Clinical trial NCT05182840
Conditions: Kidney Disease, Chronic
Sponsor: Boehringer Ingelheim
Start date: 2022-01-11; Completion date: 2023-07-10
Enrollment: 714 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with chronic kidney disease. People with and without type 2 diabetes can take part in this study.

The purpose of this study is to find out whether a medicine called BI 690517 improves kidney function in people with chronic kidney disease when taken alone or in combination with a medicine called empagliflozin.

In the first part of the study, participants take empagliflozin or placebo as tablets every day for 2 months. Placebo tablets look like empagliflozin tablets but do not contain any medicine.

In the second part, participants are divided into several groups. Depending on the group, the participants then additionally take different doses of BI 690517 or placebo as tablets for 3.5 months. In this case, placebo tablets look like BI 690517 tablets but do not contain any medicine.

Participants are in the study for about 6 months. During this time, they visit the study site about 12 times. Where possible, about 4 of the 12 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.

Participants collect urine samples at home. These samples are then analysed to assess kidney function. At the end of the trial the results are compared between the different groups. The doctors also regularly check participants' health and take note of any unwanted effects.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None arm 10: None
Interventions: intervention 1: BI 690517 intervention 2: Placebo to BI 690517 intervention 3: Empagliflozin intervention 4: Placebo to empagliflozin
Intervention descriptions: intervention 1: Film-coated tablets intervention 2: Film-coated tablets intervention 3: Empagliflozin intervention 4: Placebo to empagliflozin

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (19.0) / Saved on: 03 Nov 2020
Clinical Trial Protocol
TITLE PAGE
Document Number:
c34875109-06
EudraCT No.
2021-001434-19
BI Trial No.
1378-0005
BI Investigational
Medicinal Product(s)
BI 690517 and empagliflozin
Title
Randomised, double-blind, placebo-controlled and parallel dose 
group trial to investigate efficacy and safety of multiple doses of 
oral BI 690517 over 14 weeks, alone and in combination with 
empagliflozin, in patients with diabetic and non-diabetic chronic 
kidney disease
Lay Title
A study to test whether different doses of BI 690517 alone or in 
combination with empagliflozin improve kidney function in 
people with chronic kidney disease
Clinical Phase
Phase II
Clinical Trial Leader
Tel: 
Coordinating 
Investigator
; Tel: 
Current Version and 
Date
Final Version 4.0, 19 Aug 2022
Original Protocol 
Date
Final Version 1.0, 29 Apr 2021
Page 1 of 121
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 
Original Protocol date
29 Apr 2021
Revision date
19 Aug 2022
BI trial number
1378-0005
Title of trial
Randomised, double-blind, placebo-controlled and parallel dose 
group trial to investigate efficacy and safety of multiple doses of oral 
BI 690517 over 14 weeks, alone and in combination with 
empagliflozin, in patients with diabetic and non-diabetic chronic
kidney disease
Coordinating 
Investigator
Tel: 
Trial site(s)
Multi-centre trial conducted in approximately 30 countries
Clinical phase
Phase II
Trial rationale
The aim of this trial is to investigate the efficacy and safety of three 
oral doses of BI 690517 over 14 weeks, alone and in combination 
with empagliflozin, in male and female patients with diabetic and 
non-diabetic CKD. The results of this trial will be crucial for the 
decision about further development of BI 690517 and will support 
the dose selection for future trials
Trial objective(s)
The main objectives of the trial are to demonstrate the efficacy of BI 
690517, alone and in combination with empagliflozin, and to 
characterise the BI 690517 dose-response relationship in patients 
with diabetic and non-diabetic CKD by assessing 3 doses and 
placebo
Trial endpoints
The primary endpoint is the change from baseline in log 
transformed Urine Albumin Creatinine Ratio (UACR) measured in 
First Morning Void urine after 14 weeks.
Secondary endpoints:
UACR response I, defined as a decrease of at least 30% absolute 
change in First Morning Void urine of UACR from baseline 
to 14 weeks.

UACR response II, defined as a decrease of at least 15% absolute 
change in First Morning Void urine of UACR from baseline to 14 
weeks
Trial design
Randomised, double-blind, parallel dose group, placebo-controlled 
clinical trial to investigate the effect of three doses of BI 690517 
alone and in combination with empagliflozin over 14 weeks in 


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patients with diabetic and non-diabetic chronic kidney disease.  The 
trial will include a 1:1 randomised run-in period of 8 weeks for 
empagliflozin 10 mg/ placebo followed by a randomised treatment 
period of 14 weeks for BI 690517 / placebo in combination with the 
background medication assigned in the randomised run-in period.
Total number of 
patients randomised 
At least, 552
Number of patients per
treatment group
A minimum of 60 patients completed per arm in the Treatment 
Period, overall 480 completed patients
Diagnosis
Diabetic or non-diabetic Chronic Kidney Disease
Main inclusion and 
exclusion criteria
Inclusion: 

Male or female patients of legal adult age (according to local 
legislation) and aged ≥ 18 years at time of consent. 

eGFR ≥ 30 and < 90 mL/min/1.73 m². 

UACR ≥ 200 and < 5000 mg/g. 

Stable treatment with either ACEi or ARB (not both). 

Serum potassium ≤ 4.8 mmol/L
Exclusion: 

Current or planned SGLT2i / SGLT-1/2i treatment

Type 1 Diabetes Mellitus 
Test product(s)
BI 690517 and empagliflozin
dose
BI 690517 3 mg daily (QD) or 10 mg daily (QD) or 20 mg daily 
(QD)
Empagliflozin 10 mg daily (QD)
mode of 
administration
p.o
Comparator product(s)
Placebo matching each dose of BI 690517 and empagliflozin
dose
Not applicable
mode of
administration
p.o.
Duration of treatment
22 weeks (8 weeks run-in with empagliflozin/placebo and 14 weeks 
of treatment with BI 690517/placebo alone or in combination with
empagliflozin/ placebo)
Statistical methods
A mixed-effect model for repeated measures (MMRM) will be used 
to obtain adjusted mean changes from baseline for the treatment 
effects of continuous endpoints. This MMRM model will include 
fixed effect of treatment as categorical variable, and fixed effect of 
baseline at each visit as continuous variable. Visit will be considered 
as repeated measures with an unstructured covariance structure for 
the within-patient variability. For dose-finding, predicted average 
response for each dose group and the estimated covariance matrix 
from the MMRM will be used in the multiple comparison 
procedures and modelling (MCPMod) analysis. Several possible 
dose-response patterns will be evaluated in the MCPMod to identify 
the best-fitting model and optimal dose for further development. 


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FLOW CHART
Trial Period
Screening
Randomised Run-in Period
Treatment Period
Follow Up Period
Visit1
12
2
3
3.1
Home sampling 
without visit
4
53
6
7
8
9
9.1
Home sampling 
without visit
9.2 
Home sampling 
without visit
EoT4
FUp15
FUp1.1
Home sampling 
without visit27
FUp1.2
Home sampling 
without visit27
FUp2
27
Visit may be conducted at 
patient’s home6
X
X
X
X
Telemedicine Contact7
X
(X)
(X)
(X)
(X)
(X)
Weeks (overall)
-11
-8
-4
-2
-1
0
1
2
6
10
12
13
14
15
16
17
18
Day29
-77
-56
-28
-14
-7
1
8
15
43
71
85
92
99
106
113
120
127
Time window for visits 
(days)29
Up to 21 
days before 
Visit 2
+/- 2
+/- 2
+/- 2
+ 2
none
+/- 2
+/- 2
+/- 3
+/- 3
+/- 2
+/- 2
+/- 2
+3
+/- 2
+/- 2
+/- 3
Pre-
dose
Post-
dose
Informed consent8
X
Demographics, medical history 
including historical creatinine 
data, baseline conditions
X
Check of in-/exclusion criteria
X
X
X
Concomitant therapies
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
Physical examination
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
12-lead electrocardiogram 
(ECG), local assessment9
X
X
X
X
X
ACTH challenge test10
X
(X)
(X)
(X)
(X)
(X)
(X)
Safety laboratory (blood, 
urine)11
X
X
X
X
X
X
X
X
X
X
X
eGFR12
X
X
X
X
X
X
X
X
X
X
X


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Trial Period
Screening
Randomised Run-in Period
Treatment Period
Follow Up Period
Visit1
12
2
3
3.1
Home sampling 
without visit
4
53
6
7
8
9
9.1
Home sampling 
without visit
9.2 
Home sampling 
without visit
EoT4
FUp15
FUp1.1
Home sampling 
without visit27
FUp1.2
Home sampling 
without visit27
FUp2
27
Visit may be conducted at 
patient’s home6
X
X
X
X
Telemedicine Contact7
X
(X)
(X)
(X)
(X)
(X)
Weeks (overall)
-11
-8
-4
-2
-1
0
1
2
6
10
12
13
14
15
16
17
18
Day29
-77
-56
-28
-14
-7
1
8
15
43
71
85
92
99
106
113
120
127
Time window for visits 
(days)29
Up to 21 
days before 
Visit 2
+/- 2
+/- 2
+/- 2
+ 2
none
+/- 2
+/- 2
+/- 3
+/- 3
+/- 2
+/- 2
+/- 2
+3
+/- 2
+/- 2
+/- 3
Pre-
dose
Post-
dose
Serum cortisol14
X
X
X15
X
X
X
X
X
X
X
Biomarker sampling (serum, 
plasma, urine)
X
X
X
X
X
Pharmacogenomic sampling
X17
Optional biobanking sampling 
(serum, plasma, urine)18
X
X
X
X
X
Pregnancy test19
X
X
X
X
X
X
X
Spot urine (UACR)20
X
Train patient on FMV and 24-
hour urine sampling
X
Dispense urine container for 
FMV urine sampling
X
X
X
X
X
X
X
UACR First Morning Void21
X
X
X
X
X
X
X
X
X
X
X
X
Dispense urine container for 
24-hour urine sampling
X
X
24-hour urine sample21
X
X
Paper diary handout22
X
X
X
X
X
X
X
Collect and review paper diary 
X
X
X
X
X
X
X


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Trial Period
Screening
Randomised Run-in Period
Treatment Period
Follow Up Period
Visit1
12
2
3
3.1
Home sampling 
without visit
4
53
6
7
8
9
9.1
Home sampling 
without visit
9.2 
Home sampling 
without visit
EoT4
FUp15
FUp1.1
Home sampling 
without visit27
FUp1.2
Home sampling 
without visit27
FUp2
27
Visit may be conducted at 
patient’s home6
X
X
X
X
Telemedicine Contact7
X
(X)
(X)
(X)
(X)
(X)
Weeks (overall)
-11
-8
-4
-2
-1
0
1
2
6
10
12
13
14
15
16
17
18
Day29
-77
-56
-28
-14
-7
1
8
15
43
71
85
92
99
106
113
120
127
Time window for visits 
(days)29
Up to 21 
days before 
Visit 2
+/- 2
+/- 2
+/- 2
+ 2
none
+/- 2
+/- 2
+/- 3
+/- 3
+/- 2
+/- 2
+/- 2
+3
+/- 2
+/- 2
+/- 3
Pre-
dose
Post-
dose
Randomisation (via IRT) 
X
X
Dispense study drug(s) (via 
IRT)
X
X
X
X
X
Administer Empa/ matching 
placebo during visit23
X
X
X
X
X
X
X
X
Administer BI 690517 / 
matching placebo during visit
X
X
X
X
X
X
Treatment compliance28
X
X
X
X
X
X
X
Drug accountability (via IRT)
X
X
X
X
X
Termination of study drug (via 
IRT)
X
AEs/SAEs/AESIs24
X
X
X
X
X
X
X
X
X
X
X
X25
X26
Completion of patient 
participation 
X
1 Additional visits may have to be scheduled - for example, in case of dose reduction due to potassium elevation or when an ACTH Challenge test is required for patients whose cortisol level is ≥3 µg/dL (82.8 nmol/L)
and < 11 µg/dL (303.5 nmol/L) with suggestive signs or symptoms of adrenal insufficiency.
2 As UACR and eGFR may not be regularly tested, where allowed sites may pre-screen patients by sending a spot urine sample to measure UACR and/or a blood sample to measure eGFR to their local lab. This is 
optional and requires a specific approved pre-screening informed consent. Pre-screening results will not be collected in the CRF or used to determine final eligibility in this trial.  Pre-screening can be performed at any 
point prior to screening.  The full consent form must be signed before screening (Visit 1) procedures are performed. The Screening Period should be no more than 21 days from first screening procedure to first 
randomisation. Screening assessments may be conducted over more than one day. The Randomised run-in Period may start as soon as all screening procedures have been performed and laboratory results have been 


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received and reviewed. Therefore the 21 days prior to Visit 2 that are indicated in the flow chart may be less. Screening procedures may be repeated once during the screening period if the patient is not eligible for a 
transient medical condition (e.g. elevation of certain lab parameters due to an acute infection). 

If the patient currently does not fulfil all inclusion/exclusion criteria but may, in the opinion of the investigator, fit the criteria later on, the patient is allowed to be rescreened once, as long as screening into this 
trial is still open. Re-screening examinations will only be performed after a written informed consent has been taken again from the patient. IRT must be contacted to register the re-screening and obtain a new 
patient number.

If screening is not completed within 21 days, 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).
3Visit 5 should be no more than 7 days after Visit 4. Where the patient does not meet the additional inclusion criteria 13 and 14 based on lab tests performed at Visit 4, the eGFR and potassium cannot be re-tested and 
the patient should permanently discontinue the study. In case of unexpected delay of Visit 5, a repeat safety sample must be taken to obtain potassium and eGFR results needed to confirm eligibility for the Treatment 
Period.
4 In case a patient needs or wishes to terminate all trial treatment prematurely and if the patient agrees, the patient should undergo the procedures for End of Treatment (EoT). Please see section 6.2.5 for details.
5 Follow-up Visit 1 (FUp1) must always take place at least 7 days after the EoT visit.
6 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 6.2.2 for further details.
7 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 sampling at home 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.
Visit 3 must be performed as telemedicine contact for all patients, unless they prefer to come to the trial site instead.
3.
Phone/ video calls may also take place at any other time if needed to support the patient.
8 Informed consent must be obtained before the first screening assessment. It can be obtained on the day of the screening visit or within 4 weeks prior to the first screening assessment. The consent discussion should 
include showing the patient the home sampling kits and explaining this procedure.
9 All ECGs will be done prior to the daily dose and evaluated by the investigator or a designee. See section 5.2.4.
10 ACTH Challenge test is required for all patients at screening, and for all patients whose morning serum cortisol level at EoT (or at the time of premature discontinuation of BI 690517 / placebo) is < 18 µg/dL (496.6
nmol/L).  After the start of BI 690517 / placebo treatment at Visit 5, if morning serum cortisol level is ≥ 3 µg/dL (82.8 nmol/L) and < 11 µg/dL (303.5 nmol/L) and the patient shows suggestive signs or symptoms of 
adrenal insufficiency, an ACTH Challenge test should be performed as soon as possible.  Serum cortisol basal sample must be performed before ACTH- injection (0.25 mg). Injection time must be recorded and has to 
be done within 4 hours of the patient’s usual waking time. Post-dose samples for serum cortisol must be taken 30 (± 5) minutes after the injection, to ensure patients have normal adrenal function. The time for the post 
ACTH-injection blood samples must be recorded in the patient’s medical record. See section 5.2.5.1.
11 Patients do not need to be fasted for the blood sampling for the safety laboratory. See section 5.2.3.
12 eGFR at clinic visits will be determined from serum creatinine analysed by the central laboratory. To confirm eligibility, the eGFR at screening will be used.
13
14 Lab samples for serum cortisol must be collected within 4 hours of the patient’s usual waking time.
15 Post-dose serum cortisol should be taken 1 hour (+/- 10 minutes) after drug administration.
16
See 
 Flow Chart for samples and timings. For further instructions see section 6.1.
17 The pharmacogenomics samples may be collected at Visit 5 or anytime afterwards.
18 Optional biobanking samples will only be collected if the patient has signed the biobanking informed consent separate from the main consent for the trial. See section 5.5.
19 A pregnancy test is required for all women of child-bearing potential. This will be a serum pregnancy at Screening (Visit 1). Thereafter a urine pregnancy test will be performed. A home pregnancy test may be used 
at the Visit 3 timepoint.  If urine pregnancy test is not acceptable to local authorities, a blood test can be done at a local laboratory. More frequent pregnancy testing should be done if required by local regulation and /or 
authority or per investigator judgment.
20 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 not match inclusion criteria due to UACR 
variability, this can be repeated once. If the second result does not meet the eligibility criteria the patient should be screen failed. 
21 Please refer to FMV and 24-hour Urine Sampling Flowchart.
22 Patients will need to complete a paper diary at home in the 2 days prior to 
 to record times of trial drug intake.  Patients will also need to record start and stop times for 24-hour urine
samples in a paper diary before Visit 5 and EOT.


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23 Study medication at Visit 4, Visit 6 and EoT will be taken from the medication kit supplied at the previous visit as there is no dispensing at these visits.  At all other visits, study medication should be taken from the 
kit dispensed at the visit.
24 All AEs, SAEs and AESI will be collected from informed consent until FUp1 (end of residual effect period). Please see section 5.2.6.2.1.
25 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 trial treatment related AESIs. 
Please see section 5.2.6.2.1.
26 After the individual patient’s end of 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, but not on the CRF.
27 In the case of premature discontinuation during the Randomised Run-in Period, FUp1.1, FUP1.2 and FUp2 do not need to be conducted.  
28 At Visits 4 and 5, only compliance to Empagliflozin/placebo will be calculated.  At Visits 6, 7, 8, 9 and EOT, compliance will be calculated for both Empagliflozin/placebo and BI 690517/placebo.
29 Days and associated time windows are relative to Visit 5.


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FMV AND 24-HOUR URINE SAMPLING FLOW CHART
All samples listed in the following table should be collected by the patient, unless the patient is not able to do it.
Visit
1
2
3
3.1 Home 
sampling 
without visit
4
5
6
7
8
9
9.1 Home 
sampling 
without visit
9.2 Home 
sampling 
without visit
EoT
FUp1
FUp1.1 Home 
sampling 
without visit
FUp1.2 Home 
sampling 
without visit
FUp
2
Week of Visit
-11
-8
-4
-2
-1
0
1
2
6
10
12
13
14
15
16
17
18
Period
Screening
Randomised Run-In Period
Treatment Period
Follow-up
Start Empa/
plc Tx
Start 
BI 690517 
/ plc Tx
End Tx
Days before 
visit
0
1
0
0
8
■
7
■
1
0
33
1
0
0
0
1
0
1
0
15
▲
14
▲
8
▲
7
▲
33
1
0
0
15
●
14
●
8
●
7
●
1
0
First Morning 
Void (FMV)
X
X
X
X
X
X
X
X
X X X
X
X
X
X
X
X X
X
X
X
X
X X
24-hour urine 
sample 
X
X4
Bring samples 
to clinic visit1
X
X
X
X
X
X
X
Samples 
collected from 
home2
X
X
X
X
X
■days before planned Visit 4, ▲ days before regular EoT at week 14, ●days before FUp2
1 Samples to be brought to clinic if visit is conducted at investigational site.  If visit is conducted at patient’s home, samples may be picked up from home.
2 When samples are picked-up from home, this will be the following day at the latest. Where collection from the patient’s home is not possible, alternative arrangements will be made, e.g. 
samples taken to the investigational site
3 Start of 24-hour urine sample can be from the day after Visit 4 and up to 3 days before Visit 5; any time after Visit 9.2 and up to 3 days before EoT.    In the event of Visit 5 or EoT visit being 
delayed, the 24-hour urine samples must not be older than 10 days at the time of the visit. 24-hour urine sample must be completed before FMV samples for that visit.  
4 24-hour urine sample not required at EOT if patient discontinues prematurely prior to start of treatment with BI 690517 / matching placebo.


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Visit
Day
Time relative to 
administration (dose 
at Visit)
Time Point 
[hh:min]
Event
Drug5
admin.
2
-56
-0:30 (+ 29 /- 15 min)
-1344:30
0:00
-1344:00
X
42
-7
-0:30 (+ 29 /- 15 min)
-168:30
0:00
-168:00
X
0:30 (+/- 5 min)
-167:30
1:00 (+/- 10 min)
-167:00
2:001 (+ 15 min)
-166:00
52
1
-0:30 (+ 29 /- 15 min)
-0:30
0:00
0:00
X
0:30 (+/- 5 min)
0:30
1:00 (+/- 10 min)
1:00
2:001 (+ 15 min)
2:00
6
8
-0:30 (+ 29 /- 15 min)
167:30
0:00
168:00
X
7
15
-0:30 (+ 29 /- 15 min)
335:30
0:00
336:00
X
82
43
-0:30 (+ 29 /- 15 min)
1007:30
0:00
1008:00
X
0:30 (+/- 5 min)
1008:30
1:00 (+/- 10 min)
1009:00
2:001 (+ 15 min)
1010:00
9
71
-0:30 (+ 29 /- 15 min)
1679:30
0:00
1680:00
X
EoT2
, 3
99
-0:30 (+ 29 /- 15 min)
2351:30 
0:00
2352:00
X
0:30 (+/- 5 min)
2352:30
1:00 (+/- 10 min)
2353:00
2:001 (+ 15 min)
2354:00
FUp
13
106
-0:304 (+/- 30 min)
2519:30 
FUp
23
127
-0:304 (+/- 30 min)
3023:30
1Please note: on all occasions the 2 hour sample cannot be earlier than 2 hours after administration of the dose at the visit.
2 From the 
 the patient 
should only drink water and eat no food unless it is medically needed.
3 In the case of premature discontinuation during the Run-In phase, only 
 need to be taken 
at EoT.  No
 should be taken at FUp1 or FUp2
4 relative to usual time of drug administration during the treatment period of the study
5 Drug = empagliflozin / BI 690517 / placebo
6
 do not need to be taken if the patient has prematurely discontinued or temporarily interrupted 
empagliflozin/matching placebo and is still continuing on BI 690517 /matching placebo.  
 do 
not need to be taken if the patient has prematurely discontinued or temporarily interrupted BI 690517 /matching placebo and 
is still continuing on empagliflozin /matching placebo.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
FMV AND 24-HOUR URINE SAMPLING FLOW CHART .............................................9
TABLE OF CONTENTS ......................................................................................................11
ABBREVIATIONS AND DEFINITIONS...........................................................................15
1.
INTRODUCTION...............................................................................................19
1.1
MEDICAL BACKGROUND.............................................................................19
1.2
DRUG PROFILE................................................................................................20
1.2.1
BI 690517 .............................................................................................................20
1.2.2
Empagliflozin.......................................................................................................23
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................25
1.4
BENEFIT - RISK ASSESSMENT.....................................................................26
1.4.1
Benefits.................................................................................................................26
1.4.2
Risks .....................................................................................................................27
1.4.3
Discussion.............................................................................................................30
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................30
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........30
2.1.1
Main objectives....................................................................................................30
2.1.2
Primary endpoint(s)............................................................................................31
2.1.3
Secondary endpoint(s) ........................................................................................31
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................32
3.1
OVERALL TRIAL DESIGN.............................................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................34
3.3
SELECTION OF TRIAL POPULATION .......................................................36
3.3.1
Main diagnosis for trial entry ............................................................................36
3.3.2
Inclusion criteria .................................................................................................36
3.3.3
Exclusion criteria ................................................................................................37
3.3.4
Discontinuation of patients from treatment .....................................................39
3.3.4.1
Discontinuation of trial treatment .........................................................................40
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...................................................................................................42
4.1
INVESTIGATIONAL TREATMENTS ...........................................................42


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4.1.1
Identity of the Investigational Medicinal Products..........................................42
4.1.2
Selection of doses in the trial and dose modifications......................................44
4.1.3
Method of assigning patients to treatment groups...........................................44
4.1.4
Drug assignment and administration of doses for each patient......................45
4.1.5
Blinding and procedures for unblinding...........................................................47
4.1.5.1
Blinding.................................................................................................................47
4.1.5.2
Unblinding and breaking the code ........................................................................47
4.1.6
Packaging, labelling, and re-supply...................................................................48
4.1.7
Storage conditions...............................................................................................48
4.1.8
Drug accountability.............................................................................................48
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................49
4.2.1
Other treatments and emergency procedures..................................................49
4.2.1.1
Management of serum potassium elevation..........................................................49
4.2.1.2
Management of eGFR decrease............................................................................51
4.2.1.3
Management of serum cortisol decrease...............................................................51
4.2.2
Restrictions ..........................................................................................................51
4.2.2.1
Restrictions regarding concomitant treatment ......................................................51
4.2.2.2
Restrictions on diet and life style..........................................................................54
4.2.2.3
Contraception requirements..................................................................................54
4.3
TREATMENT COMPLIANCE........................................................................55
5.
ASSESSMENTS..................................................................................................55
5.1
ASSESSMENT OF EFFICACY........................................................................55
5.1.1
UACR...................................................................................................................55
5.2
ASSESSMENT OF SAFETY.............................................................................56
5.2.1
Physical examination ..........................................................................................56
5.2.2
Vital signs.............................................................................................................56
5.2.3
Safety laboratory parameters ............................................................................57
5.2.4
Electrocardiogram ..............................................................................................60
5.2.5
Other safety parameters.....................................................................................60
5.2.5.1
ACTH challenge test.............................................................................................60
5.2.5.2
eGFR .....................................................................................................................61
5.2.5.3
Urinary free cortisol..............................................................................................61
5.2.6
Assessment of adverse events.............................................................................62
5.2.6.1
Definitions of AEs ................................................................................................62
5.2.6.1.1
Adverse event........................................................................................................62
5.2.6.1.2
Serious adverse event............................................................................................62
5.2.6.1.3
AEs considered “Always Serious”........................................................................63
5.2.6.1.4
Adverse events of special interest.........................................................................63
5.2.6.1.5
Intensity (severity) of AEs....................................................................................64
5.2.6.1.6
Causal relationship of AEs....................................................................................65
5.2.6.2
Adverse event collection and reporting ................................................................65
5.2.6.2.1
AE Collection........................................................................................................65
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................66
5.2.6.2.3
Pregnancy..............................................................................................................66
5.2.6.2.4
Safety monitoring and adverse events with additional information collection.....67


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5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................69
5.4.1.1
Method and timing of sample collection...............................................................70
5.4.2
Pharmacogenomic biomarkers..........................................................................70
5.4.2.1
Method of sample collection...............................................................................70
5.4.2.2
Analytical determinations ..................................................................................71
5.5
BIOBANKING ....................................................................................................71
5.5.1
Methods and timing of sample collection..........................................................71
5.6
OTHER ASSESSMENTS...................................................................................71
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................71
6.
INVESTIGATIONAL PLAN.............................................................................72
6.1
VISIT SCHEDULE.............................................................................................72
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................73
6.2.1
Telemedicine Contacts........................................................................................74
6.2.2
Home Visits..........................................................................................................74
6.2.3
Screening and run-in period(s)..........................................................................75
6.2.4
Treatment period(s)............................................................................................76
6.2.5
Early discontinuation of Treatment..................................................................76
6.2.6
Follow-up period and trial completion..............................................................76
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE......................................................................................................................77
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................78
7.2
PLANNED ANALYSES.....................................................................................78
7.2.1
General considerations .......................................................................................78
7.2.2
Handling of Intercurrent Events .......................................................................79
7.2.3
Primary objective analyses.................................................................................80
7.2.3.3
Supplementary Analyses.......................................................................................81
7.2.4
Secondary objective analyses.............................................................................82
7.2.6
Safety analyses.....................................................................................................82
7.2.7
Other Analyses ....................................................................................................83
7.2.8
Interim Analyses .................................................................................................83
7.3
HANDLING OF MISSING DATA ...................................................................83
7.4
RANDOMISATION ...........................................................................................83
7.5
DETERMINATION OF SAMPLE SIZE .........................................................84
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........86


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8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................86
8.2
DATA QUALITY ASSURANCE ......................................................................87
8.3
RECORDS...........................................................................................................87
8.3.1
Source documents ...............................................................................................87
8.3.2
Direct access to source data and documents.....................................................88
8.3.3
Storage period of records ...................................................................................89
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................89
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........89
8.5.1
Collection, storage and future use of biological samples and 
corresponding data .............................................................................................89
8.6
TRIAL MILESTONES.......................................................................................90
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................90
9.
REFERENCES....................................................................................................92
9.1
PUBLISHED REFERENCES............................................................................92
9.2
UNPUBLISHED REFERENCES......................................................................94
10.
APPENDICES.....................................................................................................94
10.2
GFR CKD-EPI FORMULA...............................................................................95
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................97
11.1
GLOBAL AMENDMENT 1 ..............................................................................97
11.2
GLOBAL AMENDMENT 2 ............................................................................108
11.3
GLOBAL AMENDMENT 3 ............................................................................113


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ABBREVIATIONS AND DEFINITIONS
ACEi
Angiotensin-Converting Enzyme Inhibitor
ACTH
Adrenocorticotropic Hormone
ADME
Absorption, Distribution, Metabolism and Excretion
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
AxMP
Auxiliary Medicinal Products
AP
Alkaline Phosphatase
aPTT
Activated Partial Thromboplastin Time
ARB
Angiotensin Receptor Blocker
AS
Aldosterone Synthase
ASI
Inhibitor of Human Aldosterone Synthase
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
AUEC
Area Under the Effect Curve
b.i.d.
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
BLQ
Below the Lower Limit of Quantification
BMI
Body Mass Index
CA
Competent Authority
CK
Creatine Kinase
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CRP
C-Reactive Protein
CS
Cortisol Synthase
CTGF
Connective Tissue Growth Factor
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol


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CTR
Clinical Trial Report
CV
Cardiovascular
CYP
Cytochrome P450
DBP
Diastolic Blood Pressure
DDI
Drug-Drug Interactions
DILI
Drug Induced Liver Injury
DKA
Diabetic Ketoacidosis
DMC
Data Monitoring Committee
DPP
Dipeptidyl Peptidase-4
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
eGFR
estimated Glomerular Filtration Rate
ES
Entered Set
ESKD
End Stage Kidney Disease
EoT
End of Treatment
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FAS
Full Analysis Set
FMV
First Morning Void
FSGS
Focal Segmental Glomerulosclerosis
FUP
Follow-up
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GGT
Gammaglutamyl transferase
GLP1
Glucagon-Like Peptide-1
GMP
Good Manufacturing Practice
HbA1c
Glycated Haemoglobin
HDL
High-Density Lipoprotein
hERG
human Ether-à-go-go-Related Gene
HF
Heart Failure
HFrEF
Heart Failure with Reduced Ejection Fraction
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IMP
Investigational Medicinal Product
INR
International Normalised Ratio


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IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
K+
Potassium
KDIGO
Kidney Disease: Improving Global Outcomes
K-EDTA
Potassium Ethylenediaminetetra-Acetic Acid
LADA
Latent Autoimmune Diabetes
LC-MS/MS
Liquid Chromatography Tandem Mass Spectrometry
LDL
Low Density Lipoprotein
LLA
Lower Limb Amputation
LPLT
Last patient last treatment
LPLV
Last patient last visit
LPLVPE
Last patient last visit primary endpoint
LVEF
Left Ventricular Ejection Fraction
MAR
Missing at Random
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration 
MCPMod
Multiple Comparisons Procedure - Modelling
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Myocardial Infarction
MMRM
Mixed-effect model for repeated measures
MR
Mineralocorticoid Receptor
MRA
MR antagonist
MRD
Multiple Rising Dose
NOAEL
No-Observed-Adverse-Effect Level
NOA
Not Analysed
NOP
No Peak Detectable
NOR
No Valid Result
NOS
No Sample Available
NSAIDs
Nonsteroidal Anti-Inflammatory Drugs
NYHA
New York Heart Association
8-OHdG
8-Hydroxydesoxyguanosin
OPU
Operative Unit
PD
Pharmacodynamics


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P-gp
P-glycoprotein
p.o.
per os (oral)
PoC
Proof of Concept
PPARγ 
Peroxisome Proliferator-Activated Receptor gamma
PT
Prothrombin Time
q.d.
quaque die (once a day)
R1
First randomisation
R2
Second randomisation
RAAS
Renin-Angiotensin-Aldosterone System
RBC
Red Blood Cell
RDW
Red Blood Cell Distribution Width
REP
Residual effect period
RRR
Relative Risk Reduction
RS
Randomised Set
SAE
Serious Adverse Event
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SBP
Systolic Blood Pressure
SC
Steering Committee
SGLT-2i
Sodium-glucose cotransporter 2 inhibitor
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
T2DM
Type 2 Diabetes Mellitus
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TMF
Trial Master File
UACR
Urine Albumin Creatinine Ratio
ULN
Upper limit of normal
UTI
Urinary Tract Infection
WBC
White Blood Cell
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Chronic Kidney Disease (CKD) is the leading cause of kidney damage and end-stage kidney 
disease (ESKD). The 5-year survival rate of dialysis patients is 35%, which decreases to only 
25% in diabetic dialysis patients. As a result, CKD puts a large burden on healthcare systems 
worldwide, e.g. in the U.S. costs per patient exceed $75,000 annually. In addition to direct 
renal consequences, reduced kidney function is also a major trigger for cardio-vascular 
events. Overall, around 12% of the general population in Europe have 
CKD stages 3 to 5 [R19-1388], with considerable variation across countries, ranging from 
4.1% to 25.5% [R19-1184].
Diabetes is the main cause of CKD in most countries, accounting for 40% or more of new 
cases [R19-0901]. As glomerular filtration rate (GFR) declines, there is a linear increase in 
mortality, with 2- to 5-fold increases in patients with GFR <45 mL/min/1.73 m² compared 
with patients with GFR >60 mL/min/1.73m² [R14-4475]. Declining kidney function is 
associated with an increasing risk for coronary heart disease, stroke, and heart failure [R15-
5158; R15-2265]. Diabetic nephropathy is the leading cause of kidney damage and end-stage 
kidney disease (ESKD), accounting for >40% of patients on dialysis. 
At present, only a limited number of therapeutic options are available to delay kidney 
function decline in patients with CKD. Angiotensin-converting enzyme inhibitors (ACEis) 
and angiotensin receptor blockers (ARBs) can reduce albuminuria and slow the rate of 
progression in proteinuric diabetic kidney disease. However, in clinical trials in patients with 
diabetic nephropathy, the relative risk reduction for the composite primary endpoint of all-
cause death, ESKD and doubling of serum creatinine in trials was only moderate (16% in the 
RENAAL trial and 19% in the IDNT trial) [R02-0327; R02-2101]. 
Recently, the sodium glucose cotransporter 2 (SGLT-2) inhibitor empagliflozin has been 
shown to reduce the risk of kidney disease progression in people with type 2 diabetes. An 
exploratory analysis of the EMPA-REG OUTCOME trial indicated that empagliflozin 
reduced the incidence of the composite outcome of doubling of creatinine, the need to start 
kidney replacement therapy, or renal death by 46% (HR 0.54, 95% CI 0.40-0.75). These 
benefits were similar regardless of baseline ACEi or ARB use and there was no evidence of 
an increased risk of hyperkalaemia or acute kidney injury [P16-06807)]. In the EMPEROR-
Reduced trial, which was conducted in patients with heart failure with reduced ejection 
fraction, empagliflozin reduced the risk of the exploratory composite renal endpoint (chronic 
dialysis, kidney transplant, or sustained reduction in eGFR) by 50% in the overall trial 
population and was consistent on patients with and without CKD at baseline. Cardio-Kidney 
benefits of empagliflozin are currently being investigated in patients with CKD and a high 
risk for progression in the ongoing EMPA-KIDNEY study [P18-10838].
Increasing evidence is indicating that SGLT-2 inhibitors are likely to become a new treatment 
option for patients across a broad range of CKD phenotypes. The SGLT-2 inhibitor 
canagliflozin has received FDA approval for the treatment of patients with diabetic kidney 
disease and albuminuria >300 mg/g. In the CREDENCE trial, canagliflozin provided a 


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relative risk reduction of 30% for the composite endpoint of doubling of serum creatinine, 
ESKD or renal/CV death on top of standard of care [R19-1356]. A large-scale clinical 
outcome trial (DAPA-CKD) evaluating the SGLT-2 inhibitor dapagliflozin in patients with 
CKD (with or without type 2 diabetes and albuminuria >200 mg/g) was stopped early due to 
overwhelming efficacy. Data reported in August 2020 showed that dapagliflozin resulted in 
39% relative risk reduction (RRR) for the composite primary endpoint (≥50% eGFR 
decline/ESKD/renal or CV death). Dapagliflozin also resulted in 39% RRR for composite 
secondary endpoint of CV death and HF hospitalisation and 31% RRR for all-cause mortality
[R21-1080].
Current guideline recommendations have started to incorporate this new evidence by 
recommending SGLT2i with proven benefits as an integral part of the treatment regimen for 
patients with type 2 diabetes and CKD or CV risk [P20-09106]. Recommendations for non-
diabetic kidney disease are likely to follow soon in the light of the new and upcoming 
evidence. Despite this advance, the residual renal and cardiovascular risks for patients remain 
unacceptably high for patients with CKD, warranting continued efforts to provide new 
treatments, particularly for fast-progressing patients (with GFR reductions 
>3 ml/min/1.73m²/year) that are at considerably increased risk. 
1.2
DRUG PROFILE
1.2.1
BI 690517
BI 690517 is an oral, small-molecule inhibitor of human aldosterone synthase. It is being 
developed for the treatment of CKD in patients with and without diabetes. 
Mode of action
BI 690517 is a potent and specific inhibitor of human aldosterone synthase 
 


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1.2.2
Empagliflozin
Empagliflozin is indicated for reduction of blood glucose in patients with Type 2 Diabetes 
Mellitus (T2DM), and for cardiovascular (CV) death risk reduction in patients with T2DM 
and established CV disease.
Mode of action
Empagliflozin is an orally available SGLT-2 inhibitor, promoting urinary glucose excretion. 
Empagliflozin also reduces blood pressure, arterial stiffness and measures of myocardial 
workload, likely through various mechanisms, as well as improving other CV risk factors 
(e.g. uric acid, visceral fat mass, albuminuria; [P15-00589, P15-09541]).
Key pharmacokinetic characteristics
In humans, empagliflozin predominantly showed linear pharmacokinetics both after single
oral doses and at steady-state. Empagliflozin was rapidly absorbed, reaching peak levels at
approximately 1.5 h, followed by a biphasic decline with the terminal elimination half-life
ranging from 10 to 19 h. 
Drug interaction
! o clinically relevant pharmacokinetic interactions are anticipated with BI 690517 (see
section 1.2.1).


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Residual Effect Period
The Residual Effect Period (REP) of empagliflozin is 7 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
Data from clinical studies
Empagliflozin has been studied as part of a global development program including more than 
20,000 patients with type 2 diabetes treated in clinical studies of which more than 13,000
were treated with empagliflozin, either alone or in combination with metformin, a 
sulfonylurea, a PPARγ agonist, dipeptidyl peptidase-4 (DPP-4) inhibitors, or insulin.
In the EMPA-REG OUTCOME trial, empagliflozin was shown to be superior in reducing the 
primary endpoint, a composite of CV death, non-fatal myocardial infarction (MI), or non-
fatal stroke driven by 38% reduction of CV death compared to placebo on top of standard of 
care in patient with type 2 diabetes mellitus and established cardiovascular disease. An 
improved overall survival driven by a reduction in CV death was also observed. 
Empagliflozin reduced the risk of hospitalisation for heart failure and the composite of 
cardiovascular death or hospitalisation for heart failure compared with placebo. The risk of 
new or worsening nephropathy (including onset of macroalbuminuria, doubling of serum 
creatinine, and initiation of renal replacement therapy (i.e. haemodialysis)) was reduced in 
the empagliflozin group compared to placebo. 
In the EMPEROR-Reduced study in patients with HFrEF with LVEF<40%, with or without 
T2DM, empagliflozin significantly reduced the risk of cardiovascular death or hospitalisation 
due to heart failure compared with placebo. Additionally, empagliflozin significantly reduced 
the risk of recurrent hospitalisation due to heart failure, and significantly reduced the rate of 
eGFR decline.
In completed clinical studies, empagliflozin was well tolerated in non-diabetic healthy
volunteers, patients with type 2 diabetes, and patients with heart failure (NYHA class II-IV) 
and reduced ejection fraction with or without diabetes mellitus. The frequencies of overall 
AEs, AEs leading to discontinuation and SAEs were similar to placebo. There was an 
increase in frequency of genital infections with the use of empagliflozin. Empagliflozin 
treatment also increased urination and thirst. There was a small increase in total cholesterol, 
low density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol 
and no significant changes of LDL/HDL cholesterol ratio and in triglycerides. In addition, 
increases in haematocrit, haemoglobin and red blood cell were observed with empagliflozin. 
No clinically relevant changes in electrolytes, including potassium, were observed with 
empagliflozin. No changes to heart rate and no QTc prolongation have been observed. The 
safety profile of empagliflozin in patients with kidney impairment and decreased eGFR down 
to 15 mL/min/1.73m2 was consistent with that reported in patients with normal kidney 
function; there is no experience in patients with end-stage kidney disease and in patients on 
dialysis. 
For a more detailed description of the empagliflozin profile, please refer to the current 
Investigator’s Brochure [c01678844].


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1.3
RATIONALE FOR PERFORMING THE TRIAL
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the development and 
progression of kidney disease in patients with diabetic and non-diabetic CKD. Aldosterone is 
a key element of the RAAS and exerts its effects primarily via the mineralocorticoid receptor 
(MR). In patients with CKD and type 2 diabetes, treatment with the MR antagonist (MRA) 
finerenone in the FIDELIO DKD trial resulted in lower risks of CKD progression and 
cardiovascular events than placebo [R20-3706]. However, use of MRAs, particularly in 
patients with reduced kidney function, is limited by the risk for hyperkalaemia associated 
with MRAs.
BI 690517 is a potent and highly selective inhibitor of human aldosterone synthase (ASI). It 
is under development for the treatment of CKD in patients with and without diabetes. 
While MRAs block only MR-dependent aldosterone effects, BI 690517 acts to lower the 
circulating aldosterone level, thereby decreasing both MR-dependent and MR-independent 
effects of aldosterone. It is expected that this dual mechanism will lead to greater therapeutic 
benefit with less effect on MR-mediated electrolyte regulation (potassium (K+) effects). BI 
690517 therefore has the potential to slow or even stop the progression of CKD and may also 
have beneficial extra-renal effects on the cardiovascular system.
The main aim of this trial is to investigate the efficacy and safety of three oral doses of BI 
690517 alone and in combination with empagliflozin over 14 weeks versus placebo in male 
and female patients with CKD as adjunctive to ACEi or ARB treatment. PK and PD will also 
be investigated as a further endpoint. The results of this trial will be crucial for decisions 
about further development of BI 690517 and will support the dose selection for future trials.
In keeping with the assumption that SGLT2i will become an integral part of the standard of 
care for patients with CKD in the upcoming years, the proposed study has been designed to 
provide data on the effects of BI690517 with and without combination of 
empagliflozin. There is a strong hypothesis that the kidney-protective mode of action of both 
drugs is complementary in nature.While empagliflozin mainly impacts the tubular 
sodium handling leading to a reduced intraglomerular pressure via modulating 
the tubuloglomerular feedback mechanism, BI 690517 additionally exerts anti-fibrotic and 
and-inflammatory effects by ameliorating the deleterious effects of aldosterone. All three 
aspects are playing a pivotal role in kidney disease progression, providing a good reason to 
believe that the combination of both drugs might result in synergistic effects on slowing 
kidney disease progression.
The proposed phase II study design will allow to understand the treatment effects of BI 
690517 alone and in combination with empagliflozin which is mimicking the expected 
standard of care for the treatment of CKD and will allow an evaluation of the potential to 
further develop the combination of both drugs in phase III.


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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Potential benefits of treating patients with CKD with BI 690517 result from the prediction of 
slowing progression of the disease and risk reduction of cardiovascular events, which is only 
partially achieved by current standard of care. Treatment with BI 690517 will potentially 
result in decreased progression towards dialysis or kidney transplantation due to 
slowing/preventing the progression of kidney damage, which may directly translate into 
relevant improvements for patients’ morbidity, mortality, and quality of life. Beyond that, it 
may reduce the risk of cardiovascular events in the target population. The potential advantage 
of BI 690517 is the reduction in circulating and local aldosterone with its potentially harmful 
effects on heart and vascular tissue.
Potential benefits of SGLT2i treatment include a reduction in albuminuria and slowing of 
the annual decline in estimated glomerular filtration rate in people with type 2 diabetes. 
Additionally, cardio-kidney outcome trials have shown clinically meaningful benefits of 
SGLT2i treatment in albuminuric CKD patients with and without diabetes. Therefore, 
empagliflozin may have beneficial effects on kidney disease progression and cardiovascular 
risk. The EMPA-KIDNEY study is extending the current knowledge as it is assessing 
clinical benefits in patients with diabetic and non-diabetic CKD irrespective of the presence 
of albuminuria.
The combination of BI 690517 and empagliflozin, which have complmentary modes of 
action, have the potential to have synergistic effects on slowing kidney disease progression 
in patients with CKD.
Patients may also benefit from more frequent clinical monitoring as a result of being part of a 
clinical trial.


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1.4.2
Risks
Table 1.4.2:1 Overview of trial related risks 
Investigational Medicinal Product BI 690517
Possible or 
known risks 
of clinical 
relevance 
for this trial
Summary of data, 
rationale for the 
risk
Mitigation strategy
Potential 
adverse 
effects such 
as serum 
potassium 
increase 
Primarily related 
to the mechanism 
of action
To minimise the risk of severe or serious side 
effects, participants of this trial will only be exposed 
to doses that have been safely administered to 
healthy volunteers and patients in the preceding 
trials.1
Patients at higher risk of adverse effects related to 
the study drug will be excluded from the trial 
according to the exclusion criteria in section 3.3.3.
Drugs that may increase the potassium level will be 
restricted.
Serum potassium will be monitored closely during 
the trial and certain mitigations will be applied 
where required (see section 3.1 and 4.2.1.1)
Risks related 
to drug-drug 
interactions 
(DDI).
Pharmacokinetics 
and 
pharmacodynamics 
based DDIs (see 
section 1.2.1)
Close monitoring of patients and the prohibited co-
administration of impacted drugs such as treatment 
with a similar mechanism of action. 
For further guidance, investigators are referred to the 
Investigator’s Brochure [c09064107], Investigator 
Site File (ISF) or may contact the sponsor.
Drug-
induced liver 
injury (DILI)
Rare but severe 
event, thus under 
constant
surveillance by 
sponsors and 
regulators.
Timely detection, evaluation, and follow-up of 
laboratory alterations in selected liver laboratory 
parameters to ensure patients´ safety.
1 1378-0002 is a multiple rising dose trial that investigated the safety, tolerability, PK and PD of rising doses of BI 690517 over a treatment 
period of 14 days in healthy volunteers and 1378-0008 is a multiple rising dose trial that investigated the safety, tolerability, PK and PD of 
rising doses of BI 690517 over a treatment period of 28 days in patients with diabetic nephropathy.


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Table 1.4.2:1 Overview of trial related risks (cont’d)
Investigational Medicinal Product Empagliflozin
Possible or known 
risks of clinical 
relevance for this 
trial
Summary of 
data, rationale 
for the risk
Mitigation strategy
Potential adverse 
effects such as 
ketoacidosis, genital 
infections, 
complicated UTI 
(pyelonephritis, 
urosepsis), 
Fournier’s gangrene, 
hypoglycaemia 
(with concomitant 
use of insulin or 
sulfonylurea), and 
volume depletion
Primarily 
related to the 
mechanism of 
action
To minimise the risk of severe or serious side 
effects, participants of this trial will only be 
exposed to doses that have been safely 
administered to healthy volunteers and patients 
in trials, and that are commercially available.
Patients at higher risk of adverse effects related 
to the study drug will be excluded from the trial 
according to the exclusion criteria in section 
3.3.3.
Study treatment will be stopped in patients with 
suspected ketoacidosis or suspected Fournier’s 
gangrene. Study treatment interruption should 
be considered in patients with complicated UTI 
or with volume depletion (see section 3.3.4). 
Risks related to 
drug-drug 
interactions (DDI).
Pharmacokineti
cs and 
pharmacodyna
mics based 
DDIs
Close monitoring of patients and the prohibited 
co-administration of impacted drugs such as 
treatment with a similar mechanism of action. 
For further guidance, investigators are referred 
to the Investigator’s Brochure  [c01678844], 
Investigator Site File (ISF) or may contact the 
sponsor.
Other risks
Possible or known 
risks of clinical 
relevance for this trial
Summary of data, 
rationale for the risk
Mitigation strategy
Patients may develop 
AKI or ESKD due to 
underlying disease or 
other causes
Rare but severe event 
related to the trial 
diagnosis, requiring 
medical treatment and 
hold of some 
medications including 
investigational drugs. 
Treatment withdrawal criteria 
include AKI and ESKD as factors 
to remove the patient from 
treatment.


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Table 1.4.2:1 Overview of trial related risks (cont’d)
Other risks
Possible or known 
risks of clinical 
relevance for this trial
Summary of data, 
rationale for the risk
Mitigation strategy
Patients may develop 
SARS-CoV-2 infection
Based on the mode of 
action BI 690517 is not 
expected to have a 
significant impact on the 
susceptibility to or the 
course of an infection.
Travelling to the site or 
being at the site for trial 
visits may potentially 
increase the risk of 
contracting a SARS 
CoV-2 infection.
The underlying disease 
studied in this trial and 
the expected higher age 
of the impacted 
population increase the 
risk of hospitalisation 
and intensive care in 
case of a SARS-CoV-2
infection. 
Contracting SARS-
CoV-2 infection, as with 
all acute illnesses, has 
the potential to increase 
the risk of ketoacidosis 
in patients treated with 
empagliflozin
Even though the risks associated 
with BI 690517 treatment are 
considered low, patients with active 
or recent SARS CoV-2 infection 
will not be included in the trial (see 
section 3.3.3). In the case of severe 
SARS COV-2, the trial medication 
will be interrupted until recovery. 
Investigator and sponsor will 
closely align on the appropriate 
measures for monitoring, treatment 
and quarantine.  Measures are in 
place to ensure continued patient 
treatment, monitoring, and safety 
even if site visits are not possible 
(see sections 4.1 and 6.2). Physical 
visits to the sites may be replaced 
with home visits or telemedicine 
and procedures (including local lab 
testing) followed as far as the 
situation allows. Direct shipment of 
the trial medication will be managed 
by the site or the provider directly 
as permitted by local regulations. 
All decisions regarding the 
appropriate measures will be fully 
documented by the Sponsor. 
These measures ensure the safety of 
the patients throughout the trial.
Patients may develop 
an analphylactic shock 
or severe allergic 
reaction to 
tetracosactide 
(Synacthen® or 
equivalent for the 
ACTH challenge test) 
This tends to be more 
severe in people who 
suffer from allergies 
(especially asthma) 
Patients at higher risk of adverse 
effects related to the Synacthen®
will be excluded from the trial 
according to the exclusion criteria in 
section 3.3.3.
Patients will be monitored closely 
for at least 30 minutes after the 
injection.


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A Data Monitoring Committee (DMC) will be established to review safety data at regular 
intervals.  For further details see section 8.7.
1.4.3
Discussion
Based on pre-clinical results, BI 690517 has the potential to slow progression of kidney 
damage, delay end stage kidney disease (ESKD) and reduce the risk of cardiovascular events 
such as cardiovascular death, myocardial infarction, stroke and hospitalisation for heart 
failure, in patients with CKD. Based on results of completed clinical trials, empagliflozin also 
has the potential to slow the progression of CKD and reduce the risk of cardiovascular events.
A placebo arm for each treatment (empagliflozin and BI 690517) is needed to allow for a true 
assessment of the effects of BI 690517 given with or without empagliflozin on the UACR in 
patients with CKD. All patients will be on stable background standard of care therapy of at 
least either ACEi or ARB, and patients will only be enrolled in the trial if treatment with 
SGLT2i is not required (see section 3.3.1), therefore the inclusion of placebo treatment 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 690517 and empagliflozin. 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 690517 could provide to the 
treatment of CKD.
Overall, in the context of the unmet medical need and the anticipated effect on progression of 
CKD in humans and based on the safety profile of BI 690517, the benefit-risk evaluation of 
this compound, as well as empagliflozin, is considered favourable for the intended trial 
population.
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The trial will compare 3 doses of BI 690517 with placebo in patients with diabetic and non-
diabetic CKD randomised to empagliflozin or placebo as background therapy (established 
during the randomised run-in).
The trial will characterise the dose-response curve for BI 690517 in patients with diabetic and 
non-diabetic CKD by assessing 3 doses and placebo. The response is the change from 


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treatment period baseline in log-transformed UACR measured in First Morning Void urine 
after 14 weeks. The primary objectives are (1) to demonstrate a non-flat dose response curve, 
evaluate the quantitative treatment effect size and evaluate the dose-response relationship, (2) 
to determine an optimal dose of BI 690517 by comparing the change from treatment period 
baseline in log-transformed UACR measured in First Morning Void urine after 14 weeks 
between the 3 doses of BI 690517 and placebo.
One set of secondary objectives will be as above but in subpopulations of (1) placebo 
background therapy (2) empagliflozin background therapy.
These analyses will include all data prior to BI 690517 discontinuation, down-titration of BI 
690517, or death, regardless of change in concurrent SGLT2-inhibitor use.
2.1.2
Primary endpoint(s)
Change from treatment period baseline in log transformed Urine Albumin Creatinine Ratio 
(UACR) measured in First Morning Void urine after 14 weeks.
2.1.3
Secondary endpoint(s)
UACR response I, defined as decrease of at least 30% absolute change in First Morning Void 
urine of UACR from treatment period baseline to 14 weeks.
UACR response II, defined as decrease of at least 15% absolute change in First Morning 
Void urine of UACR from treatment period baseline to 14 weeks.
For further details regarding UACR response I and UACR response II, please see section 
7.2.4.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This trial is a multicentre, randomised, double-blind, parallel dose group, placebo-controlled 
clinical trial to investigate the effect of three doses of BI 690517 alone, and in combination 
with empagliflozin, in patients with diabetic and non-diabetic CKD who are on background 
treatment with either ACEi or ARB. Empagliflozin versus placebo use will be established 
during a 1:1 randomised run-in period.
A schematic illustration of the trial design is presented in Figure 3.1: 1.
Figure 3.1: 1 
Trial design
Patients will be screened in the trial once they have signed the informed consent. They will 
undergo a screening period of up to 3 weeks from the time of the first screening assessment.


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After their eligibility has been confirmed at screening, patients will enter the Randomised 
Run-in Period.  Patients will be randomised equally to receive either empagliflozin 10 mg or 
placebo matching to empagliflozin 10 mg in a 1:1 ratio and will continue taking the assigned 
study treatment for 8 weeks.  After 8 weeks of treatment in the Run-in Period, patients will 
enter the Treatment Period. Patients who received empagliflozin in the Run-in Period will be 
randomised equally into one of four parallel dose groups  in a 1:1:1:1 ratio (see Figure 3.1: 1) 
to receive one of 3 doses of BI 690517 (3 mg QD, 10 mg QD or 20 mg QD) in combination 
with empagliflozin, or empagliflozin alone (empagliflozin plus placebo matching to BI 
690517).  Patients who received placebo in the Run-in Period will be randomised equally into 
one of four parallel dose groups in a 1:1:1:1 ratio to receive one of 3 doses of BI 690517 (3 
mg QD, 10 mg QD or 20 mg QD) or placebo. Patients will continue receiving the assigned 
treatment for 14 weeks.
The study will be blinded to both empagliflozin and BI 690517.  As the BI 690517 film 
coated tablets of the different dose strengths (3 and 10 mg) and empagliflozin have different 
dimensions, in order to minimise possible observer bias and ensure the study is blinded 
across dose groups the patients will each take 4 tablets a day during the Treatment Period, as 
described in section 4.1.4.
Eligible patients will be randomised to treatment using a stratification algorithm that helps 
ensure balance between the treatment groups with respect to prognostic variables such as
eGFR and UACR. A target of approximately 30% of patients will be randomised during the 
run-in period in each of the disease types: diabetic kidney disease and non-diabetic kidney 
disease.  Patients with diabetes may have diabetic kidney disease, non-diabetic CKD
aetiologies, or a combination; for the purpose of categorising diabetic status, they will be 
classified as having diabetic kidney disease.
From the start of the screening until the end of the trial, at various time points patients will 
collect their First Morning Void urine for UACR analysis. These timepoints are listed in the 
FMV and 24-hour Urine Sampling Flow Chart. First morning void urine will be collected 
before the daily dose of study medication. 24-hour urine samples will also be collected prior 
to the start of the Treatment Period and at EOT. The patient will be equipped with urine 
collection containers to collect 24-hour urine and First Morning Void urine.
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 from the patient’s home to a 
central laboratory for analysis. Where this is not possible alternative arrangements will be 
made, e.g. samples taken to the investigational site. Samples taken directly prior to a physical 
visit at the site will be taken to the site to be processed by the site staff. 
Beyond analysis for safety, urine and blood samples in this trial will serve for biomarker 
analysis including UACR.
Following the Treatment Period, or at the time trial treatment in the Run-in Period or the 
Treatment Period is permanently discontinued, patients will have an End of Treatment (EoT) 
visit. This will be followed by a 4-week follow-up period off-treatment. A first follow-up 
visit (FUp1) at least 7 days later is considered as the end of the Residual Effect Period (REP). 


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Until the end of REP all AEs and changes to concomitant medication need to be collected, 
documented and reported.  Patients who discontinue prematurely during the Run-In Period 
must attend FUp1 at least.  All other patients should be encouraged to complete the full 
follow-up period.
During the follow-up period the patient will not be treated with trial medication, but should, 
if possible, continue with any background treatment they are on, and will collect additional 
urine at home. After the 4-week follow-up period the patient will have a final visit where 
again blood and urine samples will be collected. With the conclusion of this visit the trial 
participation is complete for the individual patient.
A rise in serum potassium and a drop in eGFR under treatment with BI 690517 cannot be 
excluded. Therefore, patients will be monitored closely (weekly for 2 weeks) after starting 
treatment with BI 690517 or matching placebo, and regularly thereafter. 
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 
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 understanding of drug effects and thereby better match 
patients with therapies.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial has been designed to assess efficacy and safety of BI 690517 alone, and in 
combination with empagliflozin, as likely initiated in clinical practice.  It also allows the 
opportunity to find the optimal dose of BI 690517 to be used for future development, on its 
own and / or as a fixed dose combination with empagliflozin.
Patients will initially start on 8 weeks of empagliflozin or placebo in the Randomised Run-in 
Period and will then receive 14 weeks of treatment with BI 690517 or placebo in the 
Treatment Period in addition to the empagliflozin or placebo treatment.  It is important that 
patients run in on empagliflozin first, before starting treatment with BI 690517, for safety 
reasons since both drugs have potentially similar haemodynamic effects.  8 weeks of 
empagliflozin treatment is considered sufficient to reach stable haemodynamic levels, before 
starting with BI 690517. 
A parallel group design was chosen to investigate three different dose regimens of BI 690517 
alone and in combination with empagliflozin.  The first parallel group will investigate three 
different dose regimens of BI 690517 and placebo.  The second parallel group will 


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investigate three different dose regimens of BI 690517, in combination with empagliflozin, 
versus empagliflozin+placebo. Placebo is used to control for observer and subject bias, and 
randomisation to control for assignment bias.
The study design involves two randomisations.  The first run-in randomisation to 
empagliflozin and placebo is required for two purposes.  Firstly, the run-in randomisation
will ensure an equally distributed patient population to the empagliflozin and placebo groups 
followed by second randomisation to treatment groups.  Secondly, a staggered approach
starting empagliflozin during the run-in period, followed by later initiation of BI 690517 was 
chosen to enhance patient safety.  Both, empagliflozin and BI 690517, have a haemodynamic 
effect which leads to an acute eGFR decrease. Staggered treatment initiation is planned to 
reduce such effect.
UACR was chosen as primary endpoint (First Morning Void collection) and secondary 
endpoint (responder rate) 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. Furthermore, the change in UACR correlates 
with long-term clinical and patient relevant outcomes.
Since UACR is a parameter that varies intra-individually over time, multiple measurements 
are required at treatment period baseline and during the treatment period especially towards 
the end of treatment where a stable response to the drug should be achieved. UACR 
measurements will therefore be collected on 2 consecutive days at 3 timepoints (6 
measurements in total) from Week -2 to Week 0 for treatment period baseline, and from 
Week 12 to Week 14 during the treatment period. Sequential collection of urine during a 4-
week follow-up period may deliver exploratory results of response stability and potential 
rebound effects.
 
In order to detect and mitigate the potential risk of adrenal insufficiency and Cushing’s 
syndrome, several measures will be implemented.  An ACTH Challenge test will be 
performed at screening to exclude patients with adrenal insufficiency.  Serum cortisol will be 
measured at all visits from Visit 5 until EoT and a further ACTH Challenge test will be 
performed if adrenal insufficiency is suspected.  Furthermore, free cortisol will be measured 
in 24-hour urine just prior to the start of BI 690517 treatment and at the end of BI 690517 
treatment to determine whether BI 690517 increases cortisol levels. Patients with adrenal 
insufficiency or Cushing’s syndrome will be discontinued from treatment with BI 690517.
A data monitoring committee (DMC) will be established to review safety data at regular 
intervals.  For further details see section 8.7.


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3.3
SELECTION OF TRIAL POPULATION
It is expected that at least 552 patients will be randomised to the Randomised Run-in Period 
from approximately 200 sites. Investigators are expected to be nephrologists, 
endocrinologists or general practitioners. 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. Patients already in screening at 
this time will be allowed to continue to randomisation if eligible.
A minimum of 552 patients will be randomised to the Run-in Period to ensure that at least 
480 will complete the study treatment in order to preserve the trial power by increasing 
sample size. If, during the study conduct, the drop out rate is higher than projected, 
recruitment may continue until the required number of patients complete treatment.
A log of all patients enrolled 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.
The investigator will make every effort to avoid the inclusion of a patient who does not meet 
all the inclusion criteria and/or meets at least one exclusion criterion. Should such an error 
nevertheless occur, this patient might be immediately excluded from the clinical trial based 
on individual benefit-risk assessment by the investigator. The sponsor or delegate will be 
informed as soon as possible.
3.3.1
Main diagnosis for trial entry
Chronic kidney disease.
If the investigator judges that the participant must receive empagliflozin (or any other SGLT-
2 or SGLT-1/2 inhibitor) in the context of prevailing local, national or international guidance, 
the patient should not be included in the trial due to the risk the patient may be assigned to 
placebo alone in the trial.
No potential participant currently being treated with empagliflozin (or other SGLT-2 or 
SGLT-1/2 inhibitor) should be taken off this therapy to meet the eligibility criteria.
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.


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2. Male or female patients of legal adult age (according to local legislation) and aged ≥ 18 
years at time of consent.
3. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) ≥30 
and < 90 mL/min/1.73 m2 at Visit 1 by central laboratory analysis.
4. UACR ≥ 200 and < 5,000 mg/g in spot urine (midstream urine sample) by central 
laboratory analysis at Visit 1.1
5. If the patient is taking any of the following medications they should be on a stable dose 
for at least 4 weeks prior to visit 1 and until first randomisation prior to run-in with no 
planned change of the therapy during the trial: anti-hypertensives, NSAIDs, endothelin 
receptor antagonists, low dose systemic steroids (e.g. prednisolone ≤10 mg or equivalent).
6. Treatment with a clinically appropriate, stable dose of either ACEi or ARB (but not both 
together), for ≥ 4 weeks prior to visit 1 and until first randomisation with no planned 
change of the therapy during the trial.
7. In the Investigator’s opinion, any kind of diagnosed chronic kidney disease5.  Patients 
with diabetic kidney disease must have type 2 diabetes mellitus and their treatment 
(including GLP1 receptor agonist) should be unchanged or changes deemed minor 
(according to investigator’s judgement) within 4 weeks prior to Visit 1 and until first 
randomisation. 
8. Glycated Haemoglobin (HbA1c) < 10.0% at Visit 1 measured by the central laboratory.
9. Serum potassium ≤ 4.8 mmol/L at Visit 1 measured by the central laboratory. (For further 
details, see section 4.2.1.1)
10. Seated SBP ≥ 110 and ≤ 160 mmHg and DBP ≥ 65 and ≤ 110 mmHg at Visit 1 (mean 
values from three BP measurements) and optimised anti-hypertensive treatment according 
to local standard of care and investigator’s judgement.
11. Body Mass Index (BMI) ≥ 18.5 and < 50 kg/m2 at Visit 1.
12. Women of child-bearing potential2 (WOCBP) must be ready and able to use highly 
effective methods of birth control according to section 4.2.2.3. Such methods should be 
used throughout the trial. Men must be vasectomised or willing and able to use a condom 
if their partner is a WOCBP.
Additional inclusion criteria to be assessed before second randomisation (start of Treatment 
Period):
13. Serum potassium ≤4.8 mmol/L measured by local or central laboratory within 7 days 
prior to randomisation to the Treatment Period.
14. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula) ≥20 
mL/min/1.73 m2 measured by local or central laboratory within 7 days prior to 
randomisation to the Treatment Period.
3.3.3
Exclusion criteria
1.   Treatment with inhibitors of aldosterone mediated effects (e.g., mineralocorticoid 
receptor antagonists such as spironolactone), or intake of other potassium sparing 
diuretics (e.g., amiloride) within 7 days prior to first randomisation or planned during trial 
treatment phase.
2. Treatment with other Renin Angiotensin Aldosterone System (RAAS) interventions 
(apart from either ACEi or ARB) within 4 weeks prior to Visit 1 and throughout 
screening or planned during the trial. Patients who must or wish to continue the intake of 


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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.
3. Type 1 diabetes mellitus, or history of other autoimmune causes of diabetes mellitus (e.g. 
LADA)
4. Patients at increased risk of ketoacidosis (see empagliflozin Investigator Brochure 
[c01678844]) in the opinion of the investigator.
5. Currently receiving SGLT-2 or SGLT-1/2 inhibitor or planned initiation during the trial.
6. Use of biotin (Vitamin B7, Vitamin H, or coenzyme R) at doses ≥5 mg/day (including 
food supplements) within 72 hours of Visit 1 or planned during the trial.
7. Absolute cortisol value of < 18 µg/dL (496.6 nmol/L) 30 minutes (± 5 min) after injection 
of ACTH, at Visit 1, as measured by local or central laboratory. 
8. Known history of severe symptomatic orthostatic dysregulation as judged by the 
investigator before first randomisation.3
9. Intermittent or persistent 2nd or 3rd degree atrioventricular block, sinus node dysfunction 
with clinically significant bradycardia or sinus pauses, not treated with a pacemaker.
10. Serum cortisol < 5 µg/dL (138.0 nmol/L) or any clinically relevant abnormal laboratory 
value, at Visit 1 or until first randomisation, which in the investigator’s judgement puts 
the patient at additional risk.
11. Any systemic immunosuppression therapy or immunotherapy in the last 3 months prior to 
Visit 1 or before first randomisation. This also applies to systemic steroids except oral 
prednisolone ≤10 mg or equivalent.
12. Acute kidney injury (AKI) according to the Kidney Disease: Improving Global Outcomes 
(KDIGO) definition4 [R17-2439] in the 30 days prior to Visit 1 or until first 
randomisation.
13. End stage kidney disease, maintenance dialysis, functioning kidney transplant at Visit 1
or before first randomisation; planned kidney transplant or chronic renal replacement 
therapy during the trial.
14. Heart failure, patients with NYHA III / IV or coronary heart disease not compensated by 
medical treatment.
15. Active infection with SARS-CoV-2 from Visit 1 until first randomisation, or a positive 
acute infection confirmatory test within 4 weeks prior to Visit 1.
16. Any documented active or suspected malignancy at the time of screening or history of 
confirmed malignancy within 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]) or treatment for cancer within 2 years prior to Visit 1. 
17. Major surgery (investigator’s judgement) planned during the trial.
18. History of clinically relevant allergy/ hypersensitivity that would interfere with trial 
participation including allergy to investigational product / placebo / tetracosactide 
(injection for ACTH test) or their excipients (e.g. lactose monohydrate) – see Investigator 
Brochures [c09064107] and [c01678844].
19. Patients who are unable to comply with trial procedures or have any other medical 
condition that in the investigator’s opinion poses a safety risk for the patient or may 
interfere with the trial objectives. 
20. Previous randomisation in this trial.
21. 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) or receiving other investigational treatment(s).


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22. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable trial participant or unlikely to complete the trial.
23. Women who are pregnant, nursing or who plan to become pregnant while in the trial.
24. Patients with known hepatic cirrhosis (Child Pugh A, B or C), or other liver disease 
causing impaired liver function according to investigator’s judgement.
25. Patients with one of the following aetiologies as the underlying cause: 

CKD secondary due to malignancy (e.g. Cast-Nephropathy, AL-amyloidosis)

CKD secondary to infectious disease (e.g. Hepatitis-/HIV-associated)

Autosomal-dominant polycystic kidney disease
Additional exclusion criteria to be assessed before second randomisation (start of Treatment 
Period):
26. Patients with known hepatic cirrhosis (Child Pugh A, B or C), or other liver disease 
causing impaired liver function, according to investigator’s judgement
1In case of out of range borderline results UACR testing may be repeated once before the Randomised Run-in 
Period starts.
2A 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 24 months without an alternative medical cause.
3 Severity of symptomatic orthostatic dysregulation is based on the standard Adverse Event severity 
classification (see section 5.2.6.1.5).
4Definition of AKI according to Kidney Disease: Improving Global Outcomes (KDIGO):
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 baseline, 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.
5Diagnosis can be reached by standard clinical method, no biopsy required.
3.3.4
Discontinuation of patients from treatment 
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) 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 section 5.2.6.2).


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3.3.4.1
Discontinuation of trial treatment
Permanent Discontinuation
An individual patient will permanently discontinue all randomised trial treatment if:
1. The patient develops Acute Kidney Injury as per clinical judgement by the 
investigator. The Kidney Disease: Improving Global Outcomes (KDIGO) definition 
[R17-2439] (see section 3.3.3) is going to be used for guidance.
2. The patient experiences a drop in eGFR1:

≥ 30% from the last measurement of eGFR before the first dose of 
empagliflozin / placebo up to Visit 6; and/or

≥ 40% at any time since the last measurement of eGFR before the first dose of 
empagliflozin/placebo 
3. The patient progresses to end stage kidney disease defined by either a kidney function 
decline below an eGFR1 of <15 mL/min/1.73 m2 and/or requires renal replacement 
therapy by kidney transplant or dialysis.
4. The patient wants to discontinue trial treatment. The patient will be asked to explain 
the reasons but has the right to refuse to answer. 
5. The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of the investigator, the safety of the patient cannot be guaranteed 
as he / she is not willing or able to adhere to the trial requirements in the future. 
6. 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 can
be consulted.
7. The patient can no longer receive trial treatment for medical reasons such as surgery, 
serious or severe Drug Induced Liver Injury attributable to the trial drug (see section
5.2.6.1.4), other adverse events, or other diseases. 
8. The patient requires treatment for cancer. Some exclusions apply e.g. for Basal Cell 
Carcinoma – please discuss with sponsor.
9. 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.
10. The patient does not meet the additional inclusion criteria (see section 3.3.2) or the 
additional exclusion criteria (see section 3.3.3) assessed before second randomization 
(start of Treatment Period).
An individual patient will permanently discontinue BI 690517 / placebo if:
1. The patient’s serum potassium measures ≥ 6.0 mmol/L by central or any local 
laboratory, or ≥ 5.6 mmol/L if down-titration is considered inappropriate. 
                                                
1 Where the eGFR drop occurs before the start of BI 690517 / placebo in the Treatment Period (i.e., at Visit 5), 
but the result is not available until after the patient starts BI 690517/placebo treatment, the patient must still 
permanently discontinue all randomised study treatment, including BI 690517 / placebo.


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2. The patient develops Cushing’s syndrome, adrenal insufficiency (including cortisol 
level <18 µg/dL 30 min (±5 min) after ACTH application) or the patient’s cortisol 
level is < 3 µg/dL (82.8 nmol/L) at any point in the trial. The patient must be followed 
according to local guidelines until resolution of the event and the event is going to be 
reported to the sponsor (see section 5.2.6.1.4).
An individual patient will permanently discontinue empagliflozin / placebo if:
1. Ketoacidosis is suspected.
2. Fournier’s gangrene is suspected. 
If empagliflozin / placebo is permanently discontinued during the Randomised Run-In period, 
the patient should permanently discontinue the trial.  If one of the study medications (either 
empagliflozin/placebo or BI 690517/placebo) is permanently discontinued during the 
Treatment Period / after the second randomisation at Visit 5, the patient may continue to 
receive treatment with the other study medication and should continue with scheduled study 
visits according to the Flowchart.
Treatment interruption
In the following case, all randomised study medication must be interrupted:

severe SARS-COV-2 infection
In the following cases, the empagliflozin / placebo must be interrupted:

complicated UTI

symptomatic volume depletion
In the following cases, the BI 690517 / placebo must be interrupted:

serum potassium ≥ 5.6 mmol/L (see section 4.2.1.1)

serum potassium ≥5 mmol/L if the patient is unable or unwilling to return to the 
investigational site (see section 4.2.1.1)
In these cases, trial treatment could be restarted upon recovery if medically justified, please 
see section 4.1.4.
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 6.2.5 and 6.2.6 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.


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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.
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:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further treatment and follow up of patients affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1:1 BI 690517 3 mg
Substance:
BI 690517 film-coated tablets 3 mg
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
3 mg
Posology:
QD
Method and route of administration:
Oral (p.o)


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Table 4.1.1:2 BI 690517 10 mg
Substance:
BI 690517 film-coated tablets 10 mg
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg
Posology:
QD
Method and route of administration:
Oral (p.o)
Table 4.1.1:3 Placebo matching BI 690517 3 mg
Substance:
Placebo to BI 690517 film-coated tablets 3 mg 
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
QD
Method and route of administration:
Oral (p.o)
Table 4.1.1:4 Placebo matching BI 690517 10 mg
Substance:
Placebo to BI 690517 film-coated tablets 10mg
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
QD
Method and route of administration:
Oral (p.o)
Table 4.1.1:5 Empagliflozin 10 mg
Substance:
Empagliflozin film-coated tablets 10mg
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10mg
Posology:
QD 
Method and route of administration:
Oral (p.o)
Table 4.1.1:6 Placebo matching empagliflozin 10 mg
Substance:
Placebo to empagliflozin film-coated tablets 10mg
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
QD 
Method and route of administration:
Oral (p.o)


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Table 4.1.1:7 Synacthen (for ACTH test, may be required to be an IMP in certain countries –
see section 5.2.5)
Substance:
Synacthen®
Pharmaceutical formulation:
Solution for injection or infusion.
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
250 μg
Posology:
As defined in the Flow Chart
Method and route of administration:
i.v. or i.m. injection
4.1.2
Selection of doses in the trial and dose modifications
During the Randomised Run-in Period, patients will receive either empagliflozin 10 mg or 
matching placebo. This dose was selected based on the dose used in the ongoing phase III 
empagliflozin in CKD trial (BI 1245-0137).
During the Treatment Period, patients will receive either BI 690517 or matching placebo on 
top of empagliflozin or matching placebo. The target doses of BI 690517 used for this trial 
will be 3 mg QD, 10 mg QD and 20 mg (2 x 10mg) QD. 
In healthy volunteer phase I trials, doses ranging from 0.7 to 80 mg QD were tested. 
 
 
. In the Phase 1c MRD study 1378-0008, three doses of BI 690517 (3 
mg, 10 mg and 40 mg QD) were tested over 28 days of treatment.  There was a numerical 
increase with dose for the change from baseline in serum potassium level. Since the increase 
of serum potassium tends to increase with dose, it is expected that 20 mg dose would have 
less hyperkalaemia cases compared to 40 mg dose. Therefore, to enhance patient safety 
during this trial, it is proposed to investigate 3, 10 and 20 mg (QD) doses. The other 
important factor in selection of 20 mg dose was suppression of aldosterone.  The 40 mg dose 
resulted in a substantial suppression of aldosterone, and it is expected that the lower 20 mg 
dose will result in less aldosterone suppression, reducing the risk of hyperkalaemia.
Down titration (dose reduction) may be considered based on serum potassium levels (see 
section 4.2.1.1).
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria at visit 2, each eligible patient will be 
randomised into the Randomised Run-in Period according to a randomisation plan.  Patients 
will be randomised in a 1:1 ratio via Interactive Response Technology (IRT) to either receive 
empagliflozin 10 mg QD or placebo matching to empagliflozin 10 mg QD in a blinded 
manner. 


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At Visit 5, following the Randomised Run-in Period, patients will be randomised into the 
Treatment Period via IRT according to a randomisation plan.  Patients will be randomised in 
a 1:1:1:1 ratio to receive one of three doses of BI 690517 (3 mg QD, 10 mg QD or 20 mg 
QD) or placebo, in a blinded manner, in addition to the blinded treatment assigned during the 
Run-in Period. 
Randomisation codes will be generated using 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
At Visit 2, all eligible participants will be randomised into the Run-In period to receive either 
empagliflozin 10 mg or matching placebo in a blinded manner.  The patient will be dispensed 
enough medication for the duration of the Randomised Run-in Period. The first dose of 
empagliflozin/placebo will be administered at Visit 2.  1 tablet will be taken daily for the 8-
week duration of the run-in period.  
At Visit 5 (start of the Treatment Period), participants will be be randomised into the 
Treatment period to receive one of three doses of BI 690517 (3 mg, 10 mg or 20 mg QD) or 
placebo and this will be given in addition to the empagliflozin or placebo assigned in the run-
in period.  During the Treatment period, both empagliflozin/placebo and BI 690517/placebo 
medication will be dispensed at visits 5, 7, 8 and 9. The medication will be administered 
during the visit on the days of study visits.  At the visits where medication is not dispensed 
(Visit 4, Visit 6 and EoT), medication will be administered from the kits dispensed at the 
previous visit.  At all other visits medication may be administered from the kits dispensed at 
the current visit.
Empagliflozin or matching placebo will be dispensed in wallets of 35 tablets to cover 28 days 
plus 7 days reserve:

2 wallets at Visit 2 

1 wallet at Visit 5, Visit 7, Visit 8 and Visit 9 
BI 690517 or matching placebo will be dispensed in kits to cover 28 days plus 7 days reserve.  
Each kit will contain 5 wallets. Each wallet will contain 7 days’ supply (21 tablets in total, 
comprising 7 x Tablet 2, 7 x Tablet 3 and 7 x Tablet 4 – see Table 4.1.4: 1 below).

1 kit at Visit 5, Visit 7, Visit 8 and Visit 9


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In order to blind the dose of BI 690517 or matching placebo, 4 tablets will need to be taken 
daily during the Treatment Period, according to the treatment assignments shown in Table 
4.1.4: 1.
Table 4.1.4: 1
Treatment assignments during the Treatment Period
Dose group
Tablet 1
Tablet 2
Tablet 3
Tablet 4
Empagliflozin or 
matching placebo 
BI 690517 or matching placebo 
Empagliflozin + BI 690517 3mg
10 mg active
3 mg 
active
10 mg 
placebo
10 mg 
placebo
Empagliflozin + BI 690517 10mg
10 mg active
3 mg 
placebo
10 mg 
active
10 mg 
placebo
Empagliflozin + BI 690517 20mg
10 mg active
3 mg 
placebo
10 mg 
active
10 mg 
active
Empagliflozin alone
10 mg active
3 mg 
placebo
10 mg 
placebo
10 mg 
placebo
BI 690517 3mg
10 mg placebo
3 mg 
active
10 mg 
placebo
10 mg 
placebo
BI 690517 10mg
10 mg placebo
3 mg 
placebo
10 mg 
active
10 mg 
placebo
BI 690517 20mg 
10 mg placebo
3 mg 
placebo
10 mg 
active
10 mg 
active
Placebo
10 mg placebo
3 mg 
placebo
10 mg 
placebo
10 mg 
placebo
Empagliflozin or matching placebo will be administered orally on a once daily basis (QD)
during the Run-in Period and Treatment Period. BI 690517 and/or placebo will be 
administered orally on a once daily basis (QD) during the Treatment Period, and should be 
taken at the same time as the empagliflozin or matching placebo dose.
To ensure a dose interval of about 24 hours, the medication should be taken in the morning at
approximately the same time every day. If a dose is missed by more than 12 hours, that dose
should be skipped and the next dose should be taken as scheduled. No double doses should 
be taken. Both medications should be taken together with a glass of water and can be taken 
with or without food. 
Down-titration (dose reduction) should be considered to manage serum potassium elevations 
(see section 4.2.1.1).  Down-titration to the next lower dose is performed in a blinded manner. 
If the patient has been initially assigned to the lowest dose of BI 690517 (3 mg QD), the 
patient will be down-titrated to placebo in a blinded manner.  If the patient has been initially 
assigned to the matching placebo to BI 690517, the patient will be ‘pseudo’-down-titrated to 


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placebo. Patients will only be allowed to down-titrate once during the study and no re-
escalation is allowed. Down-titration may only be performed to manage hyperkalaemia and 
not for the management of other adverse events.  
All trial medication assignments including down-titrations and replacement kits will be 
managed through the IRT system. 
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please 
see section 6.2), physical patient visits to the sites may not be feasible or 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 trial treatment. Where permitted by local law and 
regulations, trial medication may be shipped directly to the patient’s home. Shipment of trial 
medication from the site to the patient’s home will also be allowed to support regular visits 
performed at the patient’s home.
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 in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments until a snapshot after Last Patient Last Visit Primary Endpoint (LPLVPE), with 
the exception of the Trial Pharmacometrician, PK programmer and Trial Bioanalyst. This 
snapshot will be taken after the last patient completes the EoT Visit, and will be used to 
obtain efficacy, safety, and PK/PD results, to guide further development plans for BI 690517.
At the timepoint of unblinding of this snapshot, patients and investigators will continue to be 
blinded and will remain so until after database lock when the database is declared ready for 
final analysis according to the sponsor’s SOPs. Further details regarding the timepoint of 
unblinding the database for analysis are documented in the TSAP. The access to the 
randomisation code will be kept restricted until its release for analysis.
The randomisation codes will be provided to bioanalytics before the last patient completed 
the trial to exclude placebo samples from the PK analysis. Bioanalytics will not disclose the 
randomisation code or the results of their measurements prior to the LPLVPE snapshot.
In order to expedite the population PK and PK-PD analyses and ensure timely delivery of 
PK/PD results after database lock and to provide PK data to DMC for consideration when 
evaluating safety of the trial, 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 the LPLVPE snapshot.
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 


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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 
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.
Synacthen® (or equivalent) is either provided by the site or where this is necessary through 
the sponsor. Where Synacthen® is provided by the sponsor, supplies will be managed via the 
IRT system.
For details of packaging and the description of the label, refer to the ISF.
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 or 
delegate 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 or delegate 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, 
Availability of FDA Form 1572 (if applicable).


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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 at each resupply visit and EoT.
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).
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.
If a patient has an adverse event that the Investigator believes may be related to trial 
medication (either empagliflozin and/or BI 690517) then the Investigator may interrupt the 
medication. Trial treatment may be restarted at any time after a temporary reason for 
treatment discontinuation if medically justified (see section 3.3.4.1). 
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.
4.2.1.1
Management of serum potassium elevation
Increased potassium levels are not uncommon in patients with CKD and are often 
multifactorial in nature. A rise in serum potassium under treatment with BI 690517 cannot be 
excluded and therefore regular measurements of potassium levels are an integral part of the 


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visit schedule. For any episode of increased potassium level above 5.0 mmol/L, a clinical 
evaluation should be performed to make individual treatment decisions if a prompt 
intervention is required. For BI 690517 the dose might be adjusted to keep potassium levels 
in an acceptable range. The investigator should consider whether a down-titration is 
appropriate from a clinical perspective considering symptoms, relevant ECG changes, 
dynamics of potassium changes, intercurrent disorders, and lower ranges of eGFR.  For 
detailed guidance on how to manage serum potassium elevations, please refer to Table 
4.2.1.1: 1.   
Table 4.2.1.1: 1 
Management of serum potassium 
Serum 
Potassium
Actions (BI 690517 / placebo)
< 5.0 mmol/L Continue on current dose if deemed appropriate (e.g. in absence of clinical 
symptoms or slow/small increase over time)
For clinically relevant serum potassium increases to < 5.0 mmol/L, the investigator 
may consider interruption and/or down-titration of BI 690517 /placebo.
≥ 5.0 to <5.6 
mmol/L
Option 1: Continue on current dose. Recheck K+ within 72 hours. If levels continue 
to be ≥5.0 mmol/L, either continue dose with weekly monitoring, or follow Option 
2 or Option 3.
OR
Option 2: Down-titration
If down titration is deemed appropriate, the BI 690517 / placebo should be 
temporarily stopped and the next lower dose will be allocated by IRT as soon as 
possible.
After restarting on a lower dose, investigator should recheck K+ within 72 hours.  If 
levels continue to be >5.0 mmol/L, permanently discontinue.
OR
Option 3: If down titration is considered inappropriate, permanently discontinue BI 
690517 / placebo
≥ 5.6-< 6.0 
mmol/L
Option 1: Interruption followed by down titration
Study medication should be temporarily interrupted.  Investigator should recheck 
K+ every 72 hours and can restart study medication at the next lower dose once K+
falls to < 5.0mmol/L. After restarting on a lower dose, investigator should recheck 
K+ within 72 hours. If levels continue to be >5.0, permanently discontinue.
OR
Option 2: If down titration is considered inappropriate permanently discontinue BI 
690517 / placebo
≥ 6.0 mmol/L
Discontinue BI 690517 / placebo permanently.
In case of symptomatic hyperkalaemia initiation of potassium lowering treatment might be
considered as medically indicated, like diuretics, potassium binding resins or other treatments 
as described in local or global guidelines for treatment of hyperkalaemia.
If BI 690517 or matching placebo must be permanently discontinued due to raised serum 
potassium, the patient may still continue to receive empagliflozin / matching placebo (see 
section 3.3.4).


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In the event of elevated potassium ≥5 mmol/L, if the patient is unable or unwilling to return 
to the investigational site, for example during pandemic situation, the BI 690517 or matching 
placebo should be temporarily interrupted until the patient can return to the investigational 
site.
For patients taking potassium supplements, serum potassium should be monitored closely,
and if serum potassium is ≥ 4.5 mmol/L, the investigator should consider reducing or 
discontinuing the potassium supplements, according to investigator judgement.
4.2.1.2
Management of eGFR decrease
After the start of the double-blinded treatment with BI 690517 / placebo, if the eGFR 
decreases by >15% since the last visit, the investigator should recheck the eGFR and 
potassium after 48-72 hours. The decision about continuing or discontinuation of the study 
drug should be based on the criteria specified in section 3.3.4.1 and the overall assessment of 
the patient’s status. In case of increased potassium, the management of the patient should be 
done according to the rules in section 4.2.1.1.
4.2.1.3
Management of serum cortisol decrease
If, during the trial, cortisol level is < 3 µg/dL (82.8 nmol/L) the patient must be withdrawn 
from BI 690517 / placebo (see section 3.3.4).
If, during the trial, the cortisol level is ≥3 µg/dL (82.8 nmol/L) and < 11 µg/dL  (303.5
nmol/L) and the patient shows suggestive signs or symptoms of adrenal insufficiency 
(including but not limited to: fatigue, weight loss, abdominal pain, hypotension, volume 
depletion, hyperpigmentation, hypoglycaemia, hyperkalaemia, hyponatraemia), an ACTH test 
must be performed to investigate for potential adrenal insufficiency (see section 5.2.5.1). If 
absolute cortisol value is < 18 µg/dL (496.6 nmol/L) 30 minutes (± 5 min) after injection of 
ACTH, the patient should discontinue BI 690517 / placebo.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
 
 
 
 
Please refer to the list of relevant drugs in ISF.


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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.
If a patient develops hyperkalaemia they should be advised to avoid potassium-rich foods.
4.2.2.3
Contraception requirements
WOCBP (for the definition please refer to section 3.3.3) trial participants must use two 
medically approved methods of birth control throughout the trial, and for a period of at least 7 
days after last trial drug intake, one barrier method, and one highly effective non-barrier 
method. 
Highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of 
less than 1% per year when used consistently and correctly include:

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal).


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
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion
Male trial participants 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.
Based on tablet counts, treatment compliance will be calculated separately for both 
empagliflozin and BI 690517 (or matching placebo) as shown in the formula below. 
Treatment compliance (%) =
Number of tablets actually taken 100
     Number of tablets which should have been taken as 
directed by the investigator
If the number of doses taken is not between 80-120%, site staff will explain to the patient the 
importance of treatment compliance.
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
UACR
At Visit 1 (screening), a midstream urine sample for the analysis of UACR will be taken. 
UACR at screening will be analysed and calculated by the central laboratory to determine the 
eligibility of the patient.
Urinary albumin and creatinine measurements are the basis for the calculation of urine 
albumin creatinine ratio (UACR). First Morning Void (FMV) urine samples will be collected 
by the patient at home. 


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The first morning void is the urination after the patient wakes up to start their day. Thus, if 
the patient goes back to sleep after urinating early in the morning e.g. at 4am, this void does 
not need to be collected and this does not need to be documented. This applies also to any 
urinations earlier during the night in patients who have nocturia. (However, if the patient is 
an early riser and gets up ‘for good’ e.g. at 4am, this would qualify as their FMV.) Of course, 
there may be cases when a patient might go back to bed after their usual rising time. In those 
cases, the void after the usual rising time constitutes the first morning void.
After the screening period, UACR will be determined on two consecutive days to average 
biological variability at the timepoints indicated in the FMV and 24-hour Urine Sampling 
Flowchart. On each collection day a sample must be obtained from the patient’s FMV.  
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 may be reminded e.g. by telephone contacts ahead of 
sampling time points on how to collect and store their urine samples. Further collection and 
sample storage instructions are given in the laboratory manual in the ISF and instructions to 
the patient.
Urinary albumin and creatinine will be analysed at a central laboratory using routine 
validated methods. 
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart. It includes 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 blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. The blood pressure 
at screening will be performed in triplicate, and a mean of the 3 measurements will be used to 
confirm eligibility.  BP measurements should be recorded to the nearest 1 mmHg. The results 
must be included in the source documents available at the site.


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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 will be used for 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 send 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 transient medical 
condition, the patient may continue in the screening phase but not be randomised at Visit 2 
until the re-test of the lab result has shown eligibility of the patient. Ineligible lab parameters 
may only be re-tested once during the screening period.
In case the criteria for hepatic injury 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 or delegate.
The CKD-EPI Equation is used for reporting eGFR based on serum creatinine (see appendix 
section 10.2).
Table 5.2.3:1 
Safety laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelet count
MCV
MCH
MCHC
RDW


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Table 5.2.3:1 Safety laboratory tests (cont’d)
Functional lab group
Test name 
Automatic WBC differential 
(relative and absolute)
Neutrophils
Eosinophils 
Basophils 
Monocytes 
Lymphocytes
Manual differential WBC (if automatic differential 
WBC is abnormal)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin Time (PT)
International Normalised Ratio (INR)
Enzymes
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP)
Gammaglutamyl transferase (GGT)  
Creatine kinase (CK)
Lipase
Amylase
Substrates
Glucose
HbA1c (at Visit 1, Visit 5 and EoT)
Creatinine
Urea Nitrogen
Uric Acid
Total bilirubin 
Direct bilirubin
Total protein
Albumin
Globulin
Albumin / Globulin ratio
C-Reactive Protein (CRP) 
Total cholesterol 
Electrolytes
Calcium
Sodium
Potassium
Chloride
Phosphate
Bicarbonate 
(Calculated) anion gap
Hormones
Testosterone (only for female participants at Visits 5 
and EoT)
Serum cortisol (at Visit 1, Visit 5 pre- and post-dose, 
Visit 6, Visit 7, Visit 8, Visit 9, EOT)
Serum Pregnancy test (only for female participants
of childbearing potential) at Visit 1 and if urine 
pregnancy test is positive
Human Serum Chorionic Gonadotropin


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Table 5.2.3:1 Safety laboratory tests (cont’d)
Functional lab group
Test name 
Urinalysis 
Urine nitrite
Urine protein
Urine ketone
Urine bilirubin
Urine Blood
Urine leukocyte esterase
Urine pH
Specific gravity
Urine sediment (microscopic examination if 
erythrocytes, leukocytes nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (e.g. 
presence of sediment bacteria, casts in sediment, 
squamous epithelial cells, erythrocytes, leukocytes)
Urine Pregnancy test (only for female participants of 
childbearing potential) at Visits 5, 8, 9, EoT and 
FUp2
Human Chorionic Gonadotropin in the urine
Urinalysis should be performed by central laboratory only.  Local testing of urine should be 
avoided where possible, especially testing for urine glucose, as this could potentially unblind 
the investigator to treatment with empagliflozin.
In case qualitative urinalysis parameters are abnormal, a quantitative analysis will be 
performed by the central laboratory.
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. Changes in laboratory test results, if they are judged clinically relevant by 
the investigator, must be entered as adverse event(s). Minimum required safety lab 
parameters are listed in Table 5.2.3: 2.


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Table 5.2.3: 2 
Minimum required safety laboratory tests for local labs
Functional lab group
Test name 
Haematology
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelet count
Enzymes
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP)
Substrates
Creatinine
Urea Nitrogen
Total bilirubin  
Electrolytes
Sodium
Potassium
Chloride
Bicarbonate
Hormones
Serum cortisol (at Visit 5 pre- and post-dose, Visit 6, 
Visit 7, Visit 8, Visit 9, EOT)
Urine Pregnancy test (only for female participants of 
childbearing potential) at Visits 5, 8, 9, EoT and 
FUp2
Human Chorionic Gonadotropin in the urine
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flow Chart. 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. 
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.
5.2.5
Other safety parameters
5.2.5.1
ACTH challenge test
An ACTH challenge test will be performed for all patients at screening to ensure patients 
have normal adrenal function. 
An ACTH Challenge test will also be performed during the study:

between the start of BI 690517 / matching placebo treatment at Visit 5 and end of BI 
690517 / placebo treatment, if the morning serum cortisol level is ≥ 3 µg/dL (82.8


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nmol/L) and < 11 µg/dL (303.5 nmol/L) and the patient shows suggestive signs or 
symptoms of adrenal insufficiency (see section 4.2.1.3), and

after the end of BI 690517 / matching placebo treatment (either at EoT, or when BI 
690517 / placebo is prematurely permanently discontinued), if the morning serum 
cortisol level is < 18 µg/dL (496.6 nmol/L).
In these cases, the ACTH Challenge test should be performed as soon as possible.
A serum cortisol basal sample must be taken before the ACTH injection (iv or im 0.25 mg 
Synacthen®; an equivalent product may be used if Synacthen® is not authorised locally or 
provided by the sponsor). The injection time must be recorded. Serum cortisol will be 
determined 30 (±5) minutes after the injection. The time for the post-ACTH injection blood 
samples must be recorded. The ACTH Challenge test can be performed by a local or central 
laboratory.
Patients will be monitored closely for at least 30 minutes after the injection.
Alternative conduct of the ACTH test is allowed only if it is in accordance with the local 
practice of diagnosis of adrenal insufficiency. If adrenal insufficiency is diagnosed with an 
alternative conduct of ACTH test, the details of the ACTH test should be documented in the 
AESI report to the sponsor.
In this trial, the Synacthen® (or equivalent product) for the ACTH challenge test is 
considered as auxiliary medicinal product (AxMP).  In some countries, however, (for 
example, Germany) it is considered as investigational medicinal product (IMP) for regulatory 
reasons. For a more detailed description of Synacthen® please refer to the current Summary 
of Product Characteristics (SmPC).
5.2.5.2
eGFR
eGFR will be analysed and calculated by the central laboratory at the timepoints indicated in 
the Flow Chart. 
eGFR will be calculated by using the CKD-EPI formula (see section 10.2)
5.2.5.3
Urinary free cortisol
24-hour urine will be collected by the patient in containers before visits indicated in the FMV 
and 24-hour Urine Sampling Flowchart. Details of urine collection, processing and shipment 
will be provided in the Lab Manual. The patient will be given instructions and containers to 
collect the urine.  The concentration of urinary free cortisol will be measured in the urine by the 
central laboratory. 


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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
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,
-
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.


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5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency 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:
1) Potential Severe DILI
2) Events leading to lower limb amputation (LLA)
3) Ketoacidosis
4) Cushing’s syndrome
5) Adrenal insufficiency
Potential Severe DILI
A potential severe Drug Induced Liver Injury (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 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 after the start of study treatment need to be followed up according to the “DILI 
checklist” provided in the eDC system. 


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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.
Events leading to lower limb amputation (LLA)
Any event leading to a lower limb procedure of amputation, auto-amputation or disarticulation 
as defined below is considered as an AESI.
Amputation is a resection of a limb through a bone. Disarticulation is a resection of a limb 
through a joint. Auto-amputation is a spontaneous separation of non-viable portion of the 
lower limb.
Not included in this definition are debridement (removal of callus or dead tissue), procedures 
on a stump (like stump revision, drainage of an abscess, wound revision etc.) and other 
procedures (e.g., nail resection or removal) without a concomitant resection of a limb 
(amputation or disarticulation). (International Working Group of Diabetic Foot, 2015).
Each lower limb amputation, disarticulation, or auto-amputation should be reported separately. 
The SAE report should include the date of the procedure, the level of amputation or 
disarticulation, the medical condition(s) leading to the procedure and if the patient had some of 
the known risk factor(s) for lower limb amputation.
Ketoacidosis
If metabolic acidosis, ketoacidosis or DKA is suspected further investigations should be
done according to medical judgement and the clinical course until a diagnosis is made 
and/or the patient is recovered.
Due to its mechanism of action, empagliflozin may potentially modify the clinical
presentation of ketoacidosis which may occur at lower plasma glucose levels in patients 
with DM and potentially also in non-diabetic patient population. The diagnosis of
ketoacidosis in these patients can be based on arterial pH ≤ 7.30, serum bicarbonate levels
< 15mmol/L and measurement of serum beta-hydroxybutrate levels. Other diagnostic 
criteria which can support the diagnosis of ketoacidosis are urine ketones and anion gap
>10mmol/L.
Investigators should note that not all criteria mentioned above need to apply for the 
diagnosis of ketoacidosis, and clinical judgment should also be taken into consideration.
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.


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5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound (BI 690517 / empagliflozin / placebo), 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 trial drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the trial 
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.

There is an 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.


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•
After follow-up-visit 1 until the individual patient’s end of trial:
cancers of new histology and exacerbations of existing cancer, all trial drug related SAEs 
and all trial drug 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 drug related SAEs and trial drug 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 AE and SAE eCRF pages immediately (within 24 hours) of 
becoming aware of the event. 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 the AE and SAE eCRF pages.
With receipt of any further information to these events, the SAE eCRF page(s) has to be 
updated. 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.
In exceptional cases when the EDC is unavailable for longer than 24 hours, the following 
applies:
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
existing SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s
unique entry point (country specific contact details will be provided in the ISF).
Once the EDC is available again, information from the BI SAE form should be entered in the 
applicable eCRF pages.
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 


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Form for Clinical Studies (Part B).  The ISF will contain the Pregnancy Monitoring Form for 
Clinical 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 Clinical 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.
5.2.6.2.4
Safety monitoring and adverse events with additional information collection
Additional details (on top of standard AE and SAE reporting) will be collected in the eCRF 
for the adverse events: 

Acute Kidney Injury (see section 3.3.3 for definition of AKI),

Adrenal insufficiency,

Hyperkalaemia, 

Hypotensive event, 

Hypoglycaemic event, 

Events leading to lower limb amputation (LLA),

Ketoacidosis/ metabolic acidosis,

Bone fractures.


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5.4
ASSESSMENT OF BIOMARKER(S)
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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5.4.1.1
Method and timing of sample collection
Urine – exploratory biomarkers
Urine samples for exploratory biomarkers will be taken from the urine sample collected for 
safety at the timepoints shown in the Flow Chart.
Plasma aldosterone and cortisol and their precursors
Blood will be drawn into a K-EDTA blood collection tube at multiple time points as 
indicated in the PK and aldosterone profile Flow Chart.
Plasma
Blood will be drawn into a K-EDTA blood collection tube at the time points indicated in the 
Flow Chart.
Serum
Blood will be drawn into a serum separation tube at the time points indicated in the Flow 
Chart.
All urine, plasma and serum samples remaining at the end of the study will be destroyed no 
later than the sign-off of the separate biomarker report no more than two years after the last 
patient has completed the trial.
Detailed instructions for biomarker sampling, including handling and shipment of samples 
will be provided in the laboratory manual in the ISF.
5.4.2
Pharmacogenomic biomarkers
Pharmacogenomics investigates genetic variations to explain and to predict an individual’s 
response to drugs. Therefore, a blood sample for pharmacogenomic testing will be taken from 
each participant. In case of unexplainable variability in aldosterone level or of PK or PD 
parameters, DNA may be extracted from these samples and used for exploratory analysis of 
variants of the aldosterone synthase gene and genes involved in Absorption, Distribution, 
Metabolism and Excretion (ADME) of drugs. It is not intended to include these data in the 
final report. However, the data may be part of the report if necessary. All remaining samples 
will be discarded no later than 2 years after the last patient has completed the trial.
Detailed instructions for pharmacogenomics sampling, including handling and shipment of 
samples will be provided in the laboratory manual in the ISF.
5.4.2.1
Method of sample collection
One blood sample will be taken from an arm vein in a PAXgene blood DNA drawing tube at 
the time point indicated in the Flow Chart.


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5.4.2.2
Analytical determinations
Genomic DNA will be extracted from blood samples according to standard molecular 
genetics methods and analysed by Drug Metabolism Enzymes and Transporters (DMETTM) 
analysis or other standard genotyping technologies.
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.
In some countries, for example China, biobanking samples will not be collected due to 
regulatory reasons.
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 after tubes for exploratory biomarkers (see section 5.4.1) 
have been filled. The urine will be taken from the urine sample collected for safety.
As no genetic testing is planned, no dedicated sample will be taken for the analysis of DNA 
and no DNA will be extracted from any of the biobanking sampled described above.
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 empagliflozin and BI 690517 in an appropriate way.


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The scheduled measurements are appropriate to assess drug induced changes in kidney 
function with regards 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 
kidney 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.
 
Therefore, the appropriateness of all measurements applied in this trial is given.
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All visits should be scheduled according to the Flow Chart. Each visit date in the Randomised 
Run-in Period (with its window) is to be counted from Day -56 (first randomisation). All 
visits in the Treatment Period and Follow-up Period are to be counted from Day 1 (second 
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 
time windows.
All trial visits should be initiated preferentially in the morning. Patients should be instructed 
to not take their dose of the study medication at home in the morning of 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 
 From the first
 
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.
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue 
methodology which may include but will not be limited to virtual (remote) patient visits and 
assessments, home healthcare nurse visits, and direct-to-patient shipments of trial treatment. 
Such alternative measures will be mentioned in the patient information leaflet. The 
implementation of these measures will depend on patient’s consent, operational feasibility, 


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local law and regulations. If alternative methodology is implemented, the deviations from the 
original plan will be precisely documented.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study measurements and assessments should be performed according to the Flow Chart. All 
assessments should be performed before study drug administration, with the exception of the 
post-dose PK and aldosterone profile samples.
Where the following assessments occur at a visit they should be performed in the following 
order:
Vital signs 
ECG 
Blood draws including trough PK and plasma aldosterone – other PK and plasma aldosterone
samples are drawn after drug administration (see PK and aldosterone Flow Chart). Post dose-
serum cortisol at Visit 5 is also drawn after drug administration.
There will be home sampling without a visit at Week -4 (‘Visit’ 3.1 during Randomised Run-
in), Weeks 12 and 13 (‘Visits’ 9.1 and 9.2 respectively, during the Treatment Period), and at 
Weeks 16 and 17 (‘Visits’ FUp1.1 and FUp1.2 respectively, during the Follow-up Period). 
The patient will be required to collect urine samples for UACR over two consecutive days 
according to the FMV and 24-hour Urine Sampling Flow Chart at these times.
In this study the following visits may be performed as Telemedicine Contacts and Home 
Visits if all local approvals are in place. These contacts are used to help support patients with 
protocol procedures and compliance (see section 6.2.1 and 6.2.2):

Telemedicine Contact: Visit 3 

Home Visits: Visits 4, 6, 9, FUp2
All other visits must be performed at the Investigational Site. The only exception to this is in 
the event of force majeure or other disrupting circumstances where physical patient visits to 
the sites may not be feasible or may need to be restricted to ensure patient safety. Based on a 
thorough assessment of the benefits and risks, the following visits may be performed at the 
patient’s home or remotely, e.g. via telephone and/or internet-based means of 
communication:

Visit 2 (first randomisation) – may be performed as a home visit only

Visit 5 (second randomisation) – may be performed as a home visit only

Visits 7 and 8 (Treatment Period) – may be performed as a home and/or remote visit

EoT – may be performed as a home and/or remote visit

FUp1 – may be performed as a home and/or remote visit
Where Visit 2 and/or Visit 5 are conducted as a home visit, eligibility assessment and 
randomisation must be performed prior to the visit to allow time for the study medication to 
be shipped to the patient’s home.
All deviations from the original schedule of visits and procedures will be documented and the 
implications considered for the analysis of the trial data. 


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If blood sampling for central lab at the trial site is not possible, 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. Minimum required 
safety lab parameters are listed in table 5.2.3:2 . Urine pregnancy tests (for women of 
childbearing potential only, where required according to the Flow Chart) may be done at 
local lab / local doctor, or at home.  
In the event of elevated potassium > 5 mmol/L, if the patient is unable or unwilling to return 
to the investigational site, the BI 690517 or matching placebo should be temporarily 
interrupted until the patient can return to the investigational site.
If remote visits and/or lab assessments cannot be performed within the time window for the 
visit, or if patient safety cannot be guaranteed, all randomised study medication needs to be 
interrupted until the visit and lab assessments can be conducted.
6.2.1
Telemedicine Contacts
Telemedicine contacts may be via a straightforward phone call between the patient and an 
appropriately qualified member of the Investigational Site or via a video call. They 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. 
In the event of force majeure or other disrupting circumstances, where a patient is not able or 
willing to come to the site for a trial visit, the following assessments can be done remotely: 
collect and assess adverse events, concomitant therapies, assess trial medication compliance 
and review safety laboratory results.
6.2.2
Home Visits
Home visits (i.e. by a nurse or physician) 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. They may be performed at the visits
indicated in the Flow Chart, unless the patient prefers to attend the Investigational Site for the 
visit.
To support visits performed at the patient’s home, direct shipment of the trial medication will 
be managed by the site directly, for example via a courier, as permitted by local regulations.
All unused trial medication from the previous visit(s), including empty package material, will 
be shipped from the patient’s home to the site via courier. If needed, the laboratory kits and 
ancillary materials required by the nurse may also be shipped to the patient prior to the visit.
Where country regulations allow, samples taken at home will be shipped from the patient’s 
home to a central laboratory for analysis. Where this is not possible alternative arrangements 
will be made, e.g. samples taken to the investigational site.


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If the patient reports an AE during these home visits, then it is at the discretion of the 
Investigator as to whether a telemedicine contact is needed to support this assessment or even 
if the patient should attend the site.
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 and 
should be reviewed by an investigator.
In the event of force majeure or other disrupting circumstances, where a patient is not able or 
willing to come to the site for a trial visit, the following assessments can be done at the 
patient’s home: collection of blood and urine samples to be sent to the central lab, vital signs, 
weight, collection and review of paper diaries, collection of adverse events and concomitant 
therapies, assessment of trial medication compliance.
6.2.3
Screening and run-in period(s)
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. The 
patient should be recorded on the enrollment log and be registered in the IRT system as a 
screened patient before any other activities are performed. The screening period begins once 
the first screening procedure has been performed. Patients who do not start the Randomised 
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. 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.
During the screening visit, demographics information will be collected. This includes:

age on the day of informed consent (in years)

Sex (male, female in order to describe the participant`s sex at birth), 

For women: confirmation of childbearing potential in order to characterise the patient 
population and as a basis for contraception requirements 

Ethnicity and race in order to sufficiently characterise the patient population, to 
support possible subgroup analyses if needed and to support the calculation of the 
kidney function via the CKD EPI formula, unless not acceptable according to local 
regulations.
Randomised Run-in Period
The Randomised Run-in Period is 8 weeks. At the start of this period, patients will be 
randomised to receive empagliflozin or matching placebo. All visit procedures should be 
completed as indicated in the Flow Chart.


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6.2.4
Treatment period(s)
The Treatment Period is 14 weeks. During this period, patients will receive one of three doses 
of BI 690517 or placebo, in combination with Empagliflozin or matching placebo assigned 
during the run-in period. All visit procedures should be completed as indicated in the Flow 
Chart.
6.2.5
Early discontinuation of Treatment
Patients who discontinue empagliflozin/placebo prematurely during the Run-In Period and 
who do not withdraw their informed consent; and patients who discontinue both 
empagliflozin/placebo and BI 690517/placebo during the Treatment Period and who do not 
withdraw their informed consent, should return for an End of Treatment (EoT) visit.
If the patient prematurely discontinues empagliflozin/placebo during the Run-In Period:

If the patient has stopped taking empagliflozin/placebo the day of a scheduled visit or 
one day prior, the scheduled visit should be performed as an EoT Visit. Empagliflozin 
PK and safety samples should be collected. Biomarker, BI 690517 PK, aldosterone
and optional biobanking samples do not need to be collected.

If early discontinuation does not coincide with a scheduled visit, the patient should 
return for an EOT visit.  PK, aldosterone, biomarker and optional biobanking samples 
do not need to be collected, but all safety assessments must be performed as indicated 
in the Flow Chart.

The 24-hour urine sample prior to EOT does not need to be collected.
If the patient prematurely discontinues empagliflozin/placebo and BI 690517/placebo during 
the Treatment Period:

If the patient has stopped taking trial drugs the day of a scheduled visit or one day 
prior, the scheduled visit should be performed as an EoT Visit. All samples including 
PK, aldosterone profile and all biomarkers 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, aldosterone, biomarker and optional biobanking samples 
do not need to be collected, but all safety assessments must be performed as indicated 
in the Flow Chart.
After the EoT visit, all patients will start the off-treatment Follow-up Period (see section 
5.2.6).
6.2.6
Follow-up period and trial completion
The Follow-up Period is 4 weeks and consists of two visits, FUp1 and FUp2, with two
intermediate home sampling timepoints. Please see the Flow Chart for timelines and visit 
details.  No study medication is taken during the Follow-up Period.


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The Residual Effect Period (REP) in this study is 7 days, therefore visit FUp1 should be 
performed no earlier than 7 days after the End of Treatment Visit.
Other follow up visits and assessments should be scheduled relative to the EoT visit i.e., there 
will be home sampling without visit at 2 weeks and 3 weeks after EoT, and FUp2 should be 4 
weeks after EoT.
Patients who prematurely discontinue during the Run-In Period should have FUp1 as a 
minimum. Patients randomised to the Treatment Period should be encouraged to complete all 
visits and procedures in the FUp period. If the patient does not wish to complete all visits or 
procedures, they should have FUp1 as a minimum.
For patients who prematurely discontinue during the Run-In Period, aldosterone samples do 
not need to be taken at FUp1 or FUp2.
For patients who have not had 
 
collected at EOT, these samples do not need to be taken at FUp1 and/or FUp2.
Participation in this trial is concluded once FUp2 has been completed. Additional visits may 
be scheduled for continued safety monitoring after the FUp2 visit if needed in the opinion of 
the investigator. Abnormal assessments or lab values judged clinically relevant by the 
investigator will be monitored until they return to a medically acceptable level. 
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
In this study, the primary endpoint is the change from baseline in log transformed UACR 
measured in First Morning Void urine after 14 weeks. The purpose of this trial is to 
demonstrate clinical activity of BI 690517 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 3 groups of patients with BI 690517 
and placebo. In addition, MCPMod will be used to characterise the BI 690517 dose-response 
relationship separately in (1) patients on a background medication of placebo, and (2) on 
background medication of empagliflozin.
Dose effects will be assessed separately on each background therapy because both 
empagliflozin and BI 690517 have a haemodynamic effect which leads to an acute eGFR 
decrease. It will be important to assess the effects of both drugs alone, and in combination 
with a staggered treatment initiation.


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7.1
NULL AND ALTERNATIVE HYPOTHESES
For the primary endpoint, the null hypothesis is that the dose-response curve is flat across the 
3 BI 690517 doses and the placebo, whereas the alternative hypothesis of a non-flat dose-
response curve indicates a clinical benefit of BI 690517 in at least one of the doses. The null 
hypothesis of a flat dose-response curve across the 3 BI 690517 doses and the placebo will be 
assessed in the following order: (1) in all patients (regardless of background therapy), (2) in 
patients on a background medication of placebo, and (3) on background medication of 
empagliflozin.
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, while protecting the overall probability of Type I error (one-sided α of 5%, 
which corresponds to two-sided α of 10%). The pre-specified models and their parameters 
used for this test will be outlined in section 7.2.3.
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 disposition.
Randomised Set (RS): This patient set includes all entered and randomised patients based on 
the treatment groups they were randomised to at the randomisation prior to the Treatment 
Period, regardless of being treated by BI 690517 or not. 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 BI 
690517 or matching placebo. The TS is based on actual treatment patients have received and 
will be used for safety analyses.
Full Analysis Set (FAS): This patient set includes all randomised patients who had at least 
one baseline measurement of UACR at week 6, 7, or 8 and at least one post-baseline 
measurement. The FAS will be the main analysis set for the analysis of efficacy.
The pharmacokinetic set (PKS): This patient set includes all patients in the TS who provided 
at least one PK parameter that was not excluded because of protocol deviations relevant to 
the statistical evaluation of PK endpoints as defined in section 5.3.
Further analysis sets will be defined in the TSAP, if needed.


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7.2.2
Handling of Intercurrent Events
The expected intercurrent events of interest in this trial are restricted to the Treatment Period 
and are defined as:

Premature treatment discontinuation of BI 690517

Down-titration of BI 690517

Use of SGLT2i as concomitant medication 

Death
The strategies for handling intercurrent events in this trial are summarised in Table 7.2.2: 1.
Table 7.2.2: 1 Summary of strategies for handling intercurrent events
Estimand strategy 
Treatment
Intercurrent event handling
Primary
Randomised 
treatment
- BI 690517discontinuation:  include data prior to 
study medication discontinuation
- Down-titration of BI 690517: include data prior 
to down-titration
- Death: include data prior to death
- Use of SGLT2i: include all available data 
Supplementary 1
Randomised 
treatment
- BI 690517discontinuation: include all available 
data
- Down-titration of BI 690517: include all available 
data 
- Death: include data prior to death
- Use of SGLT2i: include all available data
The primary approach will include all data prior to the intercurrent event, so any data 
collected after the intercurrent event will be excluded from the primary analysis except for 
the use of SGLT2i as concomitant medication. Patients will be analysed according to their 
randomised treatment. The analysis period for the primary approach starts from 
randomisation to the Treatment Period until either intercurrent event or EoT at week 14, 
whichever comes first. This approach is analogous to a hypothetical approach with respect to 
BI 690517.
Supplementary 1 approach will include all data collected even after intercurrent event, except 
for death. Every attempt will be made to follow up with patients who discontinue treatment 
prematurely until the end of their planned study participation. Patients will be analysed 
according to their randomised treatment. The analysis period for the supplementary 1 
approach starts from randomisation to the Treatment Period until EoT at week 14. This 
approach is analogous to the treatment policy approach.
Handling of intercurrent events that are not listed will be decided by blinded review based on 
the general principle outlined and will be documented in the TSAP.


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7.2.3
Primary objective analyses
The primary objectives are to demonstrate a non-flat dose response curve, quantify the 
treatment effect, and evaluate the dose-response relationship. The primary analysis will be 
performed on the FAS.
For dose finding, multiple comparison procedures and modelling techniques (MCPMod) will 
be applied. The primary estimand of interest is the treatment effect using the primary 
approach (Table 7.2.2: 1). 
Treatment effect
The primary analysis will first address a dose-response relationship between doses of BI 
690517 and placebo by adopting an MMRM in groups testing the treatment of BI 690517.
Reduction in log transformed UACR from baseline will be used as the response variable in 
the MMRM. 
This model will include fixed effect of treatment at each visit as categorical variable, and 
fixed effect of log transformed baseline UACR at each visit as continuous variable. Visit will 
be treated as repeated measure with an unstructured covariance structure for the within-
patient variability.
Statistical model (MMRM):
	 =  + 	 +  + ,
where
~(0, Σ),
	 = reduction in log transformed UACR from baseline for participant  at visit  in 
stratum  receiving dose level  on background therapy , 
 = the baseline* measurement of log transformed UACR of participant i,
= coefficient of baseline effect at visit ,
	 = the effect of dose level  at visit  on background therapy ,
 = the effect of stratum l for having diabetic kidney disease or not, 
 = the random error associated with the th visit of the th participant. Errors are 
independent between participants,
Σ = an unstructured covariance matrix.
*: baseline is defined as the mean of all non-missing assessments at weeks -2, -1, and 0 prior to the 
treatment period.
The estimates will be produced for each background therapy separately, and for all patients 
combined. For the combined analysis, the individual estimates are weighted by the number of 
patients randomised at the second randomisation. To perform multiple comparison in the 
MCPMod across doses, predicted average response for each dose group and the standard 
errors from the MMRM will be used for the MCPMod analysis. The MCPMod analysis will 
be run for each background therapy and for all patients combined (three times in total).


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A non-flat dose-response relationship is established if for the primary endpoint, the null 
hypothesis of no dose effect (i.e., a flat dose-response curve) is rejected for at least one of the 
pre-specified dose-response models with respect to the one-sided type I error at 5% after 
multiple comparisons adjustment. 
Dose finding
The second primary objective is to determine the therapeutic dose. The trial will characterise 
the dose-response curve for BI 690517 by assessing 3 doses and placebo. The response is the 
change from baseline in log transformed UACR measured in First Morning Void urine after 
14 weeks of treatment with BI 690517 or matching placebo. Patients will be evaluated by 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 efficacy is established, the statistically significant (best 
fitting) model(s) from the candidate set will be 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 20 mg, total daily dose) will be considered.
7.2.3.3
Supplementary Analyses
Supplementary analyses will be conducted for the primary endpoint using the Supplementary 
1 estimand strategy.


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7.2.4
Secondary objective analyses
Descriptive statistics will be provided for the proportion of patients responding to UACR. An 
adjusted multiple imputation method will be used for missing UACR measurements, after 
which the response variables will be determined. As a sensitivity analysis, patients missing 
Week 14 data will be imputed as non-responders.
All secondary endpoints will be displayed for all patients and with each background 
medication separately.  
7.2.6
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 based on their actual treatments. In 
general, safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’. Adverse events will be summarised by the 
treatment at which the subject was randomised, and the treatment at the onset of AE for the 
drug-related AE. 
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Summary of participants with down-titration due to AE will be provided separately. Adverse 
event of special interest (AESI) and other specific AEs with collection of additional 
information in the eCRF (which include hyperkalaemia) will be summarised as well. 
Analysis of serum potassium will further include change from baseline, the incidence of 
serum potassium levels of 5.6 mmol/L or higher and higher than 6.0 mmol/L.


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Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Further details will be provided in the TSAP.
7.2.7
Other Analyses
Details on the further analyses will be described in TSAP if needed.
7.2.8
Interim Analyses
No interim analysis is planned but a Data Monitoring Committee (DMC) will be in place 
with tasks as described in section 8.7.
7.3
HANDLING OF MISSING DATA
In the primary analysis of continuous endpoints, missing data will not be imputed. As a 
sensitivity analysis, missing UACR data will be imputed using an adjusted multiple 
imputation model (refer to Section 7.2.3.1).  Data from this multiple imputation will be used 
to compute responder endpoints.
Missing or incomplete AE dates will be imputed according to BI standards. Handling of 
missing data for secondary endpoints as well as for sensitivity analysis will be described in 
the TSAP.
Handling of missing PK data will be performed according to the relevant internal procedures. 
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.4
RANDOMISATION
BI will arrange for the creation of the randomisation scheme and the packaging and labelling 
of trial medication. Patients will be randomised to double-blind treatment. Approximately 
equal numbers of patients will be randomised to each treatment group. The randomisation list 
will be generated using a validated system, which involves a pseudo-random number 
generator so that the resulting randomisation scheme will be both reproducible and non-


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predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
In this study, patients will undergo a 2-step randomisation, with the first randomisation 
performed prior to the Randomised Run-in and the second randomisation performed prior to 
the Treatment Period. Patients must fulfil the criteria (as described in section 3.3.2) in order 
to be randomised into the Treatment Period.  In order to ensure a balance of patients between 
treatment groups, the trial will use stratified randomisation according to prognostic variables
eGFR (< 45 and ≥ 45 mL/min/1.73 m2), UACR (≤ 750 and >750 mg/g). At the first step, 
patients will be randomised to the treatment of empagliflozin or matching placebo in a 1:1 
ratio for 8 weeks. At the second step, patients will be randomised to the Treatment Period in a 
1:1:1:1 ratio for the treatment of 3 doses of BI 690517 (3 mg QD, 10 mg QD, and 20 mg QD) 
and matching placebo for 14 weeks, on the top of empagliflozin or matching placebo from 
the first randomisation. 
7.5
DETERMINATION OF SAMPLE SIZE
The sample size calculation is conducted assuming effect size of BI 690517 versus placebo, 
(0, 0.10, 0.20, 0.35) for (placebo, BI 690517 3 mg, BI 690517 10 mg, BI 690517 20 mg total 
daily dose) in log transformed UACR measured in morning void urine after 14 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 690517 3 mg, 10 mg, and 20 mg in terms of total daily dose.
Emax: 80% of the maximum effect is achieved at 10 mg.
Exponential: 15% of the maximum effect is achieved at 10 mg.
Linear: No assumption is needed.


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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 after 14 weeks in the Treatment Period (placebo, BI 690517 3 mg, BI 690517 10 mg, 
BI 690517 20 mg), the trial will have 89.7% power to detect a non-flat curve using MCPMod
considering one-sided 5% alpha with sample size of 60 patients per treatment arm (in patients 
randomised to placebo during the run-in period). 
In a scenario with assumed effect of (0, 0.10, 0.16, 0.22) in log (UACR) change from 
baseline after 14 weeks in the Treatment Period (placebo, BI 690517 3 mg, BI 690517 10 mg, 
BI 690517 20 mg), the trial will have 83.1% power to detect a non-flat curve using MCPMod 
considering one-sided 5% alpha with sample size of 120 patients per treatment arm (all 
patients combined).
The sample size/power calculation were determined based on 10,000 simulations for the 
scenario using R4.0.2. To achieve 60 patients per group (480 total patients), 552 patients will 
be randomised during the Run-in period to account for a dropout rate of at most 15% before 
the second randomisation.  A one-sided alpha of 5% will be used to keep the sample size 
reasonably low in this Phase 2 trial.  


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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. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
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. 


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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. 
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 participant protection and reliability of the results as 
well as identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, 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.


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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.
For the CRF, data must be derived from source documents, for example:

Patient identification: sex, 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 imaging or 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 and copies of printouts)

Source documentation for telemedicine visits

Source documentation for visits performed at the patient’s home

Historical kidney-related data
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 or delegate will also monitor compliance with the protocol and GCP.


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In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please 
see section 6), site access may be restricted thus limiting the ability to perform standard site 
monitoring activities on site such as on-site source data review and source data verification. 
Therefore, some of these activities may be performed remotely or replaced by centralised 
monitoring to the extent possible, based on a documented risk assessment and in alignment 
with local regulations.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
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 World Health 
Organisation (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


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
A fit for 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.
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) 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 


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(TMF). The tasks and responsibilities, including scientific input and operational oversight,
will be agreed in contracts between the SC members and the sponsor and also summarised in 
a SC charter.
A DMC will be established. Members of the DMC are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician. 
The DMC will evaluate safety data, in particular adverse events related to serum potassium,
PK data (organised according to eGFR stratification) and some efficacy data. The DMC will 
receive urgent significant safety concerns for immediate evaluation. While DMC members 
may be unblinded, measures are in place to ensure the blinding for everyone else involved in 
the trial. Regular DMC meetings will be held at specified intervals. The DMC will 
recommend continuation, modification or termination of the trial as detailed in the DMC 
charter. DMC recommendations as well as the final BI decision will be reported to the 
appropriate Regulatory Authorities (RAs) / Health Authorities (HAs), IRBs / ECs, and to 
investigators as requested by local law. The tasks and responsibilities of the DMC are 
specified in a 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 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.
In the participating countries the trial 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..
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 Central Laboratory Manual and IRT Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P15-00589
Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, 
Espadero RM, Woerle HJ, Broedl UC, Johansen OE; SGLT-2 inhibitors 
and cardiovascular risk: proposed pathways and review of ongoing outcome 
trials.  Diabetes and Vascular Disease Research, Published online before 
print January 14, 2015, doi: 10.1177/1479164114559852; 2015.
P15-09541
Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, 
Johansen; Effects of empagliflozin on blood pressure and markers of 
arterial stiffness and vascular resistance in patients with type 2 diabetes. 
Diabetes, Obesity and Metabolism, Accepted Article, Accepted manuscript 
online: 7 SEP 2015, doi: 10.1111/dom.12572; 2015. p. 1180-1193.
P16-06807
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, Eynatten M von, Mattheus 
M, et al, EMPA-REG OUTCOME Investigators; Empagliflozin and 
progression of kidney disease in type 2 diabetes. New England Journal of 
Medicine, published June 14, 2016, doi: 10.1056/NEJMoa1515920; 2016. 
p. 323-334
P18-10838
Herrington WG, Preiss D, Haynes R, Eynatten M von, Staplin 
N, Hauske SJ, et al, The potential for improving cardio-renal outcomes by 
sodium-glucose co-transporter-2 inhibition in people with chronic kidney 
disease: a rationale for the EMPA-KIDNEY study. Clinical Kidney Journal, 
Published: 25 October 2018, doi: 10.1093/ckj/sfy090; 2018. p. 746-761.
P20-09106
de Boer IH, Caramori L, Chan JCN, et al. KDIGO 2020 clinical practice 
guideline for diabetes management in chronic kidney disease. Kidney Int 
Suppl 2020. 98:S1-S115.
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.


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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.
R14-4475
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.
R15-5158
Wang Y, 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.
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.
R17-2439
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney 
Injury Work Group;  KIDGO clinical practice guideline for acute kidney 
injury.  Kidney Int Suppl 2012 ; 2(1) ; 1-138.
R19-0901
Levey AS, Coresh J. Chronic kidney disease. Lancet 2012; 379; 165-180.
R19-1184
Stel VS, Bruck K, Fraser S, Zoccali C, Massy ZA, Jager KJ. International 
differences in chronic kidney disease prevalence: a key public health and 
epidemiologic research issue. Nephrol Dial Transplant 2017 ; 32; II129-
II135.
R19-1356
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan 
DM, et al, CREDENCE Trial Investigators;  Canagliflozin and renal 
outcomes in type 2 diabetes and nephropathy.  New England Journal of 
Medicine, published on April 14, 2019, doi: 10.1056/NEJMoa1811744; 
2019. p. 2295-2306.
R19-1388
Hill NR, Fatoba ST, Oke JL, Hirst JA, O'Callaghan CA, Lasserson DS, et 
al. Global prevalence of chronic kidney disease - a systematic review and 
meta-analysis. Plos One 2016; 11(7); e0158765


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R20-3706
Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al, 
FIDELIO-DKD Investigators;  Effect of finerenone on chronic kidney 
disease outcomes in type 2 diabetes. New England Journal of Medicine, 
published online 23 Oct 2020, doi: 10.1056/NEJMoa2025845; 2020.
R21-1080
Heerspink HJL, Steffanson BV, Correa-Rotter R, Chertow GM, Greene T, 
Hou FF, et al, DAPA-CKD Trial Committees and Investigators; 
Dapagliflozin in patients with chronic kidney disease. New England Journal 
of Medicine 2020; 383(15); 1436-1446
9.2
UNPUBLISHED REFERENCES
c09064107
Investigator’s Brochure (IB) BI 690517 for Diabetic Nephropathy
c01678844
Investigator’s Brochure (IB) BI 10773 in type 2 diabetes mellitus, CHF, 
CKD and paediatric diabetes
10.
APPENDICES


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10.2
GFR CKD-EPI FORMULA
Calculation Name
GFR CKD-EPI
Formula
Units
Decimal Places
Conventional:
Black or African American formulas:
Female with a serum creatinine value of ≤0.7 mg/dL
mL/min/
1.73m²
0


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Calculation Name
GFR CKD-EPI
Formula
Units
Decimal Places
166 x (Serum Creatinine (mg/dL) / 0.7) -0.329 x (0.993)age
Female with a serum creatinine value of >0.7 mg/dL
166 x (Serum Creatinine (mg/dL) / 0.7) -1.209 x (0.993)age
Male with a serum creatinine value of ≤0.9 mg/dL
163 x (Serum Creatinine (mg/dL) / 0.9) -0.411 x (0.993)age
Male with a serum creatinine value of >0.9 mg/dL
163 x (Serum Creatinine (mg/dL) / 0.9) -1.209 x (0.993)age
White, American Indian, Alaska Native, Asian (except 
Japanese), Native Hawaiian, Other Pacific Islander, Other 
formulas:
Female with a serum creatinine value of ≤0.7 mg/dL
144 x (Serum Creatinine (mg/dL) / 0.7) -0.329 x (0.993)age
Female with a serum creatinine value of >0.7 mg/dL
144 x (Serum Creatinine (mg/dL) / 0.7) -1.209 x (0.993)age
Male with a serum creatinine value of ≤0.9 mg/dL
141 x (Serum Creatinine (mg/dL) / 0.9) -0.411 x (0.993)age
Male with a serum creatinine value of >0.9 mg/dL
141 x (Serum Creatinine (mg/dL) / 0.9) -1.209 x (0.993)age
Japanese Formula:
Female with a serum creatinine value of ≤0.7 mg/dL
0.813 x 144 x (Serum Creatinine (mg/dL) / 0.7) -0.329 x (0.993)age
Female with a serum creatinine value of >0.7 mg/dL
0.813 x 144 x (Serum Creatinine (mg/dL) / 0.7) -1.209 x (0.993)age
Male with a serum creatinine value of ≤0.9 mg/dL
0.813 x 141 x (Serum Creatinine (mg/dL) / 0.9) -0.411 x (0.993)age
Male with a serum creatinine value of >0.9 mg/dL
0.813 x 141 x (Serum Creatinine (mg/dL) / 0.9) -1.209 x (0.993)age
Creatinine in mg/dL is rounded to 2 decimal places prior to 
applying the formula.
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
mL/min/
1.73m²
0


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Calculation Name
GFR CKD-EPI
Formula
Units
Decimal Places
to 2 decimal places. This creatinine result will be used in
the GFR Conventional formulas listed above.
Limitations/Special 
Notes:
Age is truncated to a whole number prior to performing the calculation.
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of Amendment
25 October 2021
EudraCT number
2021-001434-19
BI Trial number
1378-0005
BI Investigational Medicinal 
Product(s)
BI 690517 and empagliflozin
Title of protocol
Randomised, double-blind, placebo-controlled and 
parallel dose group trial to investigate efficacy and 
safety of multiple doses of oral BI 690517 over 14 
weeks, alone and in combination with 
empagliflozin, in patients with diabetic and non-
diabetic chronic kidney disease
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Title page; Clinical Trial Protocol Synopsis
Description of change
Co-ordinating Investigator address and phone number 
updated. 
Rationale for change
Correction
Section to be changed
Flow Chart, FMV and 24-hour Urine Sampling Flow Chart, 
3.1
Description of change
Extended the maximum screening time window to first 
randomisation from 14 to 21 days throughout the protocol.
Rationale for change
More time is needed to allow screening procedures to be 
repeated where permitted and will give sufficient buffer for 
IMP to be delivered to the site. 
Section to be changed
Flow Chart


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Description of change
Addition of serum cortisol sample at Visit 1, pre and post 
dose Visit 5, Visit 6, Visit 7, Visit 8, Visit 9, EoT, FUp1 and 
FUp2.
Addition of ACTH Challenge Test (if required) at Visit 5, 
Visit 6, Visit 7, Visit 8, Visit 9 and EoT.
Addition of 24-hour urine samples at Visit 5 and EoT.
Added ‘and 24-hour urine’ to ‘Train the patient on FMV 
sampling’.
Addition of ‘Dispense urine container for 24-hour sampling’ 
at Visits 4 and 9.
Footnote 1: ACTH Challenge Test added as an example of a 
reason for additional visit.
Footnote 10: Clarification of when ACTH Challenge Test is 
required added. 
Footnote 14: added that lab samples for serum cortisol must 
be collected before 10am.
Footnote 15: added the timing of the post-dose serum 
cortisol sample relative to drug administration.
Footnote 22 (previously #20): Added requirement to collect 
start and stop times for 24-hour urine on paper diary.
Rationale for change
Serum cortisol samples added to detect and mitigate the 
potential risk of adrenal insufficiency.  
ACTH Challenge Test added (if required based on cortisol 
levels) to investigate potential adrenal insufficiency during 
the study.
24-hour urine samples collected to measure urinary free 
cortisol to determine whether BI 690517 may increase 
cortisol levels (Cushing’s syndrome). 24-hour urine 
collection times need to be recorded by the patient on a 
paper diary.
Section to be changed
Flowchart
Description of change
Footnote 19 (previously #17): added “More frequent 
pregnancy testing should be done if required by local 
regulation and /or authority or per investigator judgment.”


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Rationale for change
In some countries pregnancy testing is required more 
frequently.
Section to be changed
Flowchart
Description of change
The text in footnote 20 (previously #18) about pre-screening 
for UACR has been moved to footnote 2.  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 patients could potentially fail screening 
for this.  Allowing pre-screening for eGFR means fewer
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
Flowchart
Description of change
Addition of “post-dose” in the split column header of Visit 
5. 
Removal of plasma aldosterone sample at Visit 2, paper 
diary handout at Visit EoT and FUp1 and collection / review 
of paper diary at Visit FUp 1 and FUp2.
Footnote 4: added ‘all trial’ to the sentence ‘In case a patient 
needs or wishes to terminate [all trial] treatment 
prematurely…’
Footnote 3: added eGFR to potassium as another safety 
parameter that must be repeated in case of an unexpected 
delay of Visit 5.
Footnote 10: In the following sentence 'in the patient’s 
medical record' was added: The time for the post ACTH-
injection blood samples must be recorded in the patient’s 
medical record.
Rationale for change
Clarifications and corrections to ensure consistency with 
other sections of the protocol.  
eGFR and potassium are both critical parameters for start of 
treatment with BI 690517. 
There will be no requirement to record the time of post 
ACTH-injection blood samples taken in the clinical 
database, as there is no analysis done with it. Instead 
adherence to the protocol is going to be monitored by 
reviewing the medical records at the site.


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Section to be changed
FMV Sampling Flowchart
Description of change
Title changed to ‘FMV and 24-hour Urine Sampling 
Flowchart’
24-hour urine samples added at Visit 5 and EOT
Footnote 3: timepoints for 24-hour urine sample specified
Rationale for change
24-hour urine samples will be collected to measure urinary 
free cortisol to determine whether BI 690517 may increase 
cortisol levels. 
Section to be changed
 Flow Chart
Description of change
Corrected footnote 3: No aldosterone samples should be 
taken at FUp1 or FUp 2.
Rationale for change
Correction.
Section to be changed
1.2.1 BI 690517
Description of change
 
Rationale for change
Correction
Section to be changed
3.1 Overall Trial Design
Description of change
Removal of diabetes as a prognostic variable for 
stratification.
Rationale for change
This was erroneously left in the original protocol by mistake.  
A third stratification factor would result in too small strata 
and was therefore not further pursued. Instead for the 
purpose of classifying diabetic status patients with diabetes 
will be classed as having diabetic kidney disease
Section to be changed
3.1 Overall Trial Design
Description of change
The following sentence:
‘To decrease the burden on patients, where country 
regulations allow, samples taken at home between visits will 
be shipped from the patient’s home to a central laboratory 
for analysis.’
Was replaced by:
‘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 from the patient’s home to a 
central laboratory for analysis.’
The following sentence; 


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‘Patients with diabetes may have diabetic kidney disease, 
non-diabetic CKD aetiologies, or a combination; for the 
purpose of stratification, they will be classed as having 
diabetic kidney disease’.
Was replaced by:
‘Patients with diabetes may have diabetic kidney disease, 
non-diabetic CKD aetiologies, or a combination; for the 
purpose of categorising diabetic status, they will be 
classified as having diabetic kidney disease’.
Rationale for change
Clarifications
Section to be changed
3.1 Overall Trial Design
Description of change
24-hour urine samples added at Visit 5 and EOT
Rationale for change
24-hour urine samples will be collected to measure urinary 
free cortisol to determine whether BI 690517 may increase 
cortisol levels.
Section to be changed
3.2 Discussion of Trial Design
Description of change
Measures to detect and mitigate the potential risk of adrenal 
insufficiency and Cushing’s syndrome added.
Rationale for change
BI 690517 has the potential to affect cortisol levels so these 
measures are required to mitigate any risks.
Section to be changed
3.3.2 Inclusion criteria and Clinical Trial Protocol Synopsis
Description of change
Added ‘of legal adult age (according to local legislation)’ to 
inclusion criterion 2.
Rationale for change
Clarification that patients must be the legal age of consent as 
well as 18 or over to enter the trial
Section to be changed
3.3.2 Inclusion criteria
Description of change
Re-numbering of additional Inclusion criteria assessed prior 
to second randomisation from 1. and 2. to 13. and 14.
Rationale for change
To enable all inclusion criteria to be distinct in trial systems.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Added “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.” to exclusion criterion #2
Rationale for change
To ensure patients don’t go into the trial if they need to take 
a restricted medication.
Section to be changed
3.3.3 Exclusion criteria


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Description of change
Addition of exclusion criterion number 6: Treatment with 
biotin (Vitamin B7, Vitamin H, or coenzyme R) at daily 
doses ≥ 5 mg (including food supplements) within 72 hours 
of Visit 1 or planned during the trial.  
Rationale for change
Intake of higher biotin doses has an influence on certain lab 
results and may display false results, e.g. for serum 
pregnancy tests and some hormone tests.
Section to be changed
3.3.3 Exclusion criteria
Description of change
For exclusion criterion 7 (previously #6), instead of an 
increase in serum cortisol of 200 nmol/L at 30 minutes post-
injection, an absolute cortisol value of < 18 µg/dL (496.6
nmol/L) will be used as the diagnostic threshold for adrenal 
insufficiency.
Rationale for change
ACTH Challenge test to be performed in accordance with 
the Cosyntropin label and current U.S. guidelines, where the
threshold for exclusion of adrenal insufficiency should be an
absolute cortisol value of >18 µg/dL 30 minutes post-
injection.
Both conventional and SI units are specified to align with 
central laboratory reporting.
Section to be changed
3.3.3 Exclusion criteria
Description of change
For exclusion criterion 10 (previously #9), ‘Serum cortisol < 
5 µg/dL (138.0 nmol/L)’ added to ‘Any clinical significant 
laboratory abnormality’.
Rationale for change
Patients with serum cortisol < 5 µg/dL are at greater risk of 
adrenal insufficiency and should not be included in the trial.
Section to be changed
3.3.3 Exclusion criteria
Description of change
For exclusion criterion 16 (previously #15), ‘at the time of 
screening’ added to ‘Any documented active or suspected 
malignancy’ and ‘confirmed’ added to ‘history of confirmed 
malignancy within two years prior to Visit 1.’
Rationale for change
To clarify that the suspected malignancy is at the time of 
screening and not within two years prior to Visit 1, and that 
any history of malignancy is confirmed.
Section to be changed
3.3.3 Exclusion criteria and 4.2.2.1 Restrictions 
Description of change
For exclusion criterion 21 (previously #20), removal of ‘for 
an oral agent which is not specified in any other exclusion 
criteria, or less that 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 tables in section 4.2.2.’


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‘Biologics are not permitted within 12 months prior to visit 
1’ also removed from Concomitant medication Restrictions 
table 4.2.2.1: 1.
Rationale for change
It is not necessary to exclude patients who were on a trial for 
a biological agent more than 30 days, up to 12 months, prior 
to Visit 1.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Footnote 4 Definition of AKI according to KDIGO changed 
from 
‘Increase in serum creatinine to ≥ 1.5 times, which is known 
or presumed to have occurred within the prior 7 days’ to 
‘Increase in serum creatinine to ≥ 1.5 times baseline, which 
is known or presumed to have occurred within the prior 7 
days’
Rationale for change
The word ‘baseline’ was omitted in error
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
An individual patient will permanently discontinue all 
randomised trial treatment if:
1. The patient develops Acute Kidney Injury as per 
clinical judgement by the investigator and/or 
according to the Kidney Disease: Improving Global 
Outcomes (KDIGO) definition [R17-2439] (see 
section 3.3.3).
was changed to:
The patient develops Acute Kidney Injury as per 
clinical judgement by the investigator. The Kidney 
Disease: Improving Global Outcomes (KDIGO) 
definition [R17-2439] (see section 3.3.3) should be 
used for guidance.
Rationale for change
The definition of AKI according to KDIGO cannot always 
be applied in an outpatient setting, therefore AKI should be 
primarily judged by the investigator based on clinical 
presentation, and KDIGO can be used for guidance.
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
Added patients who develop Cushing’s syndrome, adrenal 
insufficiency (including cortisol level <18 µg/dL 30 min (±5 
min) after ACTH application), or cortisol levels <3 µg/dL 
(82.8 nmol/L) at any point in the trial should be withdrawn 
permanently from BI 690517 / placebo.
Added requirement to permanently discontinue patients who 
permanently discontinue empagliflozin/placebo during the 
randomised run-in period.


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Rationale for change
Cortisol levels added to detect and mitigate the potential risk 
of adrenal insufficiency or Cushing’s syndrome.
Patients will only be eligible to receive BI 690517/placebo if 
they continue to receive empagliflozin/placebo. If one of the 
study medications (either empagliflozin/placebo or BI 
690517/placebo) is permanently discontinued during the 
Treatment Period / after the second randomisation at Visit 5, 
the patient may continue to receive treatment with the other 
study medication.
Section to be changed
4.1.4 Drug assignment and administration of doses for each 
patient
Description of change
Added the following statement: ‘Shipment of trial 
medication from the site to the patient’s home will also be 
allowed to support regular visits performed at the patient’s 
home.’
Rationale for change
IMP shipments to the patient’s home are required to allow 
for home health care visits as permitted by the Flow Chart.
Section to be changed
4.2.1.1 Management of serum potassium elevation
Description of change
Added ‘episode of’ to the following sentence:
For any episode of increased potassium level above 5.0 
mmol/L, a clinical evaluation should be performed to make 
individual treatment decisions if a prompt intervention is 
required.
Rationale for change
Clarified that the rules set forth in this section apply for any 
episode of hyperkalemia and may apply more than once per 
patient.
Section to be changed
4.2.1.2 Management of eGFR decrease
Description of change
New section
Rationale for change
Further eGFR monitoring is required after the start of the 
double-blinded treatment with BI 690517 / placebo, if the 
eGFR decreases by >15% since the last visit. The decision 
about continuing or discontinuation of the study drug should 
be based on the criteria specified in section 3.3.4.1 and the 
overall assessment of the patient’s status. 
Section to be changed
4.2.1.3 Management of serum cortisol decrease
Description of change
New section added
Rationale for change
If a patient’s serum cortisol level is ≥ 3 µg/dL (82.8 nmol/L) 
and < 11 µg/dL (303.5 nmol/L), an ACTH test should be 
performed. If cortisol levels are < 3 µg/dL (82.8 nmol/L) 
patient should be withdrawn. This is to detect and mitigate 
the potential risk of adrenal insufficiency.


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Section to be changed
4.2.2.1 Restrictions regarding concomitant treatment
Description of change
Rationale for change
Section to be changed
4.2.2.1 Restrictions regarding concomitant treatment
Description of change
Footnotes were added to the table to provide further 
guidance about action to be taken with trial medication if 
concomitant medications that are not permitted are taken 
during the study.
Rationale for change
Clarification that temporary concomitant use of medications 
that are not permitted do not necessarily mean that all study 
medication must be discontinued permanently. 
Section to be changed
4.2.2.3
Description of change
The following sentence has been removed: No contraceptive 
is required for the WOCBP participant’s partner.
Rationale for change
This sentence could be misleading since the female 
participant must use a barrier method of contraception (as 
well as a non-barrier method).
Section to be changed
5.1.1 UACR
Description of change
The following sentence has been removed: ‘Urinary 
creatinine may also be used for normalisation of exploratory 
urinary biomarkers (see section 5.4.1).’
Rationale for change
The additional evaluations originally mentioned will not 
apply in this trial.
Section to be changed
5.2.3 Safety laboratory parameters
Description of change
Removed total from Neutrophils and removed Lymphocyts 
total.
Rationale for change
Corrections as these were duplications. Relative and absolute 
WBC differentials already mentioned in the first column.
Section to be changed
5.2.3 Safety laboratory parameters
Description of change
Added serum cortisol to the list of hormones to be tested
Rationale for change
Serum cortisol added to detect and mitigate the potential risk 
of adrenal insufficiency.
Section to be changed
5.2.3 Safety laboratory parameters


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Description of change
Added clarification of why a safety laboratory may not be 
done at the central lab and that table 5.2.3:1 applies for local 
labs required in such cases.
Rationale for change
Clarifications
Section to be changed
5.2.5.1 ACTH Challenge Test
Description of change
Requirements for ACTH challenge tests during the study and 
at the end of treatment were added.
Rationale for change
ACTH Challenge Test added to detect and mitigate the 
potential risk of adrenal insufficiency.
Section to be changed
5.2.5.1 ACTH Challenge Test and Flowchart
Description of change
Plasma ACTH basal sample removed and only serum 
cortisol basal sample must be taken before ACTH injection.
Rationale for change
Pre-injection plasma ACTH is not required to be tested as 
part of the test for adrenal insufficiency.
Section to be changed
5.2.5.3 Urinary free cortisol
Description of change
New section added
Rationale for change
Urinary free cortisol added as an assessment to evaluate 
whether BI 690517 may increase cortisol levels.
Section to be changed
5.2.6.1.4 Adverse Events of Special Interest
Description of change
Addition of Cushing’s syndrome and adrenal insufficiency 
as AESI
Rationale for change
To investigate potential risk of BI 690517 for adrenal 
insufficiency or increase of cortisol levels (Cushing’s 
syndrome).
Section to be changed
5.3.2
Method of sample collection
Description of change
After completion of the trial the plasma samples may be 
used for further methodological investigations, e.g. for 
stability testing.
was rephrased to 
After analysis the plasma samples may be used for further 
methodological investigations, e.g. for stability testing or to 
address Health Authority questions regarding the 
results/methodology.
Rationale for change
Increase the flexibility to start analysis earlier for a potential 
need to address Health Authority questions
Section to be changed
5.4.2 Pharmacogenomic Biomarkers


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Description of change
Pharmacogenomic samples will be discarded no later than 2 
years after the last patient has completed the trial, rather than 
no later than the sign off of the CTR.
Rationale for change
Clarification since the sign off of the CTR could be 
performed at any time.
Section to be changed
5.5 Biobanking
Description of change
The following sentence was added: For China, samples for 
biobanking will not be collected, due to regulatory 
restrictions.
Rationale for change
Clarification for regulatory purposes.
Section to be changed
6.1 Visit schedule
Description of change
Rephrased the following sentence:
Patients should be instructed to not take their dose of the 
study medication at home at scheduled visit days as they will 
be dosed whilst at the study site.
With:
Patients should be instructed to not take their dose of the 
study medication at home in the morning of scheduled visit 
days as they will be dosed whilst at the study site.
Rationale for change
Clarification.
Section to be changed
6.2 Details of Trial Procedures
Description of change
Post dose- serum cortisol at Visit 5 is also drawn after drug 
administration.
Rationale for change
Clarification
Section to be changed
6.2.2 Home Visits
Description of change
Rephrased text to clarify direct to patient shipments of IMP 
and lab kits/ancillary material for home visits. 
Added instruction that where a CRO is used all source 
information should be reviewed by an investigator.
Rationale for change
Clarifications and additional information.
Section to be changed
6.2.3 Screening and run-in period(s) and 
8.3.1 Source documents
Description of change
Removed the following information to be collected by the 
site: 
• Gender identity (male, female, other in order to describe 
how the participant self-identifies regardless of their 
genotypic or phenotypic sex)
Rationale for change
There is no requirement for this trial to collect gender 
information as this has no impact on the results.


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Section to be changed
6.2.5 Early discontinuation of treatment
Description of change
Section rephrased to distinguish between the two separate 
scenarios for early discontinuation: 
1. premature discontinuation of empagliflozin/placebo 
during Run-In Period
2. premature discontinuation of both trial drugs during the 
Treatment Period
Rationale for change
Further clarification on procedures that apply in case of early 
discontinuation.
Section to be changed
6.2.6 Follow up period and trial completion
Description of change
Added the following sentences:
For patients who prematurely discontinue during the Run-In 
Period,
 
For patients who have not had 
 
Rationale for change
Further clarification on the procedures that apply during 
follow-up in the case of early discontinuation.
Section to be changed
7.2.6 Safety analysis
Description of change
Adverse events will be summarised by the treatment at 
which the subject was randomised, and the treatment at the 
onset of AE for the drug-related AE.
Rationale for change
Further information on the intended safety analysis.
Section to be changed
7.4 Randomisation
Description of change
Thresholds added to be used for stratification and prior 
diabetes removed as another stratum.
Rationale for change
Further information. A third stratification factor would result 
in too small strata and was therefore not further pursued.
11.2
GLOBAL AMENDMENT 2
Date of Amendment
30 March 2022
EudraCT number
2021-001434-19
BI Trial number
1378-0005
BI Investigational Medicinal 
Product(s)
BI 690517 and empagliflozin
Title of protocol
Randomised, double-blind, placebo-controlled and 
parallel dose group trial to investigate efficacy and 
safety of multiple doses of oral BI 690517 over 14 


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weeks, alone and in combination with 
empagliflozin, in patients with diabetic and non-
diabetic chronic kidney disease
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
FMV and 24-hour Urine Sampling Flowchart
Description of change
Addition of a footnote for 24-hour urine sample at EOT:
‘24-hour urine sample not required at EOT if patient 
discontinues prematurely prior to start of treatment with BI 
690517 / matching placebo’
Rationale for change
24-hour urine sample is required to assess the effect of BI 
690517 on urinary free cortisol, therefore this sample is not 
required at EOT if a patient discontinues prematurely during 
the Randomised Run-in period.
Section to be changed
1.4.2 
Description of change
‘Steering committee (SC)’ removed from the sentence ‘A
steering committee (SC) and Data Monitoring Committee 
(DMC) will be established to review safety data at regular 
intervals.’
Rationale for change
Only the DMC will review safety data at regular intervals.  
The SC will provide scientific input and operational 
oversight. 
Section to be changed
3.1 Overall Trial Design
Description of change
Figure 3.1:1 Trial Design updated to include duration of 
Follow Up Period (4 weeks).
Rationale for change
Correction
Section to be changed
3.1 Overall Trial Design
Description of change
‘or genetic’ removed from the sentence ‘If the patient agrees, 
banked samples may be used for future biomarker research 
and drug development projects, e.g. to identify patients that 
are more likely to benefit from a treatment or experience an 
adverse event (AE), or to gain a mechanistic or genetic 
understanding of drug effects and thereby better match 
patients with therapies.’
Rationale for change
No genetic testing of banked samples will be performed.
Section to be changed
3.2 Discussion of Trial Design, including the choice of 
control group(s)
Description of change
Measurement of 24-hour urine changed from ‘at screening’ 
to ‘just prior to the start of BI 690517 treatment,’ 
Rationale for change
Correction


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Section to be changed
3.3.1 Inclusion criteria
Description of change
Inclusion criteria #7 was changed from:
In the Investigator’s opinion, one or more of the following 
underlying kidney disease causes:

Diabetic kidney disease. These patients must have type 
2 diabetes mellitus and their treatment (including GLP1 
receptor agonist) should be unchanged or changes 
deemed minor (according to investigator’s judgement) 
within 4 weeks prior to Visit 1 and until first 
randomisation. 

Hypertensive kidney disease

Chronic glomerulonephritis defined as one of the 
following:
o IgA nephropathy, 
o Membranous nephropathy
o Focal Segmental Glomerulosclerosis (FSGS)
to:
In the Investigator’s opinion, any kind of diagnosed chronic 
kidney disease5. Patients with diabetic kidney disease must 
have type 2 diabetes mellitus and their treatment (including 
GLP1 receptor agonist) should be unchanged or changes 
deemed minor (according to investigator’s judgement) 
within 4 weeks prior to Visit 1 and until first randomisation. 
5Diagnosis can be reached by standard clinical method, no 
biopsy required.
Rationale for change
Broaden criteria to allow enrolment of patients with other 
non-diabetic kidney diseases
Section to be changed
3.3.3 Exclusion criteria
Description of change
Additional exclusion criterion: ‘Patients with known hepatic 
cirrhosis (Child Pugh A, B or C), or other liver disease 
causing impaired liver function according to investigator’s 
judgement.’ to be reviewed at screening (exclusion #24) and 
also prior to the second randomisation (exclusion # 26).
Rationale for change
 
No dedicated trial in patients with liver 
impairment has been done. Experience from other 
compounds metabolised mainly by UGT2B7 enzymes show 
that in patients with cirrhosis and liver impairment the 
exposure may increase up to 4-fold, therefore these patients 
should be excluded. These patients were to be excluded by 
exclusion criteria 10 (abnormal laboratory value) but is 
clarified with this additional criteria.
Section to be changed
3.3.3 Exclusion criteria


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Description of change
Additional exclusion criterion #25:
25. Patients with one of the following aetiologies as the 
underlying cause: 
CKD secondary due to malignancy (e.g. Cast-
Nephropathy, AL-amyloidosis)
CKD secondary to infectious disease (e.g. Hepatitis-
/HIV-associated)
Autosomal-dominant polycystic kidney disease
Rationale for change
To exclude patients with certain causes of CKD where no 
benefit to treatment is expected.
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
For #1, the sentence ‘The Kidney Disease: Improving Global 
Outcomes (KDIGO) definition [R17-2439] (see section 
3.3.3) should to be used for guidance.’ was changed to
‘The Kidney Disease: Improving Global Outcomes 
(KDIGO) definition [R17-2439] (see section 3.3.3) is going 
to be used for guidance’
Rationale for change
Administrative change
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
For #2, the % drop in eGFR will be measured from when the 
patient starts the empagliflozin/placebo treatment.
The individual patient will permanently discontinue all 
randomized trial treatment if:
The patient experiences a drop in eGFR:

≥ 30% from the last measurement of eGFR before the 
first dose of empagliflozin / placebo up to Visit 6; 
and/or

≥ 40% at any time since the last measurement of eGFR 
before the first dose of empagliflozin/placebo 
Rationale for change
Correction to add an omitted time interval specification
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
The sentence ‘The patient has repeatedly shown to be non-
compliant with important trial procedures and, in the opinion 
of both the investigator and sponsor representative, the 
safety of the patient cannot be guaranteed as he / she is not 
willing or able to adhere to the trial requirements in the 
future’ has been changed to ‘The patient has repeatedly 
shown to be non-compliant with important trial procedures 
and, in the opinion of the investigator, the safety of the 
patient cannot be guaranteed as he / she is not willing or able 
to adhere to the trial requirements in the future’
Rationale for change
Clarification that it is just the investigator’s opinion that 
should be considered.


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Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
The sentence ‘In this case the sponsor should be consulted’ 
was changed to
‘In this case the sponsor can be consulted’.
Rationale for change
Clarification.
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
The following reason to discontinue all randomised trial 
treatment was added:
The patient does not meet the additional inclusion criteria 
(see section 3.3.2) or the additional exclusion criteria (see 
section 3.3.3) assessed before second randomization (start of 
Treatment Period).
Rationale for change
Clarification that if the additional eligibility criteria for 
starting BI690517 / matching placebo are not met, the 
patient should permanently discontinue.
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
The sentence ‘The patient should be followed according to 
local guidelines until resolution of the event and the event 
should be reported to the sponsor’ was changed to ‘The 
patient must be followed according to local guidelines until 
resolution of the event and the event is going to be reported 
to the sponsor’
Rationale for change
Administrative change
Section to be changed
4.1.2 Selection of doses in the trial and dose modifications
Description of change
The sentence ‘The 40 mg dose resulted in total aldosterone 
suppression, and therefore a lower 20 mg dose is expected to 
have a partial aldosterone suppression and a reduced risk of 
hyperkalaemia.’ was changed to ‘The 40 mg dose resulted in 
a substantial suppression of aldosterone, and it is expected 
that the lower 20 mg dose will result in less aldosterone 
suppression, reducing the risk of hyperkalaemia.’
Rationale for change
Clarification that the 40 mg dose causes substantial 
suppression of aldosterone instead of total suppression and 
that 20 mg dose causes less aldosterone suppression.
Section to be changed
4.1.5 Blinding and procedures for unblinding
Description of change
‘and to provide PK data to DMC for consideration when 
evaluating safety of the trial’ was added to the sentence:
In order to expedite the population PK and PK-PD analyses 
and ensure timely delivery of PK/PD results after database 
lock and to provide PK data to DMC for consideration when 
evaluating safety of the trial, specific data must be unblinded 


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and the treatment information must be made available to 
selected individuals.
Rationale for change
Provision of unblinded PK data to the DMC will support the 
understanding of the safety data.
Section to be changed
4.2.2.1 Restrictions regarding concomitant treatment
Description of change
Addition of
 
 
Rationale for change
To be consistent with the first paragraph in the section and to 
clarify that only 
 should not be used. 
Section to be changed
6.2.5 Early discontinuation of Treatment
Description of change
The following bullet point was added under ‘If the patient 
prematurely discontinues empagliflozin/placebo during the 
Run-In Period’

The 24-hour urine sample prior to EOT does not need to 
be collected.
Rationale for change
24-hour urine sample is required to assess the effect of BI 
690517 on urinary free cortisol, therefore this sample is not 
required at EOT if a patient discontinues prematurely during 
the Randomised Run-in period
Section to be changed
8.7 Administrative Structure of the Trial
Description of change
‘PK data (organised according to eGFR stratification)’ added 
to the data that will be evaluated by the DMC
Rationale for change
PK data will support the understanding of the safety data.
Section to be changed
Appendix 10.1
Description of change
Addition of plasma aldosterone and its precursors to the list 
of exploratory biomarkers.
Rationale for change
To ensure consistency with section 5.4.1 Exploratory 
biomarkers where plasma aldosterone and its precursors are 
also included.
11.3
GLOBAL AMENDMENT 3
Date of Amendment
19 August 2022
EudraCT number
2021-001434-19
BI Trial number
1378-0005
BI Investigational Medicinal 
Product(s)
BI 690517 and empagliflozin
Title of protocol
Randomised, double-blind, placebo-controlled and 
parallel dose group trial to investigate efficacy and 


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safety of multiple doses of oral BI 690517 over 14 
weeks, alone and in combination with 
empagliflozin, in patients with diabetic and non-
diabetic chronic kidney disease
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Flowchart
Description of change
Time window for Screening ‘up to 21 days before Visit 2’ 
added
Rationale for change
Clarification to make it clear that screening period should be 
no longer than 21 days
Section to be changed
Flowchart
Description of change
Treatment compliance added for Visits 4, 5, 6, 7, 8, 9 and 
EOT (including footnote #28)
Rationale for change
Clarification to distinguish between treatment compliance, 
which is required at all visits, and drug accountability which 
is not required at visits 4 and 6 (see change below).
Section to be changed
Flowchart
Description of change
Requirement for Drug Accountability (via IRT) removed at 
Visits 4 and 6
Rationale for change
Study drugs do not need to be accounted for in IRT at visits 
4 and 6 as study drugs are not returned at these visits.
Section to be changed
Flowchart
Description of change
Footnote 2 additional sentence added: ‘The Screening Period 
should be no more than 21 days from first screening 
procedure to first randomisation.’
Rationale for change
Clarification to make it clear that screening period should be 
no longer than 21 days
Section to be changed
Flowchart
Description of change
Footnote 2 – ‘once’ added to the sentence ‘Screening 
procedures may be repeated once during the screening 
period if the patient is not eligible for a transient medical 
condition
Rationale for change
Clarification that screening procedures should not repeatedly 
be retested until an eligible result is obtained.
Section to be changed
Flowchart
Description of change
Footnote 5 additional sentence added: ‘Where the patient 
does not meet the additional inclusion criteria 13 and 14 
based on lab tests performed at Visit 4, the eGFR and 


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potassium cannot be re-tested and the patient should 
permanently discontinue the study.’
Rationale for change
Clarification
Section to be changed
Flowchart
Description of change
Footnotes 10 and 14: Change of timing of collection of the 
serum cortisol. 
Changed from ‘ before 10 am’ to ‘within 4 hours of the 
patient’s usual waking time’.
Rationale for change
Serum cortisol is affected by diurnal rhythm and this allows 
patients who are regular late risers to still participate in the 
trial whilst not affecting the validity of the results.
Section to be changed
Flowchart
Description of change
Additional footnote 27 (associated with FUp1.1, FUp1.2 and 
FUp2): In the case of premature discontinuation during the 
Randomised Run-in Period, FUp1.1, FUP1.2 and FUp2 do 
not need to be conducted.  
Rationale for change
Clarification as these visits are only relevant for patients 
who have started BI690517 / placebo treatment.
Section to be changed
Flowchart
Description of change
Footnote 29 added: Days and associated time windows are 
relative to Visit 5
Rationale for change
Clarification
Section to be changed
 Flow Chart
Description of change
Time window for the pre-dose samples changed from -0:30 
(+/- 15 min) to -0:30 (+ 29 / - 15 min)
Rationale for change
It is acceptable for the pre-dose samples to be taken 
immediately before the dose, up to 45 mins before the dose.
Section to be changed
 Flow Chart
Description of change
Footnote #3 - added that only pre-dose (-0:30) 
 
samples need to be taken at EoT in case of premature 
discontinuation during run-in phase.
Rationale for change
Clarification
Section to be changed
 Flow Chart
Description of change
Additional footnote #6 added: 
 
 
 
 
 
 


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Rationale for change
Section to be changed
Abbreviations
Description of change
LPLVPE (Last Patient Last Visit Primary Endpoint) added
Rationale for change
Abbreviation used in section 4.1.5.1
Section to be changed
3.1 Overall Trial Design
Description of change
‘A minimum of 40% of patients will be required to be 
randomised during the run-in period in each of the disease 
types: diabetic kidney disease and non-diabetic kidney 
disease.’  
Was changed to: 
‘A target of approximately 30% of patients will be 
randomised during the run-in period in each of the disease 
types: diabetic kidney disease and non-diabetic kidney 
disease.’  
Rationale for change
Based on the type of sites (e.g. general practices to sites 
specialized in nephrology) involved in this study, observed 
actual distribution of diabetic kidney disease vs. non-diabetic 
kidney disease is approximately 70% vs. 30%. Therefore,
the trial is unlikely to reach 40% of non-diabetic kidney 
disease patients within the required recruitment time, and 
reducing the minimum required from 40% to 30% will not 
affect study primary objectives or main outcomes since the 
study outcomes are combined for both disease types.
Section to be changed
3.3 Selection of Trial Population
Description of change
If a patient has been randomised in error (did not meet all 
inclusion criteria or met one or more exclusion criteria), the 
sponsor or delegate should be contacted immediately. Based 
on an individual benefit-risk assessment a decision will be 
made whether continued trial participation is possible or not.
Was changed to:
The investigator will make every effort to avoid the 
inclusion of a patient who does not meet all the inclusion 
criteria and/or meets at least one exclusion criterion. Should 
such an error nevertheless occur, this patient might be 
immediately excluded from the clinical trial based on 
individual benefit-risk assessment by the investigator. The 
sponsor or delegate will be informed as soon as possible.
Rationale for change
It should be the investigator who determines the benefit-risk 
assessment in case a patient is randomised in error, and not 
the sponsor.


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Section to be changed
3.3.3 Exclusion criteria
Description of change
‘Systemic’ and ‘or before first randomisation’ was added to 
exclusion criteria #11: ‘Any systemic immunosuppression 
therapy or immunotherapy in the last 3 months prior to 
Visit 1 or before first randomisation. This also applies to 
systemic steroids except oral prednisolone ≤10 mg or 
equivalent.’
Rationale for change
To allow local immunotherapy (e.g., cyclosporine eye drops) 
which does not have impact on study endpoints; and 
clarification that systemic immunosuppression or 
immunotherapy is not allowed before first randomisation.
Section to be changed
3.3.3 Exclusion criteria
Description of change
The following was added to exclusion criterion # 19: 
‘Patients who are unable to comply with trial procedures’
Rationale for change
Clarification to exclude patients who are unable to comply 
with trial procedures
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
Footnote #1 (associated with eGFR drop) added: ‘Where the 
eGFR drop occurs before the start of BI 690517 / placebo in 
the Treatment Period (i.e., at Visit 5), but the result is not 
available until after the patient starts BI 690517/placebo 
treatment, the patient must still permanently discontinue all 
randomised study treatment, including BI 690517 / placebo.’
Rationale for change
Clarification
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
‘and should continue with scheduled study visits.’ has been 
added to the sentence ‘If one of the study medications (either 
empagliflozin/placebo or BI 690517/placebo) is permanently 
discontinued during the Treatment Period / after the second 
randomisation at Visit 5, the patient may continue to receive 
treatment with the other study medication’.
Rationale for change
Clarification
Section to be changed
4.1.5.1 Blinding
Description of change
‘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 until the 
database is declared ready for analysis according to the 
sponsor’s SOPs.’
Was changed to:


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‘Patients, investigators and everyone involved in trial 
conduct or analysis or with any other interest in this double-
blind trial will remain blinded with regard to the randomised 
treatment assignments until a snapshot after Last Patient Last 
Visit Primary Endpoint (LPLVPE), with the exception of the 
Trial Pharmacometrician, PK programmer and Trial 
Bioanalyst. This snapshot will be taken after the last patient 
completes the EoT Visit, and will be used to obtain efficacy, 
safety, and PK/PD results, to guide further development 
plans for BI 690517. At the timepoint of unblinding of this 
snapshot, patients and investigators will continue to be 
blinded and will remain so until after database lock when the 
database is declared ready for final analysis according to the 
sponsor’s SOPs.’
‘Bioanalytics will not disclose the randomisation code or the 
results of their measurements until the database lock.’
Was changed to:
‘Bioanalytics will not disclose the randomisation code or the 
results of their measurements prior to the LPLVPE 
snapshot.’
‘It should be noted no PK/PD results will be communicated 
to the project and trial team prior to database lock.’
Was changed to:
‘It should be noted no PK/PD results will be communicated 
to the project and trial team prior to the LPLVPE snapshot.’
Rationale for change
To allow an earlier start of analysis, data will be unblinded 
after the last EoT visit instead of database lock
Section to be changed
4.1.6 Packaging, labelling, and re-supply
Description of change
‘(or equivalent)’ added to ‘Synacthen® (or equivalent) is 
either provided by the site or where this is necessary through 
the sponsor.’
Rationale for change
Clarification
Section to be changed
4.2.1.3 Management of serum cortisol decrease
Description of change
‘from BI 690517 / placebo added to the sentence, ‘If, during 
the trial, cortisol level is < 3 µg/dL (82.8 nmol/L) the patient 
must be withdrawn from BI 690517 / placebo.’
Rationale for change
Clarification
Section to be changed
4.2.2.1 Concomitant medication restrictions
Description of change
 


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Rationale for change
 
  This change will not compromise the 
integrity of the trial or introduce bias.
Section to be changed
4.2.2.1 Concomitant medication restrictions
Description of change
For 
 ‘or 
deemed minor in the opinion of the investigator’ added to 
the sentence ‘Stable dose permitted if used prior to entry, 
change should be avoided’ in the columns ‘During run-in 
and Treatment Period’ and ‘In the Follow-up Period’ and ‘in 
the opinion of the investigator’ added in the columns ‘Prior 
to trial (Visit 1)’ and ‘During screening (prior to first 
randomisation)’.
Rationale for change
Clarification
Section to be changed
4.2.2.1 Concomitant medication restrictions
Description of change
Rationale for change
Clarification
Section to be changed
5.2.3 Safety Laboratory Parameters
Description of change
Sentence added: Ineligible lab parameters may only be re-
tested once during the screening period.’
Rationale for change
Clarification that screening procedures should not repeatedly 
be retested until an eligible result is obtained.
Section to be changed
5.2.5.1 ACTH Challenge test
Description of change
Paragraph added: Alternative conduct of the ACTH test is 
allowed only if it is in accordance with the local practice of 
diagnosis of adrenal insufficiency. If adrenal insufficiency is 
diagnosed with an alternative conduct of ACTH test, the 
details of the ACTH test should be documented in the AESI 
report to the sponsor.
Rationale for change
Clarification that alternative methods of diagnosing adrenal 
insufficiency are accepted if it is in accordance with local 
practice since some countries do not use the Short Synacthen 
test as standard.
Section to be changed
5.2.5.1 ACTH Challenge Test


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Description of change
‘A serum cortisol basal sample must be taken before the 
ACTH injection (iv or im 0.25 mg Synacthen® or equivalent 
product if Synacthen® is not authorised locally).’
Was changed to
‘A serum cortisol basal sample must be taken before the 
ACTH injection (iv or im 0.25 mg Synacthen®; an
equivalent product may be used if Synacthen® is not 
authorised locally or provided by the sponsor).’
Rationale for change
Clarification
Section to be changed
5.2.5.1 ACTH Challenge Test
Description of change
‘In this trial, the Synacthen® (or equivalent product if 
Synacthen® is not authorised locally) for the ACTH 
challenge test is considered as auxiliary medicinal product 
(AxMP).’
Was changed to
‘In this trial, the Synacthen® (or equivalent product) for the 
ACTH challenge test is considered as auxiliary medicinal 
product (AxMP).’
Rationale for change
Clarification
Section to be changed
5.2.6.1.4 Adverse events of special interest
Description of change
Clarification that lab findings constituting a hepatic injury 
only need to be followed up according to the DILI checklist 
after the start of study treatment.
Rationale for change
Clarification
Section to be changed
5.5 Biobanking
Description of change
Paragraph added: ‘In some countries, for example China, 
biobanking samples will not be collected due to regulatory 
reasons.’
Rationale for change
Correction.  This should have been added in Amendment 1 
(see Appendix 11.1) but was missed from the section in 
error. Since Amendment 1, other countries will not be 
collecting biobanking samples so the sentence has been 
updated.
Section to be changed
6.2.3 Screening and run-in period(s)
Description of change
‘after discussion with the sponsor’ removed from the 
sentence ‘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.’
Rationale for change
It is not necessary to discuss with the sponsor before 
rescreening a patient.


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Section to be changed
11.2 Global Amendment 2
Description of change
Reference to exclusion criteria 11 changed to exclusion 
criteria 10 in relation to abnormal laboratory value.
Rationale for change
Correction


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34875109
6.0
clinical-trial-protocol-version-04
Randomised, double-blind, placebo-controlled and parallel dose group trial to
investigate efficacy and safety of multiple doses of oral BI 690517 over 14 weeks,
alone and in combination with empagliflozin, in patients with diabetic and
non-diabetic chronic kidney disease
Approval-Biostatistics
19 Aug 2022 17:07 CEST
Approval-Team Member Medicine
19 Aug 2022 17:08 CEST
Author-Clinical Trial Leader
19 Aug 2022 17:30 CEST
Approval-Therapeutic Area 
19 Aug 2022 18:14 CEST
Author-Trial Clinical
Pharmacokineticist
22 Aug 2022 15:32 CEST
Verification-Paper Signature
Completion
23 Aug 2022 12:45 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34875109
6.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN 
c41181505-02
BI Trial No.:
1378-0005
Title:
Randomised, double-blind, placebo-controlled and parallel dose 
group trial to investigate efficacy and safety of multiple doses of 
oral BI 690517 over 14 weeks, alone and in combination with 
empagliflozin, in patients with diabetic and non-diabetic chronic 
kidney disease
Investigational
Product(s):
BI 690517 and empagliflozin
Responsible trial 
statistician(s):
Phone: 
Date of statistical 
analysis plan:
26 June 2023
Version:
2.0
Page 1 of 31
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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 .........................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT .................................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
5.4.1
Safety endpoint(s)................................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENT(S)................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................13
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.6.1
Withdrawals ........................................................................................................14
6.6.2
Efficacy data........................................................................................................14
6.6.2.1
Primary endpoint................................................................................................14
6.6.2.2
Secondary endpoint(s) ........................................................................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINT(S) ................................................................................19
7.4.1
Primary analysis of the primary endpoint(s) ...................................................19
7.5
SECONDARY ENDPOINT(S) ..........................................................................21
7.5.1
Key secondary endpoint(s).................................................................................21
7.5.2
(Other) Secondary endpoint(s) ..........................................................................22


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7.7
EXTENT OF EXPOSURE.................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................23
7.8.1
Adverse Events ....................................................................................................23
7.8.2
Laboratory data ..................................................................................................25
7.8.3
Vital signs.............................................................................................................26
7.9
ANALYSIS OF COVID-19 IMPACT...............................................................26
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............27
9.
REFERENCES....................................................................................................28
11.
HISTORY TABLE..............................................................................................31


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LIST OF TABLES
Table 6.1:1 Study phases for analysis of AEs..........................................................................11
Table 6.3: 1 Subject sets analysed............................................................................................13
Table 6.6.2.1: 1 Principal rule of First Morning Void (FMV) UACR derivation for analysis 15
Table 11: 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
COVID-19
Corona Virus Disease 2019
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Data Base Lock
DILI
Drug Induced Liver Injury
DV
Deviation
ECG
Electrocardiogram
EDMS
Electronic Document Management System
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
EoT
End of Treatment
ES
Entered Set
FAS
Full Analysis Set
FMV
First Morning Void
F/U
Follow-Up
ICE
Intercurrent Events
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
iPD
Important Protocol Deviation
LOCF
Last Observation Carried Forward
MCP-MoD
Multiple Comparisons Procedure - Modelling
MedDRA
Medical Dictionary for Drug Regulatory 
MMRM
Mixed-effect Model for Repeated Measures


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   Term
           Definition / description
PD                      
Pharmacodynamics
PK
Pharmacokinetics
PKS
Pharmacokinetic Analysis Set
QD
Quaque die (once a day)
REP
Residual Effect Period
RMP
Risk Management Program
RPM
Report Planning Meeting
RRTS
Randomised Run-in Treated Set
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SDL                    
Subject Data Listings
SGLT2i
Sodium-Glucose co-Transporter-2 inhibitor
TEAE
Treatment Emergent Adverse Events
TMF                   
Trial Master File
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 Clinical data Analysis and 
Reporting 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.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT(S)
Change from treatment period baseline in log transformed Urine Albumin Creatinine Ratio 
(UACR) measured in First Morning Void urine after 14 weeks.
The expected intercurrent events of interest in this trial are restricted to the Treatment Period. 
The two different approaches for handling intercurrent events (ICEs) are summarised in the 
table below:
Estimand strategy 
Treatment
ICE handling rules
Primary 
Randomised 
treatment
- BI 690517 discontinuation: include data prior to
study medication discontinuation
- Down-titration of BI 690517: include data prior
to down-titration
- Death: include data prior to death
- Use of SGLT2i: include all available data
Supplementary 
Randomised
treatment
- BI 690517 discontinuation: include all available
data
- Down-titration of BI 690517: include all available
data
- Death: include data prior to death
- Use of SGLT2i: include all available data
SGLT2i = Sodium glucose co-transporter-2 inhibitor
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)
UACR response I, defined as decrease of at least 30% absolute change in First Morning Void 
urine of UACR from Treatment Period baseline to 14 weeks. 
UACR response II, defined as decrease of at least 15% absolute change in First Morning Void 
urine of UACR from Treatment Period baseline to 14 weeks. 


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5.4.1
Safety endpoint(s)
This section is not applicable as no safety endpoint has been specified in 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 and parallel dose group trial to investigate efficacy and 
safety of multiple doses of oral BI 690517 over 14 weeks, alone and in combination with
empagliflozin, in patients with diabetic and non-diabetic chronic kidney disease.
During the Run-in Period, eligible patients will be randomised in a 1:1 ratio to either receive 
empagliflozin 10 mg once a day (QD) or placebo matching to empagliflozin 10 mg QD in a 
blinded manner for 8 weeks. During the Treatment Period, patients who received 
empagliflozin or placebo matching to empagliflozin in the Run-in Period, respectively, will be
randomised in a 1:1:1:1 ratio to receive one of three doses of BI 690517 (3 mg QD, 10 mg 
QD or 20 mg QD) or placebo. The randomisation will be stratified according to prognostic 
variables eGFR (< 45 and ≥ 45 mL/min/1.73 m2), UACR (≤ 750 and >750 mg/g). Following 
the 14-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 690517 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 7.2.6 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 groups
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 (dose reduction) due to AE will be 
provided.
For the analysis of AEs, the following study phases are defined in Table 6.1: 1.
Table 6.1:1 Study phases for analysis of AEs 
Study 
Analysis 
Phase
Label
Start (inclusive)

End (exclusive)
Screening
Screening
Date of informed 
consent
Date/time of first 
administration of 
empagliflozin / placebo
  Run-in
Placebo,
Empagliflozin,
respectively
Date / time of first 
administration of 
empagliflozin / 
placebo
For patients discontinue in 
Run-in Period,
12:00 a.m on the day after last 
administration of empagliflozin 
/ placebo + REP (7 days),


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For patients continue in
Treatment Period, 12:00 a.m 
on the day after last 
administration of empagliflozin 
/ placebo + REP (7 days) or 
first administration of BI 
690517 / placebo, whichever
occurs first
  On-treatment
Placebo,
BI 690517, 
Plus
Empagliflozin 
or matching 
placebo,
respectively
Date / time of first 
administration of BI 
690517 / placebo
12:00 a.m on the day after last 
administration of BI 690517 / 
placebo + REP (7 days)
Or
12:00 a.m on the day after 
patient’s trial termination date,
  Follow-up1
F/U Placebo,
F/U BI 690517, 
plus 
Empagliflozin 
or matching 
placebo,
respectively
12:00 a.m on the 
day after last 
administration of BI 
690517 / placebo + 
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
In the case that the patient is permanently discontinued BI 690517, but is continuing on 
Empagliflozin during Treatment Period, the occurrence of AEs between REP of BI 690517 
and REP of Empagliflozin will be provided in the listing. For treatment interruptions, the 
occurrence of AEs between the start of interruption and re- start of treatment will be assigned 
to actual treatment received. 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 for discussion 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) ”.
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the meeting minutes and additionally via an accompanying Excel spreadsheet. The iPDs may 
lead to exclusion of patients from analysis sets. The documentation of the iPD categories and 


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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. iPDs will be summarised during both Run-in and Treatment Period for 
randomised set, and iPDs of patients discontinued during Run-in Period will be provided by 
listings.
Non-important Corona Virus Disease 2019 (COVID-19) related PDs will only be listed.
6.3
SUBJECT SETS ANALYSED
In addition to the subject sets for statistical analysis defined in the CTP, Section 7.2.1, the 
following subject sets will be used:  
Run-in Randomised Set (RIRS):
               This patient set includes all randomised patients of the Run-in Period, regardless of
being treated or not.
Run-in Treated Set (RITS): 
   This patient set includes all randomised patients of the Run-in Period who were
   documented to have taken at least one dose of empagliflozin or placebo. 
Full Analysis Set (FAS): 
               This patient set includes all randomised patients who had at least one baseline
               measurement of UACR at week -2, -1, or 0 and at least one post-baseline 
measurement when patients are still on treatment of BI 690517. The FAS will be 
the main analysis set for the analysis of efficacy. 
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
RIRS
RITS
RS
TS
FAS
PKS
Disposition
X
X
Exposure / Compliance
X
X
IPDs
X
Demographic/baseline
  X
X
Primary endpoint
  X
Secondary endpoint
  X
Other safety/tolerability
X
  
  X
Further endpoints
  X *
Further PK endpoints
X
* Analyses on further endpoints such as serum potassium, vital signs, and body weight, are based on TS.


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
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) at baseline is (/are) missing, all other available UACR 
samples in week -2, -1, and 0 will be used to derive UACR at baseline. 

If any UACR value after randomisation to the Treatment Period is missing, the 
missing UACR will not be imputed.

UACR values excluded from the primary analysis according to the ICEs handling 
rules will not be imputed.


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The Mixed-effect Model for Repeated Measures (MMRM) approach used for the primary 
endpoint (see Section 7.4.1) allows for missing data, assuming missing data following the 
"missing at random” assumption. Even patients with only one post-baseline assessment can be 
included in the model and can, therefore, contribute to the variance estimation. This primary 
analysis assumes that patients who had ICE(s) should have behaved similarly to those who 
remained in the study, and therefore is analogues to the hypothetical estimand strategy. 
The table below describes how/when to derive UACR values for the statistical analysis:
Table 6.6.2.1: 1 Principal rule of First Morning Void (FMV) UACR derivation for analysis
                
FMV UACR
at baseline
FMV UACR
at visit 8
FMV UACR
at visit 9
FMV UACR
at EoT
Derivation
Baseline FMV 
UACR is defined as 
the mean of all non-
missing assessments 
from week -2 until 
prior to the first 
intake of trial 
medication BI 
690517 or placebo 
in the Treatment 
Period.
Average of all 
available FMV 
UACR 
measured at 
visit 8 (week 6)
Average of all 
available FMV 
UACR 
measured at 
visit 9 (week 
10)
EoT FMV 
UACR is 
defined as the 
mean of all non-
missing 
assessments
from week 12 to 
week 14 (EoT 
visit)
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 specified in Table 6.6.2.1:1 will be used for derivation 
of UACR at baseline and EoT, and the UACR percent change from baseline to EoT will be 
calculated accordingly:
 ℎ
 (%) =  
  − 
 

 
 

Missing UACR will be imputed in the sensitivity analysis.
Details about implementation into the statistical analysis are described in Section 7.4.


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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 urine UACR. Baseline for the FMV 
urine UACR, is defined as the mean of all available samples from week -2 until 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 of BI 690517 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 of BI 690517 (which is scheduled for Visit 5). 
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 dose groups of study treatment 
(empagliflozin/ matching placebo + BI 690517/ matching placebo), 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 is:
N
number of non-missing observations
Mean
arithmetic mean
SD
standard deviation
SE                
standard error (except for PK)
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]).
Exclusion of PK parameters 


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The ADS ADPP (PK parameters) contains column variables APEXC and APEXCO
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to
‘DESC STATS’, the value will be excluded from descriptive evaluations per planned time
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME
DEVIATION’, the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a
consequence, any calculation that relies on λz) only; the value is included for all other
analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental PK/PD
analyses of Clinical Studies”. 
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 groups of study treatment, and in total. Disease characteristics during 
Run-in Period will be based on available data at Screening for randomised run-in set. Baseline 
characteristics for randomised set will be based on available data prior to the first intake of BI 
690517. Additionally, demographic and baseline characteristics will be displayed for DKD 
and non-DKD populations of the RS, respectively.    
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the CTR, based on the RS. 
Additionally, concomitant medication will also be displayed for DKD and non-DKD 
populations of the RS, respectively. 
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:


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
Is ongoing at the start of randomised trial treatment of BI 690517 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 of BI 690517.
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 BI 690517
on-treatment period (see Section 6.1 for definition of the on-treatment period).
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 of BI 690517 and starting any time during the BI690517 on-treatment 
period (see Section 6.1 for definition of the on-treatment period).
Restrictions regarding concomitant treatment during the study periods are defined in Section 
4.2.2.1 of the CTP.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned according to percentage of patients meeting the 
compliance.
Compliance of BI 690517 will be displayed by weighted average of percent compliance, 
where the weight is defined as the time interval (number of weeks) between two consecutive 
study visits at which compliance data will be collected, i.e., the weight will be 1 (week) for 
visit 6 and visit 7, and will be 4 (weeks) for visit 8, visit 9, and visit EoT, respectively.  
Number and percentage of patients with compliance categories <80%, 80%-120%, and 
>120% will also be presented.
Compliance of empagliflozin will be displayed by percent of calculated compliance based on 
study medication taken according to protocol for each visit.  
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
The primary analysis of the primary endpoint will be analysed according to the primary 
strategy of handling ICEs (see Section 5.1).
Refer to Section 7.2.2 of the CTP for a description of the statistical analysis for the change 
from baseline in log transformed FMV UACR measured at 14 weeks of trial treatment.


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The adjusted mean change in log transformed FMV UACR from baseline at 14 weeks and its 
standard error will be obtained from MMRM for the placebo and treatment groups. For the 
MMRM model, derived UACRs at baseline, visit 8, visit 9, 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 = baseline*visit visit*trt stratum / 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.
MCPMod Analysis
For the primary analysis the dose-response relationship will be modelled using following 
doses: placebo, 3mg, 10mg, and 20mg, in combination with empagliflozin or empagliflozin
matching placebo, respectively. 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. 
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


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- 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 
90% and 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.
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.


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7.5.2
(Other) Secondary endpoint(s)
For the secondary endpoints,

Patients achieving a decrease of at least 30% absolute change in First Morning Void 
urine of UACR from baseline after 14 weeks of trial treatment,

Patients achieving a decrease of at least 15% absolute change in First Morning Void 
urine of UACR from baseline after 14 weeks of trial treatment. 
Descriptive statistics will be provided for the number and percentage of responders in terms 
of UACR reduction from baseline using complete case analysis, multiple imputation, missing 
as non-responder, and last observation carried forward (LOCF).  

Complete case analysis uses patients with both baseline and Week 14 data available.         

Multiple imputation fills in missing values at Week 14 based on other data observed in 
the same patient using regression. 

Missing as non-responder imputes patients with missing Week 14 data as non-
responders. 

LOCF uses the last value observed on treatment to substitute all missing values until 
Week 14.  
The odds ratio, 95% confidence interval, and p-value will be calculated based on logistic 
regression of binary outcome adjusting for treatment, and stratification factors as covariates.


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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. Safety data will be summarised for Run-in Period and Treatment Period, 
respectively.
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 the first drug intake until 7 days after last drug intake will be assigned to 


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actual treatment groups. All AEs occurring before first drug intake of empagliflozin/ placebo 
will be assigned to ‘screening’ and all AEs occurring after EoT + 7 days will be assigned to 
‘follow-up’ (for listings only). AEs that start before first drug intake and during Run-in Period
and deteriorate under treatment will also be considered as ‘treatment-emergent’. For details on 
the treatment definition, see Table 6.1:1 in 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 empagliflozin or BI 690517 administration will be assigned to the run-in 
or on-treatment phase, respectively. In addition, a summary of patients with down-titration 
due to AE will be provided.
An overall summary of AE will be presented for treated set during Run-in and on-treatment 
periods, respectively. This will show the number and percentage of patients with any AE, 
severe AEs, any investigator defined drug-related AEs, AEs of Special Interest (AESIs), AEs 
leading to the discontinuation of empagliflozin or BI 690517, and down-titration (dose 
reduction) of BI 690517, and serious AEs (SAEs). 
Frequencies [N (%)] of patients with AEs during run-in period will be summarised by 
treatment, primary system organ class, and preferred term (using MedDRA). Separate tables 
will be provided for patients with SAEs, patients with AESIs, patients with any investigator 
defined drug-related AEs to empagliflozin, and patients with discontinuations of 
empagliflozin due to AEs.
Frequencies [N (%)] of patients with AEs during on-treatment period will be summarised by 
treatment, primary system organ class, preferred term (using MedDRA), and intensity. 
Separate tables will be provided for patients with SAEs, patients with AESIs, patients with 
fatal AEs, patients with any investigator defined drug-related AEs (with regards to 
empagliflozin or BI 690517), patients with down-titration (dose reduction) of BI 690517, 
patients with ACTH related AEs, and patients with discontinuations (of empagliflozin or BI 
690517 or ACTH) due to AEs.
In addition, summary of AEs collected on special AE eCRF pages (AE - hypotension, AE -
hyperkalaemia, AE - Ketoacidosis, AE - Adrenal insufficiency, and AE - Acute Kidney 
Injury) will be presented for both patient-based and event-based analyses.  
Subgroup analysis on hypotension based on baseline BP and the lowest BP during the episode
will be carried out. Criteria for significant (vs. non-significant) hypotensive episode are as 
follows:
-
Baseline SBP <=140: decrease 
 ! "#$ %&'()* !+ ,( % – ./ () "#$
./ () "#$
0 ≥30%;
-
Baseline SBP >140: decrease 
 ! "#$ %&'()* !+ ,( % – ./ () "#$
./ () "#$
0 ≥40%;
-
Or, lowest SBP during the episode <90.
-
Baseline DBP <=70: 
 ! 5#$ %&'()* !+ ,( % – ./ () 5#$
./ () 5#$
0 ≥30%;
-
Baseline DBP > 70: 
 ! 5#$ %&'()* !+ ,( % – ./ () 5#$
./ () "#$
0 ≥40%;
-
Or, lowest DBP during the episode <50.


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-
Lowest mean arterial pressure (MAP) during the episode<70, where MAP is 
calculated as 67 =
"#$89(5#$)
9
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 second randomisation at visit 5 is chosen as the baseline value. The laboratory data 
at EoT visit are defined as EoT values. In the case that the patient is permanently discontinued 
BI 690517, but is continuing on empagliflozin during Treatment Period, EoT for analysis of 
laboratory data will be defined as the nearest scheduled lab visit on treatment of BI 690517. 
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).


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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.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be described by descriptive 
statistics and figures of difference in vital signs from baseline (see Section 6.7) to the end of 
study. Vital signs at EoT visit are defined as EoT values. In the case that the patient is 
permanently discontinued for BI 690517, but is continuing on empagliflozin during Treatment 
Period, EoT for analysis of vital signs will be defined as the nearest scheduled visit on 
treatment of BI 690517. 
Marked changes of seated systolic blood pressure (SBP), diastolic blood pressure (DBP), 
pulse rate (PR) will be summarised by the number and the percentage of patients at each visit 
by treatment according to the definition below:  
1) Marked Increase:  SBP > 150 mmHg and an increase of  >= 25 mmHg above baseline
Marked Decrease: SBP < 100 mmHg and a decrease of  > 10 mmHg below baseline 
2) Marked Increase: DBP > 90 mmHg and an increase of  > 10 mmHg above baseline
Marked Decrease: DBP < 60 mmHg and a decrease of  > 10 mmHg below baseline
3) Marked Increase: PR > 100 bpm and an increase of  > 10 bpm above baseline
Marked Decrease: PR < 60 bpm and a decrease of > 10 bpm below baseline.
Clinically relevant findings in vital signs 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.
7.9
ANALYSIS OF COVID-19 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.


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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.
8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be released to unblind the trial database  after Last Patient Last 
visit Primary Endpoint (LPLVPE)(in Section 4.1.5.1 of the CTP). 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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11.
HISTORY TABLE
Table 11: 1 History table
Version
Date
(DD-
MMM-
YY)
Author
Sections 
changed
Brief description of change
1
19-Apr-
2023
None
2
19-June-
2023
7.5.2 (Other) 
Secondary 
endpoint(s)
Added analysis plan of secondary endpoint for clarification