Clinical trial NCT05282121
Conditions: Liver Diseases Hypertension, Portal
Sponsor: Boehringer Ingelheim
Start date: 2022-06-28; Completion date: 2024-06-07
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with liver cirrhosis caused by hepatitis B, hepatitis C or nonalcoholic steatohepatitis (NASH). People can join this study if they have high blood pressure in the portal vein (main vessel going to the liver).

The purpose of this study is to find out whether a medicine called Avenciguat (BI 685509) taken alone or in combination with a medicine called empagliflozin helps people with this condition.

Participants take Avenciguat (BI 685509) as tablets twice a day for 8 weeks. Half of the participants with NASH who also have type 2 diabetes take empagliflozin as tablets once a day in addition to Avenciguat (BI 685509).

Participants are in the study for about 3 months. During this time, they visit the study site about 10 times. At 2 of the visits, the doctors check the pressure in a liver vein to see whether the treatment works. This is done with a catheter (a long thin tube) and gives information about the pressure in the portal vein. The doctors also regularly check participants' health and take note of any unwanted effects.

Detailed description:

Arms: arm 1: Patients with Hepatitis B Virus (HBV) were administered one film-coated tablet of avenciguat orally twice a day. The two doses were ideally taken at least 10 hours apart. The starting dose was 1 milligram (mg), which, if tolerated, was up-titrated to 2 mg one week later. If this dose was also tolerated, a second up-titration to 3 mg occured after another week. Patients remained on the highest dose for the remainder of the treatment period, until 8 weeks of treatment. arm 2: Patients with Hepatitis C Virus (HCV) were administered one film-coated tablet of avenciguat orally twice a day. The two doses were ideally taken at least 10 hours apart. The starting dose was 1 milligram (mg), which, if tolerated, was up-titrated to 2 mg one week later. If this dose was also tolerated, a second up-titration to 3 mg occured after another week. Patients remained on the highest dose for the remainder of the treatment period, until 8 weeks of treatment. arm 3: Patients with Non-Alcoholic Steatohepatitis (NASH) with or without type 2 Diabetes Mellitus (T2DM) were administered one film-coated tablet of avenciguat orally twice a day. The two doses were ideally taken at least 10 hours apart. The starting dose was 1 milligram (mg), which, if tolerated, was up-titrated to 2 mg one week later. If this dose was also tolerated, a second up-titration to 3 mg occured after another week. Patients remained on the highest dose for the remainder of the treatment period, until 8 weeks of treatment. arm 4: Patients with Non-Alcoholic Steatohepatitis (NASH) with type 2 Diabetes Mellitus (T2DM) were administered one film-coated tablet of avenciguat orally twice a day. The two doses were ideally taken at least 10 hours apart. The starting dose was 1 milligram (mg), which, if tolerated, was up-titrated to 2 mg one week later. If this dose was also tolerated, a second up-titration to 3 mg occured after another week. Patients remained on the highest dose for the remainder of the treatment period, until 8 weeks of treatment.

Patients were additionally administered one 10 mg film-coated tablet of empagliflozin orally once a day.
Interventions: intervention 1: Avenciguat intervention 2: Empagliflozin
Intervention descriptions: intervention 1: one film-coated tablet orally twice a day, at least 10 hours apart. The starting dose (1 mg) was up-titrated up to 3 mg intervention 2: one 10 mg film-coated tablet of orally once a day

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (20.0) / Saved on: 20 Apr 2021
Clinical Trial Protocol
TITLE PAGE
Document Number:
c36380139-06
EudraCT No.
EU Clinical Trial No.
2021-005171-40
2023-504257-12-00
BI Trial No.
1366-0029
BI Investigational
Medicinal Product(s)
BI 685509 and empagliflozin
Title
Randomised, open-label and parallel group trial to investigate the 
effects of oral BI 685509 alone or in combination with 
empagliflozin on portal hypertension after 8 weeks treatment in 
patients with clinically significant portal hypertension (CSPH) in 
compensated cirrhosis
Lay Title
A study to test whether BI 685509 alone or in combination with 
empagliflozin helps people with liver cirrhosis caused by viral 
hepatitis or non-alcoholic steatohepatitis (NASH) who have high 
blood pressure in the portal vein (main vessel going to the liver)
Clinical Phase
II
Clinical Trial Leader
Coordinating 
Investigator
Univ.-Prof. Jonel Trebicka, MD, PhD
Current Version and 
Date
Version 6.0, 21 Aug 2023
Original Protocol 
Date
Version 1.0, 20 Dec 2021
Page 1 of 117
Proprietary confidential information.
2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original Protocol date
20 Dec 2021
Revision date
21 Aug 2023
BI trial number
1366-0029
Title of trial
Randomised, open-label and parallel group trial to investigate the 
effects of oral BI 685509 alone or in combination with empagliflozin 
on portal hypertension after 8 weeks treatment in patients with 
clinically significant portal hypertension (CSPH) in compensated 
cirrhosis
Coordinating 
Investigator
Univ.-Prof. Jonel Trebicka, MD, PhD
Trial site(s)
Multi-centre trial
Clinical phase
II
Trial rationale
In this Phase II trial, the efficacy of treatment in patients with CSPH
(defined by the presence of varices and hepatic venous pressure
gradient [HVPG] ≥ 10 mmHg), in compensated cirrhosis due to 
hepatitis B virus (HBV), hepatitis C virus (HCV) and non-alcoholic 
steatohepatitis (NASH) with or without type 2 diabetes mellitus 
(T2DM) will be assessed. The trial will evaluate the short-term 
efficacy of BI 685509 alone and in combination with empagliflozin, 
where patients will be treated for 8 weeks and the portal pressure 
will be assessed quantitatively via HVPG measurements. The trial 
will also provide supportive evidence for the planned Phase III 
development.
Trial objective(s)
The trial will investigate the safety and tolerability, of BI 685509 
and the combination of BI 685509 with empagliflozin, on top of 
standard of care, on portal hypertension in patients with clinically 
significant portal hypertension in compensated cirrhosis. The 
primary objective is to estimate the percentage change in HVPG 
from baseline measured after 8 weeks in patients with HBV, HCV 
and NASH with or without T2DM.
Trial endpoints
The primary endpoint is the percentage change in HVPG from 
baseline (measured in mmHg) after 8 weeks of treatment.
Secondary endpoints include:

occurrence of a response, which is defined as > 10% 
reduction from baseline HVPG (measured in mmHg) after 8 
weeks of treatment

occurrence of one or more decompensation events (i.e. 
ascites, variceal haemorrhage [VH], and / or overt hepatic 
encephalopathy [HE]) during the 8 week treatment period


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
occurrence of CTCAE grade 3 (or higher) hypotension or 
syncope based on Investigator judgement, during the 8 week 
treatment period

occurrence of discontinuation due to hypotension or syncope
during the 8 week treatment period
Trial design
Randomised, open-label and parallel design comparison of four 
groups over 8 weeks
Total number of 
patients enrolled
80
Number of patients per
treatment group
Approximately 20
Diagnosis
Patients with CSPH in compensated cirrhosis due to HBV, HCV,
and NASH with or without T2DM
Main inclusion and 
exclusion criteria
Main inclusion criteria

male or female who is ≥ 18 (or who is of legal age in 
countries where that is greater than 18) and ≤ 75 years old at 
screening (Visit1a)

clinical signs of CSPH as described by either one of the 
points below:
o
documented endoscopic proof of oesophageal varices 
and / or gastric varices at screening (Visit 1b) or 
within 6 months prior to screening (Visit 1b)
o
documented endoscopic-treated oesophageal varices 
as preventative treatment

CSPH defined as baseline HVPG ≥ 10 mmHg (measured at 
Visit 1c), based on a local interpretation of the pressure 
tracing

diagnosis of compensated cirrhosis due to HBV, HCV or 
NASH with or without T2DM. Diagnosis of cirrhosis must 
be based on histology (historical data is acceptable) or on
clinical evidence of cirrhosis (e.g. platelet count < 150 x 
109/L [150 x 103/μL], nodular liver surface on imaging or 
splenomegaly etc.)

willing and able to undergo HVPG measurements per 
protocol (based on Investigator judgement)

if receiving statins, must be on a stable dose for at least 3 
months prior to screening (Visit 1b), with no planned dose 
change throughout the trial

if receiving NSBBs or carvedilol, must be on a stable dose 
for at least 1 month prior to screening (Visit 1b), with no 
planned dose change throughout the trial

if receiving pioglitazone, GLP1-agonists, or vitamin E must 
be on a stable dose for at least 3 months prior to screening 
(Visit 1b), with no planned dose change throughout the trial
Main exclusion criteria


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
previous clinically significant decompensation events (e.g.
ascites [more than perihepatic ascites], VH and / or apparent 
HE)

history of other forms of chronic liver disease (e.g. alcohol-
related liver disease, autoimmune liver disease, primary 
biliary sclerosis, primary sclerosing cholangitis, Wilson’s 
disease, haemachromatosis, alpha-1 antitrypsin [A1At] 
deficiency)

patients without adequate treatment for HBV, HCV, or 
NASH (e.g. antiviral therapy in chronic HBV or HCV or 
lifestyle modification in NASH)
o
if received curative anti-viral therapy for HCV, no 
sustained virological response (SVR) or SVR 
sustained for less than 2 years prior to screening or if 
HCV RNA detectable
o
if receiving anti-viral therapy for HBV less than 6 
months prior to screening, if dose of anti-viral 
therapy not stable in the 6 months prior to screening, 
if planning a dose change during the trial or if HBV 
DNA detectable
o
weight change ≥ 5% within 6 months prior to 
screening

SBP < 100 mmHg and DBP < 70 mmHg at screening (Visit 
1a)

Model of End-stage Liver Disease (MELD) score of > 15 at
screening (Visit 1a)

hepatic impairment defined as a Child-Turcotte-Pugh score ≥ 
B8 at screening (Visit 1a)

ALT or AST > 5 times upper limit of normal (ULN) at 
screening (Visit 1a)

eGFR (CKD-EPI formula) < 20 mL/min/1.73 m2 at screening
(Visit 1a)

alpha-fetoprotein > 50 ng/mL (> 50 μg/L) at screening (Visit 
1a)

history of clinically relevant orthostatic hypotension, fainting
spells or blackouts due to hypotension or of unknown origin 
(based on Investigator judgement)

Current or planned SGLT2i / SGLT-1/2i treatment

Type 1 Diabetes Mellitus
Test product(s)
BI 685509
Empagliflozin
dose
Treatment group 1, 2, 3:
BI 685509 BID (maintenance dose)
Treatment group 4:
BI 685509 BID (maintenance dose) +
                                10 mg Empagliflozin QD
mode of 
administration
Oral
Comparator product(s)
Not applicable


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dose
Not applicable
mode of
administration
Not applicable
Duration of treatment
8 weeks
Statistical methods
For the primary endpoint, an analysis of covariates (ANCOVA)
model will be used to obtain adjusted means for the treatment effects
in the full analysis set (FAS).  This model will include treatment as a 
fixed classification effect and baseline HVPG as a linear covariate.
The random error is assumed to be normally distributed with mean 0 
and variance σ². The analysis will only be used for estimation of 
treatment effects without performing statistical tests. 
Secondary and further endpoints will be analysed descriptively.  
Safety analyses will be performed using BI standards and will be 
descriptive in nature.


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FLOW CHART
Trial Periods
Screening1
Randomised Treatment
Follow-Up
Visit
1a1
1b1
1c1
22
3
4
5
6
EoT / ED3
EoS3
Week
-6
R
1
2
4
6
8
12
Day
-42 
1
8
15
29
43
57
85
Time window for visits (days)
See footnote 1
N/A
+ 2
+ 2
+ 2
± 3
± 5
± 5
Fasting status4
NF
F
F
F
NF
NF
F
NF
F
F
Informed consent
x
Register patient in IRT system via IRT call
x
Demographics5
x
Medical history / baseline conditions5
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
Anthropometric measures6
x
x
x
x
x
x
x
x
Vital signs7
x
x22
x22
x22
x22
x
x
x
Physical examination8
x21
(x)
(x)
(x)
(x)
(x)
x
(x)
Resting 12-lead ECG7
x
x22
x22
x22
x22
x
x
x
Safety laboratory sampling
x
x
x
x
x
x
x
Pregnancy testing9 
xs
xu
xu
xu
xu
Gastroscopy1, 10
x
Hepatic venous pressure gradient (HVPG)1, 11
x
x
Ultrasound (liver and spleen)1, 12
x
x
x
x
Review of in-/exclusion criteria
x
x
x
x
Randomisation
x
IRT call
x
x
x
x
x
x


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FLOW CHART (cont)
Trial Periods
Screening1
Randomised Treatment
Follow-Up
Visit
1a1
1b1
1c1
22
3
4
5
6
EoT / ED3
EoS3
Week
-6
R
1
2
4
6
8
12
Day
-42 
1
8
15
29
43
57
85
Time window for visits (days)
See footnote 1
N/A
+ 2
+ 2
+ 2
± 3
± 5
± 5
Fasting status4
NF
F
F
F
NF
NF
F
NF
F
F
Dispense trial medication
x
x
x
x
x
Dose-titration14
x
x
x
Train patient (home BP and HR 
monitoring)15
x
(x)
Home BP and HR monitoring (by patient)15
x

  
    
      
          
Biobanking sampling19
x
x
All AEs / SAEs / AESIs20
x
x
x
x
x
x
x
x
x
x
Collect returned trial medication
x
x
x
x
x
Compliance check
x
x
x
x
x
End of trial medication
x
Completion of patient participation
x
Footnotes:
1.
The screening period consists of 3 visits (Visits 1a/b/c).  These visits should ideally be completed within a period of 4 weeks, but a maximum of 6 weeks (-42 days) will be 
permitted.  There is no minimum duration.  A patient can proceed from one visit to the next as soon as all results from the previous visit are available and if he / she remains 
eligible for the trial.  Visit 1b and 1c can be performed on the same day; in that case, the gastroscopy must be performed prior to the HVPG measurement.  The ultrasound 
 
can be performed at either Visit 1b or 1c.  Refer to Sections , 5.1.2, 5.2.5.1, 5.2.5.2 and 6.2.1 


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2.
Visit 2 = enrolment / randomisation / Day 1 of trial medication.  All assessments at this visit (excluding post-dose ECGs
[refer to Sections 5.2.4,  6.2 and 
Appendix 10.1]) should be completed before the first dose of trial medication is administered  
3.
Patients who complete 8 weeks of treatment will have an End of Treatment (EoT) visit, followed 4 weeks later by an End of Study (EoS) visit.  The last dose of trial medication 
will be administered in the evening of the day before the EoT visit.  Patients who discontinue trial medication prematurely will have an Early Discontinuation (ED) visit 
completed instead of the planned treatment period visit.  The ED visit should be performed within 7 days of discontinuing the trial medication, followed 4 weeks later by an EoS 
visit.  Refer to Section 6.2.2.1 for details of assessments that should be performed during an ED visit and the EoS visit that follows it.
4.
Fasting status: F = fasting (i.e. overnight fast, no food or drink, except water), NF = non-fasting
5.
For further details refer to Section 6.2.1
6.
Anthropometric measures = height (measured at Visit 1a only), weight, and waist and hip circumference.  Refer to Section 5.2.1.1 
7.
Measurement of vital signs should precede the 12-lead ECG, and measurement of the 12-lead ECG should precede blood sampling and intake of trial medication at visits where a 
single ECG is required.  The 12-lead ECG should be performed after the patient has rested for at least 5 minutes in a supine position.  From Visit 2 onwards, the patients home BP 
monitoring equipment should be used in the clinic to measure vital signs (refer to Sections 5.2.2, 5.2.2.1 and 5.2.4)  
8.
At Visits 1a and at the EoT / ED visit, a complete physical examination is required.  At all other marked visits, a physical examination is only required if the patient reports 
symptoms.  Refer to Section 5.2.1
9.
Pregnancy testing required in women of child-bearing potential (WOCBP) only.  xs = serum testing; xu = urine testing.  Serum pregnancy will be done at screening (Visit 1a) and 
as a reflex when urine testing is positive. More frequent pregnancy testing should be done if required by local regulation and /or authority or per investigator judgement.
Pregnancy testing at dosing visits should be completed prior to administration of trial medication.  Refer to Section 5.2.3
10. Refer to Section 5.2.5.2 for details regarding the necessity for a gastroscopy at Visit 1b  
11. For further details regarding the HVPG measurement, refer to Section 5.1.1
12. For further details regarding ultrasound of the liver and spleen, refer to Section 5.2.5.1
13.
14. For further details regarding dose-titration, refer to Section 4.1.4
15. Electronic home BP monitoring equipment will be provided for a patient to measure BP and HR on a daily basis from Visit 2 (refer to Section 5.2.2.1).  Following training on the 
use of the equipment at Visit 2, subsequent refresher training should be provided if required    
16. A paper patient reminder card will be used to record the time of dosing with trial medication on the 3 days that precede PK sampling visits (refer to Sections 5.3, 5.6.1 and 
Appendix 10.1).  Following training on completion of the diary at Visit 2, subsequent refresher training should be provided if required    
17. Biomarker sampling requires a consistent status from one sample to another in terms of fasting vs non-fasting; a fasting status is therefore defined.  For further details regarding 
sampling, refer to Section 5.4. 
18. PK sampling: except for the EoT visit, samples will be collected pre-dose, and at 30 minutes, 1 hour and 2 hours post-dose.  At the EoT visit, only a pre-dose sample will be 
collected.  The time of dosing with trial medication will be recorded on the 3 days that precede PK sampling visits.  Refer to Sections 5.3, 5.6.1 and Appendix 10.1
19. Biobanking sampling requires a consistent status from one sample to another in terms of fasting vs non-fasting; a fasting status is therefore defined.  Sampling is optional and 
requires separate informed consent.  Refer to Section 5.5
20. After the EoS visit (= individual patients end of the trial) the Investigator should report only the following: any cancers of new histology and exacerbations of existing cancer, trial 
medication related Serious Adverse Events (SAEs) and trial medication related Adverse Events of Special Interest (AESIs) of which the Investigator may become aware of. These 
should be reported only via the BI SAE form (refer to Section 5.2.6.2.1)
21. The physical examination at Visit 1a should include an assessment of the clinical criteria for Child-Turcotte-Pugh classification (refer to Appendix 10.3)


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22. During the dose-titration period (i.e. when up-titration is occurring), and at the subsesquent visit, vital signs and 12-lead ECGs will also be repeated approximately 1 hour and 2 
hours after intake of the trial medication.  Measurement of vital signs should precede the 12-lead ECG, and measurement of the 12-lead ECG should precede the 1 hour and 2 hour 
post-dose PK samples (refer to Sections 5.2.2, 5.2.4 and 5.3.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS AND DEFINITIONS...........................................................................14
1.
INTRODUCTION...............................................................................................19
1.1
MEDICAL BACKGROUND.............................................................................19
1.2
DRUG PROFILE................................................................................................19
1.2.1
BI 685509 .............................................................................................................19
1.2.2
Empagliflozin.......................................................................................................24
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................26
1.4
BENEFIT - RISK ASSESSMENT.....................................................................27
1.4.1
Benefits.................................................................................................................27
1.4.2
Risks .....................................................................................................................28
1.4.3
Discussion.............................................................................................................33
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................35
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........35
2.1.1
Main objectives....................................................................................................35
2.1.2
Primary endpoint(s)............................................................................................35
2.1.3
Secondary endpoint(s) ........................................................................................35
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS ..........................35
2.2.1
Further objectives ...............................................................................................35
2.2.2
Further endpoints ...............................................................................................36
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................38
3.1
OVERALL TRIAL DESIGN.............................................................................38
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................39
3.3
SELECTION OF TRIAL POPULATION .......................................................41
3.3.1
Main diagnosis for trial entry ............................................................................41
3.3.2
Inclusion criteria .................................................................................................42
3.3.3
Exclusion criteria ................................................................................................43
3.3.4
Discontinuation of patients from trial medication and assessments ..............45
3.3.4.1
Discontinuation of trial treatment .........................................................................46
3.3.4.2
Withdrawal of consent to trial participation .........................................................47
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................48
4.
TREATMENTS...................................................................................................49
4.1
INVESTIGATIONAL TREATMENT..............................................................49
4.1.1
Identity of the Investigational Medicinal Products..........................................49
4.1.2
Selection of doses in the trial and dose modifications......................................50


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4.1.3
Method of assigning patients to treatment groups...........................................50
4.1.4
Drug assignment and administration of doses for each patient......................51
4.1.4.1
Rules for down-titration in case of intolerance to BI 685509...............................53
4.1.4.2
Rules for re-starting up-titration in case of interruption of BI 685509.................54
4.1.5
Blinding and procedures for unblinding...........................................................54
4.1.6
Packaging, labelling, and re-supply...................................................................54
4.1.7
Storage conditions...............................................................................................55
4.1.8
Drug accountability.............................................................................................55
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................56
4.2.1
Other treatments and emergency procedures..................................................56
4.2.2
Restrictions ..........................................................................................................56
4.2.2.1
Restrictions regarding concomitant treatment ......................................................56
4.2.2.1.1
Close monitoring for AEs based on concomitant therapy ....................................57
4.2.2.2
Restrictions on diet and lifestyle...........................................................................58
4.2.2.3
Contraception requirements..................................................................................58
4.3
TREATMENT COMPLIANCE........................................................................59
5.
ASSESSMENTS..................................................................................................60
5.1
ASSESSMENT OF EFFICACY........................................................................60
5.1.1
Hepatic venous pressure gradient .....................................................................60
5.2
ASSESSMENT OF SAFETY.............................................................................62
5.2.1
Physical examination ..........................................................................................62
5.2.1.1
Anthropometric measurements (height, weight, waist and hip circumference) ...62
5.2.2
Vital signs / home blood pressure and heart rate monitoring.........................63
5.2.2.1
Home blood pressure and heart rate monitoring...................................................63
5.2.3
Safety laboratory parameters ............................................................................63
5.2.4
Electrocardiogram ..............................................................................................67
5.2.5
Other safety parameters.....................................................................................68
5.2.5.1
Ultrasound (liver and spleen)................................................................................68
5.2.5.2
Gastroscopy...........................................................................................................68
5.2.5.3
Hepatic injury adjudication...................................................................................69
5.2.6
Assessment of adverse events.............................................................................69
5.2.6.1
Definitions of AEs ................................................................................................69
5.2.6.1.1
Adverse event........................................................................................................69
5.2.6.1.2
Serious adverse event............................................................................................70
5.2.6.1.3
AEs considered “Always Serious”........................................................................70
5.2.6.1.4
Adverse events of special interest.........................................................................70
5.2.6.1.5
Intensity (severity) of AEs....................................................................................71
5.2.6.1.6
Causal relationship of AEs....................................................................................71
5.2.6.2
Adverse event collection and reporting ................................................................72
5.2.6.2.1
AE collection.........................................................................................................72
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................72
5.2.6.2.3
Pregnancy..............................................................................................................73


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5.5
BIOBANKING ....................................................................................................78
5.5.1
Methods and timing of sample collection..........................................................78
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................78
6.
INVESTIGATIONAL PLAN.............................................................................80
6.1
VISIT SCHEDULE.............................................................................................80
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................81
6.2.1
Screening period (Visit 1a to 1c)........................................................................82
6.2.2
Treatment period(s)............................................................................................83
6.2.2.1
End of treatment / Early discontinuation visit ......................................................83
6.2.3
Follow-up period and trial completion..............................................................84
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE......................................................................................................................85
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................85
7.2
PLANNED ANALYSES.....................................................................................85
7.2.1
General considerations .......................................................................................85
7.2.2
Handling of intercurrent events.........................................................................86
7.2.3
Primary objective analyses.................................................................................87
7.2.3.1
Sensitivity analyses...............................................................................................87
7.2.3.2
Subgroup analyses.................................................................................................87
7.2.4
Secondary objective analyses.............................................................................87
7.2.5
Further objective analyses..................................................................................88
7.2.6
Safety analyses.....................................................................................................88
7.2.8
Interim analyses ..................................................................................................89
7.3
HANDLING OF MISSING DATA ...................................................................89
7.4
RANDOMISATION ...........................................................................................89
7.5
DETERMINATION OF SAMPLE SIZE .........................................................89
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........91
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................91
8.2
DATA QUALITY ASSURANCE ......................................................................92
8.3
RECORDS...........................................................................................................92
8.3.1
Source documents ...............................................................................................92


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8.3.2
Direct access to source data and documents.....................................................93
8.3.3
Storage period of records ...................................................................................94
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................94
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........94
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................94
8.6
TRIAL MILESTONES.......................................................................................95
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................95
9.
REFERENCES....................................................................................................98
9.1
PUBLISHED REFERENCES............................................................................98
9.2
UNPUBLISHED REFERENCES....................................................................101
10.
APPENDICES...................................................................................................102
10.2
REMOVAL OF INDIVIDUAL PATIENTS IN CASE OF INCREASED 
LIVER ENZYMES ...........................................................................................103
10.3
CHILD-TURCOTTE-PUGH CLASSIFICATION .......................................105
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................106
11.1
GLOBAL AMENDMENT 1 ............................................................................106
11.2
GLOBAL AMENDMENT 2 ............................................................................108
11.3
GLOBAL AMENDMENT 3 ............................................................................110
11.4
GLOBAL AMENDMENT 4 ............................................................................114
11.5
GLOBAL AMENDMENT 5 ............................................................................116


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ABBREVIATIONS AND DEFINITIONS
AC
Adjudication Committee
ADME
Absorption Distribution Metabolism Excretion
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ANCOVA
Analysis of Covariance
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BDL
Bile Duct Ligation
BI
Boehringer Ingelheim
BID
bis in die (twice daily dosing)
BNP
Brain Natriuretic Peptide
BP
Blood Pressure
BPM
Beats Per Minute
CA
Competent Authority
CAP
Controlled Attenuation Parameter
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
COVID-19
Coronavirus Disease 19
Cpre
Predose concentration of the analyte in plasma
CRA
Clinical Research Associate
CRO
Contract Research Organisation
CSPH
Clinically Significant Portal Hypertension
Ct
Concentration of the analyte in plasma at time t
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events


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CTP
Clinical Trial Protocol
CV
Cardiovascular
DBL
Database Lock
DBP
Diastolic Blood Pressure
DDI
Drug-Drug Interaction
DILI
Drug Induced Liver Injury
DKA
Diabetic Ketoacidosis
DMC
Data Monitoring Committee
DM
Diabetes Mellitus
DN
Diabetic Nephropathy
DNA
Deoxyribonucleic Acid
DSI
Disease Severity Index
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
ED
Early Discontinuation
ELF
Enhanced Liver Fibrosis
EoS
End of Study (corresponds with End of Trial)
EoT
End of Treatment
ES
Enrolled Set
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
FHVP
Free Hepatic Venous Pressure
FPG
Fasting Plasma Glucose
FPI
Fasting Plasma Insulin
GCP
Good Clinical Practice
HA
Hyaluronic Acid
HbA1c
Hemoglobin A1c
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus


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HDL
High-density Lipoprotein
HE
Hepatic Encephalopathy
HERG
Human Ether-a-go-go Related Gene
HFrEF
Heart Failure with reduced Ejection Fraction
HIV
Human Immunodeficiency Viruses
HOMA-IR
Homeostatic Model Assessment for Insulin Resistance
HR
Heart Rate
HVPG
Hepatic Venous Pressure Gradient
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
ICM
Iodinated Contrast Material
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
iSTAT
Independent Statistician
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
IVC
Inferior Vena Cava
LADA
Latent Autoimmune Diabetes in Adults
LDL
Low-density Lipoprotein
LPLT
Last patient last treatment
LSM
Liver Stiffness Measurement
LVEF
Left ventricular Ejection Fraction
MedDRA
Medical Dictionary for Drug Regulatory Activities
MELD
Model for End-stage Liver Disease
MI
Myocardial Infarction
MMRM
Mixed Model with Repeated Measurements
MRD
Multiple Rising Dose
MRI
Magnetic Resonance Imaging
NAFLD
Non-Alcoholic Fatty Liver Disease


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NASH
Non-Alcoholic Steatohepatitis
NO
Nitric Oxide 
NSBB
Non-Selective Beta-Blocker
NYHA
New York Heart Association
OATP
Organic Anion Transporting Polypeptide
PD
Pharmacodynamic
PDE
Phosphodiesterase
PG
Pharmacogenomic
PK
Pharmacokinetics
PH
Portal Hypertension
PV
Pharmacovigilance
QD
Quaque Die (once a day)
REML
Restricted Maximum Likelihood
REP
Residual effect period
RNA
Ribonucleic Acid
RPM
Report Planning Meeting
RS
Randomised Set
SAE
Serious Adverse Event
SARS-CoV-2
Severe Acute Respiratory Syndrome CoronaVirus 2
SBP
Systolic Blood Pressure
sGC
soluble Guanylate Cyclase
SGLT-2
Sodium glucose co-transporter 2
SGLT2i
Sodium glucose co-transporter 2 inhibitor
SOP
Standard Operating Procedure
SSc
Systemic Sclerosis
SUSAR
Suspected Unexpected Serious Adverse Reactions
SVR
Sustained Virological Response
T2DM
Type 2 Diabetes Mellitus
TID
Ter in Die (three times a day)


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TIPS
Transjugular Intra-hepatic Portosystemic Shunt
Tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UGT
Uridine Glucuronyl Transferase 
ULN
Upper limit of normal
US
Ultrasound
UTI
Urinary Tract Infection
VAS
Visual Analogue Scale
VCTE
Vibration Controlled Transient Elastography
VH
Variceal Haemorrhage
WHO
World Health Organisation
WHVP
Wedged Hepatic Venous Pressure
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Cirrhosis is the end-stage liver condition caused by multiple chronic diseases, like hepatitis C 
virus infection (HCV), chronic alcohol abuse, or metabolic syndrome with non-alcoholic 
fatty liver disease (NAFLD). Cirrhosis by itself is a chronic condition with a high mortality. 
It is a heterogenous disease that is classified into two main prognostic stages: compensated 
and decompensated cirrhosis. This classification depends on the presence or absence of 
clinically evident decompensating events (specifically ascites [more than perihepatic ascites], 
variceal haemorrhage (VH) and / or apparent hepatic encephalopathy (HE) [P18-02639]). 
Currently, there is no treatment available for cirrhosis for reduction of fibrotic tissue or 
regeneration of hepatocytes. The main treatment goal is to delay decompensation, improve 
quality of life, and treat the symptoms of cirrhosis and especially decompensation.
Portal hypertension (PH) is the initial and main consequence of cirrhosis and is responsible 
for the majority of its complications (R17-1181, P18-02639). The only currently 
recommended clinical approaches to prevent PH-related decompensating events in patients 
with compensated cirrhosis are endoscopic variceal ligations or off-label use of non-selective 
beta-blockers (NSBBs) or carvedilol for the prophylaxis of a first variceal bleeding. 
However, not all patients with PH achieve a haemodynamic response with these current 
treatment options. NSBBs and carvedilol are currently used to prevent complications of 
cirrhosis and improve survival in patients, but these benefits only occur in less than half of 
patients treated, and mostly in those who achieve a significant decrease in portal pressure. An 
unmet need remains for a substantial number of patients who cannot tolerate treatment with 
NSBBs or carvedilol due to decreased systemic blood pressure (BP) and heart rate (HR), and 
who have a higher risk for further progression into decompensation.
Therefore, there is an existing unmet medical need to reduce portal pressure and improve 
liver perfusion in this population of patients with PH and especially clinically significant 
portal hypertension (CSPH) and compensated cirrhosis. CSPH is associated with an increased 
risk of developing varices, overt clinical decompensation (ascites, VH, and HE), postsurgical 
decompensation, and hepatocellular carcinoma (R18-2743, R20-1200, P18-02639).
1.2
DRUG PROFILE
1.2.1
BI 685509
As a primary indication, the development of BI 685509 by Boehringer Ingelheim (BI) is 
intended for slowing progression of renal damage and reduction of cardiovascular events in 
patients with chronic kidney disease. Additional intended indications are the treatment of 
CSPH in patients with compensated cirrhosis due to non-cholestatic liver disease and 
systemic sclerosis (SSc).


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Mode of action
BI 685509 is a nitric oxide (NO)-independent activator of soluble guanylate cyclase (sGC), 
which increases production of cyclic guanosine monophosphate (cGMP).  cGMP is a potent 
mediator of vasorelaxation, an inhibitor of platelet aggregation and inflammation, and is also 
crucial for proper endothelial function in the vascular bed (increased sinusoidal lumen and 
perfusion).  Accordingly, BI 685509 with its sGC-cGMP mediated mechanism of action, is 
considered an appropriate treatment option for CSPH and prevention of decompensation in 
patients with compensated cirrhosis.  Additionally, unlike NSBBs / carvedilol, there is no 
concurrent reduction in systemic BP and HR expected, which might lead to better tolerability 
in chronic treatment.  Further, cGMP also modulates liver fibrosis via inhibition of 
Transforming Growth Factor beta (TGFß) induced extracellular matrix production, fibroblast 
to myofibroblast differentiation and cell proliferation, and also promotes reduction of intra-
hepatic resistance via inhibition of hepatic stellate cell activation and vasoconstriction.
Thus, BI 685509, an sGC activator that increases production of cGMP, may have the 
potential to slow down or halt progression of further fibrogenesis, improving liver perfusion 
and reducing PH. 
Key pharmacokinetic characteristics
The pharmacokinetics of BI 685509 is characterised by rapid absorption, reaching peak 
plasma concentrations between 0.5-1.0 hour post-dose in healthy volunteers.  Thereafter, BI 
685509 plasma concentrations decline in a biphasic manner.  Systemic exposure to BI 
685509 increased proportional to dose following administration of single doses, and close to 
dose-proportional exposure was observed at steady state for the dose range tested from 
to
  The single-dose and steady-state PK parameters (AUC0-∞ and AUC0-τ,ss) 
for BI 685509 were similar, suggesting linear PK with respect to time.  Minimal amounts of 
BI 685509 were excreted unchanged in urine (< 1% of dose).  The apparent terminal 
elimination half-life was approximately 9 to 15 hours.  After multiple oral administration, 
limited accumulation was observed and steady state appears to be attained by approximately 
3 to 5 days after the start of multiple dosing.
Following single and multiple oral administrations of BI 685509, the exposures of BI 685509
(Cmax and AUC) were comparable between Chinese and Japanese subjects but may be up to
2-fold higher compared to Caucasian subjects.  This may be related to the smaller body 
weight in Asian subjects.  Although exposures were higher in Asian subjects, there were no 
notable differences with respect to BP, HR and adverse events (AEs) between Asian and 
Caucasian subjects.  This leads to the current assumption that no considerable dose 
adjustments are needed for Asian patients for the Phase II program that will recruit patients 
from Japan and other Asian countries.
Based on the PK analysis of Trial 1366-0004, the exposure to BI 685509 observed in patients 
with diabetic nephropathy (DN) with an eGFR ranging from 20 – 75 mL/min/1.73 m2 was 
comparable to exposure observed in healthy volunteers in Trial 1366-0003.  Also, as 
observed in healthy volunteers, limited accumulation after multiple dosing was observed in 
patients with DN.


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The preliminary population PK model was updated with new data becoming available.  The 
dataset for the population PK model comprised only limited patient data with eGFR between 
20 – 30 mL/min/1.73m2 from Trial 1366-0004.  Based on the population PK model, exposure 
(AUC0-24,ss and Cmax,ss) was simulated for different eGFR ranges using the highest titrated 
dosing regimen to be investigated in this trial: 
BID /
BID /
BID. Table 1.2.1: 
1 provides  the corresponding fold-change predictions of these PK exposures for differing 
degrees of renal impairment relative to the median value simulated in healthy volunteers 
(eGFR ≥ 90 mL/min/1.73m2).  For patients with eGFR of 20 mL/min/1.73m2 up to < 
90 mL/min/1.73m2 the predicted median AUC0-24,ss is 11-100% higher, and the predicted 
median Cmax,ss is 5-26% higher, respectively in comparison to healthy volunteers.  
Although the model predicted AUC0-24,ss for patients with eGFR of 20 mL/min/1.73m2 is ~ 2-
fold higher compared to healthy volunteers, the projected increase in Cmax,ss, a parameter 
which is closely associated with orthostatic dysregulation, is only marginal. 
Table 1.2.1: 1
Fold-change in PK exposure predictions in renally impaired patients 
relative to the median predicted value in healthy volunteers (eGFR ≥ 
90 mL/min/1.73m2) based on highest titrated dose of 
 BID at 
Day 168 / 24 weeks
Measure
eGFR
Median
2.5th
97.5th
AUC0-24,ss
≥ 90
1.00
0.509
2.06
60 – 90
1.11
0.655
2.31
45 – 60
1.31
0.691
2.49
30 – 45
1.63
0.865
3.08
20 – 30
2.00
1.02
3.87
Cmax,ss
≥ 90
1.00
0.439
1.84
60 – 90
1.05
0.526
1.94
45 – 60
1.10
0.464
1.93
30 – 45
1.20
0.606
2.11
20 – 30
1.26
0.589
2.27
Source: c35011958
Based on the preliminary PK analysis of hepatically impaired patients in Trial 1366-0020, the 
exposure observed in hepatic impairment patients increased with increasing dose. After 
single and multiple oral administrations, the exposure in Child-Turcotte-Pugh A patients was
comparable to Child-Turcotte-Pugh B patients. In Child-Turcotte-Pugh A patients, the steady 
state exposures of 
BID regimen (dose group 3) with last dose of
QD was 150 
nmol/L Cmax and 729 nmol*h/L AUC0-tau,ss, thus yielding an estimated total daily exposure of 
~1460 nmol*h/L. In Child-Turcotte-Pugh B patients, the exposures associated with the same 
dosing regimen was 122 nmol/L Cmax and 604 nmol*h/L AUC0-tau,ss, yielding an estimated 
total daily exposure of ~1210 nmol*h/L. The exposure observed in the
BID dosing 
regimen in hepatic impaired patients were comparable to that of the
 TID dosing 
regimen in healthy volunteers (Trial 1366-0003) and patients with DN (Trial 1366-0004).
BI 685509 was generally safe and well tolerated in patients with DN in Trial 1366-0004 with 
eGFR 20 – 75 mL/min/1.73m2 and in hepatically impaired Child-Turcotte-Pugh A and B 
patients in Trial 1366-0020.  A similar titration regimen will be used in this trial compared to 


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Trial 1366-0020 which will help detect any orthostatic dysregulation and allow adjustment of 
doses accordingly (refer to Section 4.1.4).
Drug interactions
The combination of BI 685509 with other compounds involved in the NO-sGC-cGMP 
pathway, such as NO-donors (e.g. nitrates), phosphodiesterase (PDE)-5- inhibitors, non-
specific PDE inhibitors and sGC-simulators might further increase the risk for hypotensive 
episodes and potentially reactive HR increases and the severity of these effects.  Based on in 
vitro data, BI 685509 is a weak inactivator of CYP3A4 and CYP2C8. A Drug-Drug 
Interaction (DDI) potential with CYP3A4 substrates cannot be excluded as BI 685509 is 
predicted to be a weak CYP3A4 inactivator.  DDI threshold dose for CYP2C8 inactivation
for CSPH indication is close to clinically relevant dose tested in phase II.  Thus, in addition to 
close monitoring of adverse events among patients taking CYP3A4 narrow therapeutic 
index/or sensitive substrates, CYP2C8 and CYP3A4 narrow therapeutic index/or sensitive 
substrates would also be monitored to support patient safety. Inhibitors or inducers of UGT 
(uridine glucuronyl transferase) enzymes (especially UGT1A1) may potentially impact BI 
685509 exposures in a clinically relevant manner.  BI 685509 is a substrate of P-gp 
(permeability glycoprotein) and OATP (organic anion transporting polypeptide)1B1/3 
transporters.  Co-administration of single doses of BI 685509 and the P-gp inhibitor 
itraconazole increased BI 685509 Cmax approximately 1.35-fold and AUC0-tz approximately 
1.55-fold, which is considered not clinically relevant.  OATP1B1/3 inhibition by rifampicin 
increased the exposure of BI 685509 after co-administration of single doses approximately 
2.15-fold for Cmax and 2.74-fold for AUC0-tz, which is considered clinically relevant.  Thus, 
OATP1B1/3 inhibitors will be restricted (refer to Table 1.4.2: 1 and Section 4.2.2.1).
Residual Effect Period
The Residual Effect Period (REP) of BI 685509 is 7 days. This is the period after the last 
dose with measurable drug levels and / or pharmacodynamic (PD) effects still likely to be 
present.
Data from non-clinical studies
BI 685509 activates sGC-mediated cGMP production in the presence of plasma proteins in an 
assay using human or rat platelet-rich plasma with EC50 values of 371 nM and 304 nM, 
respectively.  BI 685509 was tested in the bile duct ligation (BDL) rat model of cirrhotic PH
in which the compound (3 mg/kg and 10 mg/kg) or vehicle were gavaged twice daily from 
weeks 2-4 after BDL (n00260803). BDL rats presented with PH and prominent liver fibrosis. 
Compared to vehicle, portal pressure was significantly reduced with both doses of BI 685509 
(-5.1 mmHg for 3 mg/kg, p<0.001 and -4.5 mmHg for 10 mg/kg, p<0.01), whereas no 
significant effect on HR and mean arterial pressure was observed. Both doses of BI 685509 
significantly reduced both hepatic hydroxyproline content (-30% for 3 mg/kg, p<0.05 and -
32% for 10 mg/kg, p<0.05) and fibrotic area in chrome aniline-stained liver slices (-62% for 
3 mg/kg, p<0.001 and -50% for 10 mg/kg, p<0.01). BI 685509 treatment resulted in reduced 
levels of liver transaminases and direct target engagement of the sGC pathway could be 
demonstrated. Based on portal pressure reduction and anti-fibrotic efficacy, the 3 mg/kg dose 
is considered as the effective dose since the 10 mg/kg dose did not provide better efficacy.


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The major route of elimination for BI 685509 in rats is biliary excretion. More than 85% of 
the radioactivity was found in the faeces after oral and intravenous administration of
[14C]BI 685509 to rats. [14C]BI 685509-derived radioactivity was well distributed to most
tissues except for the central nervous system, white adipose, seminal vesicles, testis, eye lens,
bone and skeletal muscle.
So far, the toxicity profile of BI 685509 has been assessed in safety pharmacology, genetic 
toxicity, repeat dose toxicity studies in rat and monkey and embryo-foetal development 
studies in rats and rabbits.  In general, BI 685509 appears to be safe at clinically relevant 
plasma exposures.  Delayed gastric emptying and decreased intestinal transit might result in 
gastrointestinal side effects.  Only in rats, mild to moderate renal pelvis inflammation was 
observed sporadically.  This finding is deemed to be rat specific and related to the mechanism 
of action.  It seems to be unlikely that related AEs like urinary tract infections will occur in 
human subjects.  BP decreased dose dependently with compensatory increases in HR in 
respective studies in rats and monkeys.  No effects on the central nervous system or the 
respiratory system were found in respective safety pharmacology studies.  There were no BI 
685509-related effects on embryo-foetal mortality, foetal growth or dysmorphology 
(malformations) in the embryo-foetal development studies.  BI 685509 is considered non-
genotoxic and with low risk for photo-toxicity.  The proarrhythmic risk of BI 685509 due to 
effects on ventricular repolarisation is considered to be low.
Data from clinical studies
BI 685509 has been tested in a single rising dose trial, a food effect and DDI trial, two 
multiple rising dose (MRD) trials in male healthy volunteers, and one multiple oral rising 
dose trial in patients with DN.  Overall, it was well tolerated except for dose limiting 
orthostatic dysregulation.  In the single dose trials, BI 685509 appears to reduce diastolic and 
systolic BP with a compensatory increase in HR, however, up-titration and TID dosing 
markedly improved the cardiovascular tolerability of the drug.
Trial 1366-0020, an MRD trial involving hepatically impaired patients, was ongoing during 
Clinical Trial Protocol (CTP) writing.  An interim analysis was performed. 
Summary of interim analysis data from Trial 1366-0020:
In the trial, 49 patients with hepatic impairment due to various underlying liver diseases were 
treated for up to 4 weeks (24 patients with cirrhosis Child-Turcotte-Pugh A and 25 patients 
with cirrhosis Child-Turcotte-Pugh B in patients with hepatic impairment, as these are the 
intented patient population).
The treatment with BI 685509 in patients with cirrhosis of different aetiologies, with hepatic 
impairment with Child-Turcotte-Pugh A and B was safe and well-tolerated.  All AEs were of 
mild or moderate intensity.  No treatment-related SAEs, as defined by the Investigator, 
occurred, or led to treatment discontinuation.  Orthostatic intolerance occurred in the higher 
dose groups, and did not lead to treatment discontinuation, but recovered during continued 
treatment.  Treatment with BI 685509 had no effect on laboratory parameters, including liver 
enzymes and bilirubin.
The exposure was comparable between Child-Turcotte-Pugh A and B patients, and no 
differences were seen for the different underlying liver aetiologies.  Exposure of 
 BID in 


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hepatic impaired patients were similar to 
TID exposures observed in healthy volunteers
(Trial 1366-0003) and chronic kidney disease patients (Trial 1366-0004).
In addition to the safety and exposure, exploratory efficacy biomarkers were investigated in 
the Child-Turcotte-Pugh A patients.  Considering the short treatment period, especially only 
12 days on the maintenance dose, positive signals could be observed in the HepQuant® shunt 
fraction, which is a surrogate of the amount of blood shunted by the liver.  A mean reduction 
of > 10% could be observed in the two higest maintenance doses, and specifically in the 
highest dose group, all patients showed a reduction.  Spleen stiffness was assessed using the 
FibroScan® Expert 630 (Echosens), however the data was inconclusive due to high 
intraindividual variability and invalid measurements in many patients.  While the device used 
for this study (Fibroscan® Expert 630) is specifically designed for spleen stiffness 
measurements, these measurements are dependent on the experience of the operator, the size 
of the spleen, and the depth of the subcutaneous fat.
 
Summary of recent data from Trial 1366-0020:
Based on recent data from Trial 1366-0020, an effect of BI 685509 on the predicted placebo-
corrected mean change from baseline QTcF (∆∆QTcF) was seen.  As mentioned above, this 
trial included patients with cirrhosis Child-Turcotte-Pugh stage A (24 patients) and B (25 
patients).  Dosing regimens up to
BID (i.e. the same as the highest dose group in this 
trial) were used.  In both patient groups, there was a dose dependent increase of ∆∆QTcF up 
to 13.7 ms, with the upper 90% CI > 20 ms.  In one patient group (Child-Turcotte-Pugh A) 
this was concomitant with a change of the predicted placebo-corrected mean change from 
baseline heart rate (∆∆HR) of > 10 beats per minute (bpm), but not in the other patient group.  
No such effect was seen in healthy Caucasian volunteers (Trial 1366-0003) for dosing 
regimens achieving exposure relevant for this trial.  In healthy Asian volunteers (Trial 1366-
0013), at a dose regimen achieving exposure relevant for this trial (i.e. starting dose of
TID up to a final dose of
TID), increase of ∆∆QTcF was seen up to 11.7 ms with 90% 
CI < 20 ms, concomitant with an increase of ∆∆HR of nearly 10 bpm.  
BI 685509 has no effect on the human ether-a-go-go related gene (hERG) channel at doses 
used in this clinical trial, and no effect on QT-interval or T-wave morphology was seen in 
conscious animal studies.  
For a more detailed description of the BI 685509 profile, please refer to the current 
Investigator’s Brochure [c02778238].
1.2.2
Empagliflozin
Empagliflozin is available in various countries. In the US, empagliflozin is registered as 
JARDIANCE® tablets (10 mg and 25 mg) and is currently indicated:

as an adjunct to diet and exercise to improve glycemic control in adults with type 2 
diabetes mellitus (T2DM).


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
to reduce the risk of cardiovascular death in adults with T2DM and established 
cardiovascular disease.

to reduce the risk of cardiovascular death plus hospitalization for heart failure in adults 
with heart failure and reduced ejection fraction.
Empagliflozin is not approved for the treatment of patients with NASH or cirrhosis.
Mode of action
Empagliflozin is an orally available Sodium glucose co-transporter 2 (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 685509 in this 
trial (see Section 1.2.1).
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 


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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.
Preclinically, several studies demonstrated efficacy of SGLT2 inhibitors on prevention of 
liver steatosis and on the progression from NAFLD state to NASH [P16-09040, P21-06170,
P21-10425]. Empagliflozin was tested in a murine NASH model. The phenotype is 
characterized by steatohepatitis and a low degree of fibrosis induced by a combination of 
high-fat diet and the administration of streptozotocin. Treatment with empagliflozin 
prevented the development of steatosis, lobular inflammation and ballooning (NAFLD 
activity score) significantly [P16-09040]. Treatment with empagliflozin leads to an 
improvement of the lipid metabolism in the liver as indicated by a reduction of mRNAs 
coding for FAS and ACC1. Some fibrosis markers (collagen mRNAs and Sirius red staining) 
have been improved, too. However, in this specific mouse model the disease is driven by 
metabolic stimuli, it doesn’t develop fibrosis up to an F3 or F4 stage.  
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. This may lead to volume depletion and 
hypotension. 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 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].
1.3
RATIONALE FOR PERFORMING THE TRIAL
In this Phase II trial, the efficacy of treatment in patients with CSPH (defined by the presence 
of varices and HVPG ≥ 10 mmHg) in compensated cirrhosis due to HBV, HCV and NASH
with or without Type 2 Diabetes Mellitus (T2DM) will be assessed. The trial will serve to 
evaluate short-term efficacy of BI 685509 alone and in combination with empagliflozin and 
will also provide supportive evidence for the planned Phase III development together with 


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trial 1366-0021. The data of this trial will be indirectly compared with the data from trial 
1366-0021.
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.
1.4
BENEFIT - RISK ASSESSMENT
The overall safety profiles of BI 685509 and empagliflozin are outlined in the current 
Investigator’s Brochures (IB) [c02778238] and [c01678844].
1.4.1
Benefits
BI 685509 has demonstrated efficacy in pre-clinical models for cirrhosis and PH, supporting 
its potential for the treatment of PH and fibrosis.  As cGMP elevation has been associated 
with anti-fibrotic, anti-proliferative and anti-inflammatory effects, pharmacological activators 
of sGC, like BI 685509, have the potential to slow down or halt complications of cirrhosis by 
reducing PH, improving liver perfusion, and potentially having beneficial effects on the 
cardiovascular system.  This would not only improve clinical outcomes and quality of life for 
the patients, but would also reduce the need for invasive procedures and resources 
(pharmacological and non-pharmacological therapies, e.g. endoscopic variceal ligation, large 
volume paracentesis, albumin therapy, transjugular intra-hepatic portosystemic shunt [TIPS] 
and orthotopic liver transplantation), reduce overall morbidity and mortality, and improve 
survival (R19-3528, R20-1198, R20-1199).  BI 685509 is a new chemical entity at an early 
stage of development however and an individual benefit cannot be guaranteed.
The SGLT2 inhibitor empagliflozin has shown to improve the metabolic disturbances in 
metabolic driven NAFLD/NASH animal models as well as in patients. In the E-LIFT trial in 
patients with T2D and NAFLD empagliflozin reduced liver fat by about 30% and improved 
markers of inflammation [P18-05587]. BI 685509, an sGC activator has shown in cirrhotic 
animal models, to reduce fibrosis and thus the potential to improve cirrhosis. In addition to 
its anti-fibrotic effect, BI 685509 has hemodynamic effects which is assumed to be 
beneficial in portal hypertension in cirrhotic patients. Since in many NASH patients with 
compensated cirrhosis the metabolic driven insult leading to steatohepatitis still exists or is 
even further aggravated, a combination treatment of empagliflozin and BI 685509 could 
provide better efficacy than the single compounds in patients with NASH and cirrhosis. The 
combination of BI 685509 and empagliflozin, which have complementary modes of action, 
have the potential to have additive/synergistic effects on slowing progression of cirrhosis
and PH in patients with NASH and compensated cirrhosis by reducing liver fat due to action 
of empaglifozin and by reducing portal hypertension and improving liver perfusion due to 
BI 685509. Thus, this combination is expected to reduce the risk of liver-related outcomes 
and all-cause death.  


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The monitoring that is planned as part of this trial, and the intensive medical care that patients 
will receive (e.g. imaging assessments, daily measurements of vital signs etc.), may also be 
beneficial.  Furthermore, trial patients will have the opportunity to undergo HVPG 
measurement, the current gold standard to detect PH, which offers added prognostic value, a 
strong predictor of clinical decompensation.  At present HVPG measurement is only 
available at selected sites due to its invasive nature and the need for skilled technical staff to 
carry out HVPG measurements.
1.4.2
Risks
Trial participants will be exposed to trial-related risks due to exposure to the investigational 
medicinal product (BI 685509), the investigational medicinal product empagliflozin, the trial 
procedures and other risks. For details refer to Tables 1.4.2: 1, 1.4.2: 2, 1.4.2: 3 and 1.4.2:4
below
Table 1.4.2:1 
Overview of trial related risks - investigational medicinal product (BI 
685509)
Possible / known risks 
of clinical relevance
Summary of data, rationale 
for the risk
Mitigation strategy
Potential AEs such as 
hypotension / 
orthostatic 
dysregulation, 
tachycardia, peripheral 
oedema and 
gastrointestinal events 
such as diarrhoea, 
abdominal pain and 
nausea
Primarily related to the 
vasodilatory effects and 
subsequent reactions or 
gastrointestinal effects which 
are directly 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 (refer to the IB 
[c02778238] and Sections 1.2.1 and 
4.1.2).  All patients will be monitored 
for AEs, and BP and HR will be 
measured daily (by the patient at home) 
during the treatment period.  Patients 
with oedema or gastrointestinal side 
effects will be managed by standard of 
care, and patients with a known history
of orthostatic dysregulation and those 
with a SBP < 100 mmHg and a DBP < 
70 mmHg will be excluded.  In 
addition, up-titration to the maintenance 
dose within each treatment group will 
occur at weekly intervals in order to 
increase the tolerability of the trial 
medication with regards to 
cardiovascular effects.
Potential QT-interval 
prolongation
Refer to Section 1.2.1
Patients with long QT / QTcF-interval, 
patients with a family history of long 
QT syndrome, or those using 
concomitant therapies known to 
increase the risk of Torsade de Points 


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Table 1.4.2:1 
Overview of trial related risks - investigational medicinal product (BI 
685509) (cont)
Possible / known risks 
of clinical relevance
Summary of data, rationale 
for the risk
Mitigation strategy
will be excluded from the trial (refer to 
Sections 3.3.3 and 4.2.2.1).
ECGs will be performed at each visit in 
the randomised treatment period of the 
trial, and trial medication will be 
discontinued in the event of a prolonged 
QT / QTcF-interval (refer to Section 
3.3.4.1).
Risks related to drug-
drug interaction (DDI)
Refer to Section 1.2.1
Close monitoring of patients for AEs 
and restricted co-administration of 
impacted concomitant therapies such as 
treatments with a similar mechanism of 
action (i.e. activators of the NO-sGC-
cGMP pathway), clinically relevant 
therapies inhibiting the activity of 
OATP1B1/3 and clinically relevant 
UGT inhibitors.  Patients taking 
concomitant therapies that are sensitive 
CYP3A4 and CYP2C8 substrates and / 
or narrow therapeutic index CYP3A4
and CYP2C8 substrates will also be 
monitored closely.  A list, to support the 
identification of the above-mentioned 
concomitant therapies at trial sites, will 
be provided in the Investigator Site File 
(ISF).  Also refer to Sections 3.3.3 and 
4.2.2.1.  
Table 1.4.2:2
Overview risks - Investigational Medicinal Product Empagliflozin
Possible / known risks 
of clinical relevance
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 


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Table 1.4.2:2 
Overview risks - Investigational Medicinal Product Empagliflozin
(cont)
Possible / known risks 
of clinical relevance
Summary of data, rationale 
for the risk
Mitigation strategy
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).
Pharmacokinetics and 
pharmacodynamics 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.
Table 1.4.2: 3
Overview of risks – trial procedures
Possible / known risks of 
clinical relevance
Summary of data, rationale for the 
risk
Mitigation strategy
Potential risks associated 
with the HVPG 
measurement, which are 
almost exclusively related to 
the venous access, usually 
performed under local 
anaesthesia and sometimes 
mild sedation.  Common 
side effects include those 
associated with procedural 
sedation (e.g. nausea, 
vomiting, aspiration 
pneumonia, irregular 
heartbeat, breathing 
difficulties), pain at the 
insertion site, or slight 
thoracic or abdominal 
discomfort when advancing 
the catheter through the vena 
cava system into the hepatic 
vein and while inflating the 
balloon.  Specific but rare 
complications related to the 
venous access include 
haematomas at the access 
The HVPG procedure is the gold 
standard to assess portal pressure 
quantitatively, but it is invasive, 
resource-intensive, and requires 
interventional skills and expertise in 
interpreting the reliability and 
plausibility of pressure readings (refer 
to Section 5.1.1). Hence, the procedure 
is not commonly performed as part of 
clinical practice.  To date, there are no 
alternative, non-invasive parameters 
reflecting the degree of portal pressure 
with similar accuracy as HVPG.  The 
complication rate of HVPG 
measurement is low, and the pressure 
measurement itself is not painful.  
Patients may be sedated if required 
(e.g. they are nervous) or based on 
defined standards.  The procedure is 
performed using ultrasound-guidance, 
and under fluoroscopic control with 
use of ionising radiation and ICM.  
Radiation exposure is, in most cases, 
very limited and the effective dose 
received by patients (~ 5.4 mSv) is 
Risks relating to HVPG 
measurements will be 
mitigated by conducting 
the trial at sites where the 
staff is experienced in / 
have access to a nearby 
site experienced in the 
procedure.  Such sites 
will be familiar with 
preparing patients before 
the procedure, allaying 
any fears, and the 
subsequent patient 
monitoring that is 
required.  This might 
include adequate
hydration to help avoid 
e.g. contrast-induced 
renal injury, and 
educating patients 
regarding symptoms 
suggestive of 
complications.  Patients 
will be monitored for 
AEs, and those with 


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Table 1.4.2: 3
Overview of risks – trial procedures (cont)
Possible / known risks of 
clinical relevance
Summary of data, rationale for the 
risk
Mitigation strategy
site, pneumothoraces 
requiring a chest tube and 
cardiac arrhythmias (R20-
3977).  Iodinated contrast 
material (ICM) also has the 
potential to cause 
hypersensitivity and can lead 
to contrast-induced renal 
injury
inferior to most diagnostic radiology 
examinations of the abdomen and 
similar to that of a plain X-ray of the 
upper gastrointestinal tract (R20-4181, 
R20-4191, R20-3299).  The volume of 
ICM used is in the region of 7 mL
(R20-4181)
contraindications to the 
procedure will be 
excluded.  The burden of 
HVPG measurements on 
the patient will also be 
reduced as far as possible 
in terms of the chosen 
trial design (refer to 
Section 3.2)
Possible complications due 
to gastroscopy include side 
effects from procedural 
sedation (e.g. nausea, 
vomiting, aspiration 
pneumonia, irregular 
heartbeat, breathing 
difficulties), bleeding (e.g. 
due to damaged blood 
vessels or ruptured varices) 
and perforation (e.g. to the 
oesophageal lining, stomach 
or duodenum).  After the 
procedure, patients may also 
experience abdominal 
bloating / gas caused by the 
introduction of air into the 
stomach.  These side effects 
are usually short-lived  
A gastroscopy will be performed at 
screening where required (refer to 
Section 5.2.5.2).  The assessment will 
allow an assessment of the status of 
the varices.  In general, a gastroscopy 
is a safe procedure with both a 
diagnostic and interventional use in 
liver disease offered to patients with 
relevant symptoms and for variceal 
screening and treatment (R21-0296).  
The risks of serious complications are 
small
The procedure will be 
performed by 
appropriately trained 
professionals, and sites 
will be expected to follow 
local standard processes.  
Possible risks will be 
mitigated by monitoring 
patients for AEs, and 
patients with 
contraindications to 
gastroscopy will be 
excluded.  Patients who 
develop side effects will 
be managed according to 
standard of care
Ultrasound waves can heat 
the tissues slightly, and, in 
some cases, can also produce 
small pockets of gas in body 
fluids or tissues (cavitation), 
the long-term consequences 
of which are unknown  
Ultrasound imaging (sonography) of 
the liver and spleen will be performed 
primarily to assess the size and depth 
of the spleen,
 
 
Ultrasound will also be used to assess 
any safety issues such as ascites.  It is 
a safe procedure routinely carried out 
in patients with liver disease.  There 
are no absolute contraindications to 
performing an abdominal ultrasound  
Ultrasound imaging will 
be performed by 
appropriately trained 
professionals.  Risks will 
be mitigated by 
monitoring patients for
AEs  
Potential risks of blood 
sampling by venipuncture or 
through an indwelling 
catheter such as fainting, 
pain, bruising, swelling, or 
No health-related risk is expected from 
the total volume of blood withdrawn 
per patient during the trial.  Blood 
sampling is a general risk, acceptable 
in the framework of clinical trial 
Evaluation of the medical 
expertise of the trial sites 
will be part of the site 
feasibility assessment.  In 
addition, and to ensure 


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Table 1.4.2: 3
Overview of risks – trial procedures (cont)
Possible / known risks of 
clinical relevance
Summary of data, rationale for the 
risk
Mitigation strategy
rarely, transient 
inflammation or infection 
where the needle is inserted.  
In rare cases a nerve may be 
damaged inducing long-
lasting abnormal sensations 
(paraesthesia) or impaired 
sensation of touch and 
persistent pain  
participation
patient safety, all events 
or symptoms reported 
will be managed 
according to the 
judgement of the 
Investigator
Table 1.4.2: 4
Overview of risks – other risks and safety measures
Possible / 
known risks 
of clinical 
relevance
Summary of data, 
rationale for the risk
Mitigation strategy
Drug-induced 
liver injury 
(DILI)
A rare but severe event, 
thus under constant
surveillance by 
Sponsors and 
regulators.  No DILI 
cases have been 
observed in current BI 
685509 or
empagliflozin clinical 
trials
This trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver 
laboratory parameters to ensure patients´ safety.  
Removal and stopping criteria have also been defined, 
and there will be oversight of DILI by a Data 
Monitoring Committee (DMC).  Hepatic injury will 
also be adjudicated by an independent adjudication 
committee (AC).  Refer to Sections 3.2, 3.3.4.1, 
5.2.5.3, 5.2.6.1.4, 8.7 and Appendix 10.2
Unintentional 
exposure of an 
embryo or 
foetus to trial 
medication
Based on the findings in 
pre-clinical studies 
conducted to date and in 
accordance with 
international regulatory 
guidelines, the inclusion 
of WOCBP in this trial 
is justified  
To minimise the risk, WOCBP must agree to the 
requirements for pregnancy testing.  Both WOCBP 
and men able to father a child (with a female sexual 
partner of CBP) must also agree to the contraceptive 
methods described (refer to Sections 3.3.2 and 4.2.2.3)  
Patients may 
develop 
Based on the mode of 
action BI 685509 is not 
Patients with an active infection with SARS-CoV-2 
will be excluded from the trial, and in case of a 


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Table 1.4.2: 4
Overview of risks – other risks and safety measures (cont)
Possible / 
known risks 
of clinical 
relevance
Summary of data, 
rationale for the risk
Mitigation strategy
severe acute 
respiratory 
syndrome 
coronavirus 2 
(SARS-CoV-
2) or other 
severe
infection
expected to have a 
relevant impact on the 
susceptibility to or the 
course of an infection. 
However, the 
underlying disease(s) of 
the patient population in
this trial and the 
anticipated age of 
recruited patients does 
increase the risk of 
hospitalisation and 
intensive care in case of 
a SARS-CoV-2 or other 
severe infection
confirmed severe infection, trial treatment will be 
discontinued immediately and appropriate measures 
for monitoring, treatment and quarantine will be 
implemented.  There are no trial-related restrictions 
regarding COVID-19 vaccination; patients can 
participate in the trial irrespective of their vaccination
status, and vaccination during the trial is not restricted.
In the event of force majeure or other disruptive 
circumstances (e.g. pandemic, war) the investigational 
plan as per this CTP may not be feasible at a site.  
With the consent of the patient, the Sponsor and 
Investigator may agree on alternative, back-up or 
rescue methodology which may include, but will not 
be limited to, virtual patient visits and assessments, 
home healthcare nurse visits, and direct-to-patient 
shipments of trial medication.  For full details refer to 
Section 6  
A Hepatic Injury Adjudication Committee (AC) and 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
The nature of the target and the mechanism of action of BI 685509 and empagliflozin is well 
understood.
In the context of the unmet medical need and anticipated benefit of BI 685509, the benefit 
risk evaluation of the compound, as well as empagliflozin, based upon the available 
preclinical and clinical information, is favourable.
Considering the medical need for the development of a better tolerated and more effective 
treatment for patients with CSPH in compensated cirrhosis due to HBV, HCV, and NASH
with or without T2DM, the expected benefit outweighs the potential risks.
Patients with NASH, HBV, HCV, and cirrhosis with PH might benefit from the combined 
anti-fibrotic and hemodynamic effects of sGC activation (refer to Section 1.1).  Treatment 
with BI 685509 alone in HBV, HCV and NASH patients and in combination with 
empagliflozin in NASH patients with T2DM who already developed cirrhosis will potentially 
result in the prevention of related complications including decompensation (variceal 
bleeding, ascites and encephalopathy), transplantation, or liver-related death.  The potential 
risks, as described above, will be minimised by close monitoring of patients, by excluding at-
risk patients from the trial, and by involvement of a DMC – refer to Sections 3.2 and 8.7.  


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Hepatic injury will also be assessed by an independent AC for safety purposes (refer to 
Sections 3.2, 5.2.5.3 and 8.7).  Hence, overall, in the context of the unmet medical need, the 
anticipated effects of BI 685509 and empagliflozin on CSPH in patients with compensated 
cirrhosis due to NASH with or without T2DM, HBV and HCV, and based on the safety 
profile of BI 685509 and empagliflozin, the benefit-risk evaluation of the compounds is 
considered favourable for the intended population.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The trial will investigate the safety and tolerability of BI 685509 in patients with CSPH in 
compensated cirrhosis due to HBV, HCV and NASH with or without T2DM and the 
combination of BI 685509 and empagliflozin in patients with CSPH in compensated cirrhosis 
due to NASH with T2DM, on top of standard of care respectively. The primary objective is to 
estimate the percentage change in HVPG from baseline measured after 8 weeks. The primary 
analysis will be made for treated patients with baseline HVPG measurements (Full Analysis 
Set, FAS) as if all patients took treatment for the duration of the trial.
2.1.2
Primary endpoint(s)
The primary endpoint is the percentage change in HVPG from baseline (measured in mmHg) 
after 8 weeks of treatment.
2.1.3
Secondary endpoint(s)
Secondary endpoints include:
occurrence of a response, which is defined as > 10% reduction from baseline HVPG 
(measured in mmHg) after 8 weeks of treatment  
occurrence of one or more decompensation events (i.e. ascites, VH, and / or overt HE) 
during the 8-week treatment period
occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on Investigator 
judgement, during the 8-week treatment period
occurrence of discontinuation due to hypotension or syncope during the 8-week treatment 
period
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS
2.2.1
Further objectives
In addition to the main objectives defined above, further objectives of this trial include an 
evaluation of general safety,


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2.2.2
Further endpoints
Further endpoints include (but will not be limited to) those shown below.




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o
Additional further endpoints may be defined in the Trial Statistical Analysis Plan (TSAP).


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This phase II multi-national, randomised, open-label and parallel group trial to investigate the 
effects of oral BI 685509 alone and in combination with empagliflozin on portal hypertension 
after 8 weeks treatment in patients with clinically significant portal hypertension (CSPH) in 
compensated cirrhosis.
Patients will be enrolled in the trial and screened for eligibility once they have signed the 
informed consent. The screening period consists of up to 3 visits (Visits 1a, b and c) and will
last a maximum of 6 weeks.  Patients will be able to progress from one visit to the next when 
eligibility of the previous visit is confirmed.  Assessments will include a gastroscopy (if 
applicable – refer to Section 5.2.5.2), ultrasound of the liver and spleen, 
 and measurement of HVPG.  Patients who remain eligible and who 
successfully complete this period will proceed to the 8-week open label, active treatment 
period.    
In total, 80 patients with HBV, HCV or NASH (with or without T2DM) will enter the trial 
with a minimum of 20 patients in the NASH treatment group 3 and a minimum of 20 patients 
in the NASH treatment group 4.
NASH patients without diagnosis of T2DM can only enter treatment group 3 (
BID BI 
685509 alone) at Visit 2. NASH patients with diagnosis of T2DM will be randomized at visit 
2 in a 1:1 ratio into either treatment group 3 
BID BI 685509 alone) or treatment group 4
BID BI 685509 + 10mg QD empagliflozin) Although randomization is applied, the 
patients, investigators and sponsors will stay unblinded due to the open-label nature of this 
trial.
Following enrollment and randomization at visit 2, patients will begin the intake of trial 
medication(s) and will enter a dose-titration period of BI 685509.  All patients in all 4 
treatment groups will start this period on a dose of
BID BI 685509.  If the dose is 
tolerated, one week later (at Visit 3, day 8), the dose for all patients will be up-titrated to
BID BI 685509.  If this dose is tolerated, a second up-titration to
BID BI 685509 
will occur after another week (at Visit 4, day 15). Following the dose-titration period, and if 
the dose is tolerated, patients will remain on the highest dose of BI 685509 for the remainder 
of the treatment period until they reach the End of Treatment (EoT) visit and 8 weeks of 
treatment.  If the dose is not tolerated, trial medication may be interrupted or the dose can be 
reduced / down-titrated. Patients in the treatment group 4 will receive a fixed dose of 10mg 
QD empagliflozin in addition to BI 685509 starting at visit 2.
The ultrasound
of the liver and spleen, and the HVPG measurement will be 
repeated during the treatment period (refer to Figure 3.1: 1). 
                
After the 8 week treatment period all patients will enter a 4 week follow-up period without 
trial medication.  The patient’s participation in the trial will be complete when they have 
performed the last planned visit (i.e. End of Study [EoS], 4 weeks after EoT).


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Figure 3.1: 1 Trial design schematic
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A randomised, open-label and parallel group design has been chosen for this exploratory trial
with a very short treatment period, on top of standard of care.  The parallel group will enable 
comparison of four different patient groups and the open label design will provide benefit to 
all patients participating in it.
A treatment duration of 8 weeks has been chosen to allow an evaluation of short-term 
efficacy and indirect comparison to the week 8 results from trial 1366-0021.  
The patient population of this trial (HBV, HCV and NASH patients with and without T2DM) 
has been chosen as it represents a sub-set of the intended patient population for BI 685509
(patients with clinically significant portal hypertension in compensated cirrhosis due to non-
cholestatic liver diseases).  In parallel, Trial 1366-0021 is conducted to investigate efficacy 
and safety of BI 685509 in alcohol-related liver disease (ARLD) patients with a treatment 
duration of 24 weeks. The 8-week interim analysis data of Trial 1366-0021 and the final data 
of this trial will allow evaluation of the short-term efficacy and safety of BI 685509 on portal 
hypertension in the most common liver diseases. The aim of this study is to evaluate, whether 
the portal pressure can be reduced in a similar fashion as in trial 1366-0021 in patients with 
ARLD, and therefore no placebo arm is needed.
In Arm 4, a combination of BI 685509 and empagliflozin will be investigated exploratorily to 
assess the additional benefit of metabolic improvement by a SGLT2 inhibitor, in this study 
empagliflozin, in patients with NASH and T2DM.


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For details regarding the choice of renal function in the patient population, refer to Section 
1.2. 
The measurement of HVPG was chosen as the primary endpoint as it is the gold standard to 
estimate portal venous pressure in patients with cirrhosis, i.e. assessing the severity of 
sinusoidal PH (R20-4090).  It is used as an established surrogate marker for improvement and 
/ or worsening of liver fibrosis / function, since a decrease in HVPG translates into a 
clinically meaningful benefit (R20-1204).  The prognostic value of HVPG has been 
underlined by several landmark studies, showing that an HVPG ≥ 10 mmHg (i.e. CSPH) is 
predictive of the formation of varices (R20-4092), while a (pharmacologically-induced) 
decrease of HVPG modulates the respective risk of variceal growth and decompensation 
(R20-4093, R20-4091).  Hence, this also explains the choice of the secondary endpoint 
relating to the occurrence of one or more decompensation events (refer to Section 2.1.3).  
Other secondary endpoints (occurrence of significant hypotension or syncope, and occurrence 
of discontinuation due to hypotension or syncope) were chosen as they are relevant based on 
the mechanism of action of BI 685509. 
Patients will be screened for the trial based on the eligibility criteria (refer to Sections 3.3.2
and 3.3.3).  These include the selection of patients with documented endoscopically proven 
gastro-oesophageal varices or documented endoscopic-treated oesophageal varices as 
preventative treatment, as varices only occur in patients with CSPH.  At Visit 1c (the final 
visit within the screening period) patients who remain eligible following Visits 1a and 1b will 
undergo their first HVPG measurement.  Those with an HVPG ≥ 10 mmHg (based on a local 
interpretation of the pressure tracing) will remain eligible.  With this approach, the trial is 
designed to enrol patients with CSPH but the burden of the invasive HVPG procedure will be 
reduced and only performed on patients who successfully reach Visit 1c, rather than on all 
screened patients.  
Non-invasive assessments (i.e. ultrasound
of the liver and spleen and 
functional liver testing) have been chosen as part of the screening procedures to further 
investigate the patients’ status, to establish baseline values for comparison with treatment, 
 These assessments will be repeated (refer to Figure 3.1: 1 and the Flow 
Chart) to assess a time-dependency of the treatment.
Following enrolment / randomisation, the trial design includes a dose-titration period.  The 
mechanism related vasodilatation of BI 685509 can lead to orthostatic dysregulation and 
hypotensive episodes (refer to Table 1.4.2: 1).  The orthostatic dysregulation is dose-limiting 
and clinical tolerability is improved if the dose is titrated.  A BID administration also allows
the total daily exposure of BI 685509 to be further increased while high peak concentrations 
are avoided.  Hence, in this trial, a dose-titration regimen of 
BID to
BID to 
BID will be followed.  
Patients selected for this trial have a risk for further progression into decompensation, a 
severe outcome.  A DMC, independent from the Sponsor, will therefore be established to 
review safety data at intervals to identify any potential risks and / or the need for 
implementation of further safety measures.  The tasks and responsibilities of the DMC 
members will be detailed in the DMC charter (refer to Section 8.7).


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An independent AC will also be established for adjudication of hepatic injury.  The tasks and 
responsibilities of the AC members will be detailed in the AC charter (refer to Section 8.7).
3.3
SELECTION OF TRIAL POPULATION
80 patients with CSPH in compensated cirrhosis due to HBV, HCV and NASH with or 
without T2DM will be enrolled into the trial. Approximately 42 sites are planned across 
multiple countries.  It is anticipated that 2 patients will be randomised at each site.  If 
enrolment is delayed, additional sites may be recruited.
Screening of patients for this trial is competitive, i.e. screening for the trial or one of the 
treatment arms will stop at all sites at the same time once a sufficient number of patients have
been screened to deliver the required number of randomised patients. Investigators will be 
notified about the 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.
Re-testing during the screening period is allowed once (e.g. if the Investigator believes an 
ineligible laboratory test is the result of an error or extenuating circumstances, the test can be 
repeated once without the patient having to be re-screened). This excludes the gastroscopy 
and the HVPG measurement. Re-screening is also allowed once provided that the reasons for 
screen failure were reversible and have been resolved, based on Investigator judgement.  A 
patient is considered a “re-screener” if he / she was not eligible for the trial initially and is 
subsequently re-screened, going through the informed consent process for a second time, 
receiving a new unique patient number and repeating the screening period assessments.  
A log of all patients enrolled into the trial (i.e. who have signed the informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If retrospectively it is found that a patient has been enrolled 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.
3.3.1
Main diagnosis for trial entry
The trial will include patients with compensated cirrhosis due to HBV, HCV and NASH 
(with or without T2DM) with endoscopic proof of gastro-oesophageal varices, or endoscopic-
treated oesophageal varices as preventative treatment, as a sign of CSPH, together with an 
HVPG ≥ 10 mmHg.  
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.


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3.3.2
Inclusion criteria
1.
Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
2.
Male or female who is ≥ 18 (or who is of legal age in countries where that is greater than 
18) and ≤ 75 years old at screening (Visit 1a)
3.
Clinical signs of CSPH as described by either one of the points below.  Each trial patient
must have a gastroscopy during the screening period (Visit 1b) or within 6 months prior 
to screening (Visit 1b).  For further details refer to Section 5.2.5.2
(i) documented endoscopic proof of oesophageal varices and / or gastric varices at 
screening (Visit 1b) or within 6 months prior to screening (Visit 1b)
(ii) documented endoscopic-treated oesophageal varices as preventative treatment  
4.
CSPH defined as baseline HVPG ≥ 10 mmHg (measured at Visit 1c), based on a local 
interpretation of the pressure tracing (refer to Section 5.1.1 for further details)
5.
Diagnosis of compensated cirrhosis due to HCV, HBV, or NASH with or without
T2DM.  Diagnosis of cirrhosis must be based on histology (historical data is acceptable) 
or on clinical evidence of cirrhosis (e.g. platelet count < 150 x 109/L [150 x 103/µL], 
nodular liver surface on imaging or splenomegaly etc.)
Diagnosis of NASH based on either 
i. Current or historic histological diagnosis of NASH OR steatosis
OR
ii. Clinical diagnosis of NASH based on historic or current imaging 
diagnosis of fatty liver 
 US, MRI, CT) AND at least 2 
current or historic comorbidities of the metabolic syndrome 
(overweight/obesity, T2DM, hypertension, hyperlipidemia) 
6.
Willing and able to undergo HVPG measurements per protocol (based on Investigator
judgement)
7.
If receiving statins must be on a stable dose for at least 3 months prior to screening (Visit 
1b), with no planned dose change throughout the trial
8.
If receiving treatment with NSBBs or carvedilol must be on a stable dose for at least 1
month prior to screening (Visit 1b), with no planned dose change throughout the trial  
9. If receiving pioglitazone, GLP1-agonists, or vitamin E must be on a stable dose for at 
least 3 months prior to screening (Visit 1b), with no planned dose change throughout the 
trial


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10. WOCBP1 must be ready and able to use 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 from the randomisation visit (Visit 2) until 7 days after the last 
treatment in this trial.  The patient must agree to periodic pregnancy testing during 
participation in the trial.  Refer to Section 4.2.2.3 and the patient information for a list of 
contraception methods meeting these criteria 
11. Men able to father a child and who have a female sexual partner of CBP, must use a 
condom with or without spermicide, or adopt complete sexual abstinence, or be 
vasectomised (with appropriate post-vasectomy documentation of the absence of sperm 
in the ejaculate), from the randomisation visit (Visit 2) until 7 days after the last 
treatment in this trial.  Refer to Section 4.2.2.3 and the patient information for further 
details 
3.3.3
Exclusion criteria
1. Previous clinically significant decompensation events (e.g. ascites [more than perihepatic 
ascites], VH and / or overt / apparent HE)
2. History of other forms of chronic liver disease (e.g. alcohol-related liver disease (ARLD), 
autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, 
Wilson’s disease, haemachromatosis, alpha-1 antitrypsin [A1At] deficiency)
3. Patients without adequate treatment for HBV, HCV or NASH as per local guidance (e.g. 
antiviral therapy for chronic HBV or HCV infection or lifestyle modification in NASH)

if received curative anti-viral therapy for HCV, no sustained virological response 
(SVR) or SVR sustained for less than 2 years prior to screening or if HCV RNA 
detectable

If receiving anti-viral therapy for HBV, less than 6 months on a stable dose prior to 
screening, with planned dose change during the trial or HBV DNA detectable

Weight change ≥ 5% within 6 months prior screening
4. Must take, or wishes to continue the intake of, restricted concomitant therapy (refer to 
Section 4.2.2.1) or any concomitant therapy considered likely (based on Investigator 
judgement) to interfere with the safe conduct of the trial
5. SBP < 100 mmHg and DBP < 70 mmHg at screening (Visit 1a)
1A woman is considered of child-bearing potential, i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile.  Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy.  Tubal ligation is NOT a method of permanent sterilisation.  A post-
menopausal state is defined as no menses for 12 months without an alternative medical cause


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6. Model of End-stage Liver Disease (MELD) score of > 15 at screening (Visit 1a), 
calculated by the central laboratory
7. Hepatic impairment defined as a Child-Turcotte-Pugh score ≥ B8 at screening (Visit 1a), 
calculated by the site, using central laboratory results (refer to Appendix 10.3)
8. ALT or AST > 5 times upper limit of normal (ULN) at screening (Visit 1a), measured by 
the central laboratory
9. eGFR (CKD-EPI formula) < 20 mL/min/1.73 m2 at screening (Visit 1a), measured by the 
central laboratory
10. Alpha-fetoprotein > 50 ng/mL (> 50 µg/L) at screening (Visit 1a), measured by the 
central laboratory
11. An active infection with SARS-CoV-2 (or who is known to have a positive test from 
screening [Visit 1a] until randomisation [Visit 2])
12. Prior orthotopic liver transplantation
13. Prior or planned TIPS or other porto-systemic bypass procedure
14. Known portal vein thrombosis
15. History of clinically relevant orthostatic hypotension, fainting spells or blackouts due to 
hypotension or of unknown origin (based on Investigator judgement)
16. QTcF-interval >450 ms in men or >470 ms in women at screening (Visit 1a), a family 
history of long QT syndrome, or concomitant use of therapies with a known risk of 
Torsade de Pointes or planned initiation of such therapies during the trial (refer to Section 
4.2.2.1)
17. Type 1 diabetes mellitus, or history of other autoimmune causes of diabetes mellitus (e.g. 
LADA)
18. Patients at increased risk of ketoacidosis in the opinion of the investigator.
19. Contraindication to any of the trial assessments (e.g. poor patient co-operation for 
gastroscopy,
 
etc.)   
20. Major surgery (major according to the investigator’s assessment) performed within 12
weeks prior to randomisation (Visit 2) or planned during the trial, e.g. hip replacement.
21. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening (Visit 1a), except appropriately treated basal cell carcinoma of the skin 
or in situ carcinoma of uterine cervix


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22. History of (in the 6 months prior to randomisation [Visit 2]), or ongoing, chronic drug 
abuse, or not expected to comply with the protocol requirements for any other reason that, 
based on Investigator judgement, makes the patient an unreliable trial recruit or unlikely 
to complete the trial as scheduled
23. Previous randomisation in this trial, previous exposure to BI 685509, or an allergy / 
contraindication to BI 685509 and / or empagliflozin and / or any of the excipients  
24. Currently enrolled in another investigational device or drug trial, or less than 30 days or 5 
half-lives (whichever is longer) prior to randomisation (Visit 2) since ending another 
investigational device or drug trial, or receiving other investigational treatment(s) 
25. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
26. Any other medical condition2 that, based on Investigator judgement, poses a safety risk 
for the patient or may interfere with the objectives of the trial
3.3.4
Discontinuation of patients from trial medication and assessments
Patients may discontinue trial treatment after enrolment 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.
However, if the patients agree, they should stay in the trial. Even if continued trial treatment 
is not possible, they should attend further trial visits to ensure their safety and to collect 
important trial data.
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).
Patients who discontinue after randomisation will not be replaced and may not be re-enrolled 
later.  However, the Sponsor may decide to randomise more patients than originally planned, 
to account for a reduced sample size, if patients terminate early due to e.g. trial disruption 
(such as measures to control a global pandemic).
2 Examples of medical conditions may include, but are not limited to: symptomatic heart failure (New York 
Heart Association [NYHA] III/IV), known history of tachycardia, clinically relevant arrhythmias, coronary heart 
disease not compensated by medical treatment (existing unstable angina pectoris)


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3.3.4.1
Discontinuation of trial treatment
Ideally, the patient should attend all remaining visits. Should the patient not agree, at least 
phone contacts should occur at the scheduled visit time points, should that not be acceptable, 
a phone contact once a year or at the end of the planned observation period should occur to 
collect the most relevant information: vital status (please see section 5.2.6.2.1 ), outcome 
events, adverse events, or last contact date in case of lost to follow-up. 
An individual patient will discontinue trial treatment (BI 685509 and empagliflozin) if:

the patient wants to discontinue trial treatment. The patient will be asked to explain the 
reasons but has the right to refuse to answer.

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. 

the patient needs to take concomitant medication that interferes with the safety/efficacy of 
the investigational medicinal product or other trial treatment (refer to Section 4.2.2.1). If 
short-term, acute use of a restricted concomitant therapy is required (e.g. 5-7 days of 
antibiotic treatment for an infection), this will not automatically require discontinuation of 
BI 685509 or empagliflozin. Similarly, if a patient needs to modify a dose, where only a 
stable dose is permitted (e.g. NSBBs / carvedilol, statins, anti-viral therapy for HBV, 
pioglitazone, GLP1-agonists, or vitamin E), this also will not automatically require 
discontinuation. In both cases, the Sponsor should be consulted.

the patient experiences a severe infection, e.g. with SARS-CoV-2, as determined by the 
Investigator 

the patient meets the criteria for hepatic injury (refer to Section 5.2.6.1.4 and Appendix 
10.2)

the patient has an acute liver decompensation event such as VH, new-onset of ascites, 
new-onset of overt encephalopathy, or other new-onset decompensation event based on
Investigator judgement

patients with worsening of their liver function (e.g. from Child-Turcotte-Pugh A to Child-
Turcotte-Pugh B with clinical evidence of deteriorating liver function in the opinion of 
the Investigator).  Refer to Child-Turcotte-Pugh classification method in Appendix 10.3

patients with a QT or QTcF interval > 500 ms, or an increase of QT or QTcF of > 60 ms 
from the pre-dose value at Visit 2 / enrolment (baseline). Such cases must be reported as 
AEs

the patient can no longer receive trial medication for other medical reasons such as 
surgery, AEs, other diseases

the patient has not successfully completed the dose titration period (i.e. Visit 4), but has 
persistent AEs or severe effects requiring down-titration of the trial medication (refer to 
Section 4.1.4.1)

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 (CTR) until last patient last visit and any events 
thereafter will be reported in the BI Pharmacovigilance (PV) database (refer to Section 
5.2.6.2.3)


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Trial-specific procedures have also been defined for Investigators to follow in case of 
increased liver enzymes (AST, ALT, and total bilirubin) after enrolment.  For details refer to 
Section 5.2.6.1.4 and Appendix 10.2 (P09-12413).
In the event of intolerance to BI 685509 after successful completion of the dose titration 
period at Visit 4 (e.g. persistent AEs despite two down-titrations, or severe effects at any 
dose), permanent treatment discontinuation should also be considered, based on Investigator 
judgement (refer to Section 4.1.4.1).  
In addition to these criteria, the Investigator may discontinue patients at any time based on 
clinical judgement. 
If a patient permanently discontinues the trial medications before the last allocated dose, an 
Early Discontinuation (ED) visit is required ideally within 7 days of discontinuing the
medication. An EoS visit should be performed 4 weeks after the ED visit.  Refer to Sections 
6.2.2.1 and 6.2.3 for further details, including guidance with respect to trial assessments that 
should be included as part of an ED visit.
An individual patient will permanently discontinue empagliflozin if:

Ketoacidosis is suspected.

Fournier’s gangrene is suspected.
If a patient in treatment arm 4 permanently discontinues empagliflozin or BI 685509, the 
patient must permanently stop the treatment with the other trial medication as well.
In the following cases, empagliflozin must be interrupted:

Complicated UTI, including urosepsis

Symptomatic volume depletion
In case of a temporary discontinuation, trial medication (BI 685509 and/or empagliflozin)
should be restarted if medically justified; refer to Section 4.1.4 for details, including 
instructions regarding dose adjustments.
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 actions to guarantee the safety of the trial patients.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.


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If a patient withdraws consent for further trial participation, no further data will be collected 
from the respective patient.
Reporting of data of patients who discontinue/withdraw after randomization/entering the 
active treatment phase is described in Section 7.2.1.
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 (e.g. following a recommendation by the DMC), 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 sections 
3.3.4.1, 6.2.2.1 and 6.2.3.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENT
The investigational medicinal products in the trial are BI 685509 and empagliflozin.  BI will 
supply all products.  
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the investigational medicinal products are described in Tables 4.1.1: 1
to 4.1.1: 4 below.
Table 4.1.1: 1
BI 685509
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Posology:
BID
Method and route of administration:
Oral
Table 4.1.1: 2
BI 685509
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Posology:
BID
Method and route of administration:
Oral
Table 4.1.1:3
BI 685509
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Posology:
BID
Method and route of administration:
Oral


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Table 4.1.1: 4
Empagliflozin 10 mg
Substance:
Empagliflozin
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg
Posology:
QD
Method and route of administration:
Oral
4.1.2
Selection of doses in the trial and dose modifications
BI 685509 has been tested in a single rising dose trial, a food effect and DDI trial and two 
MRD trials in male healthy volunteers.  Single doses ranged from
to 5.0 mg and 
multiple doses up to
daily were tested.  Overall, BI 685509 was well tolerated except 
for dose-limiting orthostatic dysregulation.  Up-titration and 3 times daily dosing markedly 
improved the cardiovascular tolerability (refer to the IB [c02778238]).  
One multiple oral rising dose trial in patients with DN has also been completed.  Multiple 
oral doses up to
TID were found to be safe and well tolerated.  The highest total daily 
dose of
was achieved following up-titration in 2 steps over 14 days. 
An estimated human dose of
BID is predicted to achieve pharmacologically relevant 
exposure in patients with hepatic impairment [c02778238, n00261471-01].  As
is the 
maximum tolerated single dose, 2 doses 
BID and
BID) will be evaluated in the
phase II trial 1366-0021, that is conducted in parallel in patients with CSPH in compensated 
alcohol-related cirrhosis. These doses have been selected based on safety and preliminary PK 
results from the ongoing Phase I MRD hepatic impairment trial (1366-0020).
In this trial,
BI 685509 BID maintenance dose and one arm
BI 685509 BID on top 
of 10 mg empagliflozin QD will be evaluated in the 3 different patient groups, with the 
potential to down-titrate, if not tolerated. The dose of 10mg empagliflozin QD was selected 
based on the dose used in the ongoing phase III empagliflozin in CKD trial (BI 1245-0137)
[c01678844].
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will enter the 
treatment phase at visit 2. HBV patients will be assigned to treatment group 1 and HCV 
patients to treatment group 2 via an Interactive Response Technology (IRT) system. NASH 
patients with T2DM will be randomised to treatment group 3 or 4 in a 1:1 ratio via the IRT
system. NASH patients without diagnosis of T2DM will only be assigned to treatment group 
3 via IRT. Refer to Section 7.4 for further details regarding randomisation and access to the 
randomisation code.


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Note that the medication numbers, assigned via the IRT system at each dispensing visit, are 
different from the patient number (which is generated via the IRT system when a new patient 
is registered [screened] in the system).
The Investigator (and relevant designated site personnel) will be provided with instructions to 
access the IRT system. The medication list is unblinded.
4.1.4
Drug assignment and administration of doses for each patient
Trial medication will be dispensed at the investigational sites in accordance with the Flow 
Chart.  At dispensing visits patients will be given the appropriate number of medication kits
for BI 685509 (range 1-2) and empagliflozin (range 1-2) depending on the interval between 
the visits (for further kit details refer to Section 4.1.6). The last dose of BI 685509 will be 
administered in the evening of the day before the EoT visit and the last dose of empagliflozin 
in the morning of the day before the EoT visit.  
All patients will start on a dose of 
BI 685509 BID at Visit 2. Treatment group 4 will 
receive a fixed dose of 10mg empagliflozin QD in addition. 7 days later, at Visit 3, and again 
at Visit 4, 7 days after Visit 3, all patients will be up-titrated to a dose of
BI 685509 
BID, and then to the maintenance dose of 
 BI 685509 BID.  
Patients will be informed of the dose titration period and will be made aware that up-titration 
for BI 685509 is being used.  If a patient does not tolerate an up-titration, e.g. due to 
orthostatic dysregulation, the rules in Section 4.1.4.1 must be followed.  From Visit 4 
onwards, patients of the treatment group 1, 2, 3 and 4 will continue to receive the maximum 
dose of
BI 685509 (plus 10mg empagliflozin QD for group 4 only) until reaching the 
EoT visit (8 weeks after starting the trial medication).
If a patient has an AE that, based on Investigator judgement, may be related to BI 685509 or
empagliflozin, the trial medication can either be:

interrupted (i.e. the trial medication is stopped, and subsequently re-started. The up-
titration approach described above is followed.)
OR

the dose can be reduced (down-titrated) for BI 685509 if the patient has successfully 
completed the dose titration period (i.e. Visit 4). No dose reduction is allowed for 
empagliflozin.
For further details refer to Sections 4.1.4.1 and 4.1.4.2.
All trial medication assignments, including up / down-titrations for BI 685509 and provision 
of replacement kits, will be managed through the IRT system.  Down-titrations of BI 685509 
must not be performed by instructing the patient to take less than the two daily doses (refer to 
Section 4.1.4.1).  


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Table 4.1.4: 1
Drug assignment and dosage by treatment group
Randomisation Allocation
Week 1 of Treatment
Week 2 of Treatment
Week 3 of Treatment 
Onwards
Dispensed at Visit 2
Dispensed at Visit 3
Dispensed at Visit 4 
onwards
Treatment group 1, 2 and 3
(BI 685509 
BID)
 BI 685509 
    
BI 685509 
(Up-titration)
BI 685509
(Up-titration)
Treatment group 4
(BI 685509 
BID +
Empagliflozin 10mg QD)
BI 685509
+
10mg Empagliflozin
BI 685509
(Up-titration)
+
10mg Empagliflozin
BI 685509
(Up-titration)
+
10mg Empagliflozin
From the start of the treatment period (i.e. from Visit 2), and until reaching the EoT visit 8
weeks later, patients will be instructed to take BI 685509 orally twice a day (BID) and 
empagliflozin orally once a day (QD).  
Each dose of BI 685509 will consist of one film-coated tablet. It is recommended that the 
first daily dose is taken in the morning, and the second dose in the evening.  Ideally there 
should be at least 10 hours in between the intake of each dose.  BI 685509 should be taken at 
approximately the same time every day.  If a dose is missed this must not be rectified by 
taking two doses (i.e. double doses) at the next time point; if a dose is missed by more than 6 
hours, that dose should be skipped altogether and the next dose taken as scheduled.  Also 
refer to Section 4.1.4.2 for further details regarding interruption of trial medication.  Trial
medication should be taken with a glass of water and can be taken with or without food.
Patients in the treatment group 4 will be taking in addition one film-coated tablet of 
empagliflozin together with the first daily dose of BI 685509 in the morning. To ensure a 
dose interval of about 24 hours for empagliflozin the medication should be taken in the 
morning approximately the same time every day. If a dose of empagliflozin 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.
In the morning of a visit, the trial medication will be administered as part of the visit.  
Therefore, on these days, patients should be instructed not to take their morning dose in 
advance of the visits. 
 
Patients who fail to follow these instructions should have the visit re-scheduled as soon as 
possible, ideally on the following day (refer to Section 6.1).  On days with no scheduled visit 
the patient will self-administer their medication at home.  Patients should be instructed to 
bring all unused trial medication and empty wallets / packaging with them when they return 
for clinic visits to the investigational site.


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In case of a temporary interruption to treatment, refer to Sections 3.3.4.1, 4.1.4.1 and 4.1.4.2.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war; refer to 
Section 6) physical patient visits to 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 medication, and, if acceptable according to local 
law and regulations, trial medication may be shipped from the site to the patient’s home.
4.1.4.1
Rules for down-titration in case of intolerance to BI 685509
If a patient has an AE that, based on Investigator judgement, may be related to trial 
medication, the down-titration rules below must be followed.  These rules apply if the patient 
has successfully completed the dose titration period (i.e. Visit 4) and is either still taking their 
final assigned dose of trial medication, or if they have missed ≤3 consecutive doses3.  If the 
patient has not successfully completed the dose titration period (i.e. Visit 4), down-titration is 
not permitted; in case of persistent AEs or severe effects, the patient must permanently 
discontinue treatment (refer to Section 3.3.4.1).
if the patient is receiving 
BID BI 685509 the dose will be down-titrated one level to 
BID BI 685509
    
Once down-titration has taken place, no further up-titration will be permitted.  
If a patient continues to have an AE, or a new AE develops, that based on Investigator 
judgement, may be related to trial medication, a second down-titration will be permitted:

if the patient is receiving
BID BI 685509 the dose will be down-titrated to 
BID
BI 685509  
Down-titration must not be performed by taking less than the two daily doses or by splitting 
tablets so that a whole tablet is not taken.  Down-titration will be managed through the IRT 
system (refer to Section 4.1.4). After the successful completion of the dose titration period 
(i.e. Visit 4), in case of persistent AEs despite down-titration, or severe effects at any dose, 
permanent treatment discontinuation should be considered (refer to Section 3.3.4.1).  Patients 
who are down-titrated will need to return to the investigational site to receive their continuing 
supply of trial medication, either at the next scheduled visit or via an unscheduled visit.
3 One dose refers to an individual time point e.g. morning dose or evening dose.


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4.1.4.2
Rules for re-starting up-titration in case of interruption of BI 685509
An interruption of BI 685509 may have an influence on the tolerability.  Hence, if a patient 
has missed ˃ 3 consecutive doses4 of trial medication for any reason (e.g. due to an AE, or for 
compliance reasons), the rules below will apply for the safety of the patient.  If ≤ 3 
consecutive doses of trial medication have been missed and there is no related AE, then the 
next dose of trial medication should be taken as scheduled.
after an interruption of trial medication of ˃ 3 consecutive doses, the patient should re-start 
the dose titration period at 
BID BI 685509 
before any further up-titration occurs the patient must have taken the preceding dose for at 
least 7 consecutive days.  This applies throughout the treatment period
o this may mean that a patient due to be up-titrated at Visit 3 or 4 (as per Table 4.1.4: 1) 
is held at their current dose until their next scheduled visit.  They could also be up-
titrated at an unscheduled visit once this requirement is met
if interruption occurs after Visit 4, subsequent up-titration will be allowed either at a 
scheduled visit or at an unscheduled visit
Patients with an interruption of trial medication will need to return to the investigational site 
to receive their continuing supply of trial medication, either at the next scheduled visit or via 
an unscheduled visit.
4.1.5
Blinding and procedures for unblinding
Although a randomization is applied to NASH patients with T2DM, the patients, 
investigators and sponsors will stay unblinded due to the open-label nature of this trial.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated Clinical 
Research Organisation (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice. Re-supply to the sites will be managed via an 
IRT system, which will also monitor expiry dates of supplies available at the sites.
In this trial, each medication kit with BID BI 685509 will contain one wallet and each wallet 
will hold 20 film-coated tablets (i.e. seven days treatment plus three days reserve).
Each medication kit with QD empagliflozin will contain one wallet and each wallet will hold 
14 film-coated tablets (i.e. seven days treatment plus seven days reserve).  The number of kits 
dispensed at each dispensing visit, will be sufficient to cover both the planned number of 
weeks of treatment between visits, and the use of any permitted visit windows.  
For details of packaging and the description of the label, refer to the ISF.
4 One dose refers to an individual time point e.g. morning dose or evening dose.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA), as provided in the list of contacts in the ISF, must be contacted 
immediately.
4.1.8
Drug accountability
The Investigator or designee will receive the trial medication delivered by the Sponsor or 
delegate when the following requirements are fulfilled:
approval of the CTP by the Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) 
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 (CA)
availability of the curriculum vitae of the Principal Investigator
availability of a signed and dated CTP
availability of the proof of a medical license for the Principal Investigator (if applicable)
availability of FDA Form 1572 (if applicable)
Trial medication is not allowed to be used outside the context of this CTP. It must not be 
forwarded to other Investigators or clinics.  Patients should be instructed to return unused 
trial medication.
The Investigator or designee must maintain records of the medication’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 medication. 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 trial medication and trial patients. The 
Investigator or designee will maintain records that document adequately that the patients 
were provided the doses specified by the CTP and reconcile all trial medication received from 
the Sponsor. At the time of return to the Sponsor and / or appointed CRO, the Investigator or 
designee must verify that all unused or partially used trial medication has been returned by 
the clinical trial patient and that no remaining supplies are in the Investigator’s possession.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (refer to Section 3.3) 
are permissible throughout the duration of the trial. Refer to Section 4.2.2.1 for restrictions 
with respect to statins, NSBBs / carvedilol and anti-viral treatment for HBV.  All concomitant 
therapy should be carefully evaluated by the Investigator and the Sponsor should be 
contacted when there are questions.
In case of AEs in need of treatment, any concomitant therapy, based on Investigator’s
judgement, will be permitted. Diagnostics and treatment should be initiated according to 
local standard of care.
All concomitant therapies will be recorded on the appropriate pages of the eCRF.
There are no trial-related restrictions regarding COVID-19 vaccination; patients can 
participate in the trial irrespective of their vaccination status, and vaccination during the trial 
is also not restricted.
Endoscopic variceal ligation (performed according to local guidelines) is permitted during the 
trial as required.  The procedure should be recorded on the appropriate page of the eCRF.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The following concomitant therapies must not be administered to patients with diagnosis of 
NASH entered into treatment group 3 or 4.  These restrictions apply from within 5 half-lives 
after the concomitant therapy has been stopped prior to enrolment (Visit 2), until the EoS 
visit.  
Other SGLT2 or SGLT-1/2 inhibitors
The concomitant therapies mentioned below must not be co-administered with BI 685509 
(also refer to Table 1.4.2: 1).  
NO-sGC-cGMP pathway activating therapies like NO-donors (e.g. glyceryl trinitrate, 
isosorbide di- or mono-nitrate, molsidomine), PDE-5-inhibitors (e.g. sildenafil, tadalafil, 
and vardenafil), non-specific PDE inhibitors such as dipyridamole and theophylline, or 
sGC-stimulators (e.g. riociguat): These restrictions apply from within 5 half-lives after the 
concomitant therapy has been stopped prior to enrolment (visit 2), until the EoS visit.  


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Concomitant therapies with a known risk of Torsade de Pointes: These restrictions apply
from screening Visit 1a, until the EoS visit. In the event of temporary concomitant use of
such a therapy, the trial medication must be temporarily stopped and can then be re-started 
at least 5 half-lives after the concomitant therapy with the known risk of Torsade de 
Pointes has been stopped. Refer to Section 4.1.4.2 for rules for re-starting up-titration in 
case of interruption of trial medication.
Co-administation of the following concomitant therapies along with either trial medication, 
BI 685509 and empagliflozin, is not permitted within 5 half-lives after the concomitant 
therapy has been stopped prior to enrolment (visit 2), until the EoS visit.
clinically relevant OATP1B1/3 inhibitors 
clinically relevant concomitant therapies known to inhibit or induce UGT enzymes
In the event of temporary concomitant use of medication that is not permitted, BI 685509 
and/or empagliflozin must be temporarily stopped and can be re-started after a period of at 
least 5 half-lives after the concomitant therapy has been stopped. Refer to Section 4.1.4.2 for 
rules for re-starting up-titration in case of interruption of BI 685509. 
If permanent use of any of the above-mentioned prohibited therapy is required, both trial 
medications should be stopped.
A list to support the identification of the above-mentioned concomitant therapies will be 
provided in the ISF.  The list will not claim completeness.  
Furthermore, patients who are receiving statins, pioglitazone, GLP1-agonists, or vitamin E, 
must be on a stable dose for at least 3 months prior to screening (Visit 1b), with no planned 
dose change throughout the trial, and patients who are receiving NSBBs / carvedilol, must be 
on a stable dose for at least 1 month prior to screening (Visit 1b), with no planned dose 
change throughout the trial (refer to Section 3.3.2).  In addition, these concomitant therapies 
should not be initiated during the trial as they will interfere with the efficacy of the trial 
medication (refer to Section 3.3.4.1).  
If receiving anti-viral therapy for HBV, patients must be on a stable dose for at least 6 months 
prior to screening, with no planned dose change throughout the trial.
4.2.2.1.1
Close monitoring for AEs based on concomitant therapy
If a patient is taking concomitant therapy that is metabolised by CYP3A4 and/or CYP2C8, 
which has a narrow therapeutic index and / or is a sensitive substrate, close monitoring for 
AEs is recommended in this trial (also refer to Table 1.4.2: 1). A list to support the 
identification of the above-mentioned concomitant therapies will also be provided in the ISF.  
The list will not claim completeness.  


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4.2.2.2
Restrictions on diet and lifestyle
Drastic changes of diet and lifestyle in the course of the trial should be avoided. This 
includes unusual and strenuous exercise for the patient (e.g. taking up exercises that put 
pressure on the abdomen, such as weightlifting).
Alcohol consumption must be avoided throughout the trial; excessive alcohol consumption 
could lead to hypotension when taken concomitantly with BI 685509.  
The requirement for a fasting status upon arrival at clinic visits is as defined in the Flow 
Chart.  Once all visit assessments are complete that require this status, the patient may eat as 
normal.     
4.2.2.3
Contraception requirements
Women of childbearing potential (WOCBP) and men able to father a child must use 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. A list of contraception methods 
meeting these criteria is provided in the patient information.
WOCBP (for the definition refer to Section 3.3.2) must be ready and able to use a highly 
effective method of birth control from the randomisation visit (Visit 2) until 7 days after the 
last trial medication intake, if their partner is a male able to father a child. No contraceptive 
is required for the partner of the WOCBP.
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 (if local regulations 
permit):
combined (oestrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal)
progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)
intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
bilateral tubal occlusion
A male patient must use a condom with or without spermicide until at least 7 days after last 
trial medication intake if their sexual partner is a WOCBP, or, be vasectomised with 
documented absence of sperm in the ejaculate.  No contraceptive is required for the male 
patient’s partner.
Alternatively WOCBP and male patients 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 trial medication; and withdrawal are 
not acceptable.


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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 as shown in the formula 
below. Compliance will be verified by the CRA authorised by the Sponsor or delegate.
Treatment 
compliance (%) =
Number of tablets actually taken
x 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.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Hepatic venous pressure gradient
HVPG measurement will be performed at the time points specified in the Flow Chart. Sites 
must have access to the necessary infrastructure and equipment to measure HVPG (e.g. a 
hepatic haemodynamic laboratory at their site, or at a nearby institution).  Site staff 
performing the procedure must have sufficient expertise (e.g. performing in the region of 25 
or more HVPG measurements per year) with interventional skills and expertise in the reading 
of pressure tracings, since a local interpretation of the tracing from Visit 1c will be required 
for eligibility purposes (refer to Section 3.3.2).
The HVPG procedure within the trial will be conducted in a standardised fashion at all sites 
(for details refer to the HVPG manual in the ISF); training will be provided.  Each trial site 
will be asked to provide acceptable sample HVPG tracing(s) prior to commencing patient 
recruitment if not already provided for Trial 1366-0021.  Measurements of wedged hepatic 
venous pressure (WHVP) and free hepatic venous pressure (FHVP) will be performed in 
triplicate; tracings will be provided to an external Supplier and read centrally by independent 
expert(s) in PH; the central read will include a subjective assessment of the overall trace 
quality as well as a read of the relevant pressures.  The independent expert(s) will be blinded 
to the timepoint that the trace relates to.  The central read will include the traces from Visit 1c 
that have also been interpreted locally.  The results of the central read will be transferred to 
the Sponsor and will be considered the official evaluation of the trial.  In case of 
discrepancies between a local interpretation and the central evaluation (e.g. of the Visit 1c 
tracing), the central evaluation will remain valid.  
HVPG measurements should be performed using the same hepatic vein, prior to intake of the 
trial medication, after an overnight fast, and ideally in the morning.  If it is not possible to 
perform the measurement at Visit 1c in the morning an alternative time of day can be chosen; 
in this case, a fast of at least four hours is required.  The subsequent HVPG measurement 
must then be performed at approximately the same time of day as the Visit 1c measurement 
for a single patient.  
If Visit 1b and 1c are performed on the same day, the HVPG measurement must be 
performed after the gastroscopy (i.e. only once it is confirmed that the patient remains 
eligibile for the trial). At the EoT visit, the HVPG measurement should be performed on the 
day of the scheduled visit, or within seven days (if this latter approach is taken, the 
measurement should still be performed after an overnight fast / after a fast of at least four 
hours).  If this scenario is chosen for an HVPG performed during the treatment period, the 
morning dose of trial medication can be taken prior to the procedure. In the event of early 
discontinuation from the trial, refer to Section 6.2.2.1 for guidance regarding the HVPG 
measurement at the ED visit.
A summary of the HVPG procedure is as follows (R20-3977):
Under local anaesthesia and ultrasound guidance, a catheter introducer sheath is placed in the 
right internal jugular vein. Using fluoroscopic guidance, a balloon catheter is advanced into 


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the inferior vena cava (IVC) and inserted into a large hepatic vein. Correct and sufficient 
wedge position of the catheter is ensured by injecting contrast media while the balloon is 
blocking the outflow of the cannulated hepatic vein. After calibrating the external pressure 
transducer, continuous pressure recordings are obtained with triplicate recordings of the 
WHVP and FHVP. The difference between FHVP and WHVP is referred to as HVPG, with 
values ≥10 mmHg indicating CSPH. Before removing the catheter, pressure readings 
obtained in the IVC at the same level, as well as the right atrial pressure, are recorded.


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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination must be performed at the two time points specified in the 
Flow Chart; further physical examinations are only required if the patient reports symptoms. 
A complete physical examination includes, as a minimum, general appearance, neck, lungs, 
cardiovascular system, abdomen, extremities and skin.    
5.2.1.1
Anthropometric measurements (height, weight, waist and hip 
circumference)
Measurement of height, body weight, waist and hip circumference will be performed at the 
time points specified in the Flow Chart.  Height will be measured at Visit 1a only.  The 
results of anthropometric measurements must be included in the source documents available 
at the site.
Whenever possible, weight measurements should always be performed on the same weighing 
scales for one patient. In order to get comparable body weight values, the assessment should 
be performed in the following way:
shoes, coat / jackets and any headgear5 should be taken off
pockets should be emptied of heavy objects (i.e. keys, coins etc)
after bladder voiding
The measuring tape used for waist and hip circumference should be made of a material that is 
not easily stretched, such as fiberglass. Waist circumference measurements should be made 
around a patient’s bare midriff, after the patient exhales while standing without shoes and 
with both feet touching and arms hanging freely. Waist circumference should be determined 
by measuring the midpoint between the lowest rib and the iliac crest. The tape should be 
placed perpendicular to the long axis of the body and horizontal to the floor and applied with 
sufficient tension to conform to the measurement surface.
Hip circumference measurements should start at one hip, wrapping the measuring tape 
around the widest part of the buttocks, and around the other hip to the front. Coats / jackets 
should be taken off and pockets emptied to ensure a close measurement and with both feet 
touching and arms hanging freely.
5 Headgear worn for religious reasons is acceptable, but this should be worn for all weight measurements in the 
trial


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5.2.2
Vital signs / home blood pressure and heart rate monitoring
Vital signs (SBP, DBP, as well as HR [pulse rate]) will be evaluated at trial visits at the time 
points specified in the Flow Chart, prior to blood sampling and prior to the 12-lead ECG.  BP 
measurements should be recorded in the eCRF to the nearest 1 mmHg.  BP measurements 
should be performed on the non-dominant arm. HR should be measured electronically or by 
palpation, and counted for one minute. BP and HR measurements should be taken after 
patients have rested quietly, in the seated / supine position, for at least 5 minutes. The 
measurements recorded at the trial visit must be included in the source documents available at 
the site.
At screening (Visit 1a), the site should use their preferred method to measure vital signs. 
From Visit 2 onwards, vital signs should be measured using the patients home BP monitoring 
equipment (refer to Section 5.2.2.1) in order to have a consistent method for the duration of 
the trial. This includes the pre- and post-dose vital signs measurements during the dose-
titration period and at the subsequent visit (refer to the Flow Chart and Section 6.2).   
5.2.2.1
Home blood pressure and heart rate monitoring
Home BP and HR monitoring will be performed by the patient as specified in the Flow Chart.  
Electronic BP and HR monitoring equipment will be provided for this purpose.  Site staff will 
train the patient in the correct use of the equipment at Visit 2, explaining that it must be used 
only to record BP and HR measurements belonging to the patient.  Subsequent refresher 
training should be provided at subsequent visits if required.
  
Patients will be asked to measure their BP and HR every day in the morning, soon after 
waking up prior to much physical activity, and after resting seated for approximately 5 
minutes.  Measurements must be taken before administration of the morning dose of trial 
medication.  The electronic readings will be stored in the memory of the home BP and HR 
monitoring equipment.
If, at any time after trial medication intake, a patient experiences symptoms suggestive of 
hypotension (e.g. he / she feels light-headed / dizzy, sees black spots, suffers from weakness 
etc.), particularly if the symptoms occur whilst standing up, or if he / she has any other 
symptoms in between trial visits, additional BP and HR reading(s) can be taken and the 
patient should report these symptoms at the next trial visit.  The patient should bring the 
home BP and HR monitoring equipment with them to each trial visit (refer to the Flow Chart) 
for the site staff to review the electronic readings, and to use for the measurement of BP and 
HR during trial visits from Visit 2 onwards (refer to Section 5.2.2).  Any BP / HR 
measurements which, following review, are evaluated as AEs, must be included in the source 
documents available at the site (refer to Section 8.3.1).
5.2.3
Safety laboratory parameters
Safety laboratory parameters that will be assessed are listed in Table 5.2.3: 1. Sampling time 
points will be as indicated in the Flow Chart.  All analyses will be performed by a central 
laboratory; the respective reference ranges will be provided in the ISF. Refer to Table 5.2.3:2


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for a list of “minimum required safety laboratory parameters” in the event of force majeure or 
other disruptive circumstances.    
Patients should be fasted for blood sampling for the safety laboratory where that visit is 
defined as a fasting visit in the Flow Chart; where a non-fasting status is defined, the safety 
laboratory sample can be collected in a non-fasting status.  The fasting status will be recorded 
for e.g. 
  Blood samples for 
safety laboratory parameters should be drawn prior to administration of trial medication. 
Instructions regarding sample collection, sample handling / processing and sample shipping 
will be provided in the central laboratory manual in the ISF.
The central laboratory will provide laboratory reports to the Investigator. It is the 
responsibility of the Investigator to evaluate these reports. Clinically relevant abnormal 
findings, as judged by the Investigator, must be reported as AEs (refer to Section 5.2.6).
Laboratory tests may need to be repeated in case of required medical follow-up due to an AE 
or if a test was not successful due to incorrect specimen handling or storage.  Should a patient 
not fulfil all laboratory requirements to take part in the trial due to a transitional medical 
condition, the patient may continue in the screening period but cannot be randomised until 
the re-test of the laboratory result is available to determine the eligibility of the patient (refer 
to Section 3.3).
In case that the criteria for hepatic injury are fulfilled, a number of additional measures will 
be performed (refer to Section 5.2.6.1.4 for the DILI checklist which can be downloaded 
from the electronic data capture [eDC] system, and Appendix 10.2). The amount of blood 
taken from the patient concerned will be increased due to this additional sampling.
The CKD-EPI formula (isotope dilution mass spectrometry standardised) will be used for 
reporting eGFR based on serum creatinine.  
The central laboratory will transfer the results of the analysis to the Sponsor or delegate.
In case that the qualitative parameters are abnormal, a quantitative analysis will be performed 
by the central laboratory.


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Table 5.2.3: 1
Safety laboratory tests 
Category
Test name 
Short Name
(BI Laboratory Test 
Code, LBSPID)
Haematology
Haematocrit
HCT
Haemoglobin
HGB
MCV 
MCV
MCH 
MCH
MCHC
MCHC
RBC count / erythrocytes
RBC
RBC distribution width (RDW)
RDW
WBC count / leukocytes
Platelet count / thrombocytes
Reticulocytes
WBC
PLTCT
RETABS
Automatic 
WBC 
differential 
(absolute and 
percentage)
Neutrophils
Eosinophils
Basophils
Monocytes 
Lymphocytes  
SEGABS
EOSABS
BASABS
MONABS
LYMABS
Coagulation
aPTT
APTTS
PT
PRTSEC
INR
INR
Fibrinogen
FIBR
Clinical chemistry
ALT
SGPT
Alpha fetoprotein1
AFP
Albumin
ALB
Alkaline phosphatase
ALKP
AST
SGOT
Bilirubin (total)
TBILI
Bilirubin (direct)
BILID
Bilirubin (indirect)
BILII
Brain Natriuretic Peptide (BNP)
HbA1c1
hs-CRP
BNP
HBA1C
CRPHS
Creatinine, serum
CRE
CK
CK
CK-MB2
CKMBABS
eGFR
GFRE
ɣ-GT
GGT
Glucose, plasma
GLUB
LDH
LDH
Lipase
LIPASE
Protein (total)
TPRO


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Table 5.2.3: 1 Safety laboratory tests (cont)
Category
Test name 
Short Name
(BI Laboratory 
Test Code, 
LBSPID)
Clinical chemistry
Troponin I2
TPONI
Urea (BUN)
Uric acid
UREA
URIC
Electrolytes
Bicarbonate
BICARB
Calcium
CA
Chloride
CL
Magnesium
MG
Phosphate
P
Potassium
K
Sodium
NA
Lipids3
HDL
LDL
Cholesterol (total)
Triglycerides
HDL 
LDL 
CHOL
TRIGL
Hormones
Insulin, plasma11
Aldosterone4
INS
ALDOSI
Renin, plasma4
PRCSP
TSH5
TSH
Free T36
FT3
Free T46
FT4V
Pregnancy test (serum)
Human Chorionic Gonadotropin7
HCG
Pregnancy test (urine)
Human Chorionic Gonadotropin8
Not Applicable
Infections screening5
HCV antibody (qualitative)
HCAB
HCV RNA PCR9
HCVRNA
HBV surface antigen (qualitative)
HBSAG
HBV core antibody (qualitative)
HBCAB
HBV – DNA10
HBVDNAV
Urine chemistry
Urine albumin
UALBUM
Urinalysis (semi-
quantitative)
Urine nitrite
UNIT
Urine protein
UPROZ
Urine glucose
UGLU
Urine ketone
UKET
Urobilinogen
UROBZ
Urine bilirubin
UBILI
Urine blood
UHGB
Urine leukocyte esterase
ULEUKES
Urine pH
UPH
1
Only performed at screening (Visit 1a) and EoT / ED
2
If initial CK is elevated, re-test CK with CK-MB and troponin I
3
Not performed at screening (Visit 1a)


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4
Not performed at screening (Visit 1a) or EoS; collect seated after patient seated for at least 5 to 15 minutes, and once 
patient has been out of bed for at least 2 hours
5
Only performed at screening (Visit 1a)
6
Reflex in case of abnormal TSH
7
WOCBP only; only at Visit 1a, and as a reflex if urine testing is positive  
8
WOCBP only, Visit 2 onwards.  Measured locally at the site every 4 weeks using a pregnancy test kit provided by the 
central laboratory.  Serum pregnancy testing will be done as a reflex if urine testing is positive (see above).  More 
frequent pregnancy testing should be done if required by local regulation and /or authority or per investigator judgement.
Pregnancy testing at dosing visits should be completed prior to administration of the trial medication
9
Reflex in case of positive HCV antibody. Per central laboratory assay, if HCV RNA is < 15 IU/ml at screening, 
eligibility criteria are met. 
10 Reflex in case of positive HBV core antibody. Per central laboratory assay, if HBV DNA is < 20 IU/ml at screening, 
eligibility criteria are met.
11 For calculation of HOMA-IR at visit 2, 5, EoT and EoS
Based on the analysis of Fasting Plasma Insulin (FPI) and Fasting Plasma Glucose (FPG), the 
HOMA index to assess insulin resistance will be derived in the following way:
HOMA-IR =
(  	)
.
Note:
FPI (mU/L), FPG (mmol/L)
A factor of 0.05549 will be used to convert FPG values from mg/dL to mmol/L for calculation of
HOMA-IR
Table 5.2.3: 2
Minimum required safety laboratory tests (force majeure / other 
disruptive circumstances) 
Category
Test name 
Short Name
(BI Laboratory Test Code, LBSPID)
Haematology
Haemoglobin
HGB
RBC count / erythrocytes
RBC
WBC count / leukocytes
WBC
Platelet count / thrombocytes
PLTCT
Clinical 
chemistry
ALT
SGPT
Albumin
ALB
Alkaline phosphatase
ALKP
AST
SGOT
Bilirubin (total)
TBILI
Creatinine
CRE
Potassium
K
Sodium
NA
5.2.4
Electrocardiogram
The 12-lead ECGs will be recorded at the time points specified in the Flow Chart; the ECGs
should be performed prior to blood sampling and intake of trial medication (at visits where 
only a single ECG is required), and recorded after the patient has rested for at least 5 minutes 
in a supine position.  
During the dose-titration period (i.e. when up-titration is occurring) and at the subsequent 
visit, 12-lead ECGs will also be performed approximately 1 hour and 2 hours after intake of 


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trial medication. 
ECGs must be administered by a qualified physician, nurse or technologist.  The Investigator 
or delegate will evaluate whether the ECG is normal or abnormal and assess clinical 
relevance. An ECG may be repeated for quality reasons and the repeated recording used for 
analysis.  If necessary, additional ECGs may be recorded for safety reasons.  
Dated and signed print-outs of the ECG, with findings, should be documented in the patient’s 
medical record. Clinically relevant abnormal findings will be reported either as a baseline 
condition (if identified at the screening visit [Visit 1a]) or otherwise as AEs and will be 
followed up and / or treated as medically appropriate. ECG abnormalities will be carefully 
assessed by the Investigator or delegate, and if trial discontinuation criteria are met (refer to 
Section 3.3.4.1), the patient will be discontinued from the trial.  
Copies of ECGs will be sent to a central ECG Supplier for storage purposes.  This will enable 
a subsequent centralised and independent re-evaluation if necessary.    
5.2.5
Other safety parameters
5.2.5.1
Ultrasound (liver and spleen)
Ultrasound imaging of the liver and spleen will be performed after an overnight fast, using 
local site equipment, and at the time points specified in the Flow Chart.
At screening the ultrasound can be performed at either Visit 1b or 1c.  During the treatment 
period, following randomisation, ultrasound assessments should be performed on the day of 
the scheduled visit, or within seven days (if this latter approach is taken, the assessment must 
still be performed after an overnight fast).  In the event of early discontinuation from the trial, 
refer to Section 6.2.2.1 for guidance regarding testing at the ED visit.
Ultrasound is used as a safety measure to assess the condition of the liver and spleen, organ 
size and the presence of ascites (refer to Table 1.4.2: 2).  The skin-to-liver capsule distance 
(i.e. the subcutaneous thickness), portal vein diameter, the skin-to-spleen capsule distance, 
and spleen height, length and width will also be measured,
Sites will be expected to follow local standard processes prior to and during the procedure.  
5.2.5.2
Gastroscopy
A gastroscopy (i.e an upper gastrointestinal endoscopy) will be performed at the time point 
specified in the Flow Chart, and after an overnight fast.  Details such as the location and size / 
appearance of varices, the presence / absence of portal hypertensive gastropathy, and the 
presence / absence of other conditions (e.g. gastritis, duodenitis, ulcers etc.) will be collected 
in the eCRF.  


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The gastroscopy can be skipped if the condition below is met.  In all other cases, a 
gastroscopy is required at Visit 1b, and documentary evidence must be available (e.g. source 
data) following the procedure to confirm the presence of oesophageal / gastric varices.
(i)
a patient has had this procedure in the previous 6 months to Visit 1b (and there is 
documentary evidence [e.g. source data such as a referral letter etc.] available to confirm 
the presence of oesophageal / gastric varices)
If Visit 1b and 1c are performed on the same day, the gastroscopy must be performed before
the HVPG measurement.  
Sites will be expected to follow local standard processes when considering the suitability of a 
patient for the procedure, and whilst conducting the procedure (e.g. use of concomitant 
therapy and intake of water beforehand, use of procedural sedation etc.).  
5.2.5.3
Hepatic injury adjudication
An independent AC will be used to adjudicate certain hepatic events for severity and causal 
relationship with the trial medication.  For further details refer to Section 8.7.  
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 eCRF 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.


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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 
medial or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
For Japan only: An event that possibly leads to disability will be handled as ‘deemed serious 
for any other reason’ and, therefore, reported as an SAE.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency 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 PV
Department within the same timeframe that applies to SAEs; refer to Section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury 


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A hepatic injury is defined by alterations of the hepatic laboratory and clinical parameters 
after randomisation as detailed by the removal and stopping criteria in Section 3.3.4.1 and 
Appendix 10.2
These laboratory findings constitute a hepatic injury alert and patients showing these 
abnormalities need to be followed up according to the “DILI checklist” which can be 
downloaded from the eDC system. In case of clinical symptoms of hepatic injury (e.g.
encephalopathy, nausea, vomiting, pruritus, severe fatigue, icterus, etc.) without laboratory
results (ALT, AST, total bilirubin, INR) available, the Investigator should make sure these 
parameters are analysed, if necessary in an unscheduled blood test. Should the results 
meet the criteria of the hepatic injury alert, the procedures described in the DILI checklist 
should be followed.
Ketoacidosis
If metabolic acidosis, ketoacidosis or diabetic ketoacidosis (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 Diabetes Mellitus (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 AEs should be classified and recorded in the eCRF according to 
the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 dated 27 
November 2017 (R18-1357).
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, 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.


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
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, considering 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 individual patient’s end of trial (= 
the End of Study (EoS) visit): 
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only 
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 BI SAE form to the sponsor’s unique entry point
within 24 hours of becoming aware of the event, the country specific process will be 
specified in the ISF. The same timeline applies if follow-up information becomes available. 


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In specific occasions, the investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete the AE and BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for 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.


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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial.  
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements.  For China, samples for 
biobanking will not be collected, due to regulatory restrictions.
5.5.1
Methods and timing of sample collection
For all biospecimens collected, detailed instructions on sampling, preparation, processing,
shipment and storage will be provided in the central laboratory manual in the ISF. Plasma 
and serum for biobanking will be collected at the timepoints specified in the Flow Chart.  
Biobanking sampling requires a consistent status from one sample to another in terms of the 
fasting vs non-fasting; a fasting status has been chosen for this trial. 
5.7
APPROPRIATENESS OF MEASUREMENTS
This trial includes standard efficacy and safety measurements routinely performed in clinical 
practice in the chosen trial populations, as well as non-standard measurements.  Refer to


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Section 1.4.2 for further details.  Also refer to Section 3.2 for justification regarding the 
choices made.  


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6.
INVESTIGATIONAL PLAN
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 patient visits and 
assessments, home healthcare nurse visits, and direct-to-patient shipments of trial treatment. 
Such alternative measures may be described in a specific Trial Continuity Plan as part of the 
initial submission package and will also be mentioned in the patient information leaflet. The 
implementation of these measures will depend on patient’s consent, operational feasibility, 
local law and regulations. If alternative methodology is implemented, the deviations from the 
original plan will be precisely documented.
6.1
VISIT SCHEDULE
All visits should be scheduled according to the Flow Chart. Each visit date (with its’
permitted time window) should be calculated in relation to the day of 
enrolment/randomization (i.e. Day 1). During the dose titration period of the trial (i.e. from 
Visit 2 to Visit 4), scheduled trial visits must be at least 7 days apart, since a patient must 
have taken the preceding dose of BI 685509 for at least 7 consecutive days before up-titration 
occurs (refer to Section 4.1.4).  For this reason, if the permitted time window (+2 days) is 
applied to Visit 3, the permitted time window must also be applied to Visit 4 (+2 days).  
Missed visits should be re-scheduled as soon as possible ideally within the permitted time 
window for that visit.  If any visit has to be rescheduled, subsequent visits should follow the 
original visit schedule.  Unscheduled visits can be performed at the discretion of the 
Investigator at any time for safety reasons or, for instance, to provide trial medication (e.g. a 
re-start of BI 685509 following treatment interruption). 
All visits will take place at the investigational site, and ideally they should be performed in 
the morning.  In the randomised treatment period, on the morning of a visit, the trial 
medication will be administered as part of the visit.  Therefore, on these days, patients should 
be instructed not to take their morning dose in advance of their clinic visit (refer to Section 
4.1.4). 
 The fasting 
status of a patient should be in accordance with the Flow Chart and will be recorded in the 
eCRF.  Patients who fail to follow the afore-mentioned instructions should have the visit re-
scheduled as soon as possible, ideally on the following day.  
In the event of force majeure or other disrupting circumstances (refer to Section 6), 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 visit may be 
performed at the patient’s home, remotely (by phone) or as a combination of home and 
remote visit: 
Visit 6


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When scheduling such visit every effort should be made to ensure a continuous supply of trial 
medication for the patient, whilst also taking into account that the next kit(s) of trial 
medication may need to be shipped from the site to the patient’s home (refer to Section 4.1.4) 
and, that medical pre-requisites should be performed and confirmed prior to shipment of new 
supplies.  
All deviations from the original schedule of visits will be documented and the implications 
considered for the analysis of the trial data.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
At each visit, assessments should be performed as indicated in the Flow Chart and as detailed 
in Section 5.  
In the treatment period, all assessments should be performed before the trial medication is 
taken.  Exceptions to this are post-dose vital signs and ECGs
  Once the trial medication is administered / once all visit assessments are complete 
that require a fasting status, patients may eat as normal 
  
Vital signs measurements should always precede the ECG, and the ECG should always be 
measured before any blood samples are taken (refer to the Flow Chart and Sections 5.2.2 and
5.2.4).
In the event of force majeure or other disrupting circumstances the visit indicated in Section 
6.1 may have to be performed at the patient’s home, remotely (by phone) or as a combination 
of home and remote visit.  At this visit, the following assessments can be performed at the 
patient’s home or remotely:
concomitant therapy
IRT call
dispense trial medication
train patient / provide refresher training / dispense / review results (home BP and HR 
monitoring;
all AEs / SAEs / AESIs
compliance check
Trial medication will not be collected at the visit performed remotely.  Instead, the 
medication should be collected when the patient next visits the site, or when a visit is 
performed at the patient’s home (see below). 
The following assessments can be performed at the patient’s home:

anthropometric measures

vital signs

physical examination


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
resting 12-lead ECG (using a portable ECG machine) 

collect trial medication
If safety laboratory sampling via the central laboratory is not possible from the 
investigational site in the event of force majeure or other disrupting circumstances (and is 
instead performed at the patient’s home), analyses can be performed at a local laboratory. 
The results of the safety laboratory tests must be transferred to the Investigator who must 
ensure a medical review and document any clinically relevant safety issues as AEs.  For a list 
of “minimum required safety laboratory parameters” refer to Section 5.2.3 and Table 5.2.3: 2.
All deviations from the original schedule of assessments as defined in the Flow Chart will be 
documented and the implications considered for the analysis of the trial data.
6.2.1
Screening period (Visit 1a to 1c)
No trial procedures should be performed unless the patient has consented to take part in the 
trial. Once a patient has consented, he / she is considered to be enrolled in the trial and to 
have started screening.  The patient should be recorded on the enrolment log and be 
registered in the IRT system as a screened patient.  Patients who are not eligible to proceed to 
Visit 2 (i.e. they fail screening at either Visit 1a, 1b or 1c) should be registered as a screen 
failure in the IRT system and the eCRF and no further follow-up is required.  Also refer to
Section 3.3 for guidance regarding re-screening (and re-testing) during the screening period.
The screening period is defined as the period prior to randomisation and the first 
administration of trial medication.  It consists of 3 visits (refer to Flow Chart), namely Visit 
1a, Visit 1b and Visit 1c; these visits should ideally be completed within a period of 4 weeks, 
but a maximum of 6 weeks (-42 days) will be permitted prior to randomisation (i.e. Day 1, 
Visit 2).  There is no minimum duration for the screening period.  A patient can proceed from 
one visit to the next within the screening period as soon as all results from the previous visit 
are available and if he / she remains eligible for the trial.  Visit 1b and Visit 1c can be 
performed as separate visits, or, they can be performed on the same day.  If they are 
performed on the same day, the gastroscopy must be performed prior to the HVPG 
measurement; in this setting the site can choose whether to perform the ultrasound
at Visit 1b or Visit 1c.     
At Visit 1a demographic information will be collected. This includes the following:
age on the day of informed consent (in years)
sex (male / female in order to describe the patient`s sex at birth) 
for female patients: of childbearing potential yes / no 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 which requires a patient to be classified as black or non-black 
(unless not acceptable according to local regulations)


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Baseline Conditions and Medical History
Information with respect to medical history / baseline conditions will also be collected at 
Visit 1a (e.g. relevant chronic diseases, current observable conditions and other relevant 
conditions, based on Investigator judgement, which may not be observable on the day of the 
examination [e.g. because the patient is receiving concomitant therapy to treat the 
condition]).  This includes any new clinically relevant findings identified during the 
screening period.  
6.2.2
Treatment period(s)
If a patient is deemed eligible for the trial following Visits 1a, 1b and 1c, the patient will be 
randomised at Visit 2 (Day 1) by using the IRT system.  All Visit 2 assessments (refer to the 
Flow Chart) should have been completed prior to administration of the first dose of trial 
medication; exceptions are the post-dose vital signs and ECGs
 
Each patient can be randomised only once into the trial.  The randomised treatment period 
starts with Visit 2 and ends when a patient reaches the EoT visit (refer to the Flow Chart).
The last dose of BI 685509 will be administered in the evening of the day before the EoT 
visit and the last dose of empagliflozin in the morning of the day before the EoT visit.
   
Patients will be assessed regularly at scheduled visits as specified in the Flow Chart.  During 
the dose titration phase of the treatment period (refer to Section 4.1.4), scheduled visits are 
more frequent.  It is of particular importance that the time window for these visits is adhered 
to since the patient must have taken the preceding dose of BI 685509 for at least seven
consecutive days before any up-titration occurs (refer to Sections 4.1.4, 4.1.4.1 and 4.1.4.2).  
Unscheduled visits may also be arranged where necessary; assessments completed during an 
unscheduled visit will depend on the circumstances under which the visit was planned, and 
should be based on Investigator judgement.
  Patients should also be reminded to 
bring
the electronic BP and HR monitoring device with them to each 
trial visit (refer to Sections 5.2.2.1 and 5.6.1).  Refresher training should be provided as 
required. 
At every dispensing visit in the trial (refer to Flow Chart), an IRT call should be made.
6.2.2.1
End of treatment / Early discontinuation visit
Patients who successfully complete the entire 8 week treatment period should have the 
assessments for the EoT visit performed as indicated in the Flow Chart.  Such patients should 


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be registered as completed in the IRT system.  End of trial medication must also be recorded 
on the corresponding eCRF.
For patients who discontinue trial medication prematurely (for whatever reason), an ED visit 
(refer to the Flow Chart) should be completed instead of the planned treatment period visit 
(refer to Section 3.3.4).  Ideally the ED visit should be performed within seven days of 
discontinuing the trial medication.  The assessments performed at the ED visit should be in 
accordance with the Flow Chart, with the following exceptions:
HVPG: 
not required

biobanking sampling:
not required
Patients who discontinue treatment early should be registered as discontinued in the IRT 
system. End of trial medication must also be recorded on the corresponding eCRF.
At the EoT and / or ED visit, patients should be reminded about restrictions (refer to Section 
4.2.2) that still need to be observed up until the EoS visit (refer to Section 6.2.3).  Home BP 
and HR monitoring should continue between the EoT / ED visit and the EoS visit. 
6.2.3
Follow-up period and trial completion
An EoS visit should be scheduled 4 weeks after an EoT and / or ED visit (refer to the Flow 
Chart and Section 3.3.4); participation in the trial is over once this visit has been completed; 
completion must be recorded on the corresponding eCRF.  
When an EoS visit is performed after an ED visit, the assessments performed at the EoS visit 
should be in accordance with the Flow Chart, with the following exceptions:

Trial completion is defined as a patient who completes the EoS visit within the specified time 
window and who has not discontinued trial medication prematurely.  Following an EoS visit, 
the patient will return to standard medical care.  


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
In this trial, the primary endpoint is the percentage change in HVPG from baseline (measured 
in mmHg) after 8 weeks of treatment. The purpose of this trial is to demonstrate the short-
time clinical activity of BI 685509 on HBV, HCV and NASH patients.
The effects of BI 685509 will be assessed alone, and in combination with empagliflozin in 
treatment group 4 (NASH patients with T2DM).
7.1
NULL AND ALTERNATIVE HYPOTHESES
Statistical testing is not planned for this trial. All analyses will be descriptive in nature. The 
endpoints will be investigated. However, it is not planned to test a statistical hypothesis with 
regards to these variables in a confirmatory matter. Instead, they will be described and 
evaluated by descriptive statistical methods.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The analyses will be performed based on the following analysis sets:

Enrolled set (ES) – this analysis set includes all patients having signed informed 
consent and who were eligible for inclusion into the trial. The ES will be used for 
analyses of patient disposition

Randomised set (RS) – this analysis set includes all enrolled patients that were 
entered or randomised to the trial medication. The RS will be used for demographic 
and baseline disease characteristics presentation

Treated set (TS) – the treated set includes all patients who were enrolled or
randomised to the trial medication and were treated with at least one dose. The TS 
will be used for all safety analyses

Full analysis set (FAS) – this analysis set includes all enrolled or randomised patients 
who received at least one dose of trial medication and have a baseline measurement 
for the primary endpoint recorded.  The FAS will be used for the efficacy analyses
Further analysis sets will be defined in the TSAP, if needed.
Efficacy analyses will be performed based on the planned treatment (i.e. the treatment 
assignment at randomisation).  Safety analyses will be based on the actual treatment received 
at the enrolment/randomisation visit.  
Unless otherwise stated, baseline is defined as the latest measurement before the first trial 
medication intake.


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7.2.2
Handling of intercurrent events
The expected intercurrent events of interest in this trial are:

use of the following restricted concomitant therapy:
o
NO-sGC-cGMP pathway activating therapies like NO-donors (e.g. glyceryl 
trinitrate, isosorbide di- or mono-nitrate, molsidomine), PDE-5-inhibitors (e.g. 
sildenafil, tadalafil, and vardenafil), non-specific PDE inhibitors such as 
dipyridamole and theophylline, or sGC-stimulators (e.g. riociguat)  

new onset of / dose change in existing NSBB / carvedilol, pioglitazone, GLP1-
agonists and vitamin E concomitant therapy

occurrence of a decompensation event

Premature discontinuation of assigned trial medication
The strategies for handling intercurrent events in this trial are as follows:
Treatment Policy: This is the effect of randomizing patients to a treatment arm regardless of 
treatment actually being taken. All intercurrent events will be handled according to the 
treatment policy approach as defined in ICH E9(R1).


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Each analysis will reference the strategy for handling intercurrent events that it will be 
estimating. The estimand for each main analysis in this protocol is the combination of the 
relevant detailed clinical objective from section 2.1 and this strategy.
Handling of the intercurrent events that are not listed above will be decided by the review and 
will be documented in the TSAP.
7.2.3
Primary objective analyses
The primary endpoint (refer to Section 2.1.2) will be analyzed using an ANCOVA model in 
the FAS without imputing the missing data.
The model is as follows:
Percentage of HVPG change from baseline at Week 8 = overall mean
+ HVPG baseline
+ treatment
+ random error
This model includes effects accounting for the following sources of variation: ‘treatment’ is a 
fixed classification effect, and ‘HVPG at baseline’ is a linear covariate. The random error is 
assumed to be normally distributed with mean 0 and unknown variance σ².
The analysis will only be used for estimation of treatment effects without performing 
statistical tests.  Patients will be analysed according to the stratum to which they belong 
(regardless of any mis-assignment to treatment based on identification of the wrong stratum), 
as such an error occurs before randomisation and is therefore consistent with regulatory 
guidance.  Procedures to follow if the analysis fails to converge will be described in the 
TSAP.
7.2.3.1
Sensitivity analyses
Sensitivity analyses may be performed and will be described in more detail in the TSAP, if 
applicable.
7.2.3.2
Subgroup analyses
Any subgroup analyses planned for this trial will be described in the TSAP, if applicable. 
7.2.4
Secondary objective analyses
Unless otherwise stated, only descriptive statistics will be presented for the secondary 
endpoints defined in Section 2.1.3. The percentage of patients who have experienced the 
events of interest for secondary endpoints will be presented.


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7.2.5
Further objective analyses
Only descriptive statistics will be presented for futher endpoints (defined in Section 2.2.2).  
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 daysafter the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
Safety analyses will be done by “treatment at onset” principle.  All treated patients will be 
included in the safety analysis. In general, safety analyses will be descriptive in nature and 
will be based on BI standards. No hypothesis testing is planned.
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’.
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) at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
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.


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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. Full details will be specified in the DMC charter.  The 
primary role of the DMC is the ongoing evaluation of safety.
7.3
HANDLING OF MISSING DATA
No imputation of missing data is planned for the remaining enpoints.  If a patient misses a 
visit, the missing data will not be imputed. 
7.4
RANDOMISATION
BI will arrange for the randomisation and the packaging and labelling of trial medication. A 
minimum of 40 NASH patients (either with or without a diagnosis of T2DM) will enter
treatment group 3 or 4. NASH patients without diagnosis of T2DM can only enter treatment 
group 3, while NASH patients with diagnosis of T2DM will be randomized in blocks to one 
of the two treatment groups (treatment group 3 or treatment group 4) in a 1:1 ratio.
The randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to enroll 80 patients with HBV, HCV and NASH in total in this trial with a 
minimum of 20 NASH patients in treatment group 3 (with or without T2DM receiving
BI 685509) and a minimum of 20 NASH patients in treatment group 4 (with T2DM receiving 
BI 685509 on top of 10mg empagliflozin).
It will be considered as a positive signal if a mean reduction of HVPG after 8 weeks of 
treatment compared to baseline of at least 15% is observed. A true treatment effect of 20%
reduction for each treatment group and a standard deviation of 25% are assumed based on 
previous studies [R21-1984, R21-1945]. With the minimum sample size of 20 per arm in 
treatment group 3 and 4 , the probability to observe a mean reduction of HVPG ≥10% in 
each of the treatment groups 3 and 4 is at least 96.3%. This probability would be at most
18.8% in case that the mean reduction of HVPG from baseline is 5%.  Probabilities of 
achieving an assumed treatment effect within different scenarios are presented in Table 7.5: 1
.


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Table 7.5: 1
Scenarios of probabilities of achieving the assumed treatment effect
Scenarios
Assumption of mean reduction in HVPG 
from baseline to week 8 1,2
Probability that the treatment effect is 
≥ 10% per arm in treatment group 3 
and 4
Positive
20%
at least 96.3%
15%
at least 82%
Negative
5%
at most 18.8%
0%
at most 3.8%
1
SD = 25%
2
N >= 20 per arm in treatment group 3 and 4
The calculations were performed using R 4.0.2.


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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 CTP, the ethical principles laid down in 
the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for GCP, 
relevant BI 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 CTP, 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 or delegate 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 CTP or of ICH-GCP.
The BI 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 will be described in the Investigator contract. 
As a rule, no trial results should be published prior to finalisation of the CTR.
The certificate of insurance cover will be made available to the Investigator and the patients,
and will be stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or his delegate must sign (or place a seal on) and date the informed consent form. 


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If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, 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. 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 eCRF must be consistent with the source data or the discrepancies must 
be explained. The current medical history of the patient may not be sufficient to confirm 
eligibility for the trial and the Investigator may need to request previous medical histories and 
evidence of any diagnostic tests. In this case, the Investigator must make at least one 
documented attempt to retrieve previous medical records. If this fails, a verbal history from 
the patient, documented in their medical records, would be acceptable.
Copies of source documents necessary for e.g. HVPG central evaluation and hepatic injury 
adjudication will be provided to external Suppliers.  Before sending or uploading those 


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copies, the Investigator must ensure that all patient identifiers (e.g. patient’s name, initials, 
address, phone number, social security number etc.) have been properly removed or redacted 
from any copy of the patients’ source documents.
If the patient is not compliant with the CTP, any corrective action e.g. re-training must be 
documented in the patient file.
For the eCRF, 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

AEs and AESIs (onset date [mandatory], and end date [if available]), including those 
identified from measurements within the home BP and HR monitoring equipment

SAEs (onset date [mandatory], and end date [if available])

concomitant therapy (start date [where required], dose / frequency [where required], 
changes)

originals or copies of laboratory results and other imaging or testing results (e.g. 
gastroscopy, HVPG, ultrasound
results), with proper documented 
medical evaluation (in validated electronic format, if available)

ECG results


completion of patient’s participation in the trial (end date; in case of early
discontinuation, the reason for it should be documented if available)

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 CTP) to support inclusion / exclusion criteria does not make the 
patient eligible for the clinical trial
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 always be available 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.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war; refer to 
Section 6), site access may be restricted thus limiting the ability to perform standard site 


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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 WHO GCP 
handbook. 
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a patient identification number instead of the patient’s 
name. The code is only available at the site and must not be forwarded to the sponsor. In case 
patient’s records will be forwarded e.g. for SAE processing or adjudication committees, 
personal data that can identify the patient will be redacted by the site prior to forwarding. 
Access to the patient files and clinical data is strictly limited: 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.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs / IECs and patients will 
be informed as appropriate.
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


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
Sample and data usage have to be in accordance with the separate biobanking 
informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation 
 
ensures compliant usage


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 
medication (as scheduled per CTP or prematurely). Individual Investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site.
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 CTP.
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 / CA 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 BI.


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A Coordinating Investigator will be responsible to coordinate Investigators at the different 
sites participating in this trial. Tasks and responsibilities will be defined in a contract. 
Data Monitoring Committee:
A DMC will be established. Members of the DMC will be independent of BI, and will 
include physicians experienced in the treatment of the disease under investigation, and a 
statistician.  The DMC will evaluate safety data, and receive efficacy data, significant safety 
concerns, and decisions from hepatic injury adjudication for evaluation. 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 / Health Authorities, IRBs / ECs, and to Investigators as requested by 
local law. The tasks and responsibilities of the DMC will be specified in the charter.
Hepatic injury Adjudication Committee:
An independent AC will be used to adjudicate certain hepatic injury events for severity and 
causal relationship with the trial medication.  Events may either be defined by abnormal 
laboratory values and / or relevant AEs.  They will be defined in the hepatic injury AC 
charter.  For qualifying events, relevant source documents generated from any medical 
evaluations of these events will be requested.  Relevant source documents might include 
laboratory values, histological analysis, reports from ultrasound, computed tomography (CT), 
magnetic resonance imaging (MRI), hospital discharge letters and medical reports from other 
physicians.  
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, 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) in accordance with applicable regulations and BI SOPs, or 
by a CRO based on a contract. The CRO will perform project management, clinical field 
monitoring, medical monitoring, and reporting.
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.


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A central laboratory service, a central reading service for HVPG, an IRT supplier and other 
central services / equipment will be used / provided in this trial. Details will be provided in 
the respective manuals and will be available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J.  Portal hypertensive 
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Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et 
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radiology and diagnostic nuclear medicine: a catalog.  Radiology 
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defibrillators.  Can J Gastroenterol Hepatol 2017; 2017; 7298032
R21-0296
Krystallis C, Masterton GS, Hayes PC, Plevris JN.  Update of endoscopy in 
liver disease: more than just treating varices.  World J Gastroenterol 
2012;18(5):401-411


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R20-4090
Reiberger T, Puespoek A, Schoder M, Baumann-Durchschein F, Bucsics T, 
Datz C, et al.  Austrian consensus guidelines on the management and 
treatment of portal hypertension (Billroth III).  Wien Klin Wochenschr 
2017;129(Suppl 3):S135-158
R20-1204
Mandorfer M, Kozbial K, Schwabl P, Chromy D, Semmler G, Staettermay 
AF, et al.  Changes in hepatic venous pressure gradient predict hepatic 
decompensation in patients who achieved sustained virologic response to 
interferon-free therapy. Hepatology 2020;71(3);1023-1036
R20-4092
Groszmann RJ, Garcia-Tsao G, Bosch J, Grace D, Burroughs AK, Planas R, 
et al, Portal Hypertension Collaborative Group.  Beta-blockers to prevent 
gastroesophageal varices in patients with cirrhosis.  N Engl J Med 
2005;353(21);2254-2261
R20-4093
Merkel C, Marin R, Angeli P, Zanella P, Felder M, Bernardinello E, et al, 
Gruppo Triveneto per l'Ipertensione Portale.  A placebo-controlled clinical 
trial of nadolol in the prophylaxis of growth of small esophageal varices in 
cirrhosis.  Gastroenterology 2004;127(2);476-484
R20-4091
Mandorfer M, Hernandez-Gea V, Reiberger T, Garcia-Pagan JC. 
Hepatic venous pressure gradient response in non-selective beta-blocker 
treatment - is it worth measuring? Curr Hepatol Rep 2019;18;174-186
P09-12413
Guidance for industry: drug-induced liver injury: premarketing clinical 
evaluation (July 2009).  Silver Spring: U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER);2009
R18-1357
U.S. Department of Health and Human Services.  Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: November 27, 
2017).  
website.ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
CTCAE_v 5_Quick_Reference_8.5x11.pdf#search=%22CTCAE%22 
(access date: 9 April 2017); U.S.Department of Health and Human 
Services, National Institutes of Health, National Cancer Institute; 2017
R21-1984
Gupta V, Rawat R, Shalimar, Saraya A.  Carvedilol versus propranolol 
effect on hepatic venous pressure gradient at 1 month in patients with index 
variceal bleed: RCT. Hepatol Int 2017;11:181-187
R21-1945
Garcia-Tsao G, Fuchs M, Shiffman M, Borg BB, Pyrsopoulos N, Shetty K, 
et al.  Emricasan (IND-6556) lowers portal pressure in patients with 
compensated cirrhosis and severe portal hypertension.  Hepatology 
2019;69(2);717-728  


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R18-3281
Murray KF, Carithers RL.  AASLD practice guidelines: evaluation of the 
patient for liver transplantation.  Hepatology 2005;41(6):1407-1432
9.2
UNPUBLISHED REFERENCES
c01678844
Investigator’s Brochure (IB) BI 10773 in type 2 diabetes mellitus, CHF, 
CKD and paediatric diabetes. Current version
c02778238
Investigator’s Brochure (IB) BI 685509.  Current version 
c35011958
TMCP List of Analyses for BI 685509 (1366.P1/P2)
n00260803 
Soluble guanylate cyclase activator BI 685509 in rats with biliary cirrhosis 
(BDL) and portal hypertension
n00261471-01
Prediction of BI 685509 pharmacokinetics and therapeutic dose in human in 
non-alcoholic steatohepatitis (NASH). 25 May 2018


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10.
APPENDICES


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10.2
REMOVAL OF INDIVIDUAL PATIENTS IN CASE OF INCREASED 
LIVER ENZYMES
Trial-specific procedures have been defined in case of increased liver enzymes after 
enrolment as outlined below.  Baseline refers to Day 1.
Normal aminotransferases at baseline
New elevations of aminotransferases to > 2 x ULN should be followed by a repeat testing 
within 48 to 72 hours.  If elevations persist, other causes of aminotransferase elevations 
should be evaluated along with tests of hepatic function.  If no other cause is identified, 
the patient should be monitored closely.
Treatment with trial medication should be discontinued if:
o ALT or AST increases to > 8 x ULN
o ALT or AST increases to > 5 x ULN for more than 2 weeks
o ALT or AST increases to > 3 x ULN and the increase is accompanied by a concomitant 
increase in total bilirubin to > 2 x ULN or INR to > 1.5
o ALT or AST increases to > 3 x ULN and the increase is accompanied by the 
appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, and / or eosinophilia (> 5%)
Abnormal aminotransferases at baseline
If a patient develops elevations of ALT or AST to > 2 x baseline or total bilirubin 1.5 x 
baseline values, the testing should be repeated within 48 to 72 hours. If elevations persist, 
then close observation (testing and physical examination 2 to 3 times a week) should be
implemented and discontinuation of trial medication should be considered. Decision to 
discontinue the trial medication should be considered based on factors that include how 
much higher than baseline ALT and AST values were relative to ULN and how much the 
on-treatment ALT and AST values have increased relative to baseline, in addition to the 
elevation of total bilirubin or INR.
Treatment with trial medication should be discontinued if:
o baseline values were < 2 x ULN, and ALT or AST increases to > 5 x baseline values
o baseline values were ≥ 2 x ULN but < 5 x ULN, and ALT or AST increases to > 3 x 
baseline values
o baseline values were 5 x ULN, and ALT or AST increases to > 2 x baseline values
o ALT or AST increases > 2 x baseline values and the increase is accompanied by a 
concomitant increase in total bilirubin to > 2 x baseline value or INR concomitantly 
increases by > 0.2 (to prevent false positive results, another sample should be tested 
within 24 hours)
o patient (with any magnitude of aminotransferase elevation) develops signs and 
symptoms of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, and / or eosinophilia (> 5%)


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Patients should be followed up until resolution of symptoms or signs in the above stated 
situations [P09-12413]. After resolution or stabilisation the patient should complete the 
procedures for the EoT and EoS visits as outlined in the Flow Chart, Section 3.3.4.1 and
Sections 6.2.2 and 6.2.3.


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10.3
CHILD-TURCOTTE-PUGH CLASSIFICATION
Table 10.3: 1
Child-Turcotte-Pugh scoring system to assess severity of liver disease
(R18-3281)
Clinical and laboratory criteria
Points1
1
2
3
Encephalopathy
None
Mild to moderate 
(grade 1 or 2)
Severe 
(grade 3 or 4)
Ascites
Absent
Slight
Moderate
Bilirubin (mg/dL)
Bilirubin (µmol/L)
< 2
< 34.2
2-3
34.2-51.3
> 3
> 51.3
Albumin (g/dL)
Albumin (g/L)
> 3.5
> 35
2.8-3.5
> 28-35
< 2.8
< 28
Prothrombin time (seconds prolonged)
Or INR2
< 4
< 1.7
4-6
1.7-2.3
> 6
> 2.3
1Child-Turcotte-Pugh class obtained by adding the score for each parameter above (total score)
Child-Turcotte-Pugh A = 5 to 6 points (mild)
Child-Turcotte-Pugh B = 7 to 9 points (moderate)
Child-Turctotte-Pugh C = 10 to 15 points (severe)
2INR (measured by the central laboratory) will be used by the site in this trial to calculate the Child-Turcotte-Pugh score


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of Amendment
15 Feb 2022
EudraCT No.
EU Trial No.
2021-005171-40
BI Trial No.
1366-0029
BI Investigational 
Medicinal Product
BI 685509 and empagliflozin
Title of protocol
Randomised, open-label and parallel group trial to investigate 
the effects of oral BI 685509 alone or in combination with
empagliflozin on portal hypertension after 8 weeks treatment 
in
patients with clinically significant portal hypertension (CSPH) 
in
compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Correction of exclusion criteria to align with adjustment to 
Section 3.3.3 Exclusion criteria #3 (see below)
Rationale for change
See rationale for Section 3.3.3 Exclusion criteria #3 below
Section to be changed
Flow Chart
Description of change
Footnote 8 updated as by error, visit 7 is listed as a visit that 
requires a complete physical examination. This trial does not 
have a visit 7 and the reference to visit 7 was deleted:
“At visits 1a, 7 and at the EoT / ED visit, a complete physical 
examination is required. At all other marked visits, a physical 
examination is only required if the patient reports symptoms. 
Refer to Section 5.2.1“
Rationale for change
Administrative correction
Section to be changed
Section 3.3.3 Exclusion criteria #3
Description of change
Wording of exclusion criteria #3 adjusted to clarify that HBV 
DNA must always be negative in order to be eligible (see text 
in bold below):


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
if receiving anti-viral therapy for HBV less than 6 
months prior to screening, if dose of anti-viral therapy 
not stable in the 6 months prior to screening, if 
planning a dose change during the trial and or if HBV 
DNA detectable 
Rationale for change
Clarification
Section to be changed
Section 5.2.3 Table 5.2.3: 1 Safety laboratory tests
Description of change
Footnote 9 updated to confirm that reflex testing for HCV 
RNA will be triggered by HCV antibody positivity. The 
question of whether a patient has had treatment for HCV will 
not affect the reflex testing. The text in bold below was 
removed.

Reflex in case of positive HCV antibody and treated 
HCV infection
Rationale for change
Clarification
Section to be changed
Section 5.2.3 Safety laboratory parameters
Description of change
The HOMA-IR formular was missing the units and added as 
follows:
Note: FPI (mU/L), FPG (mmol/L) 
A factor of 0.05549 will be used to convert FPG values from 
mg/dL to mmol/L for calculation of HOMA-IR
Rationale for change
Administrative correction
Section to be changed
Section 5.2.6 Assessment of Adverse Events
Description of change
Wording in section 5.2.6.1, 5.2.6.2.2 and 5.2.6.2.3 was adapted 
to confirm collection of serious adverse events (SAEs) via the 
BI SAE form instead of the SAE eCRF.
Rationale for change
Administrative correction
Section to be changed
Section 7.2.2 Handling of Intercurrent Events
Description of change
By error the description of strategies for handling of 
intercurrent events was missing. The following text in bold 
was inserted for completeness:
The strategies for handling intercurrent events in this trial 
area as follows: Treatment Policy: This is the effect of 
randomizing patients to a treatment actually being taken. 
All intercurrent events will be handled according to the 
treatment policy approach as defined in ICH E9(R1).
Rationale for change
Missing text added
Section to be changed
Section 7.5 Determination of sample size
Description of change
A typing error was corrected to the probability to observe a 
mean reduction of HVPG≥ 10% in each treatment group from 


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96.4% to 96.3% to align with the number provided in table 
7.5:1. The text in bold below was corrected:
“With the sample size of 80 (20 patients per treatment group), 
the probability to observe a mean reduction of HVPG≥ 10% in 
each treatment group is 96.3%.”
Rationale for change
Correction of typing error
11.2
GLOBAL AMENDMENT 2
Date of Amendment
20 Jun 2022
EudraCT No.
EU Trial No.
2021-005171-40
BI Trial No.
1366-0029
BI Investigational 
Medicinal Product
BI 685509 and empagliflozin
Title of protocol
Randomised, open-label and parallel group trial to investigate 
the effects of oral BI 685509 alone or in combination with
empagliflozin on portal hypertension after 8 weeks treatment 
in
patients with clinically significant portal hypertension (CSPH) 
in
compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Synopsis
Description of change
Replaced “Total number of patients randomized” by “Total 
number of patients enrolled” to align the terminology with 
section 3.3 and 7.5
Rationale for change
Administrative correction
Section to be changed
Section 1.2.1 BI 658809
Description of change
Added a potential of a drug-drug interaction with CYP2C8 
substrates
Rationale for change
Updated information based on the current version of the BI 
685509 investigator brochure
Section to be changed
Section 1.2.1 BI 658809


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Description of change
Corrected a typing error in a trial number and updated 
information about trials 1366-0003 and 1366-0013 in section 
“Summary of recent data from Trial 1366-0020”
Rationale for change
Clarificaton and correction
Section to be changed
Section 1.2.2 Empagliflozin
Description of change
Added references to confirm preclinical demonstration of
efficacy of SGLT2 inhibitors on prevention of liver steatosis 
and on the progression from NAFLD state to NASH.
Rationale for change
Updated based on a recommendation from a competent 
authority
Section to be changed
Section 1.4.2 Risks
Description of change
Updated risks related to drug-drug interaction to include 
CYP2C8 substrates
Rationale for change
See rational for section 1.2.1 update above
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
Updated exclusion criteria #23 to confirm that patients with an 
allergy / contraindication to empagliflozin are excluded as well
Rationale for change
Clarification
Section to be changed
Section 3.3.4 Discontinuation of patients from trial medication 
and assessments
Description of change
In section 3.3.4.3, the bullet point number 3 was missing in the 
list to include the third reason for discontinuation of the trial
by the sponsor. This typing error was corrected
Rationale for change
Administrative change
Section to be changed
Section 4.2.2 Restrictions
Description of change
Updated section 4.2.2.1.1 to confirm close monitoring for AEs 
based on concomitant therapy that is metabolised by CYP2C8 
substrates.
Rationale for change
See rational for section 1.2.1 update above
Section to be changed
Section 9.1 Published References
Description of change
Added the following references according to the update in 
section 1.2.2: P21-06170 and P21-10425
Rationale for change
See rational for section 1.2.2 update above
Section to be changed
Section 11.1 Global Amendment 1
Description of change
Corrected typing error in the BI trial number
Rationale for change
Correction of typing error


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11.3
GLOBAL AMENDMENT 3
Date of Amendment
15 Dec 2022
EudraCT No.
EU Trial No.
2021-005171-40
BI Trial No.
1366-0029
BI Investigational 
Medicinal Product
BI 685509 and empagliflozin
Title of protocol
Randomised, open-label and parallel group trial to investigate 
the effects of oral BI 685509 alone or in combination with
empagliflozin on portal hypertension after 8 weeks treatment 
in patients with clinically significant portal hypertension 
(CSPH) in compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Adjustment to inclusion criteria to align with adjustments 
made in Section 3.3.2
Rationale for change
See rational for change of inclusion criteria #3 and #8 in 
Section 3.3.2
Section to be changed
Flow Chart
Description of change
Extended screening period and adjusted wording in the 
flowchart:
i)
“Week” and “Day” adjusted for screening period
ii) Time window for screening period removed and replaced 
with a reference to footnote 1.
iii) Footnote 1 adjusted with the bold and strikethrough text 
shown below:
“The screening period consists of 3 visits (Visits 1a/b/c).  
These visits should ideally be completed within a period 
of 4 weeks, but a maximum 3-4 of 6 weeks (-2842 days,
window + 7 days, range -21 to -28) will be permitted.  
There is no minimum duration.  A patient can …..”
Corrected hyperlink to section 5.6.1 in footnote 18
Rationale for change

To assist sites with scheduling difficulties for the required 
screening assessments, the permitted duration of the 
screening period has been increased by 2 weeks

Administrative change 
Section to be changed
Abbreviations and Definitions


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Description of change
New abbreviation added for SSc
Rationale for change
To align with other changes made via this global amendment
Section to be changed
Section 1.2 Drug Profile
Description of change
Systemic sclerosis (SSc) added as a third intended indication 
for BI 685509
Rationale for change
Updated information based on the current version of the BI 
685509 Investigator’s Brochure
Section to be changed
Section 3.1 Overall Trial Design
Description of change
Screening period duration adjusted from 4 to 6 weeks
Rationale for change
See rationale for Flow Chart above
Section to be changed
Figure 3.1: 1 Trial Design Schematic
Description of change
Screening period during adjusted from 4 to 6 weeks
Rationale for change
See rationale for Flow Chart above
Section to be changed
Section 3.3.2 Inclusion criteria
Description of change
i)
Wording of inclusion criteria #3 adjusted to include the 
bold and strikethrough text shown below:
“Clinical signs of CSPH as described by either one of the 
points below.  Each trial patient must have a gastroscopy 
during the screening period (Visit 1b) or within 36 months 
prior to screening (Visit 1b).  For further details refer to 
Section 5.2.5.2
(i)
documented endoscopic proof of oesophageal varices 
and / or gastric varices at screening (Visit 1b) or 
within 36 months prior to screening (Visit 1b)
(ii) documented endoscopic-treated oesophageal varices
as preventative treatment”  
ii) Wording of inclusion criteria #8 adjusted to include the 
bold and strikethrough text shown below:
“If receiving treatment with NSBBs or carvedilol must be on 
a stable dose for at least 31 months prior to screening (Visit 
1b), with no planned dose change throughout the trial”  
Rationale for change
i)
To ease recruitment difficulties by permitting the use of a 
historical gastroscopy over a longer period of time prior to 
screening, due to the invasive nature of this procedure
ii) To ease recruitment difficulties by reducing the amount of 
time that a stable dose of NSBBs or carvedilol is required 
prior to screening
Section to be changed
Section 4.2.2.1 Restrictions regarding concomitant treatment
Description of change
i)
Wording of restrictions for other SGLT2 or SGLT-1/2 
inhibitors adjusted to confirm that these restrictions apply
for patients with NASH entering treatment group 3 or 4


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ii) 7th paragraph adjusted to align with other changes made 
via this global amendment in relation to the stability of 
NSBBs or carvedilol prior to screening
Rationale for change
i)
Clarification
ii) See rationale for Section 3.3.2
Section to be changed
Section 5.1.1 Hepatic venous pressure gradient
Description of change
Corrected wording to confirm that only two HVPG 
measurements are performed in this trial.
In addition, the following sentence has been added to the 4th
paragraph:
“If this scenario is chosen for an HVPG performed during the 
treatment period, the morning dose of trial medication can be 
taken prior to the procedure.”  
Rationale for change
Clarification
Section to be changed
Table 5.2.3:1 Safety laboratory tests
Description of change
Wording of footnote 10 adjusted to remove the strikethrough 
text shown below:
Reflex in case of positive HBV core antibody and negative 
HBV surface antigen
Rationale for change
Correction, since HBV DNA will always be tested in case of 
positive HBV core antibody to confirm eligibility of patients 
with HBV
Section to be changed
Section 5.2.5.1 Ultrasound (liver and spleen)
Description of change
i)
ii) The words “at screening (Visit 1b or 1c)” have been 
removed from the last sentence of the penultimate 
paragraph
Rationale for change
i)
ii) Correction, since the liver and spleen parameters 
mentioned are measured each time an ultrasound is 
performed, and not just at the screening visit 
Section to be changed
Section 5.2.5.2 Gastroscopy


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Description of change
i)
Wording adjusted in the 2nd paragraph with the bold and 
strikethrough text shown below:
“The gastroscopy can be skipped if both of the conditions
below areis met.  In all other cases, a gastroscopy is 
required at Visit 1b, and documentary evidence must be 
available (e.g. source data) following the procedure to 
confirm the presence of oesophageal / gastric varices.
(i) a patient has had this procedure in the previous 36
months to Visit 1b (and there is documentary evidence 
[e.g. source data such as a referral letter etc.] available 
to confirm the presence of oesophageal / gastric 
varices)
(ii) there has been no change in the treatment of the PH 
since the gastroscopy was performed (i.e. the 
“treatment” has been monitoring alone)6”
ii) Footnote 6 has been deleted
Rationale for change
i)
See rationale for Section 3.3.2
ii) To ease recruitment difficulties, if therapy with NSBBs / 
carvedilol was initiated after a historical gastroscopy, the 
requirement for a further gastroscopy to confirm the 
persistence of varices has been removed
Section to be changed
Section 6.2.1 Screening period (Visits 1a to 1c)
Description of change
Wording adjusted for the screening period duration and 
permitted time window to reflect adjustments to the Flow 
Chart 
Rationale for change
To align with other changes made via this global amendment 
(see rationale for Flow Chart)
Section to be changed
Section 11.2 Global Amendment 2
Description of change
Corrected typing error for CYP2C8 in the 9th paragraph
Rationale for change
Correction 


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11.4
GLOBAL AMENDMENT 4
Date of Amendment
10Aug 2023
EudraCT No.
EU Clinical Trial No.
2021-005171-40
2023-504257-12-00
BI Trial No.
1366-0029
BI Investigational 
Medicinal Product
BI 685509 and empagliflozin
Title of protocol
Randomised, open-label and parallel group trial to investigate 
the effects of oral BI 685509 alone or in combination with
empagliflozin on portal hypertension after 8 weeks treatment 
in patients with clinically significant portal hypertension 
(CSPH) in compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Title page
Description of change
Added EU Clinical Trial No. 2023-504257-12-00
Rationale for change
Administrative change due to transition of the trial from the 
EU CT Directive to the EU CT Regulation
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Changed the number of patients per treatment group from 20 
to “approximately” 20
Rationale for change
To ease recruitment difficulties by permitting more than 20 
patients entering the treatment groups 3 and 4 and by not 
requiring a minimum number of patients for treatment groups
1 and 2
Section to be changed
Section 3.1 Overall Trial Design
Description of change

Removed the number of patients per treatment group

Confirmed that a minimum of 20 patients in treatment 
group 3 and a minimum of 20 patients in treatment group 
4 will be required 

Removed the randomization stop for NASH patients with 
T2DM after reaching 20 patients in the treatment group 3
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis
Section to be changed
Figure 3.1: 1 Trial Design Schematic
Description of change

Removed the number of patients per treatment group

Confirmed a minimum of 20 patients in the treatment 
group 3 and 4

Removed the randomization stop for NASH patients with 
T2DM after reaching 20 patients in the treatment group 3
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis


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Section to be changed
Section 4.1.3 Method of assigning patients to treatment 
groups
Description of change
Removed the randomization stop for NASH patients with 
T2DM after reaching 20 patients in the treatment group 3
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis
Section to be changed
Table 5.2.3: 1 Safety laboratory tests
Description of change
The following was added to footnote 9 and 10:

“Per central laboratory assay, if HCV RNA is < 15 IU/ml 
at screening, eligibility criteria are met”

“Per central laboratory assay, if HBV DNA is < 20 IU/ml 
at screening, eligibility criteria are met “
Rationale for change
Clarification for interpretation of HCV RNA and HBV DNA 
reflex results
Section to be changed
Section 7.2.3 Primary objective analyses
Description of change
Corrected the following wording to align with the definition 
of the primary endpoint (addition in bold):
“Percentage of HVPG change from baseline at Week 8…”
Rationale for change
Correction
Section to be changed
Section 7.4 Randomization
Description of change

Confirmed that a minimum of 20 patients in treatment 
group 3 and a minimum of 20 patients in treatment group 
4 will be required 

Removed the randomization stop for NASH patients with 
T2DM after reaching 20 patients in the treatment group 3
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis
Section to be changed
Section 7.5 Determination of sample size
Description of change
Wording updated to confirm that a minimum of 20 patients in 
treatment group 3 and a minimum of 20 patients in treatment 
group 4 will be required 
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis


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11.5
GLOBAL AMENDMENT 5
Date of Amendment
21 Aug 2023
EudraCT No.
EU Clinical Trial No.
2021-005171-40
2023-504257-12-00
BI Trial No.
1366-0029
BI Investigational 
Medicinal Product
BI 685509 and empagliflozin
Title of protocol
Randomised, open-label and parallel group trial to investigate 
the effects of oral BI 685509 alone or in combination with
empagliflozin on portal hypertension after 8 weeks treatment 
in patients with clinically significant portal hypertension 
(CSPH) in compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Title page
Description of change
Added EU Clinical Trial No. 2023-504257-12-00
Rationale for change
Administrative change due to transition of the trial from the 
EU CT Directive to the EU CT Regulation
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Changed the number of patients per treatment group from 20 
to “approximately” 20
Rationale for change
To ease recruitment difficulties by permitting more than 20 
patients entering the treatment groups 3 and 4 and by not 
requiring a minimum number of patients for treatment groups 
1 and 2
Section to be changed
Section 3.1 Overall Trial Design
Description of change

Removed the number of patients per treatment group

Confirmed that a minimum of 20 patients in treatment 
group 3 and a minimum of 20 patients in treatment group 
4 will be required 

Removed the randomization stop for NASH patients with 
T2DM after reaching 20 patients in the treatment group 3
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis
Section to be changed
Figure 3.1: 1 Trial Design Schematic
Description of change

Removed the number of patients per treatment group

Confirmed a minimum of 20 patients in the treatment 
group 3 and 4

Removed the randomization stop for NASH patients with 
T2DM after reaching 20 patients in the treatment group 3
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis


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Section to be changed
Section 4.1.3 Method of assigning patients to treatment 
groups
Description of change
Removed the randomization stop for NASH patients with 
T2DM after reaching 20 patients in the treatment group 3
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis
Section to be changed
Table 5.2.3: 1 Safety laboratory tests
Description of change
The following was added to footnote 9 and 10:

“Per central laboratory assay, if HCV RNA is < 15 IU/ml 
at screening, eligibility criteria are met”

“Per central laboratory assay, if HBV DNA is < 20 IU/ml 
at screening, eligibility criteria are met “
Rationale for change
Clarification for interpretation of HCV RNA and HBV DNA 
reflex results
Section to be changed
Section 7.2.3 Primary objective analyses
Description of change
Corrected the following wording to align with the definition 
of the primary endpoint (addition in bold):
“Percentage of HVPG change from baseline at Week 8…”
Rationale for change
Correction
Section to be changed
Section 7.4 Randomization
Description of change

Confirmed that a minimum of 20 patients in treatment 
group 3 and a minimum of 20 patients in treatment group 
4 will be required 

Removed the randomization stop for NASH patients with 
T2DM after reaching 20 patients in the treatment group 3
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis
Section to be changed
Section 7.5 Determination of sample size
Description of change
Wording updated to confirm that a minimum of 20 patients in 
treatment group 3 and a minimum of 20 patients in treatment 
group 4 will be required 
Rationale for change
See rational for change to the Clinical Trial Protocol Synopsis
Section to be changed
not applicable
Description of change
Global Amendment 4 (CTP V5.0) was not released and not 
submitted as incorrect signature DMS workflow was started
and the e-signature page was missing.
Rationale for change
According to the SOP BI-VQD-11930_40-106 (v14.0) a 
global amendment needs to be approved via a DMS e-
signature workflow. By mistake the approval workflow was 
started in eDMS instead of the e-signature workflow and for 
that reason also the signature page was missing in the CTP 
Version 5.0 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c36380139
6.0
clinical-trial-protocol-version-06
Randomised, open-label and parallel group trial to investigate the effects of oral BI
685509 alone or in combination with empagliflozin on portal hypertension after 8
weeks treatment in patients with clinically significant portal hypertension (CSPH) in
compensated cirrhosis


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c36380139
6.0

SAP_001.pdf: 
ABCD
BI-VQD-12681_50-415_AD-01 (4.0)
TRIAL STATISTICAL ANALYSIS PLAN
TITLE PAGE
Document No.:
c44538732-01
BI Trial No.:
1366-0029
Title:
Randomised, open label and parallel group trial to investigate the 
effects of oral BI 685509 alone or in combination with 
empagliflozin on portal hypertension after 8 weeks treatment in 
patients with clinically significant portal hypertension (CSPH) in 
compensated cirrhosis
Including Protocol Revision 6 [include c36380139-06]
Investigational
Product(s):
Avenciguat and empagliflozin
Responsible trial 
statistician(s):
Tel.: 
Date of statistical 
analysis plan:
20 JUN 2024
Version:
1.0
Page 1 of 35
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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(S).....................................................................................................9
5.1
PRIMARY ENDPOINT(S)...................................................................................9
5.1.1
Key secondary endpoint(s) ...................................................................................9
5.2
SECONDARY ENDPOINT(S).............................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................12
6.1
TREATMENT(S) ................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATION......................................................13
6.3
INTERCURRENT EVENTS..............................................................................14
6.4
SUBJECT SETS ANALYSED ...........................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................15
6.6.1
Efficacy data ........................................................................................................15
6.6.2
Safety data............................................................................................................15
6.6.3
Missing dates and times ......................................................................................16
6.6.4
Time since first diagnosis....................................................................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................17
7.
PLANNED ANALYSIS ......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........21
7.2
TREATMENT COMPLIANCE ........................................................................22
7.3
CONCOMITANT DISEASES AND MEDICATION......................................23
7.4
PRIMARY OBJECTIVE ANALYSIS ..............................................................23
7.4.1
Main analysis .......................................................................................................23
7.4.4
Supplementary analysis ......................................................................................24


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7.5
SECONDARY OBJECTIVE ANALYSIS ........................................................24
7.5.1
Key secondary objective analysis.......................................................................24
7.5.2
Subgroup analysis................................................................................................24
7.5.3
Secondary objective analysis..............................................................................24
7.7
EXTENT OF EXPOSURE .................................................................................26
7.8
SAFETY ANALYSIS..........................................................................................26
7.8.1
Laboratory data...................................................................................................26
7.8.2
Adverse Events ....................................................................................................27
7.8.2.1
Assignment of AEs to treatment ...........................................................................28
7.8.2.2
Analysis of other significant AEs..........................................................................28
7.8.2.3
AE summaries .......................................................................................................28
7.8.2.4
AEs of special interest (AESIs).............................................................................29
7.8.2.5
User-defined adverse event category (UDAEC)...................................................29
7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG ......................................................................................................................30
7.9
OTHER ANALYSIS ...........................................................................................30
7.9.1
Ultrasound............................................................................................................30
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............32
9.
REFERENCES ....................................................................................................33
11.
HISTORY TABLE..............................................................................................35


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases ...........................................................................13
Table 6.4: 1
Subject sets analysed ........................................................................................15
Table 6.7: 1
Parameter specific follow-up period for the assignment to treatment phase....17
Table 6.7: 2
Time windows for assignment of measurements to visits for statistical 
analysis .............................................................................................................18
Table 7.1: 1
Categories for summary of continuous variables .............................................22
Table 7.5.3:1 Categories for decompensation events .............................................................25
Table 7.8.1.5: 1
Definition of continuous UDAEC............................................................29
Table 11: 1
History table .....................................................................................................35


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALQ
Above Limit of Quantification
ALT
Alanine transaminase
ANCOVA
Analysis of Covariance
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical classification
BI
Boehringer Ingelheim
BIcMQ
BI-customised MedDRA query
BLQ
Below Limit of Quantification
BMI
Body mass index
CI
Confidence Interval
CTCAE
Common Terminology Criteria for Adverse Events
CTR
Clinical Trial Report
DBL
Database Lock
DBLM
Database Lock Meeting
DILI
Drug-Induced Liver Injury
DMC
Data Monitoring Committee
DBP
Diastolic blood pressure
ECG
Electrocardiogram
EoS
End of Study (corresponds with End of Trial)
EoT
End of Treatment
FAS
Full Analysis Set
FASTTM
FibroScan-AST
Fib-4
Fibrosis-4
HVPG
Hepatic Venous Pressure Gradient
WHVP             Wedged Hepatic Venous Pressure
FHVP
Free Hepatic Venous Pressure
PFHVP
Proximal Free Hepatic Venous Pressure
ICH
International Council on Harmonisation


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Term
Definition / description
IPD
Important protocol deviation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Drug Regulatory Activities
PD
Protocol deviation
PK
Pharmacokinetic
PT
Preferred term
REP
Residual effect period
RPM
Report planning meeting
SBP
Systolic blood pressure
SAE
Serious Adverse Event
SD
Standard deviation
SDL
Subject data listing
SMQ
Standardised MedDRA query
SOC
System Organ Class
TOC
Table of contents
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
ULOQ
Upper limit of quantification


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the Clinical Trial Protocol 
(CTP), and to include detailed procedures for executing the statistical analysis of the primary 
and secondary endpoints and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the CTP. In particular, the
SAP is based on the planned analysis specification as written in CTP Section 7 “Statistical 
Methods and Determination of Sample Size”. Therefore, TSAP readers may consult the CTP 
for more background information on the study, e.g., on study objectives, study design and 
population, treatments, definition of measurements and variables, planning of sample size, 
and randomisation.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
 and several
SASTM-based tools (e.g., macros for the analyses of 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, 
).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There are no changes in this TSAP compared to the statistical methods described in the CTP.


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is the percentage change in HVPG from baseline (measured in mmHg)
after 8 weeks of treatment.
The calculation of HVPG will be based on the measurements of wedged hepatic venous 
pressure (WHVP) and free hepatic venous pressure (FHVP). 
The average WHVP and the average FHVP will be calculated from the triplicate 
measurements. Either the average FHVP or the measurement proximal free hepatic venous 
pressure (PFHVP) will be used as the subtrahend for the calculation of HVPG, which will be 
rounded to one decimal place.
Based on the judgement of the central reader, if the recorded PFHVP is considered to be more
reliable than the average of the recorded triplicate FHVPs, then:
                     HVPG (mmHg)=average WHVP (mmHg) – PFHVP (mmHg);
if the average of the recorded triplicate FHVPs is considered to be more reliable than the 
recorded PFHVP, then
HVPG (mmHg)=average WHVP (mmHg) – average FHVP (mmHg).
The quality of the HVPG will be categorized into optimal, sub-optimal and not evaluable 
based on the judgement of the central reader. A frequency table will be provided to 
summarize the quality of HVPG tracings measured at baseline and week 8.
5.1.1
Key secondary endpoint(s)
Since there are no key secondary endpoints specified in the CTP, this section is not
applicable.
5.2
SECONDARY ENDPOINT(S)
Following secondary endpoints will be analysed:

Occurrence of a response, which is defined as > 10% reduction from baseline HVPG
(measured in mmHg) after 8 weeks of treatment.

Occurrence of one or more decompensation events (i.e., ascites, VH, and / or overt HE)
during the 8-week treatment period.

Occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on 
Investigator judgement, during the 8-week treatment period

Occurrence of discontinuation due to hypotension or syncope during the 8-week 
treatment period.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on the treatment to be administered, assignment to treatment, and 
selection of dose, refer to CTP Section 4.
There will be three study phases in this trial: screening, study treatment phase (with 
avenciguat and avenciguat + empagliflozin) and follow-up.


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Table 6.1: 1
Flow chart of analysis phases
Label
Interval
Start date
End date
Screening 
Screening
Date of informed consent
Date of first
administration of
study medication -1
avenciguat 
/
avenciguat 
 + 
empagliflozin 10mg
On-treatment
Date of first administration 
of study medication
Date of last intake 
of study medication 
+ X*
Follow-up*
Follow up
Date of last intake of study 
medication + X* + 1
Latest of (day of 
EOS visit, last 
contact date on EOS 
page)
*X=1, 3 or REP (7) days for safety laboratory, and AE respectively. X for other variables are defined in Table 6.7: 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.
The purpose of the definitions above is to describe all the different study/treatment intervals,
to which a patient can be assigned during the course of the trial. 
For efficacy analyses of HVPG, data up REP+1 (8 days) after last treatment intake will be 
considered as on-treatment, because an HVPG measurement at EOT is permitted within 7 
days after scheduled EOT (i.e., REP+1 day after last dose) as stated in Section 5.1.1 of the 
CTP.
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to
treatment groups, i.e., patients will be analysed in the treatment group they were assigned or 
randomised to.
AEs with an onset during the time of the incorrect study treatment will be listed separately.
6.2
IMPORTANT PROTOCOL DEVIATION
Each protocol deviation must be assessed to determine whether it is an important Protocol 
Deviation (iPD). The documentation of the iPD categories and handling of iPDs in analysis is 
included in the DV domain specification and stored within the TMF in EDMS.
The decision about which protocol deviation (PD) could generate exclusion from analysis
sets will be taken during the conduction of the trial and finalised at the last report planning
meeting (RPM).
Non-important COVID-19 related PDs will only be listed.


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6.3
INTERCURRENT EVENTS
The expected intercurrent events (ICEs) of interest in this trial are:

Use of the following restricted concomitant therapy:
-
NO-sGC-cGMP pathway activating therapies like NO-donors (e.g. glyceryl
trinitrate, isosorbide di- or mono-nitrate, molsidomine), PDE-5-inhibitors (e.g.
sildenafil, tadalafil, and vardenafil), non-specific PDE inhibitors such as dipyridamole 
and theophylline, or sGC-stimulators (e.g., riociguat)

New onset of / dose change in existing NSBB / carvedilol, pioglitazone, GLP1-
agonists and vitamin E concomitant therapy

Occurrence of a decompensation event

Premature discontinuation of assigned trial medication
The strategies for handling those intercurrent events in this trial are as follows:
Treatment Policy: This is the effect of randomizing patients to a treatment arm regardless of 
treatment actually being taken. All intercurrent events will be handled according to the 
treatment policy approach as defined in ICH E9(R1). This will be used as the primary 
strategy of implementing the Estimand Concept (EC).
6.4
SUBJECT SETS ANALYSED
The subject sets will be used as defined in the CTP, Section 7.2.1. These include the Treated
set (TS) and Full analysis set (FAS).
 

Screened set (SCR) – this analysis set includes all patients having signed informed 
consent. The SCR will be used for analyses of patient disposition.
The discussion on all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at latest at DBLM.
In Table 6.4:1 the subject sets which are to be used for each class of endpoint are illustrated.


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Table 6.4: 1
Subject sets analysed
Subject set
Class of endpoint
SCR
TS
FAS
Disposition
X
Primary endpoint
X
Secondary efficacy 
endpoints
X
Safety endpoints & 
treatment exposure
X
Demographic/baseline 
endpoints
X
Handling of Treatment Misallocations in Analysis Sets
If a subject entered the trial but was not treated, they will be reported under their 
randomised/assigned treatment group for efficacy analysis according to FAS. Such subjects 
are excluded from the safety analyses since no study medication was taken.
If a subject is randomised but took incorrect treatment during the study,
-
For efficacy analyses according to the FAS, subjects who took incorrect treatment will 
be reported under their randomised treatment group.
-
For safety analyses based on TS, the actual treatment will be used as below:
o
If a patient took at least one dose of empagliflozin, then the patient will be 
reported under the treatment group of avenciguat + empagliflozin.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Efficacy data
No imputation of missing data is planned for the efficacy endpoints. 
6.6.2
Safety data
Missing safety data will not be imputed.


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6.6.3
Missing dates and times
Missing or incomplete AE dates are imputed according to company standards (2).
If the date of first drug administration is missing but the patient was entered, the date of the 
first drug administration will be set to the date of entering the trial. If the date of first
administration is partially missing with the month and year present, the day will be set to the
date of entering the trial if entering the trial was in the same month. If entering the trial was in 
the month prior to the first drug administration the missing day will be imputed as the first 
day of the month.
Partial start and stop dates for concomitant therapies will be imputed to enable subsequent 
calculation (but not for display) by the following “worst case” approach:

If the day of the end date is missing, then the end date is set to last day of the month 
(or to the patient’s trial completion date, whichever is earlier).

If the day and month of the end date are missing, then the end date is set to 31st of 
December of the year (or to the patient’s trial completion date if it is earlier than 31st
December of the year).

If the day of the start date is missing, then the start date is set to first day of the month.

If the day and month of the start date are missing, then the start date is set to 1st
January of the year.
All other cases need to be assessed by the trial team on an individual basis, using above points 
as guidance.
6.6.4
Time since first diagnosis
For incomplete information on the date of the first diagnosis (both of cirrhosis and of chronic 
liver disease), time since first diagnosis will be calculated as follows:

If the year of first diagnosis is unknown, then the time since diagnosis will be set to 
missing.

If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th June of that year.

If only the day of the first diagnosis is unknown, time since diagnosis will be 
calculated as if diagnosed on the 15th of that month.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Regarding efficacy and safety endpoints, the term “baseline” refers to the last observed
measurement prior to administration of any study medication.
Measurements taken prior to the first intake of study medication will be considered pre-
treatment values. Pre-treatment values will be assigned to a visit according to the nominal 
visit number as recorded on the eCRF or as provided by the laboratory.
In general, the date of the first drug administration will be used to separate pre-treatment from 
on-treatment values. Measurements taken after first trial medication intake will be considered 
on-treatment values if they have been obtained up to end of the parameter specific follow-up 
period as defined in Table 6.7:1 below and will be assigned to the corresponding study
medication for efficacy and safety analyses.
Measurements taken after the end of the endpoint specific follow-up period will be considered 
post-treatment values.
Table 6.7: 1
Parameter specific follow-up period for the assignment to treatment phase
Endpoint
Last day of assignment to treatment phase
(days after study medication stop date)
Efficacy
    HVPG
8 (REP + 1)
Safety
    Adverse events
7
    Safety laboratory measurements
3
    Vital signs (including body weight, blood pressure)
1
For derivation of the last value on treatment, minimum value on treatment, and maximum 
value on treatment, all values from the relevant phase (whether or not collected in any time 
window; see Table 6.1:1 for definition of the trial phases) will be considered; these will be 
derived for analysis of laboratory and vital signs data. For identification of potentially 
clinically significant abnormal laboratory values, all values (whether selected in any time 
window) up to 7 days after last treatment intake will be considered.


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On-treatment efficacy, safety 
 measurements will be assigned to visits based on 
the extended time windows around the planned visit dates, defined relative to the day of first 
trial medication intake (see Table 6.7:2). 
Table 6.7: 2
Time windows for assignment of measurements to visits for statistical analysis
Visit 
number
/name
Planned 
day B
Time window (Days)
Visit label
Window
(per CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)*
EndA
(extended)#
V1
Screening
-42
-∞
0
On-treatment
V2
Week 0
Day 1
N/A
1
1
≤1
1
V3
Week 1
Day 8
+2
8
10
2
11
V4
Week 2
Day 15
+2
15
17
12
22
V5
Week 4
Day 29
+2
29
31
23
36
V6
Week 6
Day 43
±3
40
46
37
50
V7
Week 8/
EoT
Day 57
±3
54
60
51
Study
medication 
stop
date + XC
days
Off-treatment
V8
Week 12/
EoS
Day 85
±5
80
90
Study
medication 
stop
date + X 
days+1
Day of last 
follow-up 
A In case of premature discontinuation of the study medication, an early EoT visit has to be performed within 7 days of
medication stop date. If such an EoT Visit falls into the time window of a previous visit, measurements will be assigned to 
this previous visit and the visit value will be determined as described above. In this case, the time window for the visit that
includes the early EoT visit will end X days after the study medication stop date, including Day X. Patients will then be asked
to continue in the study according to the visit schedule. Off-treatment measurements will be assigned to visits in the same 
manner.
B Days are counted relative to the day of first treatment, which is defined as Day 1.
* Start (extended): End of extended window of last visit+1
# End (extended): Midpoint of planned days between current visit and next visit
C X is the parameter specific follow-up period for the assignment to treatment phase, refer to Table 6.7:1 for the details.
The midpoint between two on-treatment visits defines the end of a time window, with the
midpoint being included in the time window of the preceding visit. The end of the time
window of the last on-treatment visit (end of treatment (EoT)) is endpoint dependent (Table
6.7:1).
Repeated and unscheduled efficacy and safety measurements will be assigned to the nominal
visits and listed in the subject data listing according to the time windows described above. 
Only one observation per time window will be selected for analysis at an on-treatment visit -
the value which is closest to the protocol planned visit day will be selected. If there are two 


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observations which have the same difference in days to the planned day, the first value will be 
selected. If there are two observations on the same day, the first value will be selected. If there 
are multiple values within the time window of the last visit, including a value on the last day 
of drug intake, the value on the last day of drug intake is used as the value of the last visit.
Data prior to Day 1 of trial medication will be based on nominal visits and time windowing 
will not be applied. For these time points, data from the scheduled visit will always be 
selected if they are collected correctly. Unscheduled visits will only be considered if no 
correct data from the scheduled visit is available. If no correct data from a scheduled visit is 
available and multiple unscheduled correct values are available for a visit, the first correct 
value will be selected.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
Clinical Trials and Project Summaries" (3).
Disposition of the patient population participating in the trial will be summarized by the 
presentation of the frequency of patients screened, screened but not entered, entered but not 
treated, entered and treated, who completed planned treatment period, who were prematurely 
discontinued from trial medication by reasons, who completed the study, and who 
prematurely discontinued from the study. 
A frequency of patients with iPDs will be presented by treatment group for treated set. The 
frequency of patients in different analysis sets will also be presented for each treatment group. 
The iPDs per patient will be listed indicating whether the iPD led to exclusion from patient 
sets analysed.
For tables presenting descriptive analysis of the endpoints and other variables, the set of 
summary statistics is: N (number of patients with nonmissing values) / Mean / SD / Min / Q1 
(lower quartile) / Median / Q3 (upper quartile) / Max.
Statistical parameters will be displayed to a defined number of decimal places as specified in
the BI guideline "Reporting of Clinical Trials and Project Summaries" (3). 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as percentage (%) relative to the 
respective treatment group. Percentages will be based on all patients in the respective patient 
set whether they have non-missing values or not. Percentages will be rounded to one decimal 
place. The category missing will be displayed if and only if there are actual missing values. 


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section.
Descriptive statistics for demographic parameters and baseline characteristics will be 
presented by treatment, based on the TS.
For the continuous variables described below, categories are defined in Table 7.1:1. These 
variables will be presented according to the number and percentage of patients in each 
category, in addition to the display of the summary statistics for continuous variables.


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Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
(years)
< 50
50 to < 65
65 to < =75
>75
< 65
≥ 65
Weight
(kg)
≤ 70
> 70 to ≤ 80
> 80 to ≤ 90
> 90
BMI
(kg/m2)
< 25 
25 to < 30 
≥ 30 
eGFR
(mL/min/1.73 m2)
≤ 30
> 30 to ≤ 45
> 45 to ≤ 60
> 45 to ≤ 60
> 60 to ≤ 90
> 90
Time since first diagnosis of 
(years)
≤ 1
> 1 to ≤ 5
> 5 to ≤ 10
> 10
Baseline HVPG (mmHg)
≤ 12
>12
≤ 15
>15
7.2
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. 


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The compliance based on TS will be described as collected in the eCRF. Number and 
percentage of patients with compliance in following categories will be displayed at each visit 
since week 1:

“Yes”,

“No” and，

“Missing”.
7.3
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Analyses of the 
concomitant diseases and medication as well as non-drug therapies will be based on TS.
Concomitant diseases will be coded according to the most recent version of Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary (WHO-DD).
A medication/non-drug therapy will be considered concomitant to treatment if it:

is ongoing at the start of trial medication intake

starts within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
Concomitant medication use will be summarised with frequency and percentage of patients by 
Anatomical Therapeutic Chemical 3 (ATC3) class and preferred name.
7.4
PRIMARY OBJECTIVE ANALYSIS
The primary endpoint for this study is the percentage change from baseline in HVPG from 
baseline after 8 weeks of treatment.
7.4.1
Main analysis 
For the primary endpoint, the analysis of covariance (ANCOVA) will be used. The analysis 
will be performed on the FAS and include on-treatment HVPG only. If a patient misses the 
Week 8 visit, the missing data will not be imputed. 
The statistical model will be:
Percentage HVPG change from baseline at Week 8 = overall mean + HVPG baseline + 
                  treatment + random error


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This model includes treatment as fixed classification effects and baseline HVPG as a linear 
covariate. The random error is assumed to be normally distributed with mean 0 and variance 
σ². The analysis will only be used for estimation of treatment effects without performing 
statistical tests.
The main analysis will implement the primary estimand defined in Section 6.3 and be 
performed on FAS. All data collected after the intercurrent events will be used for the 
analysis. The number of patients reporting each type of intercurrent event will be summarized 
for overall and each treatment group.
If after all the steps above have been investigated without successful model convergence, then 
an ANCOVA (Analysis of Covariance) model at Week 8 only, will be performed.  If the 
above sequence of methods does not lead to convergence for a particular subgroup, then that 
analysis will not be performed or reported.
7.4.4
Supplementary analysis
For primary endpoint, the analysis in Section 7.4.1 will be repeated in

FAS excluding patients with down-titration or dose-interruption
7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Subgroup analysis
No subgroup analyses are planned for the analysis.
7.5.3
Secondary objective analysis
The secondary endpoints for this study are described in CTP Section 2.1.3. 
For the occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on 
Investigator judgement and the occurrence of discontinuation due to hypotension or syncope, 


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the numbers and percentages of patients with those events will be presented jointly and also 
separately.
For the occurrence of decompensation events, categories are defined in Table 7.5.3:1.
Table 7.5.3:1 Categories for decompensation events
Categories          
Scope 
Definition
Acites
PT - ‘Ascites’
PT - ‘Bacterascites’ 
PT - ‘Haemorrhagic ascites’
Variceal haemorrhage
Narrow
Narrow
Narrow
Broad
Broad
Broad
PT - ‘Oesophageal varices haemorrhage’
PT - ‘Oesophageal haemorrhage’
PT - ‘Bleeding varicose vein’
HLT – ‘Gastric and oesophageal 
haemorrhages’
HLT – ‘Non-site specific gastrointestinal 
haemorrhages’
Hepatic encephalopathy Narrow
Narrow
Broad
Broad
PT - ‘Hepatic encephalopathy’
PT - ‘Coma hepatic’
PT - ‘Hyperammonaemic 
encephalopathy’
PT - ‘Hyperammonaemic crisis’
Other
PT - ‘Cardiohepatic syndrome’
PT - ‘Hepatorenal syndrome’
PT - ‘Hepatorenal failure’
PT - ‘Hepatic hydrothorax’
PT - ‘Hepatopulmonary syndrome’
For all the secondary endpoints, only descriptive statistics will be presented.


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7.7
EXTENT OF EXPOSURE
A descriptive statistics table with mean, SD, median and range of the number of days a
patient was on treatment will be provided for the treated set. The tables will also provide the
sum total of the time that all patients pooled together were on treatment. A separate
listing will be created for patients who switched treatment, had dose interruption or dose 
down-titration any time indicating exposure to each treatment.
A frequency table of number and percent of patients belonging to each categorical range of
exposure weeks will be provided as well. The following are the categories of exposure-ranges
(in weeks): “0 to 4 weeks”; “> 4 to 8 weeks” and “>8 weeks”.
No temporary treatment interruption period will be reported. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the TS following BI standards. Additionally, 
AE reported to be related to study procedures will be listed based on the SCR.
7.8.1
Laboratory data
The analyses of laboratory parameters will be descriptive in nature and will be based on BI 
standards (7). Note that data from the central Laboratory will be used for all displays 
described below, unless otherwise specified.
For continuous safety laboratory parameters standardized and normalized values will be
derived as well as the differences to baseline. Normalisation means transformation to a 
standard unit and to a standard reference range. The process of normalisation, handling of 
repeat values at the same visit for by-visit displays, as well as standard analyses for safety 
laboratory data are described in the BI guidance for “Handling, Display and Analysis of 
Laboratory Data” (7). All analyses considering multiple times of the ULN (as described 
below) will be based on standardised and not normalised values. 
Laboratory parameters will be shown in conventional units. Where conventional units differ
from SI units, analyses will be repeated on SI units in the appendix.
Laboratory values will be compared to their reference ranges and frequency tables will be
provided for the number of patients within and outside the reference range at baseline and the
last measurement on treatment. Descriptive statistics will be provided by treatment group and 
total for baseline, last value on-treatment and for changes from baseline to last value on 
treatment. Frequency tables will summarise the number of patients with potentially clinically 
significant abnormalities.
Both on-treatment and post-treatment values of the following lab parameters will be presented 
graphically. The values after the treatment period will be assigned to the follow-up (EoS) 
period.


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
Haematocrit

Haemoglobin

RBC count / erythrocytes

WBC / leukocytes

Platelet count / thrombocytes

Reticulocytes

INR

ALT

Alkaline phosphatase

AST

Bilirubin (total)

Albumin

gamma-GT

eGFR
Only patients with at least one available on-treatment value will be included in the analysis of
an individual laboratory parameter. All individual data will be presented in listings.
To support analyses of liver related adverse drug effects, the frequency of patients with AST 
and/or ALT ≥ 3xULN combined with the total bilirubin ≥ 2xULN in a 30-day period after 
AST/ALT elevation will be displayed, stratified by alkaline phosphatase < 2xULN and ≥ 
2xULN (a patient can potentially be in both alkaline phosphatase strata in case of multiple 
AST/ALT and bilirubin elevations). The start of the 30-day time span is triggered by each 
liver enzyme elevation above defined thresholds. This analysis will be based on standardised 
laboratory values.
A graphical analysis of the ALT and total bilirubin during the on-treatment period will also be 
performed; the so called eDISH plot. In the graph, for each subject, 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 log 10 scale. The measurements displayed for total bilirubin and ALT may, or may 
not, occur on the same date. Two reference lines, 2xULN for total bilirubin and 3xULN for 
ALT, are drawn onto the graph 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). The same graphical analysis will be performed for AST 
and total bilirubin during the on-treatment period as well. Details on patients with elevated 
live enzymes will be listed.
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.
7.8.2
Adverse Events
AEs will be coded with the most recent version of MedDRA coding dictionary. Patients will 
be analysed according to the actual treatment received.


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Any clinically significant new finding in the physical examination, vital signs (blood pressure
and pulse symptoms) and in the 12-lead ECG starting after visit 2 will be considered as an AE 
and will be reported as such.
The 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.
7.8.2.1
Assignment of AEs to treatment
In general, the analysis of AEs will be based on the concept of treatment emergent AEs. That 
means that all AEs occurring between first drug intake till 7 days (residual effect period –
REP) after last drug intake will be assigned to the on-treatment period. All AEs occurring 
before first drug intake will be assigned to ‘screening’ and all AEs occurring after last drug 
intake + REP of 7 days will be assigned to ‘follow-up’ (for listings only). For details on the
treatment definition, see Section 6.1.
If only the start date of an AE is collected (without the start time), any AE occurrence on the 
same day as the first avenciguat administration will be assigned to the on-treatment phase.
In general, tables will only present AEs assigned to the first treatment taken except
drug-related AEs which will be presented as actual treatment taken at each given timepoint.
AEs and serious adverse events (SAEs) assigned to the following phases: screening, on-
treatment, post-treatment will be listed.
7.8.2.2
Analysis of other significant AEs
Other significant AEs will be reported and summarised according to ICH E3 criterion (5).
Thus, AEs classified as 'other significant' will include those non-serious adverse events with
‘action taken = discontinuation’ or ‘action taken = dose reduced’. 
7.8.2.3
AE summaries
An overall summary of adverse events will be presented.
The frequency of patients with adverse events will be summarised by treatment, primary SOC
and PT. The SOC will be sorted by frequency, PTs will be sorted by frequency (within SOC).  
AEs which were defined as secondary endpoints will be summarised separately. AEs will also 
be reported by intensity according to the maximum Common Terminology Criteria for 
Adverse Events (CTCAE). Separate tables will be provided for patients with other significant 
AEs according to ICH E3 (5), adverse events of special interest (AESI), for patients with 
serious adverse events, for patients with AEs leading to discontinuation, for patients with AEs 
leading to dose reduction, for patients with drug-related AEs and for patients with fatal AEs.
Note that for drug-related AEs, separate tables will be prepared for treatment group 4 – one 
for AEs related to avenciguat and one for AEs related to empagliflozin. A listing of AEs 
related to study procedure will be prepared based on enrolled set.


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For further details on summarisation of AE data, please refer to “Handling of missing and 
incomplete AE dates” (2) and “Analysis and Presentation of Adverse Event data from Clinical 
Trials” (6). 
7.8.2.4
AEs of special interest (AESIs)
The protocol defines the following adverse event as AESI:

Hepatic injury:
A hepatic injury is defined by alterations of the hepatic laboratory and clinical 
parameters after randomisation as detailed by the removal and stopping criteria in CTP 
Section 3.3.4.1 and CTP Appendix 10.2.

Ketoacidosis
If metabolic acidosis, ketoacidosis, or diabetic ketoacidosis (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.
More details refer to CTP Section 5.2.6.1.4.
An independent Adjudication Committee will adjudicate certain hepatic events for the 
severity and causal relationship with the trial medication. Adjudication assessments will be 
incorporated to the database. Frequency tables will be provided for the PTs in the specified 
SMQs of events and for the adjudication endpoints. Tables will be provided for events 
qualifying for adjudication and then separately the events that were confirmed or non-
assessable.  
7.8.2.5
User-defined adverse event category (UDAEC)
UDAEC will be summarized by dose group, primary system organ class and preferred term.
In summary, Table 7.8.2.5:1 provides the definition of UDAECs according to AE category or 
Standardized MedDRA Query (SMQ).
Table 7.8.2.5: 1
Definition of continuous UDAEC
Category
Safety topic
Definition
UDAEC
Hypotension
Investigator-reported, as a dedicated AE category on the AE 
eCRF page
UDAEC
Syncope
Investigator-reported, as a dedicated AE category on the AE 
eCRF page
UDAEC
Acute kidney injury
SMQ ‘Acute renal failure’, narrow scope
UDAEC
Peripheral edema
SMQ ‘Haemodynamic oedema, effusions and fluid overload’
UDAEC
Bleeding
SMQ ‘Haemorrhages’, narrow scope
UDAE
Liver events
Narrow sub-SMQ ‘Liver related investigations, signs, and 
symptoms’, narrow sub-SMQ ‘Cholestasis and jaundice of 
hepatic origin’, narrow sub-SMQ ‘Hepatitis, non-infectious’ 


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Category
Safety topic
Definition
and narrow sub-SMQ ‘Hepatic failure, fibrosis and cirrhosis 
and other liver damage-related conditions’
Summary of hypotension and syncope will be presented for both patient-based and event-
based analyses. ae
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:
-
Baseline SBP <=140: decrease *
+,-./ 0# 12345 /6- -74.+1- – 9:.-4- 0#
9:.-4- 0#
; ≥30%;
-
Baseline SBP >140: decrease *
+,-./ 0# 12345 /6- -74.+1- – 9:.-4- 0#
9:.-4- 0#
; ≥40%;
-
Or lowest SBP during the episode <90.
-
Baseline DBP <=70: *
+,-./ A0# 12345 /6- -74.+1- – 9:.-4- A0#
9:.-4- A0#
; ≥30%;
-
Baseline DBP > 70: *
+,-./ A0# 12345 /6- -74.+1- – 9:.-4- A0#
9:.-4- 0#
; ≥40%;
-
Or lowest DBP during the episode <50.
-
Lowest mean arterial pressure (MAP=DBP+1/3(SBP-DBP)) during the episode<70.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature.
Descriptive statistics of vital signs over time during treatment period and post-treatment 
period (pre-dose, 1 hour and 2 hour) and for the difference from baseline and pre-dose will be 
provided by treatment, including the last value, the minimum value, and the maximum value 
within the study period as described in Table 6.1:1. Figures for change from baseline and 
change from pre-dose for on-treatment visit and post-treatment visit will be provided as well.
7.8.4
ECG
Abnormal findings in 12-lead ECG 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. 
No separate listing or analysis of ECG data will be prepared.
7.9
OTHER ANALYSIS
7.9.1
Ultrasound
Descriptive analysis of change from baseline of portal vein diameter at week 8 will be 
provided. A listing of all the collected data from the ultrasound CRF page for each patient will 
be provided.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
Not applicable as no blinding procedure is needed.


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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-HTG-0035: “Handling of missing and incomplete AE dates”, current
version; KMED.
3.
KM Asset BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and 
Project Summaries", current version, KMED.
4.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses
performed within Clinical Pharmacokinetics/Pharmacodynamics”, current
version; KMED.
5.
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.
6.
KM Asset BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse Event data 
from Clinical Trials”, current version, KMED.
7.
KM Asset 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
1.0
20-JUN-24
None
This is the final TSAP.