Clinical trial NCT04750577
Conditions: Diabetic Nephropathies
Sponsor: Boehringer Ingelheim
Start date: 2021-04-27; Completion date: 2022-12-27
Enrollment: 243 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with diabetic kidney disease. The purpose of the study is to find out whether a medicine called BI 685509 improves kidney function. Three different doses of BI 685509 are tested in this study.

Participants get either one of the three doses of BI 685509 or placebo. It is decided by chance who gets which BI 685509 dose and who gets placebo. Participants take BI 685509 or placebo as tablets 3 times a day. Placebo tablets look like BI 685509 tablets but do not contain any medicine. Participants continue taking their usual medicine for diabetes and kidney disease throughout the study.

Participants are in the study for about 7 months. During this time, they visit the study site about 11 times. Where possible, about 6 of the 11 visits can be done at the participant's home instead of the study site. The trial staff may also contact the participants by phone or video call.

Kidney function is assessed based on the analysis of urine samples, which participants collect at home. At the end of the trial the results are compared between the different doses of BI 685509 and placebo. During the study, the doctors also regularly check the general health of the participants.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: Low dose followed by up-titration to medium dose. arm 4: Low dose followed by up-titration to medium dose, followed by up-titration to high-dose.
Interventions: intervention 1: Placebo matching BI 685509 intervention 2: BI 685509
Intervention descriptions: intervention 1: film-coated tablet intervention 2: film-coated tablet

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106 RD-03 (18 0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
 
Document Number:
c32274622-05
EudraCT No.
2020-002929-28
BI Trial No.
1366-0005
BI Investigational
Medicinal Product
BI 685509
Title
Randomised, double-blind (within dose groups), placebo-
controlled and parallel group trial to investigate the effects of 
different doses of oral BI 685509 given over 20 weeks on UACR 
reduction in patients with diabetic kidney disease
Lay Title
A study to test the effect of different doses of BI 685509 on 
kidney function in people with diabetic kidney disease
Clinical Phase
Phase II
Clinical Trial Leader
Phone: +
, Fax: +
Coordinating 
Investigator
Tel: +
, Fax +
Status:
Final Protocol (Revised Protocol (based on global 
amendment 4))
Version and Date
Version: 5.0
Date: 14 Mar 2022
Page 1 of 107
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
19 October 2020
Revision date
14 March 2022
BI trial number
1366-0005
Title of trial
Randomised, double-blind (within dose groups), placebo-controlled 
and parallel group trial to investigate the effects of different doses of 
oral BI 685509 given over 20 weeks on UACR reduction in patients 
with diabetic kidney disease
Coordinating 
Investigator
Tel: +
Fax +
Trial sites
Multi-centre trial
Clinical phase
II
Trial rationale
The aim of this trial is to investigate the efficacy, safety, tolerability, 
PK and PD of three oral doses of BI 685509 over 20 weeks in male and 
female patients with DKD as adjunctive to ACEi or ARB treatment 
plus local standard of care according to respective guidelines. The 
results of this trial will be crucial for the decision about further 
development of BI 685509 and will support the dose selection for 
future trials.
Trial objectives
The main objectives of the trial are to demonstrate the effectiveness of 
BI 685509 and to characterize the dose-response relationship for 
BI 685509 in patients with DKD by assessing 3 doses and placebo.
Trial endpoints
Primary endpoint:
Change from baseline in log transformed UACR measured in 10-hour 
urine after 20 weeks of trial treatment.
Secondary endpoints:
Change from baseline in log transformed UACR measured in First 
Morning Void urine after 20 weeks of trial treatment.
Proportion of patients achieving UACR decreases in 10-hour urine of 
at least 20% from baseline after 20 weeks of trial treatment.
Proportion of patients achieving UACR decreases in First Morning 
Void urine of at least 20% from baseline after 20 weeks of trial 
treatment.
Trial design
Randomised, parallel design comparison of 3 dose groups over 20 
weeks of treatment, double-blind within dose group, placebo controlled
Total number of 
patients randomised
240


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Number of patients 
on each treatment
60
Diagnosis
Diabetic Kidney Disease (DKD)
Main in- and 
exclusion criteria
Inclusion:
∀
Male or female patients aged ≥ 18 years at time of consent.
∀
eGFR ≥ 20 and < 90 mL/min/1.73 m².
∀
UACR ≥ 200 and < 3,500 mg/g.
∀
Stable treatment with either ACEi or ARB (not both).
∀
Patients with stable type 1 or type 2 diabetes mellitus.
Exclusion:
∀
Non-diabetic chronic kidney disease.
∀
planned start of chronic renal replacement therapy during the 
trial or end stage renal disease before start of trial treatment.
Test product
BI 685509
Dose
3 mg / 6 mg / 9 mg total daily dose
mode of 
administration
Per os / oral (p.o.)
Comparator product
Placebo
dose
Matching
mode of 
administration
Per os / oral (p.o.)
Duration of treatment 20 weeks
Statistical methods
The purpose of this trial is to demonstrate proof of concept of clinical 
activity of BI 685509 on the primary endpoint. For the proof of 
concept an evaluation of the benefit of BI 685509 compared to placebo 
will be conducted.
To account for the repeated nature of the primary endpoint data and the 
covariates in the model, MMRM analysis will be carried out for 
change from baseline of log transformed UACR measured in 10-hour 
urine after 20 weeks of trial treatment in each patient group. The 
analysis will include the fixed, categorical effect of treatment at each 
visit, and the fixed continuous effects of baseline log transformed 
UACR at each visit. Visit will be treated as the repeated measure with 
an unstructured covariance matrix used to model the within-patient 
measurements. The adjusted mean change from baseline (and the 
related standard error) will be calculated for each group and will be 
used for the MCPMod to determine therapeutic dose. The analyses for 
dose-finding will be performed using MCPMod whereby several 
possible dose response models (patterns) will be evaluated to identify 
the best-fitting model or subset of models.
Regarding analyses of the secondary endpoints,
1. MMRM will be used for the analysis for the change of UACR 
in First Morning Void.


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2. Descriptive statistics will be provided for the change of UACR 
in First Morning Void urine/10-hour urine and the UACR 
response rate along with figures.










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∀
If screening (including the 2 week baseline period) are not completed within 35 days prior to randomisation, the patient will be a screen failure. IRT should be contacted to record the 
screen failure. If appropriate the patient may be re-screened (see above).
iv
The timepoint of first treatment (Visit 3) defines Day 1.
v
Visits 4 and 5 must be performed at least 14 days after the previous visit.
vi
In case a patient needs or wishes to terminate the treatment prematurely the patient should have an End of Treatment (EoT) visit, if they agree. Please see section 6.2.4 for details.
vii
These visits can either be performed at the Investigational site or at the patient’s home. All local approvals for this must be in place and confirmed by the sponsor. Consent for home visits 
must also be obtained from the patient. See section 6.2.1 for further details.
viii
There are various ways that Telemedicine contacts (phone call or video call) can be used during this trial:
1.
Telemedicine contact to provide support for patient’s urine sampling. Before the patient does their first UACR and eGFR sampling at home (before Visit 2) the investigational site 
staff should contact the patient to ensure the patient is comfortable with the sampling process. The other timepoints marked as ‘(X)’ are suggested times to contact the patient if they 
are shipping samples directly from home to ensure they understand the instructions given to them. The site may, at their discretion, offer support with further home sampling according 
to the individual needs of a patient. 
2.
Telemedicine calls at visit 6 (marked as “O”) and/or FUp2. If this visit is being performed at the patient’s home by a nurse, a telemedicine contact must be established between the 
nurse, patient and an Investigator who will guide the nurse through the physical exam (see section 6.2.1).
3.
FUp1 must be performed as telemedicine contact for all patients, unless they prefer to come to the trial site.
4.
Phone/ video calls may also take place at any other time if needed to support the patient.
ix
Informed consent does not need to be obtained on the day of the screening visit but must be obtained before the first screening assessment and within 35 days of randomisation (Visit 3). 
The consent discussion should include showing the patient the home sampling kits and explaining this procedure.
x
Once screening assessments have been completed, a member of the trial team will contact the patient by phone to provide confirmation about eligibility.
xi
At Visits 3 to 8 vital signs will be measured before the morning dose and approximately 30 min and 120 min after dosing. If applicable this must occur prior to the ECG and PK samples. 
See FLOW CHART FOR PROCEDURES for further details.
xii
All ECGs should be performed after the patient has been in the supine position for 5 minutes. They should be evaluated by the investigator or a designee. See FLOW CHART FOR 
PROCEDURES for details on the timing of ECGs.
xiii
eGFR at clinic visits will be determined from serum creatinine analysed by the central laboratory and also from 
. To confirm eligibility the eGFR at screening will 
be used.
xiv
Patients do not need to be fasted on the days of PK sampling, see FLOW CHART FOR PROCEDURES for further details. For further instructions see section 6.1.
xv
The pharmacogenomic samples may be collected at Visit 3 or anytime afterwards.
xvi
Optional biobanking samples will only be collected if the patient has signed the biobanking informed consent separate form the main consent for the trial. See section 5.5.
xvii
A pregnancy test is required for all women of child-bearing potential. This will be a serum pregnancy test at Screening (Visit 1), thereafter a urine pregnancy test will be performed.
xviii
To confirm eligibility at Visit 1, UACR measured in spot urine (midstream urine sample) by the central laboratory will be used. Should the first test for UACR at screening be borderline 
out of range and not match inclusion criteria due to UACR variability, this test can be repeated once. The result must be available and eligibility confirmed before the baseline UACR 
sampling starts. If the second result does not meet the eligibility criteria the patient should be screen failed.
xix
Training on how to use the 
 device and how to do the FMV and 10-hour 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.


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xx
 performed at home can be returned by e.g. post or courier (if permitted by Country-specific regulations and other local guidance). If not allowed locally, the patient 
should return the samples to the investigational site. Countries may be exempted from microsampling if use of the 
 is not permitted in that country.
xxi
Patients will need to complete 2 different diaries. The ‘Diary for Urine and Blood Collection and Trial Drug Times’ will enable the site to record information entered during urine and 
blood collection at home and 2 days prior to PK sampling including times of trial drug intake, start and stop times of collection and volumes. The ‘Daily Diary for Trial Drug 
Intake’ will help to check the compliance of the patient and a possible need for down-titration. If the patient chooses they will be able to download an app containing the diaries to their 
phone at visit 1 or 2, or will be provided at visit 2 with an electronic device with the app installed. The app will also be used for the videocalls and can be used for patient reminders. If the 
use of the e-diary is not possible, alternatively a paper diary will be available to the patient.
xxii
The planned last dose taken by the patient will be the evening dose the day before their EoT visit. If a patient withdraws from treatment early the EoT visit should be performed as close as 
possible to their last dose.
xxiii
All AEs, SAEs and AESIs will be collected from informed consent until FUp1 (end of residual effect period). Please see section 5.2.6.2.1.
xxiv
After FUp1 until the individual patient’s end of trial, the investigator should report any cancers of new histology and exacerbations of existing cancer, all trial treatment related SAEs and 
all trial treatment related AESIs. Please see section 5.2.6.2.1.
xxv
As detailed in section 5.2.6.2.1 after the individual patient’s end of the trial the investigator does not need to actively monitor the patient for new AEs but should report any occurrence of 
cancer and trial treatment related SAEs and trial treatment related AESIs of which the investigator may become aware of by any means of communication, e.g. phone call. Those AEs 
should be reported on the BI SAE form (see section 5.2.6.2.2), but not on the CRF.




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FLOW CHART FOR PROCEDURES
In all instances when an ECG and blood samples are required at the same timepoint the ECG 
must be performed prior to the blood sampling and after the patient has been in the supine 
position for 5 minutes. Vital signs and ECGs must always be performed with sufficient time 
to allow the PK samples to remain within the time windows specified below.
Visit Day
See 
main 
flow 
chart for 
visit 
windows
PK Sampling Time 
Relative to 
Administration 
(morning dose) at 
Visit 
hh:mm
Time Point 
[hh:min]
Event
PK 
Sample 
No.
3
1
Prior to first PK blood draw and drug 
administration
Urine samples1, weight and 
Physical Exam, Vital signs then 
ECG and then blood samples
(other than PK)
---
Within 30 minutes 
prior to drug 
administration
Just before 
drug 
administration
PK Blood 
1
0:00
0:00
Drug administration
---
0:30 (+/- 5 min)
0:30 
Vital signs then PK Blood
2
1:00 (+10 min)
1:00 
ECG then PK Blood
3
2:002 (+ 15 min)
2:00 
Vital signs then ECG then PK 
Blood
4
4
15
Prior to first PK blood draw and drug 
administration
Urine samples1, Vital signs then 
ECG and then blood samples 
(other than PK)
---
Within 30 minutes 
prior to drug 
administration
335:30
PK Blood
5
0:00
336:00
Drug administration
---
0:30 (+/- 5 min)
336:30 
Vital signs then PK Blood
6
1:00 (+ 10 min)
337:00 
ECG then PK Blood
7
2:002 (+ 15 min)
338:00 
Vital signs then ECG then PK 
Blood
8
5
29
Prior to first PK blood draw and drug 
administration
Urine samples1, Vital signs then 
ECG and then blood samples 
(other than PK)
---
Within 30 minutes 
prior to drug 
administration
671:30
PK Blood
9
                                                
1 Urine samples, weight and the physical examination (where applicable) can be collected at any time before drug 
administration
2 Please note on all occasions the 2 hour PK sample cannot be earlier than 2 hours after the administration of the morning 
dose at the Visit


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Visit Day
See 
main 
flow 
chart for 
visit 
windows
PK Sampling Time 
Relative to 
Administration 
(morning dose) at 
Visit 
hh:mm
Time Point 
[hh:min]
Event
PK 
Sample 
No.
0:00
672:00
Drug administration
---
0:30 (+/- 5 min)
672:30 
Vital signs then PK Blood
10
1:00 (+ 10 min)
673:00 
ECG then PK Blood
11
2:002 (+ 15 min)
674:00 
Vital signs then ECG then PK 
Blood
12
6
43
Prior to first PK blood draw and drug 
administration
Urine samples1, weight and 
Physical Exam, Vital signs then 
ECG and then blood samples 
(other than PK)
---
Within 30 minutes 
prior to drug 
administration
1007:30
PK Blood
13
0:00
1008:00
Drug administration
---
0:30 (+/- 5 min)
1008:30 
Vital signs then PK Blood
14
1:00 (+ 10 min)
1009:00 
ECG then PK Blood
15
2:002 (+ 15 min)
1010:00 
Vital signs then ECG then PK 
Blood
16
7
85
Prior to first PK blood draw and drug 
administration
Urine samples1, Vital signs then 
ECG and then blood samples 
(other than PK)
---
Within 30 minutes
prior to drug 
administration
2015:30
PK Blood
17
0:00
2016:00
Drug administration
---
0:30 (+/- 5 min)
2016:30 
Vital signs then PK Blood
18
1:00 (+ 10 min)
2017:00 
PK Blood
19
2:002 (+ 15 min)
2018:00 
Vital signs then PK Blood
20
8
127
Prior to first PK blood draw and drug 
administration
Urine samples1, Vital signs then 
ECG and then blood samples 
(other than PK)
---
Within 30 minutes 
prior to drug 
administration
3023:30
PK Blood
21
0:00
3024:00
Drug administration
---
0:30 (+/- 5 min)
3024:30 
Vital signs then PK Blood
22
1:00 (+ 10 min)
3025:00 
PK Blood
23
2:002 (+ 15 min)
3026:00 
Vital signs then PK Blood
24
EoT
141
Prior to PK blood draw
Urine samples, weight and 
Physical Exam, at any time. Vital 
signs then ECG and then blood 
samples (other than PK)
---
N/A
3360:00 
(trough)
PK Blood
25


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Visit Day
See 
main 
flow 
chart for 
visit 
windows
PK Sampling Time 
Relative to 
Administration 
(morning dose) at 
Visit 
hh:mm
Time Point 
[hh:min]
Event
PK 
Sample 
No.
FUp2 148
N/A
N/A
Urine samples, weight and 
Physical Exam at any time. 
Vital signs then ECG and then 
blood samples.
---
FUp3 169
N/A
N/A
Urine samples and weight at any 
time. 
Vital signs then blood samples.
---


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
UACR AND EGFR SAMPLING FLOW CHART.............................................................11
FLOW CHART FOR PROCEDURES................................................................................12
TABLE OF CONTENTS ......................................................................................................15
ABBREVIATIONS................................................................................................................19
1.
INTRODUCTION...............................................................................................23
1.1
MEDICAL BACKGROUND.............................................................................23
1.2
DRUG PROFILE................................................................................................23
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................26
1.4
BENEFIT - RISK ASSESSMENT.....................................................................27
1.4.1
Benefits.................................................................................................................27
1.4.2
Risks .....................................................................................................................28
1.4.3
Discussion.............................................................................................................32
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................33
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........33
2.1.1
Main objectives....................................................................................................33
2.1.2
Primary endpoint................................................................................................33
2.1.3
Secondary endpoints...........................................................................................33
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................35
3.1
OVERALL TRIAL DESIGN.............................................................................35
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP...........................................................................................37
3.3
SELECTION OF TRIAL POPULATION .......................................................38
3.3.1
Main diagnosis for trial entry ............................................................................38
3.3.2
Inclusion criteria .................................................................................................38
3.3.3
Exclusion criteria ................................................................................................39
3.3.4
Withdrawal of patients from treatment or assessments..................................41
3.3.4.1
Discontinuation of trial treatment .........................................................................41
3.3.4.2
Withdrawal of consent to trial participation .........................................................42
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................42
4.
TREATMENTS...................................................................................................43
4.1
INVESTIGATIONAL TREATMENTS ...........................................................43
4.1.1
Identity of the Investigational Medicinal Products..........................................43
4.1.2
Selection of doses in the trial and dose modifications......................................44


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4.1.3
Method of assigning patients to treatment groups...........................................45
4.1.4
Drug assignment and administration of doses for each patient......................45
4.1.4.1
Rules for titration in case of interruption of trial treatment..................................46
4.1.4.2
Rules for down-titration in case of intolerance to trial treatment .........................47
4.1.5
Blinding and procedures for unblinding...........................................................48
4.1.5.1
Blinding.................................................................................................................48
4.1.5.2
Unblinding and breaking the code ........................................................................48
4.1.6
Packaging, labelling, and re-supply...................................................................48
4.1.7
Storage conditions...............................................................................................49
4.1.8
Drug accountability.............................................................................................49
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................49
4.2.1
Other treatments and emergency procedures..................................................49
4.2.2
Restrictions ..........................................................................................................50
4.2.2.1
Restrictions regarding concomitant treatment ......................................................50
4.2.2.2
Restrictions on diet and life style..........................................................................53
4.2.2.3
Contraception requirements..................................................................................54
4.3
TREATMENT COMPLIANCE........................................................................54
5.
ASSESSMENTS..................................................................................................55
5.1
ASSESSMENT OF EFFICACY........................................................................55
5.1.1
UACR...................................................................................................................55
5.2
ASSESSMENT OF SAFETY.............................................................................55
5.2.1
Physical examination ..........................................................................................55
5.2.2
Vital signs.............................................................................................................55
5.2.3
Safety laboratory parameters ............................................................................56
5.2.4
Electrocardiogram ..............................................................................................59
5.2.5
Other safety parameters.....................................................................................60
5.2.6
Assessment of adverse events.............................................................................60
5.2.6.1
Definitions of AEs ................................................................................................60
5.2.6.2
Adverse event collection and reporting ................................................................63
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................64
5.3.1
Assessment of pharmacokinetics .......................................................................64
5.3.2
Methods of sample collection .............................................................................65
5.3.4
Pharmacokinetic-pharmacodynamic relationship...........................................66
5.4
ASSESSMENT OF BIOMARKERS.................................................................66
5.4.2
Method and timing of sample collection ...........................................................67
5.4.3
Pharmacogenomics biomarkers.........................................................................67
5.4.4
Method of sample collection...............................................................................67
5.5
BIOBANKING ....................................................................................................68
5.5.1
Methods and timing of sample collection..........................................................68
5.6
OTHER ASSESSMENTS...................................................................................68
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................68


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6.
INVESTIGATIONAL PLAN.............................................................................70
6.1
VISIT SCHEDULE.............................................................................................70
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................70
6.2.1
Telemedicine Contacts and Home Visits...........................................................71
6.2.2
Screening and run-in period ..............................................................................72
6.2.3
Treatment period ................................................................................................72
6.2.4
Early discontinuation of Treatment..................................................................72
6.2.5
Follow-up period and trial completion..............................................................73
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................74
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................74
7.2
PLANNED ANALYSES.....................................................................................74
7.2.1
General considerations .......................................................................................74
7.2.2
Primary endpoint analyses.................................................................................75
7.2.3
Secondary endpoint analyses .............................................................................77
7.2.5
Safety analyses.....................................................................................................77
7.2.6
Other Analyses ....................................................................................................78
7.2.7
Interim Analyses .................................................................................................78
7.3
HANDLING OF MISSING DATA ...................................................................78
7.4
RANDOMISATION ...........................................................................................79
7.5
DETERMINATION OF SAMPLE SIZE .........................................................79
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........81
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................81
8.2
DATA QUALITY ASSURANCE ......................................................................82
8.3
RECORDS...........................................................................................................82
8.3.1
Source documents ...............................................................................................82
8.3.2
Direct access to source data and documents.....................................................83
8.3.3
Storage period of records ...................................................................................83
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................84
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........84
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................84
8.6
TRIAL MILESTONES.......................................................................................84
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................85
9.
REFERENCES....................................................................................................87
9.1
PUBLISHED REFERENCES............................................................................87
9.2
UNPUBLISHED REFERENCES......................................................................88
10.
APPENDICES.....................................................................................................89
10.2
GFR CKD-EPI FORMULA...............................................................................91


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10.3
DOWN-TITRATION GUIDE ...........................................................................93
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................94
11.1
GLOBAL AMENDMENT 1 ..............................................................................94
11.2
GLOBAL AMENDMENT 2 ..............................................................................94
11.3
GLOBAL AMENDMENT 3 ..............................................................................98
11.4
GLOBAL AMENDMENT 4 ............................................................................105


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ABBREVIATIONS
ACEi
Angiotensin Converting Enzyme inhibitor
ADME
Absorption, Distribution, Metabolism and Excretion
ADPKD
Autosomal Dominant Polycystic Kidney Disease
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike Information Criterion
AKI
Acute Kidney Injury
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
ARB
Angiotensin Receptor Blocker
AST
Aspartate Aminotransferase
AUC
Area under the Curve
AUCSS
Area under the concentration-time curve of the analyte in plasma at 
steadystate
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
BMI
Body Mass Index
BP
Blood Pressure
BPM
Beats per minute
CA
Competent Authority
cGMP
Cyclic Guanosine Monophosphate
CKD
Chronic Kidney Disease
CKD-EPI
CKD Epidemiology Collaboration (formula)
Cmax
Maximum measured concentration of the analyte in plasma
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
CT Manager
Clinical Trial Manager


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CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP2C8
Cytochrome P450 2C8
CYP3A4
Cytochrome P450 3A4
DBL
Database Lock
DBP
Diastolic Blood Pressure
DDI
Drug-Drug Interaction
DG
Dose Group
DILI
Drug Induced Liver Injury
DKD
Diabetic Kidney Disease
DMETTM
Drug Metabolism Enzymes and Transporters
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
(e)COA
(electronic) Clinical Outcome Assessment
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
EoT
End of Treatment
ES
Entered Set
ESRD
End Stage Renal Disease
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
FDA
Food and Drug Administration
FMV
First Morning Void
FUp
Follow-up
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GLP1
Glucagon-Like Peptide 1
GMP
Good Manufacturing Practice
HbA1c
Glycated haemoglobin
hERG
Human Ether-a-go-go Related Gene


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HR
Heart Rate
IB
Investigator’s Brochure
ICE
Intercurrent Event
ICH
International Council on Harmonisation
IDNT
Irbesartan Diabetic Nephropathy Trial
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
K-EDTA
Potassium ethylenediaminetetraacetic acid
KDIGO
Kidney Disease: Improving Global Outcomes
LPLT
Last Patient Last Treatment
LPLV
Last Patient Last Visit
MAR
Missing at Random
MCPMod
Multiple Comparison Procedure with Modelling
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed-effect Model for Repeated Measures
MRD
Multiple Rising Dose
NIDDM
non-insulin-dependent diabetes mellitus
NO
Nitric Oxide
NSAID
Non-steroidal anti-inflammatory drug(s)
NYHA
New York Heart Association
OATP1B1/3
Organic Anion-Transporting Polypeptide 1B1 and 1B3
OPU
Operative Unit
PD
Pharmacodynamics
PDE5
Phosphodiesterase type 5
P-gp
P-glycoprotein
PK
Pharmacokinetics
PKS
Pharmacokinetic Set
p.o.
per os (oral)


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PoC
Proof of Concept
PV
Pharmacovigilance 
QD
quaque die (once daily)
RAAS
Renin Angiotensin Aldosterone System
RENAAL
Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist 
Losartan (trial)
REP
Residual Effect Period
RS
Randomised Set
SAE
Serious Adverse Event
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SBP
Systolic Blood Pressure
SC
Steering Committee
sGC
Soluble Guanylate Cyclase
SGLT2
Sodium-Glucose co-Transporter-2
SGLT2i
SGLT2 Inhibitor
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TID
ter in die (3 times a day) 
tmax
Timepoint of Maximum Plasma Concentration
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
Tx
Treatment
UACR
Urine Albumin Creatinine Ratio
UGT
Uridine 5’-diphosphate -glucuronosyltransferase
ULN
Upper Limit of Normal 
UPE
Urinary Protein Excretion
Vx
Visit x 
WHO
World Health Organisation
WOCBP
Woman of Child-Bearing Potential 








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In the patient MRD trial a responder was defined as a patient whose decrease from baseline in 
Urine albumin creatinine ratio (UACR) was at least 20%. For UACR measured in morning 
void urine, 15.8 to 27.8% of analysed patients receiving BI 685509 in DG1 to DG3 (3 to 5 
patients) were responders, compared with 1 patient (7.1%) receiving placebo. For UACR 
measured in 10-hour urine, ≥50% of analysed patients receiving BI 685509 in DG2 and DG3 
(8 to 10 patients) were responders, compared with no patients receiving placebo [c30365927-
01].
Based on recent data from a clinical trial (1366-0020) in patients with cirrhosis Child-Pugh 
stage A (24 patients) and B (25 patients), an effect of BI 685509 on the predicted placebo-
corrected change from baseline QTcF (∆∆QTcF) was seen. Dosing regimens up to 3 mg bid, 
similar to the highest dose group in this trial, were used. In both patient groups, there was a 
dose dependent increase of ∆∆QTcF up to 13.7 ms, with the upper 90% CI >20 ms. In one 
patient group (Child-Pugh B) this was concomitant with a change of the predicted placebo-
corrected change from baseline heart rate (∆∆HR) of > 10 beats per minute (bpm), but not in 
the other patient group. No such effect was seen in a healthy Caucasian volunteers trial 
(1366-0010) for dosing regimens used in this trial. In a healthy Asian volunteers trial (1366-
0013), at a dose regimen relevant for this study (i.e. starting with 1 mg tid up to a final dose 
of 3 mg tid), an increase of ∆∆QTcF was seen up to 11.7 ms with 90% CI <20 ms, 
concomitant with an increase of ∆∆HR of nearly 10 bpm.
BI 685509 has no effect on human ether-a-go-go related gene (hERG) channel at doses used 
in this clinical trial, and no effect on QT-interval was seen in conscious animal studies.
For a more detailed description of the BI 685509 profile, please refer to the current 
Investigator’s Brochure (IB) [c02778238].
1.3
RATIONALE FOR PERFORMING THE TRIAL
Although ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB) have 
demonstrated efficacy in slowing the progression of diabetic kidney disease, the relative risk 
reduction was moderate (16% in the RENAAL [Reduction of Endpoints in NIDDM with the 
Angiotensin II Antagonist Losartan] trial and 19% in the IDNT [Irbesartan Diabetic 
Nephropathy Trial]) for the triple composite primary endpoint of all-cause death, ESRD and 
doubling of serum creatinine [R02-0327], [R02-2101]. The residual risk remains high. Even 
with the advent of SGLT2 inhibitors that will provide an additional treatment option for 
renally compromised patients, there is still a large unmet medical need for effective and safe 
treatments that can further slow, halt or reverse the progression of diabetic kidney disease, 
and positively impact the patient’s quality of life.
The aim of this trial is to investigate the efficacy, safety, tolerability, PK and PD of three oral 
doses of BI 685509 over 20 weeks in male and female patients with DKD as adjunctive to 
ACEi or ARB treatment, plus other local standard of care according to respective guidelines. 
The results of this trial will be crucial for the decision about further development of 
BI 685509 and will support the dose selection for future trials.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see section 5.5). If the patient agrees, banked 


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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
Potential benefits of treating DKD patients with BI 685509 result from the prediction of 
slowing progression of the disease and prevention of cardiovascular events, which is only 
partially achieved by current standard of care. Treatment with BI 685509 will potentially 
result in decreased progression towards dialysis or kidney transplantation due to preventing 
the progression of renal damage, which may directly translate into relevant improvements for 
patients’ morbidity, mortality, and quality of life. Beyond that, it may reduce the number of 
cardiovascular events in the target population.
Patients may also benefit from more frequent clinical monitoring as a result of being part of a 
clinical trial.




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Table 1.4.2: 1
Overview of trial related risks cont.
Investigational Medicinal Product BI 685509
Possible or known 
risks of clinical 
relevance for this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Potential QT-interval 
prolongation
See section 1.2
Patients with long QT / 
QTcF-interval, patients 
with a family history of 
long QT syndrome, or 
those using concomitant 
therapies known to 
increase the risk of 
Torsade de Points will be 
excluded from the trial 
(refer to Sections 3.3.3 and 
4.2.2.1).
ECGs will be performed at 
each visit in the 
randomised treatment 
period of the trial, and trial 
medication will be 
discontinued in the event 
of a prolonged QT / 
QTcF-interval (refer to 
Section 3.3.4.1)




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Table 1.4.2: 1
Overview of trial related risks cont.
Investigational Medicinal Product BI 685509
Possible or known 
risks of clinical 
relevance for this trial
Summary of data, 
rationale for the risk
Mitigation strategy
Patient may be injured 
by self-collection of
blood.
Patients need to take blood 
from the tip of their finger 
to allow frequent 
creatinine measurements 
for eGFR calculation as a 
safety marker and 
exploratory biomarker for 
kidney function.
A minimally invasive medical 
device called 
 
kit, to take blood from the tip of 
their finger. This
tool has 
been established for easy-to use 
capillary blood collection at home. 
Patients will be trained on how to 
use this. Patients with diabetes are 
used to glucose determination in 
blood at home.
Patients may develop 
AKI or ESRD.
Rare but severe event 
related to the trial 
diagnosis. Patients with 
such an event will need to 
receive different treatment 
and are unlikely to benefit 
from treatment with 
BI 685509.
Treatment withdrawal criteria 
include AKI and ESRD as factors 
to remove the patient from 
treatment.
Patients may develop 
SARS-CoV-2 or other 
severe infection
Based on the mode of 
action BI 685509 is not 
expected to have a 
relevant impact on the 
susceptibility to or the 
course of an infection. The 
underlying disease studied 
in this trial and the 
expected higher age of the 
impacted population 
increase the risk of 
hospitalization and 
intensive care in case of a 
SARS-CoV-2 or other 
severe infection.
In case of a confirmed severe 
infection, trial treatment will be 
discontinued immediately and 
appropriate measures for 
monitoring, treatment and 
quarantine will be implemented.
During a period of an increased 
risk of a severe infection, physical 
visits to the sites should be 
replaced with home visits or 
telemedicine and procedures 
(including lab testing) followed as 
far as the situation allows (see 
section 6.2.1). Direct shipment of 
the trial medication will be 
managed by the site or the 
provider directly as permitted by 
local regulations. These measures 
ensure the safety of the patients 
throughout the trial.


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A steering committee (SC) consisting of the coordinating investigators in trial 1366-0022 (a 
matching trial to investigate BI 685509 in non-diabetic CKD) and other selected investigators 
as well as members of the BI trial team will meet in regular intervals and look at blinded 
safety data to identify potential risks that need further safety measures. A charter will be 
available before trial initiation to define the specific data reviews and meeting intervals.
1.4.3
Discussion
Based on pre-clinical results, BI 685509 has the potential to slow progression of renal 
damage, delay end stage renal disease (ESRD) and reduce cardiovascular events such as 
cardiovascular death, myocardial infarction, stroke and hospitalisation for heart failure, in 
patients with DKD. In addition, clinical studies in healthy volunteers and DKD patients have 
shown that it is well tolerated when up-titrated to the doses to be administered in this trial.
A placebo arm is needed to allow for a true assessment of the effects of BI 685509 on the 
UACR in patients with DKD. All patients will be on stable background standard of care 
therapy of at least either ACEi or ARB, therefore the inclusion of a placebo arm is considered 
to be ethically justifiable.
Patients will be carefully monitored for side effects during the trial. The sponsor will 
continuously assess the risks and benefits of the trial based on accumulating clinical data 
from all clinical trials with BI 685509. Any significant change in risk-benefit ratio will be 
communicated to Investigators and patients.
It cannot be excluded that hitherto unknown AEs will be detected in this trial, but given the 
well characterised mode of action and the careful monitoring throughout the trial, the sponsor 
feels that the risks to participating patients are minimized and justified when compared with 
the potential benefit that a successful clinical development of BI 685509 could provide to the 
treatment of diabetic kidney disease.
Overall, in the context of the unmet medical need and the anticipated effect on progression of 
DKD in humans and based on the safety profile of BI 685509, the benefit-risk evaluation of 
the compound is considered favourable for the intended trial population.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objectives of the trial are to demonstrate the effectiveness of BI 685509 and to 
characterize the dose-response relationship for BI 685509 in patients with DKD by assessing 
3 doses and placebo.
2.1.2
Primary endpoint
Change from baseline in log transformed Urine Albumin Creatinine Ratio (UACR) measured 
in 10-hour urine after 20 weeks of trial treatment.
2.1.3
Secondary endpoints
Change from baseline in log transformed UACR measured in First Morning Void urine after 
20 weeks of trial treatment.
Proportion of patients achieving UACR decreases in 10-hour urine of at least 20% from 
baseline after 20 weeks of trial treatment.
Proportion of patients achieving UACR decreases in First Morning Void urine of at least 20% 
from baseline after 20 weeks of trial treatment.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
This trial is a multicentre, randomised, double-blind (within dose groups), parallel, placebo-
controlled clinical trial to compare three doses of BI 685509 with placebo in patients with 
diabetic kidney disease who are on background treatment with either ACEi or ARB plus any 
other standard of care according to respective local guidelines.
A schematic illustration of the trial design is presented in Figure 3.1: 1.
Figure 3.1: 1 Trial design
Patients will be enrolled (screened) in the trial once they have signed the informed consent. 
They will undergo a screening period of up to 3 weeks from the time of informed consent.
After their eligibility has been confirmed at screening, patients will continue in a 2-week 
baseline run in period. Patients who successfully complete the screening and baseline run-in 
period and meet the inclusion / exclusion criteria will be randomised equally into one of three 
parallel dose groups, and in each dose group to treatment either with BI 685509 or matching 
placebo in a 3:1 ratio (see Figure 3.1: 1).
From the start of the run-in until the end of the trial, at various time points patients will 
collect their urine for UACR sampling. These timepoints are listed in the UACR and eGFR 
flow chart. For each day that UACR is collected patients will start by collecting a First 
Morning Void urine in the container provided. As soon as the First Morning Void sample is 
collected the clock starts for the 10-hour urine collection. During this 10-hour period every 
time the patient urinates, they collect their urine into the provided container. An aliquot of 
this urine will be taken and used as the 10-hour UACR sample.
Once at each time point of urine collection patients will also give blood samples for eGFR 
analysis. For each time point where a physical visit to the site is not foreseen, the patient will 


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be equipped with a 
 kit to take blood at home, and urine collection 
containers to sample urine from their First Morning Voids and 10-hour collection container.
To decrease the burden on patients, where local regulations allow, samples taken at home 
between visits or when a home visit occurs will be shipped by the patient or a nurse or 
equivalent function visiting the patient for analysis at a central laboratory. Where this is not 
possible alternative arrangements will be made, e.g. samples taken to the investigational site. 
After end of treatment patients will continue with a 4-week follow-up with further urine and 
blood sampling. Beyond analysis for safety, urine and blood samples in this trial will serve 
for biomarker analysis including UACR and eGFR.
The trial will be stratified according to SGLT2 inhibitor use and type of diabetes at the time 
of randomisation. SGLT2 inhibitors are a promising class of drugs for DKD patients and it is 
anticipated that their use might increasingly become standard of care. [P20-09106].To avoid a 
confounding effect, treatment with SGLT2 inhibitors will have to be kept stable prior to trial 
participation and throughout trial treatment (see section 4.2.2.1). An approximate of 10% 
patients on Type 1 Diabetes Mellitus patients will be expected.
All patients will start on 1 mg TID BI 685509 or matching placebo. If the medication is 
tolerated, up-titration to 2 mg TID BI 685509 or matching placebo will occur after 2 weeks 
for patients in dose groups 2 and 3, and up-titration to 3 mg TID BI 685509 or matching 
placebo will occur after another 2 weeks for patients in dose group 3. Patients will receive 20
weeks of treatment in total, which is expected to be the duration required to obtain stable 
effects.
Following the 20-week treatment period, or at the time trial treatment is permanently 
discontinued, patients will have an End of Treatment (EoT) visit, which will be the start of a 
4-week follow-up period. A first follow-up telephone call (FUp1) at least 7 days later is
considered as the end of the Residual Effect Period (REP). Until the end of REP all AEs and 
changes to concomitant medication need to be collected, documented and reported.
During the entire follow-up period the patient will not be treated with trial medication, but 
should if possible continue with any background treatment they were on, and will collect 
additional urine and/or blood samples at home. At the end of the 4-week follow-up a last 
physical visit will occur where again blood and urine samples will be collected. Depending 
on local regulations and approvals this visit may occur at the site or the patient’s home. With 
the conclusion of this visit the trial participation is complete for the individual patient.
Historical serum creatinine data will be collected in the trial over a period of 3 years before 
start of treatment. This may be used in future to explore the benefit of BI 685509 in patients 
with rapid CKD progression.
Database lock will occur after the last patients have completed their final visit.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
A parallel group design was chosen to compare three different dose regimens, including a 
placebo control within each dose group, to find the optimal dose for phase III. Placebo 
control is used to control for observer and subject bias, and randomisation to control for 
assignment bias.
UACR was chosen as primary endpoint (10-hour collection) and secondary endpoint
(responder rate and First Morning Void (FMV)) because it was shown in previous phase II 
trials by others in CKD that it is sensitive, differentiating different doses, broad in its 
dynamic range and reaching a stable plateau within a reasonable time after start of treatment. 
It has been accepted by authorities as dose finding biomarker in CKD. In the MRD phase I 
trial in patients (1366-0004) UACR in 10-hour urine collected over the day (approximately 
starting with the morning dose) showed a greater difference to placebo compared to FMV 
urine. It is considered that 10-hour urine is able to capture the drug effect during the dosing 
schedule, while FMV urine contains the urine produced over night. While a 10-hour urine at 
daytime may be easier for patient to collect, a 24-h collection would be more burdensome and 
prone to error during night time collection. Also 10-hour UACR may be superior to FMV 
urine as the latter is depending on many factors such as nocturia and time of the first 
urination in the morning.
Furthermore, the change in UACR upon treatment within approximately 16 weeks of full 
dose correlates with long-term patient relevant outcomes. Based on this and including a 4-
week up-titration, until the target dose is achieved, the full duration of treatment has been 
selected to be 20 weeks. Since UACR is a parameter that varies intra-individually over time, 
multiple measurements are required at baseline and during the treatment period especially 
towards the end of treatment where a stable response to the drug should be achieved.
Sequential collection of urine during a 4-week follow-up period may deliver exploratory 
results of response stability and potential rebound effects.
To further characterise haemodynamic effects and potential early benefit on renal function 
serum creatinine will be measured at regular intervals for exploratory analysis.
In this parallel design, double-blind conditions regarding the patient’s treatment (active or 
placebo) are maintained within each dose group. It is not feasible to apply double-blind 
conditions between dose groups because the individual tablet strengths and matching placebo 
look different. Therefore investigators will know which dose group their patient is in but will 
be blinded to whether they are on active drug or placebo. Patients will be blinded to both the 
dose group they are on and whether they are taking active drug or placebo. Keeping 
investigators blinded to the dose group would require patients to take multiple tablets three 
times a day on top of the extensive background medication they already receive, which is 
considered too burdensome for this clinical trial. However, in order to minimise possible 
observer bias with regard to dose dependent effects, the dose group will be blinded to the 
patient as much as possible by applying the following measures:
The trial medication label will not include dose strengths so the dose will not be identifiable 
to the patient from the label.


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Every effort should be made by the trial team and sites staff that the patient is not informed 
about the dose group assignment.
Up-titration or “pseudo-titration” will occur for all patients two weeks after start of trial 
medication and again after another two weeks, regardless of dose group (see Table 4.1.4: 1). 
Pseudo-titration is a term used to describe when patients are told that they are potentially 
assigned to a higher dose, but actually remain on the same dose:
o
Patients in Dose Group 1 (1 mg TID) will be “pseudo-titrated” to 1 mg TID after 
two weeks and to 1 mg TID two weeks after that.
o
Patients in Dose Group 2 (2 mg TID) will be up-titrated from 1 mg TID to 2 mg 
TID after two weeks and then “pseudo-titrated” to 2 mg TID two weeks after that.
o
Patients in Dose Group 3 (3 mg TID) will be up-titrated from 1 mg TID to 2 mg 
TID after two weeks and to 3 mg TID two weeks after that.
However, in case the patient experiences a related adverse event or for any other reason the 
patient pauses trial treatment, the investigator will need to decide whether a down-titration is 
needed based on the rules reflected in section 4.1.4 and the dose group the patient is assigned 
to. The patient will not know the specific rules. This will eliminate an additional burden of 
the patient to visit the site for a sham-downtitration if the patient is staying on the lowest dose 
already.
3.3
SELECTION OF TRIAL POPULATION
It is expected that 240 patients will be randomised from approximately 100 sites. Screening 
of patients for this trial is competitive, i.e. screening for the trial will stop at all sites at the 
same time once a sufficient number of patients has been screened. Investigators will be 
notified about screening completion and will then not be allowed to screen additional patients 
for this trial unless screening needs to be re-opened due to a higher rate of screen failures.
A log of all patients screened into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is randomised in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Diabetic kidney disease.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
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. Male or female patients aged ≥ 18 years at time of consent.
3. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) ≥20 
and < 90 mL/min/1.73 m2 at Visit 1 by central laboratory analysis. eGFR must remain ≥ 


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20 mL/min/1.73 m2 after Visit 1 up to the start of Visit 3, measured by central or any local 
laboratory analysis.
4. UACR ≥ 200 and < 3,500 mg/g in spot urine (midstream urine sample) by central 
laboratory analysis at Visit 1.1
5. Treatment with the highest tolerated dose of either ACEi or ARB (but not both together), 
and stable dose for ≥ 4 weeks before Visit 1 with no planned change of the therapy during 
the trial.
6. If the patient is taking any of the following medications they should be on a stable dose at
least 4 weeks prior to visit 1 until start of treatment, with no planned change of the 
therapy during the trial: anti-hypertensives, NSAIDs, endothelin receptor antagonists, 
systemic steroids or SGLT2 inhibitors.
7. Patients with stable type 1 or type 2 diabetes mellitus, diagnosed before informed 
consent. Treatment (including SGLT2 inhibitor and/or GLP1 receptor agonist) should 
have been unchanged or changes deemed minor (according to investigator’s judgement) 
within 4 weeks before Visit 1 and until start of trial treatment.
8. Glycated Haemoglobin (HbA1c) < 10.0% at Visit 1 measured by the central laboratory.
9. Seated SBP ≥ 110 and ≤ 160 mmHg and DBP ≥ 65 and ≤ 110 mmHg at Visit 1 and 
optimized anti-hypertensive treatment according to local standard of care and 
investigator’s judgement.2
10. Body Mass Index (BMI) ≥ 18.5 and < 50 kg/m2 at Visit 1.
11. Male patients able to father a child must be willing to use condoms if their sexual partner 
is a Women of child-bearing potential3 (WOCBP). WOCBP must be ready and able to 
use highly effective methods of birth control per ICH M3 (R2). Such methods should be 
used throughout the trial. A list of contraceptive methods meeting these criteria is 
provided in the patient information and in section 4.2.2.3 of the protocol.
3.3.3
Exclusion criteria
1. Treatment with Renin Angiotensin Aldosterone System (RAAS) interventions (apart from 
either ACEi or ARB), phosphodiesterase-5 inhibitors, non-specific phosphodiesterase 
inhibitors (such as dipyridamole and theophylline), NO donors including nitrates, sGC-
stimulators/activators (other than trial treatment) or any other restricted medication
(including OATP1B1/3 inhibitors, UGT inhibitors/inducers) as provided in the 
Investigator Site File (ISF) within 4 weeks prior to visit 1 and throughout screening and 
baseline run-in. Patients who must or wish to continue the intake of restricted medications 
(see section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial are also excluded.
2. Any clinically relevant laboratory value from screening until start of trial treatment, 
which in the investigator’s judgement puts the patient at additional risk.
3. Biopsy or otherwise confirmed non-diabetic chronic kidney disease, or non-diabetic 
chronic kidney disease in the opinion of investigator, e.g., Autosomal Dominant 
Polycystic Kidney Disease (ADPKD), uncontrolled lupus nephritis. The presence of a 
hypertensive etiology does not need to be excluded unless it is evident this is the only 
cause for the CKD.
4. Any immunosuppression therapy or immunotherapy in the last 3 months prior to visit 1 
and throughout screening and baseline run-in (except prednisolone ≤10 mg or equivalent).


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5. Acute kidney injury (AKI) according to the Kidney Disease: Improving Global Outcomes 
(KDIGO) definition4 [R17-2439] in the 30 days prior to Visit 1 until the start of trial 
treatment.
6. Planned start of chronic renal replacement therapy during the trial or end stage renal 
disease before start of trial treatment.
7. Known history of moderate or severe symptomatic orthostatic dysregulation as judged by 
the investigator before start of trial treatment5.
8. The patient has an active infection with SARS-CoV-2 (or is known to have a positive 
test) from screening until randomisation.
9. 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]).
10. Major surgery (investigator’s judgement) planned during the trial.
11. History of clinically relevant allergy/ hypersensitivity that would interfere with trial 
participation including allergy to investigational product/ placebo or its excipients (see 
Investigator Brochure [c02778238])
12. Any other medical condition6 that in the investigator’s opinion poses a safety risk for the 
patient or may interfere with the trial objectives. 
13. Previous randomisation in this trial.
14. Currently enrolled in another investigational device or drug trial, 
∀or less than 30 days or 5 half-lives (whichever is longer) prior to Visit 1 since ending 
another investigational device or drug trial(s) for an oral agent which is not specified 
in any other exclusion criteria,
∀or less than 12 months prior to Visit 1 since ending another investigational device or 
drug trial(s) for a biological agent which is not specified in exclusion criteria or 
restrictions table in section 4.2.2,
∀or receiving other investigational treatment(s).
15. 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.
16. Women who are pregnant, nursing or who plan to become pregnant while in the trial.
17. QTcF-interval > 450 ms in men or > 470 ms in women at any time from screening 
(Visit 1) until start of treatment.
18. A family history of long QT syndrome.
19. Concomitant use of therapies with a known risk of Torsade de Pointes at screening 
(Visit 1) and throughout screening and baseline run-in or planned initiation of such 
therapies during the trial (refer to Section 4.2.2.1).
1In case of borderline out of range results UACR testing may be repeated once before the baseline sampling starts.
2A patient with a seated SBP between >160≤180 mmHG at Visit 1 may be re-screened according to the guidance in the flow 
chart and section 6.2.2. Anyone with a SBP over 180mmHg should be excluded. This re-screening should only occur after 
appropriate adjustment to their medication and sufficient time to ensure their medication is stable in accordance with the 
protocol.
3A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined 
as no menses for 12 months without an alternative medical cause.
4Definition of AKI can be found in section 3.3.4.1
5Severity of symptomatic orthostatic dysregulation is based on the standard Adverse Event severity classification.
6Examples of medical conditions may include, but is not limited to:
- symptomatic heart failure (NYHA III/IV)
- known history of tachycardia and/or atrial fibrillation


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- clinically relevant arrhythmias
- coronary heart disease not compensated by medical treatment (supine pulse rate > 70 beats per minute, existing angina 
pectoris).
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; 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 on treatment, or at 
least to collect important trial data (UACR and eGFR sampling) according to the flow chart.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment 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 5.2.6.2.1 and 
5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:
∀
The patient wants to discontinue trial treatment, without the need to justify the decision.
∀
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 interferes with the safety of the 
investigational medicinal product, refer to sections 4.2.1 and 4.2.2. If there is no safety 
concern then the Sponsor will review on a case-by-case basis as to whether it is 
appropriate for the patients to continue.  This decision will be based on factors such as 
duration of treatment, dose etc. 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 develops Acute Kidney Injury as per clinical judgment by the Investigator.
The Kidney Disease: Improving Global Outcomes (KDIGO) definition[R17-2439] should 
be used for guidance:
o
Increase in serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 μmol/L) within 48 hours; 
or
o
Increase in serum creatinine to ≥ 1.5 times, which is known or presumed to have 
occurred within the prior 7 days; or
o
Urine volume < 0.5 mL/kg/h for 6 hours.
∀
The patient progresses to end stage renal disease and needs to obtain renal replacement 
therapy.
∀
Patients with a QT or QTcF interval > 500 ms, or an increase of QT or QTcF of > 60 ms 
from the pre-dose value at Visit 3 (baseline). Such cases must be reported as AEs.
∀
The patient experiences a severe infection, e.g. with SARS-CoV-2 that precludes their 
safe participation in the trial, as determined by the investigator.


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∀
The patient can no longer receive trial treatment for any other medical reasons such as 
surgery, serious or severe Drug Induced Liver Injury (DILI) attributable to the trial drug 
(see section 5.2.6.1.4), other adverse events, or other diseases.
∀
The patient has discontinued trial treatment for at least 10 consecutive days* or has not 
taken medication at a total of 14 days* during the trial. In case of a temporary reason, trial 
treatment should be restarted if medically justified, please see section 4.1.4 for dose 
adjustments. * a missed day is classed as all 3 doses being missed
∀
A female patient becomes pregnant. The patient will be followed up until birth or 
otherwise termination of the pregnancy. The data of the patient will be collected and 
reported in the clinical trial report until last patient last visit and any events thereafter will 
be reported in the BI Pharmacovigilance database. See section 5.2.6.2.3.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
Please see section 6.2.4 for details of the procedures to be performed if trial treatment is 
discontinued.
The sponsor may decide to replace patients if patients terminate early due to a pandemic 
outbreak.
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 treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see section 6.2.4.
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 efficacy or safety information invalidating the earlier positive benefit-risk-assessment, 
please see section 3.3.4.1.
Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
Further follow up of patients affected will occur as described in section 6.2.4.
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
The trial medication (BI 685509 and matching placebo) will be provided by Boehringer 
Ingelheim. 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the Investigational Medicinal Products are described in Table 4.1.1: 1
to 6.
Table 4.1.1: 1
BI 685509 1 mg
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
1 mg 
Posology:
TID
Method and route of administration:
Oral (p.o)
Table 4.1.1: 2
BI 685509 2 mg
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
2 mg
Posology:
TID
Method and route of administration:
Oral (p.o)
Table 4.1.1: 3
BI 685509 3 mg
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
3 mg 
Posology:
TID
Method and route of administration:
Oral (p.o)
Table 4.1.1: 4
Placebo matching BI 685509 1 mg
Substance:
Placebo to BI 685509 film-coated tablets 1 mg 
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
TID
Method and route of administration:
Oral (p.o)


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Table 4.1.1: 5
Placebo matching BI 685509 2 mg
Substance:
Placebo to BI 685509 film-coated tablets 2 mg 
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
TID
Method and route of administration:
Oral (p.o)
Table 4.1.1: 6
Placebo matching BI 685509 3 mg
Substance:
Placebo to BI 685509 film-coated tablets 3 mg 
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
TID
Method and route of administration:
Oral (p.o)
4.1.2
Selection of doses in the trial and dose modifications
The target doses of BI 685509 used for this trial will be 1 mg TID, 2 mg TID and 3 mg TID. 
These doses were selected based on the safety and PK results of the 1366-0004 phase I MRD 
trial.
In healthy volunteer phase I trials doses starting with 0.5 mg QD were tested. At 1 mg TID 
the first signal of slight pharmacodynamic (PD) effects on blood pressure and heart rate was 
seen. Doses higher than 3 mg TID were not well tolerated.


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4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria at Visit 3, each eligible patient will be 
randomised according to a randomisation plan.
Table 4.1.3: 1
Dose Groups and Treatments
Target dose starting Visit 5
Randomisation ratio
Patients to be enrolled
Dose 
Group 1
1 mg BI 685509 TID
3
60
Placebo matching 1 mg 
BI 685509 TID
1
20
Dose 
Group 2 
2 mg BI 685509 TID
3
60
Placebo matching 2 mg 
BI 685509 TID
1
20
Dose 
Group 3
3 mg BI 685509 TID
3
60
Placebo matching 3 mg 
BI 685509 TID
1
20
Randomisation codes will be generated through a validated software and kept blinded to the 
trial team, sites and patients. An Interactive Response Technology (IRT) system will be used 
to screen patients, perform drug assignment, manage initial/ re-supply ordering of drug 
supplies and handle emergency un-blinding.
The investigator will receive all necessary instructions from the sponsor to access the IRT. 
Detailed IRT functions and procedures will be documented in the User Requirement 
Specifications mutually agreed by the sponsor and the IRT vendor. Note that the medication 
number is different from the patient number (the latter is generated during screening via the 
IRT System).
4.1.4
Drug assignment and administration of doses for each patient
All patients, regardless of dose group assigned, will start on a dose of 1 mg TID of BI 685509 
or matching placebo. Up-titration or pseudo up-titration will occur after 14 days and after 28 
days in each dose group, until the maximum planned dose for that dose group is reached. 
Patients who do not tolerate an up-titration, e.g., due to orthostatic dysregulation, should 
follow the guidance in section 4.1.4.2.
The treatment assignments and dose regimen are detailed in Table 4.1.4: 1.


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Table 4.1.4: 1
Treatment assignments and dose regimen
Randomisation 
Allocation
Weeks 1 & 2
Weeks 3 & 4
Weeks 5 to 20
Dispensed at Visit 3
Dispensed at Visit 4
Dispensed at 
Visits 5, 6,7 & 8
Dose Group 1
1 mg BI 685509 or 
matching placebo TID
1 mg BI 685509 or 
matching placebo TID
1 mg BI 685509 or 
matching placebo TID
Dose Group 2 
1 mg BI 685509 or 
matching placebo TID
2 mg BI 685509 or 
matching placebo TID
2 mg BI 685509 or 
matching placebo TID
Dose Group 3
1 mg BI 685509 or 
matching placebo TID
2 mg BI 685509 or 
matching placebo TID
3 mg BI 685509 or 
matching placebo TID
It is recommended that the first daily dose is taken in the morning, the middle dose around 
lunchtime, and the third dose in the evening (one tablet at each time point). There must be at 
least 4 hours in between trial medication intake. If a dose is missed this should not be 
rectified by taking two doses at the next time point. The medication should be taken with a 
glass of water and can be taken with or without food. The last dose of trial medication will be 
administered in the evening of the day before the EoT visit.
All trial medication assignments including up/down-titrations and replacement kits will be 
managed through the IRT system. Standard up-titrations in the first 4 weeks have to be done 
in the same manner for all patients to blind the patient to the dose group they’re assigned to. 
If no true up-titration is required for a patient at regular timepoints (i.e. Visit 4 and again at 
Visit 5), then the patient will still get new medication on the same dose as before. All patients 
will be told that the medication could either be the same or a higher dose depending on the 
treatment and dose group to which the patient is allocated.
During a COVID-19 or similar pandemic, physical visits to the sites may need to be restricted 
to ensure patient safety. Based on a thorough assessment of the benefits and risks, the 
investigator may still decide to continue the trial treatment and trial medication may be 
shipped to the patient’s home if acceptable according to local law and regulations (for more 
details see section 6.2.1). Shipment of trial medication to the patient’s home will also be 
allowed to support regular visits performed at the patient’s home.
Potential down-titrations (dose reductions) can be done based on the dose group known by 
the investigational site. This will be managed via the IRT system. Dose reductions must not 
be performed by instructing the patient to take less than the three daily doses. While the 
patient will not get to know the precise rules as listed in sections 4.1.4.1 and 4.1.4.2, the 
patient will be informed that down-titrations may be needed as decided by the investigator.
4.1.4.1
Rules for titration in case of interruption of trial treatment
Since an interruption of trial medication may have an influence on the tolerance, the 
following rules will apply for the safety of the patient:


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An interruption of trial treatment is defined as any occurrence where 4 consecutive doses* or 
more were not administered (i.e. missed or dosing temporarily discontinued).*One dose 
refers to an individual timepoint e.g. morning dose, or middle dose or evening dose.
o
If less than 4 consecutive doses of trial medication are missed then the next dose 
of trial medication should be taken as scheduled.
After an interruption of trial treatment the patient should be restarted at 1 mg BI 685509/ 
placebo TID independent from the dose the patient was on before unless the patient was 
down-titrated due to an adverse event (see section 4.1.4.2) in which case:
o
If they had been on 2 mg/3 mg BI 685509/ placebo they would re-start on 1 mg 
BI 685509/ placebo.
o
If they had been on 1 mg BI 685509/ placebo then they should restart on placebo 
(matching 1 mg BI 685509).
Before any up-titration occurs the patient must have taken the preceding dose for at least 7 
consecutive days. This applies throughout the treatment period.
o
This may mean that a patient due to be up-titrated at Visit 4 or 5 (as per Table
4.1.4: 1) is held at their current dose until their next scheduled visit. They could 
also be up-titrated at an unscheduled visit once this requirement is met.
If interruption for any reason occurs after Visit 5, subsequent up-titration will be allowed 
either at a scheduled or unscheduled visits.
Patients with an interruption on 2 mg or 3 mg or matching placebo will need to return to the 
clinic either for the next scheduled or an unscheduled visit to receive 1 mg tablets before 
continuation of trial treatment.
4.1.4.2
Rules for down-titration in case of intolerance to trial treatment
If a patient has an adverse event that the Investigator believes may be related to trial 
medication then the Investigator may either interrupt a patient’s trial medication (re-start to 
follow the rules above (see section 4.1.4.1) or dose reduce the patient as described below. See 
Appendix 10.3 for a schematic guidance on down-titration:
If the patient is on 1 mg TID or matching placebo the patient will be down-titrated to placebo 
matching 1 mg.
If the patient is on 2 mg TID or 3 mg TID (or corresponding matching placebo) and interrupts 
trial treatment
o
less than 4 consecutive doses, then the patient will be down-titrated one level i.e.

2 mg /placebo goes to 1 mg TID/ placebo.

3 mg/ placebo goes to 2 mg TID/ placebo.
o
4 consecutive doses or more, then the patient will be down-titrated to 1 mg TID or 
placebo.
Dose-reduction must NOT be performed by taking less than the three daily doses or by 
splitting tablets so that a whole tablet isn’t taken.
If the patient experiences a second adverse event that the Investigator believes is related and 
they have already had an interruption/ down-titration, then the patient should permanently 
discontinue trial treatment.
In case of persistent adverse events despite dose reduction, or severe effects at any dose, 
permanent treatment discontinuation should be considered.
Uptitration for patients who were down-titrated or interrupted for a related AE is not 
permitted.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators and everyone involved in trial conduct or analysis or with any other 
interest except the Trial Pharmacometrician, PK programmer and Trial Bioanalyst in this 
double-blind trial will remain blinded with regard to the randomised treatment assignments
within each dose group until after database lock. The access to the randomisation code will be 
kept restricted until its release for analysis.
The randomisation codes will be provided to bioanalytics prior to last patient completed to 
allow for the exclusion from the analyses of PK samples taken from placebo patients. 
Bioanalytics will not disclose the randomisation code or the results of their measurements 
until the trial is officially unblinded.
In order to expedite the population PK and PK-PD analyses and ensure timely delivery of 
PK/PD results after DBL, specific data must be unblinded and the treatment information must 
be made available to selected individuals. The unblinding procedure and logistics specific to 
this purpose will be provided in a separate document. It should be noted no PK/PD results 
will be communicated to the project and trial team prior to database lock.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
Pharmacovigilance (PV) database system and not be shared further.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP).
Re-supply to the sites will be managed via an IRT system, which will also monitor expiry 
dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate CRA (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
Approval of the clinical trial protocol by the IRB / ethics committee,
Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,
Approval/notification of the regulatory authority, e.g. competent authority,
Availability of the curriculum vitae of the Principal Investigator,
Availability of a signed and dated clinical trial protocol,
Availability of the proof of a medical license for the Principal Investigator (if applicable),
Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor’s appointed CRO, the investigator or designee must verify that all unused or partially 
used drug supplies have been returned by the clinical trial patient and that no remaining 
supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Patients should keep their existing therapies as stable as possible, particularly their therapy 
with either ACEi or ARB from screening at Visit 1 until the end of follow-up at Visit Follow-
up 2 (FUp2).


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New therapies should only be initiated if necessary for medical reasons. Please see the 
inclusion / exclusion criteria (sections 3.3.2 and 3.3.3 respectively) and Table 4.2.2.1: 1 for 
full details of restrictions.
Background therapies (ACEi/ARB) or any other standard of care medications are not 
considered part of the clinical trial supplies, and therefore will not be provided.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Mitigation of the potential risks can be achieved by close monitoring of patients and the 
prohibited co-administration of drugs with 
 
. Special caution is warranted when administering BI 685509 in 
combination with drugs metabolized via CYP3A4, because the exposure of such drugs may 
potentially increase. In addition, BI 685509 must not be co-administered with OATP1B1/3 
inhibitors and drugs known to inhibit or induce UGT enzymes, as this may impact BI 685509 
exposures in a clinically relevant manner. List of relevant drugs can be found in the 
investigator site file.
In addition, intake of concomitant therapies with a known risk of Torsade de Pointes must not 
be co-administered with BI 685509 (also refer to Table 1.4.2: 1). These restrictions apply 
from screening (Visit 1), until Visit FUp3. In the event of temporary concomitant use of such 
a therapy, trial medication must be temporarily stopped and can then be re-started after a 
period of at least 5 half-lives after the concomitant therapy with the known risk of Torsade de 
Pointes has been stopped, as long as the interruption rules are followed. Refer to Section 
4.1.4.1 for rules for re-starting up-titration in case of interruption of trial medication.
Table 4.2.2.1: 1
Concomitant medication restrictions
Medication
Prior to trial 
(Visit 1)
During 
screening/ 
run-in 
During 
Treatment 
Period
In the Follow-
up Period
Either ACEi or 
ARB
Stable dose for 
≥ 4 weeks 
before Visit 1
required
combination of 
ACEi and 
ARB not 
allowed
Stable dose 
required;
combination of 
ACEi and 
ARB not 
allowed
Stable dose
required;
combination of 
ACEi and 
ARB not 
allowed
Stable dose
required;
combination 
of ACEi and 
ARB not 
allowed


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Table 4.2.2.1: 1 Concomitant medication restrictions cont.
Medication
Prior to trial 
(Visit 1)
During 
screening/ 
run-in 
During 
Treatment 
Period
In the Follow-
up Period
Other RAAS 
intervention
Not permitted 
within ≥4 weeks 
prior to visit 1
Not permitted
Not permitted
Not permitted
Anti-hypertensive 
treatment
During the 4 
weeks prior to 
visit 1 permitted 
if the dose is 
stable throughout
Stable dose 
permitted 
Stable dose 
permitted
Stable dose 
permitted
NSAIDs
During the 4 
weeks prior to 
visit 1 permitted 
if the dose is 
stable throughout
Stable dose 
permitted
Stable dose 
permitted if 
used prior to 
entry, 
otherwise 
should be 
avoided. Use 
alternative 
where possible
Stable dose 
permitted if 
used prior to 
entry, 
otherwise 
should be 
avoided. Use 
alternative 
where possible
Endothelin 
receptor 
antagonists
During the 4 
weeks prior to 
visit 1 permitted 
if the dose is 
stable throughout
Stable dose 
permitted
Stable dose 
permitted
Stable dose 
permitted
Systemic steroids
(im, iv, po)
Permitted during 
the 4 weeks prior 
to visit 1 if the 
dose is stable 
throughout and is 
planned to 
remain stable 
throughout the 
trial and at a dose 
of prednisolone 
≤10 mg or 
equivalent.
Not permitted 
except 
prednisolone 
(≤10 mg or 
equivalent)
Should be 
avoided if 
alternatives are 
available, 
Prednisolone 
(≤10 mg or 
equivalent) is 
permitted
Should be 
avoided if 
alternatives 
are available.
Prednisolone 
(≤10 mg or 
equivalent) is 
permitted


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Table 4.2.2.1: 1 Concomitant medication restrictions cont.
Medication
Prior to trial (Visit 
1)
During 
screening/ 
run-in 
During 
Treatment 
Period
In the 
Follow-up 
Period
Immunosuppression 
therapy or 
immunotherapy (for 
systemic steroids see 
above)
Not permitted 3 
months prior to visit 
1
Not 
permitted
Not 
permitted
Not 
permitted
SGLT2 inhibitors
During the 4 weeks 
prior to visit 1 
permitted if the dose 
is stable throughout
Stable dose 
permitted, 
initiation 
not 
permitted
Stable dose 
permitted, 
initiation not 
permitted
Stable dose 
permitted, 
initiation not 
permitted
Other anti-diabetic 
treatment (e.g. 
GLP1R agonists)
During the 4 weeks 
prior to visit 1 
permitted if the dose 
is stable throughout
Stable dose 
permitted
Stable dose 
permitted
Stable dose 
permitted
Phosphodiesterase-5
inhibitors, non-
specific 
phosphodiesterase 
inhibitors (such as 
dipyridamole and 
theophylline)
Not permitted within 
4 weeks prior to visit 
1
Not 
permitted
Not 
permitted
Not 
permitted
NO donors including 
nitrates*
Not permitted within 
4 weeks prior to visit 
1
Not 
permitted
Not 
permitted
Not 
permitted
sGC-stimulators / 
activators (other 
than BI 685509)
Not permitted within 
4 weeks prior to visit 
1
Not 
permitted 
Not 
permitted
Not 
permitted
Chronic renal 
replacement therapy
Not permitted
Not 
permitted
Not 
permitted
Not 
permitted
Treatment for cancer
Not permitted two 
years prior to visit 1. 
Some exclusions 
apply e.g. for Basal 
Cell Carcinoma –
please discuss with 
sponsor
Not 
permitted
Not 
permitted
Not 
permitted
* In case a sublingual nitrate is needed for suspected acute coronary syndrome, when the patient is on trial treatment, close
monitoring of the blood pressure is required.


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Table 4.2.2.1: 1 Concomitant medication restrictions cont.
4.2.2.2
Restrictions on diet and life style
There are no restrictions on diet and life style. Drastic changes of diet and lifestyle in the 
course of the trial should be avoided. This includes unusual and strenuous exercise for the 
patient.
Medication
Prior to trial 
(Visit 1)
During 
screening/ 
run-in 
During 
Treatment 
Period
In the Follow-
up Period
Other 
Investigational 
Medicinal Product 
or Investigational 
Device
Not permitted 
within 30 days
or 5 half-lives 
(whichever is 
longer) prior 
to visit 1. 
Biologics are 
not permitted 
within 12 
months prior 
to visit 1.
Not permitted
Not permitted
Not permitted
Treatment with 
clinically relevant 
OATP1B1/3 
inhibitors and 
clinically relevant 
UGT inhibitors/ 
inducers as provided 
in the Investigator.
Site File (ISF)
Not permitted 
within ≥4 
weeks prior to 
visit 1
Not permitted
Not permitted
Permitted
Drugs with known 
risk of Torsade de 
Pointes
Not permitted 
at least 5 half-
lives of such 
drug prior to 
visit 1
Not permitted
Not permitted
Not permitted
Herbal or natural 
products (Including 
Traditional Chinese 
Medicine)
Recommended 
to be stopped. 
Should not be 
initated at or 
after screening
Initiation not 
permitted. If 
used at a stable 
dose prior to 
screening may 
be continued
Initiation not 
permitted. If 
used at a stable 
dose prior to 
screening may 
be continued
Initiation not 
permitted. If 
used at a 
stable dose 
prior to 
screening may 
be continued


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4.2.2.3
Contraception requirements
WOCBP (for the definition please refer to section 3.3.3) trial participants, must use a highly 
effective method of birth control throughout the trial, and for a period of at least 7 days after 
last trial drug intake, if their sexual partner is a male able to father a child. No contraceptive
is required for the WOCBP participant’s partner.
Highly effective methods of birth control per ICH M3 (R2) that results in a low failure rate of 
less than 1% per year when used consistently and correctly include (examples depending on 
approval status in each country):
Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal).
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
Bilateral tubal occlusion.
A male trial participant must be vasectomised with documented absence of sperm or use a 
condom until at least 7 days after last trial drug intake , if their sexual partner is a WOCBP. 
No contraceptive is required for the male participant’s partner.
Alternatively, WOCBP participants and male participants able to father a child must abstain 
from male-female sex. This is defined as being in line with the preferred and usual lifestyle of 
the patient. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation 
methods; declaration of abstinence for the duration of exposure to study drug; and withdrawal 
are not acceptable.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
A patient will be considered as non-compliant in taking their trial medication if they have 
missed 4 consecutive doses or more. There are permitted exceptions to this, please see 
sections 3.3.4.1 (discontinuation of trial treatment) and 4.1.4 (withdrawal and assignment and 
administration) for further details.
A patient would also be considered as non-compliant if the patient, in the investigator’s 
opinion, has not followed the drug administration guidance on a consistant basis, e.g. 
repeatedly not taking 3 tablets a day, or repeatedly not following the dosing interval.
Compliance will be verified by the CRA authorised by the sponsor.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
UACR
Urinary albumin and creatinine measurements are the basis for the calculation of urine
albumin creatinine ratio (UACR). FMV and 10-hour urine samples will be collected by the 
patient at home. 
The first morning void is the first urination after the patient wakes up at their usual time to 
start their day. Thus, if the patient goes back to sleep after urinating early in the morning this 
void does not need to be collected or documented. This applies also to any urinations earlier 
during the night in patients who have nocturia. There may be cases when a patient might go 
back to bed after their usual rising time. In those cases, the void at their usual rising time 
constitutes the first morning void.
Starting with the baseline run-in period, UACR will be determined on two consecutive days 
to average biological variability at the timepoints indicated in the flow chart. On each 
collection day a sample must be obtained from the patient’s FMV and from the total of urine 
collected over 10 hours after the FMV on the same day. Intake of trial medication in the 
morning should always occur after the FMV has been collected. Containers for collection of 
urine will be provided by the same central lab that will perform specimen management. An 
appropriate number of containers 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. Urinary creatinine may also be used for normalisation of exploratory 
urinary biomarkers (see section 5.4.1).
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. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flow chart, prior to the 12-lead 
ECG and prior to blood sampling as applicable.


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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. At Visits 3 to 8 vital 
signs will be measured before dosing and approximately 30 min and 120 min after dosing. 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 and UACR for eligibility and safety 
analyses, the respective reference ranges will be provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
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. Should a 
patient not fulfil all lab requirements to take part in the trial due to a transitional medical 
condition, the patient may continue in the run-in phase but not be randomised until the re-test 
of the lab result has shown eligibility of the patient.
To test the eGFR throughout the trial, a small capillary blood volume will be collected by the 
patient (if needed with assistance by the site staff or caregiver) with the 
 at the 
time points indicated in the flow chart. Therefore during each period of home based urine 
collection for UACR analysis patients will need to draw one blood sample on their own and 
ship 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 samples collected at visits will be 
compared to the eGFR calculations based on the common safety blood sample to show 
comparability for future trials.
In case the criteria for a potential severe DILI are fulfilled, a number of additional measures 
will be performed (please see section 5.2.6.1 and the DILI Checklist provided in the eDC
system. The amount of blood taken from the patient concerned will be increased due to this
additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
The CKD-EPI Equation is used for reporting eGFR based on serum creatinine (see appendix 
section 10.2).


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Table 5.2.3: 1 
Safety laboratory tests
Short name
Name of assay
Substrate
Other information
Blood serum 
HCT
Haematocrit
Haematocrit
HGB
Haemoglobin
Haemoglobin
RBC
Red blood cell counts
Erythrocytes
WBC
White blood cell counts
Leukocytes
PLTCT
Platelets
Platelets
RETABS
Reticulocytes absolute
Reticulocytes
NEUABS
Neutrophils absolute
Neutrophils
EOSABS
Eosinophils absolute
Eosinophils
BASABS
Basophils absolute
Basophils
MONABS
Monocytes absolute
Monocytes
LYMABS
Lymphocytes absolute
Lymphocytes
SGPT
ALT/SGPT, SGPT
Alanine 
Aminotransferase
SGOT
AST/SGOT, SGOT
Aspartate 
Aminotransferase
ALKP
Alkaline phosphatase
Alkaline 
Phosphatase
GGT
GGT
Gamma Glutamyl 
Transferase
LDH
LDH
Lactate 
Dehydrogenase
CK
Creatine kinase
Creatine Kinase
CREE
Creatinine, Enzymatic
Creatinine
Enzymatic
GFRE
GFR/Creatinine cl.-calc 
(CKD-EPI)
GFR from 
Creatinine Adjusted 
for BSA
CKD-EPI 
ALGORITHM
TBILI
Bilirubin, total
Bilirubin
BILID
Bilirubin, direct
Direct Bilirubin
If total bilirubin is 
elevated
TPRO
Protein, total
Protein


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Table 5.2.3: 1 Safety laboratory tests cont.
Short name
Name of assay
Substrate
Other information
Blood serum 
ALB
Albumin
Albumin
UREA
Urea
Urea
UREA
URIC
Uric acid
Urate
HBA1C
Hgb A 1c,glycated
Hemoglobin A1C
Visit 1 and EoT
NA
Sodium
Sodium
K
Potassium
Potassium
MG
Magnesium
Magnesium
CA
Calcium
Calcium
P
Phosphate
Phosphate
TRIGL
Triglyceride
Triglycerides
CHOL
Cholesterol, total
Cholesterol
HDLCHOLD
HDL cholesterol (direct)
HDL Cholesterol
LDLCHOLD
LDL cholesterol (direct)
LDL Cholesterol
Urinalysis
UNIT
Urine nitrite (qual)
Nitrite
QUALITATIVE 
MEASUREMENT
UPROZ
Urine protein (qual)
Protein
QUALITATIVE 
MEASUREMENT
UGLU
Urine glucose (qual)
Glucose
QUALITATIVE 
MEASUREMENT
UKET
Urine ketone (qual)
Ketones
QUALITATIVE 
MEASUREMENT
UROBZ
Urobilinogen (qual)
Urobilinogen
QUALITATIVE 
MEASUREMENT
UBILI
Urine bilirubin (qual)
Bilirubin
QUALITATIVE 
MEASUREMENT
URBCZ
Urine RBC (qual)
Erythrocytes
QUALITATIVE 
MEASUREMENT
UWBCZ
Urine WBC (qual)
Leukocytes
QUALITATIVE 
MEASUREMENT
UPH
Urine pH
pH


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In case qualitative parameters are abnormal, a quantitative analysis will be performed by the 
central laboratory.Pregnancy testing in WOCBP will be performed at Visit 1 (serum),
thereafter pregnancy tests will be on urine.
If blood sampling for safety at the trial site or patient’s home through a member of site staff 
or CRO is not possible (due to a force majeure), safety lab analyses can be performed at a 
local lab. The results of the lab tests must be transferred to the investigator who ensures 
medical review and proper documentation in the eCRF. In case only central lab is 
implemented in the eCRF, a clinically relevant safety issue has to be entered as adverse 
event. Minimum required safety lab parameters are:
Table 5.2.3: 2 
Minimum required safety laboratory tests for local labs
Short name
Name assay
Substrate
Other information
Blood serum
HGB
Haemoglobin
Haemoglobin
RBC
Red blood cell count
Erythrocytes
WBC
White blood cell count
Leukocytes
PLTCT
Platelets
Platelets
SGPT
ALT/SGPT, SGPT
Alanine 
Aminotransferase
SGOT
AST/SGOT, SGOT
Aspartate 
Aminotransferase
ALKP
Alkaline phosphatase
Alkaline 
Phosphatase
CREE
Creatinine, Enzymatic
Creatinine
Preferably enzymatic, 
but any other method 
is acceptable
TBILI
Bilirubin, total
Bilirubin
UREA
Urea
Urea
UREA
NA
Sodium
Sodium
K
Potassium
Potassium
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified physician, nurse or technologist and 
results will be recorded as scheduled in the flow chart. Vitals signs will be measured before 
the ECG is taken. The ECG should be performed after the patient has rested for at least 5 
minutes in a supine position and prior to blood sampling. The investigator or a designee will 
evaluate whether the ECG is normal or abnormal and assess clinical relevance. ECGs may be 
repeated for quality reasons and a repeated recording used for analysis.


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Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate. ECG abnormalities will be carefully assessed by the investigator, and 
if trial discontinuation criteria are met (refer to Section 3.3.4.1), the patient will be 
discontinued from the trial.
Copies of ECGs will be sent to a central ECG vendor for storage and if required to enable a 
subsequent centralised and independent re-evaluation.
5.2.5
Other safety parameters
N/A
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 should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀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.
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,


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-
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.
For Japan only: An event that possibly leads to disability will be handled as ‘deemed serious 
for any other reason’ and, therefore, reported as an SAE.
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 eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in section 5.2.6.2.
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
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:
∀
Severe orthostatic dysregulation as judged by the investigator
∀
Severe hypotension as judged by the investigator
∀
Syncope
∀
Potential Severe DILI:
A potential severe DILI that requires follow-up is defined by the following alterations 
of hepatic laboratory parameters: 
∀
An elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of 


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total bilirubin ≥2 fold ULN measured in the same blood sample, or in samples 
drawn within 30 days of each other, or
∀
ALT and/or AST elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in 
the eDC system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab 
results (ALT, AST, total bilirubin) available, the investigator should make sure these 
parameters are analysed, if necessary in an unscheduled blood test. Should the results 
meet the criteria of hepatic injury alert, the procedures described in the “DILI 
checklist” should be followed.
5.2.6.1.5
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.
5.2.6.1.6
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 given study treatment, 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 


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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).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
From signing the informed consent onwards until the follow-up visit 1 all AEs (non-serious 
and serious) and all AESIs.
After follow-up-visit 1 until the individual patient’s end of trial:
cancers of new histology and exacerbations of existing cancer, all trial treatment related 
SAEs and all trial treatment related AESIs.
After the individual patient’s end of the trial: 
the investigator does not need to actively monitor the patient for new AEs but should report
any occurrence of cancer and trial treatment related SAEs and trial treatment related AESIs of 
which the investigator may become aware of by any means of communication, e.g. phone 
call. Those AEs should be reported on the BI SAE form (see section 5.2.6.2.2), but not on the 
CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.


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5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Studies and not the SAE form is to be 
completed. If there is an SAE and/or AESI associated with the pregnancy an SAE form must 
be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
PK sampling times and periods are indicated in the Flow Chart for Procedures. Date and 
clock time of drug administration(s) and PK sampling will be recorded in the eCRF. Patients 
do not need to come fasted to visits, but the fasting status needs to be recorded for PK 
sampling.
Noncompartmental PK parameters will be calculated based on actual sampling times using a
validated PK software (Phoenix® WinNonlin® 8.1). Further PK parameters will be calculated 
as feasible and may include, but are not limited to:
Cmax (maximum measured concentration of the analyte in plasma)
tmax (time from dosing to maximum measured concentration of the analyte in plasma)
AUCt1-t2 (area under the concentration-time curve of the analyte in plasma over the time 
interval t1 to t2 after single dose administration)
Cmax,N (maximum measured concentration of the analyte in plasma following N doses)
tmax,N (time from last dosing to maximum measured concentration of the analyte in plasma 
after administration of N doses)
AUCt1-t2,N (area under the concentration-time curve of the analyte in plasma over the time 
interval t1 to t2 after administration of Nth dose)
Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over a 
uniform dosing interval τ)
tmax,ss (time from last dosing to maximum measured concentration of the analyte in plasma at 
steady state over a uniform dosing interval τ)


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AUCt1-t2,ss (area under the concentration-time curve of the analyte in plasma over the time 
interval t1 to t2 at steady state)
Cpre,N (Predose concentration of the analyte in plasma immediately before administration of 
the Nth dose after N-1 doses were administered)
Cpre,ss (Predose concentration of the analyte in plasma at steady state immediately before 
administration of the next dose)
RA,Cmax (accumulation ratio of the analayte in plasma at steady state after multiple dose 
administration over a uniform dosing interval τ, expressed as ratio of Cmax at steady state and 
after single dose)
RA,Cmax,N (accumulation ratio of the analayte in plasma after administration of Nth dose over a 
uniform dosing interval τ, expressed as ratio of Cmax after the Nth dose and after single dose)
Additional PK parameters may be calculated as appropriate.
Individual plasma concentration data and the PK parameters calculated thereof will be 
tabulated and graphically displayed. A subject’s PK data will be flagged and excluded from 
the PK analyses in case of protocol deviations relevant to the evaluation of PK or in case of 
PK non-evaluability (as revealed during data analysis, based on the criteria specified below). 
Reasons for exclusion of a subject’s data will be documented in the CTR.
Protocol deviations relevant to the evaluation of PK may be
Incorrect trial medication taken
Incorrect dose of trial medication taken
PK non-evaluability applies, if for example
The subject experienced emesis that occurred in the time window of two times median tmax
(median tmax is to be determined excluding the subject(s) experiencing emesis)
The subject has missing samples/concentration data at important phases of the PK disposition 
curve
5.3.2
Methods of sample collection
For quantification of analyte plasma concentrations of BI 685509 blood will be taken from an 
antecubital or forearm vein at the times indicated in the flow chart. Blood will be withdrawn 
by means of either an indwelling venous catheter or by venipuncture with a metal needle. 
Further details of sample processing for plasma generation will be described in the study-
specific lab manual (see ISF).
After analysis the samples may be used for further methodological investigations (e.g., for 
stability testing or assessment of metabolites) or to address Health Authority questions
regarding the results/methodology. However, only data related to the analyte and/or its 
metabolite(s) will be generated by these additional investigations. The study samples will be 
discarded after completion of the additional investigations, but no later than 5 years after the 
final study report has been archived.


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5.3.4
Pharmacokinetic-pharmacodynamic relationship
The PK and PD data from this study may be used for an exploratory investigation of the PK-
PD relationship of BI 685509. A population PK-PD analysis may be performed at the project 
level using a non-linear mixed effects modelling approach. This analysis will not be part of 
the CTR, but will be reported separately.
5.4
ASSESSMENT OF BIOMARKERS
This section refers to exploratory biomarkers. Established biomarkers of efficacy and safety 
are described and discussed in sections 5.1 and 5.2.




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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.
5.5.1
Methods and timing of sample collection
Sampling will be performed at the time points specified in the flow chart.
Plasma banking: Blood will be drawn into a K-EDTA blood collection tube.
Serum banking: Blood will be drawn into a serum separation tube.
Urine banking: Urine will be taken at the timepoints shown in the flow chart, after tubes for 
exploratory biomarkers (see section 5.4.2) have been filled. The urine will be taken from the 
urine sample collected for safety.
For all biospecimens collected, detailed instructions on sampling, preparation, processing,
shipment and storage are provided in the laboratory manual. Samples will be stored at an 
external biobanking facility contracted by the sponsor.
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 monitor safety aspects and to determine efficacy, PK and PD markers 
of BI 685509 in an appropriate way.
The scheduled measurements are appropriate to assess drug induced changes in kidney 
function with regard to albuminuria (UACR), and safetywise in vital signs, standard 
laboratory values, and ECG. While UACR is widely accepted as a PD marker for efficacy in 
renal trials, safety lab, vital signs and ECG are standard to examine the safety of the 
investigational product and to descriptively identify differences between different doses and 
placebo.
Instead of the widely used FMV, serial 10-hour urine sampling over day were selected as an 
appropriate measure for the primary endpoint, as this is supposed to correlate with the 
immediate effect of BI 685509 after administration and has shown a relevant change in 




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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All visits should should be scheduled according to the flow chart. Each visit date (with its 
window) is to be counted from Day 1 (randomisation). If any visit has to be rescheduled, 
subsequent visits should follow the original visit schedule. The trial medication packs contain 
sufficient medication to allow for these time windows.
All trial visits should be initiated preferentially in the morning. Patients should be instructed 
to not take their morning dose of the study medication at home at scheduled visit days as they 
will be dosed whilst at the study site.
Patients do not need to come fasted to study visits, but their fasting status will have to be 
recorded in the CRF for PK sampling timepoints. From the first PK sample before 
administration of BI 685509 until the PK sample 2 hours after administration the patient 
should only drink water and eat no food unless it is medically needed.
Unscheduled visits will be possible at the discretion of the investigator at any time in order to 
check the safety of the patient or to provide trial medication e.g following an interruption. 
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 and 
Flow Chart for Procedures. All assessments should be performed before study drug 
administration.
Where the following assesments occur at a visit they should be performed in the following 
order:
Vital signs – see flow chart and Flow Chart for Procedures
ECG – see flow chart and Flow Chart for Procedures
Blood draws including trough PK and 
 – other PK samples are drawn after
drug administration (see Flow Chart for Procedures)
Spot urine (mid-stream) samples can be collected at any time prior to trial medication. 
Aliquots should be taken from the urine sample in the following order: first safety and 
pregnancy sample (if applicable), then if applicable biomarkers, followed by biobanking (if 
consent obtained).
Please see 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 and Flow Chart for Procedures – overview of what procedures should be 
performed and at what timepoints.
Section 5.2.1 – Physical Exam
Section 5.2.2 – Vital Signs


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Section 5.2.3 – Laboratory Tests
Section 5.2.4 – Electrocardiograms
Section 6.2.1 – Telemedicine Contacts and Home Visits
6.2.1
Telemedicine Contacts and Home Visits
In this study Telemedicine Contacts and Home Visits may be performed if all local approvals 
are in place and confirmed by the sponsor.
These contacts are used to help support patients with protocol procedures and compliance. 
The Home visits can be used to reduce the burden of participation on patients, and also to 
encourage participation following the COVID-19 or similar pandemic in case a patient is 
otherwise not able to travel to the site.
Telemedicine contacts should be performed as indicated in the flow chart but may also be 
performed at any time during the course of the trial to support patients with the home 
sampling and/ or following up on AEs or trial medication compliance. This may be via a 
straightforward phone call between the patient and an appropriately qualified member of the 
Investigational Site or via a video call using a smartphone/ tablet application. If the 
telemedicine contact is being done during a home visit to support a physician guided physical 
exam this must be done as a video call.
The following visits may be performed at the patient’s home, i.e. a home visit by a nurse or 
physician:
Visit 2 (Run-in)
Visits 7 and 8 (Treatment Phase)
FUp3 
Unscheduled visits where a physical exam is not required
If the patient reports an AE during these visits then it’s at the discretion of the Investigator as 
to whether a telemedicine contact is need to support this assessment or even if the patient 
should attend the site.
The following visits may be performed at the Patient’s home by a physician. If allowed by 
local regulations these visits may also be performed by a nurse if they are qualified to 
perform a physical exam or if they are guided by a physician via a video call i.e. a home visit 
with telemedicine. The guided physical exam cannot be done via a phone call as the 
physician must observe the nurse who is doing the physical examination:
Visits 6 and FUp2
Home visits may be performed either by an appropriately qualified member of the 
Investigational Site team or by a CRO working on behalf of the sponsor. Where a CRO is 
used all source information will be made available/ transferred to the Investigational Site.
To support visits performed at the patient’s home direct shipment of the trial medication will 
be managed by the site or the provider directly as permitted by local regulations. Unused 
medication provided at a previous visit may be returned to the site via a courier. If needed 


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also the laboratory kits and ancillary materials required by the nurse may be shipped to the 
patient prior to the visit.
All other visits must be performed at the Investigational Site. The only exception to this is if 
COVID-19 or similar pandemic restrictions are in place. In these exceptional cases, if the 
scheduled visits at the trial site are impossible, they may be performed at the patient’s home 
or as a telemedicine contact or as a combination, based on a thorough benefit-risk assessment 
(see section 1.4.2). Critical safety measures will remain in place. All home visits/telemedicine 
contact need to be discussed with and approved by the sponsor`s trial team. Local regulatory 
and legal requirements of the participating country still apply.
6.2.2
Screening and run-in 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 considered to be enrolled in the trial and 
have started screening. The patient should be recorded on the enrolment log and be registered 
in the IRT system as a screened patient before any other activites are performed. Patients who 
do not start the run-in period should be registered as a screen failure in the IRT system.
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.
Run-in Period
The run-in period for this trial lasts for two weeks prior to randomisation. During this period
the patient will start to collect their UACR samples as described in the flow chart and in 
section 5.1.1.
6.2.3
Treatment period
The treatment period in this trial is 20 weeks. All visit procedures should be completed as 
indicated in the flow chart.
6.2.4
Early discontinuation of Treatment
Patients who discontinue treatment prematurely and who do not withdraw their informed 
consent should return for an End of Treatment visit.
If the patient has stopped taking trial drug the day of a scheduled visit or one day prior, the
scheduled visit should be performed as an EoT Visit. All samples including PK and all 
biomarkers (
, UACR and others) should be collected in addition to safety samples. If 
the early discontinuation does not coincide with a scheduled visit, the patient should return 
for an EoT Visit. PK or biomarker samples should not be collected, but all safety assessments 
must be performed as indicated in the flow chart.


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The patient should be encouraged to complete all visits and procedures in the FUp period (see 
section 6.2.5). If the patient does not wish to complete all visits or procedures, they should 
have FUp1 as a mimimum.
6.2.5
Follow-up period and trial completion
The Follow-up Period consists of three visits, FUp1, FUp2 and FUp3 with a timepoint for 
UACR and 
 in between these visits, please see the flow chart for timelines 
and visit details.
The Residual Effect Period (REP) in this study is 7 days, visit FUp1 should therefore be 
performed no earlier than 7 days after the End of Treatment Visit.
FUp visits FUp2 and FUp3 should also be scheduled relative to the EoT Visit, i.e. FUp2 will
be 2 weeks after EoT, 3 weeks after EoT there will be home sampling without visit, and FUp 
3 should be 4 weeks after EoT.
Visit FUp3 may be conducted as a Home visit where permitted (see section 6.2.1), however 
should a patient have any adverse event(s) that require assessment then the Investigator may 
request they attend the site for a full assessment.
Participation in this trial is concluded once FUp3 has been completed.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This is a Phase II, randomised, double-blind (within dose groups), placebo-controlled and 
parallel group trial to investigate the effect of different doses of BI 685509 on UACR 
reduction over 20 weeks in patients with diabetic kidney disease.
The primary endpoint for patients is Change from baseline in log transformed UACR 
measured in 10-hour urine after 20 weeks of trial treatment. The purpose of this trial is to 
demonstrate PoC (proof of concept) of clinical activity of BI 685509 on the primary endpoint 
and to determine the optimal dose for phase III. The methodology for dose finding employing 
both multiple comparison procedures and modelling techniques (MCPMod) will be applied to 
the 4 groups of patients, i.e. the patients on BI 685509 in each of the three dose groups and 
the combined patients from all dose groups who are not on BI 685509.
7.1
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis is that there is a flat dose response curve for Change from baseline in log 
transformed UACR measured in 10-hour urine after 20 weeks of trial treatment comparing 
the placebo and the BI 685509 dose groups whereas the alternative hypothesis is that, there is 
a non-flat dose response curve indicating a benefit of BI 685509 in at least one of the patient 
groups.
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of Type I error (one-sided α of 5 
%). The pre-specified models and their parameters used for this test are outlined in section 
7.2.1.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The following analysis sets will be defined for statistical analyses:
Entered Set (ES): This patient set includes all patients who signed informed consent. The ES
will be used for the analysis of patient desposition.
Randomised Set (RS): This patient set includes all entered and randomised patients. The RS
will be used for the analyses of protocol deviations as well as demographics and baseline 
characteristics.
Treated Set (TS): This patient set includes all patients who received at least one dose of study
medication. The TS is used for safety analyses and exposure.
Full Analysis Set (FAS): The patient set includes all patients who had at least one baseline 
measurement of UACR in week -2, -1, or 0 and at least one post-baseline measurement after 
week 6. The FAS is the main analysis set for the analysis of efficacy.






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group (0.22 difference in mean log transformed UACR) compared to placebo. For PoC, 
patients will be analyzed as randomised, according to the primary approach in Table 7.2.2: 1.
The same process will be repeated for the supplemental 1 and 2 approaches in Table 7.2.2: 1.
Dose finding
The second primary objective is to determine therapeutic dose. The trial will characterize the 
dose-response curve for BI 685509 in patients with diabetic kidney disease (DKD) by 
assessing 3 doses and placebo. The response is the change from baseline in log transformed 
UACR measured in 10-hour urine after 20 weeks of trial treatment. Patients will be evaluated 
in the dose group they were assigned to at randomisation for primary analysis in the 
MCPMod analysis.
The analyses for dose-finding will be performed using MCPMod whereby several possible 
dose response models (patterns) will be evaluated to identify the best-fitting model or subset 
of models (refer to Figure 7.5: 1). If PoC is established, the statistically significant (best 
fitting) model(s) from the candidate set are refitted to the data to generate new estimates for 
all model parameters from the data. The final model will be obtained via model averaging 
across the significant models based on Akaike Information Criterion (AIC). The target 
dose(s) can be estimated from that model by incorporating information on the minimum 
clinically relevant effect and accounting for safety. Doses within the dose range investigated 
(0 to 9 mg, total daily dose) will be considered.
7.2.3
Secondary endpoint analyses
The analysis for the change of UACR in FMV urine will be performed by using MMRM.
Descriptive statistics will be provided for the change of UACR in FMV urine/10-hour urine
and the UACR response rate along with figures.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 7 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
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.




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7.4
RANDOMISATION
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
In order to ensure a balance of patients who are on SGLT2 inhibitors and who are type 1 or 2 
diabetes mellitus compared with those who are not, the trial will be stratified according to 
SGLT2 inhibitor use and type of diabetes mellitusat randomisation. Patients will be 
randomised to 1 mg tid, matching placebo, 2 mg tid, matching placebo, 3 mg tid, and 
matching placebo in a 3:1:3:1:3:1 ratio. There will be 60 patients on BI 685509 and 20 on 
placebo in each dose group (240 in total).
7.5
DETERMINATION OF SAMPLE SIZE
The sample size calculation is conducted assuming effect size of BI 685509 versus placebo, 
(0, 0.10, 0.20, 0.35) for (placebo, BI 685509 3 mg, BI 685509 6 mg, BI 685509 9 mg total 
daily dose) in log transformed UACR measured in 10-hour urine after 20 weeks of trial 
treatment from baseline. The pre-specified models in Figure 7.5: 1 are used for testing null 
hypothesis. The following models have been selected as the candidate set of possible dose 
response patterns based on current expectation. Assuming the following dose groups will be 
tested: placebo, active BI 685509 3 mg, 6 mg, and 9 mg in terms of total daily dose.
Emax: 80% of the maximum effect is achieved at 6 mg.
Exponential: 20% of the maximum effect is achieved at 3 mg.
Linear: No assumption is needed.
Quadratic: 50 % of the maximum effect is achieved at a dose of 3 mg.
90 % of the maximum effect is achieved at a dose of 6 mg.
Sigmoid emax: 30 % of the maximum effect is achieved at a dose of 3 mg.
  90 % of the maximum effect is achieved at a dose of 6 mg.


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Figure 7.5: 1 Shape of the considered dose response patterns for the MCPMod analysis 
(dose reflects planned daily dose)
In a scenario with assumed effect of (0, 0.10, 0.20, 0.35) in log (UACR) change from 
baseline to week 16 for (placebo, BI 685509 3 mg, BI 685509 6 mg, BI 685509 9 mg total 
daily dose), 88.5% of statistical power considering one-sided 5% alpha was achieved with 
sample size per treatment from 60. The sample size/power calculation were determined based 
on 10,000 simulations for the scenario using R3.6.1.


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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 Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014, the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997) 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) 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. See section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to section 4.1.8.
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 (substance, trial number, patient number, date patient was 
informed).
Dates of patient’s visits, including dispensing of trial medication.
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 to a treatment 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. 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.
ECG results (original or copies of printouts).
For electronic patient reported outcomes the electronic record is the source document.
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.
Source documentation for telemedicine visits.
Source documentation for visits performed at the patient’s home.
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.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
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 has 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.
8.6
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”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site.


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Last Patient Last Visit for Primary Endpoint (LPLV PE) is defined as the date when the 
last patient in the entire trial has had the EoT visit or withdrawn from the trial whatever is 
later.
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.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
A Steering Committee (SC, alternatively: sGC operations committee) consisting of external 
experts involved in the trial and sponsor representatives will be established. The SC may 
cover multiple phase II trials taking place at the same time. The composition of the SC will 
be documented in the Trial Master File (TMF). The tasks and responsibilities will be agreed 
in contracts between the SC members and the sponsor and also summarised in a SC charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to:
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.


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Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P20-09106
Ronco P, Rovin B, KDIGO Work Group. KDIGO 2020 Clinical Practice 
Guideline for Diabetes Management in Chronic Kidney Disease. Off. J Int. 
Soc. Nephr. 2020. 98(4S).
R02-0327
Brenner BM, Cooper ME, Zeeuw D de, Keane WF, Mitch WE, Parving 
HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, RENAAL Study 
Investigators. Effects of losartan on renal and cardiovascular outcomes in 
patients with type 2 diabetes and nephropathy. N Engl J Med. 2001. 
345(12): 861-869.
R02-2101
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, 
Atkins RC, Rohde R, Raz I, Collaborative Study Group. Renoprotective 
effect of the angiotensin-receptor antagonist irbesartan in patients with 
nephropathy due to type 2 diabetes. N Engl J Med. 2001. 345(12): 851-860.
R14-4466
Eleftheriadis T, Antoniadi G, Pissas G, Liakopoulos V. The Renal 
Endothelium in Diabaetic Nephropathy. Renal Fail. 2013. 35(4): 592-599.
R14-4467
Brown Ke, Dhaun N, Goddard J, Webb DJ. Potential Therapeutic Role of 
Phosphodiesterase Type 5 Inhibition in Hypertension and Chronic Kidney 
Disease. Hypertension. 2014. 63(1): 5-11.
R14-4475
Muntner P, Bowling CB, Gao L, Rizk D, Judd S, Tanner RM, McClellan
W, Warnock DG. Age-specific association of reduced estimated glomerular
filtration rate and albuminuria with all-cause mortality. Clin J Am Soc 
Nephrol. 2011. 6: 2200-2207.
R15-2265
Udell JA, Bhatt DL, Braunwald E, Cavender MA, Mosenzon O, Steg PG, 
Davidson JA, Nicolau JC, Corbalan R, Hirshberg B, Frederich R, Im K, 
Umez-Eronini AA, He P, McGuire DK, Leiter LA, Raz I, Scirica BM. 
SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and 
cardiovascular outcomes in patients with type 2 diabetes and moderate or 
severe renal impairment: observations from the SAVOR-TIMI 53 trial. 
Diabetes Care. 2015. 38(4): 696-705.
R15-5158
WangY, Katzmarzyk PT, Horswell R, Zhao W, Johnson J, Hu G. Kidney 
function and the risk of cardiovascular disease in patients with type 2 
diabetes. Kidney Int. 2014. 85(5): 1192-1199.
R17-2439
Kellum JA, Lameire N, KDIGO Work Group. Kidney International 
Supplements. KDIGO Clinical Practice Guideline for Acute Kidney Injury. 
Off. J Int. Soc. Nephr. 2012. 2: 1.


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9.2
UNPUBLISHED REFERENCES
c02778238
Investigator´s Brochure. BI 685509. Current Version.
c30365927-01
Clinical Trial Report. 1366-0004. Randomised, double-blind, placebo-
controlled trial to investigate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of 3 multiple rising oral doses of BI 685509 over 28 
days in male and female patients with diabetic nephropathy. 08 May 2020.


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10.
APPENDICES


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Creatinine in mg/dL is rounded to 2 decimal places prior to 
applying the formula.
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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10.3
DOWN-TITRATION GUIDE


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
15 Dec 2020
EudraCT number
EU number
2020-002929-28
BI Trial number
1366-0005
BI Investigational Medicinal 
Product(s)
BI 685509
Title of protocol
Randomised, double-blind (within dose groups), 
placebo-controlled and parallel group trial to 
investigate the effects of different doses of oral 
BI 685509 given over 20 weeks on UACR 
reduction in patients with diabetic kidney disease
Global Amendment due to urgent safety reasons
Global Amendment
X
Version 2.0 is considered to be the initial version of the CTP and includes some 
modifications after version 1.0 has been archived. The original version 1.0 of this protocol 
was not submitted to any authorities, ethics committees or institutional review board for 
approval of the clinical trial.
11.2
GLOBAL AMENDMENT 2
Date of amendment
29 July 2021 
EudraCT number
EU number
2020-002929-28
BI Trial number
1366-0005
BI Investigational Medicinal 
Product(s)
BI 685509
Title of protocol
Randomised, double-blind (within dose groups), 
placebo-controlled and parallel group trial to 
investigate the effects of different doses of oral 
BI 685509 given over 20 weeks on UACR 
reduction in patients with diabetic kidney disease
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Flow Chart
Description of change
Added the column header “Post dose” and a cross to indicate 
post dose ECG at Visit 3. The post dose ECG was already 
mentioned in footnote xxii. 


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Added new footnote xxii to explain timing of the planned 
last dose.
Rationale for change
Correction and clarification.
Section to be changed
Flow Chart, UACR and GFR Sampling Flow Chart and 
Section 3.1
Description of change
Extended the maximum time before randomisation from 28 
to 35 days throughout the protocol.
Rationale for change
More time is needed to allow screening procedures to be 
repeated where permitted. 
Safety assessment such as vital signs, safety labs and 
physical examination will be performed again at Visit 2 
and/or Visit 3 therefore there will be recent safety 
assessments prior to receiving the first dose of IMP. 
Section to be changed
Flow Chart 
Description of change
Rephrased footnote xviii from:
“Should the first test for UACR at screening not match 
inclusion criteria due to UACR variability, this can be 
repeated once.”
To:
“Should the first test for UACR at screening be borderline 
out of range and not match inclusion criteria due to UACR 
variability, this test can be repeated once. The result must be 
available and eligibility confirmed before the baseline 
UACR sampling starts.”
Rationale for change
Clarification that the spot urine retest needs to be done and 
results received prior to start of baseline UACR sampling.
Section to be changed
1.4.2 Risks
Description of change
Removed “at home”.
Rationale for change
Clarification. This relates to 
blood sampling. It’s 
intended that patients will use the 
 to take 
capillary blood themselves both at home and also at the 
(applicable) site visit.
Section to be changed
3.1 Overall trial design
Description of change
Clarified that shipment of samples from patient’s home can 
also be done by a nurse or equivalent function visiting the 
patient. Also clarified that this is applicable for both samples 
collected between visits and when home visits are 
performed. 


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Rephrased text to clarify that the FUp3 Visit may occur at 
the site or the patient’s home. Added local regulations and 
approvals as a requirement for Home Health Care services. 
Removed analysis of 
 as this is exploratory 
analysis.
Rationale for change
Clarifications
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Added further requirement to inclusion criterion #3: 
eGFR must remain ≥ 20 mL/min/1.73 m2 after Visit 1 up to 
the start of Visit 3, measured by central or any local 
laboratory analysis.
Rationale for change
To ensure patient safety the eGFR value must not drop 
below 20 ml/min/1.73 m2 prior to visit 3. For the samples 
drawn at visit 3 and onwards withdrawal criteria have to be 
considered.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Rephrased inclusion criterion #6: 
From:
“Stable on anti-hypertensives, NSAIDs, endothelin receptor 
antagonists, systemic steroids, within at least 4 weeks prior 
to Visit 1 until start of trial treatment, with no planned 
change of the therapy during the trial.”
To:
“If the patient is taking any of the following medications 
they should be on a stable dose at least 4 weeks prior to visit 
1 until start of treatment, with no planned change of the 
therapy during the trial: anti-hypertensives, NSAIDs, 
endothelin receptor antagonists, systemic steroids or SGLT2 
inhibitors.”
Rationale for change
Clarification
Section to be changed
4.1.4 and 4.1.4.2 Drug assignment and administration of 
doses for each patient
Description of change
Moved the descriptions of shipments to patients in a 
pandemic situation from section 4.1.4.2 to section 4.1.4 and 
added a statement that shipments will also be allowed for 
regular visits at the patient’s home.
Rationale for change
Clarification
Section to be changed
4.2.2.1 Restrictions regarding concomitant treatment


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Description of change
Footnote added: “* In case a sublingual nitrate is needed for 
suspected acute coronary syndrome, when the patient is on 
trial treatment, close monitoring of the blood pressure is 
required.”
Rationale for change
Clarification on use of restricted nitrates in an emergency.
Section to be changed
4.3 Treatment Compliance 
Description of change
Removal of tablet count recorded in the CRF.
Rationale for change
Implementation of the administrative letter. Tablet counts 
are not required for compliance calculation, but will be 
provided through accountability procedures at the site.
Section to be changed
5.1.1 UACR
Description of change
Definition of FMV added.
Rationale for change
Clarification.
Section to be changed
5.2.3
Safety laboratory parameters and Flow Chart
Description of change
Replaced requirement to test non-sterilized women <65 
years of age with the requirement to test women of child 
bearing potential for pregnancy.
Added clarification of why a safety laboratory may not be 
done at the central lab and added requirement to check S-
creatinine to the minimum tests at the local lab.
Added further explanation that capillary blood draws using 
the 
 should always be performed by the 
patient unless assistance is required.
Rationale for change
Pregnancy testing requirements have been updated as it is 
unnecessary for a women who is not, for whatever reason, of 
child bearing potential to undergo pregnancy testing. 
S-creatinine has been added as an important lab parameter to 
monitor kidney function.
Further clarifications.
Section to be changed
5.3.2 Methods of Sample Collection
Description of change
Rephrased the following:
“After completion of the trial the plasma samples may be 
used for further methodological investigations, e.g., for 
stability testing, assessment of metabolites. However, only 
data related to the analyte and/or its metabolite(s) will be 
generated by these additional investigations. The study 
samples will be discarded after completion of the additional 
investigations, but no later than 5 years after the final study 
report has been signed.”


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To:
“After analysis the samples may be used for further 
methodological investigations (e.g., for stability testing or 
assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only 
data related to the analyte and/or its metabolite(s) will be 
generated by these additional investigations. The study 
samples will be discarded after completion of the additional 
investigations, but no later than 5 years after the final study 
report has been archived.“
Rationale for change
Samples may be used for the described purposes directly 
after their originally intended analysis.
Section to be changed
5.4.1 Exploratory biomarkers
Description of change
Added further explanation on capillary blood draws, which 
can be assisted by site staff/nurse or a caregiver.
Rationale for change
Further clarification.
Section to be changed
6.2.1
Telemedicine Contacts and Home Visits
Description of change
Added further clarification on shipments to and from 
patient’s home and physical examinations by a qualified 
nurse.
Rationale for change
Clarifications.
Section to be changed
7.2.5
Safety analyses
Description of change
Adverse events will be summarized by the treatment to 
which the subject was randomised, and the treatment at the 
onset of AE for the drug-related AE rather than the treatment 
at end of the up-titration period as was before.
Rationale for change
The original wording was reliant on a patient completing the 
up-titration period which may not be the case for all patients. 
The new wording is aligned with the Sponsor’s Company 
standards.
Section to be changed
8.3.1 Source documents
Description of change
Deleted the following sentence: 
“This includes the values for eGFR and UACR and their 
method of analysis at or before screening to confirm 
eligibility.”
Rationale for change
Since this is performed by the central lab and the sentence 
before already mentions all inclusion criteria, this sentence 
has been removed for clarification.
11.3
GLOBAL AMENDMENT 3
Date of amendment
13 October 2021


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EudraCT number
EU number
2020-002929-28
BI Trial number
1366-0005
BI Investigational Medicinal 
Product(s)
BI 685509
Title of protocol
Randomised, double-blind (within dose groups), 
placebo-controlled and parallel group trial to 
investigate the effects of different doses of oral 
BI 685509 given over 20 weeks on UACR 
reduction in patients with diabetic kidney disease
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
3.1
Description of change
Removed duplicate Figure 3.1: 1 from previous protocol 
version with 2 weeks screening instead of now 3 weeks.
Rationale for change
Correction. The removal of the figure was missed in global 
amendment 2.
Section to be changed
Flow Chart and Flow Chart for Procedures (Formerly PK 
Flow Chart) 
Description of change
Addition of ECGs at visits where there were previously no 
ECGs: three ECGs at visits 4, 5 and one ECG at Visits 7 and 
8. At Visits 3 and 6 an additional ECG will be done to the 
two already performed.
The main Flow Chart also reflects the number of times these 
ECGs occur.
Footnote xii has been updated to reflect this.
Rationale for change
More frequent ECG monitoring introduced as a response to 
the recent additional data mentioned in – see section 1.2.
Section to be changed
Flow Chart
Description of change
Where multiple assessments/ procedures are done e.g. 
ECGs, PK sampling the numbers have been added to the 
flow chart
Rationale for change
For clarity
Section to be changed
Flow Chart
Description of change
All AEs footnote reference for FUp1 and FUp2 changed
Rationale for change
Typographical error, the references had been written the 
wrong way round.
Section to be changed
Flow Chart


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Description of change
The text in footnote xviii about pre-screening for UACR has 
been moved to footnote iii. In addition eGFR has been added 
as a test that patients can be pre-screened for if consent is 
given.
Rationale for change
The text about eGFR has been added as this is not always 
done regularly and several patients have failed screening for 
this. Allowing pre-screening for eGFR means less 
unnecessary screening procedures for patients who would 
not be eligible due to eGFR.
The UACR pre-screening text has been moved as it is more 
appropriate to have all screening text together.
Section to be changed
Flow chart footnote ix
Description of change
The text “……. And within 35 days of randomisation (visit 
3)” has been added.
Rationale for change
For clarity and consistency.
Section to be changed
Flow chart footnote xi
Description of change
The following text has been added:
“…..If applicable this must occur prior to the ECG and PK 
samples. See FLOW CHART FOR PROCEDURES for 
details on the timing of ECGs."
Rationale for change
For clarity and consistency.
Section to be changed
Flow Chart for Procedures (Formerly PK Flow Chart)
Description of change
The PK flow chart has been expanded to include all the 
assessments/ procedures to be performed and the order in 
which they should be done.
The PK Flow Chart has been renamed to “Flow Chart for 
Procedures”. These changes apply throughout the protocol.
Rationale for change
It is important that procedures are done within the order 
mentioned in section 6.2. The table has been added to make 
this easier to follow and to include the timings.
Section to be changed
UACR and GFR sampling flow chart
Description of change
Reference added to flow chart for visit windows.
Rationale for change
For clarity.
Section to be changed
Section 1.2 Drug Profile
Description of change
The following text was added:
Based on recent data from a clinical trial (1366-0020) in 
patients with cirrhosis Child-Pugh stage A (24 patients) and 
B (25 patients), an effect of BI 685509 on the predicted 


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placebo-corrected change from baseline QTcF (∆∆QTcF) 
was seen. Dosing regimens up to 3 mg bid, similar to the 
highest dose group in this trial, were used. In both patient 
groups, there was a dose dependent increase of ∆∆QTcF up 
to 13.7 ms, with the upper 90% CI >20 ms. In one patient 
group (Child-Pugh B) this was concomitant with a change of 
the predicted placebo-corrected change from baseline heart 
rate (∆∆HR) of > 10 beats per minute (bpm), but not in the 
other patient group. No such effect was seen in a healthy 
Caucasian volunteers trial (1366-0010) for dosing regimens 
used in this trial. In a healthy Asian volunteers trial (1366-
0013), at a dose regimen relevant for this study (i.e. starting 
with 1 mg tid up to a final dose of 3 mg tid), an increase of 
∆∆QTcF was seen up to 11.7 ms with 90% CI <20 ms, 
concomitant with an increase of ∆∆HR of nearly 10 bpm.
BI 685509 has no effect on human ether-a-go-go related 
gene (hERG) channel at doses used in this clinical trial, and 
no effect on QT-interval was seen in conscious animal 
studies.
Rationale for change
To provide new information this also serves as the detailed 
rationale behind the additional measures being included in 
this amendment.
Section to be changed
Section 1.4.2, Table 1.4.2:1 Overview of Trial Related Risks
Description of change
Potential QT-interval prolongation was added as a risk along 
with the summary of data, rationale for the risk and the 
mitigation strategy.
Rationale for change
Updated due to the new data available.
Section to be changed
Section 3.2 discussion of the trial design
Description of change
From: 
“In order for patients and investigators to be blinded to dose 
group, patients would be subjected to taking multiple tablets 
three times a day on top of the extensive background 
medication they already receive, which is considered too 
burdensome for this clinical trial.”
To:
“Therefore Investigators will know which dose group their 
patient is in but will be blinded to whether they are on active 
or placebo medication. Patients will be blinded to both the 
dose group they are on and whether they are taking active 
drug or placebo. Keeping Investigators blinded to the dose 
group would require patients to take multiple tablets three 
times a day on top of the extensive background medication 


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they already receive, which is considered too burdensome 
for this clinical trial.” 
Rationale for change
To clarify blinding within this trial.
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
Exclusion criteria 11) Removal of lactose monohydrate as an 
example of an excipient.
Rationale for change
Lactose monohydrate is not used in the Phase II formulation.
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
Addition of the following exclusion criteria:
17. QTcF -interval > 450 ms in men or > 470 ms in women 
at any time from screening (Visit 1) until start of treatment.
18. A family history of long QT syndrome.
19. Concomitant use of therapies with a known risk of 
Torsade de Pointes at screening (Visit 1) and throughout 
screening and baseline run-in or planned initiation of such 
therapies during the trial (refer to Section 4.2.2.1 ).
Rationale for change
Added to ensure patients with QTc prolongation or with the 
potential for QTc prolongation do not participate.
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
“• 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.
Was rephrased to:
“•The patient needs to take concomitant medication that 
interferes with the safety of the investigational medicinal 
product, refer to sections 4.2.1 and 4.2.2.  If there is no 
safety concern then the Sponsor will review on a case-by-
case basis as to whether it’s appropriate for the patients to 
continue.  This decision will be based on factors such as 
duration of treatment, dose etc. 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.”
Rationale for change
The patient may remain on trial treatment in an exceptional 
case once the patient uses restricted medication, if there are 
no safety concerns. The patient will be analysed according to 
the TSAP.
Section to be changed
3.3.4.1 Discontinuation of Trial Treatment
Description of change
The following was added:


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Patients with a QT or QTcF interval > 500 ms, or an 
increase of QT or QTcF of > 60 ms from the pre-dose value 
at Visit 3 (baseline). Such cases must be reported as AEs.
Rationale for change
An additional patient safety measure.
Section to be changed
3.3.4.1 Discontinuation of Trial Treatment
Description of change
“The patient develops Acute Kidney Injury according to the 
Kidney Disease: Improving Global Outcomes (KDIGO) 
definition[R17-2439]” 
Was changed to:
“The patient develops Acute Kidney Injury as per clinical 
judgment by the Investigator. The Kidney Disease: 
Improving Global Outcomes (KDIGO) definition[R17-2439] 
should be used for guidance”
Rationale for change
The KDIGO guidelines are for use within a clinical setting. 
Patients with low urine output for reasons other than AKI, 
for example poor fluid intake, potentially could have been 
incorrectly discontinued.
Section to be changed
4.1.4
Description of change
The following text was added: “The last dose of trial 
medication will be administered in the evening of the day 
before the EoT visit.“
Rationale for change
Clarification. 
Section to be changed
4.2.2.1 Restrictions Regarding Concomitant Medication and 
Table 4.2.2.1:1 Concomitant Medication Restrictions 
Description of change
The following text was added:
“In addition, intake of concomitant therapies with a known 
risk of Torsade de Pointes must not be co-administered with 
BI 685509 (also refer to Table 1.4.2: 1). These restrictions 
apply from screening (Visit 1), until Visit FUp3. In the event 
of temporary concomitant use of such a therapy, trial 
medication must be temporarily stopped and can then be re-
started after a period of at least 5 half-lives after the 
concomitant therapy with the known risk of Torsade de 
Pointes has been stopped, as long as the interruption rules 
are followed. Refer to Section 4.1.4.1 for rules for re-starting 
up-titration in case of interruption of trial medication.”
The restricted medication table was updated to include drugs 
with known risk of Torsade de Pointes.
Rationale for change
Update to exclude medications that could impact QTc


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Section to be changed
Table 4.2.2.1:1 Concomitant Medication Restrictions
Description of change
The following was added for systemic steroids prior to trial 
(Visit 1):
“…….. and planned to remain stable throughout the trial, i.e. 
must be at a dose of prednisolone ≤10 mg or equivalent.”
Rationale for change
Clarification.
Section to be changed
5.2.2 Vital signs
Description of change
“Vital signs will be evaluated at the time points specified in 
the flow chart.”
Was changed to:
“Vital signs will be evaluated at the time points specified in 
the flow chart, prior to the 12-lead ECG and prior to blood 
sampling as applicable.”
Rationale for change
For consistency with other changes in this amendment to 
ensure vitals are done prior to ECG.
Section to be changed
5.2.4 Electrocardiogram
Description of change
Text was added to state that ECGs should be performed 
prior to blood draws and after the patient has been in the 
supine position for 5 minutes.
Text was also added about the review of ECGs and also 
about the collection and storage of ECGs
Rationale for change
To ensure ECGs are accurate, any anomalies are correctly 
reported and to include a new storage procedure.
Section to be changed
6.2 Details of Trial Procedures at Selected Visits
Description of change
Text relating to number of vital signs and ECG assessments 
was removed to just leave the reference to the Flow Chart. 
The Flow Chart for Procedures was added.
Rationale for change
For clarity.
Section to be changed
10.3 Down-titration Guide
Description of change
In the first step on the flow chart added in “or more” to the 
following:
Has the Patient missed 4 or more consecutive doses?
Rationale for change
For consistency with other sections of the protocol


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11.4
GLOBAL AMENDMENT 4
Date of amendment
14 March 2022
EudraCT number
EU number
2020-002929-28
BI Trial number
1366-0005
BI Investigational Medicinal 
Product(s)
BI 685509
Title of protocol
Randomised, double-blind (within dose groups), 
placebo-controlled and parallel group trial to 
investigate the effects of different doses of oral 
BI 685509 given over 20 weeks on UACR 
reduction in patients with diabetic kidney disease
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
1.2 Drug Profile
Description of change
The combination of BI 685509 with other compounds 
involved in the NO-sGC-cGMP pathway, such as nitrates 
and PDE5 inhibitors, non-specific PDE inhibitors, sGC-
simulators might further increase the risk for hypotensive 
episodes and potentially reactive heart rate increases and the 
severity of these effects.
Was expanded to:
The combination of BI 685509 with other compounds 
involved in the NO-sGC-cGMP pathway, such as NO-
donors including nitrates and PDE5 inhibitors, non-specific 
PDE inhibitors, sGC-simulators might further increase the 
risk for hypotensive episodes and potentially reactive heart 
rate increases and the severity of these effects.
Rationale for change
All NO donors as belonging to NO-sGC-cGMP pathway 
activating drugs must not be administered due to possible 
synergistic effects with BI 685509.
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Exclusion criterion #1 was changed from:
Treatment with Renin Angiotensin Aldosterone System 
(RAAS) interventions (apart from either ACEi or ARB), 
phosphodiesterase inhibitors, nitrates, sGC-
stimulators/activators (other than trial treatment) or any 
other restricted medication (including OATP1B1/3 
inhibitors, UGT inhibitors/inducers) as provided in the 
Investigator Site File (ISF) within 4 weeks prior to visit 1 
and throughout screening and baseline run-in.  Patients who 
must or wish to continue the intake of restricted medications 




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NO donors including nitrates
Rationale for change
Exclusion of PDE inhibitors and NO donors specified to 
match the IB. NO-sGC-cGMP pathway activating drugs 
must not be administered due to possible synergistic effects 
with BI 685509. 
Section to be changed
7.2.1
Description of change
The TS is used for safety analyses as well as demographics 
and baseline characteristics.
was replaced with:
The TS is used for safety analyses and exposure.
Rationale for change
The wording ‘as well as demographics and baseline 
characteristics’ in definition of Treated Set (TS) in 7.2.1 was 
deleted since Randomised Set (RS) needs to be used for 
demographics and baseline characteristics; TS will be used 
for safety and exposure.


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Technical Version Number:
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Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F


SAP_001.pdf: 
 
TRIAL STATISTICAL ANALYSIS PLAN
c41327713-01
BI Trial No.:
1366-0005
Title:
Randomised, double-blind (within dose groups), placebo 
controlled and parallel group trial to investigate the effects of 
different doses of oral BI 685509 given over 20 weeks on UACR 
reduction in patients with diabetic kidney disease
Investigational
Product(s):
BI 685509
Responsible trial 
statistician(s):
Phone: +
Fax: +
Date of statistical 
analysis plan:
23 JAN 2023
Version:
2
Page 1 of 31
Proprietary confidential information
! 2023 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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINT(S) ..................................................................................8
5.2
SECONDARY ENDPOINT .................................................................................8
5.2.1
Key secondary endpoint(s)...................................................................................8
5.2.2
Secondary endpoint(s) ..........................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENT(S)................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................11
6.3
SUBJECT SETS ANALYSED...........................................................................12
6.5
POOLING OF CENTRES .................................................................................12
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................13
6.6.1
Withdrawals ........................................................................................................13
6.6.2
Efficacy data........................................................................................................13
6.6.2.1
Primary endpoint................................................................................................13
6.6.2.2
Secondary endpoint(s) ........................................................................................14
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS ..................14
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINT(S) ................................................................................18
7.4.1
Primary analysis of the primary endpoint(s) ...................................................18
7.5
SECONDARY ENDPOINT(S) ..........................................................................20
7.5.1
Key secondary endpoint(s).................................................................................20


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7.5.2
(Other) Secondary endpoint(s) ..........................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse Events ....................................................................................................21
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................24
7.9
ANALYSIS OF COVID19 IMPACT ................................................................25
7.10
POOLING OF TRIALS .....................................................................................26
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............27
9.
REFERENCES....................................................................................................28
11.
HISTORY TABLE..............................................................................................31


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LIST OF TABLES
Table 6.3: 1 
Subject sets analysed ........................................................................................12
Table 6.6.2.1: 1 
Principal rule of UACR derivation for MMRM.......................................13
Table 10: 1
History table .....................................................................................................31


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
      Definition/description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BI
Boehringer Ingelheim
BMI
Body Mass Index
BP
Blood Pressure
C-SSRS
Columbia-Suicide Severity Rating Scale
COVID-19
Corona Virus Disease 2019
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBP
Diastolic Blood Pressure
DILI
Drug Induced Liver Injury
DV
Deviation
ECG
Electrocardiogram
EDMS
Electronic Document Management System
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
   EoS
End of Study
EoT
End of Treatment
ES
Entered Set
FAS
Full Analysis Set
FMV
First Morning Void
F/U
Follow-Up
GLP1R
Glucagon-Like Peptide 1 Receptor
ICE
Intercurrent Events
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
iPD
Important Protocol Deviation


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Term
      Definition/description
LOCF
Last Observation Carried Forward
MAP
Mean Arterial Pressure
MCP-
MoD
Multiple Comparisons Procedure - Modelling
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effect Model Repeat Measurement
PD
Pharmacodynamics
PK
Pharmacokinetics
PKS
Pharmacokinetic Analysis Set
REP
Residual Effect Period
RPM
Report Planning Meeting
RS
Randomised Set
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SDL
Subject Data Listings
SGLT2i
Sodium-Glucose co-Transporter-2 Inhibitor
TEAE
Treatment-Emergent Adverse Events
tid
Ter in die (3 times a day)
TMF
Trial Master File
TOM
Trial Oversight Meeting
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UACR
Urine Albumin Creatinine Ratio
ULN
Upper Level of Normal


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP (Trial Statistical Analysis Plan) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g. on study objectives, study design, and population, 
treatments, definition of measurements and variables, planning of sample size, and 
randomisation.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g. macros for the analyses of Adverse Event [AE] data or laboratory 
data; Report Appendix Generator system [RAGe] for compilation/formatting of the Clinical 
Trial Report [CTR] appendices). Pharmacokinetic (PK) parameters will be calculated using 
WinNonlinTM software (version 8.1,
).
Analyses of the biomarker and gene expression data are described in a separate biomarker
analysis report, unless otherwise specified in this document.
The trial data is stored in the Boehringer Ingelheim (BI) Rave (BRAVE) database system.
SAS® Version 9.4 and R version 4.0.2 will be used for statistical analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
This section is not applicable as no change has been made.
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT(S)
Please refer to the protocol.
The three different approaches for handling intercurrent events (ICEs) are summarised in the 
table below:
Estimand strategy 
name
Treatment
ICE handling
Primary approach
Randomised 
treatment
Study med d/c: include data prior to study med d/c.
Death: include data prior to death.
SGLT2i initiation/discontinuation: include data prior to 
SGLT2i start/stop.
Supplementary 1
Randomised
treatment
Study med d/c: include all available data.
Death: include data prior to death.
SGLT2i initiation/discontinuation: include all 
available data.
Supplementary 2
Actual final
treatment
Study med d/c: include data prior to study med d/c.
Death: include data prior to death.
SGLT2i initiation/discontinuation: include data prior to 
SGLT2i start/stop.
SGLT2i = Sodium-Glucose co-Transporter-2 Inhibitor
Note that the table above should be used along with Table 6.6.2.1:1 to derive endpoints for primary, 
supplementary 1, and supplementary 2 analysis.
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
5.2.2
Secondary endpoint(s)
Please refer to the protocol.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatment to be administered, assignment of treatment groups, 
and selection of doses, refer to CTP Sections 3 and 4. This phase II trial will be performed as 
a double-blind, placebo-controlled comparison of BI 685509 to investigate the effects of 3 
different doses of oral BI 685509 given over 20 weeks on urine albumin creatinine ratio 
(UACR) reduction in patients with diabetic kidney disease.
Eligible patients will be randomised in the trial in a 3:1 ratio (BI 685509 3 times a day 
[tid]/placebo tid) within dose groups and will be treated for 20 weeks. The randomisation will 
be stratified by type of diabetic kidney disease and use of SGLT2i at randomisation. 
Following the 20-week treatment period, or at the time trial treatment is permanently 
discontinued, patients will have an End of Treatment (EoT) visit, which will be the start of a 
4-week follow-up period.
Section 1.2 of the CTP: The Residual Effect Period (REP) of BI 685509 is 7 days. This is the 
period after the last dose with measurable drug levels and/or pharmacodynamic (PD) effects 
still likely to be present.
Section 7.2.5 of the CTP: Statistical analysis and reporting of AEs will concentrate on 
treatment-emergent adverse events (TEAEs), i.e. all AEs that occur between start of treatment 
and end of the REP. AEs that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’. AEs will be summarised by the treatment to 
which the patient was randomised, and the treatment at the onset of AE for any drug-related 
AE. In addition, summary of patients with down-titration due to AE will be provided.
For the analysis of AEs, the following study phases are defined:
Study analysis phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed 
consent
Date/time of first 
administration of study drug
On-treatment
Placebo,
BI 685509, 
respectively
Date/time of first 
administration of study 
drug
12:00 a m on the day after last 
administration of study drug + 
REP (7 days), 
or
12:00 a m on the day after 
patient’s trial termination date, 
whichever occurs earlier
Follow-up1
F/U Placebo,
F/U BI 685509, 
respectively
12:00 a m on the day 
after last administration 
of study drug + REP (7 
days)
12:00 a m on the day after 
patient’s trial termination date
1 Follow-up phase might not exist, e.g. if the patient’s trial termination date is within 7 days after last 
administration of study drug.


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For treatment interruptions, the occurrence of AEs between the start of interruption and re-
start of treatment will be assigned to the randomised treatment. These cases will be flagged in 
the safety listings as occurring during the off-treatment period. AEs will be displayed by dose 
group and will be provided in the CTR.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Handling of important protocol deviations (iPDs) in the analysis is included in the deviation
(DV) domain specifications and stored within the Trial Master File (TMF) in the Electronic 
Document Management System (EDMS).
Consistency check listings (for identification of violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Trial Oversight Meeting (TOM) prior to Data Base Lock
(DBL) or at the Report Planning Meetings (RPMs). At these meetings, it will be decided 
whether a discrepant data value can be used in analyses or whether it must be corrected in the 
clinical database. Each protocol deviation must be assessed to determine whether it is an iPD. 
For definition of iPDs, and for the process of identification of these, refer to "Identify and 
Manage Important Protocol Deviations (iPD)” (3).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the TOM minutes and additionally via an accompanying Excel spreadsheet. The iPDs may 
lead to exclusion of patients from analysis sets (e.g. the Per Protocol Set). The documentation 
of the iPD categories and how to handle iPDs in the analysis is included in the DV domain 
specifications and stored within the TMF in EDMS. If the data show other iPDs, this domain 
will be supplemented accordingly.
Non-important Corona Virus Disease 2019 (COVID-19) related PDs will only be listed.


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6.3
SUBJECT SETS ANALYSED
The subject sets for statistical analysis will be used as defined in the CTP, Section 7.2.1. 
Table 6.3: 1 illustrates the data sets which are to be used for each category class of endpoints.
Table 6.3: 1
Subject sets analysed
Class of endpoint
     ES
     RS
     TS
   FAS
   PKS
Disposition
       X
Exposure
       X
IPDs
       X
Demographic/baseline
       X
Primary endpoint
       X
Secondary endpoint
       X
Other safety/tolerability
       X
Further efficacy endpoints
      X*
Further PK endpoints
       X
* Analyses on further endpoints such as serum potassium, vital signs, and body weight, are based on TS since 
  they are not efficacy endpoints.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Withdrawals
The reasons for withdrawal from treatment will be reported as indicated on the electronic case 
report form (eCRF).
6.6.2
Efficacy data
6.6.2.1
Primary endpoint
Missing data for primary analysis will not be imputed:
∀
If some UACR value(s) for UACR at baseline is (/are) missing, all available UACR 
samples in week -2, -1, and 0 will be used to derive UACR at baseline.
∀
If any UACR value after randomisation is missing, the missing UACR will not be 
imputed; missing UACR due to ICEs will not be imputed.
The Mixed-effect Model for Repeated Measures (MMRM) approach used for the primary 
analysis (see Section 7.4.1) allows for missing data, assuming the missing data mechanism is 
ignorable. Even patients with only one post-baseline assessment can be included in the model 
and can, therefore, participate in variance estimation. The statistical model assumes that 
patients who had an ICE would have behaved similarly to those who remained in the study. 
The table below describes how/when to derive UACR values for MMRM:
Table 6.6.2.1: 1
Principal rule of UACR derivation for MMRM
                    UACRs
                    for MMRM
UACR
at baseline
UACR
at visit 6
UACR
at visit 7
UACR
at EoT
Visits need to be 
included
First Morning Void 
(FMV) or 10-hour 
urine UACR baseline 
is defined as the 
mean of all non-
missing assessments 
from Visit 2 until 
prior to the first 
intake of trial 
medication.
All available 
scheduled 
visits at visit 6
All available 
scheduled 
visits at visit 7
All 
available 
scheduled 
visits 
between 
visit 8 and 
EoT
Derivation 
Average of all available UACR measurements defined at each visit
Note: all available/scheduled UACR measurements will be used: no imputation for missing UACR 
measurement; this rule will be applied to FMV and 10-hour urine samples, respectively.


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Sensitivity analyses will be conducted to investigate the potential effect of ICE handling 
approaches on the results of the primary analysis. Details about implementation of the 
sensitivity statistical analyses are described in Section 7.4.
6.6.2.2
Secondary endpoint(s)
The principal rule of UACR derivation for MMRM in Table 6.6.2.1:1 will be used for 
derivation of UACR at baseline and EoT.
For the change from baseline in log transformed UACR measured in 10-hour urine (/FMV
urine) after 20 weeks of trial treatment, the same rule as in the primary endpoint will be 
applied for statistical analysis.
Missing UACR imputation might be considered as well.
Details about implementation into the statistical analysis are described in Section 7.
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS
Section 2.2.2 of the CTP:
Throughout this protocol, the term “baseline” refers to the last observation prior to the first 
intake of trial medication, with the exception of FMV and 10-hour urine UACR. Baseline 
for the FMV and 10-hour urine UACR, is defined as the mean of all available samples prior 
to Visit 2 up to and including those prior to the first intake of trial medication. This does not 
include the UACR measured in spot urine at Screening.
Measurements taken after start of administration of trial treatment will be considered on-
treatment values based on the definition in Section 6.1, and will be assigned to visits for 
statistical analysis, if applicable, as defined below.
Analysis of AE data, potentially clinically significant abnormal laboratory values, 
concomitant medication, or non-drug therapies, as well as use of rescue therapy will not be 
based on visits. Therefore, no assignment to time windows will be necessary for such data.
The derivation of the last value, minimum value, and maximum value of laboratory and 
vital signs data will consider all on-treatment values (whether or not selected in any time 
window; see Section 6.1 for definition of the on-treatment period) within the period of 
interest; these will be derived for analysis of laboratory and vital signs data.
All other safety and efficacy measurements will be assigned to visits based on extended 
time windows around the planned visit dates, defined relative to the day of first trial 
treatment (which is scheduled for Visit 3).


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Repeated and unscheduled efficacy and safety measurements (except for laboratory data) 
will be handled similarly to scheduled measurements and will also be assigned to a time 
window depending upon the date of measurement. For handling of laboratory 
measurements, see also Section 7.8.2.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI standards "Standards for reporting of 
clinical trials and project summaries" (6), with the exception of those generated for PK 
calculations following BI standards for PK/PD analysis (7,8).
The individual values of all patients will be listed, sorted by use of SGLT2i (Yes/No), type of 
diabetes mellitus (type 1/type 2), dose group of study treatment (placebo/BI 685509), patient 
number, and visit (if visit is applicable in the respective listing). AE listings will be sorted by 
study treatment (see Section 7.8.1 below for details). The listings will be contained in 
Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics of continuous variables (for non-PK 
parameters) is:
N
number of non-missing observations
Mean
arithmetic mean
SD
standard deviation
SE        
standard error
Min
minimum
Median
median
Max
maximum
For plasma concentrations, as well as for PK parameters, the following descriptive statistics 
will additionally be calculated:
CV
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%). Percentages 
will be rounded to one decimal place. The category missing will be displayed if and only if 
there actually are missing values. Percentages will be based on all patients in the respective 
patient set whether they have non-missing values or not.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. The data will be 
summarised by dose group of study treatment, and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the CTR, based on the RS.
Concomitant diseases and concomitant non-drug therapies will be coded according to the 
most recent version of the Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary. The coding version number will be displayed as a 
footnote in the respective output.
The frequency [N (%)] of patients with different concomitant diseases (baseline conditions) 
will be presented.
A medication/non-drug therapy will be considered concomitant to treatment if it
∀
Is ongoing at the start of randomised trial treatment or
∀
Starts within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
A medication/non-drug therapy will be considered as prior medication/non-drug therapy, if 
the end date of the medication/therapy is at any time prior to the start of the randomised trial 
treatment.
Concomitant medication use will be summarised with frequency and percentage of patients by 
ATC3 class and preferred name. Summaries will be presented for concomitant medication 
starting any time prior to start of trial treatment and starting any time during the on-treatment 
period (cf. Section 6.1).
Concomitant use of non-drug therapies will be summarised with frequency and percentage. 
Summaries will be presented for concomitant non-drug therapies starting any time prior to 
start of trial treatment and starting any time during the on-treatment period (cf. Section 6.1).
Restrictions regarding concomitant treatment during the study periods are defined in Section 
4.2.2.1 of the CTP.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned according to percentage of patients meeting the 
compliance. Descriptive statistics will be provided overall (see Section 5.4.2).


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7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
The primary endpoint will be analysed in combination with the primary approach of handling 
ICEs (see Section 5.1). The FAS is the main analysis set for the analysis of efficacy: the 
patient set includes all patients who had at least one baseline measurement of 10 hour UACR 
in week -2, -1, or 0 and at least one post-baseline measurement after week 6.
Refer to Section 7.2.2 of the CTP for a description of the statistical analysis for the change 
from baseline in log transformed UACR measured in 10-hour urine at 20 weeks of trial 
treatment.
The adjusted mean reduction in log transformed UACR in 10-hour urine from baseline at 
20 weeks and its standard deviation will be obtained from MMRM for the placebo and 
treatment groups. For the MMRM model, derived UACRs at baseline, visit 6, visit 7, and 
EoT, which were described in Section 6.6.2.1, will be used.
SAS code for the MMRM model will be based on the following structure:
PROC MIXED DATA=alldat cl method=reml; 
CLASS visit trt subject;
MODEL chg = base*visit visit*trt typediabetes  SGLT2ibase / ddfm=kr s CL; 
REPEATED visit / subject= subject type=un r rcorr;
LSMEANS visit*trt /pdiff=all om cl alpha=0.05 slice=visit;
RUN;
In the event of model non-convergence, the methods described in Section 10.1 will be 
attempted (in order) to overcome it.
Multiple Comparisons Procedure - Modelling (MCP-Mod) Analysis
For the primary analysis, the dose-response relationship will be modelled using the total daily 
doses: 3 mg, 6 mg, and 9 mg. The multiple comparison procedure will then be implemented 
using optimal contrast tests which control the family-wise type I error rate at a one-sided α = 
0.05. For the MCPMod test, the optimal contrasts of each candidate model are calculated 
using the R-function optCont.
For the final evaluation, the contrast will be provided using the expected model means from 
the candidate set and the estimated variance-covariance matrix extracted from the MMRM 
model.
Once the significance of a dose-response signal is established, the dose-response profile and 
the target dose can be estimated using a model averaging approach for significant models.


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To select a dose estimation model out of the set of significant models, estimates for each dose 
group will be calculated and will be based on the final dose-response model. The choice of the 
target dose will be based upon efficacy as well as considering safety and other relevant 
information.
The following displays are planned:
- Table of the updated contrast coefficients per dose group and candidate model, together with 
the MCPMod test statistics and p-values for each model and the critical value
- For averaging model, figure of the dose-response curve
- For all significant model shapes, figures of the dose-response curve plus 90% and 95%
confidence bands (of the predicated shape) and 90% and 95% CIs per dose (estimated from 
MMRM)
- For all significant model shapes, figure with the placebo corrected dose-response curve plus 
95% confidence band (of the predicated shape).
Estimates for each dose group will be calculated and will be based on the final dose-response
model. R code to perform the evaluations is available in Section 10.2.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
The analysis of the change of UACR in FMV urine after 20 weeks of trial treatment will be 
performed by using the same MMRM/MCPMod as for the primary analysis.
For the secondary endpoints,
∀
Proportion of patients achieving UACR decreases in 10-hour urine of at least 20% 
from baseline after 20 weeks of trial treatment
∀
Proportion of patients achieving UACR decreases in FMV urine of at least 20% from 
baseline after 20 weeks of trial treatment
the following analyses will be implemented:
∀
A logistic regression with Last Observation Carried Forward (LOCF)
∀
A logistic regression excluding patients with missing UACR at baseline/EoT
∀
A two sample proportion test with LOCF
∀
A two sample proportion test excluding patients with missing UACR at baseline/EoT
Treatment, SGLT2i use at baseline, and type of diabetes will be used as covariates in the 
logistic regression model.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the CTR based on the TS. The date and 
time of each drug administration will be listed for each patient.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS following BI standards. No hypothesis testing 
is planned. All safety analyses will be performed on treatment set.
7.8.1
Adverse Events
Analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and NOT on the number of AEs.
Furthermore, for analysis of AE attributes such as duration, severity, etc. multiple AE
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the
following applies:
∀
The same MedDRA lowest level term was reported for the occurrences
∀
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the 
day after the end of the first occurrence)
∀
Treatment did not change between the onset of the occurrences OR treatment 
changed between the onset of the occurrences, but no deterioration was 
observed for the later occurrence
For further details on summarisation of AE data, please refer to "Analysis and presentation of 
adverse event data from Clinical Trials" (9) and "Handling of missing and incomplete AE da
(4).
The analysis of AEs will be based on the concept of TEAEs. That means that all AEs 
occurring between first drug intake until 7 days after last drug intake will be assigned to the 
randomised treatment. All AEs occurring before first drug intake will be assigned to 
‘screening’ and all AEs occurring after last drug intake + 7 days will be assigned to ‘follow-
up’ (for listings only). AEs that start before first drug intake and deteriorate under treatment 
will also be considered as ‘treatment-emergent’. For details on the treatment definition, see 
Section 6.1.
If only the start date of an AE is collected (without start time), any AE occurrence on the 
same day as the first BI 685509 administration will be assigned to the on-treatment phase. 
AEs will also be summarised by the treatment at the onset of AE for any drug-related AE. In 
addition, a summary of patients with down-titration due to AE will be provided.
An overall summary of AEs will be presented.


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Frequencies [N (%)] of patients with AEs will be summarised by dose group, primary system 
organ class, preferred term (using MedDRA), and intensity. Separate tables will be provided 
for patients with serious AEs (SAEs), patients with AEs of Special Interest (AESIs), patients 
with fatal AEs, and patients with discontinuations due to AEs.
Regarding AESIs, summaries of AESIs of hypotension and syncope will be presented for both 
patient-based and event-based analyses. An individual episode of hypotension will be 
considered as significant or non-significant based on baseline BP and the lowest BP during 
the episode. Criteria for significant hypotensive episode are:
∀
For patients with baseline SBP <=140: decrease ((lowest SBP during the episode –
baseline SBP)/(baseline SBP)) ≥30%
∀
For patients with baseline SBP >140: decrease ((lowest SBP during the episode –
baseline SBP)/(baseline SBP)) ≥40%
∀
Or, lowest SBP during the episode <90
∀
For patients with baseline DBP <=70: ((lowest DBP during the episode – baseline 
DBP)/(baseline DBP)) ≥30%
∀
For patients with baseline DBP >70: ((lowest DBP during the episode – baseline 
DBP)/(baseline SBP)) ≥40%
∀
Or, lowest DBP during the episode <50
∀
Lowest mean arterial pressure (MAP) during the episode <70
Details of the AESI of Hypotension and Syncope will be also listed.
Category
Safety topic
Definition
AESI
Hypotension
Investigator-reported, as a dedicated AE category 
on the AE eCRF page
AESI
Syncope
Investigator-reported, as a dedicated AE category 
on the AE eCRF page
In addition, potential DILI, acute kidney injury, and QT-interval prolongation are defined as 
follows:
∀
Potential DILI, defined as: Narrow sub-SMQ ‘Liver related investigations, signs and 
symptoms’, narrow sub-SMQ ‘Cholestasis and jaundice of hepatic origin’, narrow 
sub-SMQ ‘Hepatitis, non-infectious’ and narrow sub-SMQ ‘Hepatic failure, fibrosis 
and cirrhosis and other liver damage-related conditions’, or investigator-reported 
AESIs.
∀
Acute kidney injury, defined as: SMQ ‘Acute renal failure’, narrow scope
∀
QT-interval prolongation, defined as: SMQ ‘Torsade de points/QT prolongation’, 
narrow scope excluding the PT ‘Syncope’.
Summaries of potential DILI, acute kidney injury, and QT-interval prolongation will be 
presented for patient-based analyses.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Handling, Display and Analysis of Laboratory Data" (11). Note that data from the central 
Laboratory will be used for all displays described below, unless otherwise specified.
The analysis of continuous laboratory parameters will be based on normalised values, which 
means transforming to a standard unit and to a standard reference range. The last assessment 
before the first randomised treatment prior to the first drug administration at visit 3 is chosen 
as the baseline value.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be based upon normalised values and provided by visit, including summaries 
of the last value on treatment, the minimum and maximum value on treatment.
Laboratory values will be compared to their reference ranges; a shift table will be provided for 
the number of patients within and outside the reference range at baseline and at the last 
measurement on treatment. This analysis will be based on standardized laboratory values.
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on converted values and converted reference ranges using SI lab units. These 
rules will be listed in the SDL appendix of the CTR. Frequency tables will summarise the 
number of patients with potentially clinically significant abnormalities.
Patients having an abnormal lab value at baseline will be presented separately. A separate 
listing will present potentially clinically significant abnormal lab values.
All individual laboratory data will be listed. Values outside the reference range will be 
flagged. In addition, potentially clinically significant values will be flagged in the listing.
To support analyses of liver related adverse drug effects, the frequency of patients with 
Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT) ≥ 3x upper level 
of normal (ULN) combined with a total bilirubin ≥ 2xULN, and the frequency of patients with 
AST and/or ALT ≥ 10xULN, will be displayed. This analysis will be based on standardized 
laboratory values. A graphical analysis of the ALT and total bilirubin values during the on-
treatment period will also be performed; the so called eDISH plot. In the graph, for each 
patient, the peak total bilirubin is presented as a fold increase over the ULN against the peak 
ALT as a fold increase over the ULN, on a log10 scale. Two reference lines, 2xULN for total 
bilirubin and 3xULN for ALT, are drawn onto the graph in order to divide the plane into four 
quadrants. Normal cases are in the lower left quadrant, potential DILI cases are in the upper 
right quadrant (Hy’s Law quadrant), while the lower right quadrant is known as the Temple’s 
corollary range (ALT ≥ 3xULN and total bilirubin < 2xULN).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
Results from the pregnancy test will only be listed.


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7.8.3
Vital signs
The analyses of vital signs (SBP,DBP, and pulse rate) will be described by differences of vital 
signs from baseline (see Section 6.7) to the EoS visit.
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.


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7.9
ANALYSIS OF COVID19 IMPACT
There is currently an outbreak of the respiratory disease COVID-19 worldwide which has 
impacted the conduct of this trial. This public health emergency has raised more difficulties 
for patients to meet protocol-specified procedures, including administering or using the 
investigational product or adhering to protocol-mandated visits and laboratory/diagnostic 
testing. Site personnel or trial patients are also under the risk to get infection with COVID-
19.
Consequently, there are unavoidable protocol deviations due to COVID-19 illness and/or 
COVID-19 public and individual health control measures. To assess the impact on patients’ 
safety and drug efficacy in this trial, the following analyses are planned:
Disposition, PD, and iPD:
Frequency of the patient with missing visits or early discontinuation due to COVID-19 will be 
listed. PDs and iPDs related to COVID-19 will be also listed if any.
In addition, if there is any case, COVID-19 infection will be reported.
This study started after the COVID-19 disruption. Therefore, evaluations of efficacy or AE
assessments by prior versus post disruption are not applicable in this trial.


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7.10
POOLING OF TRIALS
A list of trials that might be covered in the efficacy analysis of BI 685509 is summarized here, 
including how each trial will contribute to the understanding of the efficacy of the compound, 
and how studies will be pooled and combined.
Study groupings are defined based mainly on design characteristics of the clinical studies and 
address general or particular aspects of the efficacy of the investigational therapy. 
Table 7.10: 1 summarizes plans of a pooled analysis of two trials with BI 685509. The table 
displays treatment arms included in each of the defined study groupings and describes what 
summaries/analyses will be presented for the defined study grouping.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be released to unblind the trial database after the last patient 
has completed their EoS/Follow-up visit and all data has been entered and cleaned as defined 
in the “Data Ready to be Unblinded and/or Final Trial Closure Notification” (RUN) form.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
2.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-
domain- specification)”, template, current version, KMED.
3.
BI-VQD-12045_40-413: Identify and Manage Important Protocol Deviations 
(iPD)”, version 3.0, Group “Med Clinical Development & Operations”.
https://bi-docs-vault-quality.veevavault.com/ui/#permalink=V0Z00000002G042
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, 
current version; KMED.
5.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses 
performed within Clinical Pharmacokinetics/Pharmacodynamics”, current 
version; KMED.
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and 
Project Summaries”, current version; KMED.
7.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetic 
and Pharmacodynamic Noncompartmental Analyses”, current version; KMED.
8.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and 
PK/PD Data Files”, current version; KMED.
9.
KM Asset BI-KMED-BDS-HTG-0066: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED.
10.
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical 
Study Reports, current version, EMA webpage.
11.
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory 
Data”, current version; KMED.


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APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
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Title: 
                                                                                                                   
Signatures (obtained electronically) 
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