Clinical trial NCT06082843
Conditions: Hypertension, Portal Liver Cirrhosis
Sponsor: Boehringer Ingelheim
Start date: 2024-01-03; Completion date: 2024-05-30
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with advanced liver cirrhosis caused by hepatitis B, hepatitis C, alcohol-related liver disease, non-alcoholic steatohepatitis or other causes. People can join the study if they have high blood pressure in the portal vein (main vessel going to the liver) and bleeding in the esophagus or fluid accumulation in the belly. The purpose of this study is to find out whether a medicine called avenciguat helps people with this condition.

Participants are put into 2 groups by chance. One group takes avenciguat tablets and the other group takes placebo tablets. Placebo tablets look like avenciguat tablets but do not contain any medicine. Participants take a tablet twice a day for 8 weeks.

Participants are in the study for 2 to 3 months. During this time, they visit the study site regularly. At 2 of the visits, the doctors check the pressure in the liver vein by inserting a catheter (a long thin tube) that gives information about pressure in the portal vein. The change in blood pressure is then compared between the 2 groups to see whether the treatment works. The doctors also regularly check participants' health and take note of any unwanted effects.

Detailed description:

Arms: arm 1: Participants with stabilized decompensated cirrhosis due to non-cholestatic liver disease, following their first decompensation event, received 1 milligram (mg), 2 mg, or 3 mg film-coated tablets of placebo-matching avenciguat (BI 685509) orally twice daily (bid). Participants started the treatment with a 1 mg film-coated tablet of placebo-matching avenciguat administered bid. One week later (Visit 3), the dosage was increased to 2 mg film-coated tablets bid, and after another week, participants started on 3 mg film-coated tablet bid (Visit 4), which was maintained for the rest of the treatment. arm 2: Participants with stabilized decompensated cirrhosis due to non-cholestatic liver disease, following their first decompensation event, received 1 milligram (mg), 2 mg, or 3 mg film-coated tablets of avenciguat (BI 685509) orally twice daily (bid), up to a total dose of 6 milligrams (mg). The treatment period began (Visit 2) with a 1 mg film-coated tablet of avenciguat administered bid. If the dose was well-tolerated, it was increased to 2 mg film-coated tablets bid after one week (Visit 3), followed by an increase to the maintenance dose of 3 mg film-coated tablet one week later (Visit 4). If the maintenance dose of avenciguat was not well-tolerated, it was reduced, with the participants remaining on the highest tolerated dose for the rest of the treatment period.
Interventions: intervention 1: Placebo intervention 2: Avenciguat
Intervention descriptions: intervention 1: Placebo-matching Avenciguat intervention 2: 1 millligram (mg), 2 mg, or 3 mg film-coated tablet

Protocol documents:
Prot_000.pdf: 
BI-VQD-12177_40-106_AD-03 (22.0)
Clinical Trial Protocol
TITLE PAGE
Document Number:
c42374778-02
EudraCT No.
EU Clinical Trial No.
2023-506083-13-00
Universal Trial No.
U1111-1293-6879 
BI Trial No.
1366-0055
BI Investigational
Medicinal Product
BI 685509
Title
Randomised, double-blind, placebo-controlled and parallel group 
trial to investigate the effects of one dose (up-titration to a fixed 
dose regimen) of oral BI 685509 on portal hypertension after         
8 weeks treatment in patients with clinically significant portal 
hypertension (CSPH) in decompensated cirrhosis after their first 
decompensation event, who are stabilized CTP 5-7
Lay Title
A study to test whether BI 685509 helps people with liver 
cirrhosis and high blood pressure in the portal vein (main vessel 
going to the liver) who had bleeding in the esophagus or fluid 
accumulation in the belly
Clinical Phase
II
Clinical Trial Leader
Coordinating 
Investigator
Current Version and 
Date
Final Version 2.0 29 Nov 2023
Original Protocol Date
07 Jul 2023
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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
Latest revision date
07 Jul 2023
29 Nov 2023
BI trial number
EU CT number
Universal trial 
number
1366-0055
2023-506083-13-00
U1111-1293-6879 
Title of trial
Randomised, double-blind, placebo-controlled and parallel group 
trial to investigate the effects of one dose (up-titration to a fixed dose 
regimen) of oral BI 685509 on portal hypertension after 8 weeks 
treatment in patients with clinically significant portal hypertension 
(CSPH) in decompensated cirrhosis after their first decompensation 
event, who are stabilized CTP 5-7
Coordinating 
Investigator
Trial sites
Multi-center trial
Clinical phase
II
Trial rationale
In this Phase 2 trial, the efficacy of treatment in patients with CSPH
in decompensated cirrhosis after their first decompensation event 
due to non-cholestatic liver disease will be assessed. The trial will 
evaluate the short-term efficacy of BI 685509, 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 2I development.
Benefit-risk 
assessment and 
ethical considerations
Trial participants with cirrhosis with PH might benefit from the 
combined anti-fibrotic and hemodynamic effects of sGC activation. 
Treatment with BI 685509 in trial participants, who already 
developed decompensated cirrhosis will potentially result in the 
secondary prevention of related complications including further 
decompensation (variceal bleeding, ascites and encephalopathy), 
transplantation, or liver-related death.  The potential risks, as 
described above, will be minimised by close monitoring of trial 
participants, by excluding at-risk trial participants from the trial, and 
by involvement of a DMC.  Hepatic injury will also be assessed by 
an independent AC for safety purposes.  Hence, overall, in the 


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context of the unmet medical need, the anticipated effects of BI 
685509 on CSPH in trial participants with decompensated cirrhosis 
due to non-cholestatic liver diseases based on the safety profile of BI 
685509, the benefit-risk evaluation of the compound is considered 
favourable for the intended population.
Trial objectives
The trial will investigate the safety and tolerability, of BI 685509, on 
top of standard of care, on portal hypertension in patients with 
clinically significant portal hypertension in decompensated cirrhosis
after their first decompensation event. The primary objective is to 
estimate the percentage change in HVPG from baseline measured 
after 8 weeks in patients with decompensated cirrhosis.
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

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, double-blind, parallel group, placebo-controlled 
comparison of treatment with BI 685509 over 8 weeks
Total number of trial 
participants 
randomised
Approximately 40
Number of trial 
participants per 
treatment group
Approximately 20
Diagnosis, 
main inclusion and 
exclusion criteria
Patients with CSPH in decompensated cirrhosis due to non-
cholestatic liver disease after their first decompensation event 
(variceal haemorrhage or first event of clinically significant 
ascites), who are stabilized (CTP 5-7)
Main Inclusion criteria:
1.
Signed and dated written informed consent in accordance with 
ICH-GCP and local legislation prior to admission to the trial


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2.
Male or female 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.
Diagnosis of cirrhosis due to non-cholestatic liver disease 
(including HCV, HBV, NASH, alcohol-related liver disease, 
autoimmune hepatitis, Wilson’s disease, haemachromatosis, 
alpha-1 antitrypsin [A1At] deficiency)
4.
One previous clinically significant decompensation event with 
clinical resolution at least 4 weeks prior start of screening 
(visit 1a):
a.
First variceal haemorrhage
b.
First episode of clinically significant ascites (requiring 
intervention in lifestyle [fluid and salt restriction] or 
medical treatment)
5.
Willing and able to undergo HVPG measurements per 
protocol (based on Investigator judgement)
Main exclusion criteria:
1.
History of cholestatic chronic liver disease (e.g. primary 
biliary cholangitis, primary sclerosing cholangitis)
2.
Trial participants 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)
3.
If received curative anti-viral therapy for HCV, SVR sustained 
for less than 1 years prior to screening 
4.
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
5.
Weight change ≥ 5% within 6 months prior screening in 
patients with NASH  
6.
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
7.
SBP < 100 mmHg or DBP < 70 mmHg at screening (Visit 1a)


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8.
Hepatic impairment defined as a Child-Turcotte-Pugh score 
≥8 at screening
Trial intervention and 
test product
BI 685509
Dose and mode of 
administration
Comparator 
product(s)
Placebo
Dose and mode of 
administration
Matching
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. This model will include treatment, use (or not) of NSBBs or 
carvedilol and type of first decompensation event 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 hypothesis testing.
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
22
3
4
5
6
EoT / ED3
EoS3
Week
-4
R
1
2
4
6
8
10
Day
-28
1
8
15
29
43
57
71
Time window for visits (days)
See footnote 1
N/A
+ 2
+ 2
+ 2
± 3
± 5
± 5
Fasting status4
NF
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
Anthropometric measures6
x
x
x
x
x
x
x
x
Vital signs7
x
x21
x21
x21
x21
x
x
x
Physical examination8
x20
(x)
(x)
(x)
(x)
(x)
x
(x)
Resting 12-lead ECG7
x
x21
x21
x21
x21
x
x
x
Safety laboratory sampling
x
x
x
x
x
x
x
Pregnancy testing9 
xs
xu
xu
xu
xu
Hepatic venous pressure gradient (HVPG)10
x
x
Ultrasound (liver and spleen)11
x
x
x
x
Review of in-/exclusion criteria
x
x
x
Randomisation
x


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FLOW CHART cont.
Trial Periods
Screening1
Randomised Treatment
Follow-Up
Visit
1a1
1b1
22
3
4
5
6
EoT / ED3
EoS3
Week
-4
R
1
2
4
6
8
10
Day
-28
1
8
15
29
43
57
71
Time window for visits (days)
See footnote 1
N/A
+ 2
+ 2
+ 2
± 3
± 5
± 5
Fasting status4
NF
F
F
NF
NF
F
NF
F
F
IRT call
x
x
x
x
x
x
Dispense trial medication
x
x
x
x
x
Dose-titration13
x
x
x
Train patient (home BP and HR 
monitoring)14
x
(x)
Home BP and HR monitoring (by trial 
participant)14
x
→
→
→
→
→
→
Train / dispense / review trial participant
reminder card15
x
x
x
x
x
x
Biobanking sampling18
x
x
All AEs / SAEs / AESIs19
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
X22
Completion of trial participant participation
x


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Footnotes:
1.
The screening period consists of 2 visits (Visits 1a/b).  These visits should ideally be completed within a period of 4 weeks.  There is no minimum duration.  A trial participant
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.  Refer to Sections 5.1.2, 5.2.5.1, 
5.2.5.2 and 6.2.1 
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.
Trial participants who complete 8 weeks of treatment will have an End of Treatment (EoT) visit, followed 2 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.  Trial participants 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 2 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 trial participant has rested for at least 5 minutes in a supine position.   From Visit 2 onwards, 
the trial participants 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 trial participant
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. For further details regarding the HVPG measurement, refer to Section 5.1.1
11. For further details regarding ultrasound of the liver and spleen, refer to Section 5.2.5.1
14. 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    
17.
18. 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
19. After the EoS visit (= individual trial participants 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)
20. 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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21. 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 
(refer to Sections 5.2.2, 5.2.4 and 5.3).
22. Last trial dose will be administered at home the evening prior to the EoT visit.


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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 – BI 685509...........................................................................19
1.2.1
Key characteristics of BI 685509 .......................................................................20
1.2.2
Data from non-clinical studies ...........................................................................22
1.2.3
Data from clinical studies...................................................................................23
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................24
1.4
BENEFIT - RISK ASSESSMENT.....................................................................24
1.4.1
Benefits.................................................................................................................25
1.4.2
Risks .....................................................................................................................25
1.4.3
Discussion.............................................................................................................29
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................31
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........31
2.1.1
Main objectives....................................................................................................31
2.1.2
Primary endpoint................................................................................................31
2.1.3
Secondary endpoints...........................................................................................31
2.2
FURTHER OBJECTIVES AND FURTHER ENDPOINTS ..........................31
2.2.1
Further objectives ...............................................................................................31
2.2.2
Further endpoints ...............................................................................................31
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................33
3.1
OVERALL TRIAL DESIGN.............................................................................33
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................34
3.3
SELECTION OF TRIAL POPULATION .......................................................35
3.3.1
Main diagnosis for trial entry ............................................................................36
3.3.2
Inclusion criteria .................................................................................................36
3.3.3
Exclusion criteria ................................................................................................37
3.3.4
Discontinuation of trial participants from treatment or assessments............39
3.3.4.1
Discontinuation of trial treatment .........................................................................40
3.3.4.2
Withdrawal of consent to trial participation .........................................................42
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................42
4.
TREATMENTS...................................................................................................43
4.1
INVESTIGATIONAL TREATMENTS ...........................................................43
4.1.1
Identity of the Investigational Medicinal Products..........................................43


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4.1.2
Selection of doses in the trial and dose modifications......................................44
4.1.3
Method of assigning trial participants to treatment groups ...........................44
4.1.4
Drug assignment and administration of doses for each trial participant......45
4.1.4.1
Rules for down-titration in case of intolerance to BI 685509...............................47
4.1.4.2
Rules for re-starting up-titration in case of interruption of BI 685509.................47
4.1.5
Blinding and procedures for unblinding...........................................................48
4.1.5.1
Blinding.................................................................................................................48
4.1.5.2
Emergency unblinding and breaking the code......................................................48
4.1.6
Packaging, labelling, and re-supply...................................................................49
4.1.7
Storage conditions...............................................................................................49
4.1.8
Drug accountability.............................................................................................49
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................50
4.2.1
Other treatments and emergency procedures..................................................50
4.2.2
Restrictions ..........................................................................................................50
4.2.2.1
Restrictions regarding concomitant treatment ......................................................50
4.2.2.1.1
Close monitoring for AEs based on concomitant therapy ....................................51
4.2.2.2
Restrictions on diet and lifestyle...........................................................................52
4.2.2.3
Contraception requirements..................................................................................52
4.3
TREATMENT COMPLIANCE........................................................................53
5.
ASSESSMENTS..................................................................................................54
5.1
ASSESSMENT OF EFFICACY........................................................................54
5.1.1
Hepatic venous pressure gradient .....................................................................54
5.2.1
Physical examination ..........................................................................................56
5.2.1.1
Anthropometric measurements (height, weight, waist and hip circumference) ...56
5.2.2
Vital signs / home blood pressure and heart rate monitoring.........................56
5.2.2.1
Home blood pressure and heart rate monitoring...................................................57
5.2.3
Safety laboratory parameters ............................................................................57
5.2.4
Electrocardiogram ..............................................................................................61
5.2.5
Other safety parameters.....................................................................................62
5.2.5.1
Ultrasound (liver and spleen)................................................................................62
5.2.5.2
Hepatic injury adjudication...................................................................................62
5.2.6
Assessment of adverse events.............................................................................62
5.2.6.1
Definitions of AEs ................................................................................................62
5.2.6.1.1
Adverse event........................................................................................................62
5.2.6.1.2
Serious adverse event............................................................................................63
5.2.6.1.3
AEs considered “Always Serious”........................................................................63
5.2.6.1.4
Adverse events of special interest.........................................................................64
5.2.6.1.5
Intensity (severity) of adverse events....................................................................64
5.2.6.1.6
Causal relationship of adverse events...................................................................64
5.2.6.2
Adverse event collection and reporting ................................................................65
5.2.6.2.1
AE Collection........................................................................................................65
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................65
5.2.6.2.3
Pregnancy..............................................................................................................66


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5.5
BIOBANKING ....................................................................................................70
5.5.1
Methods and timing of sample collection..........................................................71
5.6
OTHER ASSESSMENTS...................................................................................71
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................71
6.
INVESTIGATIONAL PLAN.............................................................................72
6.1
VISIT SCHEDULE.............................................................................................72
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................73
6.2.1
Screening period (Visit 1a and 1b) ....................................................................74
6.2.2
Treatment period(s)............................................................................................75
6.2.2.1
End of treatment / Early discontinuation visit ......................................................75
6.2.3
Follow-up period and trial completion..............................................................76
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE......................................................................................................................77
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................77
7.2
PLANNED ANALYSES.....................................................................................77
7.2.1
General considerations .......................................................................................77
7.2.2
Handling of Intercurrent Events .......................................................................78
7.2.3
Primary objective analyses.................................................................................79
7.2.3.1
Sensitivity Analyses..............................................................................................79
7.2.3.2
Subgroup Analyses ...............................................................................................79
7.2.4
Secondary objective analyses.............................................................................79
7.2.5
Further objective analyses..................................................................................79
7.2.6
Safety analyses.....................................................................................................79
7.2.8
Interim Analyses .................................................................................................80
7.3
HANDLING OF MISSING DATA ...................................................................80
7.4
RANDOMISATION ...........................................................................................81
7.5
DETERMINATION OF SAMPLE SIZE .........................................................81
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........82
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................82
8.2
DATA QUALITY ASSURANCE ......................................................................83
8.3
RECORDS...........................................................................................................83
8.3.1
Source documents ...............................................................................................83


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8.3.2
Direct access to source data and documents.....................................................84
8.3.3
Storage period of records ...................................................................................85
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................85
8.5
STATEMENT OF CONFIDENTIALITY AND TRIAL PARTICIPANT 
PRIVACY ............................................................................................................85
8.5.1
Collection, storage and future use of biological samples and 
corresponding data .............................................................................................86
8.6
TRIAL MILESTONES.......................................................................................86
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................87
9.
REFERENCES....................................................................................................89
9.1
PUBLISHED REFERENCES............................................................................89
9.2
UNPUBLISHED REFERENCES......................................................................91
10.
APPENDICES.....................................................................................................92
10.2
REMOVAL OF INDIVIDUAL PATIENTS IN CASE OF INCREASED 
LIVER ENZYMES .............................................................................................93
10.3
CHILD-TURCOTTE-PUGH CLASSIFICATION .........................................95
10.4
TRIAL PARTICIPANT FEEDBACK..............................................................95
11.
CONFIDENTIALITY STATEMENT DESCRIPTION OF GLOBAL 
AMENDMENT(S)...............................................................................................96
11.1
GLOBAL AMENDMENT 1 ..............................................................................96


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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
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
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
CTP
Clinical Trial Protocol
CTP
Child-Turcotte-Pugh score


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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
HDL
High-density Lipoprotein


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HE
Hepatic Encephalopathy
HERG
Human Ether-a-go-go Related Gene
HFrEF
Heart Failure with reduced Ejection Fraction
HIV
Human Immunodeficiency Viruses
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
LDL
Low-density Lipoprotein
LPLT
Last trial participant last treatment
LSM
Liver Stiffness Measurement
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
NASH
Non-Alcoholic Steatohepatitis
NO
Nitric Oxide 
NSBB
Non-Selective Beta-Blocker
NYHA
New York Heart Association


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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
SBP
Systolic Blood Pressure
sGC
soluble Guanylate Cyclase
SOP
Standard Operating Procedure
SSc
Systemic Sclerosis
SUSAR
Suspected Unexpected Serious Adverse Reactions
SVR
Sustained Virological Response
TID
Ter in Die (three times a day)
Tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated Set
TSAP
Trial Statistical Analysis Plan


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UGT
Uridine Glucuronyl Transferase 
ULN
Upper limit of normal
US
Ultrasound
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 
are endoscopic variceal ligations or off-label use of non-selective beta-blockers (NSBBs) or 
carvedilol for primary and secondary prophylaxis of variceal bleeding. However, not all 
patients with PH achieve a hemodynamic 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 and 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). 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 – 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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1.2.1
Key characteristics of BI 685509
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
  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 of qd or bid 
regimens, 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 2 program that will recruit patients from Japan and other Asian 
countries.Based on the PK analysis of Trials 1366-0004 and 1366-0005, the exposure to BI 
685509 observed in patients with diabetic nephropathy (DN) with an eGFR ranging from 16 
– 95 mL/min/1.73 m2 was slightly higher compared 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.A population PK model 
updated with data from 1366-0005 was used for simulations. 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:
 TID / 
TID. Table 1.2.1: 1 provides the corresponding fold-change predictions of these PK 


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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 9-59% higher, 
and the predicted median Cmax,ss is 10-28% higher in comparison to healthy volunteers.  
Although the model predicted AUC0-24,ss for patients with eGFR of 20 mL/min/1.73m2 is ~ 
1.6-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 56 / 8 weeks
Measure
eGFR
Median
2.5th
97.5th
AUC0-24,ss
≥90
1.00
0.349
2.83
60 – 90
1.09
0.431
2.76
45 – 60
1.25
0.453
3.34
30 – 45
1.37
0.536
3.79
20 – 30
1.59
0.585
4.49
Cmax,ss
≥90
1.00
0.379
2.39
60 – 90
1.10
0.437
2.75
45 – 60
1.15
0.445
2.71
30 – 45
1.16
0.469
2.84
20 – 30
1.28
0.539
3.17
Source: c35011958
Based on the PK 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,ss, 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,ss, and 604 nmol*h/L AUC0-tau,ss, yielding an estimated 
total daily exposure of ~1210 nmol*h/L [c34995868-01].  The exposure observed in the
BID dosing regimen in hepatic impaired patients were comparable to that of the 
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 phase 1 Trial 
1366-0004 and phase 2 Trial 1366-0005 with eGFR 20 – 90 mL/min/1.73m2 and in 
hepatically impaired Child-Turcotte-Pugh A and B patients in Trial 1366-0020. The adverse 
events reported so far are anticipated from the mode of action of BI 685509 or can be 
attributed to the studied condition or concomitant diseases. A similar titration regimen will be 
used in this trial compared to 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 


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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 2.  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 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.
1.2.2
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. 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.
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 


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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.
1.2.3
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.
Summary of 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). Doses up to
 bid were used.
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.
An effect of BI 685509 on the predicted placebo-corrected mean change from baseline QTcF 
(∆∆QTcF) was seen.  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
[c34995868-01].  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.   


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There is no known effect of BI 685509, nor its metabolite BI 685144, on hERG channel at 
plasma concentrations reached in the studies in humans, even considering the individual 
patients with highest Cmax. BI 685509 and BI 685144 did not show inhibitory effects on other 
cardiac ion channels, including Nav1.5, Kv4.3, Cav1.2 and Kir 2,1, at tested concentrations 
providing approximately 100 folds to the Cmax achieved in the clinical trials (please refer to 
IB [c02778238].
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. 
 Further optimisation and training since 
the initial study will allow complete assessment of this novel technique during the current 
studies and will allow spleen stiffness to be used as a non-invasive biomarker for portal 
hypertension. 
For a more detailed description of the BI 685509 profile, please refer to the current 
Investigator’s Brochure [c02778238].
1.3
RATIONALE FOR PERFORMING THE TRIAL
In this Phase 2 trial, the efficacy of treatment in patients with CSPH (defined by HVPG ≥10 
mmHg) in decompensated cirrhosis due to non-cholestatic liver diseases will be assessed. 
The trial will serve to evaluate short-term efficacy of BI 685509 and will also provide 
supportive evidence for the planned Phase 2I development together with trials 1366-0021 and 
1366-0029. The data of this trial will be indirectly compared with the data from trials 1366-
0021 and 1366-0029.
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 is outlined in the current Investigator’s Brochures 
(IB) [c02778238]  .


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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 within 
development however and an individual benefit cannot be guaranteed.
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 trial procedures and other risks. For details refer to Tables 
1.4.2: 1, 1.4.2: 2 and 1.4.2: 3 below.


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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 trial 
participants will be monitored for AEs, 
and BP and HR will be measured daily 
(by the trial participant at home) during 
the treatment period.  Trial participants 
with oedema or gastrointestinal side 
effects will be managed by standard of 
care, and trial participants with a known 
history of orthostatic dysregulation and 
those with a SBP <100 mmHg or 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 1.2.3
Trial participants with long QT / QTcF-
interval, trial participants with a family 
history of long QT syndrome, or those 
using concomitant therapies known to 
increase the risk of Torsade de Points 
will be excluded from the trial (refer to 
Sections 3.3.3 and 4.2.2.1).
ECGs will be performed at each visit in 
the randomised treatment period of the 
trial, and trial medication will be 
discontinued in the event of a prolonged 
QT / QTcF-interval (refer to Section 
3.3.4).


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Table 1.4.2: 1 (cont.)
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
Risks related to drug-drug 
interaction (DDI)
Refer to Section 1.2.1
Close monitoring of trial participants 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.  Trial participants 
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 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 
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, 
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


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Table 1.4.2: 2 (cont.)
Overview of risks – trial procedures
Possible / known risks of 
clinical relevance
Summary of data, rationale for the 
risk
Mitigation strategy
vein and while inflating 
the balloon.  Specific but 
rare complications related 
to the venous access 
include haematomas at the 
access 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
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 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)
regarding symptoms 
suggestive of 
complications.  Patients 
will be monitored for 
AEs, and those with 
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)
Potential risks of blood 
sampling by venipuncture or 
through an indwelling 
catheter such as fainting, 
pain, bruising, swelling, or 
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  
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 
participation
Evaluation of the medical 
expertise of the trial sites 
will be part of the site 
feasibility assessment.  In 
addition, and to ensure 
patient safety, all events 
or symptoms reported 
will be managed 
according to the 
judgement of the 
Investigator


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Table 1.4.2: 3
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 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, 5.2.5.2, 
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)  
A Hepatic Injury Adjudication Committee (AC) and Data Monitoring Committee (DMC) 
independent from the sponsor 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 is well understood.
In the context of the unmet medical need and anticipated benefit of BI 685509, the benefit 
risk evaluation of the compound 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 trial participants with CSPH in decompensated cirrhosis the expected benefit
outweighs the potential risks.
Trial participants with 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 in 
trial participants, who already developed decompensated cirrhosis will potentially result in 
the secondary prevention of related complications including further decompensation (variceal 
bleeding, ascites and encephalopathy), transplantation, or liver-related death.  The potential 
risks, as described above, will be minimised by close monitoring of trial participants, by 
excluding at-risk trial participants from the trial, and by involvement of a DMC – refer to 
Sections 3.2 and 8.7.  Hepatic injury will also be assessed by an independent AC for safety 


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purposes (refer to Sections 3.2, 5.2.5.2 and 8.7).  Hence, overall, in the context of the unmet 
medical need, the anticipated effects of BI 685509 on CSPH in trial participants with 
decompensated cirrhosis due to non-cholestatic liver diseases based on the safety profile of 
BI 685509, the benefit-risk evaluation of the compound 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 
decompensated cirrhosis due to non-cholestatic liver diseases on top of standard of care. The 
primary objective is to estimate the percentage change in HVPG from baseline measured 
after 8 weeks in comparison to placebo. The primary analysis will be made for treated 
patients with baseline HVPG measurements (Full Analysis Set, FAS) as if all trial 
participants took treatment for the duration of the trial.
2.1.2
Primary endpoint
The primary endpoint is the percentage change in HVPG from baseline (measured in mmHg) 
after 8 weeks of treatment.
2.1.3
Secondary endpoints
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 further 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,
2.2.2
Further endpoints


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This phase 2 multi-national, randomised, placebo-controlled and parallel group trial to 
investigate the effects of oral BI 685509 on portal hypertension after 8 weeks treatment in 
patients with clinically significant portal hypertension (CSPH) in decompensated cirrhosis 
after the first decompensation event, who are stabilized (CTP 5-7).
Trial participants will be enrolled in the trial and screened for eligibility once they have 
signed the informed consent.  The screening period consists of up to 2 visits (Visits 1a and b) 
and will last a maximum of 4 weeks.  Trial participants will be able to progress from one visit 
to the next when eligibility of the previous visit is confirmed.  Assessments will include 
ultrasound of the liver and spleen,
 and measurement of 
HVPG.  Trial participants who remain eligible and who successfully complete this period will 
proceed to the 8-week randomised, placebo-controlled treatment period.    
In total, 40 trial participants will be randomized in a 1:1 ratio, with 20 trial participants in the 
active treatment arm, and 20 trial participants in the placebo arm. The randomization will be 
stratified by use (or not) of NSBBs / carvedilol and type of first decompensation event 
(ascites or variceal haemorrhage).
Following randomization at visit 2, trial participants will begin the intake of trial 
medication(s) and will enter a dose-titration period of BI 685509 or matching placebo.  If the 
dose is tolerated, one week later (at Visit 3, day 8), the dose for all will be up-titrated to
BID 685509 or matching placebo.  If this dose is tolerated, a second up-titration to 
BID 
BI 685509 or matching placebo will occur after another week (at Visit 4, day 15). Following 
the dose-titration period, and if the dose is tolerated, trial participants 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. 
The ultrasound and
, and the HVPG measurement will be 
repeated during the treatment period (refer to Figure 3.1: 1). 
                
After the 8 week treatment period all trial participants will enter a 2 week follow-up period 
without trial medication.  The trial participant’s participation in the trial will be complete 
when they have performed the last planned visit (i.e. End of Study [EoS], 2 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, double-blind, placebo-controlled and parallel group design has been chosen 
for this trial, on top of standard of care. The randomised double-blind design will control for 
assignment bias.  Placebo as control was chosen to show the efficacy of BI 685509 compared 
to placebo plus standard of care.
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 trials 1366-0021 and 1366-0029.  
The trial participant population of this trial has been chosen as it represents the intended 
patient population to be treated with for BI 685509 (patients with clinically significant portal 
hypertension in decompensated cirrhosis due to non-cholestatic liver diseases).  
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 trial participants 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 further 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. 


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Trial participants will be screened for the trial based on the eligibility criteria (refer to
Sections 3.3.2 and 3.3.3).  At Visit 1b (the final visit within the screening period) trial 
participants who remain eligible following Visits 1a will undergo their first HVPG 
measurement.  
Non-invasive assessments (i.e. ultrasound and
 have been chosen as part of the screening procedures to further 
investigate the trial participants’ status, to establish baseline values for comparison with 
treatment, and to gain further insight into the use of non-invasive methods to investigate liver 
function and portal pressure.  These assessments will be repeated (refer to Figure 3.1: 1 and 
the Flow Chart) to assess a time-dependency of the treatment.
Following 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.  
Trial participants selected for this trial have a risk for further decompensation.  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).
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
40 trial participants with CSPH in decompensated cirrhosis due to non-cholestatic liver 
disease will be randomized into the trial. Approximately 20 sites are planned across multiple 
countries. It is anticipated that 2 trial participants will be randomised at each site.  If 
enrolment is delayed, additional sites may be recruited.
Screening of trial participants for this trial is competitive, i.e. screening for the trial will stop 
at all sites at the same time once a sufficient number of trial participants have been screened 
to deliver the required number of randomised trial participants. Investigators will be notified 
about the screening completion and will then not be allowed to screen additional trial 
participants for this trial. Trial participants 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 trial participant having to be re-screened). Re-screening is also
allowed once provided that the reasons for screen failure were reversible and have been 
resolved, based on Investigator judgement.  A trial participant is considered a “re-screener” if 


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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 trial participant
number and repeating the screening period assessments.  
A log of all trial participants 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 randomized 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.
This trial will include an option for participants to complete anonymized questionnaires to 
provide feedback on their clinical trial experience. Providing this feedback is not required for 
trial participation, and information collected from these questionnaires will not be analysed as 
part of the clinical data for the trial (see Section 10.4)
3.3.1
Main diagnosis for trial entry
The trial will include trial participants with decompensated cirrhosis due to non-cholestatic 
liver disease after the first decompensation event, who are stabilized (CTP 5-7).  
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1.
Signed and dated written informed consent in accordance with ICH-GCP and 
local legislation prior to admission to the trial
2.
Male or female 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.
Diagnosis of cirrhosis due to non-cholestatic liver disease (including HCV, HBV, 
NASH, alcohol-related liver disease, autoimmune hepatitis, Wilson’s disease, 
haemachromatosis, alpha-1 antitrypsin [A1At] deficiency)
4.
One previous clinically significant decompensation event with clinical resolution 
at least 4 weeks prior start of screening (visit 1a):
a.
First variceal haemorrhage
b. First episode of clinically significant ascites (requiring intervention in lifestyle 
[fluid and salt restriction] or medical treatment)
5.
Willing and able to undergo HVPG measurements per protocol (based on 
Investigator judgement)


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6.
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
7.
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  
8.
For patient with alcohol-related cirrhosis, abstinence from significant alcohol 
misuse / abuse for a minimum of 2 months prior to screening (Visit 1a), and the 
ability to abstain from alcohol throughout the trial (both evaluated based on 
Investigator judgement)
9.
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 
10.
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.
History of cholestatic chronic liver disease (e.g. primary biliary cholangitis, 
primary sclerosing cholangitis)
2.
Trial participants 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)
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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3.
If received curative anti-viral therapy for HCV, SVR sustained for less than 1 
years prior to screening 
4.
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
5.
Weight change ≥5% within 6 months prior screening in patients with NASH  
6.
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
7.
SBP <100 mmHg or DBP <70 mmHg at screening (Visit 1a)
8.
Hepatic impairment defined as a Child-Turcotte-Pugh score ≥8 at screening
9.
Model of End-stage Liver Disease (MELD) score of >15 at screening (Visit 1a), 
calculated by the central laboratory
10.
ALT or AST >5 times upper limit of normal (ULN) at screening (Visit 1a), 
measured by the central laboratory
11.
eGFR (CKD-EPI formula) < 20 mL/min/1.73 m2 at screening (Visit 1a), measured 
by the central laboratory
12.
Platelet count <50x109/L
13.
Alpha-fetoprotein >50 ng/mL (>50 µg/L) at screening (Visit 1a), measured by the 
central laboratory
14.
Prior orthotopic liver transplantation
15.
Prior or planned TIPS or other porto-systemic bypass procedure during the trial 
conduct
16.
Known portal vein thrombosis
17.
History of clinically relevant orthostatic hypotension, fainting spells or blackouts 
due to hypotension or of unknown origin (based on Investigator judgement)
18.
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)


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19.
Contraindication to any of the trial assessments (e.g. poor patient co-operation for 
HVPG,
   
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
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 matching placebo / or any of their 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 condition 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 trial participants from treatment or assessments
Trial participants may discontinue trial treatment or withdraw consent to trial 
participation as a whole (“withdrawal of consent”) with very different implications;
please see Sections 3.3.4.1 and 3.3.4.2.
However, if the trial participants 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 trial participant selection, 
appropriate explanation of the trial requirements and procedures prior to trial enrolment,
as well as the explanation of the consequences of withdrawal.


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The decision to discontinue trial treatment or withdraw consent to trial participation and
the reason must be documented in the trial participant files and CRF. If applicable, 
consider the requirements for AE collection reporting (see Section 5.2.6.2).
Trial participants who discontinue after randomisation will not be replaced and may not 
be re-enrolled later.  However, the Sponsor may decide to randomise more trial 
participants than originally planned, to account for a reduced sample size, if trial 
participants terminate early due to e.g. trial disruption (such as measures to control a 
global pandemic).
3.3.4.1
Discontinuation of trial treatment
An individual trial participant will discontinue trial medication if:

the trial participant wants to discontinue trial treatment. The trial participant will be 
asked to explain the reasons but has the right to refuse to answer. 

the trial participant develops an AE:
o
CTCAE Grade 3 or higher and the AE was assessed by the Investigator as 
related to the trial treatment; OR
o
CTCAE grade 4 or higher regardless of attribution to the trial treatment

the trial participant 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 trial participant cannot be guaranteed as he / she is not willing or able to 
adhere to the trial requirements in the future. 

the trial participant 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. Similarly, if a trial participant
needs to modify a dose, where only a stable dose is permitted (e.g. NSBBs / 
carvedilol, statins, anti-viral therapy for HBV), this also will not automatically require 
discontinuation.  In both cases, the Sponsor should be consulted. 

the trial participant meets the criteria for hepatic injury (refer to Section 5.2.6.1.4 and 
Appendix 10.2)

the trial participant has an acute liver decompensation event such as VH, therapy-
refractory ascites, overt encephalopathy, or other decompensation event based on 
Investigator judgement

trial participants with worsening of their liver function (e.g. increase of Child Turcotte 
Pugh score of more than 2 points with clinical evidence of deteriorating liver function 
in the opinion of the Investigator).  Refer to Child-Turcotte-Pugh classification 
method in Appendix 10.3

trial participants 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 / randomization (baseline).  Such cases 
must be reported as AEs

the trial participant can no longer receive trial medication for other medical reasons 
such as surgery, AEs, other diseases 


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
the trial participant´s treatment assignment has been unblended due to an emergency 
situation

the trial participant 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 trial participant becomes pregnant. The trial participant will be followed up 
until birth or otherwise termination of the pregnancy. The data of the trial participant
will be collected and reported in the Clinical Trial Report (CTR) until last trial 
participant last visit and any events thereafter will be reported in the BI 
Pharmacovigilance (PV) database (refer to Section 5.2.6.2.3)
Trial-specific procedures have also been defined for Investigators to follow in case of 
increased liver enzymes (AST, ALT, and total bilirubin) after randomisation.  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 trial participants at any time 
based on clinical judgement. 
If a trial participant permanently discontinues the trial medication 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 2 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.
Boehringer Ingelheim will closely monitor and medically review all adverse events CTCAE 
Grade 3 and higher.  
Boehringer Ingelheim will pause the enrollment of new patient in the trial and ensure the 
clinical data is reviewed by the data monitoring committee (DMC) for safety before 
proceeding with the trial if one of the following occurs: 
1. more than two patients develop a CTCAE grade 3 or higher in the same category; 
OR
2. two or more patients meet the individual patient stopping criteria related to adverse 
event 
In case of a temporary discontinuation, trial medication (BI 685509) 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 trial 


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participants or take any other appropriate actions to guarantee the safety of the trial 
participants.
3.3.4.2
Withdrawal of consent to trial participation
Trial participants may withdraw their consent to trial participation at any time without the
need to justify the decision.
If a trial participant wants to withdraw consent, the investigator should be involved in the 
discussion with the trial participant 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.
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 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:

Failure to meet expected enrolment goals overall or at a particular trial site

New efficacy or safety information invalidating the earlier positive benefit-risk
assessment; please see Section 3.3.4.1.

Deviations from GCP, the trial protocol, or the contract impairing the appropriate 
conduct of the trial

Further treatment and follow up of trial participants affected will occur as described in 
Section 3.3.4.1.

The investigator/the trial site will be reimbursed for reasonable expenses incurred in 
case of trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational medicinal products in the trial is BI 685509 and placebo to match BI 
685509.  Boehringer Ingelheim 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: 6 below.
Table 4.1.1: 1
BI 685509 
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablet
Unit strength:
Posology:
BID
Mode of administration:
Oral
Table 4.1.1: 2
BI 685509 
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablet
Unit strength:
Posology:
BID
Mode of administration:
Oral
Table 4.1.1: 3
BI 685509 
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablet
Unit strength:
Posology:
BID
Mode of administration:
Oral
Table 4.1.1: 4
Placebo to match BI 685509 
Substance:
Placebo to match BI 685509 
Pharmaceutical formulation:
Film-coated tablet
Unit strength:
Not applicable
Posology:
BID
Mode of administration:
Oral


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Table 4.1.1: 5
Placebo to match BI 685509 
Substance:
Placebo to match BI 685509 
Pharmaceutical formulation:
Film-coated tablet
Unit strength:
Not applicable
Posology:
BID
Mode of administration:
Oral
Table 4.1.1: 6
Placebo to match BI 685509 
Substance:
Placebo to match BI 685509 
Pharmaceutical formulation:
Film-coated tablet
Unit strength:
Not applicable
Posology:
BID
Mode 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 
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 phase 1 multiple oral rising dose trial and one phase 2 trial in trial participants with DN 
have 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 
mg BID is predicted to achieve pharmacologically relevant 
exposure in trial participants with hepatic impairment [c02778238, n00261471-01].  As 
is the maximum tolerated single dose, 2 doses 
 BID and 
BID) is being evaluated 
in the phase 2 trial 1366-0021 currently, that is conducted in trial participants with CSPH in 
compensated alcohol-related cirrhosis. These doses have been selected based on safety and 
PK results from the Phase I MRD hepatic impairment trial (1366-0020).  In addition,
BI 
685509 BID maintenance dose is also being evaluated in 3 trial participants groups (HBV, 
HCV and NASH) in trial 1366-0029. 
In this trial,
BI 685509 BID maintenance dose will be evaluated in trial participants with 
CSPH in decompensated cirrhosis due to non-cholestatic liver diseases, with the potential to 
down-titrate, if not tolerated just as in trials 1366-0021 and 1366-0029
4.1.3
Method of assigning trial participants to treatment groups
After the assessment of all in- and exclusion criteria, each eligible trial participant will be 
randomised in a blinded fashion to treatment groups according to a randomisation plan in a 


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1:1 ratio at Visit 2 via an Interactive Response Technology (IRT) system.  Refer to Section 
7.4 for further details regarding randomisation and access to the randomisation code.  
Note that the medication numbers, assigned via the IRT system at each dispensing visit, are 
different from the trial participant number (which is generated via the IRT system when a 
new trial participant is registered [screened] in the system).
The Investigator (and relevant designated site personnel) will be provided with instructions to 
access the IRT system.  
4.1.4
Drug assignment and administration of doses for each trial participant
Trial medication will be dispensed at the investigational sites in accordance with the Flow 
Chart.  At dispensing visits trial participants will be given the appropriate number of 
medication kits for BI 685509 (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.  
All trial participants, regardless of the treatment group they are assigned to, will start at Visit 
2 on a dose of 
 BI 685509 BID or matching placebo.  At Visit 3, 7 days later, and again 
at Visit 4, a further 7 days after Visit 3, all trial participants will be up-titrated first to a dose 
of 
BI 685509 BID or matching placebo, and then to a dose of 
BI 685509 BID or 
matching placebo.  In this way the blind across treatment groups will be maintained (refer to 
Table 4.1.4: 1).  Trial participants will be informed about the dose titration period and will be 
made aware that up-titration for BI 685509 is being used. If a trial participant 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, trial participants will continue to receive the maximum 
dose of 3mg   BI 685509 BID (unless a down-titration is required), until reaching the EoT 
visit 8 weeks after starting the trial medication.
If a trial participant has an AE that, based on Investigator judgement, may be related to BI 
685509, 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 trial participant has 
successfully completed the dose titration period (i.e. Visit 4). 
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 trial participant 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
(BI 685509
BID)
 BI 685509
 BI 685509
(Up-titration)
 BI 685509
(Up-titration)
Treatment group 2
(Placebo to BI 685509)
 BI 685509
matching placebo
 BI 685509
matching placebo
(Up-titration)
 BI 685509
matching placebo
(Up-titration)
From the start of the treatment period (i.e. from Visit 2), and until reaching the EoT visit 8 
weeks later, trial participants will be instructed to take BI 685509 orally twice a day (BID).  
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.
In the morning of a visit, the trial medication will be administered as part of the visit.  
Therefore, on these days, trial participants should be instructed not to take their morning dose 
in advance of the visits. 
 Trial 
participants 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 trial participant will self-administer their medication at home.  Trial participants 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.
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 trial participant visits to sites may not be feasible or may need to be 
restricted to ensure trial participant 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 
trial participant’s home.


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4.1.4.1
Rules for down-titration in case of intolerance to BI 685509
If a trial participant 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 trial 
participant 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 
doses1.  If the trial participant 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 trial 
participant must permanently discontinue treatment (refer to Section 3.3.4.1).
•
if the trial participant is receiving 
 BID BI 685509 the dose will be down-titrated 
one level to 2 mg BID BI 685509    
Once down-titration has taken place, no further up-titration will be permitted.  
If a trial participant 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 trial participant 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).  Trial 
participants 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.
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 trial 
participant has missed ˃ 3 consecutive doses1 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 trial 
participant.  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 trial participant 
should re-start the dose titration period at 
BID BI 685509 / matching placebo 
•
before any further up-titration occurs the trial participant must have taken the 
preceding dose for at least 7 consecutive days.  This applies throughout the treatment 
period
o
this may mean that a trial participant 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
Trial participants 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.
1 Footnote: One dose refers to an individual time point e.g. morning dose or evening dose. 


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Trial participants, investigators, central reviewers, and everyone involved in trial conduct or
analysis or with any other interest in this double-blind trial will remain blinded regarding the 
randomised treatment assignments until the database is declared ready for analysis according 
to the sponsor’s SOPs. Further details regarding the timepoint of unblinding the database for 
analysis are documented in the TSAP.
The access to the randomisation code will be kept restricted until its documented release per 
sponsor SOP.
The randomisation codes will be provided to bioanalytics before the last trial participant
completes the trial to allow for the 
  Bioanalytics will not disclose the randomisation code or 
the results of their measurements until the trial is officially unblinded after the database lock 
(DBL).
 specific data must be unblinded and the treatment information must 
be made available to selected individuals (e.g.
).  
The unblinding procedure and logistics specific to this purpose will be provided in a separate 
document.  It should be noted 
will be communicated to the project and trial 
team prior to DBL.
A DMC, independent from the Sponsor, will perform an unblinded safety evaluation at 
intervals specified in the DMC charter in order to ensure that trial participants are protected 
from potential harm (refer to Section 8.7).  A trial independent statistician (iSTAT) will be 
assigned to prepare tables and listings as well as the summary reports for the DMC based on 
the agreed upon format and layout.  Randomisation codes will be provided to the iSTAT.  All 
information, including AEs, mortality, laboratory parameters, and decisions from hepatic 
injury adjudication will be provided in an unblinded fashion.  This will be accomplished by 
using coded labels and by providing the DMC members with the decoding information 
separately, if needed.
4.1.5.2
Emergency unblinding and breaking the code
Emergency unblinding will be available to the Investigator via IRT.  It must only be used in 
an emergency situation when the identity of the trial medication must be known to the 
Investigator in order to provide appropriate medical treatment or otherwise assure safety of 
trial participants.  The reason for unblinding must be documented in the source documents 
and / or appropriate eCRF page.  If a trial participant is unblinded by the Investigator, the trial 
participant has to be discontinued from the trial (refer to Section 3.3.4.1).
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s PV group to access the 
randomisation code for individual trial participants during trial conduct.  The access to the 


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code will only be given to authorised PV representatives for processing in the PV database 
system and not be shared further.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by Boehringer Ingelheim 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). 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.
4.1.7
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.  Trial participants should be instructed to return 
unused trial medication.


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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 trial participant, and the return to the Sponsor or 
warehouse / drug distribution center or alternative disposal of unused medication.  If 
applicable, the Sponsor or warehouse / drug distribution center 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 participants.  The 
Investigator or designee will maintain records that document adequately that the trial 
participants 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 participant and that no remaining supplies are in the 
Investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
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 trial participant 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.
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 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, 


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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.  
•
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.
•
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 
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. 
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, trial participants who are 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, and 
trial participants 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, trial participants 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 trial participant 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 trial participant (e.g. taking up exercises that 
put pressure on the abdomen, such as weightlifting).
Alcohol consumption should be avoided throughout the trial; excessive alcohol consumption 
could lead to hypotension when taken concomitantly with BI 685509. 
During the treatment period, trial participants will be asked if they have consumed any 
alcohol, and where necessary, reminders should be issued to abstain from alcohol 
consumption.   
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 trial participant 
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 trial participant 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 trial participant 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 trial 
participant’s partner.
Alternatively, WOCBP and male trial participants able to father a child must abstain from 
male-female sex.  This is defined as being in line with the preferred and usual lifestyle of the 
trial participant.  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
Trial participants 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 actually taken 100
Number of 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 trial 
participant 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 hemodynamic 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 1b and EoT visit will 
be recorded in the trial participant source documents and the eCRF.  
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 trial 
participant recruitment if not already provided for Trials 1366-0021 or 1366-0029.  
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 1b 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 1b 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 1b 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 1b measurement 
for a single trial participant.  
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 
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 


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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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5.2.1
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 trial participant 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 trial participant.  In order to get comparable body weight values, the 
assessment should be performed in the following way:
•
shoes, coat / jackets and any headgear 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 trial participant’s bare midriff, after the trial participant 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.
5.2.2
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 trial 
participants 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.


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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 trial participants 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 trial participant as specified in the 
Flow Chart.  Electronic BP and HR monitoring equipment will be provided for this purpose.  
Site staff will train the trial participant 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 trial 
participant.  Subsequent refresher training should be provided at subsequent visits if required.
  
Trial participants 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 trial participant 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 trial participant should report these symptoms at the next trial visit.  The trial participant
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
for a list of “minimum required safety laboratory parameters” in the event of force majeure or 
other disruptive circumstances.    
Trial participants 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. 
 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.


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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 trial 
participant not fulfil all laboratory requirements to take part in the trial due to a transitional 
medical condition, the trial participant 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 trial participant (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 trial participant 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.
Table 5.2.3: 1
Safety laboratory tests
Category
Test name 
Short Name
(BI Laboratory Test Code, 
LBSPID)
Haematology
WBC count / leukocytes
WBC
Platelet count / thrombocytes
PLTCT
Reticulocytes
Haemoglobin
RBC count / erythrocytes
RETABS
HGB
RBC
Automatic WBC 
differential 
(absolute and
percentage) 
Neutrophils
SEGABS
Eosinophils
EOSABS
Basophils
BASABS
Monocytes 
MONABS
Lymphocytes  
LYMABS


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Table 5.2.3: 1 (cont.)
Safety laboratory tests
Category
Test name 
Short Name
(BI Laboratory Test Code, 
LBSPID)
Coagulation
aPTT
APTTS
PT
PRTSEC
INR
INR
Fibrinogen
FIBR
Clinical chemistry
ALT
SGPT
Alpha fetoprotein4
AFP
Albumin
ALB
Alkaline phosphatase
ALKP
AST
SGOT
Bilirubin (total)
TBILI
Bilirubin (direct)
BILID
Bilirubin (indirect)
BILII
hs-CRP
CRPHS
Creatinine, serum
CRE
CK
CK
CK-MB1
CKMBABS
eGFR
GFRE
ɣ-GT
GGT
Glucose
GLUB
LDH
LDH
Lipase
LIPASE
Phosphatidylethanol (PEth)2
PETH
Protein (total)
TPRO
Troponin I1
TPONI
Urea (BUN)
UREA
Uric acid
Brain Natriuretic Peptide (BNP)
URIC
BNP


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Table 5.2.3: 1 (cont.)
Safety laboratory tests
Category
Test name 
Short Name
(BI Laboratory Test Code, 
LBSPID)
Electrolytes
Bicarbonate
BICARB
Calcium
CA
Chloride
CL
Magnesium
MG
Phosphate
P
Potassium
K
Sodium
NA
Lipids4
HDL
LDL
Cholesterol (total)
Triglycerides
HDL 
LDL 
CHOL
TRIGL
Hormones
TSH4
Free T35
Free T45
TSH
FT3
FT4V
Pregnancy test (serum)
Human Chorionic Gonadotropin6
HCG
Pregnancy test (urine)
Human Chorionic Gonadotropin7
Not Applicable
Infections screening4
HCV antibody (qualitative)
HCV RNA PCR8
HBV surface antigen (qualitative)
HBV core antibody (qualitative)
HBV – DNA9
HCAB
HCVRNA
HBSAG
HBCAB
HBVDNAV
Urine chemistry
Urine albumin
UALBUM
Urinalysis (semi-
quantitative)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine blood
Urine leukocyte esterase
Urine pH
UNIT
UPROZ
UGLU
UKET
UROBZ
UBILI
UHGB
ULEUKES
UPH
1.
If initial CK is elevated, re-test CK with CK-MB and troponin I
2.
Not performed at screening (Visit 1a). PEth, an alcohol-specific biomarker, will be measured during the treatment
period for data analysis purposes
3.
Not performed at screening (Visit 1a);
4.
Only performed at screening (Visit 1a)


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5.
Reflex in case of abnormal TSH
6.
WOCBP only; only at Visit 1a, and as a reflex if urine testing is positive  
7.
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
8.
Reflex in case of positive HCV antibody 
9.
Reflex in case of positive HBV core antibody 
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 
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 
trial medication.  These ECGs should precede the 1 hour and 2 hour
(refer to Section 5.3.1).
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 trial 
participant’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 trial participant will be discontinued from the trial.  


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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.
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.  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, since large distances can affect the ability to sufficiently 
measure
Sites will be expected to follow local standard processes prior to and during the procedure.
  
5.2.5.2
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
Data and information necessary for the thorough assessment of AEs, SAEs, and AESIs will 
be reported to the sponsor via eCRF. This may include specific data and information not 
prospectively specified in this protocol.
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 trial participant or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.


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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 appropriate  eCRF :

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:

Results in death,

Is life-threatening, which refers to an event in which the trial participant 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 intrial participant 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 trial participant 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”.


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5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the Sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs; please see  
Section 5.2.6.2.2.
The following are considered as AESIs:
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 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.
5.2.6.1.5
Intensity (severity) of adverse events
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 adverse events
Medical judgement should be used to determine the relationship between the AE 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 
therapy, concomitant diseases and relevant history. 
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).


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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.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the trial drug. 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced.
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
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 participant files .
Per default SAEs/AESIs should be reported via the eCRF in the EDC system. If the EDC 
system is not or no longer available (e.g. after database lock), the BI paper SAE form should 
be used; please see Section 5.2.6.2.2. The following must be collected and documented:
•
From signing the informed consent onwards until the individual participant’s end of 
trial (= the End of Study [EoS] visit, please see Section 6.2.3): all AEs (serious and 
non-serious) and all AESIs. 
•
After the individual participant’s end of trial: 
the investigator does not need to actively monitor the participant for new AEs but 
should only report any occurrence of cancer of new histology 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.
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 or SAE eCRF pages 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 in 
addition. 
With receipt of any further information to these events, follow-up reports have 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 participant’send of trial 
must be followed up until they have resolved, have been assessed as “chronic” or “stable”, or 
no further information can be obtained.
Should the EDC system not be available for more than 24 hours, reporting must occur via the 
BI paper SAE forms.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a trial participant has been 
enrolled in the clinical trial and has taken trial medication, the investigator must report any 
drug exposure during pregnancy in a trial participant immediately (within 24 hours) by means 
of Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Studies is to be completed. However, 
a SAE and/or AESI associated with the pregnancy it must be reported as described in Section
5.2.6.2.2.


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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial.  
Biobanking will only occur after a separate biobanking informed consent has been given in 


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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. 
5.6
OTHER ASSESSMENTS
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 
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 
execution of the investigational plan as per this clinical trial protocol may not be feasible. 
With the consent of the participant, the sponsor and investigator may agree on alternative, 
back-up or rescue methodology which may include but will not be limited to virtual trial 
participant visits and assessments, home healthcare nurse visits, direct-to-participant/direct-
from-participant shipments of trial treatment or bio-sample pick up from the participant’s 
home. The implementation of these measures will depend on participant’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 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 trial participant 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, trial 
participants 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 trial participant should be in accordance with the Flow Chart and will 
be recorded in the eCRF.  Trial participants 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 
trial participant visits to the sites may not be feasible or may need to be restricted to ensure 
trial participant safety.  Based on a thorough assessment of the benefits and risks, the 
following visit may be performed at the trial participant’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 trial participant, whilst also taking into account that the next kit(s) of trial 
medication may need to be shipped from the site to the trial participant’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, trial participants 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 trial participant’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 trial participant’s home or remotely:

concomitant therapy

IRT call

dispense trial medication

train trial participant / 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 trial participant next visits the site, or when a visit is 
performed at the trial participant’s home (see below). 
The following assessments can be performed at the trial participant’s home:

anthropometric measures

vital signs

physical examination

resting 12-lead ECG (using a portable ECG machine) 


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
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 trial participant’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 and 1b)
No trial procedures should be performed unless the trial participant has consented to take part 
in the trial.  Once a trial participant has consented, he / she is considered to be enrolled in the 
trial and to have started screening.  The trial participant should be recorded on the enrolment 
log and be registered in the IRT system as a screened trial participant.  Trial participants who 
are not eligible to proceed to Visit 2 (i.e. they fail screening at either Visit 1a or 1b) 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 2 visits (refer to Flow Chart), namely Visit 
1a and Visit 1b; these visits should ideally be completed within a period of 4 weeks, (i.e. Day 
1, Visit 2).  There is no minimum duration for the screening period.  A trial participant 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.  
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 trial participant`s sex at birth) 
•
for female trial participants: of childbearing potential yes / no in order to characterise 
the trial participant population and as a basis for contraception requirements 
•
ethnicity and race in order to sufficiently characterise the trial participant 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 trial participant to be
classified as black or non-black (unless not acceptable according to local regulations)
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 


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examination [e.g. because the trial participant 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 trial participant is deemed eligible for the trial following Visits 1a  and 1b, the trial 
participant 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 trial participant can be randomised only once into the trial.  The 
randomised treatment period starts with Visit 2 and ends when a trial participant 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.
   
Trial participants 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 trial participant 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.
  Trial participants 
should also be reminded to bring
and 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 
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 3.3.4.1).  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:


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
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 2 weeks after an EoT and / or ED visit (refer to the Flow 
Chart and Section 3.3.4.1); 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:
For an individual patient, trial completion is defined as completion of 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 trial participants with CSPH in decompensated 
cirrhosis after the first decompensation event.
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 trial participants having signed 
informed consent and who were eligible for inclusion into the trial. The ES will be 
used for analyses of trial participant disposition
•
Randomised set (RS) – this analysis set includes all enrolled trial participants that 
were 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 trial participants who were 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 trial 
participants 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 / carvedilolconcomitant 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 trial participants 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).
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.


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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 change of HVPG from baseline at Week 8 = overall mean
+ HVPG baseline
+ treatment + use of NSBBs or carvedilol
+ type of first decompensation event
+ random error
This model includes effects accounting for the following sources of variation: ‘treatment’, 
‘use of NSBBs or carvedilol’ and ‘type of first decompensation event’ are a fixed 
classification effects, 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 hypothesis testing.  
Trial participants 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 trial participants who have experienced 
the events of interest for secondary endpoints will be presented.
7.2.5
Further objective analyses
Only descriptive statistics will be presented for further 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 


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with an onset between start of treatment and end of the REP, a period of 7 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
Safety analyses will be done by “treatment at onset” principle.  All treated trial participants 
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 trial participants 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.
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 endpoints.  If a trial participant
misses a visit, the missing data will not be imputed.  


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7.4
RANDOMISATION
BI will arrange for the randomisation and the packaging and labelling of trial medication.  
The trial will be performed as a double-blind design with respect to placebo and active BI 
685509.  Trial participants will be randomised in blocks to one of the two treatment groups in 
a 1:1 ratio.  The randomisation will be stratified by use (or not) of NSBBs or carvedilol and 
type of first decompensation event (ascites or variceal haemorrhage) (refer to Section 3.1).   
The randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the assigned treatment will be reproducible but at the same 
time non-predictable.  The block size will be documented in the CTR.  Access to the codes 
will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to enrol 40 trial participants in total in this trial: 20 trial participants per 
treatment group (active vs. placebo).
It will be considered as a positive signal if a mean percentage reduction of HVPG from 
baseline after 8 weeks of treatment of at least 15% is observed. it was assumed that the mean 
percentage reduction of HVPG from baseline at week 8 would be: 0% and 20% for placebo 
and BI 685509, respectively(with a standard deviation of 25% in each group) based on 
previous studies [R21-1984, R21-1945]. With the sample size of 40 (20 trial participants per 
treatment group), the probability to observe a mean percentage reduction of HVPG≥ 10% in 
BI 685509 is 89.3%. This probability would be only 26.5% in case that the mean percentage 
reduction of HVPG from baseline is 5%.  Probabilities of achieving an assumed treatment 
effect within different scenarios are presented in Table 7.5: 1.
Table 7.5: 1
Scenarios of probabilities of achieving the assumed treatment effect
Scenarios
Assumption of mean percentage reduction in 
HVPG from baseline to week 8 1,2
Probability that the observed treatment 
effect is ≥ 10% 
Positive
20%
89.3%
15%
73.5%
Negative
5%
26.5%
0%
10.3%
SD = 25%
N=20 per treatment group
The calculations were performed using R 4.1.2.


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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. 


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The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial participant protection and reliability of the results as 
well as identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB/IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual trial participants will be provided by the sponsor. See Section 4.1.5.2 for 
rules about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient.  Source data, as well as reported 
data, should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate.  Changes to the data should be traceable (audit trail).
Data reported on the 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 


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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 
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. 
HVPG, ultrasound 
, 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 


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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; please 
see Section 6), site access may be restricted, thus limiting the ability to perform standard site 
monitoring activities on site such as on-site source data review and source data verification. 
Therefore, some of these activities may be performed remotely or replaced by centralized 
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 sites:
The trial sites must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND TRIAL PARTICIPANT
PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of trial participant 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 participant identification number instead of the trial 
participant’s name. The code is only available at the site and must not be forwarded to the 
sponsor. In case participant’s records will be forwarded e.g. for SAE processing or 
adjudication committees, personal data that can identify the trial participant will be redacted 
by the site prior to forwarding. Access to the participant files and clinical data is strictly 
limited: personalised treatment data may be given to the trial participant’s personal physician 
or to other appropriate medical personnel responsible for the trial participant’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 trial 
participants will be informed as appropriate.


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8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the separate biobanking 
informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation 
 
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 first act of recruitment represents the start of the trial and is defined as the date when the 
first trial participant in the whole trial signs informed consent.
The end of the trial is defined as the date of the last visit of the last trial participant in the 
whole trial (“Last Participant Completed”).
The “Last Participant Last Treatment” (LPLT) date is defined as the date on which the last 
trial participant in the whole trial is administered the last dose of trial treatment (as scheduled 
per protocol or prematurely). Individual investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC/competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.


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A final report of the clinical trial data will be written only after all trial participants 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 trial 
participant (EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
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. While DMC 
members may be unblinded, measures are in place to ensure the blinding for everyone else 
involved in the trial Regular DMC meetings will be held at specified intervals. The DMC 
will recommend continuation, modification or termination of the trial as detailed in the DMC 
charter.  DMC recommendations, as well as the final BI decision, will be reported to the 
appropriate regulatory authorities / 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


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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.
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
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
P18-02639
Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J.  Portal hypertensive 
bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 
practice guidance by the American Association for the Study of Liver 
Diseases.  Hepatology 2017;65(1):310–335
R17-1181
GBD 2013 Mortality and Causes of Death Collaborators.  Global, regional, 
and national age-sex specific all-cause and cause-specific mortality for 240 
causes of death, 1990–2013: a systematic analysis for the Global Burden of 
Disease Study 2013.  Lancet 2015;385(9963):117–171
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
R18-2743
Villanueva C, Albillos A, Genesca J, Abraldes JG, Calleja JL, Aracil C, et 
al.  Development of hyperdynamic circulation and response to beta-
blockers in compensated cirrhosis with portal hypertension.  Hepatology 
2016;63(1):197-206
R18-3281
Murray KF, Carithers RL.  AASLD practice guidelines: evaluation of the 
patient for liver transplantation.  Hepatology 2005;41(6):1407-1432
R19-3528
Abraldes JG, Trebicka J, Chalasani N, D’Amico G, Rockey DC, Shah VH, 
et al.  Prioritization of therapeutic targets and trial design in cirrhotic portal 
hypertension.  Hepatology 2019;69(3):1287-1299
R20-1198
Turco L, Villanueva C, Mura V la, García-Pagán JC, Reiberger T, Genescà 
J, et al.  Lowering portal pressure improves outcomes of patients with 
cirrhosis, with or without ascites: a meta-analysis.  Clin Gastroenterol 
Hepatol 2020;18(2):313-327
R20-1199
Bosch J, Abraldes JG, Groszmann R.  Current management of portal 
hypertension.  J Hepatol 2003;38(Suppl):S54-S68


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R20-1200
D'Amico G, Pasta L, Morabito A, D'Amico M, Caltagirone M, Malizia G, 
et al.  Competing risks and prognostic stages of cirrhosis: a 25-year 
inception cohort study of 494 patients.  Aliment Pharmacol Ther 
2014;39(10):1180-1193
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
R20-3299
Mettler FA, Huda W, Yoshizumi TT, Mahesh M.  Effective doses in 
radiology and diagnostic nuclear medicine: a catalog.  Radiology 
2008;248(1):254-263
R20-3977
Reiberger T, Schwabl P, Trauner M, Peck-Radosavljevic M, Mandorfer M.  
Measurement of the hepatic venous pressure gradient and transjugular liver 
biopsy.  J Vis Exp 2020 (160); e58819
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
R20-4091
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
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
R20-4181
Hari A, Nair HK, Gottardi A de, Baumgartner I, Dufour JF, Berzigotti A.  
Diagnostic hepatic hemodynamic techniques: safety and radiation exposure.  
Liver Int 2017;37:148-154
R20-4191
Lin EC.  Radiation risk from medical imaging.  Mayo Clin Proc 
2010;85(12):1142-1146


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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   
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
9.2
UNPUBLISHED REFERENCES
c02778238
Investigator’s Brochure (IB) BI 685509.  Current version 
c35011958
TMCP List of Analyses for BI 685509 (1366.P1/P2)
c34995868-01
Clinical trial protocol 1366-0020, hepatic impairment trial. Last version
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
10.4
TRIAL PARTICIPANT FEEDBACK
Optional Trial Participant Feedback Questionnaires:
This trial will include an option for participants to complete anonymized questionnaires, 
‘Trial Participant Feedback Questionnaire’, to provide feedback on their clinical trial 
experience. Individual participant level responses will not be reviewed by investigators. 
Responses will be used by the sponsor to understand where improvements can be made in the 
clinical trial process. These questionnaires will not collect data about the participant’s 
disease, symptoms, treatment effect, or AEs and therefore will not be part of the trial data or 
clinical trial report. The questionnaires will be implemented after local regulatory approval 
and after consent of the trial participant. Providing feedback is optional and not required for 
participation in the trial.


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11.
CONFIDENTIALITY STATEMENT DESCRIPTION OF
GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of Amendment
29-Nov-2023
EudraCT No.
EU Trial No.
2023-506083-13-00
BI Trial No.
1366-0055
BI Investigational 
Medicinal Product
BI 685509
Title of protocol
Randomised, double-blind, placebo-controlled and parallel 
group trial to investigate the effects of one dose (up-titration to 
a fixed dose regimen) of oral BI 685509 on portal hypertension 
after 8 weeks treatment in patients with clinically significant 
portal hypertension (CSPH) in decompensated cirrhosis after 
their first decompensation event, who are stabilized CTP 5-7
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Main exclusion criteria: “primary biliary sclerosis” replaced 
by “primary biliary cholangitis”. 
Rationale for change
Correction/clarification 
Section to be changed
ABBREVIATIONS AND DEFINITIONS
Description of change
Deletion of abbreviation : 
SARS-CoV-2 : Severe Acute Respiratory Syndrome 
CoronaVirus 2
Rationale for change
No reference of SARS-CoV2 is mentioned in the text 
Section to be changed
3.3.3
Exclusion criteria
Description of change
Deletion of the bold text :
Exclusion Criteria #1.History of cholestatic chronic liver 
disease (e.g. primary biliary sclerosing cholangitis,)
Rationale for change
Correction / clarification
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
Deletion of the following paragraph : 
Ideally, the trial participant should attend all remaining visits. 
Should the trial participant not agree, at least phone contacts 
should occur at the scheduled visit time points, should that not 
be acceptable, a phone contact once or at the end of the 
planned observation period should occur to collect the most 
relevant information: vital status, outcome events, adverse 


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events (please see section 5.2.6.2.1), or last contact date in case 
of lost to follow-up.”
Rationale for change
deletion as it is no applicable for our study  
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
Text added : 

the trial participant develops an AE:
o
CTCAE Grade 3 or higher and the AE was 
assessed by the Investigator as related to the 
trial treatment; OR
o
CTCAE grade 4 or higher regardless of 
attribution to the trial treatment
Rationale for change
Request from Health Authority
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
Text added : 
Boehringer Ingelheim will closely monitor and medically 
review all adverse events CTCAE Grade 3 and higher.  
BI will pause the enrollment of new patient in the trial and 
ensure the clinical data is reviewed by the data monitoring 
committee (DMC) for safety before proceeding with the trial if 
one of the following occurs: 
1.
more than two patients develop a CTCAE grade 3 or 
higher in the same category; 
OR 
2.
two or more patients meet the individual patient 
stopping criteria related to adverse event
Rationale for change
Request from Health Authority
Section to be changed
5.2.3
Safety laboratory parameters / 
Description of change
Text added in Table 5.2.3: 1 Safety laboratory tests: 
-
Haematology: Haemoglobin
-
RBC count / erythrocytes
-
Automatic WBC differential (absolute and percentage)
-
Brain Natriuretic Peptide (BNP)
Rationale for change
Correction as these parameters were mentioned in different 
section of the protocol but not listed in the table 
Section to be changed
Table 5.2.3: 1 Safety laboratory tests
Description of change
Correction of the Superscript number of the following 
parameters:  
Alpha fetoprotein1 correct to Alpha fetoprotein4 
CK-MB2 corrected to CK-MB1
Phosphatidylethanol (PEth)3 corrected to Phosphatidylethanol 
(PEth)2
Troponin I2 corrected to Troponin I1


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Infections screening6 corrected to Infections screening4    
Rationale for change
Correction  
Section to be changed
Table 5.2.3: 1 Safety laboratory tests
Description of change
The text in bold has been added to footnote#2 and deleted in 
footnote #3
i.) Footnote #2 : Not performed at screening (Visit 1a). PEth, an 
alcohol-specific biomarker, will be measured during the 
treatment period for data analysis purposes 
ii.) Footnote#3 : 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
Rationale for change
i.
Clarification for the purpose of the assessment of PEth 
ii.
Correction as it not applicable for the safety parameters 
linked to superscript 3 
Section to be changed
7.2.1
General considerations
Description of change
Deletion of bold text : 
this analysis set includes all enrolled trial participants that were 
entered or randomised
Rationale for change
Administrative correction


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c42374778
2.0
clinical-trial-protocol-version-02-bi-685509
Randomised, double-blind, placebo-controlled and parallel group trial to investigate
the effects of one dose (up-titration to a fixed dose regimen) of oral BI 685509 on
portal hypertension after 8 weeks treatment in patients with clinically significant
portal hypertension (CSPH) in decompensated cirrhosis after their first
decompensation event, who are stabilized CTP 5-7
Approval-Biostatistics
30 Nov 2023 12:05 CET
Approval-Clinical Trial Leader
30 Nov 2023 12:43 CET
Approval-Team Member Medicine
30 Nov 2023 14:27 CET
Approval-Clinical Trial Leader
30 Nov 2023 14:42 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c42374778
2.0

SAP_001.pdf: 
ABCD
BI-VQD-12681-S-G_50-415_AD-01 (5.0)
TRIAL STATISTICAL ANALYSIS PLAN
TITLE PAGE
Document No.:
c43185880-01
BI Trial No.:
1366-0055
Title:
Randomised, double-blind, placebo-controlled and parallel group 
trial to investigate the effects of one dose (up-titration to a fixed 
dose regimen) of oral BI 685509 on portal hypertension after 8 
weeks treatment in patients with clinically significant portal 
hypertension (CSPH) in decompensated cirrhosis after their first 
decompensation event, who are stabilized CTP 5-7
Investigational
Product(s):
BI 685509 (Avenciguat)
Responsible trial 
statistician(s):
Phone:
Date of statistical 
analysis plan:
01 JUL 2024
Version:
1.0
Page 1 of 33
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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
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................7
5.
ENDPOINTS(S).....................................................................................................8
5.1
PRIMARY ENDPOINT(S)...................................................................................8
5.2
SECONDARY ENDPOINT(S).............................................................................8
5.2.1
Key secondary endpoint(s) ...................................................................................8
5.2.2
Secondary endpoint(s)...........................................................................................8
6
GENERAL ANALYSIS DEFINITIONS...........................................................12
6.1
TREATMENT(S) ................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
INTERCURRENT EVENTS..............................................................................13
6.4
SUBJECT SETS ANALYSED ...........................................................................13
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 ......................................................................................15
6.6.4
Time since first diagnosis....................................................................................16
6.6.5
PK data.................................................................................................................16
6.6.6
Biomarker data....................................................................................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................16
7
PLANNED ANALYSIS ......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........20
7.2
CONCOMITANT DISEASES AND MEDICATION......................................21
7.3
TREATMENT COMPLIANCE ........................................................................22
7.4
PRIMARY OBJECTIVE ANALYSIS ..............................................................22
7.4.1
Main analysis .......................................................................................................22


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7.4.4
Supplementary analysis ......................................................................................22
7.5
SECONDARY OBJECTIVE ANALYSIS ........................................................22
7.5.1
Key secondary objective analysis.......................................................................22
7.5.2
Secondary objective analysis..............................................................................23
7.5.2.1
Main analysis.........................................................................................................23
7.7
EXTENT OF EXPOSURE .................................................................................24
7.8
SAFETY ANALYSIS..........................................................................................24
7.8.1
Adverse Events ....................................................................................................24
7.8.1.1
Assignment of AEs to treatment ...........................................................................24
7.8.1.2
Analysis of other significant AEs..........................................................................25
7.8.1.3
AE summaries .......................................................................................................25
7.8.1.4
AEs of special interest (AESIs).............................................................................25
7.8.1.5
User-defined adverse event category (UDAEC)...................................................25
7.8.2
Laboratory data...................................................................................................27
7.8.3
Vital signs.............................................................................................................28
7.8.4
ECG ......................................................................................................................28
7.9
OTHER ANALYSIS ...........................................................................................28
7.9.1
Ultrasound............................................................................................................28
7.9.2
Biomarker analyses.............................................................................................28
7.9.3
PK analyses ..........................................................................................................29
7.10
HANDLING OF DMC ANALYSIS...................................................................29
8
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............30
9
REFERENCES ....................................................................................................31
11
HISTORY TABLE..............................................................................................33


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phase.............................................................................12
Table 6.4: 1
Subject sets analysed ........................................................................................14
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 .............................................21
Table 7.5.3:1 Categories for decompensation events .............................................................23
Table 7.8.1.5: 1
Definition of continuous UDAEC............................................................26
Table 11: 1
History table .....................................................................................................33


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ALQ
Above Limit of Quantification
ALT
Alanine transaminase
ANCOVA
Analysis of Covariance
AST
Aspartate transaminase
BLQ
Below Limit of Quantification
BMI
Body mass index
DBP
Diastolic blood pressure
FHVP
Free hepatic venous pressure
Fib-4
Fibrosis-4
HVPG
Hepatic Venous Pressure Gradient
LLOQ
Lower limit of quantification
PFHVP
Proximal free hepatic venous pressure
RS
Randomised Set
SBP
Systolic blood pressure
SD
Standard deviation
TS
Treated Set
ULN
Upper Limit of Normal
ULOQ
Upper limit of quantification
WHVP
Wedged Hepatic Venous Pressure


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3. INTRODUCTION
As per ICH E9 (9.1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
, and a number 
of SASTM-based tools (e.g., macros for the analyses of 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
The Avenciguat program in patients with clinically significant portal hypertension (CSPH) is 
decided to be discontinued in May 2024. No subject has finished the 8-week treatment 
duration, leading to no HVPG data at Week 8 collected. Therefore, planned analysis around 
HVPG data in the CTP, i.e.,

percentage change in HVPG from baseline after 8 weeks of treatment,

occurrence of a response, which is defined as > 10% reduction from baseline HVPG after 
8 weeks of treatment,
will not be performed. Only listing will be prepared.
Consequently, the reporting of intercurrent event, which supports HVPG analysis, is no 
longer of interest. All subjects are decided to be early discontinued. 


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is defined as the percentage change from baseline in HVPG (measured 
in mmHg) after 8 weeks of treatment.
The average wedged hepatic venous pressure (WHVP) and the average free hepatic venous 
pressure FHVP (FHVP) will be calculated based on the triplicate measurements.
Either the average FVPG or the measured proximal free hepatic venous pressure (PFHVP) 
will be used as the subtrahend for the calculation of HVPG (rounded to one decimal place).
Based on the judgment of the central reader, if the recorded PFHVP is considered to be more 
reliable than the recorded FHVP, then: 
                     HVPG (mmHg)=average WHVP (mmHg) – PFHVP (mmHg);
if the recorded FHVP is considered to be more reliable than the recorded PFHVP, then
HVPG (mmHg)=average WHVP (mmHg) – average FHVP (mmHg).
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Since there are no key secondary endpoints specified in the CTP, this section is not 
applicable.
5.2.2
Secondary endpoint(s)
The secondary endpoints will be used as defined in CTP Section 2.1.3.


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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 treatment study phases in this trial: screening, double-blind study 
treatment phase (with Avenciguat and matching placebo) and follow-up.
Table 6.1: 1
Flow chart of analysis phase
Label
Interval
Start date
End date
Screening 
Screening
Date of informed consent
Date of first 
administration of 
double-blind study 
medication - 1
Placebo/
Avenciguat 3mg
On-treatment 
Date of first administration 
of double-blind 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 (date of 
EOS visit, last 
contact date on EOS 
page)
* X=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. Note that the term “treatment
regimen” can also cover time periods with no active treatment.
For efficacy analyses of HVPG, data up to REP+1 (8 days) after last treatment intake will be 
considered as on-treatment, because a HVPG measurement at EOT is allowed to be done 
within 7 days after scheduled EOT (i.e, REP+1 days after last dose) as Section 5.1.1 of the 
CTP states “HVPG measurements 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)
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to
treatment groups, i.e. patients will be analyzed in the treatment group they were randomized
to.
In addition, AEs with an onset during the time of the incorrect study treatment will be listed
separately.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Each protocol deviation must be assessed to determine whether it is an important Protocol 
Deviation (iPD). The documentation of the iPD categories and how to handle iPDs in the 
analysis are done in the DV domain.
Handling of iPDs in analysis is included in the DV domain specifications 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 course of the study and finalised at the last report planning
meeting (RPM), i.e. before unblinding.
6.3
INTERCURRENT EVENTS
Not applicable as described in Section 4.
6.4
SUBJECT SETS ANALYSED
The subject sets will be used as defined in the CTP, Section 7.2.1. These include the Enrolled 
set (ES), Randomised set (RS), Treated set (TS) and Full analysis set (FAS). In addition, the 
following subject sets for the analysis of PK parameters and biomarkers will be used.

Screened set (SCR) – this analysis set includes all patients having signed informed 
consent. The SCR will be used for analyses of patient disposition

PK parameter analysis set (PKS): This set includes all subjects in the treated set (TS) 
who provide at least one PK endpoint that was not excluded due to a protocol 
deviation relevant to the evaluation of PK or due to PK non-evaluability (as specified 
in the following subsection ‘Pharmacokinetics’). Thus, a subject will be included in 
the PKS, even if he/she contributes only one PK parameter value to the statistical 
assessment. Descriptive analyses of PK parameters will be based on the PKS.

Biomarker set (BMS): This set includes all subjects from the Treated Set (TS) who 
provide at least one evaluable measurement assessing the liver or spleen stiffness 
using FibroScan® or an exploratory biomarker (refer to CTP Section 5.4), that was not 
excluded due to a protocol deviation relevant to the evaluation of biomarkers.
The discussion on all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at latest at the 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 analyzed
Subject set
Class of endpoint
SCR
RS
TS
FAS
PKS
BMS
Disposition
X
Primary endpoint
X*
Secondary efficacy and 
further efficacy endpoints
X*
Secondary and further 
safety endpoints 
(including liver 
decompensation) & 
treatment exposure
X
Demographic/baseline 
endpoints
X
Further PK endpoints
X
Further biomarker 
endpoints
X
* Planned analysis around HVPG data in the CTP will not be performed, as described in Section 4. 
Handling of Treatment Misallocations in Analysis Sets
If a patient was administered incorrect treatment during the study, for efficacy analyses:
-
subjects who took incorrect treatment will be reported under their randomized 
treatment group. In the case of stratification error at randomisation, the subjects will
be analyzed according to the stratum to which they actually belong to (regardless of 
any mis-assignment to treatment based on identification of the wrong stratum from 
IRT), as such an error occurs before randomisation and is therefore consistent with 
regulatory guidance.
If a patient was administered incorrect treatment during the study, then for safety the 
following will be used in addition:
-
If a patient is planned to receive Avenciguat, then patients will be reported under the 
planned treatment from the randomisation visit for safety analyses because the overall 
safety profile is expected to be driven by the amount of drug received in totality over 
the entire treatment duration. It is not expected that the safety profile will deviate from 
the planned treatment regimen if the subject receives only one or two kits of the 
incorrect medication at only some dosing occasions.
-
If a patient is planned to receive Placebo, then patients will be reported under their 
randomised treatment group for safety analysis if the patient was administered no 
Avenciguat kits at any visit. If the patient was administered at least one kit of BI 


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685509 during the treatment period, then the patient will be assigned to Avenciguat
treatment group.
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.
An analysis of the changes from baseline to the last available value under treatment and the
minimum and maximum post baseline will be determined for quantitative safety laboratory
variables.
6.6.3
Missing dates and times
Missing or incomplete AE dates are imputed according to BI standards (9.2).
If the date of first drug administration is missing but the patient was randomised, the date of
the first drug administration will be set to the date of randomisation. If the date of first 
administration is partially missing with the month and year present, the day will be set to the
date of randomisation if randomisation was in the same month. If randomisation 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.


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6.6.4
Time since first diagnosis
For incomplete information on the date of the first diagnosis of cirrhosis, 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 calculated 
as if diagnosed on the 15th of that month.
6.6.5
PK data
Missing data of PK data are handled according to BI standards (9.4).
6.6.6
Biomarker data
For disease specific protein markers (refer to CTP Section 5.4) the following handling of data 
below or above the limit of quantification will be applied:

BLQ data will be replaced by 0.5 · LLOQ. Hereby LLOQ will be the maximum used 
lower reference limit for classification of BLQs. All values lower than LLOQ will be 
imputed (regardless of whether they are classified as BLQ or not).

ALQ data will be replaced by ULOQ, if ULOQs are available and are greater than 
observed study values (i.e. the highest solution was applied for the measurement). 
Otherwise, ALQ data will be excluded from the analysis.
Otherwise, missing data (NOS - no sample, NOR - no valid result, NOA - not analysed) will 
not be imputed.
The handling of other biomarkers (e.g. genetic variants in disease genes) will be given in a 
separate biomarker SAP.
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.


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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)
Fibroscan data
8
Biomarkers
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.
On-treatment efficacy, safety and biomarker 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). 


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Table 6.7: 2
Time windows for assignment of measurements to visits for statistical analysis
Visit 
number
/name
Planned 
day
Time window (Days)
Visit label
Window
(per CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)*
End 
(extended)*
V1
Screening
-28
-∞
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
±5
52
62
51
Study
medication 
stop
date + 
X#days
Off-treatment
V8
Week 10/
EoS
Day 71
±5
66
76
Study
medication 
stop
date + X#
days +1
Day of last 
follow-up 
value
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
# X= 3 days for safety laboratory; X=1 day for biomarkers and vital sign, respectively; X= 8 days (REP +1) for HVPG and 
fibroscan data.
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 
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 


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available and multiple unscheduled correct values are available for a visit, the first correct 
value will be selected.
7
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
Clinical Trials and Project Summaries" (9.3).
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 and 
treated, entered but not treated, who completed Week 8 visit (V7), who were prematurely 
discontinued treatment by reason, who completed the study, and who prematurely
discontinued study. 
A frequency of patients with iPDs will be presented by treatment group for TS. 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 
analyzed.
For tables presenting descriptive analysis of the endpoints and other variables, the set of 
summary statistics are: 
N (number of patients with non-missing 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" (9.3). 
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. 
For PK analyte concentrations, as well as PK parameters, the following descriptive statistics 
will additionally be calculated:

CV
arithmetic coefficient of variation

gMean geometric mean

gCV
geometric coefficient of variation

P10 
10th percentile

Q1 
1st quartile

Q3 
3rd quartile

P90 
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 


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the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits.
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 RS.
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
> 60 to ≤ 90
> 90
Time since first diagnosis of 
(years)
≤ 1
> 1 to ≤ 5
> 5 to ≤ 10
> 10
Baseline HVPG
≤ 12
> 12
≤ 15
> 15
7.2
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 RS.
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).


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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 Table 6.1:1 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.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. 
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 (visit 3):

“Yes”,

“No”, and

“Missing”.
7.4
PRIMARY OBJECTIVE ANALYSIS
7.4.1
Main analysis 
As described in Section 4, planned analysis around HVPG data in the CTP, including primary 
object analysis, will not be performed.
7.4.4
Supplementary analysis
No supplementary analyses are planned.
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.


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7.5.2
Secondary objective analysis
7.5.2.1
Main analysis
The secondary endpoints for this study are described in CTP Section 2.1.3 and only 
descriptive statistics will be presented.
For the occurrence of decompensation events, categories are defined in Table 7.5.2:1.
Table 7.5.2:1 Categories for decompensation events
Categories          
Scope 
Definition
Acites
PT - ‘Ascites’
PT - ‘Bacterascites’ 
PT - ‘Haemorrhagic ascites’
Variceal haemorrhage
Narrow
Narrow
Narrow
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’


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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”.
No temporary treatment interruption (≤ 3 doses) 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 Adverse Events
AEs will be coded with the most recent version of MedDRA coding dictionary. Patients will 
be analyzed according to the actual treatment received.
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 (randomisation visit) 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.
7.8.1.1
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 Table 6.1:1. 
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, in-text AE 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.


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AEs and serious adverse events (SAEs) assigned to the following phases: screening, each 
treatment group (placebo, Avenciguat), post-treatment for each treatment group will be listed.
7.8.1.2
Analysis of other significant AEs
Other significant AEs will be reported and summarised according to ICH E3 criterion (9.5).
Thus, AEs classified as 'other significant' will include those non-serious adverse events with 
‘action taken = discontinuation’ or ‘action taken = dose reduced’. 
7.8.1.3
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 and 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 (9.5), for patients with serious adverse events, for patients with AEs leading to 
dose reduction, for patients with AEs leading to discontinuation, for patients with AEs leading 
to death, for patients with drug-related AEs, and drug-related serious AEs.
For further details on summarisation of AE data, please refer to “Handling of missing and 
incomplete AE dates” (9.2) and “Analysis and Presentation of Adverse Event data from 
Clinical Trials” (9.6). 
7.8.1.4
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.
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.  
7.8.1.5
User-defined adverse event category (UDAEC)
UDAEC will be summarized by dose group, primary system organ class and preferred term. 
In summary, Table 7.8.1.5:1 provides the definition of UDAECs according to AE category or 
Standardized MedDRA Query (SMQ).


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Table 7.8.1.5: 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’ 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. 
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 
	
    	 –  
 
 ≥30%;
-
Baseline SBP >140: decrease 
	
    	 –  
 
 ≥40%;
-
Or, lowest SBP during the episode <90.
-
Baseline DBP <=70: 
	
 "   	 –  "
 "
 ≥30%;
-
Baseline DBP > 70: 
	
 "   	 –  "
 
 ≥40%;
-
Or, lowest DBP during the episode <50.
-
Lowest mean arterial pressure (MAP = DP + 1/3(SP – DP)) during the episode<70.
The severity of hypotension will be categorised based on the CTCAE grades collected from 
the eCRF:
-
CTCAE grade 1 – mild
-
CTCAE grade 2 – moderate
-
CTCAE grade 3, 4 or 5 – severe


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7.8.2
Laboratory data
The analyses of laboratory parameters will be descriptive in nature and will be based on BI 
standards (9.7). 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” (9.7). 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 (see 
Section 6.7) and the last measurement on treatment. Descriptive statistics will be provided by 
treatment group 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.
Additionally, graphical analysis of the following lab parameters over time until EOS will be 
performed:

Haemoglobin

RBC count / erythrocytes

WBC count / leukocytes

Platelet count / thrombocytes

Reticulocytes

PT/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 30 days 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 


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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 or 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 in order to divide the plane into four quadrants. Normal cases 
are in the lower left quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law 
quadrant), while the lower right quadrant is known as the Temple’s corollary range (ALT ≥ 
3xULN and total bilirubin < 2xULN). The same graphical analysis will be repeated on AST 
and total bilirubin. 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 analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time (pre-dose, 1 hour, 2 hours) and for the difference 
from baseline and pre-dose (see Section 6.7) will be provided by treatment within a study
period as described in Table 6.1:1. Figures for change from baseline and change from pre-
dose for both 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
A listing for portal vein diameter will be provided.
7.9.2 Biomarker analyses
For all the biomarkers defined in Section 5.4.7, descriptive statistics will be presented.
In detail, for each marker the observed value will be analysed for the BMS via mean, standard 
deviation, median, Q1, Q3, normalized IQR (0.7413*IQR), minimum, maximum and gMean.
Other exploratory biomarkers may be reported in a separate biomarker report.


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7.9.3 PK analyses
Noncompartmental PK parameters will be calculated based on actual sampling times using a 
validated PK software (Phoenix® WinNonlin® 8.1).
Individual plasma concentration data and the PK parameters calculated thereof will be
tabulated and graphically displayed. A patient’s PK data will be flagged and excluded from
the PK analyses in case of protocol deviations relevant to the evaluation of PK or in case of
PK non-evaluability (refer to CTP Section 5.3.1).
7.10 HANDLING OF DMC ANALYSIS
An external data monitoring committee (DMC), independent of the trial and project teams, 
will be set-up on project level to review all available safety data as well as selected efficacy 
data in an unblinded manner at regular intervals following first-patient-in. A separate DMC 
SAP which describes the analyses required for assessment by the DMC will be produced and 
finalised prior to first patient randomised into the trial. Further details are provided in a DMC 
charter.


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


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9
REFERENCES
9.1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline
Topic E9; Note For Guidance on Statistical Principles for Clinical Trials, current
version
9.2
BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE dates”, 
current version; KMED.
9.3
KM Asset BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials 
and Project Summaries", current version, KMED.
9.4
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses
performed within Clinical Pharmacokinetics/Pharmacodynamics”, current
version; KMED.
9.5
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.
9.6
KM Asset BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse 
Event data from Clinical Trials”, current version, KMED.
9.7
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
01-JUL-24
None
This is the final TSAP.