to first occurrence of the following composite endpoint: onset of 
kidney failure, a sustained decrease of eGFR ≥ 57% from baseline over at least 4 
weeks, or renal death.
3.
Study Design
The primary and secondary objectives in this phase III study are mainly based on time to 
specified events. The key objectives are to delay the time to the first event of a composite or 
single type of event.
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, and 
event-driven study.


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A total of 1068 primary efficacy endpoint events will have a minimum 90% power to 
demonstrate superiority of finerenone to placebo using a logrank test at a two sided 
significance level of 3.3333%, assuming a 20% relative risk reduction, i.e. a true hazard ratio 
of 0.80 (the hazard ratio that will be observed in the study will be different, i.e. closer to 1 due 
to treatment discontinuations). The study will stop when at least 1068 primary efficacy 
endpoints accrue across both treatment arms.
With an assumed study duration of 44 months (duration of recruitment period: 33 months, 
equal recruitment pattern during the accrual period, maximum treatment period of the last 
subject recruited: 11 months), the planned total number of subjects to be randomized is 
estimated to be 4690 subjects, assuming an annual placebo event rate of 12%, a common 
annual lost to follow-up rate of 0.7% in both treatment groups, an annual finerenone 
discontinuation rate of 5% and assuming that placebo discontinuation will not change the 
hazard. 4800 subjects were originally planned to be randomized taking a certain ramp-up 
during recruitment into account. Assuming a screening failure rate of 50%, 9600 subjects 
were planned to be screened. Due to the observation of a slower-than-assumed event rate 
during the study conduct phase, the required number of randomized subjects was increased to 
approximately 5800. 
As all randomized patients (except for cases with critical GCP violations) will belong to the 
Full Analysis Set (FAS) and be part of the efficacy analyses, 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 run-in 
period and 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.
Figure 3–1
Overall study design


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Run-in Period (up to 16 weeks)
Subjects with written informed consent who complete the Run-in Visit and meet all eligibility 
criteria will be enrolled into a mandatory Run-in Period, the purpose of which is to ensure that 
the subject’s SoC therapy including treatment with ACEIs or ARBs is optimized and that all 
inclusion and exclusion criteria are met at the Screening Visit. The Run in Period will last for 
a minimum of 4 weeks and a maximum of 16 weeks.
In the absence of documentation of diagnosis of high or very high albuminuria, the subject 
may still be enrolled into the study as albuminuria will be measured at the Run in Visit; in this 
case, the Run in Period must last for a minimum of 12 weeks and a maximum of 16 weeks.
Screening Period (up to 2 weeks)
At the end of the run-in period, a screening visit to confirm the subject’s eligibility will take 
place within ≤14 days prior to the planned randomization. At this visit, it will be assessed 
whether the subject still meets all the inclusion and none of the exclusion criteria.
For those subjects without a prior documented diagnosis of high or very high albuminuria, the 
Screening Visit must be performed at least 12 weeks after the Run-in Visit, and albuminuria 
should then be re-evaluated. If the subject still suffers from high or very high albuminuria 
whilst on SoC treatment, and fulfills all other eligibility criteria, she/he can be randomized 
into the study.
Treatment period 
Eligible subjects will be randomized to receive once daily (OD) oral doses of finerenone (10 
mg and 20 mg) or placebo in addition to their SoC therapy.
There will be up to 4 planned visits (including randomization at Visit 1) in the first 4 months, 
thereafter visits will take place every 4 months until the end of the study. Study drug dose can 
be up-titrated from Visit 2 (Month 1) onwards or down-titrated at any point (even between 
scheduled visits). Subjects may be seen at any time throughout the study, in addition to 
scheduled visits, at the discretion of the investigator. 
All randomized patients, including any patient who has experienced a health event considered 
for the pre-specified primary or secondary endpoints, should continue to receive study drug 
until the trial is completed provided there are no safety grounds for discontinuing treatment. 
If the study drug is temporarily discontinued, it should be re-introduced as soon as medically 
justified in the opinion of the investigator. Any changes in the study drug dose, including 
interruption/permanent discontinuation or restart of study drug, must be recorded in the 
electronic case report form (eCRF).
It is planned that all randomized subjects will remain in the trial until either: 
a. an instruction is received from the sponsor after the projected number of primary 
endpoints is positively adjudicated, or 
b. the trial is terminated prematurely at the recommendation of the independent DMC. 
Discontinuation of study drug (for any reason) does not constitute the subject’s withdrawal 
from the study, except if the investigator believes that it is in the best interest of the subject or 
if the subject withdraws consent.


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Follow-up period 
The period between the subject’s last intake of study drug and last visit in the study is referred 
to as the “Follow-up Period”. If a subject withdraws from study drug permanently but does 
not withdraw from the study, this would apply to the period between the Premature 
Discontinuation (PD) Visit, which should take place as soon as possible following permanent 
discontinuation of study drug, and the End-of-Study (EOS) Visit. In the case where a subject 
discontinues treatment at the EOS Visit, the Follow up Period applies to the period between 
the EOS visit and Post-treatment (PT) visit.
During this period, subjects are expected to continue to attend all protocol specified study 
visits, and should be encouraged to perform all assessments (with the exception of local 
laboratory assessments) as described in the visit schedule.
All subjects who withdraw consent can be followed up for vital status if they do not sign the 
‘Declaration of Objection’ form. In addition, vital status can be obtained by the investigator 
from publicly available data sources. The collection of vital status must be obtained within the 
timelines provided by Bayer.
End of study 
The end of the study as a whole will be reached as soon as the last visit of the last subject of 
the study has been reached in all centers in all participating countries.
After notification of study termination, for all subjects still participating in the study, an EOS 
Visit should be scheduled as soon as possible (but within 4 weeks at the latest) to determine 
whether the subject had an event for inclusion in the primary or secondary endpoints.
Subjects who are still on treatment will discontinue study drug treatment at the EOS Visit and 
must perform the PT Visit (4 weeks + 5 days) after their last dose of study drug.
Subjects who are no longer taking study drug must also be contacted as soon as possible after 
issue of the notification of study termination and asked to attend the EOS visit.
4.
General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.4
(SAS Institute Inc., Cary, NC, USA). 
The analysis will be based on the Global Standard Tables (Version 3.0 or higher) and the 
Clinical Pharmacology Standards (CLIPS) (Version 1.2 or higher) where appropriate.  
The validity of subjects for allocation to various analysis sets will be assessed in an ongoing 
manner in several validity review meetings and decisions will be documented in the validity 
review reports prior to unblinding (potential conditional validity for per-protocol set [PPS] 
and pharmacokinetic analysis set [PKS]). This SAP may be updated based on the results of 
the validity review meetings.
Only adjudicated outcome events will be used for all efficacy analyses except for that 
specified in section 6.2.3.6.
A log-normal distribution is assumed for serum creatinine and UACR. For all other metric 
variables, a normal distribution is assumed. The distributional assumptions will be 


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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, lower quartile, median, upper quartile, 
and maximum will be calculated for metric data. The geometric mean and SD will be 
provided instead of the arithmetic mean and SD for the variables where log-normal 
distributions are assumed. Frequency tables will be generated for categorical data.
The laboratory parameter eGFR will be calculated based on the CKD-EPI formula for all 
analyses specified in this SAP.
All subjects will be analyzed according to the planned treatment group in FAS (the intent-to-
treat or ITT principle). All subjects will be analyzed according to the actual treatment in the 
safety analysis set (SAF). If a subject receives both treatments due to a bottle error, the 
treatment actually received for the majority of the time in the study will be used in SAF.
The stratified analyses mentioned in this SAP will be conducted in consideration of the 
randomization stratification factors region, eGFR category and type of albuminuria unless 
specified otherwise, see also section 4.5.4. The strata variables type of albuminuria and eGFR 
category used in the statistical analysis will be based on the screening UACR and eGFR 
assessments and corrected via the interactive voice/web response system (IxRS) if necessary. 
All subjects will be analyzed according to their correct stratification category. If screening 
values are not available, the run-in values will be used. If a subject’s actual UACR / eGFR 
combination results in a stratification group that does not exist in the study (e.g. in 16244, 
very high albuminuria and eGFR ≥75 mL/min/1.73m2) then the stratification group the 
investigator originally specified in IxRS will be kept.
In case of stratification errors, the primary analysis will also be repeated based on the 
stratification category used in the randomization as a sensitivity analysis.
4.2
Handling of Dropouts
A subject who has been randomized and discontinues study participation prematurely for any 
reason is defined as a “dropout”, even if no study drug has been taken. Dropouts will not be 
replaced.
Data from subjects who prematurely terminated the study will be used to the maximum extent 
possible.
The number of subjects discontinuing the epochs, together with the primary reason for 
discontinuation, will be summarized as described in section 6.1.1.
The number of subjects 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 “Time to end of study” and “Time to end of study 
treatment” will be provided.
All dropouts and subjects prematurely discontinuing study treatment will be evaluated with 
respect to
•
baseline characteristics
•
potential differences between the treatment groups in the proportion of patient 
withdrawals or in the timing of withdrawals


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•
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 Case Report Form (CRF).
General rules
When appropriate, the following rules will be implemented so as not to exclude subjects 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 end 
of study will be considered to have started prior to study medication start and end after stop 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 minimum and maximal possible dates, i.e.:
•
first month of the year, or first day of the month for a partially missing start date, and
•
last month of the year, or last day of the month for a partially missing end date.
If a subject 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 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 taken. 
•
In case the range of possible values is further restricted, e.g. because a patient 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.
The same principle also applies to partially missing death dates, e.g. if only the year of 
death is available, but there is a last contact in the given year, then the date of death is 
imputed as the median of this date and the end of the given year.
In case a death date is completely missing, it will be imputed on the basis of the last known 
contact when the subject was still alive and the first known contact when the subject was dead 


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(e.g. from the subject 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-renal and 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.
For the analyses of the secondary endpoint UACR at Month 4, the closest post-baseline set of 
measurements to day 120 (+/-30days) will be taken as Month 4. If there is no set of 
measurements within this time frame, the subject will be excluded from the primary analysis 
of UACR at Month 4.
A worst case approach will be applied for determining whether an AE with partially missing 
dates is treatment-emergent or not, i.e. if it is possible that the adverse event start date is 
within a period of study drug intake +3 days, then the adverse event is considered treatment-
emergent.
If intensity of the AE 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 subject, the event will be 
reported as related to study drug. 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 formal interim analysis is planned when 2/3 of the required total number of primary 
efficacy 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 in the analysis of the primary and the key secondary efficacy endpoint at the 
interim analysis (two-sided p-value <0.00270).
For a detailed description of the testing procedure, including an adjustment of the significance 
level for the interim analysis, please see section 4.7.
In case of an early stop of the study for success, the final analysis reported in the CSR will 
consider all events up to the subjects’ 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 and will be based on the same final clean database as 
done for the final analysis reported in the CSR (instead of the interim analysis database). For 
this sensitivity analysis, censoring dates after the datacut date will be reset to the datacut date.
For a lack of efficacy, a non-binding futility approach will be utilized at the time of the 
planned interim analysis. If the conditional probability of rejecting the null hypothesis for the 
primary comparison, given the assumed and current event rates, falls to an unacceptably low 
level (as specified in the DMC Charter), the DMC may consider recommending early 
termination of the study.


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A detailed plan for the routine DMC safety analyses and the interim analysis is covered in the 
DMC charter, the analysis planned to be provided to the DMC is described in a separate DMC 
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.
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, in case that prior to randomization, no assessment from 
the central laboratory is available. Otherwise baseline will be missing. The measurement from 
the Run-in Visit will not be used as a baseline value unless otherwise specified.
If more than one measurement was planned for a scheduled visit, for example blood pressure 
measurements and heart rate, the mean value of these measurements per time point prior to 
randomization will be used as the baseline value.
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
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 and will be listed only unless there are 
no values from the central laboratory available for baseline.
In case of retests for Run-in and Screening visits, the closest measurement prior to 
randomization will be used for analysis instead of the scheduled measurements. At all visits 
starting at Visit 1 and if not stated otherwise, only the values at scheduled measurements will
be used for analysis. In the unexpected case that more values than planned are available for a 
scheduled visit, only the first valid value will be used.


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For the derived visit “Any time post-baseline” (applicable for efficacy) this will include any 
measurement after date of randomization, including unscheduled assessments. For the derived 
visit “Any treatment-emergent” (applicable for safety), only assessments on or after study 
medication start date until 3 days after the date of any temporary or permanent interruption of 
study drug, including unscheduled assessments, will be considered.
For those laboratory values which are <LLOQ (Lower limit of quantification), half the value 
of the LLOQ will be used for analysis. Differences between 2 values <LLOQ will be assigned 
values of 0. Ratios between 2 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. This rule 
does not apply to the finerenone plasma concentration data.
In case of log-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.
Urinalysis is assessed 3 times per visit. UACR will be determined 3 times at each visit from 
first morning void urine samples collected on 3 consecutive days. For the analyses of UACR, 
the 3 measurements at one visit will be combined provided that at least 2 measurements are 
available. First, the coefficient of variation (CV) will be calculated for the 3 values as follows
considering the log-normal distribution for UACR [7]:
 = 	

 −1,
where  is the standard deviation of the 3 log-transformed UACR values. If the coefficient 
of variation exceeds 25%, the median from the measurements will be used for the analyses. 
The median in case of an even number of values will be defined as the geometric mean from 
the 2 middle values. If the coefficient of variation is 25% at the most, the geometric mean will 
be used. If 2 or 3 scheduled assessments are missing or invalid and unscheduled assessments 
have been performed, then the set of unscheduled measurements closest to the planned visit
will be used to determine the UACR at the respective visit if performed within 30 days before 
or after the planned time point for all visits from Visit 3 (Month 4) onwards (with the 
following exception: only samples with 2/3 of values no later than 30 days (for “last on-
treatment” analysis) or 3 days (for “last treatment-emergent” analysis) after last study drug 
intake will be considered). For Visit 1, 2 out of 3 samples have to be on or before the day of 
randomization and have to lead to non-missing values in order for the set of samples to be 
valid for baseline calculation; otherwise (also including the case when there is one valid 
sample at Visit 1), the set of screening samples will be considered for baseline.
In the case of ESRD, the UACR and eGFR values after the onset date of ESRD will be 
excluded from all efficacy analyses, but included in the safety analyses.
For the stratification group type of albuminuria at screening (high or very high), the 
classification supplied from the central lab via IxRS will be used. The rule that has been 
applied by the central lab for this classification is, if there are 3 values, the median value 
should be taken; if 2 values, then the arithmetic mean value, regardless of degree of variation 
between the values. The lab reports from the run-in and screening visits will include the type 
of albuminuria, to assist the investigators in reducing stratification and randomization errors.


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4.5.4
Subgroup analyses
Exploratory subgroup analysis will be performed for the primary and secondary efficacy 
variables. The subgroup analyses will include the randomization stratification factors. The list 
of key subgroups (in addition to the stratification factors) and other subgroups analysed is 
specified below. Analysis will include descriptive statistics, graphical display of estimated 
treatment effects with 95%-CIs in a forest plot and a statistical test for interaction.
Stratification factors:
•
Region (North America, Latin America, Europe, Asia, Others)
•
eGFR category at screening (eGFR 25 to <45, 45 to <60 and ≥60 mL/min/1.73m2) 
•
Type of albuminuria at screening (high albuminuria, very high albuminuria) 
Persistent high albuminuria is defined as UACR of ≥30 mg/g (≥3.4 mg/mmol) but <300 mg/g 
(<33.9 mg/mmol) in 2 out of 3 first morning void samples. Persistent very high albuminuria is 
defined as UACR of ≥300 mg/g (≥33.9 mg/mmol) in 2 out of 3 first morning void samples.
Key subgroups (in addition to stratification factors)
•
History of CVD (present, absent)
•
Sex (male, female)
•
Race (white, black, Asian, other)
•
Age at run-in visit (<65, ≥65 years)
•
eGFR category at baseline (eGFR <25, 25 to <45, 45 to <60 and ≥60 mL/min/1.73m2)
•
Type of albuminuria at baseline (normalbuminuria (UACR <30 mg/g), high 
albuminuria, very high albuminuria)
•
Baseline serum potassium value (≤median and > median in the FAS)
• 
UACR at baseline (≤median and > median in the FAS)
•
Systolic blood pressure at baseline (≤median and > median in the FAS)
•
Baseline BMI (<30, ≥30 kg/m2)
•
Hemoglobin A1C (≤7.5% / > 7.5%)
•
SGLT-2 inhibitors treatment at baseline (yes, no)
•
GLP-1 agonists treatment at baseline (yes, no)
Other subgroups
•
Baseline serum potassium value (≤4.5, >4.5 mmol/L)
•
Baseline serum potassium (by quartiles in the FAS: ≤Q1, >Q1 and ≤Q2, >Q2 and 
≤Q3, >Q3) 
•
Baseline serum potassium value (< 4.8 mmol/L, ≥4.8 to 5.0 mmol/L, > 5.0 mmol/L)
•
Baseline hemoglobin A1C (by quartiles in the FAS: ≤Q1, >Q1 and ≤Q2, >Q2 and 
≤Q3, >Q3)
•
Baseline C-reactive protein (by quartiles in the FAS: ≤Q1, >Q1 and ≤Q2, >Q2 and 
≤Q3, >Q3)


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•
Systolic blood pressure at baseline (<130 mmHg, 130 to <160 mmHg, and ≥160 
mmHg)
•
Age at run-in visit (18 to 44 years, 45 to 64 years, 65 to 74 years, 75 years and over)
•
Ethnicity (hispanic or latino, not hispanic or latino, not reported)  
•
Baseline BMI (<20, 20 to <25, 25 to <30, 30 to <35, ≥35 kg/m2)
•
Baseline weight (<60, 60 to <90, ≥90 kg)
•
eGFR at baseline 25 to < 45 ml/min/1.73m² and baseline serum potassium value >4.5 
mmol/L (yes, no) 
•
ACEI at baseline (yes, no)
•
ARB at baseline (yes, no)
•
Beta-blocker at baseline (yes, no)
•
Diuretic at baseline (yes, no)
•
Statins at baseline (yes, no)
•
Other anti-diabetic treatment at baseline: insulin and analogues (yes, no); DPP-4 
inhibitors (yes, no); biguanides (yes, no); sulfonylureas (yes, no); alpha glucosidase 
inhibitors (yes, no); meglitinides (yes, no); thiazolidinediones (yes, no)
•
Potassium supplementation at baseline (yes, no)
•
Potassium lowering agents (including binders) at baseline (yes, no)
•
Potency of concomitant CYP3A4 inhibitor medication at baseline (strong, weak,
moderate, unclassified, none)
•
Potency of concomitant CYP3A4 inducer medication at baseline (strong, weak, 
moderate, unclassified, none)
•
Baseline waist circumference (normal [men <94cm, women<80cm], increased [men 
94-102cm, women 80-88cm], substantially increased [men >102cm, women >88cm])
If the result for a subgroup cannot be calculated due to a small sample size or number of 
events, then this subgroup will be dropped.
Individual country analyses, e.g. for Japan, required for regulatory purposes, will be included 
in a country-specific study SAP.
For the safety variables

Number of subjects with hospitalization for hyperkalemia

Number of subjects discontinuing study drug permanently due to hyperkalemia

Number of subjects with hospitalization for worsening of renal function

Number of subjects discontinuing study drug permanently due to worsening of 
renal function
Exploratory subgroup analyses will be performed in the following selected subgroups:

eGFR category at baseline (eGFR 25 to <45, 45 to <60 and ≥60 mL/min/1.73m2)


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
Baseline serum potassium value (≤4.5, >4.5 mmol/L)

Anti-diabetic treatment at baseline: DPP-4 inhibitors (yes, no); GLP-1 agonists 
(yes, no); SGLT-2 inhibitors (yes, no)

Potency of concomitant CYP3A4 inhibitor medication at baseline (strong, weak, 
moderate, unclassified, none)
4.6
Validity Review
The results of the validity review meetings will be documented in the validity review reports 
and may comprise decisions and details relevant for statistical evaluation. Any changes to the 
statistical analysis prompted by the results of the validity review meetings will be documented 
in an amendment and, if applicable, in a supplement to this SAP.
4.7
Testing procedure and multiplicity adjustment
If the decision will be to stop the study early for success (see section 4.4 for a description of 
the stopping rules), the final primary analyses, both for the primary and secondary efficacy 
endpoints, will be performed at a two-sided significance level of 0.270%. Only if both the 
primary and the key secondary efficacy endpoint achieve this significance level, the 
corresponding null hypotheses can be rejected and the remaining secondary endpoints will
also be tested at a two-sided level of 0.270% according to the following hierarchy:

Time to all-cause mortality 

Time to all-cause hospitalization

Change in UACR from baseline to Month 4

Time to first occurrence of the following renal composite endpoint: onset of kidney 
failure, a sustained decrease in eGFR of ≥ 57% from baseline over at least 4 weeks or 
renal death.
If the decision will be not to stop the study early for success, the final primary analyses will 
be performed as follows: 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 requires a small 
adjustment to the final analysis that is slightly lower than p = 0.05 to maintain the overall 
significance level at 5%. The weighted Bonferroni-Holm procedure will be used for the 
hierarchical testing of the primary and secondary efficacy endpoints with the following 
adjusted alpha levels, which apply for an information fraction of 2/3:
•
If the primary renal composite endpoint achieves statistical significance at a two-sided 
p value ≤ 0.03282695, the secondary CV endpoint will be tested at the two sided 
0.04967388 level.
•
Alternatively, if the secondary CV endpoint achieves statistical significance at a two 
sided p value ≤ 0.01576184, the primary renal composite endpoint will be tested at the 
two-sided 0.04967388 level.
•
Only if both the renal and CV endpoints achieve formal statistical significance, the 
remaining secondary endpoints will be tested at a two-sided level of 0.04967388
according to the hierarchy above.


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According to Tang and Geller (1999) [9] this procedure controls the overall familywise error 
rate at 5%.
If the testing strategy stops at one point due to a non-significant result, the testing of the 
remaining secondary efficacy variables will be performed in an explorative manner only.
5.
Analysis Sets
Subjects will be excluded from all below-mentioned analysis sets if they are related to critical 
GCP violations.
5.1
Safety analysis set (SAF)
All randomized subjects who have taken at least 1 dose of study drug (with the exception 
described in Section 5).
5.2
Full analysis set (FAS)
All randomized subjects (with the exception described in Section 5).
5.3
Per-protocol analysis set (PPS) 
All subjects of the FAS without any of the following validity findings:
•
The subject is younger than 18 years (the lower age limit may be higher if legally 
required in the participating country)
•
Subject without type 2 diabetes mellitus
•
Subject with no clinical diagnosis of DKD (no persistent high/very high albuminuria at 
run-in or screening visit (UACR<30mg/g (3.4 mg/mmol)).
•
Subject with clinical diagnosis of DKD and persistent high albuminuria, but eGFR < 
25 mL/min/1.73 m² or ≥75 mL/min/1.73 m² or missing at run-in or screening, or for 
patients who switched study after screening only at the screening visit
•
Subject with clinical diagnosis of DKD and persistent very high albuminuria, but 
eGFR < 25 mL/min/1.73 m² or ≥60 mL/min/1.73 m² or missing at run-in or screening 
visit, or for patients who switched study after screening only at the screening visit
•
Subject with clinical diagnosis of DKD and persistent high albuminuria, but no history 
of diabetic retinopathy in the medical history
•
UACR >5000 mg/g (565 mg/mmol) or missing at the run-in visit or screening visit
•
Dialysis for acute renal failure within 12 weeks prior to the run-in visit 
•
Subject was not treated with any ACEI or ARB starting from run-in visit
•
Participation in another clinical study or treatment with another investigational product 
30 days prior to randomization except for the run-in and screening of study 17530
•
Known significant non-diabetic renal disease, including clinically relevant renal artery 
stenosis
•
Investigational drug other than the study drug is used concomitantly or within 30 days 
from stop of study drug


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•
An ACE inhibitor and an ARB OR more than 1 ACE inhibitor OR more than 1 ARB 
were used in combination during study drug treatment for more than 30 days
•
Eplerenone, spironolactone, any renin inhibitor, or potassium sparing diuretic were 
used during study drug treatment for more than 30 days
•
Potent CYP3A4 inducers were taken for more than 30 days during study drug 
treatment
•
Wrong study medication (incorrect treatment (placebo or verum)) was dispensed to 
subject
•
The subject is not compliant (<80%)
•
The subject is not compliant (>120%)
•
Subject was randomized but never received any study medication 
•
Visit 1 was done on the same day as screening and/or run-in visit
5.4
Pharmacokinetic analysis set (PKS)
All finerenone-treated subjects (with the exception described in Section 5) with at least 1 valid 
finerenone plasma concentration and without validity findings which would interfere with the 
evaluation of the pharmacokinetic (PK) data.
5.5
Listing only set (LOS)
All other subjects enrolled who were not randomized or were excluded from FAS will be 
classified as LOS. Their data will be presented in the individual subject data listings but will 
not be included in any statistical analysis.
5.6
Assignment of analysis sets
The allocation of each subject to analysis sets will be documented before the database lock 
(conditional validity for PPS and PKS).
Final decisions regarding the assignment of subjects to analysis sets will be made during the 
validity review meetings and documented in the validity review reports.
If a subject has no signed informed consent or subject is a minor, then all data should be 
deleted from all databases and such a subject cannot be considered valid for any analysis set.
6.
Statistical Methodology
6.1
Population characteristics
Population characteristic analyses, except for subject disposition, will be performed for the 
FAS, if not stated otherwise.
6.1.1
Disposition
The number of subjects enrolled, randomized and valid for the SAF, FAS, PPS and PKS will 
be summarized overall and by treatment group, region, country and study site. The number of 
subjects 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 subjects with important deviations and validity findings will 


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be presented overall and by country 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, age group (as defined in the subgroup analysis), sex, race, 
ethnicity, region (North America, Europe, Asia, Latin America and others; see section 9.3), 
body weight, body height, BMI, hip and waist circumference, waist-hip ratio, smoking history 
(never, former, current smoker) and alcohol consumption (abstinent, light, moderate, heavy). 
Other baseline characteristics include baseline UACR, serum potassium, categories for serum 
potassium (≤4.5 mmol/L and >4.5 mmol/L), eGFR (calculated by CKD-EPI formula), serum 
creatinine, HbA1c, values for vital signs parameters (i.e. systolic blood pressure, diastolic 
blood pressure and heart rate) and additional subgroup categories as described in section 
4.5.4.
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.
The non-stratified demographic and other baseline characteristics table will be repeated for all 
other analysis sets.
As stated in section 4.2, demographics and other baseline characteristics will also be presented 
separately for subjects discontinuing the study (dropouts) and for subjects discontinuing 
treatment with study drug. 
6.1.3
Medical History
Medical history will be coded using the MedDRA dictionary. Medical history will be 
presented for each MedDRA Primary System Organ Class and Preferred Term by treatment 
group and overall in a summary table. Additional medical history terms by the following 
Project specific Bayer MedDRA Queries (PBMQs), Bayer MedDRA Labeling Groupings 
(MLGs) or selected Preferred Terms will also be presented, including the following:
•
Hyperlipidemia (MLG)
•
Hypertension (MLG)
•
Diabetic Retinopathy (Preferred Term)
•
Diabetic Neuropathy (PBMQ)
•
Atrial fibrillation/flutter (PBMQ)
•
Ischaemic Stroke/Transitory Ischemic Attack (TIA) (PBMQ)
•
Myocardial Infarction (Preferred Term)
•
Coronary Artery Disease (Preferred Term)
•
Myocardial Ischaemia and Angina pectoris (MLG)
•
Peripheral Artery Disease (Preferred Term)
•
Cardiac Failure (MLG)
•
Coronary Artery Bypass Graft (CABG) (PBMQ)


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•
Percutaneous coronary intervention (PCI) (PBMQ)
•
Carotid endarterectomy (Preferred Term)
•
Periodontal disease (Preferred Term)
The medical history tables will be repeated for SAF.
6.1.4
Prior and Concomitant Medications
Concomitant medications will be coded using the WHO Drug Dictionary (WHO-DD). The 
number of subjects who took at least one concomitant medication, the number of subjects who 
took at least one medication that started and ended before administration of study drug, the 
number of subjects who took at least one concomitant medication that started after start of 
study drug and the number of subjects who took at least one medication ongoing at baseline 
(i.e. starting before or on the day randomization and ending at least one day after the day of 
randomization) will be presented by treatment group and overall using ATC classes and 
subclasses.
The concomitant medication tables will be repeated for SAF.
The concomitant medication tables will be repeated summarizing the number of subjects with 
medications in the Standard or Bayer Drug Groupings of interest:
•
ACEIs
•
ARBs
•
Beta-blockers
•
Diuretics
•
Loop diuretics
•
Thiazide diuretics
•
Potassium-sparing diuretics
•
Potassium supplements
•
Potassium lowering agents (including binders)
•
Alpha blocking agents
•
Calcium channel blockers
•
Centrally acting antihypertensives
•
Strong CYP3A4 inhibitors
•
Moderate CYP3A4 inhibitors
•
Weak CYP3A4 inhibitors
•
Unclassified CYP3A4 inhibitors
•
Strong CYP3A4 inducers
•
Moderate CYP3A4 inducers
•
Weak CYP3A4 inducers
•
Unclassified CYP3A4 inducers


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•
Oral anticoagulants
• 
NSAIDS (excluding acetylsalicylic acid)
•
Acetylsalycylic acid and its salts
•
Statins
•
Erythropoetin stimulating agents
•
ARNIs
•
Platelet aggregation inhibitors (excluding heparin)
Anti-diabetic drugs
•
Insulin and analogues
•
Dipeptidyl Peptidase 4 inhibitors
•
Glucagon-like peptide-1 agonists
•
SGLT-2 inhibitors
•
Biguanides
•
Sulfonylureas
•
Alpha glucosidase inhibitors
•
Meglitinides 
•
Thiazolidinediones.
A subject will be counted only once within each ATC class / subclass or Bayer drug grouping, 
respectively.
A supporting listing will be provided including all medications classified as a weak, moderate 
or strong CYP3A4 inhibitors and inducers according to the protocol together with the 
respective classification information.
The percentage of patients who are on maximum labeled dose of ACEIs and ARBs (yes / no)
4 weeks before the Screening Visit, and reasons why not on maximum labeled dose will be 
presented by treatment group and overall. In addition, the percentage of patients at baseline 
above maximum, at maximum, between minimum and maximum, at minimum and below 
minimum labeled dose, using the dose ranges in Table 8-1 of the protocol, will be presented 
by treatment group and overall.
For potassium lowering agents, ACEIs, ARBs and diuretics, shift tables for changes of use for 
baseline vs. any time post-baseline will be provided.
6.1.5
Treatment duration, extent of exposure and compliance
The analyses described in this section will be repeated for the SAF and PPS if they differ in 
sample size from the FAS. 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. In 
addition, treatment duration will be categorized to ≤1 month, 1 - 4 months, then 4 monthly 


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intervals, and presented with the corresponding number and percentage of subjects. 
Cumulative treatment duration will be categorized to at least one dose, at least 1 month, at 
least 4 months, then further 4 monthly intervals. Cumulative treatment exposure over the 
study in person-years will be given. A table will be presented with the absolute and relative 
frequencies of subjects still on study medication at each visit. Kaplan-Meier plots for “Time 
to end of study treatment” will be provided by treatment group, as also described in section 
4.2.
The above analyses will be repeated for study duration, from the day of randomization to the 
End of Study 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, also by eGFR category at screening.
The overall titration status, regardless of actual or sham up-titration, will be summarized with 
absolute and relative frequencies per treatment group, differentiated by patients starting on 
10 mg or 20 mg:

For subject starting on 10 mg: never up-titrated, up-titrated once, and up-titrated more 
than once.

For subjects starting on 20 mg: never down-titrated, down-titrated once, and down-
titrated more than once.
Furthermore, the dose status will be summarized with absolute and relative frequencies per 
treatment group for each visit with regard to the question “Was 20 mg study drug dispensed at 
visit?” and the reason why 20 mg was not dispensed. The number of subjects not dispensed 
with 20 mg as well as associated reason will also be presented overall, i.e. on the patient level.
In addition, the number of patients with study drug down-titrated to 10 mg or temporarily 
interrupted (dose recorded as 0 mg) as well as associated reason will be summarized with 
absolute and relative frequencies per treatment group.
The compliance (as percentage) will be calculated as follows:
100 * Number of taken tablets / Number of planned tablets
The number of planned tablets is calculated as follows:
(Days from randomization to last intake of study drug + 1) * Number of planned tablets per 
day.
All tablets, including the dummy placebo tablets, will be counted. For subjects who withdraw 
prematurely from the study drug, compliance will be calculated up to the time of last dose.
The compliance will be summarized descriptively by treatment group and overall. In addition, 
percent of compliance will be categorized into 3 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
6.2.1.1
Primary efficacy variable: primary analysis
The primary efficacy variable is the time to first occurrence of the composite endpoint of 
onset of kidney failure, a sustained decrease of eGFR ≥ 40% from baseline over at least 4 
weeks, or renal death. All events classifying for the primary endpoint have to be adjudicated 
positively by an independent adjudication committee.
The primary analysis of the primary efficacy variable will be performed in the FAS.
Events for inclusion in the primary analysis 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, 
renal events will be counted up to the day of the last visit when complete information on all 
components of the composite renal endpoint is available with an additional rule for events 
occurring after this visit. To account for events of kidney failure or renal death after the last 
eGFR is recorded at a clinic visit, such events will be included in the efficacy analysis if they 
occur in the period up to one day before the next planned clinic visit. This period would be a 
maximum of 5 months, given the next scheduled clinic visit should take place 4 months later, 
plus a time window for late attendance of one month. In addition, should the subject have a 
non-renal death in this period then the date of death will be used as the censoring date. 
Randomized subjects without an event of the renal composite 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 non-renal death using a time window of 5 months as above if a 
subsequent clinic visit had been planned. Subjects without any information about the primary 
composite endpoint after baseline will be censored at Day 1.
The weighted Bonferroni-Holm procedure which will be used for the hierarchical testing of 
the primary and secondary efficacy endpoints, is described in section 4.7. In order to evaluate 
whether finerenone is superior to placebo in prolonging the time to the first event of the 
primary composite endpoint, the following null hypothesis will be tested using the logrank 
test at the two-sided significance level given above:
H0: λfinerenone,k(t) = λplacebo,k(t) for all time points t ≥ 0 and each stratum 
The alternative hypothesis will be:
H1: λfinerenone,k(t) ≠λplacebo,k(t) for at least one time point t ≥ 0 and at least one stratum ,
where λfinerenone,k denotes the hazard rate of the finerenone treatment group in stratum  and 
λplacebo,k denotes the hazard rate of the placebo treatment group in stratum . In this context, 
the hazard rate is defined as the instantaneous risk of a primary composite event at a given 
time point provided that no such event has yet taken place. The test statistic of the stratified 
logrank test compares the observed number of events with the number of events expected 
under the null hypothesis H0 in each treatment group per stratum.  
The following decision rule to test the null hypothesis will be applied. According to the size 
of this study and the expected number of events, it is justified to assume under H0 a 
sufficiently close approximation of the logrank test (see reference 4) to the normal 


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distribution. If the logrank test statistic (i.e. the standardized difference of the observed 
number of events and expected number of events stratified by the stratification factors region, 
type of albuminuria and eGFR category) is larger than the critical quantile from the normal 
distribution, the null hypothesis will be rejected in favor of the alternative hypothesis.
The nominal significance levels and the critical values at the final analysis will be adjusted to 
account for the interim analysis, see section 4.7 for more details.
In order to provide a point estimate of the hazard ratio and a corresponding two-sided 95%
confidence interval, a stratified Cox proportional hazard regression model will be used. The 
stratification variables will be included in the STRATA statement in SAS PROC PHREG, 
which will assume proportional hazards for each level of one particular stratification factor.
Kaplan Meier curves will be provided for the cumulative incidence risk of outcome events by 
treatment groups.
To derive the logrank test statistic and the corresponding p-value, SAS program code 
corresponding to the following will be used:
PROC LIFETEST DATA = <dataset> ALPHA=0.05 METHOD=KM;
  TIME ttevalue * ttecnsr(1);
  STRATA {stratumn} / GROUP=trtgrpn  TEST=(logrank);
RUN;
/*
where
dataset  = name of sub-dataset including all ITT subjects 
randomized 
trtgrpn  = variable coding randomized treatment group
ttevalue = time to first occurrence of primary efficacy 
outcome event
ttecnsr  = censoring index (1 = right-censored, 0 = event)
stratumn = variables for stratification factors 
*/
For the Cox proportional hazard regression SAS program code corresponding to the following 
will be used:
PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(1) = trtgrpn / RL TIES=EFRON 
ALPHA=0.05;
  STRATA {stratumn};
RUN;
6.2.1.2
Primary efficacy variable: supportive analysis
The primary analysis of the primary efficacy variable will be repeated in the PPS as a 
supportive analysis. For the PPS analysis, the censoring rules for the primary analysis 


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specified in Section 6.2.1.1 will be further restricted to events occurring up to 30 days after
last study drug intake.
Accordingly, subjects with censoring or event date more than 30 days after last study drug 
intake in the primary analysis will be censored at the date of last study drug intake +30 days.
The following supportive analyses of the primary efficacy variable will be performed in the 
FAS and PPS unless specified otherwise.
The originally planned presentation of absolute and relative frequency of subjects with an 
event of the primary composite endpoint will be superseeded by the Kaplan-Meier estimates 
described below.
Kaplan-Meier estimates of the time to the first event of the primary composite endpoint 
(including 95% confidence interval, calculated based on a normal approximation and using 
the Greenwood formula for the standard deviation [4]), overall survival rates at appropriate 
time points and Kaplan-Meier curves will be presented for each treatment group. In this 
context, “survival” means no event of the respective primary efficacy endpoint. These 
analyses will be presented in total and for each level of the stratification factors.
For the primary composite endpoint and the individual events, the incidence rate per 100 
patient-years will be presented by treatment group, which is defined as the number of subjects 
with an event divided by the time a patient is at risk for the respective event, i.e. either the 
time from randomization until the first event or the censoring time, multiplied by 365.25*100. 
Kaplan-Meier plots, logrank tests and Cox proportional hazards regression for the time to first 
event of the individual components will also be provided as part of exploratory efficacy (see 
section 6.2.3).
An ‘on-treatment’ analysis will also be performed, repeating the inferential statistics 
(stratified logrank test and stratified Cox regression model) on the FAS. For the on-treatment 
analysis, as described for the PPS analysis above, the censoring rules for the primary analysis 
will be adapted by further restricting to events occurring up to 30 days after last study drug 
intake.
The logrank test as well as the Cox regression model will also be performed without including 
stratification factors. The plausibility of the proportional hazards assumption will be assessed 
by visually examining the plot of the log of the negative log of Kaplan-Meier estimates of the 
survival function versus log time for evidence of non-parallelism, and by including a 
treatment by log-transformed time interaction into the Cox model. For the latter, the SAS code 
is adapted as follows:
PROC PHREG DATA = <dataset>;
  MODEL ttevalue * ttecnsr(1) = trtgrpn trtltime / RL 
TIES=EFRON ALPHA=0.05;
  STRATA {stratum};
  trtltime = trtgrpn*log(ttevalue);
RUN;
The significance of the interaction will be tested at the 5% type I error level. If the interaction 
is significant and there is strong evidence of non-proportionality from the plots, time-
dependent hazard ratios will be estimated with the model that includes the interaction term.


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The censoring mechanism of subjects without an event of the primary composite endpoint at 
the time of analysis is assumed to be non-informative for the primary efficacy analysis. This 
also implies that the primary analysis is valid under a missing at random (MAR) assumption. 
Sensitivity analyses will be performed, assessing the impact of a potential informative 
censoring of subjects lost to follow-up or with withdrawn consent. Non-renal deaths will be 
treated as censored observations as in the primary analysis.
A summary of the amount of missing data by treatment arm will be given, including number 
of subjects who have incomplete follow-up on the respective endpoint.
Robustness with respect to missing data will be investigated with a tipping point analysis on 
the FAS (based on the ITT approach). The analysis will:
•
Estimate the hazard at time of loss to follow-up, using a Weibull survival model fitted 
to the population of subjects who prematurely discontinued study treatment and
adjusted for treatment group and stratification factors.
•
Inflate the hazard only in the finerenone group by a known factor; assumes non-
informative censoring in the control group.
•
Impute events to the end of the study 1000 times, calculate the hazard ratios with the 
stratified Cox model specified in section 6.2.1.1 and combine them using standard 
multiple imputation combining rules.
•
Increase the inflation factor until upper limit of two-sided confidence interval for the 
hazard ratio crosses 1.0; this will be the “tipping point”. The actual confidence level of 
the above mentioned confidence interval will depend on whether the study is stopped 
for overwhelming efficacy at the interim analysis or not, and on the p-value of the 
primary analysis of the key secondary endpoint. The confidence intervals will be as 
follows:
•
At the interim analysis: Use two-sided 99.73% confidence interval
•
At the final analysis: 
o
p-value of primary analysis of key secondary endpoint < 0.01576184: 
Use two-sided 95.032612% confidence interval
o
p-value of primary analysis of key secondary endpoint ≥0.01576184: 
Use two-sided 96.717305% confidence interval
The tipping point will show how much higher the event risk after drop-out would need to be 
in the finerenone group so that statistical significance is lost. Since there is no particular 
reason to assume that the event rate should be higher, a large tipping point will indicate 
robustness of the study results. Technical details of the model are provided in section 9.1.
6.2.2
Analysis of secondary efficacy variables
6.2.2.1
Secondary efficacy variables: primary analysis
Secondary efficacy variables are as follows:
•
Time to first occurrence of the following CV composite endpoint: cardiovascular (CV) 
death or non-fatal CV events (i.e. myocardial infarction, stroke, or hospitalization for 
HF)
•
Time to all-cause mortality 


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•
Time to all-cause hospitalization
•
Change in UACR from baseline to Month 4 
•
Time to first occurrence of the following renal composite endpoint: onset of kidney 
failure, a sustained decrease in eGFR of ≥ 57% from baseline over at least 4 weeks or 
renal death.
The primary analysis of the secondary efficacy variables will be conducted in the FAS.
See section 4.7 for the testing hierarchy for secondary endpoints and for multiplicity 
adjustment of significance levels.
The primary analysis of the secondary time-to-event endpoints will be conducted analogously 
to the primary analysis of the primary composite endpoint, with modifications to the 
censoring rules as the events will differ. In the event of premature termination from the study 
with no subsequent follow-up information, subjects without any information about the 
composite endpoint after baseline will be censored at Day 1, and the following censoring rules 
will also apply:
•
CV events will be counted up to the day of withdrawal from the study or non-CV 
death. Randomized subjects without an event of the CV composite endpoint at the 
time of analysis will be censored at the date of their last contact up to and including 
the EOS visit or date of non-CV death.
•
Hospitalization events will be counted up to the day of withdrawal from the study or 
death. Randomized subjects without a hospitalization event at the time of analysis will 
be censored at the date of their last contact up to and including the EOS visit or date of 
death.
•
All-cause mortality will be counted up to the last date vital status could be obtained.  
Randomized subjects without such an event at the time of analysis will be censored at 
the last date vital status could be obtained up to and including the EOS visit. 
An ANCOVA model will be fitted to the logarithmized ratios of UACR at Month 4 to UACR 
at baseline including the factors treatment group, the stratification factors region, type of 
albuminuria and eGFR category and the logarithmized baseline UACR as covariate.  
Corresponding two-sided 95% confidence intervals will be computed. As the baseline UACR 
defines the type of albuminuria, the log-transformed baseline UACR will be nested as 
covariate in type of albuminuria.
6.2.2.2
Secondary efficacy variables: supportive analysis
The primary analysis of the secondary efficacy time-to-event endpoints will be repeated in the 
PPS as a supportive analysis. For the PPS analysis, the censoring rules for the secondary 
analysis specified in Section 6.2.2.1 will be further restricted to events occurring up to 30 days 
after last study drug intake.
Accordingly, subjects with censoring or event date more than 30 days after last study drug 
intake in the primary analysis will be censored at the date of last study drug intake +30 days.
The supportive analyses of the secondary time-to-event endpoints will correspond to those 
done for the primary composite endpoint in the FAS and PPS (see section 6.2.1.2), except for 
the ‘on-treatment’ and tipping point analysis which will only be performed for the key 
secondary endpoint based on the FAS.


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UACR at Month 4 in the PPS will be analyzed using an ANCOVA as described above. In 
addition, the following sensitivity analyses accounting for missing data at Month 4 will be 
conducted:
•
On-treatment LOCF approach, only including data up to 30 days after stop of study 
medication (FAS and PPS).
•
Baseline observation carried forward analysis (BOCF), imputing the baseline value for 
missing data and thus including all subjects with missing Month 4 data with a value of 
1 for the ratio of UACR baseline to Month 4 (FAS).
•
Multiple imputation analysis (FAS): For reproducibility, the SAS seed number for 
creating the random numbers will be set to the study (16244). Further details are given 
in section 9.2.
For all PPS analyses of UACR at month 4, only data up to 30 days after stop of treatment will 
be considered, all other data will be set to missing before employing the above-mentioned 
imputation techniques. 
6.2.3
Analysis of other exploratory efficacy variables
Other exploratory efficacy variables will be as follows:
•
Time to onset of kidney failure
•
Time to onset of ESRD
•
Time to onset of eGFR decrease to less than 15 mL/min/1.73 m² sustained over at least 
4 weeks
•
Time to onset of eGFR decrease of ≥ 40 % sustained over at least 4 weeks
•
Time to onset of eGFR decrease of ≥ 57% sustained over at least 4 weeks
•
Time to CV death
•
Time to non-CV, non-renal death
•
Time to first CV hospitalization (either hospitalization for HF, other cardiovascular 
hospitalization or adjudicated CV event associated with hospitalization)
-
Causes for other cardiovascular hospitalizations include unstable angina,
arrhythmia, and peripheral arterial disease.
-
CV events associated with hospitalization include (if not already considered as 
“other cardiovascular hospitalization”) CV death, new onset of atrial 
fibrillation/flutter, non-fatal myocardial infarction, non-fatal stroke and transient 
ischemic attack.
•
Time to first hospitalization for HF
•
Time to first non-fatal stroke
•
Time to first non-fatal myocardial infarction
•
Time to first occurrence of the composite endpoint of CV death, non-fatal stroke or 
non-fatal myocardial infarction
•
Time to first occurrence of the composite endpoint of CV death or hospitalization for 
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•
Time to first occurrence of the composite endpoint of CV death, kidney failure, eGFR 
decrease of ≥ 57% sustained over at least 4 weeks or renal death
•
Number of subjects with new diagnosis of atrial fibrillation or atrial flutter
•
Number of subjects with new diagnosis of HF
•
Change in UACR from baseline
•
Change in eGFR from baseline
•
Regression from very high to high albuminuria and high albuminuria to 
normalbuminuria accompanied by a decrease in UACR of at least 30% from baseline
•
Number of subjects with UACR decrease of at least 30% from baseline at any time 
post-baseline
•
Number of subjects with UACR decrease of at least 50% from baseline at any time 
post-baseline
•
Change in QoL summary scores measured by the following health-related quality of 
life (HRQoL) questionnaires: Kidney Disease Quality of Life (KDQOL 36) and
EuroQol Group 5 dimension, 5 level questionnaire (EQ 5D 5L)
All these other efficacy variables will be analyzed in FAS and PPS (as applicable) in an 
explorative manner. For all PPS analyses, only data points and events up to 30 days after stop 
of study drug will be considered.
6.2.3.1
Components of primary and secondary composite endpoints
Consistent with the methods for the primary and secondary efficacy variables, components or 
composites of the components of the primary and secondary time-to-event endpoints (as
included in the list of other exploratory efficacy variables above) will be analyzed as 
exploratory time-to-event variables using the stratified logrank test stratified by the 
stratification factors. A point estimate of the hazard ratio and a corresponding two-sided 95% 
confidence interval will be calculated using a stratified Cox proportional hazard regression 
model. Kaplan Meier curves will be provided for the cumulative proportions of events by 
treatment groups.
6.2.3.2
UACR and albuminuria
UACR during the study will be summarized descriptively by treatment group and visit 
including ratios to baseline. These analyses will be performed overall and separated by the 
stratification factors (region, type of albuminuria at screening and eGFR category at 
screening).
The log-transformed ratio of UACR to baseline at each visit up to the last visit with a 
reasonable number of subjects with UACR measurements will be analyzed by a mixed model 
repeated measures (MMRM) with the factors treatment group, visit, treatment-by-visit 
interaction, factors for the stratification levels, log-transformed baseline value as covariate 
nested within type of albuminuria and log-transformed baseline value by visit interaction. 
Pairwise ratios between the finerenone and the placebo treatment group will be calculated and 
corresponding two-sided 95% confidence intervals will be computed.
An on-treatment analysis including measurements restricted to up to 30 days after last intake 
of study drug will be performed using the same model as above.The SAS procedure PROC 


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MIXED will be used estimating covariance patterns within subjects to adjust for the within 
subject variance. For each treatment group a separate covariance pattern will be estimated 
based on an unstructured covariance. In case of convergency issues, an alternative covariance 
matrix will be used, with Toeplitz matrix as first choice alternative.
Frequency tables will be generated for the number of subjects with a relative decrease and 
increase in UACR of ≥30%, ≥40% and ≥50% from baseline UACR. The analysis will be 
performed for each visit and for any time post baseline. The analysis will also be performed 
stratified for each level of the stratification factors.
A shift table will be provided displaying the number of subjects who changed from baseline to 
each visit from very high albuminuria to high albuminuria, from very high albuminuria to 
normalbuminuria (UACR <30mg/g), from high albuminuria to normalbuminuria (UACR 
<30mg/g), from high albuminuria to very high albuminuria and from normalbuminuria
(UACR <30mg/g) to high and very high albuminuria by treatment group and overall. The 
albuminuria category changes will only be considered as shifts if they are accompanied by a 
UACR decrease or increase of at least 30% from baseline to each visit.
The additional categorical UACR efficacy variables will be summarized for presence or 
absence of the event using logistic regression with the factors treatment group and 
stratification levels. Pairwise differences between the finerenone and the placebo treatment 
group will be calculated and corresponding two-sided 95% confidence intervals will be 
computed.
6.2.3.3
Decrease in eGFR
eGFR will be summarized descriptively by treatment group and visit including absolute and 
relative changes to baseline. These analyses will be performed overall and separated by the 
stratification factors.
The absolute change of eGFR to baseline at each visit until the last visit with a reasonable 
number of subjects with eGFR measurements will be analyzed by a mixed model with the 
factors treatment group, visit, treatment-by-visit interaction, factors for the stratification 
levels, baseline value as covariate (nested within eGFR category) and baseline by visit 
interaction. Pairwise differences between the finerenone and the placebo treatment group will 
be calculated and corresponding two-sided 95% confidence intervals will be computed.
An on-treatment analysis including measurements restricted to up to 30 days after last intake 
of study drug will be performed using the same model as above.
The SAS Procedure PROC MIXED will be used estimating covariance patterns within 
subjects to adjust for the within subject variance. For each treatment group a separate 
covariance pattern will be estimated based on an unstructured covariance.
Frequency tables will be generated for the number of subjects with a relative decrease in 
eGFR of ≥30, ≥40%, ≥50% and ≥57% from baseline eGFR. The analysis will be performed 
for each visit and for any time post baseline.
For each patient with 1 or more post-baseline eGFR measurements, the annualized change in 
eGFR will be calculated by fitting the patient’s eGFR assessments into a linear regression 
model with time in years as the independent variable. The derived annualized change will be 
analyzed using an ANCOVA model including baseline, treatment group and stratification 
factors as fixed-effects.


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The following additional analysis of acute and chronic eGFR slopes will be performed.
•
Change in eGFR from baseline (Visit 1) to the PD or EOS Visit
•
Acute eGFR changes from baseline to Month 4
•
Change in eGFR from Month 4 to the PD or EOS Visit
•
Correlation analyses between short term eGFR changes between baseline and Month 4 
after randomization, and long term eGFR decline (chronic slope).
An ANCOVA model will be fitted to the eGFR efficacy variables including the factors 
treatment group, the stratification factors and the baseline eGFR as covariate. Corresponding 
two-sided 95% confidence intervals will be computed. In addition, correlation analyses 
between short term eGFR changes between baseline and Month 4 after randomization, and 
long term eGFR decline (chronic slope) will be performed.
6.2.3.4
Health-related quality of life
The KDQOL-36 will be used. The items of the KDQOL 36 are grouped as follows:
•
Items 1-12: Physical Component Summary (PCS) / SF-12 physical health composite 
on physical functioning, role-physical, bodily pain, general health, vitality, social 
functioning, role-emotional, mental health 
•
Items 1-12: Mental Component Summary (MCS) / SF-12 mental health composite on 
physical functioning, role-physical, bodily pain, general health, vitality, social 
functioning, role-emotional, mental health (including a different weighting than the 
PCS)
•
Items 13-16: Burden of Kidney Disease; interference with daily life, time to deal with 
kidney disease, frustration, feeling like a burden
•
Items 17-27: Symptoms / Problems; general health, activity limits, ability to 
accomplish desired tasks, depression/anxiety, energy level, social activities (item 28 
concerning dialysis will be only collected in patients on dialysis)
•
Items 29-36: Effects of Kidney Disease; impact of fluid & diet limits, ability to work 
around the house and to travel, feeling depending on medical team, stress or worries, 
sex life, personal appearance
Domain scores for each of the 5 domains (Physical Component Summary, Mental Component 
Summary, Burden of Kidney Disease, Symptoms / Problems, and Effects of Kidney Disease) 
will be calculated according to the KDQOL scoring instruction (see reference 1). The 
KDQOL-36 domain scores will be presented by visit and treatment group by means of 
number of observations, number of missing values, minimum, first quartile, mean, SD, 
median, third quartile, and maximum, including the changes from baseline. In addition to the 
analysis of the KDQOL-36 for the overall population, this will be repeated for patients with or 
without ESRD and/or dialysis at any point during the study.
The absolute change of the PRO to baseline at each visit up to the last visit with a reasonable 
number of subjects with PRO measurementswill be analyzed by a mixed model with the 
factors treatment group, visit, treatment by visit interaction, factors for the stratification levels, 
baseline value as covariate and baseline by visit interaction. Pairwise differences between the 
finerenone and the placebo treatment group will be calculated and corresponding two-sided 
95% confidence intervals will be computed.


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The SAS Procedure PROC MIXED will be used estimating covariance patterns within 
subjects to adjust for the within subject variance. For each treatment group a separate 
covariance pattern will be estimated based on an unstructured covariance.
For the EQ-5D, summary scores will be calculated out of the 5 dimensions according to the 
scoring instructions from Europe (UK as a representative country within Europe) and the US 
(see reference 2) and to the EQ-5D Value Sets (see reference 3). The values and the changes 
from baseline of the summary scores and the EQ Visual Analogue scale (VAS) will be 
summarized by treatment group and visit using the same descriptive statistics as for KDQOL.
The EQ 5D 5L will be analyzed similarly to the KDQOL-36.
6.2.3.5
New diagnosis of atrial fibrillation, new diagnosis of heart failure and 
regression of albuminuria
These other exploratory efficacy variables will be summarized for presence or absence of the 
event using logistic regression with the factors treatment group and stratification levels (type 
of albuminuria, region and eGFR category). Pairwise differences between the finerenone and 
the placebo treatment group will be calculated and corresponding two-sided 95% confidence 
intervals will be computed.
6.2.3.6
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 adverse events. No statistical testing of these events will be 
performed, as the adjudicated outcome events are components of the primary, secondary and 
exploratory efficacy variables.
An overall summary of all outcome events will be generated by treatment group.
The number of subjects 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, outcome events by maximum intensity 
and outcome events by worst outcome will be summarized by treatment group using 
MedDRA terms grouped by Primary System Organ Class and Preferred Term.
The incidence rate of outcome events per 100 patient-years will also be provided by treatment 
group using MedDRA terms grouped by Primary System Organ Class and Preferred Term. 
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 subject in case no such event is 
recorded.
Outcome events will be listed separately in the section 14.2 tables.
6.3
Pharmacokinetics/pharmacodynamics
6.3.1
Pharmacokinetics
The plasma concentration versus time data of Visit 3 (Month 4) and at subsequent yearly
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).


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Evaluation of the concentration data will be performed using Population PK methods, 
followed by PK/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
Not applicable.
6.4
Safety
All analyses on safety and tolerability data will be performed in the SAF.
6.4.1
Adverse events
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, latest version available prior to data base freeze). A listing will be provided 
linking the original investigator terms and the coded terms. AEs will also be presented 
grouped by SMQs.
AEs that started or worsened after the first dose of study drug up to 3 days after any 
temporary or permanent interruption of study drug will be considered as treatment-emergent 
AEs (TEAEs).
An overall summary of all AEs and TEAEs will be generated by treatment group.
The number of subjects with TEAEs, pre-randomization AEs, post-treatment AEs occurring 
more than 3 days after any temporary or permanent stop of study drug, treatment-emergent 
SAEs, treatment-emergent study drug-related AEs, treatment-emergent study drug-related 
SAEs, treatment-emergent SAEs and TEAEs causing permanent discontinuation of study 
drug, treatment-emergent non-serious AEs, non-serious AEs, TEAEs by maximum intensity, 
treatment-emergent SAEs by maximum intensity, drug-related TEAEs by maximum intensity, 
TEAEs by worst outcome and treatment-emergent SAEs by worst outcome will be 
summarized by treatment group using MedDRA terms grouped by Primary System Organ 
Class and Preferred Term.
To comply with local regulatory requirements in Japan, some cardiovascular disease-related 
outcome events will also be documented as (S)AEs in Japan. These will be included in the 
outcome event tables (see section 6.2.3.6), and to avoid double-counting of such events, they 
will not be included in the adverse event summary tables or listings. A separate listing will be 
generated for all AEs excluded from the AE analysis due to double reporting in Japan.
In case of events with different intensity within a subject, the maximum reported intensity will
be used. If intensity is missing, the event will be considered as severe. If the same event is 
considered as both unrelated and related to the study drug within a subject, the event will be 
reported as related to study drug. If the drug relationship is missing, the event will be 
considered as being related to the study drug.
These further safety variables are listed in section 10.3.4 of the protocol:
•
Number of subjects with hospitalization for hyperkalemia
•
Number of subjects discontinuing study drug permanently due to hyperkalemia
•
Number of subjects with hospitalization for worsening of renal function


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•
Number of subjects discontinuing study drug permanently due to worsening of renal 
function
These will be summarized by treatment group using frequency counts. For the number of 
subjects with these events, the summary will be provided once for all events and once for all 
treatment-emergent events.
Separate tables summarizing TEAEs, study drug-related TEAEs, and SAEs that occurred in 
more than 5% of the subjects will be provided.
Deaths, SAEs and AEs leading to permanent study drug discontinuation will be listed 
separately.
6.4.2
Laboratory parameters
The number of subjects with treatment-emergent (until 3 days after any temporary or 
permanent interruption 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, HbA1c, clinical chemistry 
and urinalysis. Geometric statistics and ratios to baseline will be presented for creatinine and 
UACR 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.
The following special safety parameters will be further assessed by displaying the number of 
subjects with treatment-emergent safety events. This will also be performed by visit and by 
stratification factors. The summaries will be performed for the number of subjects with:
•
Absolute value of serum potassium >5.5 mmol/L and >6.0 mmol/L,
•
Relative decrease from baseline in eGFR of ≥30%, ≥40%, ≥50% and ≥57%
•
Absolute value of eGFR <30 mL/min/1.73m².
The percentage of subjects with the respective treatment-emergent events (non-stratified) will 
be compared between the finerenone and the placebo or active control group by applying 
separate explorative χ² tests with continuity correction. If the expected number of subjects in 
at least 1 cell of the 2x2 contingency table is less than 5 (see reference 5), Fisher’s exact test 
will be applied instead of the χ 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, due to the computational burden of exact unconditional confidence limits, Wald 
asymptotic confidence limits will be calculated.
6.4.3
Vital Signs
The analysis of vital signs includes blood pressure and pulse measurements. Averages of non-
missing values will be calculated and used for the statistical analysis. If only 1 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. The analysis will be repeated for SBP stratified by 


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baseline SBP <130 mmHg, 130 to <160 mmHg and ≥160 mmHg and SBP above and below 
median.
6.4.4
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.
7.
Document history and changes in the planned statistical analysis
SAP version 0.1 dated 14 DEC 2015 submitted for internal review
SAP version 0.2 dated 29 JAN 2016 submitted to the FDA
SAP version 0.3 dated 08 JUL 2016 submitted for internal review
Approved SAP version 1.0 dated 03 AUG 2016
Approved SAP version 2.0 dated 07 JUN 2019
Approved SAP version 3.0 dated 12 SEP 2019
Approved SAP version 4.0 dated 14 FEB 2020
7.1
Overview of Changes to SAP – from version 1.0 to version 2.0
Editorial, administrative, and typographical corrections were made that do not affect the 
content of the overall integrated SAP. These changes are not described in this section.
The SAP, Version 1.0, dated 03 AUG 2016, was amended with the changes resulting from 
global CSP amendments, the latest being global amendment 4, forming integrated CSP 
Version 3.0, dated 26 FEB 2019. SAP modifications resulting from the integrated CSP 
Version 3.0 are primarily:

administrative, typographical and consistency-related corrections,

definition of treatment-emergent adverse events and laboratory parameters to also 
consider temporary interruptions of study drug as well as modification of special 
safety variables for hyperkalemia and worsening of renal function to only consider 
permanent discontinuations of study drug, and

replacement of the date of first intake of study drug with the randomization date as the 
baseline date for all analyses (except those explicitly requiring start of study drug 
intake as a reference).
In addition, the following changes were introduced in SAP Version 2.0, dated 07 June 2019.
Modification 1: Update on sample size 
Rationale: Due to the lower-than-expected event rate, the sample size of the study was 
increased by approximately 1000 subjects. As this has no impact on the original planning 
assumptions, the protocol text remained unchanged, but for descriptive purposes the expected 
sample size was added in the SAP
Sections affected:

Section 3:Study Design


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Modification 2: Exclusion from analysis sets due to critical GCP violations
Rationale: After detection of issues with investigator fraud and duplicate subjects, it was 
decided and agreed with the FDA to exclude the affected subject records from all analysis sets 
(except for the listings only set) as this data could not have been trusted.
Sections affected:

Section 3: Study Design

Section 5: Analysis Sets
Modification 3: Types of events used for efficacy analyses
Rationale: It was clarified that only events adjudicated by an independent adjudication
committee will be used for all efficacy analyses (except for those explicitly mentioning 
investigator-reported events).
Sections affected:

Section 4.1: General Principles

Section 6.2.1.1 Primary efficacy variable: primary analysis
Modification 4: Stratification groups
Rationale: It was clarified that if the corrected stratification group (due to incorrect allocation 
at randomization) does not exist in the study, the stratification group the investigator 
originally specified in the IxRS will be kept. This is in line with the randomization and 
ensures that no strata with few patients are opened up which would result in potential non-
convergence of the stratified Cox model, for example.
Sections affected:

Section 4.1: General Principles
Modification 5: Handling of missing data for study drug exposure, clinical events, UACR at 
Month 4 and adverse events
Rationale: Texts were added to describe the handling of missing data for study drug exposure 
(conservative approach maximizing time on higher dose, but avoiding overlaps) and for 
clinical events (elaboration on median imputation rule). The handling of missing start dates 
for adverse events was simplified and aligned with the definition of treatment-emergence (see 
change related to Integrated CSP Version 3.0 above). For the analysis of UACR at Month 4, it 
was clarified that the closest set of measurements in the timeframe of Month 4, i.e. on days 
120 (+/-30days), is used, regardless of whether it is labeled as the month 4 visit to also 
consider unscheduled visits or other visits in case these should be closer to the relevant date.
Sections affected:

Section 4.3: Handling of Missing Data


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Modification 6: Primary analysis when stopping at the interim analysis
Rationale: The significance level which would remain for the final analysis after conducting 
the interim analysis was made more precise and specified as 4.967388%. Furthermore, it was 
clarified that in case of stopping at the interim analysis, the primary analysis reported in the 
CSR will take all events up to the subjects’ respective EoS visits into account as would be the 
case for the final analysis if the study does not stop prematurely.
Sections affected:

Section 4.4 Interim Analysis and Data Monitoring
Modification 7: Derivation of the coefficient of variation, window for on-treatment/PPS 
analysis and baseline flag for UACR 
Rationale: The formula for the coefficient of variation was added. The time window to 
consider unscheduled measurements in case a scheduled measurement is missing at a given 
visit for an efficacy analysis and to consider for the on-treatment analysis was set to 30 days 
in line with the time window for the on-treatment analysis/PPS analysis for clinical events. 
The 30 days window also applies to investigator-reported clinical events. However, a 3 days 
window is still used for any safety analyses of UACR. In addition, the derivation of baseline 
UACR was clarified to require a set of two non-missing values on or before day of 
randomization; otherwise the screening set of UACR measurements would be used. 
Sections affected:

Section 4.5.3 Other data handling

Section 6.2.3.6 Outcome events reported by the investigators
Modification 8: eGFR and UACR values after onset of ESRD for efficacy analyses
Rationale: It was clarified that UACR and eGFR values after onset of ESRD would be 
excluded from all efficacy analyses because they would be strongly related to the event of 
ESRD and thus would not be meaningful in themselves.
Sections affected:

Section 4.5.3 Other data handling
Modification 9: Addition of subgroup factors and analyses for medical history and 
concomitant medications 
Rationale: Additional subgroup factors (UACR at baseline below and above median and 
potency of concomitant CYP3A4 inducer medication) were added for reasons of 
completeness. A new analysis was added for concomitant medications ongoing at baseline, 
i.e., at randomization, which was not adequately captured before as the other analyses for 
concomitant medication are in relation to the dates of first intake of study drug, and which is 
also relevant considering that there are several subgroup factors for concomitant medications 


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at baseline. Furthermore, analyses for concomitant medications and medical history will also 
be repeated on the SAF because it is certain that the SAF will differ from the FAS.
Sections affected:

Section 4.5.4: Subgroup Analyses

Section 6.1.3: Medical History

Section 6.1.4: Prior and Concomitant Medications
Modification 10: Titration status
Rationale: The analyses for titration related to different questions on the eCRF were 
restructured and split up into three different analyses/tables for easier interpretability. 
Sections affected:

Section 6.1.5 Treatment duration, extent of exposure and compliance
Modification 11: Description of primary analyses for the primary and secondary efficacy 
time-to-event variables
Rationale: The description of the hypotheses was made more accurate by adequately taking 
into account the stratification factors. At the same time, survival rates were exchanged with 
hazard rates to create an obvious link from the hypothesis to the hazard ratio which is given as 
the primary output of the Cox model. However, this exchange has no impact on the content, 
as survival rates and hazard rates can be translated into each other and the hypotheses of 
equality of survival rates and of equality of the hazard rates (per stratum) are thus equivalent. 
Furthermore, the SAS code for the Cox model was corrected to the stratified Cox model 
specified in the text (by means of adding the stratification factors to the STRATA statement). 
Sections affected:

Section 6.2.1.1: Primary efficacy variable: primary analysis
Modification 12: Modifications and additions to the sensitivity analyses for the primary and 
secondary efficacy variables
Rationale: The analysis of number of (recurrent) events per 100 patient-years was replaced by 
an analysis of incidence rate, no longer considering recurrent events because this is not 
meaningful for the clinical events in this study as most of them usually do not happen more 
than once. An on-treatment analysis was added for the FAS in line with the protocol. Further 
supportive analyses were added to check the proportional hazards assumption for the Cox 
model (plot of the log of the negative of Kaplan-Meier estimates versus log time and Cox 
model including treatment by log-transformed time as an interaction). More details were given 
for the tipping point analysis, and it was clarified that this analysis and the newly added on-
treatment analysis will only be done for the primary and key secondary renal endpoint based 
on the FAS.


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Sections affected:

Section 6.2.1.2: Primary efficacy variable: supportive analysis

Section 6.2.2.2: Secondary efficacy variables: supportive analysis

Section 9.1: Appendix A: Technical details missing data imputation model for time to 
event
Modification 13: Censoring rules for on-treatment/PPS analysis of key renal endpoint
Rationale: Censoring rules for the key secondary renal composite endpoint were clarified to 
consider both the time window of 30 days after treatment discontinuation as usual for this 
type of analysis in this SAP and the 5 months after the last visit with information of all 
components of the renal composite endpoint as done for the FAS analysis of this endpoint.
Sections affected:

Section 6.2.2.2: Secondary efficacy variables: supportive analysis
Modification 14: Modification of list of further efficacy time-to-event endpoints
Rationale: Further exploratory time-to-event endpoints were added for the sake of 
completeness to adequately depict all the single components as well as reasonable sub-
composites of the previously mentioned primary and secondary composite endpoints.
Sections affected:

Section 6.2.3.1: Exploratory time to event variables
Modification 15: Deletion of analysis for relationship between a change in UACR from 
baseline to month 4 and the incidence of cardiovascular and renal events
Rationale: This analysis was removed because it was not deemed appropriate to compare the 
relationship between two post-baseline events in the described manner as the possibility of 
confounding with the factor treatment cannot be excluded. 
Sections affected:

Section  6.2.3.2: UACR and albuminuria
7.2
Overview of Changes to SAP – from version 2.0 to version 3.0
Major changes compared to version 2.0:

Full specification of testing procedure and multiplicity adjustment, moved to new 
section 4.7.

Deeper specification of imputation rules for missing event dates (section 4.3)

Correction of data handling for UACR measurements (section 4.5.3)

Definition of subgroup analyses for safety events (section 4.5.4)

Alignment of cut-off values for baseline UACR/blood pressure categories


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
Drop of name of investigator in disposition tables (section 6.1.1)

Deletion of information from the combined treatment and follow-up epoch (section 
6.1.1)

Correction of ACEIs/ARBs baseline analysis (section 6.1.4)

Amount of missing data will be summarized (section 6.2.1.2)

Superseding frequency tables at certain time points by more powerful KM estimates 
(section 6.2.1.2)

Specification of UACR analysis (section 6.2.2.1)

Specification of analysis for components of primary and secondary endpoints (section 
6.2.3.2)

Specification of censoring rules for exploratory efficacy variables (section 6.2.3.6)

Clarification about analysis of certain safety parameters (Hyperkalemia, worsening of 
renal function) (section 6.4.1)
7.3
Overview of Changes to SAP – from version 3.0 to version 4.0
Major changes compared to version 3.0:

Clarifiaction on imputation rules for partially missing death dates (section 4.3)

Additional subgroups added, “key” and “important” subgroups re-ordered (section 
4.5.4)

Platelet aggregation inhibitors (excluding heparin) added to the list of concomitant 
medications (section 6.1.4)

Clarification that time-to-event analysis on-treatment and for PPS will be censored at 
the end-of-study visit (sections 6.2.1.2 and 6.2.2.2)

Deletion of one endpoint and addition of three endpoints to the list  of other 
exploratory efficacy variables (section 6.2.3)

Specification of Toeplitz as first choice alternative covariance matrix in case of 
convergency issues in PROC MIXED (section 6.2.3.2)

Deletion of analyses for the iohexol substudy, since the results of the substudies will 
be reported separately, and not in the clinical study report (section 6.2.3.3)

Change from time-to-event analyses to logistic regression for other exploratory 
efficacy analyses (New diagnosis of atrial fibrillation, new diagnosis of heart failure 
and regression of albuminuria) (section 6.2.3.5)

A separate listing will be generated for all AEs excluded from the AE analysis due to 
double reporting in Japan (section 6.4.1)

For the other safety events, summary will be provided once for all events and once for 
all treatment-emergent events (section 6.4.1)

Alignment of use of “treatment-emergent” (for safety) and “on-treatment” (for 
efficacy) analyses (e.g., section 6.4.2)


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
Wald confidence limits for treatment differences in certain laboratory parameters will 
be calculated, due to the computational burden of exact unconditional confidence 
limits (section 6.4.2)
8.
References
1. http://www.rand.org/health/surveys_tools/kdqol.html (6th September 2013).
2. EQ-5D-5L User Guide, Version 2.0, EuroQoL Group, 2013.
3. Szende, A., Oppe, M., Devlin, N. (2007): EQ-5D Value Sets: Inventory, Comparative 
Review and User Guide. Chapter 4. Springer.
4. Collett, D. (2003): Modelling Survival Data in Medical Research, Chapter 2. Chapman 
and Hall.
5. Agresti, A. (2007): An Introduction to Categorical Data Analysis, Chapter 2, Second 
Edition, New York: John Wiley & Sons.
6. Little, R. J., et al. (2016): The treatment of missing data in a large cardiovascular 
clinical outcomes study. Clinical Trials, 13(3): 344-351.
7. Koopmans, L. H., Owen, D. B., Rosenblatt, J. I. (1964): Confidence intervals for the 
coefficient of variation for the normal and log normal distributions. Biometrika. 51: 
25–32.
8. Carpenter, J. R., Kenward, M. G. (2007): Missing data in randomized controlled trials 
- a practical guide. National Health Service Coordinating Centre for Research 
Methodology: Birmingham.
9. Tang, D. I.,  Geller, N. L. (1999): Closed testing procedures for group sequential 
clinical trials with multiple endpoints. Biometrics, 55(4): 1188-1192.


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9.
Appendix
9.1
Appendix A  Technical details missing data imputation model for time to 
event
To investigate the impact of missing data under a missing not at random (MNAR) assumption 
a methodology similar to pattern-mixture-models will be employed as described by Little et 
al. (2016) [6]. In this approach, a Weibull survival model will be fitted to all subjects who 
prematurely discontinued study treatment in order to estimate the individual hazard rates for 
patients with withdrawn consent or loss to follow-up, but without a previous endpoint event.
Based on these individual hazard estimates at the time of censoring (possibly penalized 
through inflation), event times for patients alive but censored before the global cut-off date 
(notification of study termination + 4 weeks) will be imputed. 
Details:
The SAS LIFEREG procedure will be used where the natural logarithm of the survival time 
 = () is modeled. The survival function has the form

















w
w
S
exp
exp
)
(
,
where µ is the location parameter (intercept) and σ is the scale parameter in the SAS output. 
The observed hazard rates (scale and shape parameters) for individual subjects are obtained 
from a Weibull model fitted to all subjects who prematurely discontinued study treatment, 
adjusted for treatment group (coded 0=placebo, 1=finerenone) and the stratification factors. 
The Weibull probability density function is re-parametrized to have the following form
g(t| λ, β) = (β/λ) (t/λ)β-1 exp(-(t/λ)β),
where λ= exp(µ) is the new scale parameter = exp(µ) and β = 1/σ is the re-parametrized shape 
parameter.
With this re-parametrization, the hazard function is given by
h(t| λ, β) = (β/λ) (t/λ)β-1
and the survival function can be written as
S2(t)= exp(-(t/λ)β).


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For subjects with consent withdrawn or who are lost to follow-up and who did not experience 
a primary efficacy endpoint, random variables will be simulated using the conditional time to 
event distribution after the last contact date given that no event was observed before. If this 
randomly generated variable has a value less than the elapsed time between the last contact 
date and the global cut-off date, i.e. the date when all subjects should have performed their 
EOS visit (notification of study termination + 4 weeks), the subject will be counted as having 
observed an event at the last contact date plus the random variable. Otherwise, the subject is 
re-adjusted to be censored at the global cut-off date.
These imputed events will be added to the observed events in the study and the primary 
efficacy variable will be re-analyzed. This process will be repeated 1000 times. For the final 
analysis, the hazard ratio with 95.032612% or 96.717305% confidence intervals (the actual 
confidence level will depend on the p-value of the primary analysis of the key secondary 
endpoint and is adjusted for the interim analysis, for further details see Section 6.2.1.2) will be 
estimated for each imputed data set and then combined using standard multiple imputation 
combining rules.
Details: 
When the survival time  follows a Weibull distribution with survival function S2, then the 
conditional distribution function of time  after the last contact date/censoring date () is 
given for 	 ≥0 by: 
 = Pr( ≤	 + | > ) = 1 −Pr( > 	 + | > )
    = 1 −Pr( > 	 + )
Pr( > )
= 1 −(	 + )
()
With the estimated shape parameter β and the scale parameter λ from the underlying Weibull 
model, this results in:
 = 1 −exp *−+	 + 
,
-
.
/ exp *−+
, -
.
/
0
≡ log(1 − ) = −4
5678
9 :
.
+ 4
78
9 :
.
≡	 = λ× *4
78
9 :
.
−log(1 − )/
= .
⁄
−
If  is replaced with a random variable with uniform distribution between 0 and 1, the random 
variable x can be generated using the inverse transformation technique from 
λ× *4
78
9 :
.
−log(1 −?@AB(′DAEF?G′)/
= .
⁄
−.


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In addition, the estimated hazard rates for the finerenone group will be inflated by a known 
factor k, with 1000 simulations performed at each rate of inflation. Inflation will be done until 
the upper limit of the confidence interval of the combined estimate of the hazard ratio crosses 
1.
Details: 
The imputation above is repeated with different inflation factors for the subjects in the 
finerenone group. The individual hazard rates is multiplied with , leading to
k × (β/λ) (t/λ)β-1
with new scale parameter s = λ/(k1/β).


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9.2
Appendix B  Technical details missing data imputation model for UACR
The evaluation of the secondary efficacy endpoint UACR is the ratio of change from baseline 
to Month 4 in UACR. In case of a missing value at Month 4 (on or off treatment) the subject 
will be excluded from this analysis. This strategy leads to unbiased estimates of the treatment 
effect only if the missing data are “missing completely at random” (MCAR), i.e. the 
missingness is independent of both observed and unobserved outcomes. Although this 
condition might hold approximately, they are unlikely to hold exactly. In accordance with the 
EMA “Guideline on missing data in confirmatory clinical trials” other ways of handling 
missing data will be investigated.
The frequency, proportion and the reasons for dropouts will be tabulated within the main 
analysis. In addition the frequency and proportion for time of dropout as well as for the 
overall pattern of missing observations will be given. To investigate whether missingness 
seems to be “missing at random”, the mean UACR at baseline will be summarized for those 
with and without a post-baseline UACR. These analyses will be done for all patients grouped 
together, and stratified by treatment. For the ratio of change to Month 4 analysis, as UACR is 
only recorded at baseline and then at Month 4, the pattern of UACR over time up to Month 4 
cannot be systematically investigated further.  However, if there are sufficient dropouts with 
UACR at Month 4, the ratio of change to from baseline to Month 4 will be summarized by 
those still on study treatment and those having terminated study treatment.
Missing not at random (MNAR) means that missingness depends both on observed and 
unobserved outcomes. This requires an explicit model for the patient’s statistical behavior 
after drop-out. A fixed increase above the group average for patients dropping out can be 
assumed, where the pattern and size of the increase is varied across several sensitivity 
analyses. This is sometimes called the delta method of sensitivity analysis in a pattern mixture 
framework (see reference 8, Chapter 6).
The following scenarios of no penalty and fixed penalties after drop-out will be investigated, 
where different values are assigned to the treatment groups:
Penalties after drop-out (ratio baseline : Month 4), based on an expected ratio from baseline to 
Month 4 on finerenone of 0.70.
•
Placebo 0 / finerenone 0
•
Placebo 0 / finerenone +0.15
•
Placebo 0 / finerenone +0.30
•
Placebo +0.15 / finerenone +0.15
•
Placebo +0.15 / finerenone +0.30
•
Placebo +0.30 / finerenone +0.30
•
Tipping point analysis: Placebo 0 / finerenone +X, X is the value where the p-
value of the difference between placebo and finerenone becomes 0.05 (two-sided).
To properly account for the incompleteness of the data, multiple imputation will be used to 
draw sets of completed data that will then be modified according to the scenarios given above. 
Multiple imputation will be done using SAS PROC MI using the following generic code, 
where stratification group are coded as dummy variables using the first factor in each 
stratification group as the respective reference groups:


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PROC MI data=<dataset> seed=<study number> nimpute=50 
out=<output dataset>;
BY trtgrpn;
MCMC niter=500 nbiter=500;
VAR logUACRbase logUACRmonth4 <stratumn>
RUN;
After modifying the completed data sets according to the scenarios, the ANCOVA of the main 
analysis will be performed at Month 4 for each completed data set. The results are them 
combined using SAS PROC MIANALYZE.
For each scenario, the ratio of treatment difference at Month 4 from baseline will be given 
with a 95%-confidence interval and a p-value. In addition, the minimum and maximum of 
observed treatment differences over the imputed data sets will be presented.


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9.3
Appendix C  Region grouping
The following regions have been defined as used for stratification:  
-
North America, 
-
Latin America, 
-
Europe, 
-
Asia, 
-
Others 
Region grouping is based on the location of a country to that continent, which in most cases is 
unambiguous. These rules have been used for the following countries:
-
Israel and Saudi Arabia are geographically located in Asia, and have been allocated to 
that region.
-
Turkey and Russia are located in both Europe and Asia; they have been allocated to 
region Europe.
-
Mexico is allocated to region Latin America.
-
Puerto Rico is in the Caribbean and an unincorporated US territory; it is therefore 
linked to the US and included in North America.
-
Others includes countries in Africa and Australasia: South Africa, Australia and New 
Zealand.
The IxRS stratification scheme has Italy, China and Japan as their own individual 
stratification groups, due to the ioxehol substudy (Italy) and regulatory requirements to 
demonstrate consistency with the main study (China, Japan). For region groupings, Italy will 
be included with Europe, China and Japan with Asia.