Evaluation of Homogeneity Between eGFR Slopes Derived From Retrospective Clinical Practice Data and eGFR Slopes Derived From Prospectively Collected, Protocol-driven Data
Phase: PHASE2
Conditions: Chronic Kidney Disease
Sponsor: Boehringer Ingelheim

001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
TITLE PAGE
Document Number:
c35391746-03
EudraCT No.
Not applicable
BI Trial No.
1366-0026
BI Investigational
Medicinal Product
Not applicable
Title
Evaluation of homogeneity between eGFR slopes derived from
retrospective clinical practice data and eGFR slopes derived from
prospectively collected, protocol-driven data
Lay Title
A study to examine past estimated Glomerular Filtration Rate
(eGFR) slope as a risk marker for rapid kidney function decline in 
people with chronic kidney disease
Clinical Phase
Phase II: “Low-interventional” study (collection of 
serum/capillary creatinine values) in parallel to phase II dose-
finding clinical program for BI 685509 (sGC activator) and BI 
690517 (AS-inhibitor)
Clinical Trial Leader
Tel.: 
Coordinating 
Investigators
Tel: 
Tel.: 
Version and Date
Version: 3.0
Date: 25 Apr 2022
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Proprietary confidential information.
2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
06 Apr 2021
Revision date
25 Apr 2022
BI trial number
1366-0026
Title of trial
Evaluation of homogeneity between eGFR slopes derived from
retrospective clinical practice data and eGFR slopes derived from
prospectively collected, protocol-driven data.
Coordinating 
Investigators
Tel: 
Tel.: 
Trial sites
Multi-centre trial
Clinical phase
II
Trial rationale
The trial intends to establish the potential role of eGFR slope as a
biomarker to determine rapid progression of chronic kidney disease. 
The eGFR slopes might subsequently be used to enrol patients at 
high renal risk into phase III trials of BI 685509/BI 690517. 
Trial objectives
Main objective: 
The aim of this trial is to examine homogeneity between eGFR 
slopes derived via retrospective and prospective eGFR values. 

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Trial 
endpoints/outcomes
Primary Outcome:
Homogeneity (eGFR slope shift table) between eGFR slopes derived 
from retrospective and prospective eGFR values.
Secondary Outcome:
Not applicable.
Trial design
Non-randomized, low-intervention design with no trial drug 
administration except background therapy. The trial will consist of 
a retrospective phase of up to 5.5 years prior to Screening visit (i.e.
visit 1), and a prospective phase of 48 weeks duration.
Total number of 
patients enrolled
600 Patients (400 fast progressors with an eGFR slope 
≥3ml/min/1.73m²/year and 200 slow progressors with an eGFR 
slope between 1 and 3ml/min/1.73m²/year)
Number of patients
on each treatment
Not applicable.
Diagnosis
Chronic Kidney Disease (CKD)
Main in- and 
exclusion criteria
Inclusion criteria:

Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial.

Patients with available medical records for data extraction.

Male or female patients aged ≥ 18 years at time of consent.

Clinical diagnosis of CKD.

Retrospective eGFR decline of at least1 ml/min/1.73m²/year.

eGFR 20 – 90 ml/min/1.73m² at Visit 1 calculated from serum 
creatinine measured by a central laboratory.

Optimal and stable background treatment according to locally 
applicable guidelines.

At least 4 serum creatinine values in the retrospective phase:
-
The most recent creatinine value not more than 6 months
prior to Visit 1 (Screening Visit).
-
The most recent and oldest serum creatinine values should
be no less than 1 year apart and no greater than 5 years apart
-
There should be no gap of creatinine values of 2 years or
longer.
Exclusion criteria:

Changes in CKD or other key background treatments (including 
dose changes) known to impact eGFR values, over the past 4 to 
8 weeks (depending on class of drugs).

Autosomal Dominant Polycystic Kidney Disease (ADPKD), 
uncontrolled lupus nephritis, in the opinion of the investigator.

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
Any iv immunosuppressive therapy in the last 3 months prior to 
Visit 1 or treatment with >45 mg prednisolone (or equivalent).

Acute kidney injury (AKI) according to the Kidney Disease: 
Improving Global Outcomes (KDIGO) definition2 in the 30 days 
prior to Visit 1 until the start of trial assessments.

Planned start of chronic renal replacement therapy during the 
trial or end stage renal disease (i.e < 15 ml/min at 2 
measurements 30 days apart) before start of trial.

Medical history of cancer or treatment for cancer in the last two 
years prior to Visit 1 (except appropriately treated basal cell 
carcinoma of the skin, in situ carcinoma of uterine cervix, and 
prostatic cancer of low grade [T1 or T2]).

Major surgery (investigator’s judgement) planned during the 
trial.

Currently enrolled in an investigational device or drug trial, i.e., 
less than 30 days before Visit 1 since ending another 
investigational device or drug trial(s) or receiving other 
investigational treatment(s).

Chronic alcohol or drug abuse or any condition that, in the 
investigator’s opinion, makes them an unreliable trial subject or 
unlikely to complete the trial.

Any medical condition or clinically relevant laboratory value, 
that will put the patient at increased risk.
Test product
N/AP
Dose
N/AP
mode of 
administration
N/AP
Comparator 
product
N/AP
dose
N/AP
mode of 
administration
N/AP
Duration of 
treatment
N/AP
Statistical methods
Retrospective and prospective slopes will be derived using a linear 
random slope model. The prospective eGFR slope for each patient 
will be derived using eGFR values in the prospective phase as the 
dependent variable and time in the prospective phase as the 
continuous independent variable with random intercept and random 
slope. The trial targets to be included in the linear random slope 
model and the most appropriate data to be used for this analysis will 
be determined based on residual variance. Details will be found in 
the Trial Statistical Analysis Plan (TSAP).
The retrospective eGFR slope for each patient will be derived
similarly using the data in the retrospective phase. Summary 

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statistics (mean, SD, min, median, max) will be provided for the 
overall population and by patient population (DKD vs. ndCKD).
The residual variance (i.e. mean squared error) of the slope estimates 
will be estimated using the linear random slope model, for both the 
retro- and prospective slopes, to assess the reliability of slope 
estimation.
Homogeneity will be primarily evaluated via a shift analysis: 
- A shift table of patients with categories of eGFR slopes of 1 to < 3 
(slow progression) and ≥ 3 mL/min/1.73m2/year (fast progression), 
in each of the retrospective and prospective phases, will be provided. 
The shift analysis will be considered as the primary analysis to 
evaluate homogeneity.
Further analyses include:
- A categorical analysis of the number and proportion of patients 
with eGFR slopes >1, > 3 and >5 mL/min/1.73m2/year will be 
provided, for both retro- and prospective phases, via tabular and 
graphical presentations.
- Histograms will be plotted for retro- and prospective slopes to 
evaluate their distributions graphically.
- The Pearson’s linear correlation coefficient between retro- and 
prospective slopes will be derived for overall population and by 
patient population.
- A descriptive summary of the proportion of “shifters” and non-
"shifters”.
A “shifter” is defined as a patient whose:
Retrospective relative to prospective slope category shifts from slow
to fast or fast to slow, respectively and
Percent change from retrospective to prospective phase slope 
exceeds 20%.
- McNemar’s test will also be conducted to further assess the 
homogeneity between retro- and prospective slopes for categories of 
< 3 and > 3 mL/min/1.73m2.
In addition to the above analyses,
- A descriptive summary of the percent change in retrospective to 
prospective slopes will be provided.

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Furthermore, the association between retrospective and prospective 
slopes will be assessed as a continuous endpoint, the details of which 
will be provided in the TSAP.
Further details of analyses will be provided in the TSAP.

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FLOW CHART
Procedures should be performed in the order they appear in this flowchart.
Trial Periods
Screening
Prospective Period
Sampling at Home 
and Clinic visits
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Weeks
Screening1
-2 to 0
Baseline
1
4
8
12
16
20
24
28
32
36
40
44
48/
EOT
Days
-14 to 0
1
28
56
84
112
140
168
196
224
252
280
308
336
Permitted visit 
window (days)
-
0
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
Informed2 consent
X
Demographics medical 
history including 
historical creatinine 
data, baseline 
conditions.
X
X
Check of in-/exclusion 
criteria
X
Background3 therapies 
(e.g: ACEis, ARBs and 
SGLT2)
X
X
X
X
X
X
Height
X
Weight
X
Physical examination
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Optional biobanking 
sampling (serum, 
plasma, urine)
X
First Morning Void
Urine4
X
X

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Trial Periods
Screening
Prospective Period
Sampling at Home 
and Clinic visits
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Weeks
Screening1
-2 to 0
Baseline
1
4
8
12
16
20
24
28
32
36
40
44
48/
EOT
Days
-14 to 0
1
28
56
84
112
140
168
196
224
252
280
308
336
Permitted visit 
window (days)
-
0
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
Train patient on Urine
and Mitra® sampling5
X
Provide Home sampling 
kits (for Urine and 
Mitra® Cartridges)
X
X
X
X
Mitra® micro sampling 
at home6
X
X
X
X
X
X
X
X
Mitra® micro sampling
at clinic visits
X
X
X
X
X
Provide training on 
smartphone/ tablet 
application including 
provision of app 
/device7
X
X
X
X
Mitra® micro sampling 
at Home paper diary 
handout (where 
electronic capture is not 
used)
X
X
X
X
Review of home Mitra®
sampling and Urine via 
application or paper 
diary (to be collected)
X
X
X
X
eGFR (central 
laboratory)8
X
X
X
X
X
X
Safety laboratory
X
X
X
X
X

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Trial Periods
Screening
Prospective Period
Sampling at Home 
and Clinic visits
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Weeks
Screening1
-2 to 0
Baseline
1
4
8
12
16
20
24
28
32
36
40
44
48/
EOT
Days
-14 to 0
1
28
56
84
112
140
168
196
224
252
280
308
336
Permitted visit 
window (days)
-
0
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
± 4
All AEs/SAEs
X
X
X
X
X
X
Completion of patient 
participation 
X

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1. Screening assessments may be conducted over more than one day. The baseline may 
start as soon as all screening procedures have been performed and laboratory results 
have been received and reviewed. Therefore the 14 days prior to enrollment that are 
indicated in the flow chart may be less. The timepoint of baseline (Visit 2) defines 
Day 1.

Screening procedures may be repeated if the patient is not eligible due to a transient 
medical condition (e.g. elevation of certain lab parameters due to an acute infection).

If the patient currently does not fulfil all inclusion/exclusion criteria but may in the 
opinion of the investigator fit the criteria later, the patient can be re-screened once if
screening into this trial is still open. Re-screening examinations will only be 
performed after a written informed consent has been obtained again from the patient
and is to be documented in relevant source document.

If screening is not completed within 14 days, the patient will be a screen failure. If 
appropriate the patient may be re-screened (see above).

Once screening assessments have been completed, a member of the trial team will 
contact the patient by phone to provide confirmation about eligibility.
2. Informed consent does not need to be obtained on the day of the screening visit but 
must be obtained before the first screening assessment. The consent discussion should 
include showing the patient the home sampling kits and explaining the procedures 
involved in the trial.
3. Any changes to the background therapies that could have an impact on eGFR slopes 
during trial must be captured in the relevant section of eCRF/source doucments.
4. First Morning Void Urine for UACR estimation. Patients are advised to collect their 
urine 2 times for each visit planned in the protocol (total 4 urine samples). i.e. a day 
before baseline visit and on baseline visit (Visit 2/Day 1) and on day before EOT visit 
and on EOT visit.
5. Training on how to use the Mitra® microsampling device and how to do the FMV 
urine sampling will be provided to the patient at the screening visit. This will include 
instructions regarding sample shipments / what to bring in for clinic visits.
6. At home (using Mitra® Device) blood samples will be collected on a biweekly basis 
for the first 12 weeks and thereafter on a 4-weekly basis until Week 48. If site visit 
coincides, Mitra® device sample will be collected in combination with venous sample 
on site. When Mitra® microsampling is performed at home, Mitra® cartridges can be 
returned by e.g. post or courier (if permitted by country-specific regulations and other 
local guidance). If shipment is not allowed locally, the patient should return Mitra®
cartridges to the investigational site.
7. If the patient chooses to, they will be able to download the app to their phone at visit 1 
or 2. The app will also be used for the video calls and can be used for patient 
reminders. If this is not possible, alternatively a paper diary will be handed out to the 
patient.

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8. eGFR at clinic visits will be determined from serum creatinine analysed by the central 
laboratory and also from Mitra® micro-sampling. To confirm eligibility the eGFR at 
screening will be used.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................7
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................15
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................18
1.4
BENEFIT - RISK ASSESSMENT.....................................................................19
1.4.1
Benefits.................................................................................................................19
1.4.2
Risks .....................................................................................................................19
1.4.3
Discussion.............................................................................................................20
2.
TRIAL OBJECTIVES AND OUTCOMES......................................................21
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY OUTCOMES........21
2.1.1
Main objective .....................................................................................................21
2.1.2
Primary outcome.................................................................................................21
2.1.3
Secondary outcome .............................................................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
3.1
OVERALL TRIAL DESIGN.............................................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP...........................................................................................24
3.3
SELECTION OF TRIAL POPULATION .......................................................24
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................24
3.3.3
Exclusion criteria ................................................................................................25
3.3.4
Withdrawal of patients from assessments ........................................................25
3.3.4.1
Discontinuation of trial.......................................................................................25
3.3.4.2
Withdrawal of consent to trial participation....................................................26
3.3.4.3
Discontinuation of the trial by the sponsor.......................................................26
4.
TREATMENTS...................................................................................................27
4.1
INVESTIGATIONAL TREATMENTS ...........................................................27
4.1.1
Identity of the Investigational Medicinal Products..........................................27
4.1.2
Selection of doses in the trial and dose modifications......................................27
4.1.3
Method of assigning patients to treatment groups...........................................27
4.1.4
Drug assignment and administration of doses for each patient......................27
4.1.5
Blinding and procedures for unblinding...........................................................27

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4.1.6
Packaging, labelling, and re-supply...................................................................27
4.1.7
Storage conditions...............................................................................................27
4.1.8
Drug accountability.............................................................................................27
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................27
4.2.1
Other treatments and emergency procedures..................................................27
4.2.2
Restrictions ..........................................................................................................28
4.2.2.1
Restrictions regarding concomitant treatment ................................................28
4.2.2.1.1
Restrictions on diet and lifestyle...........................................................................28
4.2.2.2
Contraception requirements..............................................................................28
4.3
TREATMENT COMPLIANCE........................................................................28
5.
ASSESSMENTS..................................................................................................29
5.1
ASSESSMENT OF EFFICACY........................................................................29
5.1.1
Creatinine ............................................................................................................29
5.1.2
UACR...................................................................................................................29
5.2
ASSESSMENT OF SAFETY.............................................................................29
5.2.1
Physical examination ..........................................................................................29
5.2.2
Vital signs.............................................................................................................30
5.2.3
Safety laboratory parameters ............................................................................30
5.2.3.1
Safety laboratory tests...........................................................................................31
5.2.4
Electrocardiogram ..............................................................................................31
5.2.5
Other safety parameters.....................................................................................31
5.2.6
Assessment of adverse events.............................................................................32
5.2.6.1
Definitions of AEs ................................................................................................32
5.2.6.1.1
Adverse event........................................................................................................32
5.2.6.1.2
Serious adverse event............................................................................................32
5.2.6.1.3
AEs considered “Always Serious”........................................................................32
5.2.6.1.4
Intensity (severity) of AEs....................................................................................33
5.2.6.1.5
Causal relationship of AEs....................................................................................33
5.2.6.2
Adverse Event Collection and Reporting..............................................................34
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................34
5.3.1
Assessment of pharmacokinetics .......................................................................34
5.3.2
Methods of sample collection .............................................................................34
5.3.4
Pharmacokinetic-pharmacodynamic relationship...........................................34
5.4
ASSESSMENT OF BIOMARKERS.................................................................34
5.4.1
Exploratory biomarkers.....................................................................................34
5.4.2
Pharmacogenomics biomarkers.........................................................................34
5.5
BIOBANKING ....................................................................................................34
5.5.1
Methods and timing of sample collection..........................................................35
5.6
OTHER ASSESSMENTS...................................................................................35
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................35
6.
INVESTIGATIONAL PLAN.............................................................................36
6.1
VISIT SCHEDULE.............................................................................................36
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................36

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6.2.1
Remote patient visits by telephone ....................................................................36
6.2.2
Screening period..................................................................................................37
6.2.3
Treatment period ................................................................................................37
6.2.4
Early discontinuation of Treatment..................................................................37
6.2.5
Trial completion ..................................................................................................37
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................38
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................38
7.2
PLANNED ANALYSES.....................................................................................38
7.2.1
General considerations .......................................................................................38
7.2.2
Primary outcome analyses..................................................................................38
7.2.3
Secondary outcome analyses..............................................................................39
7.2.5
Safety analyses.....................................................................................................40
7.2.6
Other Analyses ....................................................................................................40
7.2.7
Interim Analyses .................................................................................................40
7.3
HANDLING OF MISSING DATA ...................................................................41
7.4
RANDOMISATION ...........................................................................................41
7.5
DETERMINATION OF SAMPLE SIZE .........................................................41
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........42
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................42
8.2
DATA QUALITY ASSURANCE ......................................................................43
8.3
RECORDS...........................................................................................................43
8.3.1
Source documents ...............................................................................................43
8.3.2
Direct access to source data and documents.....................................................44
8.3.3
Storage period of records ...................................................................................44
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................44
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........45
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................45
8.5.2
Future use of the trial data.................................................................................45
8.6
TRIAL MILESTONES.......................................................................................46
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................46
9.
APPENDICES.....................................................................................................47
9.1
TRIAL BIOMARKER PLAN............................................................................47
10.
REFERENCES....................................................................................................48
10.1
PUBLISHED REFERENCES............................................................................48
10.2
GFR CKD-EPI FORMULA...............................................................................50
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................51
11.1
GLOBAL AMENDMENT 1 ..............................................................................51

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ABBREVIATIONS
ACEi
Angiotensin Converting Enzyme inhibitor
ADPKD
Autosomal Dominant Polycystic Kidney Disease
AE
Adverse Event
AKI
Acute Kidney Injury
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
ARB
Angiotensin Receptor Blocker
AST
Aspartate Aminotransferase
BI
Boehringer Ingelheim
BMI
Body Mass Index
BP
Blood Pressure
CA
Competent Authority
cGMP
Cyclic Guanosine Monophosphate
CKD
Chronic Kidney Disease
CKD-EPI
CKD Epidemiology Collaboration (formula)
cGMP
Cyclic Guanosine Monophosphate
COVID-19
Corona Virus Disease 2019
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT Leader
Clinical Trial Leader
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DBP
Diastolic Blood Pressure
DKD
Diabetic Kidney Disease
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EOT
End of Treatment
ESRD
End Stage Renal Disease
EU
European Union

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EudraCT
European Clinical Trials Database
FC
Flow Chart
FDA
Food and Drug Administration
FMV
First Morning Void
FUp
Follow-up
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GMP
Good Manufacturing Practice
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
K-EDTA
Potassium ethylenediaminetetraacetic acid
KDIGO
Kidney Disease: Improving Global Outcomes
LPLV
Last Patient Last Visit
MedDRA
Medical Dictionary for Drug Regulatory Activities
N/AP
Not applicable
NO
Nitric Oxide
Non DKD
Non Diabetic Kidney Disease
NSAID
Non-steroidal anti-inflammatory drug(s)
PCR
Proteine Creatinine Ratio
PD
Pharmacodynamics
PV
Pharmacovigilance 
SAE
Serious Adverse Event
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SBP
Systolic Blood Pressure
sGC
Soluble Guanylate Cyclase
SGLT2
Sodium-Glucose Co-Transporter-2
SGLT2i
SGLT2 Inhibitor
SOP
Standard Operating Procedure
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
UACR
Urine Albumin Creatinine Ratio

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Chronic Kidney Disease (CKD) is frequently characterized by poor clinical outcomes and 
high healthcare utilization costs, and its increasing worldwide prevalence represents a 
significant public health challenge[R17-2620].Although the vast majority of patients with 
CKD have early-stage disease,[R13-4387, R10-1168, R21-0998] patients with late-stage disease 
and especially those with End-Stage Renal Disease (ESRD), suffer from an especially high 
burden of comorbid conditions, have extremely poor outcomes, and consume a 
disproportionate amount of health care resources [P21-03068] It is, thus, important to explore 
additional interventions to slow kidney disease progression/transition to ESRD and 
appropriately consider patients who are most prone to experience a progressive disease 
course.
At present, only a limited number of pharmaceutical therapeutic options are available to delay 
renal decline in CKD patients. ACE inhibitors (ACEis) and angiotensin receptor blockers
(ARBs) have demonstrated efficacy in this regard. However, the relative risk reduction in the 
respective trials is only moderate (16% in RENAAL and 19% in IDNT for the composite 
primary endpoint of all-cause death, ESRD and doubling of serum creatinine). The SGLT2 
inhibitor canagliflozin, has shown a relative risk reduction of 30% for the composite endpoint 
of doubling of serum creatinine, ESRD or renal/CV death on top of Standard of Care 
(SoC).The recently published results from DAPA-CKD confirm and expand the CREDENCE 
data showing a 39% relative risk reduction for the primary composite endpoint of sustained 
decline in eGFR of at least 50%, end stage renal disease and CV/renal death. Notably, the 
results in DAPA-CKD are very similar for the diabetic and non-diabetic sub-populations of 
the study. In summary, data from the canagliflozin and dapagliflozin programs are largely 
consistent and render it likely that SGLT2 inhibitors will become an essential pillar for the 
treatment of renal patients in the future.
Despite the advances summarized in the paragraph above, the residual renal and 
cardiovascular risk for patients remains unacceptably high, warranting continued efforts to 
provide further treatment options. Unfortunately, in has been challenging in the past to 
accurately identify the patients at considerably increased risk of suffering renal function 
decline and subsequent renal outcome events. One of the traditional ways to determine risk in 
this population has been through the measurement of single/few eGFR as well as UACR 
values and use this approach to include patients into the respective clinical outcome trials. 
Although this approach is relatively easy to implement and does definitely identify a certain 
percentage of those at highest risk, it is far from optimal. There is a considerable percentage 
of patients who display increased UACR / decreased eGFR values but will ultimately not 
decline or only decline very slowly. The reverse does also occur, i.e. patients with UACR / 
eGFR wirhin an acceptable range that subsequently deline precipitously and thus get exposed 
to a significantly elevated risk of renal events. Hence, it would benefit patients and clinicians 
to have an improved method of identifying high-risk patients.
One approach to potentially better identify these patients at increased risk could be the use of 
eGFR slopes, i.e. considering not only single/few eGFR values but calculating an eGFR slope 

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that would represent the development of eGFR over time and thus be a more realistic 
reflection of renal function over a longer time frame.
This study is intended to investigate the usefulness of eGFR slopes derived from
retrospective routine clinical practice data, compare those retrospective slopes with those 
generated in a prospective fashion and successively identify rapidly progressing CKD 
patients. It has been devised as a supportive study to the currently ongoing /planned phase II 
programs (BI 685509, BI 690517 etc.) to support inclusion of high-risk renal patients into
future phase III trials.
1.2
DRUG PROFILE
Not applicable.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Many studies have confirmed the importance of eGFR and albuminuria as measures of 
progressive renal function loss. However, baseline eGFR and albuminuria do not correlate 
with progression for all individuals. A large proportion of individuals do not progress despite 
their high albuminuria and low eGFR values, and many individuals progress without having 
high levels of albuminuria and/or low eGFR. Including non-progressive patients in clinical 
trials results in the need for longer and larger clinical trials. Given that fast progressing CKD 
disease is associated with worse clinical outcomes, it is critical for clinicians to appropriately 
determine a progressing patient. While many other factors influence the rate of progression, 
including age,[R21-1003, R21-1004] comorbid conditions, such as diabetes mellitus or 
hypertension,[ R21-1004, R15-5162, R21-0999] race-ethnicity,[R21-1000] and genetic 
mutations[R21-1001], these factors do not completely account for the observed variability in 
kidney disease progression [R21-1002].
Current clinical practice guidelines consider assessing the future risk of kidney disease 
progression from the past slope of eGFR over time [R13-4387]. Despite the general 
acceptance of this practice, only a limited number of studies have evaluated past eGFR 
decline as a predictor of ESRD after taking into account the current level of eGFR [R21-1138]. 
In clinical practice, both the level of creatinine at the point of assessment and its past eGFR 
trajectory over time are often available, but the relative contribution of each to the risk of 
subsequent ESRD is not clear.  As an additional aspect, other factors, such as diet, 
medications, background diseases and different laboratories might also affect past eGFR 
values and therefore slopes and must not be disregarded in this context.
During a Scientific Advice Meeting in 2019 with the European Medicines Agency (EMA), 
the use of eGFR slopes was discussed as a potential future endpoint in clinical trials as well 
as a potential risk marker for renal events, the latter to a lesser degree though. 
During this meeting and based on subsequent additional written feedback, EMA generally 
supported this approach but advised further evaluation of retrospective eGFR slopes and how 
this may be based on data available from clinical patient records. To further inform the use of 
retrospective eGFR measures in the establishment of eGFR slopes, and subsequent selection 

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of high renal risk patients, BI intends to conduct a study to examine retrospective eGFR 
slopes and generate additional prospective data among the same population. 
This study will provide information on the availability, frequency and continuity of 
retrospective eGFR and UACR/PCR data in patient medical records, as collected via routine 
clinical practice. The study will also compare eGFR slopes derived via retrospective serum
creatinine values collected up to 5.5 years prior to visit 1 in routine clinical practice, with 
prospectively generated eGFR values and resulting slopes. In addition, methodological 
aspects of slope establishment, such as varying baseline eGFR and UACR/PCR levels, length 
of baseline period,
 
 will be explored.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking section 5.5. If the patient agrees, banked samples may be 
used for future biomarker research and drug development projects, e.g. to identify patients 
that are more likely to benefit from a treatment or experience an adverse event (AE), or to 
gain a mechanistic or genetic understanding of drug effects and thereby better match patients 
with therapies.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
This study will provide additional information on how high-risk renal disease patients might 
be more accurately identified for future trials. It will contribute to providing the participating 
patients with a better assessment of their own risk for progression and potentially respective 
treatment considerations. Patients may also benefit from more frequent clinical monitoring as 
a result of being part of the study. In conclusion, the benefit/risk assessment is considered 
acceptable.
1.4.2
Risks
During this study, 1 venous blood sample for serum creatinine (5 mL) will be collected at 
screening, and 3 venous blood samples for serum creatinine (5 mL), chemistry (5 mL), and 
hematology (2 mL) will be collected during site visits at baseline, and Week 12, Week 24, 
Week 36 and Week 48 (end of study). 2 tubes (5 mL and 2 mL) are used for assessing the
safety parameters (chemistry and hematology) and 1 tube (5 mL) for serum creatinine. No 
office/hospital visits beyond those will be required. Additional blood collection by finger 
prick (2 x 10 microL per time point) will be conducted on a biweekly basis for the first 12 
weeks and every 4 weeks thereafter at home (until Week 48) using the Mitra® micro 
sampling device*. There is minimal risk posed to patients with the use of the Mitra® device 
sampling. Most CKD patients are expected to provide venous blood samples for eGFR 
assessment at least every 3 – 6 months as a part of clinical practice. Hence, the blood 
collection planned in this study will be associated with a minimal risk for patients beyond 
what they would be exposed to in routine clinical practice.
* The Mitra® Microsampling Device is CE-certified under the European Directive on In 
Vitro Diagnostic Medical Devices (Council Directive 98/79/EC) and was registered at the 

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U.S. Food and Drug Administration (FDA) as a Class 1 Medical Device. A method for the 
measurement of creatinine in human capillary blood using LC-MS/MS (including extraction 
of the sample from the inert porous plastic tip of the Mitra® device and stability for up to 
three months) has been established following the 2018 FDA Guidance on Bioanalytical 
Method Validation.
Sampling with the Mitra® Microsampling Device is straightforward: after performing a 
finger prick with the supplied lancet the device is placed adjacent to the forming blood drop 
and approximately 10 microL of blood is absorbed by the porous tip of the device. This is 
done for both tips in the cartridge, which is then closed and sent away for analysis. The 
procedure can be easily performed by the patient or a caregiver.
1.4.3
Discussion
No study drug administration is involved in the prospective phase of this study. However, all 
patients will be on stable background standard of care therapy according to locally applicable 
guidelines. Moreover, the site visit schedule approximates routine practice for progressive 
CKD patients, and Mitra® sampling risks are very low. Patients may also benefit from more 
frequent clinical monitoring as a result of being part of the study. It will provide the 
participating patients with a better assessment of their own risk for progression and 
potentially respective treatment considerations.
Overall, in the context of the unmet medical need in fast progressing CKD patients, careful 
monitoring throughout the trial and the limited risk associated with venus/capillary blood 
collection the benefit-risk evaluation of the study is considered favourable for the intended 
trial population.

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2.
TRIAL OBJECTIVES AND OUTCOMES
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY OUTCOMES
2.1.1
Main objective
The aim of this trial is to examine homogeneity between eGFR slopes derived via 
retrospective and prospective eGFR values.
2.1.2
Primary outcome
Homogeneity (eGFR slope shift table) between eGFR slopes derived from retrospective and 
prospective eGFR values.
2.1.3
Secondary outcome
Not applicable.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
This trial is a multicentre, non-randomized, low-intervention trial that does not involve 
administration of study drug and includes both a retrospective and prospective phase in 
patients with chronic kidney disease who are on stable background treatment according to 
respective local guidelines.
The trial targets to enrol at least 33% (up to 60%) of non DKD patients; the remaining 
patients will consist of DKD patients.
In this study, eGFR slopes will be calculated from historically available creatinine values 
(retrospective phase of study) that were collected during routine clinical care of the patients 
prior to enrolment in this study. In the prospective phase of the study, creatinine values will 
be systematically collected at predefined time points. The eGFR slopes will then be 
calculated from the retrospective and prospective phases.
A schematic illustration of the trial design is presented in Figure 3.1: 1.
# Retrospective phase: At least 4 Serum 
Creatinine measurements at minimum. However, it 
is desirable to have as many as available. 
Prospective phase: 48 weeks duration.
Site visits – Blood sample collection at baseline and every 12 
weeks (i.e. Week 12, Week 24, Week 36, Week 48). Urine sample 
collection (for UACR determination) at baseline and Week 48. At 
home (using Mitra® Device) blood samples will be collected on a 
biweekly basis for the first 12 weeks and thereafter on a 4-weekly
basis until Week 48. If site visit coincides, Mitra® device sample 
will be collected in combination with venous sample on site. 
* Screening period of up to 2 weeks between retrospective and prospective phases.
# Baseline visit is considered as Visit 2/Day1 of prospective phase
Figure 3.1: 1 Trial design
Patients will be screened in the trial once they have signed the informed consent. They will 
undergo a screening period of up to 2 weeks from the time of informed consent. All available 
historical eGFR values, UACR/PCR within the 5.5 years prior to screening Visit 1 will be 

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collected for each patient. Patients who successfully complete the screening and meet the 
inclusion / exclusion criteria, including the availability of requisite historical eGFR data, will 
qualify for enrollment into the 48 weeks prospective phase of the study (see Figure 3.1: 1).
Retrospective phase:
To be documented in the CRF:

All available serum creatinine values (at least 4 serum creatinine values should be 
available for a patient with the most recent creatinine value not more than 6 months prior 
to Visit 1 (Screening Visit). The most recent and oldest serum creatinine values should be 
no less than 1 year apart and no greater than 5 years apart and there should be no gap of 
creatinine values of 2 years or longer.

All available UACR values or respective values to determine UACR.

All available PCR values or respective values to determine PCR.

Medications that could potentially have an impact on calculation of slopes during the 
retrospective phase e.g. ACEi/ARB.

Medical history as outlined in the CRF.
Prospective Phase:
The serum eGFR and UACR value obtained at the Baseline Visit will be used as the first 
eGFR and UACR value. The prospective eGFR slope (i.e. the individual rate of eGFR 
decline) will be established over 48 weeks, during which time the patient will be on 
background optimal standard of care. Patients need to attend the investigational site in person 
six times during the study (at Screening Visit, baseline visit, 12 weeks, 24 weeks, 36 weeks
and 48 weeks visit) for venous blood samples, and collection of data with regards to the 
patients’ current treatments and other medications. In order to minimize the number of visits 
required, all other eGFR values will be calculated from the finger prick blood samples taken 
at home using the Mitra® micro sampling device during the prospective phase of the study. 
Mitra® samples taken at home between visits will be shipped by the patient to the central 
laboratory or the site, if allowed by local regulations. Where this is not possible alternative 
arrangements will be made, e.g. samples taken to the investigational site. Samples taken 
directly prior to a physical visit will be taken to the site to be processed by the site staff. To 
allow a comparison of the patient kits with conventional collection methods, sites will use the 
Mitra® kits to process samples in parallel to the collection of a certain volume of blood. Both 
serum and Mitra® measurements will form the basis for the eGFR slope calculation.
Patients will be advised to collect 2 UACR samples for each visit planned in the protocol 
(total 2 visits and 4 urine samples). i.e a day before baseline visit and on baseline visit (Visit 
2/Day 1) and also on day before EOT visit and on EOT visit.  The patient will be equipped 
with urine collection containers to sample urine from their First Morning Voids in collection 
container (latter only for visit at which urine collection is scheduled, i.e. baseline and Week 
48).
Throughout the study duration, AEs as defined in section 5.2.6.2 and changes to background 
medication will be collected, documented and reported. Patients who receive ARBs, ACEis 
and SGLT2 inhibitors will be required to maintain stable treatment during the trial duration.

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At the end of the 48 weeks prospective phase period, or at the time that a patient is 
permanently discontinued, patients will have an EOT visit. Database lock will occur after the 
last patients have completed their final visit.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
Not applicable.
3.3
SELECTION OF TRIAL POPULATION
The study population will consist of both diabetic chronic kidney disease (DKD) as well as 
non-diabetic chronic kidney disease (ndCKD). The proportion of ndCKD population required 
to be enrolled in the study is in the range of 33%-60%. The selected Chronic Kidney Disease 
population will only include approximately 33% of patients with eGFR decline at least 1 
ml/min/1.73m²/year and approximately 66% of rapid progressors with eGFR decline of at 
least 3ml/min/1.73m²/year or 8% eGFR decline/year determined via retrospective eGFR 
assessments.
3.3.1
Main diagnosis for trial entry
Both diabetic chronic kidney disease as well as non-diabetic chronic kidney disease patients 
will be screened.
3.3.2
Inclusion criteria
1. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
2. Patients with available medical records for data abstraction to meet the objectives of 
the study.
3. Male or female patients aged ≥ 18 years at time of consent.
4. Body Mass Index (BMI) ≥ 18.5 and < 50 kg/m2 at Visit 1.
5. Clinical diagnosis of CKD.
6. eGFR decline of at least 1ml/min/1.73m²/year based on historical data from
(electronic) medical records.
7. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) 20 
– 90 ml/min/1.73m² at Visit 1 calculated from serum creatinine measured by a central 
laboratory.
8. Patients are expected to be on optimal and stable background treatment (according to 
local therapy guidelines).
9. At least 4 serum creatinine values in the retrospective phase:
- The most recent creatinine value not more than 6 months prior to Visit 1
(Screening Visit).
-
The most recent and oldest serum creatinine values should be no less than 1 year 
apart and no greater than 5 years apart.
- There should be no gap of creatinine values of 2 years or longer.

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3.3.3
Exclusion criteria
1. Changes in CKD or other key background treatments (including dose changes) known 
to impact eGFR values, over the past 4 weeks for ACEis and ARBs and 8 weeks for 
SGLT2 inhibitors prior to Screening.
2. Autosomal Dominant Polycystic Kidney Disease (ADPKD), uncontrolled lupus 
nephritis, in the opinion of investigators.
3. Any iv immune suppression therapy within the last 3 months prior to Visit 1 or 
anyone currently on >45 mg prednisolone (or equivalent).
4. Acute kidney injury (AKI) according to the Kidney Disease: Improving Global 
Outcomes (KDIGO) definition in the 30 days prior to Visit 1 until the start of trial 
assessments.
5. Planned start of chronic renal replacement therapy during the trial or end stage renal 
disease (i.e < 15 ml/min at 2 measurements 30 days apart) before start of trial 
assessments.
6. Medical history of cancer or treatment for cancer in the last two years prior to Visit 1 
(except appropriately treated basal cell carcinoma of the skin, in situ carcinoma of 
uterine cervix, and prostatic cancer of low grade [T1 or T2]).
7. Major surgery (investigator’s judgement) planned during the trial.
8. Currently enrolled in an investigational device or drug trial, i.e., less than 30 days 
before Visit 1 since ending an investigational device or drug trial(s) or receiving 
investigational treatment(s).
9. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, 
makes them an unreliable trial subject or unlikely to complete the trial.
10. Any medical condition or clinically relevant laboratory value, that will put the patient 
at increased risk.
3.3.4
Withdrawal of patients from assessments
Patients may discontinue assessments or withdraw consent to trial participation as a whole
(“withdrawal of consent”); please see sections 3.3.4.1 and 3.3.4.2 below.
Every effort should be made to keep the patients in the trial, if possible. Measures to control 
the withdrawal rate include careful patient selection, appropriate explanation of the trial 
assessments and procedures prior to trial enrolment, as well as the explanation of the 
consequences of withdrawal. 
The decision to discontinue the trial or withdraw consent to trial participation and the reason
must be documented in the patient files and CRF. If applicable, consider the requirements for 
Adverse Event collection reporting (please see sections 5.2.6.1 and 5.2.6.2).
3.3.4.1
Discontinuation of trial 
An individual patient will discontinue trial if:

The patient wants to discontinue trial assessement, without the need to justify the 
decision.

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
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future. 

The patient needs to take concomitant medication that is not permitted, see section 4.2.2.
However, if the patient needs to modify a dose, where a stable dose is permitted only, this 
will not automatically require a discontinuation. In this case the sponsor should be 
consulted.

The patient progresses to end stage renal disease and needs to obtain renal replacement 
therapy.

The patient experiences a severe infection, e.g. with SARS-CoV-2, as determined by the 
investigator.

The patient can no longer provide trial assessments for any other medical reasons such as 
surgery, serious adverse events with other concomitant medications, adverse events, or 
other diseases.

The patient has missed trial assessments for at least 2 consecutive site visits or has not 
given the trial assessments at a total of 60 days during the trial. In case of a temporary 
reason, trial assessment should be restarted if medically justified.
Please see section 6.2.5 for details of the procedures to be performed if trial assessments are
discontinued.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial discontinuation and withdrawal of 
consent to trial participation.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site.

New trial data or information invalidating the earlier positive benefit-risk-assessment, 
please see section 1.4.

Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
No trial medication will be provided or administered by Boehringer Ingelheim.
4.1.1
Identity of the Investigational Medicinal Products
Not applicable.
4.1.2
Selection of doses in the trial and dose modifications
Not applicable.
4.1.3
Method of assigning patients to treatment groups
Not applicable.
4.1.4
Drug assignment and administration of doses for each patient
Not applicable
4.1.5
Blinding and procedures for unblinding
Not applicable
4.1.6
Packaging, labelling, and re-supply
Not applicable
4.1.7
Storage conditions
Not applicable
4.1.8
Drug accountability
Not applicable
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
No other treatments and standard of care medications are provided as part of this clinical trial 
Also, there are no special emergency procedures to be followed.

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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Patients should keep their existing therapies as stable as possible, particularly their therapy 
with ACEi/ARB or SGLT2 inhibitors from screening at Visit 1 until the End of trial visit. It is 
recommended to avoid medication exposures that might impact eGFR slopes in a clinically 
relevant manner. New therapies should only be initiated if necessary. Should an investigator 
anticipate starting a patient on ACEi/ARB or SGLT2 inhibitor over the subsequent 48 weeks
after enrolment, the investigator is to judge with caution if the respective patient should be 
included in the trial since initiating the patient on ACEi/ARB or SGLT2i could distort the 
results of this study. Any specific usage of such relevant drugs must be reported in relevant 
source documentation and filed in the investigator site file. Medications that could potentially 
have an impact on calculation of slopes during the retrospective phase e.g. ACEi/ARB, 
should be documented in the CRF.
4.2.2.1.1
Restrictions on diet and lifestyle
There are no restrictions on lifestyle. However, any drastic changes of diet and lifestyle 
during the trial should be avoided.
4.2.2.2
Contraception requirements
Not applicable as there is no trial drug involved.
4.3
TREATMENT COMPLIANCE
N/AP

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
No efficacy assessments are planned in this trial.
5.1.1
Creatinine
Serum creatinine:
Samples for the determination of serum creatinine will be collected at the time points 
indicated in the flow chart and analysed at a central laboratory using the enzymatic method.
Creatinine from capillary blood:
Using the Mitra® microsampling device (with two tips per cartridge, each capable of 
absorbing 10 uL of blood) two blood samples will be collected after a finger prick with the 
supplied lancet at the time points indicated in the flow chart. The closed cartridge will be 
shipped to the central laboratory. Details of shipment procedures will be provided in the 
laboratory manual in the ISF and the instructions to the patient. Samples will be analysed 
using a validated mass spectroscopy method.
All capillary blood samples remaining at the end of the study will be destroyed no later than 
the sign-off of the clinical trial report.
5.1.2
UACR
Urine samples for the determination of urine albumin creatinine ratio (UACR) will be 
collected by the patient at home from first morning void (FMV) urine at the baseline visit and 
the end of trial visit. At each visit, the patient will collect an FMV urine sample on the day 
before the visit and the day of the visit itself. An appropriate number of urine cups will be 
provided to the patient for collection at home. Patients will be reminded e.g. by telephone 
contacts ahead of sampling time points on how to collect and store their urine samples. 
Further collection and sample storage instructions are given in the laboratory manual in the 
ISF and instructions to the patient.
Urinary albumin and creatinine will be analysed at a central laboratory using routine 
validated methods. 
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the flow
chart. Assessments include at a minimum general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, and skin. 
Measurement of height and body weight will be performed at the time points specified in the 
flow chart.
The results must be included in the source documents available at the site. 

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5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flow chart, prior to blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. BP measurements 
should be recorded to the nearest 1 mmHg. The results must be included in the source 
documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. For the sampling time 
points please see the flow chart.
A central laboratory result will be used to confirm eGFR for eligibility; the respective 
reference ranges will be provided in the ISF.
To ensure sufficient hydration, patients should be strongly encouraged to come not fasted to 
their study visits.
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. Where samples are collected by the patient 
directly, appropriate instructions in lay language will be provided.
The central laboratory will provide reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to section 5.2.6).
Lab tests may need to be repeated in case of required medical follow-up due to an adverse 
event or if a test was not successful due to incorrect specimen handling or storage. 
To test the eGFR throughout the trial, the site will collect a small capillary blood volume 
from the patient with the Mitra® tool at visits indicated in the flow chart. The Mitra® tool will 
also allow the patient to collect blood at home. Therefore, at home patients will need to 
collect one blood sample on their own (one Mitra® cardridge with two sampling tips) and 
ship them to the central lab or the site, if permitted by local legislation. Alternatively, the 
patient will need to take the specimens to the site directly.
The central laboratory will transfer the results of the analysis to the CRO.
The CKD-EPI Equation is used for reporting eGFR based on serum creatinine (see appendix 
section 10.2).

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5.2.3.1
Safety laboratory tests
Safety lab samples will be collected at the time points shown in the flow chart. Sample
analyses will be performed at a central lab. The results of the lab tests must be transferred to 
the investigator who ensures medical review and proper documentation in the eCRF. 
Clinically relevant procedure related safety issues have to be entered as adverse event (if 
applicable, see 5.2.6.2). The required safety lab parameters are:
Table 5.2.3.1: 1
Safety laboratory tests
Short name
Name assay
Substrate
Other information
Blood serum
HGB
Haemoglobin
Haemoglobin
N/
RBC
Red blood cell count
Erythrocytes
N/
WBC
White blood cell count
Leukocytes
N/
PLTCT
Platelets
Platelets
N/
SGPT
ALT/SGPT, SGPT
Alanine 
Aminotransferase
N/
SGOT
AST/SGOT, SGOT
Aspartate 
Aminotransferase
N/
ALKP
Alkaline phosphatase
Alkaline 
Phosphatase
N/
TBILI
Bilirubin, total
Bilirubin
N/
UREA
Urea
Urea
N/AP
NA
Sodium
Sodium
N/
K
Potassium
Potassium
N/
5.2.4
Electrocardiogram
N/AP.
5.2.5
Other safety parameters
N/AP

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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following are also considered AEs:

Worsening of the underlying disease or of other pre-existing conditions.

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only, if applicable.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:

results in death,

is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe,

requires inpatient hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability or incapacity,

is a congenital anomaly / birth defect,

is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency (EMA) initiative on Important Medical 
Events, Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the ISF. These events should always 
be reported as SAEs as described in section 5.2.6.2.

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Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.5
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the concomitant mediations being used in 
this trial, considering all relevant factors, including pattern of reaction, temporal relationship, 
de-challenge or re-challenge, confounding factors such as concomitant medication, 
concomitant diseases and relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

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5.2.6.2
Adverse Event Collection and Reporting
This interventional clinical trial does not involve administration of any study medication. 
Therefore, the following applies:
The following must be collected and documented on the appropriate CRF(s) by the 
investigator: from signing the informed consent onwards until the End of trial visit - all AEs
associated with trial procedure (non-serious and serious). AEs have to be followed up until 
they are resolved.
In addition, the investigator should report to BI all adverse events related to any BI products
as determined by the investigator via established channels of reporting in the country e.g. 
local forms or call center number. This includes any drug exposure during pregnancy with 
and without adverse events.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
No Pharmacokinetic assessments planned in this trial.
5.3.2
Methods of sample collection
N/AP
5.3.4
Pharmacokinetic-pharmacodynamic relationship
N/AP
5.4
ASSESSMENT OF BIOMARKERS
5.4.1
Exploratory biomarkers
No exploratory biomarker assessments planned in this trial.
5.4.2
Pharmacogenomics biomarkers
No pharmacogenomic investigations are planned.
5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements.

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5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see flow chart.
Approximately 20 mL blood will be drawn for plasma and serum banking purposes. In 
addition, 10 mL of urine will be collected.
5.6
OTHER ASSESSMENTS
N/A
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to estimate eGFR slopes and UACR to monitor the risk of dieseae 
progression in an appropriate way.
Therefore, the appropriateness of all measurements applied in this trial is given.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All visits should be scheduled according to the flow chart. Each visit date (with its window) 
is to be counted from Day 1 (Baseline visit). If any visit has to be rescheduled, subsequent 
visits should follow the original visit schedule.
All trial visits should be initiated preferentially in the morning. Patients should be instructed 
to take their FMV urine samples at home before attending the scheduled visit at the study 
site.
To ensure sufficient hydration, patients should be strongly encouraged to come not fasted to 
their study visits.
Unscheduled visits will be possible at the discretion of the investigator at any time in order to 
check the safety of the patient e.g following an interruption of 2 consecutive site visits. 
If the reason for removal of a patient from treatment is an adverse event or a clinically 
significant laboratory test result, the patient must be followed-up until complete resolution or 
stabilisation of the event or until follow-up is agreed adequate by the Investigator and 
sponsor.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study measurements and assessments should be performed according to the flow chart. All 
assessments should be performed preferentially in the morning.
Where the following assesments occur at a visit they should be performed in the following 
order:

Vital signs – see flow chart for when additional measurements are required

Venous Blood draws and Mitra® sampling – (see flow chart)
Please refer to the following sections for specific details about alternatives to visits at the site
(the type of visit needs to be recorded on the CRF):

Flow chart – overview of what procedures should be performed and at what timepoints.

Section 5.2.1 – Physical exam

Section 5.2.2 – Vital signs

Section 5.2.3 – Safety laboratory parameters

Section 6.2.1 –Remote patient visits by telephone
6.2.1
Remote patient visits by telephone
Remote patient visits conducted by telephone can replace scheduled patient visits at the site, 
if COVID-19 or similar pandemic restrictions are in place and due to this pandemic a patient 
is not able or willing to travel to the site and if local regulatory and legal regulations allow 
telephone visits. Implementation of remote patient visits by telephone need to be approved by 
the sponsor. Local regulatory and legal requirements of the participating country still apply.

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6.2.2
Screening period
Screening Period
No trial procedures should be done unless the patient has consented to taking part in the trial. 
Once informed consent is obtained, the patient is enrolled in the trial and has started 
screening. The patient should be recorded on the enrolment log or relevant source document
as a screened patient before any other activites are performed. Patients who do not fulfil all 
eligibility criteria for a reason stated in the protocol should be registered as a screen failure in 
relevant source document. Patients who do not fulfil all eligibility criteria for a reason that 
later resolves and allows eligibility criteria to be met, may be re-screened after discussion 
with the sponsor. Re-screening will only be allowed once.
The footnotes to the flow chart provide details about when screening procedures may be 
repeated and when re-screening is allowed.
6.2.3
Treatment period
N/AP
6.2.4
Early discontinuation of Treatment
N/AP
6.2.5
Trial completion
Patients should be encouraged to complete all visits and procedures up to the Week 48 visit 
which is at the same time the End of Trial Visit.
Patients who discontinue the trial prematurely and who do not withdraw their informed 
consent should return for a trial completion visit or End of Trial visit and undergo the 
assessments as indicated in the flow chart. All samples including venous blood, Mitra® (for 
creatinine values) and UACR should be collected in addition to safety samples.  

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
No formal statistical hypothesis is planned for this trial.
7.2
PLANNED ANALYSES
7.2.1
General considerations
All available patient data will be included for the estimation of the retrospective slope. The 
Patient data will be stratified according to SGLT2 inhibitors use. Data up to the time at which 
patients dropped, either in or out of SGLT2 or an unexpected case where a change in 
ACEi/ARB dose occurs, will be included in the estimation of the prospective slope.
 
 
Further Analysis Sets will also be defined in the TSAP, if needed.
7.2.2
Primary outcome analyses
Retrospective and prospective slopes will be derived using a linear random slope model. The 
prospective eGFR slope for each patient will be derived using eGFR values in the prospective 
phase as the dependent variable and time in the prospective phase as the continuous 
independent variable with random intercept and random slope. The trial targets to be included 
in the linear random slope model and the most appropriate data to be used for this analysis 
will be determined based on residual variance.  Details will be found in the TSAP.
The retrospective eGFR slope for each patient will be derived similarly using the data in the 
retrospective phase. Summary statistics (mean, SD, min, median, max) will be provided for 
the overall population and by patient population (DKD vs. ndCKD).
The residual variance (i.e. mean squared error) of the slope estimates will be estimated using 
the linear random slope model, for both the retro- and prospective slopes, to assess the 
reliability of slope estimation.
Homogeneity will be primarily evaluated via a shift analysis: 

A shift table of patients with categories of eGFR slopes of 1 to < 3 (slow progression) and 
≥ 3 mL/min/1.73m2/year (fast progression), in each of the retrospective and prospective 
phases, will be provided. The shift analysis will be considered as the primary analysis to 
evaluate homogeneity.
Further analyses include:

A categorical analysis of the number and proportion of patients with eGFR slopes >1, > 3 
and >5 mL/min/1.73m2/year will be provided for both retro- and prospective phases via 
tabular and graphical presentations.

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
Histograms will be plotted for retro- and prospective slopes to evaluate their distributions 
graphically.

The Pearson’s linear correlation coefficient between retro- and prospective slopes will be 
derived for overall population and by patient population.

A descriptive summary of the proportion of “shifters” and non-"shifters”.

A “shifter” is defined as a patient whose:
1) Retrospective relative to prospective slope category shifts from slow to fast or fast 
to slow, respectively and
2) Percent change from retrospective to prospective phase in slope exceeds 20%. 

McNemar’s test will also be conducted to further assess the homogeneity between retro-
and prospective slopes for categories of < 3 and ≥ 3 mL/min/1.73m2.
In addition to the above analyses,

- A descriptive summary of the percent change in retrospective to prospective slopes will 
be provided.
Furthermore, the association between retrospective and prospective slopes will be assessed as 
a continuous endpoint, the details of which will be provided in the Trial Statistical Analysis 
Plan (TSAP).
7.2.3
Secondary outcome analyses
Not applicable.

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7.2.5
Safety analyses
The safety analyses are limited to the “AE’ related to study procedures. Adverse events will 
be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). Standard 
BI summary tables and listings will be produced. 
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of (MedDRA) at 
database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Further details will be provided in the TSAP.
7.2.6
Other Analyses
Other analysis details will be documented in the TSAP.
7.2.7
Interim Analyses
An interim analysis can be considered at any time but might be triggered by the following 
combinations of number of patients and follow-up in case of substantial recruitment or 
feasibility issues:
300 patients with 40 weeks follow-up
400 patients with 32 weeks follow-up
500 patients with 24 weeks follow-up.
The purpose of a potential interim analysis is based on recruitment/feasibility. Its purpose is
to best utilize all available data collected up to these timepoints, if it is identified that 
enrolment is not sufficient to reach our recruitment goal by the currently targeted study end.
If performed, the appropriate type of analyses will be based on the percentage of the total 
number of expected patients in the cohort and what types of data are present, at the timepoint 
at which the interim analysis occurs. At a minimum, summary statistics for study endpoints 
will be provided for the overall population and by-patient population (DKD vs. ndCKD) for 
both the retrospective and prospective phases. Additionally, shift tables of patients to 
categories of retro- and prospective phases will also be provided.

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Please note, however, if it is observed that enrolment meets or execeeds the expected 
recruitment goals, then the right is reserved not to perform the above proposed interim 
analyses.
7.3
HANDLING OF MISSING DATA
In the primary analysis of all continuous endpoints, missing data will not be imputed. 
Missing or incomplete AE dates will be imputed according to BI standards.
 
 
7.4
RANDOMISATION
Not applicable.
7.5
DETERMINATION OF SAMPLE SIZE
The trial will be conducted in a cohort of 600 patients, pending feasibility and enrolment 
period. To obtain a good representation of subjects across eGFR slopes spectrum, 600 
patients will be enrolled. The goal is to achieve 400 fast progressors with an eGFR slope 
≥3ml/min/1.73m²/year and 200 slow progressor patients with an eGFR slope between 1 and 
3ml/min/1.73m²/year).
The sample size determination is not based on statistical considerations, but on feasibility, 
and there is no formal statistical hypothesis defined in the study. However, the sample size of 
600 patients is considered adequate to evaluate the homogeneity of the retro- and prospective 
slopes. If the true (unobserved) proportion of patients have an eGFR slope ≥ 3
mL/min/1.73m2 based on retrospective data and in the prospective observed period is 70%, 
600 patients will provide an estimate of the proportion of at least 67% with a probability of 
95%.
On the other hand, if the true (unobserved) proportion of patients have an eGFR slope ≥3 
mL/min/1.73m2 based on retrospective data and in the prospective the observed period is 
50%, 600 patients will provide an estimate of the proportion of at least 47% with a 
probability of 95%. Results based on these parameters would be considered less than success, 
i.e. that we are less likely to be able to suggest or “conclude” that the retrospective and 
prospective slopes are homogeneous.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI and CRO Standard Operating Procedures (SOPs), the 
EU directive 2001/20/EC / EU regulation 536/2014, and other relevant regulations.
Investigators and site staff must adhere to these principles. Deviation from the protocol, the 
principles of ICH GCP or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
The certificate of insurance cover is made available to the investigator and the patients and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA)) as applicable according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible.
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 

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If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions. The consent and re-consenting 
process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor or sponsor’s designee.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.

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For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations).

Patient participation in the trial (trial number, patient number, date patient was informed).

Medical history (including trial indication and concomitant diseases, if applicable).

Medication history.

Adverse events and outcome events (onset date (mandatory), and end date (if available)).

Serious adverse events (onset date (mandatory), and end date (if available)).

Concomitant therapy (start date, changes).

Originals or copies of laboratory results and other testing results, with proper documented 
medical evaluation (in validated electronic format, if available).

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient into a clinical trial, there must be documented evidence in 
the source data (e.g. medical records) that the trial participant meets all inclusion criteria 
and does not meet any exclusion criteria. This includes the values for eGFR and their 
method of analysis at or before screening to confirm eligibility. The absence of records 
(either medical records, verbal documented feedback of the patient or testing conducted 
specific for a protocol) to support inclusion/exclusion criteria does not make the patient
eligible for the clinical trial.

In case electronic data are available that can be uploaded to the CRF via an electronic 
interface, the data stored and secured on the system to collect the data will be considered 
the source data and the data transferred must be a validated copy of it.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.

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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular:

Sample and data usage have to be in accordance with the separate biobanking informed 
consent.

The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place.

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage.

A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data.

Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF.
8.5.2
Future use of the trial data
The trial data are planned to be included in a database which also includes retrospective data
from other phase II clinical trials primarily. Inclusion of a patient’s data in this database is
voluntary and not a prerequisite for participation in the trial and will only occur after
informed consent has been given in accordance with local ethical and regulatory
requirements.
The mixed effect model with repeated measures will be performed using the database to
estimate the subject-level slope to identify the fast progressing patients for the Phase III 
clinical development.

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8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI). Coordinating and a Co-coordinating 
Investigator are responsible to coordinate investigators at the different sites participating in 
this trial. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The trial will be performed in accordance with applicable regulations. The majority of the 
organisation of the trial will be delegated to a Clinical Research Organisation (CRO) with 
which the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the clinical trial. The SOPs to be followed will be documented. Data 
Management and Statistical Evaluation will be done by the CRO according to CRO SOPs.
Central laboratory services will be used in this trial. Details will be provided in the Central 
Laboratory Manual, available in the ISF.

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9.
APPENDICES
9.1
TRIAL BIOMARKER PLAN
Urine:
Albumin
Creatinine
Capillary blood (collected with Mitra® microsampling device):
Creatinine

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10.
REFERENCES
10.1
PUBLISHED REFERENCES
R17-2620
Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Köttgen A, Levey AS, 
Levin A: Evolving importance of kidney disease: From subspecialty to 
global health burden. Lancet 382: 158–169, 2013
R13-4387
Kidney Disease: ImprovingGlobalOutcomes (KDIGO) CKDWorkGroup: 
KDIGO 2012 clinical practice guideline for the evaluation and management 
of chronic kidney disease. Kidney Int Suppl 3: 1–150, 2013
R10-1168
Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente 
F, Levey AS: Prevalence of chronic kidney disease in the United States. 
JAMA 298: 2038–2047, 2007
R21-0998
Grams ME, Chow EK, Segev DL, Coresh J: Lifetime incidence of CKD 
stages 3-5 in the United States. Am J Kidney Dis 62: 245–252, 2013
P21-03068
US Renal Data System: USRDS 2010 Annual Data Report: Atlas of 
Chronic Kidney Disease and End-Stage Renal Disease in the United States, 
Bethesda, MD, National Institutes of Health, National Institute of Diabetes 
and Digestive and Kidney Diseases, 2010
R21-1003
Levin A, Djurdjev O, Beaulieu M, Er L: Variability and risk factors for 
kidney disease progression and death following attainment of stage 4 CKD 
in a referred cohort. AmJ Kidney Dis 52: 661–671, 2008
R21-1004
Johnson ES, Thorp ML, Platt RW, Smith DH: Predicting the risk of dialysis 
and transplant among patients with CKD: A retrospective cohort study. Am 
J Kidney Dis 52: 653–660, 2008
R15-5162
Fox CS, Matsushita K, Woodward M, Bilo HJG, Chalmers J, Heerspink 
HJL, Lee BJ, Perkins RM, Rossing P, Sairenchi T, Tonelli M, Vassalotti 
JA, Yamagishi K, Coresh J, de Jong PE, Wen C-P, Nelson RG; Chronic 
Kidney Disease Prognosis Consortium: Associations of kidney disease 
measures with mortality and end-stage renal disease in individuals with and 
without diabetes: A meta-analysis. Lancet 380: 1662–1673, 2012
R21-0999
Mahmoodi BK, Matsushita K, Woodward M, Blankestijn PJ, Cirillo M, 
Ohkubo T, Rossing P, Sarnak MJ, Stengel B, Yamagishi K, Yamashita K, 
Zhang L, Coresh J, de Jong PE, Astor BC; Chronic Kidney Disease 
Prognosis Consortium: Associations of kidney disease measures with 
mortality and end-stage renal disease in individuals with and without 
hypertension: A meta-analysis. Lancet 380: 1649–1661, 2012
R21-1000
Derose SF, Rutkowski MP, Crooks PW, Shi JM, Wang JQ, Kalantar-Zadeh 
K, Kovesdy CP, Levin NW, Jacobsen SJ: Racial differences in estimated 
GFR decline, ESRD, and mortality in an integrated health system. Am J 
Kidney Dis 62: 236–244, 2013
R21-1001
Freedman BI, Parekh RS, Kao WH: Genetic basis of nondiabetic end-stage 
renal disease. Semin Nephrol 30: 101–110, 2010

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R21-1002
Tangri N, Kitsios GD, Inker LA, Griffith J, Naimark DM, Walker S, 
Rigatto C, Uhlig K, Kent DM, Levey AS: Risk prediction models for 
patients with chronic kidney disease: A systematic review. Ann Intern Med 
158: 596–603, 2013
R21-1138
Turin TC, Coresh J, Tonelli M, Stevens PE, de Jong PE, Farmer CK, 
Matsushita K, Hemmelgarn BR: Short-term change in kidney function and 
risk of end-stage renal disease. Nephrol Dial Transplant 27: 3835– 3843, 
2012

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10.2
GFR CKD-EPI FORMULA
Calculation Name
GFR CKD-EPI
Formula
Units
Decimal
Places
Conventional:
Black or African American formulas:
Female with a serum creatinine value of ≤0.7 mg/dL
166 x (Serum Creatinine (mg/dL) / 0.7) -0.329 x (0.993)age
Female with a serum creatinine value of >0.7 mg/dL
166 x (Serum Creatinine (mg/dL) / 0.7) -1.209 x (0.993)age
Male with a serum creatinine value of ≤0.9 mg/dL
163 x (Serum Creatinine (mg/dL) / 0.9) -0.411 x (0.993)age
Male with a serum creatinine value of >0.9 mg/dL
163 x (Serum Creatinine (mg/dL) / 0.9) -1.209 x (0.993)age
White, American Indian, Alaska Native, Asian, Native 
Hawaiian, Other Pacific Islander, Other formulas:
Female with a serum creatinine value of ≤0.7 mg/dL
144 x (Serum Creatinine (mg/dL) / 0.7) -0.329 x (0.993)age
Female with a serum creatinine value of >0.7 mg/dL
144 x (Serum Creatinine (mg/dL) / 0.7) -1.209 x (0.993)age
Male with a serum creatinine value of ≤0.9 mg/dL
141 x (Serum Creatinine (mg/dL) / 0.9) -0.411 x (0.993)age
Male with a serum creatinine value of >0.9 mg/dL
141 x (Serum Creatinine (mg/dL) / 0.9) -1.209 x (0.993)age
Creatinine in mg/dL is rounded to 2 decimal places prior to 
applying the formula.
mL/min/
1.73m²
0
SI:
Serum creatinine in µmol/L will be rounded to zero decimal 
place and converted to mg/dL by multiplying by 0.01131. This 
creatinine value in mg/dL will be rounded
to 2 decimal places. This creatinine result will be used in
the GFR Conventional formulas listed above.
mL/min/
1.73m²
0
Limitations/Special 
Notes:
Age is truncated to a whole number prior to performing the calculation.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
19 May 2021
EudraCT number
EU number
Not applicable
BI Trial number
1366-0026
BI Investigational Medicinal 
Product(s)
Not applicable
Title of protocol
Evaluation of homogeneity between eGFR slopes 
derived from retrospective clinical practice data 
and eGFR slopes derived from prospectively 
collected, protocol-driven data
Global Amendment due to urgent safety reasons
No
Global Amendment
Yes
Section to be changed
Flow chart
Description of change
Training of patient on Mitra sampling and urine 
collection will be at Screening instead of 
Baseline.
Rationale for change
Correction of an error
Section to be changed
Section 1.4.2
Description of change
During this study, 2 venous blood samples (each 
2 mL) will be collected during site visits at 
baseline, and Week 12, Week 24, Week 36 and 
Week 48 (end of study) in separate tubes. 1 tube 
(2mL) is used for assessing the safety parameters 
and the other tube (2mL) for serum creatinine. 
Was changed to:
During this study, 2 venous blood samples (each 
2 mL) 1 venous blood sample for serum 
creatinine (5 mL) will be collected at 
screening, and 3 venous blood samples for 
serum creatinine (5 mL), chemistry (5 mL), 
and hematology (2 mL) will be collected during 
site visits at baseline, and Week 12, Week 24, 
Week 36 and Week 48 (end of study) in separate 
tubes. 1 tube (2mL) is 2 tubes (5 mL and 2 mL) 
are used for assessing the safety parameters 
(chemistry and hematology) and the other tube 
(2mL) 1 tube (5 mL) for serum creatinine.
Rationale for change
Blood sample volumes and number of blood 
samples per visit that are needed for the 
respective analyses required correction.

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11.2.
GLOBAL AMENDMENT 2
Date of amendment
25 Apr 2022
EudraCT number
EU number
Not applicable
BI Trial number
1366-0026
BI Investigational Medicinal 
Product(s)
Not applicable
Title of protocol
Evaluation of homogeneity between eGFR slopes 
derived from retrospective clinical practice data 
and eGFR slopes derived from prospectively 
collected, protocol-driven data
Global Amendment due to urgent safety reasons
No
Global Amendment
Yes
Section to be changed
Study Protocol Synopsis - Trial design
Description of change
Non-randomized, low-intervention design with no 
trial drug administration except background 
therapy. The trial will consist of a retrospective 
phase of up to 3.5 years prior to Screening visit 
(i.e. visit 1), and a prospective phase of 48 weeks
duration.
Was changed to:
Non-randomized, low-intervention design with no 
trial drug administration except background 
therapy. The trial will consist of a retrospective 
phase of up to 5.5 3.5 years prior to Screening 
visit (i.e. visit 1), and a prospective phase of 48 
weeks duration.
Rationale for change
To allow patients to participate in the clinical trial 
that have the required minimum of 4 creatinine 
values only within a broader time span.
Section to be changed
Study Protocol Synopsis – Inclusion criteria
Description of change
Inclusion criterion

eGFR 20 – 75 ml/min/1.73m² at Visit 1 
calculated from serum creatinine measured by 
a central laboratory.
Was changed to:

eGFR 20 – 90 75 ml/min/1.73m² at Visit 1 
calculated from serum creatinine measured by 
a central laboratory.
Rationale for change
To broaden the study population.
Section to be changed
Study Protocol Synopsis – Inclusion criteria
Description of change
Inclusion criterion

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
At least 4 serum creatinine values in the 
retrospective phase. The most recent and 
oldest serum creatinine values should be no 
less than 2 years apart and no greater than 3 
years apart.
Was changed to:

At least 4 serum creatinine values in the 
retrospective phase:
-
The most recent creatinine value not 
more than 6 months prior to Visit 1 
(Screening Visit).
-
The most recent and oldest serum 
creatinine values should be no less than 1
2 years apart and no greater than 5 3 years 
apart
-
There should be no gap of creatinine 
values of 2 years or longer.
Rationale for change
To allow patients to participate in the clinical trial 
that have the required minimum of 4 creatinine 
values only within a broader time span and at the 
same time ensure robust eGFR slope assessments.
Section to be changed
Section 1.3 Rationale for performing the trial
Description of change
The study will also compare eGFR slopes derived 
via retrospective serum creatinine values 
collected up to 3.5 years prior to visit 1 in routine 
clinical practice, with prospectively generated 
eGFR values and resulting slopes.
Was changed to:
The study will also compare eGFR slopes derived 
via retrospective serum creatinine values 
collected up to 5.5 3.5 years prior to visit 1 in 
routine clinical practice, with prospectively 
generated eGFR values and resulting slopes.
Rationale for change
To allow patients to participate in the clinical trial 
that have the required minimum of 4 creatinine 
values only within a broader time span.
Section to be changed
Section 3.1 Overall Trial Design
Description of change
In figure 3.1: 1
Retrospective part (42 months)
Was changed to:
Retrospective part (66 42 months)
Rationale for change
To allow patients to participate in the clinical trial 
that have the required minimum of 4 creatinine 
values only within a broader time span.

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Section to be changed
Section 3.1 Overall Trial Design
Description of change
All available historical eGFR values, UACR/PCR
within the 3.5 years prior to screening Visit 1 will 
be collected for each patient.
Was changed to:
All available historical eGFR values, UACR/PCR
within the 5.5 3.5 years prior to screening Visit 1 
will be collected for each patient.
Rationale for change
To allow patients to participate in the clinical trial 
that have the required minimum of 4 creatinine 
values only within a broader time span.
Section to be changed
Section 3.1 Overall Trial Design
Description of change
To be documented in the CRF:
All available serum creatinine values (at least 4 
serum creatinine values should be available for a 
patient). The most recent and oldest serum 
creatinine values should be no less than 2 years 
apart and no greater than 3 years apart.
Was changed to:
To be documented in the CRF:
All available serum creatinine values (at least 4 
serum creatinine values should be available for a 
patient with the most recent creatinine value 
not more than 6 months prior to Visit 1 
(Screening Visit)). The most recent and oldest 
serum creatinine values should be no less than 1 2
years apart and no greater than 5 3 years apart
and there should be no gap of creatinine values 
of 2 years or longer.
Rationale for change
To allow patients to participate in the clinical trial 
that have the required minimum of 4 creatinine 
values only within a broader time span and at the 
same time ensure robust eGFR slope assessments.
Section to be changed
Section 3.3.2 Inclusion criteria
Description of change
Inclusion criterion
7. eGFR (Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] formula) 20 – 75
ml/min/1.73m² at Visit 1 calculated from serum 
creatinine measured by a central laboratory.
Was changed to:
7. eGFR (Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] formula) 20 – 90 75
ml/min/1.73m² at Visit 1 calculated from serum 
creatinine measured by a central laboratory.
Rationale for change
To broaden the study population.

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Section to be changed
Section 3.3.2 Inclusion criteria
Description of change
Inclusion criterion
9. At least 4 serum creatinine values in the 
retrospective phase. The most recent and oldest 
serum creatinine values should be no less than 2 
years apart and no greater than 3 years apart.
Was changed to:
9. At least 4 serum creatinine values in the
retrospective phase:
-
The most recent creatinine value not 
more than 6 months prior to Visit 1 
(Screening Visit). 
-
The most recent and oldest serum 
creatinine values should be no less than 1
2 years apart and no greater than 5 3 years 
apart 
-
There should be no gap of creatinine 
values of 2 years or longer.
Rationale for change
To allow patients to participate in the clinical trial 
that have the required minimum of 4 creatinine 
values only within a broader time span and at the 
same time ensure robust eGFR slope assessments.

 
 
 
 
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Document Name: 
 
 
 
                                                                                                                 
 
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c35391746
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clinical-trial-protocol-version-03
Evaluation of homogeneity between eGFR slopes derived from retrospective clinical
practice data and eGFR slopes derived from prospectively collected, protocol-driven
data
Author-Clinical Trial Leader
25 Apr 2022 14:19 CEST
Approval-Biostatistics
25 Apr 2022 15:35 CEST
Approval-Therapeutic Area 
25 Apr 2022 16:21 CEST
Approval
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Verification-Paper Signature
Completion
27 Apr 2022 13:27 CEST

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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c35391746
3.0