Clinical trial NCT05013008
Conditions: Chronic Kidney Disease Type 2 Diabetes Mellitus
Sponsor: Bayer
Start date: 2021-08-18; Completion date: 2021-12-31
Enrollment: 951 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Researchers are looking for a better way to treat people who have chronic kidney disease (CKD), a long-term, progressive decrease in the kidneys' ability to work properly. When CKD happens in people with type 2 diabetes mellitus, a condition characterized by high blood sugar levels, CKD is also referred to as diabetic kidney disease (DKD).

FIGARO-BM is an add-on study in which blood draws that were collected in the FIGARO-DKD study are further analyzed. No additional blood draws (also referred to as biological samples) or data will be obtained from the participants, nor will any additional or new study intervention be introduced. No visit or patient contact other than for obtaining the agreement by the patients (also called informed consent) will be required.

Inflammation and scarring are both seen as responsible for worsening of chronic kidney disease. There is much information from animal studies that the study treatment finerenone (BAY94-8862) works against inflammation and against scarring (also called fibrosis) in organs such as the kidney.

In this exploratory study researchers want to learn more about the study treatment finerenone (BAY94-8862). To find this out, this study will examine substances called biomarkers in blood draws from participants in the FIGARO-DKD study. Biomarkers are used as indicators of biological processes, disease processes or responses to medication. The biomarkers that will be examined stand for inflammation, organ scarring (also called fibrosis), blood vessel function and congestion.

The main question of this study is whether there are differences between these biomarkers in the group of participants who received finerenone and the group of participants who received a placebo in the FIGARO-DKD study. A placebo looks like a treatment but does not have any medicine in it. To answer this question, the researchers will compare the levels of these biomarkers between the two groups at different time points after starting the study treatment. Blood samples for this study will be obtained from FIGARO-DKD study sites with a high number of participants who had been treated with finerenone or placebo for at least 24 months. This information will be combined with other information from biomarker examinations already available in the FIGARO-DKD study.

Detailed description:

Arms: arm 1: Participants received finerenone 10 mg or 20 mg once daily in addition to standard of care therapy in previous interventional Phase 3 trial FIGARO-DKD. No new intervention was administered in this biomarker study. arm 2: Participants received matching placebo once daily in addition to standard of care therapy in previous interventional Phase 3 trial FIGARO-DKD. No new intervention was administered in this biomarker study.
Interventions: intervention 1: Finerenone (Kerendia, BAY94-8862) intervention 2: Placebo
Intervention descriptions: intervention 1: Oral tablet; starting at 10 mg or 20 mg; once daily; received in previous interventional Phase 3 trial FIGARO-DKD; no new intervention was administered in this biomarker study. intervention 2: Oral tablet; starting at 10 mg or 20 mg; once daily; received in previous interventional Phase 3 trial FIGARO-DKD; no new intervention was administered in this biomarker study.

Protocol documents:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
A non-blinded retrospective biomarker add-on study to 
FIGARO-DKD for Bioprofiling the pharMacodynamic response 
to finerenone in FIGARO-DKD subjects (FIGARO-BM) 
NCT Number: 
NCT05013008 
Document Date: 
24 JUN 2021 
 
 


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Title Page
Protocol Title: 
A non-blinded retrospective biomarker add-on study to FIGARO-DKD for Bioprofiling the 
pharMacodynamic response to finerenone in FIGARO-DKD subjects (FIGARO-BM)
Protocol Number:
21952
Version Number:
1.0
Compound Number:
Finerenone (BAY 94-8862)
Study Phase:
N/A
Acronym: FIGARO-BM
Sponsor Name: Bayer AG
Legal Registered Address:
Bayer AG, 51368 Leverkusen, Germany 
Regulatory Agency Identifier Number(s):
IND: not applicable
EudraCT: 2021-003053-37 
Protocol Date: 
24 JUN 2021
Name:
Role:
Global Clinical Leader
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the sponsor’s medically responsible person is filed in the TMF and available on 
request.
Medical Monitor name and contact information will be provided separately.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation.  Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
PPD


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Table of Contents
Title Page................................................................................................................................... 1
Table of Contents ..................................................................................................................... 2
Table of Tables ......................................................................................................................... 3
1.
Protocol Summary ............................................................................................................ 4
1.1
Synopsis........................................................................................................................... 4
1.2
Schema............................................................................................................................. 5
1.3
Schedule of Activities (SoA) ........................................................................................... 5
2.
Introduction....................................................................................................................... 6
2.1
Study Rationale................................................................................................................ 6
2.2
Background...................................................................................................................... 6
2.2.1
Diabetic Kidney Disease (DKD).................................................................................. 6
2.2.2
Mineralocorticoids Receptor Antagonists (MRAs) in Treatment of DKD and 
cardiovascular diseases................................................................................................. 7
2.2.3
Role of inflammation and fibrosis................................................................................ 7
2.3
Benefit/Risk Assessment ................................................................................................. 7
2.3.1
Risk Assessment........................................................................................................... 8
2.3.2
Benefit Assessment ...................................................................................................... 8
2.3.3
Overall Benefit: Risk Conclusion................................................................................. 8
3.
Objectives and Endpoints................................................................................................. 9
4.
Study Design ...................................................................................................................... 9
4.1
Overall Design ................................................................................................................. 9
4.2
Scientific Rationale for Study Design ........................................................................... 10
4.3
Limitations of the Study ................................................................................................ 11
4.4
Justification for Dose..................................................................................................... 11
4.5
End of Study Definition................................................................................................. 11
5.
Study Population............................................................................................................. 11
5.1
Inclusion Criteria ........................................................................................................... 11
5.2
Exclusion Criteria .......................................................................................................... 12
5.3
Lifestyle Considerations ................................................................................................ 12
5.4
Screen Failures............................................................................................................... 12
5.5
Criteria for Temporarily Delaying................................................................................. 12
6.
Study Intervention(s) and Concomitant Therapy........................................................ 12
6.1
Study Intervention(s) Administered............................................................................... 12
6.2
Preparation/Handling/Storage/Accountability............................................................... 12
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 12
6.4
Study Intervention Compliance ..................................................................................... 12
6.5
Dose Modification ......................................................................................................... 12
6.6
Treatment of Overdose .................................................................................................. 13
6.7
Concomitant Therapy .................................................................................................... 13
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 13
7.1
Discontinuation of Study Intervention........................................................................... 13
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 13


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7.3
Lost to Follow Up.......................................................................................................... 13
8.
Study Assessments and Procedures............................................................................... 13
8.1
Efficacy Assessments .................................................................................................... 13
8.2
Safety Assessments........................................................................................................ 13
8.3
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting.. 13
8.4
Pharmacokinetics........................................................................................................... 13
8.5
Genetics and/or Pharmacogenomics.............................................................................. 13
8.6
Biomarkers..................................................................................................................... 14
8.6.1
Biomarker analysis ..................................................................................................... 14
8.6.2
Timing of sample collection....................................................................................... 14
8.6.3
Specimen type(s) ........................................................................................................ 14
8.6.4
Sample storage............................................................................................................ 14
8.6.5
Analytical procedure and quality controls.................................................................. 15
8.6.6
Data Pooling ............................................................................................................... 15
8.6.7
Reporting .................................................................................................................... 15
8.7
Immunogenicity Assessments........................................................................................ 15
8.8
Health Economics or Medical Resource Utilization and Health Economics ................ 15
9.
Statistical Considerations ............................................................................................... 15
9.1
Statistical Hypotheses.................................................................................................... 15
9.2
Sample Size Determination ........................................................................................... 15
9.3
Analysis Set ................................................................................................................... 16
9.4
Statistical Analyses........................................................................................................ 17
9.5
Interim Analysis............................................................................................................. 17
10. Supporting Documentation and Operational Considerations .................................... 17
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 17
10.1.1
Regulatory and Ethical Considerations ...................................................................... 17
10.1.2
Financial Disclosure ................................................................................................... 18
10.1.3
Informed Consent Process.......................................................................................... 18
10.1.4
Data Protection ........................................................................................................... 18
10.1.5
Committees Structure ................................................................................................. 18
10.1.6
Dissemination of Clinical Study Data ........................................................................ 18
10.1.7
Data Quality Assurance.............................................................................................. 19
10.1.8
Source Documents...................................................................................................... 19
10.1.9
Study and Site Start and Closure................................................................................ 20
10.1.10 Publication Policy....................................................................................................... 20
10.2
Appendix 2: Abbreviations............................................................................................ 22
11. References ........................................................................................................................ 24
Table of Tables
Table 9–1: Estimated power for the primary endpoint ............................................................ 16
Table 9–2: Analysis sets........................................................................................................... 16


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1.
Protocol Summary
1.1
Synopsis
Protocol Title:
A non-blinded retrospective biomarker add-on study to FIGARO-DKD for Bioprofiling the 
pharMacodynamic response to finerenone in FIGARO-DKD subjects (FIGARO-BM)
Brief Title:
FIGARO-BM
Rationale:
A large body of evidence in animals demonstrates beneficial, anti-fibrotic and anti-
inflammatory effects of finerenone treatment. In humans, persistent inflammation and fibrosis 
are characteristic features of chronic kidney disease and are independent predictors of disease 
progression. Yet, there is limited data in humans to support finerenone’s mode-of-action 
(MoA) with regards to anti-fibrotic and anti-inflammatory activity. This analysis aims at
contributing to a better understanding of the underlying mechanisms of drug efficacy and 
pharmacodynamics (PD) with particular focus on inflammation and fibrosis besides general 
bioprofiling and pathway analysis.
Objectives and Endpoints:
Objectives
Estimands/Endpoints
Primary

To investigate long-term effect of 
finerenone treatment, in addition to 
standard-of-care, on circulating blood 
biomarkers associated with fibrosis, 
congestion, inflammation and vascular 
function

Change in plasma biomarker levels after 36 
months (Visit 11) of treatment versus 4 
months (Visit 3) of treatment in a set of 27 
pre-defined biomarkers (provided in the 
SAP)
Overall Design:
FIGARO-BM (#21952) is a retrospective, non-interventional study to the multi-center, 
interventional Phase 3 trial FIGARO-DKD (#17530). Samples which had been collected in
FIGARO-DKD will be analyzed by OLINK proteomics technology in FIGARO-BM.
Samples for analysis in FIGARO-BM will be obtained from FIGARO-DKD trial sites with 
large enrollment numbers, from subjects who had been treated with finerenone or placebo for 
at least 24 months. Certain countries require a local protocol addendum to FIGARO-DKD 
(#17530) to conduct this planned biomarker analyses using OLINK technology, instead of a 
separate study protocol described in this document as FIGARO-BM (#21952). Biomarker 
data acquired under FIGARO-DKD #17530 will be pooled and reported together with 
biomarker data acquired under FIGARO-BM #21952.


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Brief Summary:
Study #21952 in subjects with DKD will examine the mid- to long-term PD response to 
finerenone (vs placebo) after up to 36 months of treatment and will characterize relevant
biological pathways which may be affected by treatment. The focus is on markers related to 
fibrosis and inflammation due to the mode-of-action of finerenone and preclinical and clinical
evidence for finerenone and other MRAs. 
Only existing stored biosample leftovers from FIGARO-DKD (#17530) will be used. No 
additional biological samples or data will be obtained from the subject, nor will any additional 
or new study intervention be introduced. No visit or patient contact other than for obtaining 
IC will be required.
Commercially available exploratory biomarker panels (OLINK Explore®) will be employed
for analyses of the samples and all endpoints will be exploratory. OLINK Explore® couples 
antibody-array-based analyte-capturing with next generation sequencing (NGS) for analyte 
identification, thereby allowing simultaneous detection of hundreds of proteins and extensive 
bioprofiling of the response to finerenone.
Number of Participants for Reconsenting:
The targeted number of participants for final analysis is approximately 600 (or more) 
FIGARO-DKD patients (at a 1:1 randomization for finerenone versus placebo
Intervention Groups and Duration:
No new intervention will be administered in this retrospective biomarker study.
Data Monitoring/Other Committee:
Not applicable.
1.2
Schema
Not applicable.
1.3
Schedule of Activities (SoA)

Obtain informed consent from former study participants of FIGARO-DKD to 
perform further analyses of existing biosamples (already collected in FIGARO-
DKD).


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2.
Introduction
This protocol describes a biomarker add-on study to the Phase 3 trial FIGARO-DKD 
(#17530). While the original trial, FIGARO-DKD, investigated the efficacy and safety of 
finerenone (a next-generation, non-steroidal mineralocorticoid-receptor antagonist [MRA]) on 
the reduction of cardiovascular morbidity and mortality in subjects with type 2 diabetes 
mellitus and the clinical diagnosis of diabetic kidney disease in addition to standard of care, 
this study (#21952) will solely perform exploratory biomarker analyses. All analyses will be 
done on existing leftover samples from selected FIGARO-DKD patients. No additional 
biological samples or data will be collected, and no new or additional study intervention will 
be performed. The sponsor will obtain informed consent from former participants of 
FIGARO-DKD subjects to consent to this additional biomarker analysis on their sample 
leftovers. Biomarkers described in this protocol (analytes) will be analyzed by novel 
proteomics technology (OLINK Explore®) allowing quantitative measurements of a multitude 
of markers in a small sample volume.
2.1
Study Rationale
This study focuses on biomarkers of inflammation and fibrosis. 
Persistent inflammation and fibrosis are characteristic features in patients with chronic  
kidney disease (CKD) and are independent predictors of disease progression. While a large 
body of evidence in animals demonstrates beneficial, anti-fibrotic and anti-inflammatory 
effects of finerenone treatment, there is limited data in humans to support the mode-of-action 
(MoA) with regards to anti-fibrotic and anti-inflammatory effects. 
This analysis may contribute to a better understanding of the underlying mechanisms of drug 
efficacy and pharmacodynamics (PD) with regards to inflammation and fibrosis and will 
further knowledge of the biological pathways which underpin drug efficacy and PD. Due to 
the exploratory nature, this biomarker study is purely hypothesis-generating and will 
investigate the effect of treatment on biomarkers in the context of physiological and 
pathological pathway networks.
2.2
Background
2.2.1
Diabetic Kidney Disease (DKD)
Diabetic kidney disease (DKD) is a clinical syndrome affecting individuals with diabetes. It is 
defined by albuminuria on at least 2 occasions separated by 3 to 6 months and eGFR of less 
than 60 mL/min/1.73m2 (1). DKD is the most frequent cause of end-stage renal disease 
(ESRD) in western countries (2). The risk of cardiovascular (CV) events and death increases 
in patients with DKD with decreasing glomerular filtration rate (GFR) and increasing 
albuminuria (3, 4). Patients with non–dialysis-dependent chronic kidney disease (NDD-CKD) 
are 10 times more likely to die of CV diseases (CVD) than the general population (5). As type 
2 diabetes mellitus (T2DM) will rise rapidly throughout the world within the next years (6), 
and alongside DKD, 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. Interventions 
to improve outcomes related to DKD focus on reducing risk, including counseling on lifestyle 
modifications (i.e. smoking cessation and dietary modifications to reduce proteinuria and aid 
in weight loss) and interventions aimed at glycemic control, dyslipidemia, and hypertension
(7). Therefore, angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin-receptor 


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blockers (ARBs) are standard of care (SoC) therapy in patients with DKD and are often 
prescribed to patients with DKD at early stages (7). However, they slow but neither halt nor 
reverse kidney disease progression (8). 
2.2.2
Mineralocorticoids Receptor Antagonists (MRAs) in Treatment of 
DKD and cardiovascular diseases
Long-term renin-angiotensin system (RAS) blockade with ACEIs and ARBs results in 
incomplete suppression of serum aldosterone levels. This is known as the ‘aldosterone 
breakthrough’ phenomenon (9). It is associated with increased urinary albumin excretion and 
more rapid decline in estimated GFR (eGFR). This phenomenon is probably due to an 
increase in potassium and angiotensin serum levels in patients treated with ACEIs/ARBs, and 
it provides the scientific rationale for an additive benefit of mineralocorticoid-receptor (MR)
blockade.
Inappropriate release of aldosterone contributes to organ damage found in chronic renal 
failure, heart failure (HF), myocardial infarction and hypertension. The MR is extensively 
expressed in the CV system including kidney mesangial cells, the heart, endothelial cells and 
vascular smooth muscle cells. 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. Chronically elevated aldosterone release 
participates in the generation of vascular, myocardial, and renal fibrosis, and eventually end-
organ damage, dysfunction, and failure (10). The actual mechanisms behind the pathological 
effects of aldosterone in DKD have not yet been fully elucidated. 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 (11). Steroidal MRAs currently on the market for the 
treatment of chronic heart failure (CHF) (spironolactone and eplerenone) have several 
disadvantages – particularly, an increased risk of hyperkalemia - which limit their use in 
clinical practice. None of the steroidal MRAs are currently approved for the treatment of 
patients with CKD as they have a high risk of hyperkalemia (12, 13). Finerenone is a novel, 
potent, and non-steroidal MRAs with superior selectivity vs. spironolactone in vitro and with 
improved potency and efficacy vs. eplerenone, which suggests an improved efficacy and 
safety profile and thus a potential treatment option for CKD in T2DM and HF (14).
2.2.3
Role of inflammation and fibrosis
By propagating inflammation and fibrosis, aldosterone plays a pivotal role in renal vascular 
damage. In hypertensive rat models, MRAs attenuated renal damage and supported the 
protective effect of aldosterone blockage in renal disease (15). Other preclinical data from 
ischemia models of AKI1-to-CKD progression in several species pointed towards a role of 
MRAs in polarizing macrophages to a less inflammatory phenotype. Along with these 
findings, kidney fibrosis was reduced (16). Finerenone was shown in animal models to act by 
targeting inflammatory and fibrotic pathways in the heart and kidney, reducing cardiac 
remodeling, and decreasing the release of inflammatory and profibrotic biomarkers (17).
2.3
Benefit/Risk Assessment
This study will only include patients who had participated in the FIGARO-DKD trial.
                                                
1 AKI = Acute Kidney Injury


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2.3.1
Risk Assessment
Participating in this study bears no foreseeable risk to the patient. There is no intervention, no 
blood nor data collected beyond what was already obtained during FIGARO-DKD.
2.3.2
Benefit Assessment
Patients with advanced kidney disease show high levels of fibrosis in the kidney. Therefore, 
data to substantiate anti-fibrotic activity of finerenone will open new treatment options for the 
patient beyond currently available treatment regimens which target other aspects of kidney 
pathophysiology.
This retrospective study offers the possibility to better characterize mid- to long-term PD 
effects of finerenone and to bioprofile the response to finerenone with particular focus on 
established aldosterone-driven, fibrosis- and inflammation-related pathways. The results of 
this study will be used to guide the decision on further development of finerenone by 
contributing to a better understanding of underlying mechanisms for better outcomes in future 
use of finerenone. 
2.3.3
Overall Benefit: Risk Conclusion
The benefit-risk assessment is considered positive and justifies the conduct of this study 
within the selected cohort of patients with CKD and T2DM.


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3.
Objectives and Endpoints
The endpoints below all rely on data derived with an exploratory biomarker panel 
(OLINK technology) and hence, all analyses are considered exploratory in nature.
Objectives
Estimands/Endpoints
Primary

To investigate long-term effect of 
finerenone treatment, in addition to 
standard-of-care, on circulating blood 
biomarkers associated with fibrosis, 
congestion, inflammation and vascular 
function

Change in plasma biomarker levels after 36
months (Visit 11) of treatment versus 4 
months (Visit 3) of treatment in a set of 27 
pre-defined biomarkers (provided in the 
SAP)
Other pre-specified

To characterize mid- to long-term PD 
effects of finerenone and profiling the 
response to finerenone (vs placebo) in 
patients with DKD to describe biological 
pathways

Change in plasma biomarker levels after 12 
months (Visit 5), 24 months (Visit 8) and 36 
months (Visit 11), 48 months (Visit 14) 2 of 
treatment versus 4 months (Visit 3) of 
treatment

To further investigate the study intervention 
and similar drugs (e.g. mode-of-action-
related effects, safety) and to further 
investigate pathomechanisms deemed 
relevant to renal and cardiovascular 
diseases and associated health problems

Change in various biomarkers (e.g. 
diagnostic, safety, pharmacodynamic, 
monitoring, prognostic or potentially 
predictive biomarkers)

To assess relationship between 
pharmacokinetics of finerenone and PD
effects

Change in biomarker levels at 12 months
(Visit 5), 24 months (Visit 8) and 36 months
(Visit 11) of treatment compared to exposure
4.
Study Design
4.1
Overall Design
FIGARO-BM (#21952) is a retrospective, non-interventional add-on study to the multi-center, 
interventional Phase 3 trial FIGARO-DKD (#17530). Blood plasma samples which were 
initially collected for pharmacokinetic (PK) analysis during the conduct of FIGARO-DKD 
study will be analyzed by OLINK proteomics technology (refer to Section 8.6 for details on 
biomarkers and intended technology) in FIGARO-BM.
This biomarker study will contact selected subjects from multiple centers in several countries
who had participated in FIGARO-DKD and subjects will be re-consented for further 
biomarker analyses. Sites with a large number of subjects in FIGARO-DKD – preferentially
with ~8 or more valid3 subjects per site who were on treatment with finerenone (or placebo) 
                                                
2 Depending on availability of samples for visit
3 Valid Subjects does not include subjects with known fatal outcome and/or subjects which otherwise do not 
meet enrolment criteria. Subjects with very high baseline risk (eGFR ≤25 mL/min/1.73m2) or low baseline risk 
(normal albuminuria and eGFR≥60 mL/min/1.73m2) will be excluded because the treatment effect on 
biomarkers is less likely to be observed in these subjects and would need a higher number of subjects per arm 
(see Section 9.2).


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for at least 24 months - will be selected in order to investigate mid- to long-term treatment 
effects of finerenone in a cross-section of subjects from FIGARO-DKD. Countries will be 
selected based on above-average recruitment in FIGARO-DKD, short anticipated turn-around 
time to first patient first consent, and a sufficient number of sites and potentially available 
subjects interested in participation in this study.
Certain countries require a local protocol addendum to the parent study FIGARO-DKD 
#17530 to conduct this planned biomarker analyses using OLINK technology, instead of a 
separate study protocol described in this document as FIGARO-BM (#21952). Biomarker 
data acquired under FIGARO-DKD will be pooled and reported together with biomarker data 
acquired under FIGARO-BM.
The pooled data is intended to include approximately 600 (or more) FIGARO-DKD patients
from 60 (or more) sites.
4.2
Scientific Rationale for Study Design
The overall rationale is described in detail in Section 2.1.
This study uses exploratory, commercially available biomarker panels (OLINK Explore®). 
Hence all endpoints are also exploratory in nature. OLINK Explore® is a novel technology 
which uses proteomics coupled to NGS4-detection methodologies (18). This is a very recent 
technology, which allows extensive bioprofiling of the PD response to finerenone. At the time 
FIGARO-DKD was set up, these technologies were not available. Since the introduction of 
OLINK Explore® to the market in mid-2020 only few groups have conducted similar analyses 
(e.g. (18-20)). The biomarker studies - which were carried out in ARTS (#14563 (22) and 
later, as sub-studies to FIGARO-DKD (#17530, report in preparation), FIDELIO-DKD 
(#16244 (21)) or) - suggest potential antifibrotic activity and warrant further investigation of 
circulating fibrosis markers. 
The primary endpoint of FIGARO-BM focuses on fibrosis and inflammatory markers which 
have been reported in literature in the context of CVDs (see for example: (19)). FIGARO-BM
will investigate first and foremost whether finerenone treatment (compared to placebo) affects
markers of fibrosis and inflammation after mid- to long-term treatment. Impacting circulating 
levels of fibrosis-related biomarkers is generally assumed to be of long-term benefit to 
patients with CKD as kidney fibrosis is the common endpoint of CKD from various etiologies
(16). Therefore, modulating fibrosis markers may reflect treatment efficacy and hence may 
translate into a clinically relevant benefit to the patient.
Taken together, multiple lines of evidence support that finerenone acts via inflammatory and 
fibrosis-related pathways. Yet, human data on fibrosis biomarker panels from randomized 
clinical trials (RCTs) with finerenone is missing to this point. While an individual biomarker 
of fibrosis or inflammation may not be informative to understand the intricate network of
pathologic (or physiologic) processes and a potential interaction with the intervention, a 
network analysis of a large number of biomarkers may provide insights into linkages of 
                                                
4 Next generation sequencing (NGS) is used as a detection method in order to identify specific protein labels. 
There is no genetic information assessed, collected or analyzed. The current commercial version of this OLINK 
biomarker panel includes 1536 biomarkers but is expected to be extended to 3000 markers or more by the end of 
the year 2021.


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pathways and how or if they are affected by treatment. In addition, biomarkers will be 
assessed longitudinally. Hence, this bioprofiling approach allows to analyze physiologically 
linked biomarkers over time which may more convincingly demonstrate remodeling events 
along the time axis than individual markers alone - without consideration of their context and 
time trajectory.
4.3
Limitations of the Study
Since PK blood samples were not collected at baseline in the main study, no changes from 
baseline will be analyzed. Hence, the focus of this study will be on mid- (i.e. ≥12 months of 
treatment) to long-term biomarker changes. Given that organ remodeling is a slow process 
over months to years, this limitation is considered acceptable. In addition, the study is a 
retrospective analysis of biomarkers from selected patients, sites and countries. It is likely that 
the focus on larger sites will lead to selection bias. In addition, patients with fatal outcome are 
no longer available for consenting, excluding risk analyses with regards to death. Yet, the 
emphasis is on understanding biological pathways and better describe the mode-of-action of 
finerenone in humans.
4.4
Justification for Dose
Not applicable.
4.5
End of Study Definition
The end of the study is defined as the date when the last subject provides consent into the 
study globally.
5.
Study Population
This study will only include patients who were enrolled in the FIGARO-DKD study (see CSP 
FIGARO-DKD study #17530) and had received up to 20 mg finerenone or placebo for
≥24 months.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:

Signed informed consent to participate in FIGARO-BM5

Randomized in the FIGARO-DKD trial

For each participant, PK plasma samples from Visit 3 and at least 2 other Visits 
(Visit 5, Visit 8, Visit 11) must be available on storage from the main study
FIGARO-DKD.6,7
                                                
5 Capable of giving signed informed consent as described in Section 10.1.3 which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
6 Participants with a complete set of PK blood samples up until 36 months of treatment (Visit 3, Visit 5, Visit 8, 
Visit 11) should be prioritized by sites over those which have incomplete sets of PK samples. 
7 Note that some subjects may have additional and/or unscheduled visits (PK samplings) which may be analyzed.


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5.2
Exclusion Criteria 

Subjects which did not show overall compliance of 80 to 120% with study 
intervention in FIGARO-DKD 

Subjects which were not part of the full analysis set (FAS) of FIGARO-DKD.

Subjects with known fatal outcome 

Subjects with baseline eGFR ≤25 mL/min/1.73m2

Subjects with low baseline risk (normal albuminuria and 
eGFR≥60 mL/min/1.73m2)

Sponsor request (after discussion with the investigator), for reasons such as a 
significant protocol deviation
5.3
Lifestyle Considerations
Not applicable. 
5.4
Screen Failures
Not applicable.
5.5
Criteria for Temporarily Delaying
Not applicable.
6.
Study Intervention(s) and Concomitant Therapy
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
None.
6.2
Preparation/Handling/Storage/Accountability
Not applicable.
6.3
Measures to Minimize Bias: Randomization and Blinding
Not applicable.
6.4
Study Intervention Compliance
Not applicable. 
6.5
Dose Modification
Not applicable.


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6.6
Treatment of Overdose
Not applicable.
6.7
Concomitant Therapy
Not applicable. 
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1
Discontinuation of Study Intervention 
Not applicable.
7.2
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request

If the participant withdraws consent, the sponsor may retain and continue to use 
any data collected before such a withdrawal of consent.
7.3
Lost to Follow Up
Not applicable.
8.
Study Assessments and Procedures
Protocol waivers or exemptions are not allowed. There are no study specific procedures for 
this biomarker study except for requesting the re-consent for use of existing samples. For 
details on biomarkers and sample analysis, refer to Section 8.6.
8.1
Efficacy Assessments 
Not applicable.
8.2
Safety Assessments
Not applicable. There will be no study-specific safety assessments in this study. Safety of the 
participants was monitored within the FIGARO-DKD study.
8.3
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting
Not applicable.
8.4
Pharmacokinetics
Not applicable.
8.5
Genetics and/or Pharmacogenomics
Not applicable.


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8.6
Biomarkers
8.6.1
Biomarker analysis
This study will analyze only blood-based biomarkers. Genetic biomarkers will not be 
measured.
The primary analyses will be carried out using the OLINK Explore® assay. The current 
version of the OLINK Explore® will provide biomarker data for 1536 biomarkers including 
hundreds of CV and inflammatory biomarkers8. “Biomarkers of primary interest” are 
summarized in the statistical analysis plan (SAP) and constitute the primary study endpoint. 
The full list of all biomarkers analyzed will be given in the study report. 
The list of “biomarkers of primary interest” consists primarily of biomarkers of inflammation 
and fibrosis which have been published previously in the context of inflammation-related 
fibrosis and CKD. The list includes e.g. metallomatrix protein-2 (also known as CCL2), C-C 
motif chemokine 16 (CXCL16), connective tissue growth factor (CTGF, also known as CCN 
family member 2), or N-terminal pro-brain natriuretic peptide (NT-proBNP9). 
Confirmatory analyses, e.g. to confirm biomarkers results from the primary analyses by 
using alternative methodologies - such as e.g. research-use immunoassays, routine clinical 
chemistry or immunoassay platforms (e.g. Roche Cobas, Abbott Architect, Siemens Centaur), 
high performance liquid chromatography (HPLC) or mass spectrometry, may be carried out.
Further biomarkers related to the mode of action or the safety of finerenone and similar 
drugs may be examined. The same applies to further biomarkers deemed relevant to renal and 
cardiovascular diseases and associated health problems. These investigations may include e.g. 
diagnostic, safety, PD, monitoring, or potentially predictive biomarkers.
8.6.2
Timing of sample collection
Not applicable10.
8.6.3
Specimen type(s)
Leftover samples, originally collected for PK analysis (lithium heparin plasma) in FIGARO-
DKD (#17530), will be used for this biomarker study. For details on sample collection refer to
the study documentation of FIGARO-DKD (#17530 - e.g. sample handling sheets or lab 
manual).
8.6.4
Sample storage
Samples may be stored for a maximum of 15 years (or according to local regulations) 
following finalization of the study report for this study at a facility selected by the sponsor to 
enable further analyses.
                                                
8 This panel is subject to regular adaptations by the manufacturer to consider newly identified biomarkers. For 
this study, the latest available OLINK Explore Panel will be used. The composition of OLINK Explore® along 
with the UniProtID and gene names for each biomarker is published on www.olink.com. The complete protein 
list for the current Explore® can be found here: https://www.olink.com/content/uploads/2021/03/explore-1536-
assay-list-20210227-web.xlsx (as of 31 May 2021 - Note: This link is not automatically updated.)
9 NT-proBNP has also been analyzed in two other substudies of FIGARO-DKD using different analytical 
methodologies. Results for these substudies have been or, for still ongoing analyses under protocol #17530, 
will be reported under separated cover.
10 There will be no new sample collection in the course of this biomarker study. 


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8.6.5
Analytical procedure and quality controls
Details of the analytical procedures and quality controls (if applicable) will be provided by the 
analytical laboratory (e.g. validation/analytical report) at the end of the study.
8.6.6
Data Pooling
Biomarker data acquired under FIGARO-DKD #17530 will be pooled and reported together 
with biomarker data acquired under FIGARO-BM #21952 (see also Section 4.1).
8.6.7
Reporting
Biomarker investigations as described herein (see Section 3) as “Primary” (see Section 3 or 
within the SAP) will be reported in a clinical study report. Other exploratory analyses may be 
reported separately (e.g. in a biomarker evaluation report).
8.7
Immunogenicity Assessments
Not applicable.
8.8
Health Economics or Medical Resource Utilization and Health 
Economics
Not applicable.
9.
Statistical Considerations 
9.1
Statistical Hypotheses
All analyses for this study are exploratory. 
The primary objective (Section 3) is to analyze the change in plasma biomarker levels after 
36 months (Visit 11) of treatment versus 4 months (Visit 3) of treatment in a set of 27 pre-
defined biomarkers (provided in the SAP) in treatment group compared to placebo, based on 
the biomarker full analysis set (BFAS) as defined in Section 9.3. A two-sided moderated t-
tests (23) between treatment and placebo group on the log-transformed ratios of biomarker 
levels from Visit 11 to Visit 3, based on the complete OLINK panel, will be used in the 
analysis. This analysis will be adjusted for relevant baseline covariates. P-values of the 27 
biomarkers of primary interest will be adjusted for multiple testing according to Benjamini 
and Hochberg (24). A biomarker is considered to be affected by treatment, if the adjusted p-
value is less or equal to 5%.
Summary statistics and line plots (mean with geometric standard deviation [gsd]- or standard 
deviation [sd] error bars over time) for the ratio to Visit 3 will be generated.
The remaining biomarkers will be analyzed according to SAP or under separate cover. Refer 
to SAP for further details.  
9.2
Sample Size Determination 
Table 9–1 summarizes the results of a power simulation based on the following assumptions:

Beneficial effect of finerenone on 4 of the 27 biomarkers with a ratio of biomarker 
levels from Visit 11 to Visit 3 (month 4) under finerenone of 10%, 15% or 20%
compared to placebo.

Inter-subject variability of 25% (geometric standard deviation of 1.25)


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
Intra-subject variability from Visit 3 to Visit 11 of 20% (gsd of 1.2)

Assay-variability of 10% (gsd of 1.1)
Table 9–1: Estimated power for the primary endpoint
Treatment 
effect size
Number of 
subjects per 
arm
Power to detect 
4 biomarkers
Power to detect 
3 biomarkers or 
more
Power to detect 
2 biomarkers or 
more
Power to detect 
1 biomarkers or 
more
10%
75
2.5%
5.4%
9.5%
16.8%
100
4.5%
9.2%
15.2%
24.2%
250
26.4%
42.0%
55.2%
67.4%
300
37.4%
55.4%
66.9%
77.4%
400
57.6%
74.4%
83.6%
90.3%
15%
75
13.4%
24.3%
34.9%
48.0%
100
24.2%
39.3%
51.8%
63.8%
250
86.1%
94.8%
97.7%
99.2%
300
94.2%
98.8%
99.5%
99.9%
400
99.4%
100.0%
100.0%
100.0%
20%
75
45.0%
62.4%
74.0%
83.4%
100
67.3%
82.0%
89.5%
94.3%
250
99.9%
100.0%
100.0%
100.0%
300
100.0%
100.0%
100.0%
100.0%
400
100.0%
100.0%
100.0%
100.0%
Power estimations are based on the methodology described in Section 9.4 and Monte-Carlo 
simulations with 10,000 iterations per scenario. Numbers in bold indicate the anticipated number 
of subjects per arm (total subjects = 600). Grey shading indicates a power of ≥80%
As shown in Table 9–1, the intended patient number of 600 with 300 subjects per arm 
(finerenone and placebo 1:1) would lead to a power of 94.2% to correctly detect all 4 
biomarkers with beneficial effect at an estimated effect size of 15% between visit 3 (4 
months) and visit 11 (36 months).
For description of the panels refer to Section 8.6. All simulations concerning sample size 
determination were conducted using R.
9.3
Analysis Set
Analysis sets are defined in Table 9–2:
Table 9–2: Analysis sets
Participant Analysis Set
Description
BFAS (Biomarker Full 
Analysis Set)
All participants with valid informed consent for this 
biomarker study and which meet study enrollment
criteria as defined in Section 5.


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9.4
Statistical Analyses
Selected demographics and disposition tables from FIGARO-DKD will be repeated for the 
biomarker subset. For details refer to the corresponding SAP.
For a detailed analysis plan and further exploratory analyses refer to SAP.
9.5
Interim Analysis
There will be no formal interim analysis. The study is unblinded.
10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the 
following:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. Any substantial 
modification of the protocol will be submitted to the competent authorities as 
substantial amendments for approval, in accordance with ICH Good Clinical 
Practice and national and international regulations.

Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations


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10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participants or their legally authorized representative and answer all questions 
regarding the study. 

Participants must be informed that their participation is voluntary. Participants will 
be required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participants. 
10.1.4
Data Protection

Participants will be assigned the same unique identifier by the sponsor as in the 
FIGARO-DKD study. Any participant records, datasets or biological samples that 
are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.5
Committees Structure
Due to the non-interventional nature, no committee structure has been established for this 
retrospective biomarker study. No additional subject data will be collected in this study.
10.1.6
Dissemination of Clinical Study Data
Results of clinical drug trials will be provided on EU Clinical Trials Register in line with the 
applicable laws and regulations. Result summaries of Bayer's sponsored clinical trials in drug 
development Phases 2, 3 and 4 and Phase 1studies in patients are provided in the Bayer Trial 
Finder application after marketing authorization approval in line with the position of the 


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global pharmaceutical industry associations laid down in the "Joint Position on the Disclosure 
of Clinical Trial Information via Clinical Trial Registries and Databases".
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in patients for medicines and indications approved in the United States and European Union 
on or after 01 JAN 2014 as necessary for conducting legitimate research.
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.
10.1.7
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data, biomarker data). The investigator is responsible for verifying that data entries 
are accurate and correct.

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling 
of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals (e.g.,
Contract Research Organizations).

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor. 
10.1.8
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported in the CRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the Source Data 
Location List (SDLL) or equivalent.

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 


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
Study monitors will perform ongoing source data review to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

No source data verification will be performed
10.1.9
Study and Site Start and Closure
First Act of Recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first patient first consent. 
Study/Site Termination
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
For study termination:

Discontinuation of further study intervention development
For site termination:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator

Total number of participants included earlier than expected.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant
and should assure appropriate participant therapy and/or follow-up.
10.1.10
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 


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support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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10.2
Appendix 2: Abbreviations
ACEI(s)
angiotensin-converting-enzyme inhibitor(s)
AKI
acute kidney injury
ARB(s)
angiotensin-receptor blocker(s)
BFAS
biomarker full analysis set
BM
biomarker
CCL2
metallomatrix protein-2
CHF
chronic heart failure
CKD
chronic kidney disease
CRF
case report form
CSP
clinical study protocol
CTGF
connective tissue growth factor
CV
cardiovascular
CVD
cardiovascular disease
CXCL16
C-C motif chemokine 16
DKD
diabetic kidney disease
eGFR
estimated glomerular filtration rate
ESRD
end-stage renal disease
GCP
good clinical practice
GFR
glomerular filtration rate
gsd
geometric standard deviation
HF
heart failure
HPLC
high performance liquid chromatography
IC
informed consent
ICF
informed consent form


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IEC
Independent Ethics Committee
IRB
Institutional Review Board
MoA
mode-of-action
MR
mineralocorticoid-receptor
MRA
mineralocorticoid-receptor antagonist
NDD-CKD
non–dialysis-dependent chronic kidney 
disease
NGS
next generation sequencing
NT-proBNP
N-terminal pro-brain natriuretic peptide
PD
pharmacodynamics
PK
pharmacokinetics
RAS
renin-angiotensin system
RCTs
randomized clinical trials
SAE
Serious adverse event
SAP
statistical analysis plan
sd
standard deviation
SoC
standard of care
T2DM
type 2 diabetes mellitus


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heart failure with left ventricular systolic dysfunction and mild (Part A) or moderate (Part B) 
chronic kidney disease versus placebo (Part A) or versus placebo and spironolactone (Part B). 
Bayer AG, D-51368 Leverkusen, Germany 26 MAR 2013.
23.
Smyth GK. Linear models and empirical bayes methods for assessing differential 
expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3.
24.
Y. BYH. Controlling the false discovery rate: a practical and powerful approach to 
multiple testing. Journal of the Royal Statistical Society Series B. 1995;57:289-300.

SAP_001.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
A non-blinded retrospective biomarker add-on study to 
FIGARO-DKD for Bioprofiling the pharMacodynamic response 
to finerenone in FIGARO-DKD subjects (FIGARO-BM) 
NCT Number: 
NCT05013008 
Document Date: 
13 JUL 2022 
 
 


Statistical Analysis Plan 
BAY 94-8862 / 21952 
Page: 1 of 9
 
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
Title page 
A non-blinded biomarker add-on study to FIGARO-DKD for 
Bioprofiling the pharMacodynamic response to finerenone in 
FIGARO-DKD subjects (FIGARO-BM) 
 
Bayer study drug 
BAY 94-8862 / Finerenone  
Study purpose: 
Biomarker study 
Clinical study 
phase: 
III 
Date: 
13 JUL 2022 
Study No.: 
 
21952 
Version: 
2.0 
Author: 
 
 
 
 
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


Statistical Analysis Plan 
Protocol No.: BAY 94-8862 / 21952 
Page: 2 of 9
 
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
 
Table of Contents 
 
Title page ................................................................................................................................... 1 
Table of Tables ......................................................................................................................... 2 
Abbreviations ............................................................................................................................ 3 
1. 
Introduction ....................................................................................................................... 3 
2. 
Study Objectives ................................................................................................................ 3 
3. 
Study Design ...................................................................................................................... 4 
4. 
General Statistical Considerations .................................................................................. 4 
4.1 
General Principles ............................................................................................................ 4 
4.2 
Handling of Missing Data ................................................................................................ 4 
4.3 
Interim Analyses and Data Monitoring ........................................................................... 4 
4.4 
Data Rules ........................................................................................................................ 4 
5. 
Analysis Sets ...................................................................................................................... 5 
6. 
Statistical Methodology .................................................................................................... 5 
6.1 
Population characteristics ................................................................................................ 5 
6.1.1 
Disposition .................................................................................................................... 5 
6.1.2 
Demography and baseline characteristics..................................................................... 5 
6.1.3 
Medical history ............................................................................................................. 5 
6.1.4 
Prior and Concomitant Medication............................................................................... 5 
6.1.5 
Treatment duration, extent of exposure and compliance .............................................. 5 
6.2 
Efficacy ............................................................................................................................ 5 
6.2.1 
Main efficacy analysis .................................................................................................. 6 
6.3 
Pharmacokinetics/pharmacodynamics ............................................................................. 6 
6.4 
Safety ............................................................................................................................... 6 
7. 
Changes to the analyses specified in the study protocol ................................................ 6 
8. 
Document history and changes in the planned statistical analysis ............................... 6 
9. 
References .......................................................................................................................... 7 
10. Appendix ............................................................................................................................ 8 
10.1 Determination of sample size........................................................................................... 8 
10.2 List of Biomarkers ........................................................................................................... 9 
 
Table of Tables 
Table 10-1 Estimated power for the primary endpoint .............................................................. 8 
 
 
 
 


Statistical Analysis Plan 
Protocol No.: BAY 94-8862 / 21952 
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Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
 
Abbreviations 
 
BFAS 
Biomarker Full Analysis Set 
gsd 
Geometric standard deviation 
LOD 
Limit of Detection 
mBFAS 
Modified Biomarker Full Analysis Set 
NPX 
Normalized Protein expression 
QC 
Quality Check 
SAP 
Statistical Analysis Plan 
sd 
Standard deviation 
1. 
Introduction 
This statistical analysis plan describes a biomarker add-on study to the Phase 3 trial FIGARO-
DKD (#17530). While the original trial, FIGARO-DKD, investigated the efficacy and safety 
of finerenone (a next-generation, non-steroidal mineralocorticoid-receptor antagonist [MRA]) 
on the reduction of cardiovascular morbidity and mortality in subjects with type 2 diabetes 
mellitus and the clinical diagnosis of diabetic kidney disease in addition to standard of care, 
this study (#21952) will solely perform exploratory biomarker analyses. All analyses will be 
done on existing leftover samples from selected FIGARO-DKD patients. Biomarkers 
described in this protocol (analytes) will be analyzed by novel proteomics technology 
(OLINK Explore®) allowing quantitative measurements of a multitude of markers in a small 
sample volume.  
This SAP considers the main analysis of only 27 biomarkers as listed in section 10.2. Further 
analyses will be specified under separate cover in a biomarker analysis plan. 
2. 
Study Objectives 
Objectives and endpoints are listed in the table below: 
Objectives 
Estimands/Endpoints 
Primary 
 
• 
To investigate long-term effect of 
finerenone treatment, in addition to 
standard-of-care, on circulating blood 
biomarkers associated with fibrosis, 
congestion, inflammation and vascular 
function 
• 
Change in plasma biomarker levels after 36 
months (Visit 11) of treatment versus 4 
months (Visit 3) of treatment in a set of 27 
pre-defined biomarkers (see section 10.2) 
Other pre-specified 
 
• 
To characterize mid- to long-term PD 
effects of finerenone and profiling the 
response to finerenone (vs placebo) in 
patients with DKD to describe biological 
pathways 
• 
Change in plasma biomarker levels after 12 
months (Visit 5), 24 months (Visit 8) and 36 
months (Visit 11), 48 months (Visit 14) 1 of 
treatment versus 4 months (Visit 3) of 
treatment 
 
1 Depending on availability of samples for visit 


Statistical Analysis Plan 
Protocol No.: BAY 94-8862 / 21952 
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Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
 
• 
To further investigate the study intervention 
and similar drugs (e.g. mode-of-action-
related effects, safety) and to further 
investigate pathomechanisms deemed 
relevant to renal and cardiovascular 
diseases and associated health problems 
• 
Change in various biomarkers (e.g. 
diagnostic, safety, pharmacodynamic, 
monitoring, prognostic or potentially 
predictive biomarkers) 
• 
To assess relationship between 
pharmacokinetics of finerenone and PD 
effects 
• 
Change in biomarker levels at 12 months 
(Visit 5), 24 months (Visit 8) and 36 months 
(Visit 11) of treatment compared to exposure 
3. 
Study Design 
Data from subjects consented under FIGARO-DKD (addendum approach) will be analyzed 
together with biomarker data acquired under FIGARO-BM.  
The pooled data is intended to include approximately 600 (or more) FIGARO-DKD patients 
from 60 (or more) sites. 
4. 
General Statistical Considerations 
4.1 
General Principles 
The statistical evaluation will be performed by using the software package SAS release 9.4 or 
higher (SAS Institute Inc., Cary, NC, USA). The main efficacy analysis will be performed in 
R on a validated server. 
4.2 
Handling of Missing Data 
Missing data will not be imputed, unless otherwise specified. 
4.3 
Interim Analyses and Data Monitoring 
Not applicable. 
4.4 
Data Rules 
The QC-flag, which is provided by OLINK, will be coded in a four-digit-code according to 
the table below: 
 
Value = 0 
Value = 1 
Description 
1st digit 
Data point passed 
OLINKs QC-metrics 
Data point failed some 
of OLINKs QC-metrics 
Pass/Fail of OLINKs predefined QC 
metrics 
2nd digit 
No outlier 
Outlier 
Outlier status, based on PCA 
3rd digit 
No outlier 
Outlier 
Outlier status, based on NPX 
median and range 
4th digit 
NPX > LOD 
NPX < LOD 
Above limit of detection or not 
Data, which is QC-flagged by OLINKs predefined QC metrics (i.e. value = 1 in the first 
digit), will be set to missing for all analyses. 
Visit 3 data will be considered as baseline measurements.  
Demographic and baseline characteristics will be obtained from the FIGARO-DKD data. 
NPX data is on log2-scale. 
For further data rules, refer to the FIGARO-DKD SAP. 


Statistical Analysis Plan 
Protocol No.: BAY 94-8862 / 21952 
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Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
 
5. 
Analysis Sets 
BFAS (Biomarker Full Analysis Set): 
All participants with valid informed consent for this biomarker study and which meet study 
enrollment criteria as defined in the study protocol. 
mBFAS (modified Biomarker Full Analysis Set): 
All participants with valid informed consent for this biomarker study, which meet the 
following criteria: 
• Study enrollment criteria as defined in the study protocol. 
• Analyzed biomarker samples at Visit 3 (4 months) and Visit 11 (36 months). 
Biomarker samples that were shipped at ambient temperatures were not analyzed. 
• On Treatment at Visit 3 (4 months) and Visit 11 (36 months) . 
6. 
Statistical Methodology 
6.1 
Population characteristics 
Population characteristics from FIGARO-DKD will be repeated for the modified Biomarker 
Full Analysis Set. Detailed information on the respective analyses are described in the 
FIGARO-DKD SAP. 
6.1.1 
Disposition 
The number of subjects overall as well as by treatment group, region, country and study site 
will be repeated for the mBFAS. 
6.1.2 
Demography and baseline characteristics  
The demographic and other baseline characteristics tables will be repeated for the mBFAS. 
For these tables the baseline definition of FIGARO-DKD will be used instead of Visit 3. 
6.1.3 
Medical history 
The medical history tables will be repeated for the mBFAS. 
6.1.4 
Prior and Concomitant Medication 
The prior and concomitant medication tables will be repeated for the mBFAS. 
6.1.5 
Treatment duration, extent of exposure and compliance 
The treatment duration, extent of exposure and compliance tables will be repeated for the 
mBFAS. 
6.2 
Efficacy 
All efficacy analyses will be performed on the 27 biomarkers listed in section 10.2. The 
remaining biomarkers analysed in the OLINK panel will only be included as prior 
information for the moderated t-test. 


Statistical Analysis Plan 
Protocol No.: BAY 94-8862 / 21952 
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Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
 
6.2.1 
Main efficacy analysis 
The primary efficacy variable is the change in plasma biomarker levels after 36 months (Visit 
11) of treatment versus 4 months (Visit 3) of treatment of subjects on treatment at both visits. 
The NPX differences (corresponding to log-transformed ratio to baseline) of biomarker levels 
will be analysed for the set of 27 pre-defined biomarkers in treatment group compared to 
placebo, based on the modified Biomarker Full Analysis Set (mBFAS) as defined in section 5.  
The hypotheses ‘H0
𝑖: 𝛽𝑖= 0’ (i=1,…,27) will be tested at a two-sided significance level of 
5%, where 𝛽𝑖 is the estimator for the difference in log-transformed ratios of biomarker levels 
of Visit 11 to Visit 3 between treatment and placebo group for the i-th of the 27 pre-specified 
biomarkers. The analysis will be adjusted for a selection of baseline characteristics and 
strafication factors. The selection of the adjustment covariates is related to the biomarker pre-
processing of OLINK. The p-values obtained from the moderated t-statistics [1] testing the 
difference between treatment and placebo group on the log-transformed ratios of biomarker 
levels from Visit 11 to Visit 3, based on the OLINK Explore 1536 panel, will be adjusted for 
multiple testing according to Benjamini and Hochberg [2]. According to this method the false 
discovery rate can be controlled by ordering the 27 p-values 𝑝𝑖 (i=1,…,27) by ascending value 
and comparing the i-th p-value with the adjusted significance level of 
𝑖
27 ∙ 5% respectively. 
Alternatively the i-th p-value 𝑝𝑖 can be adjusted as min ((min
𝑗≥𝑖
27
𝑗∙𝑝𝑖) , 1), as described by 
Benjamini, Heller and Yekutieli [3]. 
The study will be considered as successful if at least one adjusted p-value is below the 
significance level of 5%. 
Summary statistics and line plots (geometric mean with geometric standard deviation [gsd]- 
error bars over time) as well as boxplots for the ratio of Visit 11 to Visit 3 will be generated.  
6.3 
Pharmacokinetics/pharmacodynamics 
Not applicable. 
6.4 
Safety 
Not applicable. 
7. 
Changes to the analyses specified in the study protocol 
According to the protocol, the primary endpoint should be analyzed in the Biomarker Full 
Analysis Set (BFAS) including all subjects with signed informed consent. As the analysis is 
only feasible, if also a biomarker is measured, an new analysis set was defined including 
subjects with signed informed consent and a biomarker measurement. The primary analysis 
will be conducted in this modified Biomarker Full Analysis Set (mBFAS). 
8. 
Document history and changes in the planned statistical analysis 
SAP version 0.1 dated 08 DEC 2021 submitted for internal review 
SAP version 0.2 dated 11 FEB 2022 submitted for internal review 
Approved SAP version 1.0 dated 06 APR 2022 


Statistical Analysis Plan 
Protocol No.: BAY 94-8862 / 21952 
Page: 7 of 9
 
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
 
Approved SAP supplement version 2.0 dated 13 JUL 2022 
• As delivery of second batch of biomarkers will take place earlier than expected, all 
biomarkers will be included in the primary analysis as described in the protocol, 
instead of only the first batch as described in SAP version 1.0. 
• Added coding-table of OLINKs QC-flag, which was not available for SAP v. 1.0. 
• Added statement on scale of NPX data. 
• Added more detailed description of Benjamini-Hochberg procedure. 
9. 
References 
[1] G. Smyth, „Linear models and empirical Bayes methods for assessing differential 
expression in microarray experiments,“ in Statistical Application in Genetics and 
Molecular Biology. vol 3, Melbourne, 2004, pp. 1-26. 
[2] H. Y. Benajmini Y, „Controlling the false discovery rate: a practical and powerful 
approach to multiple testing.,“ Journal of the Royal Statistical Society Series B, 57, pp. 
289-300, 1995. 
[3] Y. Benjamini, R. Heller and D. Yekutieli, "Selective inference in complex research," 
Philosophical Transactions of the Royal Society, vol. 367, pp. 1-17, 2009. 
 
 


Statistical Analysis Plan 
Protocol No.: BAY 94-8862 / 21952 
Page: 8 of 9
 
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
 
10. 
Appendix  
10.1 
Determination of sample size 
Table 10-1 summarizes the results of a power simulation based on the following assumptions: 
• Two sided test, significance level of 5%. 
• Beneficial effect of finerenone on 4 of the 27 biomarkers with a ratio of biomarker 
levels from Visit 11 to Visit 3 (month 4) under finerenone of 10%, 15% or 20% 
compared to placebo. 
• Inter-subject variability of 25% (geometric standard deviation of 1.25) 
• Intra-subject variability from Visit 3 to Visit 11 of 20% (geometric standard deviation 
of 1.2) 
• Assay-variability of 10% (geometric standard deviation of 1.1) 
 
Table 10-1 Estimated power for the primary endpoint 
Treatment 
effect size  
Number of 
subjects per 
arm  
Power to detect 
4 biomarkers  
Power to 
detect 3 
biomarkers 
or more  
Power to 
detect 2 
biomarkers 
or more  
Power to detect 
1 biomarkers or more 
10%  
75 
2.5%  
5.4%  
9.5%  
16.8% 
  
100 
4.5%  
9.2%  
15.2%  
24.2% 
  
250 
26.4%  
42.0%  
55.2%  
67.4% 
  
300 
37.4%  
55.4%  
66.9%  
77.4% 
  
400 
57.6%  
74.4%  
83.6%  
90.3% 
15%  
75 
13.4%  
24.3%  
34.9%  
48.0% 
  
100 
24.2%  
39.3%  
51.8%  
63.8% 
  
250 
86.1%  
94.8%  
97.7%  
99.2% 
  
300 
94.2%  
98.8%  
99.5%  
99.9% 
  
400 
99.4%  
100.0%  
100.0%  
100.0% 
20%  
75 
45.0%  
62.4%  
74.0%  
83.4% 
  
100 
67.3%  
82.0%  
89.5%  
94.3% 
  
250 
99.9%  
100.0%  
100.0%  
100.0% 
  
300 
100.0%  
100.0%  
100.0%  
100.0% 
  
400 
100.0%  
100.0%  
100.0%  
100.0% 
Power estimations are based on the methodology described in section 9.4 and Monte-Carlo 
simulations with 10,000 iterations per scenario.Numbers in bold indicate the anticipated number of 
subjects per arm (total subjects = 600). Greyshading indicates a power of ≥80% 
As shown in Table 10-1, the intended patient number of 600 with 300 subjects per arm 
(finerenone and placebo 1:1) would lead to a power of 94.2% to correctly detect all 4 
biomarkers with beneficial effect at an estimated effect size of 15% between visit 3 (4 
months) and visit 11 (36 months). For description of the panels refer to the study protocol. All 
simulations concerning sample size determination were conducted using R. 


Statistical Analysis Plan 
Protocol No.: BAY 94-8862 / 21952 
Page: 9 of 9
 
 
Reference Number: RD-SOP-1119 
Supplement Version: 10 
 
 
10.2 
List of Biomarkers 
 
Uniprot  
Protein name 
Gene name 
P07911 
Uromodulin  
UMOD 
Q03167 
Transforming growth factor beta receptor type 3  
TGFBR3 
O15467 
C-C motif chemokine 16  
CCL16 
P02452 
Collagen alpha-1 
COL1A1 
P04275 
von Willebrand factor  
VWF 
P05121 
Plasminogen activator inhibitor 1 // PAI-1 
SERPINE1 
P16581 
E-selectin  
SELE 
Q9H2A7 
C-X-C motif chemokine 16  
CXCL16 
Q9UBP4 
Dickkopf-related protein 3  
DKK3 
P01033 
Metalloproteinase inhibitor 1  
TIMP1 
Q16627 
C-C motif chemokine 14  
CCL14 
P15144 
Aminopeptidase N  
ANPEP 
Q99969 
Retinoic acid receptor responder protein 2  
RARRES2 
P07585 
Decorin  
DCN 
P09237 
Matrilysin // MMP7 
MMP7 
Q03405 
Urokinase plasminogen activator surface receptor  
PLAUR 
P29279 
CCN family member 2 // CTGF 
CCN2 
Q13219 
Pappalysin-1  
PAPPA 
P01137 
Transforming growth factor beta-1 proprotein 
TGFB1 
Q13261 
Interleukin-15 receptor subunit alpha  
IL15RA 
P35442 
Thrombospondin-2 
THBS2 
P14780 
Matrix metalloproteinase-9  
MMP9 
P19438 
Tumor necrosis factor receptor superfamily 
member 1A  
TNFRSF1A 
P13500 
C-C motif chemokine 2 // / MCP-1 
CCL2 
P12931 
Proto-oncogene tyrosine-protein kinase Src  
SRC 
P02760 
Protein AMBP 
AMBP 
O95388 
WNT1-inducible-signaling pathway protein 1 
//CCN4 
WISP1