Clinical trial NCT05161481
Conditions: Hypertension, Portal
Sponsor: Boehringer Ingelheim
Start date: 2022-04-27; Completion date: 2024-06-12
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with liver cirrhosis and high blood pressure in the portal vein (main vessel going to the liver). The purpose of this study is to find out whether a medicine called Avenciguat helps people with this condition.

Participants are put into 3 groups randomly, which means by chance. Participants in 2 groups take different doses of Avenciguat as tablets twice a day. Participants in the placebo group take placebo as tablets twice a day. Placebo tablets look like Avenciguat tablets but do not contain any medicine.

Participants are in the study for about 8 months. During this time, they visit the study site about 14 times. At 3 of the visits, the doctors check the pressure in a liver vein. This is done with a catheter (a long thin tube) and gives information about the pressure in the portal vein. The change in blood pressure is then compared between the 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 received Avenciguat combined with matching placebo tablets twice daily (BID). At Visit 2 (Week 1), each dose included one 1 mg Avenciguat tablet and one 2 mg placebo tablet (four tablets daily). At Visit 3 (Week 2), the dose was up titrated to 2 mg Avenciguat BID (one 1 mg placebo tablet and one 2 mg Avenciguat tablet (four tablets daily)). From Visit 4 onward (Week 3+), a pseudo up-titration was applied, with participants taking one 2 mg Avenciguat tablet and one 3 mg placebo tablet per dose (four tablets daily) to maintain blinding. This regimen continued for 24 weeks, with doses taken with water, with or without food. arm 2: Participants received Avenciguat with matching placebo tablets twice daily (BID). At Visit 2 (Week 1), each dose contained one 1 mg Avenciguat tablet and one 2 mg placebo tablet (four tablets daily). At Visit 3 (Week 2), the dose was up titrated to 2 mg Avenciguat BID (one 1 mg placebo tablet and one 2 mg active tablet (four tablets daily)). From Visit 4 onward (Week 3+), the dose was further up titrated to 3 mg Avenciguat BID (one 2 mg placebo tablet and one 3 mg active tablet per dose (four tablets daily)). This regimen was maintained for 24 weeks, with doses taken with water, with or without food. arm 3: Participants in this dose group received matching placebo twice daily (BID) throughout the study period. At Visit 2 (Week 1), each dose consisted of one 1 mg placebo tablet and one 2 mg placebo tablet (four tablets daily). At Visit 3 (Week 2), a pseudo up-titration was implemented, maintaining the same tablets (one 1 mg and one 2 mg placebo per dose) for blinding. From Visit 4 onward (Week 3+), a second pseudo up-titration adjusted the dose to one 2 mg placebo tablet and one 3 mg placebo tablet per dose (four tablets daily). All doses were taken with water, with or without food.
Interventions: intervention 1: Avenciguat (BI 685509) intervention 2: Placebo matching Avenciguat (BI 685509)
Intervention descriptions: intervention 1: Participants received Avenciguat twice daily (BID) throughout the study. Up-titration depended on the assigned dose group. At Visit 2 (Week 1), each dose included one 1 mg Avenciguat tablet. At Visit 3 (Week 2), the dose was increased to one 2 mg Avenciguat tablet per dose. From Visit 4 onward (Week 3+), participants received one 3 mg Avenciguat tablet per dose. This regimen continued for 24 weeks, with all doses taken with water, with or without food. intervention 2: Participants received matching placebo twice daily (BID) throughout the study. At Visit 2 (Week 1), each dose included one 1 mg and one 2 mg placebo tablet (four tablets daily). A pseudo up-titration was applied at Visit 3 (Week 2), maintaining the same tablet composition to preserve blinding. From Visit 4 (Week 3) onward, a second pseudo up-titration adjusted each dose to one 2 mg and one 3 mg placebo tablet (four tablets daily). All doses were taken with water, with or without food.

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (19.0) / Saved on: 03 Nov 2020
Clinical Trial Protocol
TITLE PAGE
Document Number:
c34798591-07
EudraCT No.
EU Trial No.
2021-001285-38
BI Trial No.
1366-0021
BI Investigational
Medicinal Product
BI 685509
Title
Randomised, double-blind, placebo-controlled and parallel 
group trial to investigate the effects of two doses (up-titration to 
a fixed dose regimen) of oral BI 685509 on portal hypertension 
after 24 weeks treatment in patients with clinically significant 
portal hypertension (CSPH) in compensated cirrhosis
Lay Title
A study to test whether two different doses of BI 685509 help 
people with liver cirrhosis and high blood pressure in the portal 
vein (main vessel going to the liver)
Clinical Phase
II
Clinical Trial Leader
Tel:
Fax:
Coordinating 
Investigator
Tel:
Fax:
Current Version and 
Date
Version 7.0, 02 Nov 2023
Original Protocol 
Date
Version 1.0, 27 May 2021
Page 1 of 121
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
27 May 2021
Revision date
02 Nov 2023
BI trial number
1366-0021
Title of trial
Randomised, double-blind, placebo-controlled and parallel group 
trial to investigate the effects of two doses (up-titration to a fixed 
dose regimen) of oral BI 685509 on portal hypertension after 24 
weeks treatment in patients with clinically significant portal 
hypertension (CSPH) in compensated cirrhosis
Coordinating 
Investigator
Trial sites
Multi-centre trial
Clinical phase
II
Trial rationale
In this Phase II trial the efficacy of treatment in patients with CSPH 
(defined by the presence of varices and hepatic venous pressure 
gradient [HVPG] ≥ 10 mmHg), in compensated alcohol-related 
cirrhosis, will be assessed.  This will be the first trial in the clinical 
development of BI 685509 where patients will be treated for 24 
weeks, and where the portal pressure will be assessed quantitatively 
via HVPG measurements.  The trial will evaluate both short-term 
and long-term efficacy. The long-term assessment will be used to 
rule out any adaptation to sGC activation on portal pressure on 
chronic treatment. The trial will also provide supportive evidence 
for the planned Phase III development 
Trial objectives
The trial will compare two doses of BI 685509 with placebo, on top 
of standard of care, in patients with CSPH in compensated alcohol-
related cirrhosis.  The primary objective is to estimate the mean 
difference between treatment groups with placebo in percentage 
change in HVPG from baseline measured after 24 weeks.  Safety 
and tolerability will also be investigated.
Trial endpoints
The primary endpoint is the percentage change in HVPG from 
baseline (measured in mmHg) after 24 weeks of treatment.
Secondary endpoints include:
percentage change in HVPG from baseline (measured in mmHg) 
after 8 weeks of treatment
response defined as > 10% reduction from baseline HVPG 
(measured in mmHg) after 8 weeks of treatment
response defined as > 10% reduction from baseline HVPG 
(measured in mmHg) after 24 weeks of treatment


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occurrence of one or more decompensation events (i.e. ascites, 
variceal haemorrhage [VH], and / or overt hepatic 
encephalopathy [HE]) during the 24 week treatment period
occurrence of CTCAE grade 3 (or higher) hypotension or 
syncope based on Investigator judgement, during the first 8 weeks 
of the treatment period
occurrence of CTCAE grade 3 (or higher) hypotension or 
syncope based on Investigator judgement, during the 24 week 
treatment period
occurrence of discontinuation due to hypotension or syncope 
during the first 8 weeks of the treatment period
occurrence of discontinuation due to hypotension or syncope 
during the 24 week treatment period
Trial design
Randomised, double-blind, parallel group, placebo-controlled 
comparison of treatment with BI 685509 over 24 weeks 
Total number of 
patients randomised
78
Number of patients per
treatment group
26
Diagnosis
Patients with CSPH in compensated alcohol-related cirrhosis
Main inclusion and 
exclusion criteria
Main inclusion criteria
male or female who is ≥ 18 (or who is of legal age in countries 
where that is greater than 18) and ≤ 75 years old at screening 
(Visit 1a)
clinical signs of CSPH as described by either one of the points 
below:
o documented endoscopic proof of oesophageal varices and / or 
gastric varices at screening (Visit 1b) or within 6 months prior 
to screening (Visit 1b) 
o documented endoscopic-treated oesophageal varices as 
preventative treatment  
CSPH defined as baseline HVPG ≥ 10 mmHg (measured at Visit 
1c), based on a local interpretation of the pressure tracing
diagnosis of compensated alcohol-related cirrhosis.  Diagnosis 
must be based on histology (historical data is acceptable) or on 
clinical evidence of cirrhosis (e.g. platelet count < 150 x 109/L 
[150 x 103/µL], nodular liver surface on imaging or 
splenomegaly)
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)
willing and able to undergo HVPG measurements per protocol 
(based on Investigator judgement)
if receiving statins, must be on a stable dose for at least 3 months 
prior to screening (Visit 1b), with no planned dose change 
throughout the trial


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if receiving NSBBs or carvedilol, must be on a stable dose for at 
least 1 month prior to screening (Visit 1b), with no planned dose 
change throughout the trial
Main exclusion criteria
previous clinically significant decompensation events (e.g. ascites 
[more than perihepatic ascites], VH and / or apparent HE)
history of other forms of chronic liver disease (e.g. non-alcoholic 
steatohepatitis [NASH], Hepatitis B virus [HBV], untreated HCV, 
autoimmune liver disease, primary biliary cholangitis, primary 
sclerosing cholangitis, Wilson’s disease, haemachromatosis, 
alpha-1 antitrypsin [A1At] deficiency)  
alcohol-related liver disease (ARLD) without adequate treatment 
(e.g. lifestyle modification) or with ongoing pathological drinking 
behaviour (misuse / abuse based on Investigator judgement)
SBP < 100 mmHg and DBP < 70 mmHg at screening (Visit 1a) 
Model of End-stage Liver Disease (MELD) score of > 15 at 
screening (Visit 1a)
hepatic impairment defined as a Child-Turcotte-Pugh score ≥ B8 
at screening (Visit 1a) 
ALT or AST > 5 times upper limit of normal (ULN) at screening 
(Visit 1a)
eGFR (CKD-EPI formula) < 20 mL/min/1.73 m2 at screening 
(Visit 1a)
alpha-fetoprotein > 50 ng/mL (> 50 µg/L) at screening (Visit 1a)
history of clinically relevant orthostatic hypotension, fainting spells 
or blackouts due to hypotension or of unknown origin (based on 
Investigator judgement)
Test product
BI 685509  
dose
Treatment group 1: 
BI 685509 BID (maintenance dose)
Treatment group 2:
BI 685509 BID (maintenance dose
mode of 
administration
Oral
Comparator product
Placebo
dose
Matching
mode of
administration
Oral
Duration of treatment
24 weeks
Statistical methods
For the primary endpoint, restricted maximum likelihood estimation 
based on a mixed-effect for repeated measures analysis will be used
to obtain adjusted means for the treatment effects. This model will 
include discrete fixed effects for treatment at each visit and use of 
NSBBs or carvedidol (yes / no) at baseline and continuous fixed 
effect for baseline HVPG at each visit. The analysis will only be 
used for estimation of treatment effects without performing 
statistical tests.  Secondary and further endpoints will be analysed 
descriptively. 


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Safety analyses will be performed using BI standards and will be 
descriptive in nature.


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FLOW CHART
Trial Periods
Screening1
Randomised Treatment
Follow-Up
Visit
1a1
1b1
1c1
22
3
4
5
6
7
8
9
10
EoT / ED3
EoS3
Week
-6
R
1
2
4
6
8
12
16
20
24
28
Day
-42 
1
8
15
29
43
57
85
113
141
169
197
Time window for visits (days)
See footnote 1
N/A
+ 2
+ 2
+ 2
± 3
± 3
± 5
± 5
± 5
± 5
± 5
Fasting status4
NF
F
F
F
NF
NF
F
NF
F
NF
NF
NF
F
F
Informed consent
x
Register patient in IRT system via IRT call
x
Demographics5
x
Medical history / baseline conditions5
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Anthropometric measures6
x
x
x
x
x
x
x
x
x
x
x
x
Vital signs7
x
x23
x23
x23
x23
x
x
x
x
x
x
x
Physical examination8
x22
(x)
(x)
(x)
(x)
(x)
x
(x)
(x)
(x)
x
(x)
Resting 12-lead ECG7
x
x23
x23
x23
x23
x
x
x
x
x
x
x
Safety laboratory sampling
x
x
x
x
x
x
x
x
x
x
x
Pregnancy testing9
xs
xu
xu
xu
xu
xu
xu
xu
xu
Gastroscopy1, 10
x
Hepatic venous pressure gradient (HVPG)1, 11
x
x
x
Ultrasound (liver and spleen)1, 12
x
x
x
x
x
Review of in-/exclusion criteria
x
x
x
x


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FLOW CHART contd.
Trial Periods
Screening1
Randomised Treatment
Follow-Up
Visit
1a1
1b1
1c1
22
3
4
5
6
7
8
9
10
EoT / ED3
EoS3
Week
-6
R
1
2
4
6
8
12
16
20
24
28
Day
-42 
1
8
15
29
43
57
85
113
141
169
197
Time window for visits (days)
See footnote 1
N/A
+ 2
+ 2
+ 2
± 3
± 3
± 5
± 5
± 5
± 5
± 5
Fasting status4
NF
F
F
F
NF
NF
F
NF
F
NF
NF
NF
F
F
Randomisation
x
IRT call
x
x
x
x
x
x
x
x
x
x
Dispense trial medication
x
x
x
x
x
x
x
x
x
Dose-titration14
x
x
x
Train patient (home BP and HR monitoring)15
x
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
Home BP and HR monitoring (by patient)15
x










Biobanking sampling19
x
x
x
PRO completion (EQ-5D-5L, SF-36v2, 
CLDQ)20
x
x
All AEs / SAEs / AESIs21
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Collect trial medication
x
x
x
x
x
x
x
x
x
Compliance check
x
x
x
x
x
x
x
x
x
End of trial medication
x
Completion of patient participation
x


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Footnotes:
1.
The screening period consists of 3 visits (Visits 1a/b/c).  These visits should ideally be completed within a period of 4 weeks, but a maximum of 6 weeks (-42 days) will be permitted.  
There is no minimum duration.  A patient can proceed from one visit to the next as soon as all results from the previous visit are available and if he / she remains eligible for the trial.  Visit 
1b and 1c can be performed on the same day; in that case, the gastroscopy must be performed prior to the HVPG measurement.  The ultrasound and
can be 
performed at either Visit 1b or 1c.  Refer to Sections 5.1.1, 5.1.2, 5.2.5.1, 5.2.5.2 and 6.2.1 
2.
Visit 2 = randomisation / Day 1 of trial medication.  All assessments at this visit (excluding post-dose vital signs and ECGs,
[refer to 
Sections 5.2.4, 5.6.1, 6.2 and Appendix 10.1]) should be completed before the first dose of trial medication is administered  
3.
Patients who complete 24 weeks of treatment will have an End of Treatment (EoT) visit, followed 4 weeks later by an End of Study (EoS) visit.  The last dose of trial medication will be 
administered in the evening of the day before the EoT visit.  Patients who discontinue trial medication prematurely will have an Early Discontinuation (ED) visit completed instead of the 
planned treatment period visit.  The ED visit should be performed within 7 days of discontinuing the trial medication, followed 4 weeks later by an EoS visit.  Refer to Section 6.2.2.1 for 
details of assessments that should be performed during an ED visit and the EoS visit that follows it  
4.
Fasting status: F = fasting (i.e. overnight fast, no food or drink, except water), NF = non-fasting  
5.
For further details refer to Section 6.2.1
6.
Anthropometric measures = height (measured at Visit 1a only), weight, and waist and hip circumference.  Refer to Section 5.2.1.1
7.
Measurement of vital signs should precede the 12-lead ECG, and measurement of the 12-lead ECG should precede blood sampling and intake of trial medication at visits where a single 
ECG is required.  The 12-lead ECG should be performed after the patient has rested for at least 5 minutes in a supine position. From Visit 2 onwards, the patients home BP monitoring 
equipment should be used in the clinic to measure vital signs (refer to Sections 5.2.2, 5.2.2.1 and 5.2.4)    
8.
At Visits 1a, 7 and at the EoT / ED visit, a complete physical examination is required.  At all other marked visits, a physical examination is only required if the patient reports symptoms.  
Refer to Section 5.2.1
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.  Pregnancy testing at dosing visits should be completed prior to administration of trial medication.  Refer to Section 5.2.3
10. Refer to Section 5.2.5.2 for details regarding the necessity for a gastroscopy at Visit 1b  
11. For further details regarding the HVPG measurement, refer to Section 5.1.1
12. For further details regarding ultrasound of the liver and spleen, refer to Section 5.2.5.1 
13.
14. For further details regarding dose-titration, refer to Section 4.1.4
15. Electronic home BP monitoring equipment will be provided for a patient to measure BP and HR on a daily basis from Visit 2 (refer to Section 5.2.2.1).  Following training on the use of 
the equipment at Visit 2, subsequent refresher training should be provided if required    
16.
 
Following training on completion of the diary at Visit 2, subsequent refresher training should be provided if required    
17.
18.
19. Biobanking sampling requires a consistent status from one sample to another in terms of fasting vs non-fasting; a fasting status is therefore defined.  Sampling is optional and requires 
separate informed consent.  Refer to Section 5.5
20.


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21. After the EoS visit (= individual patients end of the trial) the Investigator should report only 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 and only via the BI SAE form 
(refer to Section 5.2.6.2.1)
22. The physical examination at Visit 1a should include an assessment of the clinical criteria for Child-Turcotte-Pugh classification (refer to Appendix 10.3)
23. 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


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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...........................................................................16
1.
INTRODUCTION...............................................................................................20
1.1
MEDICAL BACKGROUND.............................................................................20
1.2
DRUG PROFILE................................................................................................20
1.2.1
Key characteristics of BI 685509 .......................................................................21
1.2.2
Data from pre-clinical studies............................................................................23
1.2.3
Data from clinical studies...................................................................................24
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................25
1.4
BENEFIT - RISK ASSESSMENT.....................................................................26
1.4.1
Benefits.................................................................................................................26
1.4.2
Risks .....................................................................................................................26
1.4.3
Discussion.............................................................................................................30
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................32
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........32
2.1.1
Main objectives....................................................................................................32
2.1.2
Primary endpoint................................................................................................32
2.1.3
Secondary endpoints...........................................................................................32
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................35
3.1
OVERALL TRIAL DESIGN.............................................................................35
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP...........................................................................................36
3.3
SELECTION OF TRIAL POPULATION .......................................................38


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3.3.1
Main diagnosis for trial entry ............................................................................38
3.3.2
Inclusion criteria .................................................................................................39
3.3.3
Exclusion criteria ................................................................................................40
3.3.4
Discontinuation of patients from trial medication or assessments.................42
3.3.4.1
Discontinuation of trial medication...................................................................42
3.3.4.2
Withdrawal of consent to trial participation....................................................44
3.3.4.3
Discontinuation of the trial by the Sponsor......................................................44
4.
TREATMENTS...................................................................................................45
4.1
INVESTIGATIONAL TREATMENTS ...........................................................45
4.1.1
Identity of the investigational medicinal products...........................................45
4.1.2
Selection of doses in the trial and dose modifications......................................46
4.1.3
Method of assigning patients to treatment groups...........................................47
4.1.4
Drug assignment and administration of doses for each patient......................47
4.1.4.1
Rules for down-titration in case of intolerance to trial medication................49
4.1.4.2
Rules for re-starting up-titration in case of interruption of trial 
medication............................................................................................................50
4.1.5
Blinding and procedures for unblinding...........................................................51
4.1.5.1
Blinding................................................................................................................51
4.1.5.2
Unblinding and breaking the code ....................................................................51
4.1.6
Packaging, labelling, and re-supply...................................................................52
4.1.7
Storage conditions...............................................................................................52
4.1.8
Drug accountability.............................................................................................52
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................53
4.2.1
Other treatments and emergency procedures..................................................53
4.2.2
Restrictions ..........................................................................................................54
4.2.2.1
Restrictions regarding concomitant treatment ................................................54
4.2.2.1.1
Close monitoring for AEs based on concomitant therapy...............................54
4.2.2.2
Restrictions on diet and lifestyle........................................................................55
4.2.2.3
Contraception requirements..............................................................................55
4.3
TREATMENT COMPLIANCE........................................................................56


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5.
ASSESSMENTS..................................................................................................57
5.1
ASSESSMENT OF EFFICACY........................................................................57
5.1.1
Hepatic venous pressure gradient .....................................................................57
5.2
ASSESSMENT OF SAFETY.............................................................................59
5.2.1
Physical examination ..........................................................................................59
5.2.1.1
Anthropometric measurements (height, weight, waist and hip 
circumference).....................................................................................................59
5.2.2
Vital signs / home blood pressure and heart rate monitoring.........................60
5.2.2.1
Home blood pressure and heart rate monitoring.............................................60
5.2.3
Safety laboratory parameters ............................................................................60
5.2.4
Electrocardiogram ..............................................................................................64
5.2.5
Other safety parameters.....................................................................................65
5.2.5.1
Ultrasound (liver and spleen).............................................................................65
5.2.5.2
Gastroscopy .........................................................................................................65
5.2.5.3
Hepatic injury adjudication...............................................................................66
5.2.6
Assessment of adverse events.............................................................................66
5.2.6.1
Definitions of adverse events..............................................................................66
5.2.6.1.1
Adverse event.......................................................................................................66
5.2.6.1.2
Serious adverse event..........................................................................................66
5.2.6.1.3
Adverse events considered “Always Serious” ..................................................67
5.2.6.1.4
Adverse events of special interest ......................................................................67
5.2.6.1.5
Intensity (severity) of adverse events ................................................................67
5.2.6.1.6
Causal relationship of adverse events ...............................................................68
5.2.6.2
Adverse event collection reporting....................................................................68
5.2.6.2.1
Adverse event collection .....................................................................................68
5.2.6.2.2
Adverse event reporting to the Sponsor and timelines....................................69
5.2.6.2.3
Pregnancy ............................................................................................................69


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5.5
BIOBANKING ....................................................................................................74
5.5.1
Methods and timing of sample collection..........................................................74
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................76
6.
INVESTIGATIONAL PLAN.............................................................................77
6.1
VISIT SCHEDULE.............................................................................................77
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................78
6.2.1
Screening period (Visits 1a to 1c) ......................................................................79
6.2.2
Treatment period ................................................................................................80
6.2.2.1
End of Treatment / Early Discontinuation visit...............................................81
6.2.3
Follow-Up (End of Study) and trial completion...............................................81
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE....................................................................................................82
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................82
7.2
PLANNED ANALYSES.....................................................................................82
7.2.1
General considerations .......................................................................................82
7.2.2
Handling of intercurrent events.........................................................................83
7.2.3
Primary objective analyses.................................................................................83


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7.2.4
Secondary objective analyses.............................................................................84
7.2.6
Safety analyses.....................................................................................................84
7.2.8
Interim analyses ..................................................................................................85
7.3
HANDLING OF MISSING DATA ...................................................................86
7.4
RANDOMISATION ...........................................................................................86
7.5
DETERMINATION OF SAMPLE SIZE .........................................................86
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE.................................................................88
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................88
8.2
DATA QUALITY ASSURANCE ......................................................................89
8.3
RECORDS...........................................................................................................89
8.3.1
Source documents ...............................................................................................89
8.3.2
Direct access to source data and documents.....................................................90
8.3.3
Storage period of records ...................................................................................91
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................91
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........91
8.5.1
Collection, storage and future use of biological samples and 
corresponding data .............................................................................................91
8.6
TRIAL MILESTONES.......................................................................................92
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................92
9.
REFERENCES....................................................................................................95
9.1
PUBLISHED REFERENCES............................................................................95
9.2
UNPUBLISHED REFERENCES......................................................................98
10.
APPENDICES.....................................................................................................99


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10.2
REMOVAL OF INDIVIDUAL PATIENTS IN CASE OF INCREASED 
LIVER ENZYMES ...........................................................................................100
10.3
CHILD-TURCOTTE-PUGH CLASSIFICATION .......................................102
11.
DESCRIPTION OF GLOBAL AMENDMENTS..........................................103
11.1
GLOBAL AMENDMENT 1 ............................................................................103
11.2
GLOBAL AMENDMENT 2 ............................................................................105
11.3
GLOBAL AMENDMENT 3 ............................................................................112
11.4
GLOBAL AMENDMENT 4 ............................................................................113
11.5
GLOBAL AMENDMENT 5 ............................................................................115
11.6
GLOBAL AMENDMENT 6 ............................................................................119


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ABBREVIATIONS AND DEFINITIONS
A1At
Alpha-1 antitrypsin
AC
Adjudication Committee
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ANCOVA
Analysis of Covariance
ARLD
Alcohol-Related Liver Disease
AUC
Area Under the concentration-time Curve
BDL
Bile Duct Ligation
BI
Boehringer Ingelheim
BID
Bis In Die (twice a day)
BP
Blood Pressure
BPM
Beats Per Minute
CA
Competent Authority
cGMP
cyclic Guanosine MonoPhosphate
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum measured concentration of the analyte in plasma
COVID-19
Coronavirus Disease 19
Cpre
Predose concentration of the analyte in plasma
CRA
Clinical Research Associate
CRO
Contract Research Organisation
CSPH
Clinically Significant Portal Hypertension
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol


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CTR
Clinical Trial Report
DBL
Database Lock
DBP
Diastolic Blood Pressure
DDI
Drug-Drug Interaction
DILI
Drug-Induced Liver Injury
DMC
Data Monitoring Committee
DN
Diabetic Nephropathy
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
ED
Early Discontinuation
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
FHVP
Free Hepatic Venous Pressure
Fib-4
Fibrosis-4
GCP
Good Clinical Practice
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HE
Hepatic Encephalopathy
HERG
Human Ether-a-go-go Related Gene
HR
Heart Rate
HVPG
Hepatic Venous Pressure Gradient
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
ICM
Iodinated Contrast Material


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IEC
Independent Ethics Committee
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
LPLT
Last Patient Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
MELD
Model for End-stage Liver Disease
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
OATP
Organic Anion Transporting Polypeptide
PD
Pharmacodynamic
PDE
Phosphodiesterase
P-gp
Permeability glycoprotein
PH
Portal Hypertension
PV
Pharmacovigilance


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QD
Quaque Die (once a day)
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
RPM
Report Planning Meeting
RS
Randomised Set
SAE
Serious Adverse Event
SARS-CoV-2
Severe Acute Respiratory Syndrome CoronaVirus 2
SBP
Systolic Blood Pressure
sGC
soluble Guanylate Cyclase
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)
TIPS
Transjugular Intra-hepatic Portosystemic Shunt
TGFß
Transforming Growth Factor beta
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UGT
Uridine Glucuronyl Transferase 
ULN
Upper Limit of Normal
VCTE
Vibration Controlled Transient Elastography
VH
Variceal Haemorrhage
WHVP
Wedged Hepatic Venous Pressure
(WO)CBP
(Women Of) Child-Bearing 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 approved 
clinical approaches to prevent PH-related decompensating events in patients with 
compensated cirrhosis are endoscopic variceal ligations or off-label use of non-selective beta-
blockers (NSBBs) or carvedilol for the prophylaxis of a first variceal bleeding.  However, not 
all patients with PH achieve a haemodynamic response with these current treatment options.  
NSBBs and carvedilol are currently used to prevent complications of cirrhosis and improve 
survival in patients, but these benefits only occur in less than half of patients treated, and 
mostly in those who achieve a substantial decrease in portal pressure.  An unmet need 
remains for a substantial number of patients who cannot tolerate treatment with NSBBs or 
carvedilol due to decreased systemic blood pressure (BP) and heart rate (HR), and who have 
a higher risk for further progression into decompensation. 
Therefore, there is an existing unmet medical need to reduce portal pressure and improve 
liver perfusion in this population of patients with PH and especially clinically significant 
portal hypertension (CSPH) and compensated cirrhosis.  CSPH is associated with an 
increased risk of developing varices, overt clinical decompensation (ascites, VH, and HE), 
postsurgical decompensation, and hepatocellular carcinoma (R18-2743, R20-1200, P18-
02639).
1.2
DRUG PROFILE
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).  
For a more detailed description of the profile of BI 685509 refer to the current Investigator’s 
Brochure (IB) [c02778238].


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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 (PK) characteristics
The pharmacokinetics of BI 685509 is characterised by rapid absorption, reaching peak 
plasma concentrations between 0.5-1.0 hour post-dose in healthy volunteers.  Thereafter, BI 
685509 plasma concentrations decline in a biphasic manner.  Systemic exposure to BI 
685509 increased proportional to dose following administration of single doses, and close to 
dose-proportional exposure was observed at steady state for the dose range tested from 
to
The single-dose and steady-state PK parameters (AUC0-∞and AUC0-τ,ss) for 
BI 685509 were similar, suggesting linear PK with respect to time.  Minimal amounts of BI 
685509 were excreted unchanged in urine (< 1% of dose).  The apparent terminal elimination 
half-life was approximately 9 to 15 hours.  After multiple oral administration, limited 
accumulation was observed and steady state appears to be attained by approximately 3 to 5 
days after the start of multiple dosing.
Following single and multiple oral administrations of BI 685509, the exposures of BI 685509
(Cmax and AUC) were comparable between Chinese and Japanese subjects but may be up to
2-fold higher compared to Caucasian subjects.  This may be related to the smaller body 
weight in Asian subjects.  Although exposures were higher in Asian subjects, there were no 
notable differences with respect to BP, HR and adverse events (AEs) between Asian and 
Caucasian subjects.  This leads to the current assumption that no considerable dose 
adjustments are needed for Asian patients for the Phase II program that will recruit patients 
from Japan and other Asian countries.
Based on the PK analysis of Trial 1366-0004, the exposure to BI 685509 observed in patients 
with diabetic nephropathy (DN) with an eGFR ranging from 20 – 75 mL/min/1.73 m2 was
comparable to exposure observed in healthy volunteers in Trial 1366-0003. Also, as 


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


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BI 685509 was generally safe and well tolerated in patients with DN in Trial 1366-0004 with 
eGFR 20 – 75 mL/min/1.73m2 and in hepatically impaired Child-Turcotte-Pugh A and B 
patients in Trial 1366-0020.  A similar titration regimen will be used in this trial compared to 
Trial 1366-0020 which will help detect any orthostatic dysregulation and allow adjustment of
doses accordingly (refer to Section 4.1.4).
Drug interactions
The combination of BI 685509 with other compounds involved in the NO-sGC-cGMP 
pathway, such as NO-donors (e.g. nitrates), phosphodiesterase (PDE)-5- inhibitors, non-
specific PDE inhibitors and sGC-simulators might further increase the risk for hypotensive 
episodes and potentially reactive HR increases and the severity of these effects.  Based on in-
vitro data, BI 685509 is a weak inactivator of CYP3A4 and CYP2C8.  A Drug-Drug 
Interaction (DDI) potential with CYP3A4 substrates cannot be excluded as BI 685509 is 
predicted to be a weak CYP3A4 inactivator.  DDI threshold dose for CYP2C8 inactivation 
for the CSPH indication is close to the clinically relevant dose tested in Phase II.  Thus, in 
addition to close monitoring of AEs among patients taking CYP3A4 narrow therapeutic index 
/ or sensitive substrates, CYP2C8 and CYP3A4 narrow therapeutic index / or sensitive 
substrates will also be monitored to support patient safety.  Inhibitors or inducers of UGT 
(uridine glucuronyl transferase) enzymes (especially UGT1A1) may potentially impact BI 
685509 exposures in a clinically relevant manner.  BI 685509 is a substrate of P-gp 
(permeability glycoprotein) and OATP (organic anion transporting polypeptide)1B1/3
transporters.  Co-administration of single doses of BI 685509 and the P-gp inhibitor 
itraconazole increased BI 685509 Cmax approximately 1.35-fold and AUC0-tz approximately 
1.55-fold, which is considered not clinically relevant. OATP1B1/3 inhibition by rifampicin 
increased the exposure of BI 685509 after co-administration of single doses approximately 
2.15-fold for Cmax and 2.74-fold for AUC0-tz, which is considered clinically relevant.  Thus, 
OATP1B1/3 inhibitors will be restricted (refer to Table 1.4.2: 1 and Section 4.2.2.1).
Residual Effect Period
The Residual Effect Period (REP) of BI 685509 is 7 days. This is the period after the last 
dose with measurable drug levels and / or pharmacodynamic (PD) effects still likely to be 
present.
1.2.2
Data from pre-clinical studies
BI 685509 activates sGC-mediated cGMP production in the presence of plasma proteins in an 
assay using human or rat platelet-rich plasma with EC50 values of 371 nM and 304 nM, 
respectively.  BI 685509 was tested in the bile duct ligation (BDL) rat model of cirrhotic PH
in which the compound (3 mg/kg and 10 mg/kg) or vehicle were gavaged twice daily from 
weeks 2-4 after BDL (n00260803). BDL rats presented with PH and prominent liver fibrosis. 
Compared to vehicle, portal pressure was significantly reduced with both doses of BI 685509 
(-5.1 mmHg for 3 mg/kg, p<0.001 and -4.5 mmHg for 10 mg/kg, p<0.01), whereas no 
significant effect on HR and mean arterial pressure was observed. Both doses of BI 685509 
significantly reduced both hepatic hydroxyproline content (-30% for 3 mg/kg, p<0.05 and -
32% for 10 mg/kg, p<0.05) and fibrotic area in chrome aniline-stained liver slices (-62% for 
3 mg/kg, p<0.001 and -50% for 10 mg/kg, p<0.01). BI 685509 treatment resulted in reduced 


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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 
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.
Trial 1366-0020, an MRD trial involving hepatically impaired patients, was ongoing during 
Clinical Trial Protocol (CTP) writing. An interim analysis was performed.
Summary of interim analysis data from Trial 1366-0020:
In the trial, 49 patients with hepatic impairment due to various underlying liver diseases were 
treated for up to 4 weeks (24 patients with cirrhosis Child-Turcotte-Pugh A and 25 patients 
with cirrhosis Child-Turcotte-Pugh B in patients with hepatic impairment, as these are the 
intented patient population.
The treatment with BI 685509 in patients with cirrhosis of different aetiologies, with hepatic 
impairment with Child-Turcotte-Pugh A and B was safe and well-tolerated. All AEs were of 
mild or moderate intensity. No treatment-related SAEs, as defined by the Investigator, 


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occurred, or led to treatment discontinuation. Orthostatic intolerance occurred in the higher 
dose groups, and did not lead to treatment discontinuation, but recovered during continued 
treatment. Treatment with BI 685509 had no effect on laboratory parameters, including liver 
enzymes and bilirubin.
The exposure was comparable between Child-Turcotte-Pugh A and B patients, and no 
differences were seen for the different underlying liver aetiologies. Exposure of 
 BID in 
hepatic impaired patients were similar to 
 TID exposures observed in healthy volunteers
(Trial 1366-0003) and chronic kidney disease patients (Trial 1366-0004).
In addition to the safety and exposure, exploratory efficacy biomarkers were investigated in 
the Child-Turcotte-Pugh A patients. Considering the short treatment period, especially only 
12 days on the maintenance dose, positive signals could be observed in the HepQuant® shunt 
fraction, which is a surrogate of the amount of blood shunted by the liver. A mean reduction 
of > 10% could be observed in the two higest maintenance doses, and specifically in the 
highest dose group, all patients showed a reduction. Spleen stiffness was assessed using the 
FibroScan® Expert 630 (Echosens), however, due to being a rather new technique, the data 
generated was inconclusive. 
Summary of recent data from Trial 1366-0020:
Based on recent data from Trial 1366-0020, an effect of BI 685509 on the predicted placebo-
corrected change from baseline QTcF (∆∆QTcF) was seen.  As mentioned above, this trial 
included patients with cirrhosis Child-Pugh stage A (24 patients) and B (25 patients).  Dosing 
regimens up to
BID (i.e. the same as the highest dose group in this trial) were used.  In 
both patient groups, there was a dose dependent increase of ∆∆QTcF up to 13.7 ms, with the 
upper 90% CI > 20 ms.  In one patient group (Child Pugh A) this was concomitant with a 
change of the predicted placebo-corrected change from baseline heart rate (∆∆HR) of > 10 
beats per minute (bpm), but not in the other patient group.  No such effect was seen in healthy 
Caucasian volunteers (Trial 1366-0003) for dosing regimens achieving exposure relevant for 
this trial.  In healthy Asian volunteers (Trial 1366-0013), at a dose regimen achieving 
exposure relevant for this trial (i.e. starting dose of
 TID up to a final dose of 
TID), 
increase of ∆∆QTcF was seen up to 11.7 ms with 90% CI < 20 ms, concomitant with an 
increase of ∆∆HR of nearly 10 bpm.  
BI 685509 has no effect on the human ether-a-go-go related gene (hERG) channel at doses 
used in this clinical trial, and no effect on QT-interval or T-wave morphology was seen in 
conscious animal studies (for further details refer to the current Investigator’s Brochure (IB) 
[c02778238]).  
1.3
RATIONALE FOR PERFORMING THE TRIAL
In this Phase II trial the efficacy of treatment in patients with CSPH (defined by the presence 
of varices and HVPG ≥ 10 mmHg) in compensated alcohol-related cirrhosis will be assessed.  
This will be the first trial in the clinical development of BI 685509 where patients will be 
treated for 24 weeks, and where the portal pressure will be assessed quantitatively via HVPG 


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measurements.  The trial will serve to evaluate both short-term and long-term efficacy.  The 
long-term assessment will be used to rule out any adaptation to sGC activation on portal 
pressure on chronic treatment.  The trial will also provide supportive evidence for the planned 
Phase III development.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (refer to 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 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 profile of BI 685509 is outlined in the current Investigator’s Brochure (IB) 
[c02778238].
1.4.1
Benefits
BI 685509 has demonstrated efficacy in pre-clinical models for cirrhosis and PH, supporting 
its potential for the treatment of PH and fibrosis.  As cGMP elevation has been associated 
with anti-fibrotic, anti-proliferative and anti-inflammatory effects, pharmacological activators 
of sGC, like BI 685509, have the potential to slow down or halt complications of cirrhosis by 
reducing PH, improving liver perfusion, and potentially having beneficial effects on the 
cardiovascular system.  This would not only improve clinical outcomes and quality of life for 
the patients, but would also reduce the need for invasive procedures and resources 
(pharmacological and non-pharmacological therapies, e.g. endoscopic variceal ligation, large 
volume paracentesis, albumin therapy, transjugular intra-hepatic portosystemic shunt [TIPS] 
and orthotopic liver transplantation), reduce overall morbidity and mortality, and improve 
survival (R19-3528, R20-1198, R20-1199).  BI 685509 is a new chemical entity at an early 
stage of development however and an individual benefit cannot be guaranteed.  
The 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 invasiveness and technical difficulty.
1.4.2
Risks
Trial participants will be exposed to trial-related risks due to exposure to the trial medication,
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 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 1.2.3 and 4.1.2).  
All patients will be monitored for AEs, and BP and HR will be 
measured daily (by the patient at home) during the treatment period.  
Patients with oedema or gastrointestinal side effects will be 
managed by standard of care, and patients with a known history of 
orthostatic dysregulation and those with a SBP < 100 mmHg and a 
DBP < 70 mmHg will be excluded.  In addition, up-titration to the 
maintenance dose within each treatment group will occur at weekly 
intervals in order to increase the tolerability of the trial medication 
with regards to cardiovascular effects.
Potential QT-
interval 
prolongation
Refer to Section
1.2.3
Patients with long QT / QTcF-interval, patients with a family 
history of long QT syndrome, or those using concomitant therapies
known to increase the risk of Torsade de Points will be excluded 
from the trial (refer to Sections 3.3.3 and 4.2.2.1).
ECGs will be performed at each visit in the randomised treatment 
period of the trial, and trial medication will be discontinued in the 
event of a prolonged QT / QTcF-interval (refer to Section 3.3.4.1).
Risks related to 
DDI
Refer to Section 
1.2.1
Close monitoring of patients for AEs and restricted co-
administration of impacted concomitant therapies such as treatments 
with a similar mechanism of action (i.e. activators of the NO-sGC-
cGMP pathway), clinically relevant therapies inhibiting the activity 
of OATP1B1/3 and clinically relevant UGT inhibitors.  Patients 
taking concomitant therapies that are sensitive CYP3A4 and 
CYP2C8 substrates and / or narrow therapeutic index CYP3A4 and 
CYP2C8 substrates will also be monitored closely.  A list, to 
support the identification of the above-mentioned concomitant 
therapies at trial sites, will be provided in the Investigator Site File 
(ISF).  Also refer to Sections 3.3.3 and 4.2.2.1.  


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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 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
The HVPG procedure is the gold standard 
to assess portal pressure quantitatively, 
but, it is invasive, resource-intensive, and 
requires interventional skills and expertise 
in interpreting the reliability and 
plausibility of pressure readings (refer to 
Section 5.1.1), hence, the procedure is not 
commonly performed as part of clinical 
practice.  To date, there are no alternative, 
non-invasive parameters reflecting the 
degree of portal pressure with similar 
accuracy as HVPG.  The complication rate 
of HVPG measurement is low, and the 
pressure measurement itself is not painful.  
Patients may be sedated if required (e.g. 
they are nervous) or based on defined
standards. The procedure is performed 
using ultrasound-guidance, and under 
fluoroscopic control with use of ionising 
radiation and ICM.  Radiation exposure is, 
in most cases, very limited and the 
effective dose received by patients (~ 5.4 
mSv) is 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)
Risks relating to HVPG 
measurements will be 
mitigated by placing the 
trial at sites who are 
experienced in / have access 
to a nearby site experienced 
in the procedure.  Such sites 
will be familiar with 
preparing patients before the 
procedure, allaying any 
fears, and the subsequent 
patient monitoring that is 
required.  This might 
include adequate hydration 
to help avoid e.g. contrast-
induced renal injury, and 
educating patients regarding 
symptoms suggestive of 
complications.  Patients will 
be monitored for AEs, and 
those with contraindications 
to the procedure will be 
excluded.  The burden of 
HVPG measurements on the 
patient will also be reduced 
as far as possible in terms of 
the chosen trial design (refer 
to Section 3.2)
Possible complications due to 
gastroscopy include side effects 
from procedural sedation (e.g. 
nausea, vomiting, aspiration 
pneumonia, irregular heartbeat, 
breathing difficulties), bleeding 
(e.g. due to damaged blood 
vessels or ruptured varices) and 
perforation (e.g. to the 
oesophageal lining, stomach or 
duodenum).  After the 
procedure, patients may also 
experience abdominal bloating / 
gas caused by the introduction 
of air into the stomach.  These 
side effects are usually short-
lived  
A gastroscopy will be performed at 
screening where required (refer to Section 
5.2.5.2).  The assessment will allow an 
assessment of the status of the varices.  In 
general, a gastroscopy is a safe procedure 
with both a diagnostic and interventional 
use in liver disease offered to patients with 
relevant symptoms and for variceal 
screening and treatment (R21-0296).  The 
risks of serious complications are small
The procedure will be 
performed by appropriately 
trained professionals, and 
sites will be expected to 
follow local standard 
processes.  Possible risks 
will be mitigated by 
monitoring patients for AEs, 
and patients with 
contraindications to 
gastroscopy will be 
excluded.  Patients who 
develop side effects will be 
managed according to 
standard of care


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Table 1.4.2: 2 contd.     Overview of risks – trial procedures
Possible / known risks of 
clinical relevance
Summary of data, rationale for the risk
Mitigation strategy
Ultrasound waves can heat the 
tissues slightly, and, in some 
cases, can also produce small 
pockets of gas in body fluids or 
tissues (cavitation), the long-
term consequences of which are 
unknown  
Ultrasound imaging (sonography) of the 
liver and spleen will be performed 
primarily to assess the size and depth of 
the spleen,
  Ultrasound will 
any safety issues 
such as ascites.  It is a safe procedure 
routinely carried out in patients with liver 
disease.  There are no absolute 
contraindications to performing an 
abdominal ultrasound  
Ultrasound imaging will be 
performed by appropriately 
trained professionals.  Risks 
will be mitigated by 
monitoring patients for AEs  
Potential risks of blood 
sampling by venepuncture 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
Risks associated with
assignment to the placebo
treatment group
The placebo control group will control for 
observer and patient bias, and will enable 
the evaluation of the absolute effects of BI 
685509.  The current standard of care for 
the trial population depends on the 
presence and size of gastro-oesophageal 
varices and consists of either monitoring 
alone or combination treatment with 
NSBBs or carvedilol and / or endoscopic 
treatments to prevent bleeding.  NSBBs 
and carvedilol are currently the only 
available pharmacological therapy of 
CSPH but not all patients benefit from 
them (refer to Section 1.1.).  The use of a 
placebo-control group over a 24 week 
treatment period is considered acceptable, 
also taking into account the 10- and 20-
year survival after development of varices 
of 42% and 21% respectively for patients 
with compensated cirrhosis (R20-1200)  
This trial will be run on top 
of current standard of care; 
stable doses of NSBBs / 
carvedilol are permitted 
within the trial (refer to 
Sections 3.3.2 and 4.2.2.1), 
and endoscopic variceal 
ligation is also permitted as 
required (refer to Section 
4.2.1).  According to the 
medication assignment 
planned, approximately 
33% of patients (26) will be 
randomised to the placebo 
treatment group


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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, 
3.3.4.1, 5.2.5.3, 5.2.6.1.4, 8.7 and Appendix 10.2
Unintentional 
exposure of an 
embryo or 
foetus to trial 
medication
Based on the findings in 
pre-clinical studies 
conducted to date and in 
accordance with 
international regulatory 
guidelines, the inclusion of 
WOCBP in this trial is 
justified  
To minimise the risk, WOCBP must agree to the 
requirements for pregnancy testing.  Both WOCBP and men 
able to father a child (with a female sexual partner of CBP) 
must also agree to the contraceptive methods described 
(refer to Sections 3.3.2 and 4.2.2.3)  
Patients may 
develop severe 
acute 
respiratory 
syndrome 
coronavirus 2 
(SARS-CoV-2) 
or other severe 
infection
Based on the mode of 
action BI 685509 is not 
expected to have a 
relevant impact on the 
susceptibility to or the 
course of an infection. 
However, the underlying 
disease(s) of the patient 
population in this trial and 
the anticipated age of 
recruited patients does 
increase the risk of 
hospitalisation and 
intensive care in case of a 
SARS-CoV-2 or other 
severe infection 
Patients with an active infection with SARS-CoV-2 will be 
excluded from the trial, and in case of a confirmed severe 
infection, trial treatment will be discontinued immediately 
and appropriate measures for monitoring, treatment and 
quarantine will be implemented.  There are no trial-related 
restrictions regarding COVID-19 vaccination; patients can 
participate in the trial irrespective of their vaccination 
status, and vaccination during the trial is not restricted.  In 
the event of force majeure or other disruptive circumstances 
(e.g. pandemic, war) the investigational plan as per this CTP 
may not be feasible at a site.  With the consent of the 
patient, the Sponsor and Investigator may agree on 
alternative, back-up or rescue methodology which may 
include, but will not be limited to, virtual patient visits and 
assessments, home healthcare nurse visits, and direct-to-
patient shipments of trial medication.  For full details refer 
to Section 6
1.4.3
Discussion
Patients with alcohol-related liver disease (ARLD), cirrhosis, and PH might benefit from the 
combined anti-fibrotic and anti-portal hypertensive effects of sGC activation (refer to Section 
1.1).  Treatment with BI 685509 in patients who already developed cirrhosis will potentially 


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result in the prevention of related complications including decompensation (variceal 
bleeding, ascites and encephalopathy), transplantation, or liver-related death.  The potential 
risks, as described above, will be minimised by close monitoring of patients, by excluding at-
risk patients from the trial, and by involvement of a DMC – refer to Sections 3.2 and 8.7.  
Hepatic injury will also be assessed by an independent AC for safety purposes (refer to 
Sections 3.2, 5.2.5.3 and 8.7).  Hence, overall, in the context of the unmet medical need, the 
anticipated effects of BI 685509 on CSPH in patients with compensated alcohol-related 
cirrhosis, and 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 compare two doses of BI 685509
and 
 BID) with placebo, on top of 
standard of care, in patients with CSPH in compensated alcohol-related cirrhosis.  The 
primary objective is to estimate the mean difference between treatment groups with placebo 
in percentage change in HVPG from baseline measured after 24 weeks.  The primary 
treatment comparison will be made for treated patients with baseline HVPG measurements 
(Full Analysis Set, FAS) as if all patients took randomised treatment for the duration of the 
trial.  Safety and tolerability will also be investigated.
2.1.2
Primary endpoint
The primary endpoint is the percentage change in HVPG from baseline (measured in mmHg) 
after 24 weeks of treatment.
2.1.3
Secondary endpoints
Secondary endpoints include:
percentage change in HVPG from baseline (measured in mmHg) after 8 weeks of 
treatment
response defined as > 10% reduction from baseline HVPG (measured in mmHg) after 8 
weeks of treatment 
response defined as > 10% reduction from baseline HVPG (measured in mmHg) after 24 
weeks of treatment 
occurrence of one or more decompensation events (i.e. ascites, VH, and / or overt HE) 
during the 24 week treatment period
occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on Investigator 
judgement, during the first 8 weeks of the treatment period
occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on Investigator 
judgement, during the 24 week treatment period
occurrence of discontinuation due to hypotension or syncope during the first 8 weeks of 
the treatment period
occurrence of discontinuation due to hypotension or syncope during the 24 week treatment
period


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This multi-national, placebo-controlled, parallel group trial will compare two doses of BI 
685509 
BID and 
 BID) to placebo, on top of standard of care, in patients with 
CSPH in compensated alcohol-related cirrhosis.  Treatment assignment will be randomised 
and double-blind.  
Patients will be enrolled in the trial and screened for eligibility once they have signed the 
informed consent. The screening period consists of up to 3 visits (Visits 1a, b and c) and will
last a maximum of 6 weeks.  Patients will be able to progress from one visit to the next when 
eligibility of the previous visit is confirmed.  Assessments will include a gastroscopy (if 
applicable – refer to Section 5.2.5.2), ultrasound of the liver and spleen
and measurement of HVPG.  Patients who remain eligible and who 
successfully complete this period will proceed to the randomised 24 week double-blind 
treatment period.    
In total, 78 patients will be randomised.  Randomisation to one of three treatment groups (i.e. 
one of the two doses of BI 685509 or placebo) will occur at Visit 2 in a 1:1:1 ratio, and it will 
be stratified by use (or not) of pharmacological treatment of PH (NSBBs / carvedilol).    
Following randomisation patients will begin the intake of trial medication and will enter a 
dose-titration period.  All patients in all treatment groups will start this period on a dose of  
 BID 685509 or matching placebo.  If the dose is toler
one week later (at Visit 3, day 
8), the dose for all treatment groups will be up-titrated to
BID 685509 or matching 
placebo.  For the
BID dose treatment group only, and if the dose is tolerated, a second 
up-titration to
D 685509 or matching placebo will occur after another week (at Visit 
4, day 15).  However, as this is a double-blind trial, patients randomised both to
BID
685509 and to placebo will also have a dose-titration at Visit 4 (day 15).  For these treatment 
groups the dose-titration will be a pseudo-titration (i.e. those randomised to
BID BI 
685509 will remain on that dose, and those randomised to placebo will remain on placebo).  
Following the dose-titration period, and if the dose is tolerated, patients will remain on their 
maximum planned maintenance dose for the remainder of the treatment period until they 
reach the End of Treatment (EoT) visit and 24 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
of the liver and spleen, and the HVPG measurement will be 
repeated during the randomised treatment period (refer to Figure 3.1: 1). 
After approximately 60 randomised patients have completed Visit 7 (week 8 of treatment)
and the HVPG procedure, there will be an interim analysis.  Recruitment will continue whilst 
the analysis takes place.  The results of the interim analysis will establish short-term efficacy 
and allow assessment of an internal development milestone.  For further details regarding the 
interim analysis refer to Section 7.2.8.


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After the 24 week randomised treatment period all patients will enter a 4 week follow-up 
period without trial medication.  The patient’s participation in the trial will be complete when 
they have performed the last planned visit (i.e. End of Study [EoS], 4 weeks after EoT).
Figure 3.1: 1 Trial design schematic 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
A randomised, double-blind, placebo-controlled and parallel group design has been chosen 
for this trial, on top of standard of care.  The parallel group will enable comparison of three 
different treatment groups, and the randomised double-blind design will control for 
assignment bias.  For further details regarding the placebo control group refer to Table 1.4.2: 
2.
      
A treatment duration of 24 weeks has been chosen as this should be sufficient to show 
changes in PH, and hence allow an evaluation of long-term efficacy, and to rule out any 
adaptation to sGC activation on portal pressure.  An interim analysis after 8 weeks of 
treatment has been included to allow an early evaluation of short-term efficacy (for internal 
purposes) and to assess a time-dependency of the treatment.  
The patient population of this trial has been chosen as it represents a sub-set of the intended 
patient population for BI 685509.  ARLD was chosen as the underlying liver disease based on 
favourable results from a trial feasibility assessment.  The use of NSBBs or carvedilol has 
been included as a randomisation stratification factor since the use of these concomitant 
therapies can influence the HVPG lowering effect.  
For details regarding the choice of renal function in the patient population, refer to Section 
1.2.  


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The measurement of HVPG was chosen as both the primary, and a secondary endpoint as it is 
the gold standard to estimate portal venous pressure in patients with cirrhosis, i.e. assessing 
the severity of sinusoidal PH (R20-4090).  It is used as an established surrogate marker for 
improvement and / or worsening of liver fibrosis / function, since a decrease in HVPG 
translates into a clinically meaningful benefit (R20-1204).  The prognostic value of HVPG 
has been underlined by several landmark studies, showing that an HVPG ≥ 10 mmHg (i.e. 
CSPH) is predictive for the formation of varices (R20-4092), while a (pharmacologically-
induced) decrease of HVPG modulates the respective risk of variceal growth and 
decompensation (R20-4093, R20-4091).  Hence, this also explains the choice of the 
secondary endpoint relating to the occurrence of one or more decompensation events (refer to 
Section 2.1.3).  Other secondary endpoints (occurrence of significant hypotension or syncope, 
and occurrence of discontinuation due to hypotension or syncope) were chosen as they are 
relevant based on the mechanism of action of BI 685509. 
Patients will be screened for the trial based on the eligibility critera (refer to Sections 3.3.2 
and 3.3.3).  These include the selection of patients with documented endoscopically proven 
gastro-oesophageal varices, or documented endoscopic-treated oesophageal varices as 
preventative treatment, as varices only occur in patients with CSPH.  At Visit 1c (the final 
visit within the screening period) patients who remain eligible following Visits 1a and 1b will 
undergo their first HVPG measurement.  Those with an HVPG ≥ 10 mmHg (based on a local 
interpretation of the pressure tracing) will remain eligible.  With this approach, the trial is 
designed to enrol patients with CSPH but the burden of the invasive HVPG procedure will be 
reduced and only performed on patients who successfully reach Visit 1c, rather than on all 
screened patients.  
Non-invasive assessments (i.e. ultrasound
of the liver and spleen and 
functional liver testing) have been chosen as part of the screening or baseline / Visit 2 
procedures to further investigate the patients’ status, to establish baseline values for 
comparison on treatment,
 These assessments will be repeated (refer to 
Figure 3.1: 1 and the Flow Chart) to assess a time-dependency of the treatment.
Following randomisation, the trial design includes a dose-titration period.  The mechanism 
related vasodilatation of BI 685509 can lead to orthostatic dysregulation and hypotensive 
episodes (refer to Table 1.4.2: 1).  The orthostatic dysregulation is dose-limiting and clinical 
tolerability is improved if the dose is titrated.  A BID administration also allows the total 
daily exposure of BI 685509 to be further increased while high peak concentrations are 
avoided.  Hence, in this trial, a dose-titration regimen of 
 BID to 
 BID to 
 BID
will be followed.  
Patients selected for this trial have a risk for further progression into decompensation, a 
severe outcome.  A DMC, independent from the Sponsor, will therefore be established to 
review unblinded safety data at intervals to identify any potential risks and / or the need for 
implementation of further safety measures.  The tasks and responsibilities of the DMC 
members will be detailed in the DMC charter (refer to Section 8.7).


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An independent AC will also be established for blinded 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
78 patients with CSPH in compensated alcohol-related cirrhosis will be randomised into the 
trial.  Approximately 70 sites are planned across multiple countries.  It is anticipated that 
around 2 patients will be randomised at each site.  If enrolment is delayed, additional sites 
may be recruited.
Recruitment of patients for this trial will be competitive, i.e. screening will stop at all sites at 
the same time once a sufficient number of patients have been screened to deliver the required 
number of randomised patients.  Investigators will be notified about the completion of 
screening and will not be allowed to screen additional patients thereafter.  Patients already in 
screening at this time will be allowed to continue to randomisation if eligible.
Re-testing during the screening period is allowed once (e.g. if the Investigator believes an 
ineligible laboratory test is the result of an error or extenuating circumstances, the test can be 
repeated once without the patient having to be re-screened).  This excludes the gastroscopy 
and the HVPG measurement.  Re-screening is also allowed once provided the reasons for 
screen failure were reversible and have been resolved, based on Investigator judgement.  A 
patient is considered a “re-screener” if he / she was not eligibile for the trial initially and is 
subsequently re-screened, going through the informed consent process for a second time, 
receiving a new unique patient number and repeating the screening period assessments.  
If, retrospectively, it is found that a patient has been randomised in error (i.e. 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.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with trial medication or 
not.
3.3.1
Main diagnosis for trial entry
The trial will include patients in compensated alcohol-related cirrhosis with endoscopic proof 
of gastro-oesophageal varices, or endoscopic-treated oesophageal varices as preventatitve 
treatment, as a sign of CSPH, together with an HVPG ≥ 10 mmHg.  
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.


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3.3.2
Inclusion criteria
1.
Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
2.
Male or female who is ≥ 18 (or who is of legal age in countries where that is greater than 
18) and ≤ 75 years old at screening (Visit 1a)
3.
Clinical signs of CSPH as described by either one of the points below.  Each trial patient 
must have a gastroscopy during the screening period (Visit 1b) or within 6 months prior 
to screening (Visit 1b).  For further details refer to Section 5.2.5.2

documented endoscopic proof of oesophageal varices and / or gastric varices at 
screening (Visit 1b) or within 6 months prior to screening (Visit 1b)

documented endoscopic-treated oesophageal varices as preventative treatment  
4.
CSPH defined as baseline HVPG ≥ 10 mmHg (measured at Visit 1c), based on a local 
interpretation of the pressure tracing (refer to Section 5.1.1 for further details)
  
5.
Diagnosis of compensated alcohol-related cirrhosis.  Diagnosis must be based on 
histology (historical data is acceptable) or on clinical evidence of cirrhosis (e.g. platelet 
count < 150 x 109/L [150 x 103/µL], nodular liver surface on imaging or splenomegaly)
6.
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)
7.
Willing and able to undergo HVPG measurements per protocol (based on Investigator
judgement)
8.
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
9.
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
10. WOCBP1 must be ready and able to use highly effective methods of birth control per 
ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly from the randomisation visit (Visit 2) until 7 days after the last 
treatment in this trial.  The patient must agree to periodic pregnancy testing during 
participation in the trial. Refer to Section 4.2.2.3 and the patient information for a list of 
contraception methods meeting these criteria
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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11. Men able to father a child and who have a female sexual partner of CBP, must use a 
condom with or without spermicide, or adopt complete sexual abstinence, or be 
vasectomised (with appropriate post-vasectomy documentation of the absence of sperm 
in the ejaculate), from the randomisation visit (Visit 2) until 7 days after the last 
treatment in this trial.  Refer to Section 4.2.2.3 and the patient information for further 
details 
3.3.3
Exclusion criteria
1.
Previous clinically significant decompensation events (e.g. ascites [more than perihepatic 
ascites], VH and / or apparent HE)
2.
History of other forms of chronic liver disease (e.g. non-alcoholic steatohepatitis 
[NASH], Hepatitis B virus [HBV], untreated HCV, autoimmune liver disease, primary 
biliary cholangitis, primary sclerosing cholangitis, Wilson’s disease, haemachromatosis, 
alpha-1 antitrypsin [A1At] deficiency)  
3.
Has received curative anti-viral therapy with direct-acting anti-virals within the last 2 
years for HCV, or, if such treatment was > 2 years ago and there is no sustained 
virological response (SVR) at screening (Visit 1a), or, must take curative anti-viral 
therapy with direct-acting anti-virals throughout the trial (refer to Section 4.2.2.1)
4.
ARLD without adequate treatment (e.g. lifestyle modification) or with ongoing 
pathological drinking behaviour (misuse / abuse based on Investigator judgement)
5.
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
6.
SBP < 100 mmHg and DBP < 70 mmHg at screening (Visit 1a) 
7.
Model of End-stage Liver Disease (MELD) score of > 15 at screening (Visit 1a), 
calculated by the central laboratory
8.
Hepatic impairment defined as a Child-Turcotte-Pugh score ≥ B8 at screening (Visit 1a), 
calculated by the site, using central laboratory results (refer to Appendix 10.3)  
9.
ALT or AST > 5 times upper limit of normal (ULN) at screening (Visit 1a), measured by 
the central laboratory
10. eGFR (CKD-EPI formula) < 20 mL/min/1.73 m2 at screening (Visit 1a), measured by the 
central laboratory
11. Alpha-fetoprotein > 50 ng/mL (> 50 µg/L) at screening (Visit 1a), measured by the 
central laboratory


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12. An active infection with SARS-CoV-2 (or who is known to have a positive test from 
screening [Visit 1a] until randomisation [Visit 2])
13. Prior orthotopic liver transplantation
14. Prior or planned TIPS or other porto-systemic bypass procedure
15. Known portal vein thrombosis
16. History of clinically relevant orthostatic hypotension, fainting spells or blackouts due to 
hypotension or of unknown origin (based on Investigator judgement)
17. 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
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 at screening (Visit 1a) or planned initiation of such therapies during 
the trial (refer to Section 4.2.2.1)
19. Major surgery (based on Investigator judgement) performed within 3 months prior to 
randomisation (Visit 2) or planned during the trial, e.g. hip replacement
20. Contraindication to any of the trial assessments (e.g. poor patient co-operation for 
gastroscopy,
  
21. 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
22. Any other medical condition2 that, based on Investigator judgement, poses a safety risk 
for the patient or may interfere with the objectives of the trial
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  
2Examples of medical conditions may include, but are not limited to: symptomatic heart failure (New York Heart 
Association [NYHA] III/IV), known history of tachycardia, clinically relevant arrhythmias, coronary heart disease not 
compensated by medical treatment (existing unstable angina pectoris)


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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 whilst in the trial
3.3.4
Discontinuation of patients from trial medication or assessments
Patients may discontinue trial medication after randomisation, or withdraw consent to trial 
participation as a whole (“withdrawal of consent”) with very different implications; refer to
Sections 3.3.4.1 and 3.3.4.2 below.  Every effort should be made to keep the patients in the 
trial, if possible on trial medication.  Measures to control the withdrawal rate include careful 
patient selection, appropriate explanation of the trial requirements and procedures prior to 
trial enrolment, as well as the explanation of the consequences of withdrawal.
The decision to discontinue trial medication after randomisation, or withdraw consent to trial
participation, and the reason (if available) must be documented in the patient files and 
electronic CRF (eCRF). If applicable, consider the requirements for Adverse event collection 
reporting (refer to Section 5.2.6.2).
Patients who discontinue following randomisation will not be replaced and may not be re-
enrolled later.  However, the Sponsor may decide to randomise more patients than originally 
planned, to account for a reduced sample size, if patients terminate early due to e.g. trial 
disruption (such as measures to control a global pandemic).
3.3.4.1
Discontinuation of trial medication
An individual patient will discontinue trial medication if:

the patient wants to. The patient will be asked to explain the reasons but has the right to 
refuse to answer

the patient has repeatedly shown to be non-compliant with important trial procedures and, 
in the opinion of both the Investigator and Sponsor representative, the safety of the 
patient cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future 

the patient needs to take concomitant therapy that interferes with the safety / efficacy of 
the trial medication (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.  Similarly, if a patient needs to modify 
a dose, where only a stable dose is permitted (e.g. NSBBs / carvedilol, statins), this also 
will not automatically require discontinuation. In both cases the Sponsor should be 
consulted

the patient experiences a severe infection, e.g. with SARS-CoV-2, as determined by the 
Investigator 

the patient meets the criteria for hepatic injury (refer to Section 5.2.6.1.4 and Appendix 
10.2)


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
the patient has an acute liver decompensation event such as VH, new-onset of ascites, 
new-onset of overt encephalopathy, or other new-onset decompensation event based on
Investigator judgement

patients with worsening of their liver function (e.g. from Child-Turcotte-Pugh A to Child-
Turcotte-Pugh B with clinical evidence of deteriorating liver function in the opinion of 
the Investigator).  Refer to Child-Turcotte-Pugh classification method in Appendix 10.3

patients with a QT or QTcF interval > 500 ms, or an increase of QT or QTcF of > 60 ms 
from the value at Visit 2 / randomisation (baseline). Such cases must be reported as AEs

the patient can no longer receive trial medication for other medical reasons such as
surgery, AEs, other diseases the patient is unblinded by the Investigator (refer to Section 
4.1.5.2)

the patient has not successfully completed the dose titration period (i.e. Visit 4), but has 
persistent AEs or severe effects requiring down-titration of the trial medication (refer to 
Section 4.1.4.1)

a female patient becomes pregnant. The patient will be followed up until birth or 
otherwise termination of the pregnancy. The data of the patient will be collected and 
reported in the Clinical Trial Report (CTR) until last patient last visit and any events
thereafter will be reported in the BI Pharmacovigilance (PV) database (refer to Section 
5.2.6.2.3)
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 trial medication after successful completion of the dose titration 
period at Visit 4 (e.g. persistent AEs despite two down-titrations, or severe effects at any 
dose), permanent treatment discontinuation should also be considered, based on Investigator 
judgement (refer to Section 4.1.4.1).  
In addition to these criteria, the Investigator may discontinue patients at any time based on 
clinical judgement.
If a patient permanently discontinues 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 4 weeks after the ED visit.  Refer to Sections 6.2.2.1 and 
6.2.3 for further details, including guidance with respect to trial assessments that should be 
included as part of an ED visit.
In case of a temporary discontinuation, trial medication 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, BI will review the benefit-risk-
assessment and, if needed, pause or discontinue the trial medication for all patients or take 
any other appropriate action to guarantee the safety of the trial patients.


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3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the Investigator should be involved in the discussion 
with the patient and explain the difference between trial medication discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial medication discontinuation (refer to Section 3.3.4.1 above).  If a patient 
withdraws consent for further trial participation, no further data will be collected from the 
respective patient.
3.3.4.3
Discontinuation of the trial by the Sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment (e.g. following a recommendation by the DMC).  For further details refer to 
Section 3.3.4.1
3. Deviations from GCP, the CTP, or the contract impairing the appropriate conduct of the 
trial.
Further treatment and follow up of patients affected will occur as described in Sections
3.3.4.1, 6.2.2.1 and 6.2.3.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational medicinal products in the trial are BI 685509 and placebo to match BI 
685509.  BI will supply all products.  
4.1.1
Identity of the investigational medicinal products
The characteristics of the investigational medicinal products are described in Tables 4.1.1: 1
to 4.1.1: 6 below.
Table 4.1.1: 1
BI 685509
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Posology:
BID
Method and route of administration:
Oral
Table 4.1.1: 2
BI 685509
 
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Posology:
BID
Method and route of administration:
Oral
Table 4.1.1: 3
BI 685509
 
Substance:
BI 685509
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Posology:
BID
Method and route of administration: Oral


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Table 4.1.1: 4
Placebo to match BI 685509
Substance:
Placebo to match BI 685509 
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
BID
Method and route of administration:
Oral
Table 4.1.1: 5
Placebo to match BI 685509
Substance:
Placebo to match BI 685509 
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
BID
Method and route of administration: Oral
Table 4.1.1: 6
Placebo to match BI 685509
Substance:
Placebo to match BI 685509 
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable
Posology:
BID
Method and route of administration: Oral
4.1.2
Selection of doses in the trial and dose modifications
BI 685509 has been tested in a single rising dose trial, a food effect and DDI trial and two 
MRD trials in male healthy volunteers.  Single doses ranged from 
 to 
 and 
multiple doses up to 
 daily were tested.  Overall, BI 685509 was well tolerated except 
for dose-limiting orthostatic dysregulation.  Up-titration and 3 times daily dosing markedly 
improved the cardiovascular tolerability (refer to the IB [c02778238]).  
One multiple oral rising dose trial in patients with DN has also been completed.  Multiple 
oral doses up to 
 TID were found to be safe and well tolerated.  The highest total daily 
dose of 
was achieved following up-titration in 2 steps over 14 days. 
A human dose of 
 BID is predicted to achieve relevant exposure in patients with 
hepatic impairment (c02778238, n00261471-01).  As 
is the maximum tolerated single 


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dose, only 2 doses 
 BID and 
BID) will be evaluated in this trial, as measurable 
differences are not expected between a very low dose and placebo. These doses have been 
selected based on safety and preliminary PK results from the ongoing Phase I MRD hepatic 
impairment trial (1366-0020).
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised
in a blinded fashion to treatment groups according to a randomisation plan in a 1:1:1 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 patient number (which is generated via the IRT system when a new patient 
is registered [screened] in the system).
The Investigator (and relevant designated site personnel) will be provided with instructions to 
access the IRT system. 
4.1.4
Drug assignment and administration of doses for each patient
Trial medication will be dispensed at the investigational sites in accordance with the Flow 
Chart.  At dispensing visits patients will be given the appropriate number of medication kits
(range 1-4) depending on the interval between the visits (for further kit details refer to 
Section 4.1.6).  The last dose of trial medication will be administered in the evening of the 
day before the EoT visit.  
All patients, 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 patients will either be up-titrated or pseudo 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.  Pseudo up-titration will be used at a visit instead of a true up-
titration when the maximum planned maintenance dose for a treatment group has been 
reached; in this way the blind across treatment groups will be maintained (refer to Table 
4.1.4: 1).  Patients will be informed about the dose titration period and will be made aware 
that up-titration or pseudo-titration is being used.  If a patient does not tolerate an up-titration, 
e.g. due to orthostatic dysregulation, the rules in Section 4.1.4.1 must be followed.  From 
Visit 4 onwards, patients will continue to receive the maximum planned maintenance dose for 
the treatment group they are assigned to (unless a down-titration is required), until reaching 
the EoT visit 24 weeks after starting the trial medication.
If a patient has an AE that, based on Investigator judgement, may be related to trial 
medication, the trial medication can either be:

interrupted (i.e. the trial medication is stopped, and subsequently re-started by following 
the up-titration approach described above)


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OR

the dose can be reduced (down-titrated) if the patient 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 and provision of replacement 
kits, will be managed through the IRT system.  Down-titrations must not be performed by 
instructing the patient to take less than the two daily doses (refer to Section 4.1.4.1).  
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) 
2 tablets per dose
4 tablets per day
 BI 685509 
AND
 BI 685509 
matching placebo
 BI 685509 
matching placebo
AND
BI 685509 
 BI 685509 
AND
 BI 685509 
matching placebo
Up-titration
Pseudo up-titration
Treatment group 2
(BI 685509 
BID)
2 tab
er dose
4 tablets per day
BI 685509 
AND
BI 685509 
matching placebo
 BI 685509 
matching placebo
AND
BI 685509 
 BI 685509
matching placebo 
AND
BI 685509
Up-titration
Up-titration
Treatment group 3
(Placebo to BI 685509)
2 tablets per dose
4 tablets per day
 BI 685509 
matching placebo
AND
 BI 685509 
matching placebo
BI 685509 
matching placebo
AND
BI 685509 
matching placebo
 BI 685509
matching placebo
AND
BI 685509 
matching placebo
Pseudo up-titration
Pseudo up-titration
From the start of the randomised treatment period (i.e. from Visit 2), and until reaching the 
EoT visit 24 weeks later, patients will be instructed to take the trial medication orally twice a
day (BID).  Each dose will consist of two film-coated tablets, hence 4 tablets will be taken 
per day.  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.  Doses of the trial medication 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.


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On the morning of a visit, the trial medication will be administered as part of the visit.  
Therefore, on these days, patients should be instructed not to take their morning dose in 
advance of the visits.  
Patients who fail to follow these instructions should have the visit re-scheduled as soon as 
possible, ideally on the following day (refer to Section 6.1).  On days with no scheduled visit 
the patient will self-administer their medication at home.  Patients should be instructed to 
bring all unused trial medication and empty wallets / packaging with them when they return 
for clinic visits to the investigational site.
In case of a temporary interruption to treatment, refer to Sections 3.3.4.1, 4.1.4.1 and 4.1.4.2.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war; refer to 
Section 6) physical patient visits to sites may not be feasible or may need to be restricted to 
ensure patient safety.  Based on a thorough assessment of the benefits and risks, the 
Investigator may still decide to continue trial medication, and, if acceptable according to local 
law and regulations, trial medication may be shipped from the site to the patient’s home.
4.1.4.1
Rules for down-titration in case of intolerance to trial medication
If a patient has an AE that, based on Investigator judgement, may be related to trial 
medication, the down-titration rules below must be followed.  These rules apply if the patient 
has successfully completed the dose titration period (i.e. Visit 4) and is either still taking their 
assigned dose of trial medication, or if they have missed ≤3 consecutive doses3. If the patient 
has not successfully completed the dose titration period (i.e. Visit 4), down-titration is not
permitted; in case of persistent AEs or severe effects, the patient must permanently 
discontinue treatment (refer to Section 3.3.4.1).    
if the patient is currently receiving either
BID BI 685509 or 
BID 685509 (or 
corresponding matching placebo) the dose will be down-titrated one level i.e.
o
 BID BI 685509 / matching placebo down-titrates to 
 BID BI 685509 / 
matching placebo
o
BID BI 685509 / matching placebo down-titrates to 
 BID BI 685509 / 
matching placebo
Once down-titration has taken place, no further up-titration will be permitted.  
3One dose refers to an individual time point e.g. morning dose or evening dose.


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If a patient continues to have an AE, or a new AE develops, that based on Investigator 
judgement, may be related to trial medication, a second down-titration will be permitted.  
Depending on the randomisation assignment, this may be a pseudo down-titration i.e.:

if the patient is currently receiving 
 BID BI 685509 or matching placebo the dose 
will be down-titrated to 
BID BI 685509 matching placebo (a patient previously 
down-titrated to 
 BID BI 685509 matching placebo will be pseudo down-titrated)

if the patient is currently receiving
BID BI 685509 or matching placebo the dose 
will be down-titrated to 
BID BI 685509 / matching placebo  
Down-titration must not be performed by taking less than the two daily doses or by splitting 
tablets so that a whole tablet is not taken.  Down-titration will be managed through the IRT 
system (refer to Section 4.1.4).   After the successful completion of the dose titration period 
(i.e. Visit 4), in case of persistent AEs despite down-titration, or severe effects at any dose, 
permanent treatment discontinuation should be considered (refer to Section 3.3.4.1).  Patients 
who are down-titrated will need to return to the investigational site to receive their continuing 
supply of trial medication, either at the next scheduled visit or via an unscheduled visit.
4.1.4.2
Rules for re-starting up-titration in case of interruption of trial medication
An interruption of trial medication may have an influence on the tolerability.  Hence, if a 
patient has missed ˃ 3 consecutive doses4 of trial medication for any reason (e.g. due to an 
AE, or for compliance reasons), the rules below will apply for the safety of the patient.  If ≤3
consecutive doses of trial medication have been missed and there is no related AE, then the 
next dose of trial medication should be taken as scheduled.
after an interruption of trial medication of ˃ 3 consecutive doses, the patient should re-start 
the dose titration period at 
 BID BI 685509 / matching placebo independent of the 
dose the patient was receiving previously
before any further up-titration occurs the patient must have taken the preceding dose for at 
least 7 consecutive days.  This applies throughout the treatment period
o this may mean that a patient due to be up-titrated at Visit 3 or 4 (as per Table 4.1.4: 1) 
is held at their current dose until their next scheduled visit.  They could also be up-
titrated at an unscheduled visit once this requirement is met
if interruption occurs after Visit 4, subsequent up-titration will be allowed either at a 
scheduled visit or at an unscheduled visit
Patients with an interruption of trial medication will need to return to the investigational site
to receive their continuing supply of trial medication, either at the next scheduled visit or via 
an unscheduled visit.
4One 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
Patients, Investigators, central reviewers, and everyone involved in trial conduct or analysis
or with any other interest in this double-blind trial (except as noted below) will remain 
blinded with regard to the randomised treatment assignment until the database is declared 
ready for analysis according to the Sponsor’s SOPs. Further details regarding the time point 
of unblinding the database for analysis will be documented in the TSAP.  One interim 
analysis will also be performed.  For details (e.g. timing, access to unblinded data, and how 
results will be controlled) refer to Section 7.2.8.
The access to the randomisation code will be kept restricted until its release for analysis.
A DMC, independent from the Sponsor, will perform an unblinded safety evaluation at 
intervals specified in the DMC charter in order to ensure that patients 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
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 patient is unblinded by the Investigator, the patient has 
to be discontinued from the trial (refer to Section 3.3.4.1).


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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 patients during trial conduct. The access to the 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 BI or a designated Clinical 
Research Organisation (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice. Re-supply to the sites will be managed via an 
IRT system, which will also monitor expiry dates of supplies available at the sites.
In this trial, each medication kit will contain one wallet and each wallet will hold 40 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)


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Trial medication is not allowed to be used outside the context of this CTP. It must not be 
forwarded to other Investigators or clinics. Patients should be instructed to return unused 
trial medication.
The Investigator or designee must maintain records of the medication’s delivery to the trial
site, the inventory at the site, the use by each patient, and the return to the Sponsor or
warehouse / drug distribution centre or alternative disposal of unused medication. If 
applicable, the Sponsor or warehouse / drug distribution centre will maintain records of the 
disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the trial medication and trial patients. The 
Investigator or designee will maintain records that document adequately that the patients 
were provided the doses specified by the CTP and reconcile all trial medication received from 
the Sponsor. At the time of return to the Sponsor and / or appointed CRO, the Investigator or 
designee must verify that all unused or partially used trial medication has been returned by 
the clinical trial patient and that no remaining supplies are in the Investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (refer to Section 3.3) 
are permissible throughout the duration of the trial. Refer to Section 4.2.2.1 for restrictions 
with respect to statins and NSBBs / carvedilol.  All concomitant therapy should be carefully 
evaluated by the Investigator and the Sponsor should be contacted when there are questions.
In case of AEs in need of treatment, any concomitant therapy, based on Investigator’s
judgement, will be permitted. Diagnostics and treatment should be initiated according to 
local standard of care.
All concomitant therapies will be recorded on the appropriate pages of the eCRF.
There are no trial-related restrictions regarding COVID-19 vaccination; patients can 
participate in the trial irrespective of their vaccination status, and vaccination during the trial 
is also not restricted.
Endoscopic variceal ligation (performed according to local guidelines) is permitted during the 
trial as required. The procedure should be recorded on the appropriate page of the eCRF.


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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).  These restrictions apply from within 5 half-lives prior to 
randomisation (Visit 2), until the EoS visit.  
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)  
clinically relevant concomitant therapies known to inhibit or induce UGT enzymes
clinically relevant OATP1B1/3 inhibitors 
A list to support the identification of the above-mentioned concomitant therapies will be 
provided in the ISF.  The list will not claim completeness.  
In addition, intake of concomitant therapies with a known risk of Torsade de Pointes must not 
be co-administered with BI 685509 (also refer to Table 1.4.2: 1).  These restrictions apply 
from screening (Visit 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.
Furthermore, patients 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 patients 
who are receiving NSBBs / carvedilol, must be on a stable dose for at least 1 month prior to 
screening (Visit 1b), with no planned dose change throughout the trial (refer to Section 3.3.2).  
In addition, these concomitant therapies should not be initiated during the trial as they will 
interfere with the efficacy of the trial medication (refer to Section 3.3.4.1).  
Within the last 2 years, and throughout the entire trial (from screening [Visit 1a] to the EoS 
visit), treatment of HCV with curative anti-viral therapy with direct-acting anti-virals is also 
prohibited, since anti-viral therapy may contribute to reduced portal pressure (refer to Section 
3.3.3).
4.2.2.1.1
Close monitoring for AEs based on concomitant therapy
If a patient is taking concomitant therapy that is metabolised by CYP3A4 and / or CYP2C8, 
which has a narrow therapeutic index and / or is a sensitive substrate, close monitoring for 
AEs is recommended in this trial (also refer to Table 1.4.2: 1).  A list to support the 


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identification of the above-mentioned concomitant therapies will also be provided in the ISF.  
The list will not claim completeness.  
4.2.2.2
Restrictions on diet and lifestyle
Drastic changes of diet and lifestyle in the course of the trial should be avoided. This 
includes unusual and strenuous exercise for the patient (e.g. taking up exercises that put 
pressure on the abdomen, such as weightlifting).
Alcohol consumption must be avoided throughout the trial; excessive alcohol consumption 
could lead to hypotension when taken concomitantly with BI 685509.  During the treatment 
period, patients 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 patient may eat as 
normal.    
4.2.2.3
Contraception requirements
WOCBP (for the definition refer to Section 3.3.2) must be ready and able to use a highly 
effective method of birth control from the randomisation visit (Visit 2) until 7 days after the 
last trial medication intake, if their partner is a male able to father a child.  No contraceptive 
is required for the partner of the WOCBP.
Highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of 
less than 1% per year when used consistently and correctly include (if local regulations 
permit):
combined (oestrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal)
progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)
intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
bilateral tubal occlusion
A male patient must use a condom with or without spermicide until at least 7 days after last 
trial medication intake if their sexual partner is a WOCBP, or, be vasectomised with 
documented absence of sperm in the ejaculate.  No contraceptive is required for the male 
patient’s partner.
Alternatively WOCBP and male patients able to father a child must abstain from male-female 
sex. This is defined as being in line with the preferred and usual lifestyle of the patient.  
Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods; 
declaration of abstinence for the duration of exposure to trial medication; and withdrawal are 
not acceptable.


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4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the Sponsor or delegate.
Treatment 
compliance (%) =
Number of tablets actually taken
x 100
Number of tablets which should have been taken as 
directed by the Investigator
If the number of doses taken is not between 80-120%, site staff will explain to the patient the 
importance of treatment compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Hepatic venous pressure gradient
HVPG measurement will be performed at the time points specified in the Flow Chart.  Sites 
must have access to the necessary infrastructure and equipment to measure HVPG (e.g. a 
hepatic haemodynamic laboratory at their site, or at a nearby institution).  Site staff 
performing the procedure must have sufficient expertise (e.g. performing in the region of 25 
or more HVPG measurements per year) with interventional skills and expertise in the reading 
of pressure tracings, since a local interpretation of the tracing from Visit 1c will be required 
for eligibility purposes (refer to Section 3.3.2).  
The HVPG procedure within the trial will be conducted in a standardised fashion at all sites
(for details refer to the HVPG manual in the ISF); training will be provided.  Each trial site 
will be asked to provide acceptable sample HVPG tracing(s) prior to commencing patient 
recruitment.  Measurements of wedged hepatic venous pressure (WHVP) and free hepatic 
venous pressure (FHVP) will be performed in triplicate; tracings will be provided to an 
external Supplier and read centrally by independent expert(s) in PH; the central read will
include a subjective assessment of the overall trace quality as well as a read of the relevant 
pressures.  The independent expert(s) will be blinded to the timepoint that the trace relates to.  
The central read will include the traces from Visit 1c that have also been interpreted locally.  
The results of the central read will be transferred to the Sponsor and will be considered the 
official evaluation of the trial.  In case of discrepancies between a local interpretation and the 
central evaluation (e.g. of the Visit 1c tracing), the central evaluation will remain valid.  
HVPG measurements should be performed using the same hepatic vein, prior to intake of the 
trial medication, after an overnight fast, and ideally in the morning.  If it is not possible to 
perform the measurement at Visit 1c in the morning an alternative time of day can be chosen; 
in this case, a fast of at least four hours is required. All subsequent HVPG measurements 
must then be performed at approximately the same time of day as the Visit 1c measurement 
for a single patient. 
If Visit 1b and 1c are performed on the same day, the HVPG measurement must be 
performed after the gastroscopy (i.e. only once it is confirmed that the patient remains 
eligibile for the trial).  During the treatment period, following randomisation, 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).  If an alternative time of day (i.e. not in the morning, 
see above) has been chosen for treatment period HVPGs, 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):


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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 
transducer, continuous pressure recordings are obtained with triplicate recordings of the 
WHVP and FHVP. The difference between FHVP and WHVP is referred to as HVPG, with 
values ≥10 mmHg indicating CSPH. Before removing the catheter, pressure readings 
obtained in the IVC at the same level, as well as the right atrial pressure, are recorded.


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


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


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


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Category
Test name 
Short Name
(BI Laboratory Test Code, LBSPID)
MCV
MCV
MCH
MCH
MCHC
MCHC
RBC count / erythrocytes
RBC
RBC distribution width (RDW)
RDW
WBC count / leukocytes
WBC
Platelet count / thrombocytes
PLTCT
Reticulocytes
RETABS
Automatic WBC differential 
(absolute)
Neutrophils
SEGABS
Eosinophils
EOSABS
Basophils
BASABS
Monocytes 
MONABS
Lymphocytes  
LYMABS
Coagulation
aPTT
APTTS
PT
PRTSEC
INR
INR
Fibrinogen
FIBR
Clinical chemistry
ALT
SGPT
Alpha fetoprotein1
AFP
Albumin
ALB
Alkaline phosphatase
ALKP
AST
SGOT
Bilirubin (total)
TBILI
Bilirubin (direct)
BILID
Bilirubin (indirect)
BILII
hs-CRP
CRPHS
Creatinine, serum
CRE
CK
CK
CK-MB2
CKMBABS
eGFR
GFRE
ɣ-GT
GGT
Glucose
GLUB
LDH
LDH
Lipase
LIPASE
Phosphatidylethanol (PEth)3
PETH
Protein (total)
TPRO
Troponin I2
TPONI
Urea (BUN)
UREA
Uric acid
URIC
Electrolytes
Bicarbonate
BICARB
Calcium
CA
Chloride
CL
Magnesium
MG
Phosphate
P
Potassium
K
Sodium
NA
Table 5.2.3: 1 contd. Safety laboratory tests


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Category
Test name 
Short Name
(BI Laboratory Test Code, LBSPID)
Lipids4
HDL
HDL
LDL
LDL
Cholesterol (total)
CHOL
Triglycerides
TRIGL
Hormones
Aldosterone5
ALDOSI
Renin, plasma5
PRCSP
TSH6
TSH
Free T37
FT3
Free T47
FT4V
Pregnancy test (serum)
Human Chorionic Gonadotropin8
HCG
Pregnancy test (urine)
Human Chorionic Gonadotropin9
Not Applicable
Infections screening6
HCV antibody (qualitative)
HCAB
HCV RNA PCR10
HCVRNA
HBV surface antigen (qualitative)
HBSAG
HBV core antibody (qualitative)
HBCAB
HBV – DNA11
HBVDNAV
Urine chemistry
Urine albumin
UALBUM
Urinalysis (semi-
quantitative)
Urine nitrite
UNIT
Urine protein
UPROZ
Urine glucose
UGLU
Urine ketone
UKET
Urobilinogen
UROBZ
Urine bilirubin
UBILI
Urine blood
UHGB
Urine leukocyte esterase
ULEUKES
Urine pH
UPH
1
Only performed at screening (Visit 1a) and EoT / ED
2
If initial CK is elevated, re-test CK with CK-MB and troponin I
3
Not performed at screening (Visit 1a).  PEth, an alcohol-specific biomarker, will be measured during the treatment 
period for data analysis purposes   
4
Not performed at screening (Visit 1a)
5
Not performed at screening (Visit 1a) or Visits 9, 10 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
6
Only performed at screening (Visit 1a)
7
Reflex in case of abnormal TSH
8
WOCBP only; only at Visit 1a, and as a reflex if urine testing is positive
9
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).  Pregnancy 
testing at dosing visits should be completed prior to administration of the trial medication
10 Reflex in case of positive HCV antibody and / or HCV infection that has been treated in the past.  Per central laboratory 
assay, if HCV RNA is < 15 IU / ml at screening (Visit 1a), eligibility criteria are met
11 Reflex in case of positive HBV core antibody and negative HBV surface antigen.  Per central laboratory assay, if HBV 
DNA is < 20 IU / ml at screening (Visit 1a), eligibility criteria are met


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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 after the measurement of vital signs, prior to blood sampling and intake 
of trial medication (at visits where only a single ECG is required), and recorded after the 
patient has rested for at least 5 minutes in a supine position.  
During the dose-titration period (i.e. when up-titration is occurring) and at the subsequent 
visit, 12-lead ECGs will also be performed approximately 1 hour and 2 hours after intake of 
trial medication. 
ECGs must be administered by a qualified physician, nurse or technologist. The Investigator 
or delegate will evaluate whether the ECG is normal or abnormal and assess clinical 
relevance. An ECG may be repeated for quality reasons and the repeated recording used for 
analysis.  If necessary, additional ECGs may be recorded for safety reasons.  
Dated and signed print-outs of the ECG, with findings, should be documented in patient’s 
medical record. Clinically relevant abnormal findings will be reported either as a baseline 
condition (if identified at the screening visit [Visit 1a]) or otherwise as AEs and will be 
followed up and / or treated as medically appropriate.  ECG abnormalities will be carefully 
assessed by the Investigator or delegate, and if trial discontinuation criteria are met (refer to 
Section 3.3.4.1), the patient will be discontinued from the trial.  
Copies of ECGs will be sent to a central ECG Supplier for storage purposes.  This will enable
a subsequent centralised and independent re-evaluation if necessary.    


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5.2.5
Other safety parameters
5.2.5.1
Ultrasound (liver and spleen)
Ultrasound imaging of the liver and spleen will be performed after an overnight fast, using 
local site equipment, and at the time points specified in the Flow Chart.  
At screening the ultrasound can be performed at either Visit 1b or 1c.  During the treatment 
period, following randomisation, ultrasound assessments should be performed on the day of 
the scheduled visit, or within seven days (if this latter approach is taken, the assessment must 
still be performed after an overnight fast).  In the event of early discontinuation from the trial, 
refer to Section 6.2.2.1 for guidance regarding testing at the ED visit.
Ultrasound is used as a safety measure to assess the condition of the liver and spleen, organ 
size and the presence of ascites (refer to Table 1.4.2: 2).  The skin-to-liver capsule distance 
(i.e. the subcutaneous thickness), portal vein diameter, the skin-to-spleen capsule distance, 
and spleen height, length and width will also be measured, 
 
Sites will be expected to follow local standard processes prior to and during the procedure.  
5.2.5.2
Gastroscopy
A gastroscopy (i.e an upper gastrointestinal endoscopy) will be performed at the time point 
specified in the Flow Chart, and after an overnight fast.  Details such as the location and size / 
appearance of varices, the presence / absence of portal hypertensive gastropathy, and the 
presence / absence of other conditions (e.g. gastritis, duodenitis, ulcers etc.) will be collected
in the eCRF.  
The gastroscopy can be skipped if the condition below is met.  In all other cases, a 
gastroscopy is required at Visit 1b, and documentary evidence must be available (e.g. source 
data) following the procedure to confirm the presence of oesophageal / gastric varices.
(i)
a patient has had this procedure in the previous 6 months to Visit 1b (and there is 
documentary evidence [e.g. source data such as a referral letter etc.] available to confirm 
the presence of oesophageal / gastric varices)
If Visit 1b and 1c are performed on the same day, the gastroscopy must be performed before
the HVPG measurement.  
Sites will be expected to follow local standard processes when considering the suitability of a 
patient for the procedure, and whilst conducting the procedure (e.g. use of concomitant 
therapy and intake of water beforehand, use of procedural sedation etc.).  


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5.2.5.3
Hepatic injury adjudication
An independent AC will be used to adjudicate certain hepatic events for severity and causal 
relationship with the trial medication.  For further details refer to Section 8.7.  
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the eCRF and BI SAE form (if 
applicable):
worsening of the underlying disease or of other pre-existing conditions changes in vital 
signs, ECG, physical examination and laboratory test results, if they are judged clinically 
relevant by the Investigator
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A SAE is defined as any AE, which fulfils at least one of the following criteria:
results in death
is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe
requires inpatient hospitalisation or prolongation of existing hospitalisation
results in persistent or significant disability or incapacity
is a congenital anomaly / birth defect
is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse 


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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
Adverse events considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI 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 trial medication and must be reported 
as described in Section 5.2.6.2, sub-sections “AE collection” and “AE reporting to the 
Sponsor and timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the Sponsor’s PV
Department within the same timeframe that applies to SAEs; refer to Section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury 
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).


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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 a reasonable possibility of a causal relationship 
could be:
the event is consistent with the known pharmacology of the trial medication
the event is known to be caused by or attributed to the trial medication class
a plausible time to onset of the event relative to the time of trial medication exposure
evidence that the event is reproducible when the trial medication is re-introduced
no medically sound alternative aetiologies that could explain the event (e.g. pre-existing or 
concomitant diseases, or co-medications)
the event is typically drug-related and infrequent in the general population not exposed to 
drugs (e.g. Stevens-Johnson syndrome)
an indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
no plausible time to onset of the event relative to the time of trial medication 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 
medication concerned)
continuation of the event despite the withdrawal of the trial medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).  Of note, 
this criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger
there is an alternative explanation, e.g. situations where other drugs or underlying diseases 
appear to provide a more likely explanation for the observed event than the trial 
medication concerned
disappearance of the event even though the trial medication treatment continues or 
remains unchanged
5.2.6.2
Adverse event collection reporting
5.2.6.2.1
Adverse event collection
The Investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
Investigator:


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from signing the informed consent onwards until the individual patient’s end of trial (= the 
EoS visit): all AEs (serious and non-serious) and all AESIs
after the individual patient’s end of trial: the Investigator does not need to actively monitor 
the patient for new AEs but should only report any occurrence of cancer and trial 
medication related SAEs and trial medication related AESIs of which the Investigator may 
become aware of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (refer to Section 5.2.6.2.2), but not on the eCRF
5.2.6.2.2
Adverse event reporting to the Sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form 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. In specific 
occasions, the Investigator could inform the Sponsor upfront via telephone. This does not 
replace the requirement to complete the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for the initial 
information.  All (s)AEs, including those persisting after an individual patient’s end of trial
must be followed up until they have resolved, have been assessed as “chronic” or “stable”, or 
no further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in 
the clinical trial and has taken trial medication, the Investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form for Clinical Studies to the Sponsor’s unique entry 
point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the 
trial specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).  The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and / or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE 
form is to be completed. If there is an SAE and / or AESI associated with the pregnancy an 
SAE form must be completed in addition.


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


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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 
investigational plan as per this CTP may not be feasible at a site. With the consent of the 
patient, the Sponsor and Investigator may agree on alternative, back-up or rescue 
methodology which may include, but will not be limited to, virtual patient visits and 
assessments, home healthcare nurse visits, and direct-to-patient shipments of trial medication. 
Such alternative measures will be mentioned in the patient information, as appropriate. The 
implementation of these measures will depend on patient’s consent, operational feasibility, 
local law and regulations.  If alternative methodology is implemented, the deviations from the 
original plan will be precisely documented.
6.1
VISIT SCHEDULE
All visits should be scheduled according to the Flow Chart. Each visit date (with its’
permitted time window) should be calculated in relation to the day of randomisation (i.e. Day 
1). During the dose titration period of the trial (i.e. from Visit 2 [randomisation] to Visit 4), 
scheduled trial visits must be at least 7 days apart, since a patient must have taken the 
preceding dose 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 following treatment
interruption). 
All visits will take place at the investigational site, and ideally they should be performed in 
the morning.  In the randomised treatment period, on the morning of a visit, the trial 
medication will be administered as part of the visit.  Therefore, on these days, patients should 
be instructed not to take their morning dose in advance of their clinic visit (refer to Section 
4.1.4). 
status of a patient should be in accordance with the Flow Chart and will be recorded in the 
eCRF.  Patients who fail to follow the afore-mentioned instructions should have the visit re-
scheduled as soon as possible, ideally on the following day.  
In the event of force majeure or other disrupting circumstances (refer to Section 6), physical 
patient visits to the sites may not be feasible or may need to be restricted to ensure patient 
safety.  Based on a thorough assessment of the benefits and risks, the following visits may be 
performed at the patient’s home, remotely (by phone) or as a combination of home and 
remote visits:
Visit 6
Visit 9


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Visit 10
When scheduling such visits every effort should be made to ensure a continuous supply of 
trial medication for the patient, whilst also taking into account that the next kit(s) of trial 
medication may need to be shipped from the site to the patient’s home (refer to Section 4.1.4) 
and, that medical pre-requisites should be performed and confirmed prior to shipment of new 
supplies.  
All deviations from the original schedule of visits will be documented and the implications 
considered for the analysis of the trial data.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
At each visit, assessments should be performed as indicated in the Flow Chart and as detailed 
in Section 5.  
In the randomised treatment period, all assessments should be performed before the trial 
medication is taken.  Exceptions to this are post-dose vital signs and ECGs,
  Once the trial medication is administered 
/ once all visit assessments are complete that require a fasting status, patients may eat as 
normal 
.  
Vital signs measurements should always precede the ECG, and the ECG should always be 
measured before any blood samples are taken (refer to the Flow Chart and Sections 5.2.2 and 
5.2.4).
In the event of force majeure or other disrupting circumstances the visits indicated in Section 
6.1 may have to be performed at the patient’s home, remotely (by phone) or as a combination 
of home and remote visits.  At these visits, the following assessments can be performed at the 
patient’s home or remotely:
concomitant therapy
pregnancy testing (urine)
IRT call
dispense trial medication
train patient / provide refresher training / dispense / review results (home BP and HR 
monitoring;
all AEs / SAEs / AESIs
compliance check


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


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age on the day of informed consent (in years)
sex (male / female in order to describe the patient`s sex at birth) 
for female patients: of childbearing potential yes / no in order to characterise the patient 
population and as a basis for contraception requirements 
ethnicity and race in order to sufficiently characterise the patient population, to support 
possible subgroup analyses if needed, and to support the calculation of the kidney function 
via the CKD EPI formula which requires a patient to be classified as black or non-black 
(unless not acceptable according to local regulations)
Information with respect to medical history / baseline conditions will also be collected at 
Visit 1a (e.g. relevant chronic diseases, current observable conditions and other relevant 
conditions, based on Investigator judgement, which may not be observable on the day of the 
examination [e.g. because the patient is receiving concomitant therapy to treat the 
condition]).  This includes any new clinically relevant findings identified during the 
screening period.  
6.2.2
Treatment period
If a patient is deemed eligible for the trial following Visits 1a, 1b and 1c, the patient will be 
randomised at Visit 2 (Day 1) by using the IRT system.  All Visit 2 assessments (refer to the 
Flow Chart) should have been completed prior to administration of the first dose of trial 
medication; exceptions are the post-dose vital signs and ECGs,
  Each patient can be randomised only once into the trial.  The randomised 
treatment period starts with Visit 2 and ends when a patient reaches the EoT visit (refer to the 
Flow Chart).  The last dose of trial medication will be administered in the evening of the day 
before the EoT visit.  
   
Patients will be assessed regularly at scheduled visits as specified in the Flow Chart.  During 
the dose titration phase of the treatment period (refer to Section 4.1.4), scheduled visits are 
more frequent.  It is of particular importance that the time window for these visits is adhered 
to since the patient must have taken the preceding dose 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.


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bring
and the electronic BP and HR monitoring device with them to each 
trial visit (refer to Sections 5.2.2.1 and 5.6.2).  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 24 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).  Ideally the ED visit should be performed within seven days of 
discontinuing the trial medication.  The assessments performed at the ED visit should be in 
accordance with the Flow Chart, with the following exceptions:
HVPG: 
not required


biobanking sampling:
not required
Patients who discontinue treatment early should be registered as discontinued in the IRT 
system.  End of trial medication must also be recorded on the corresponding eCRF.
At the EoT and / or ED visit, patients should be reminded about restrictions (refer to Section 
4.2.2) that still need to be observed up until the EoS visit (refer to Section 6.2.3).  Home BP 
and HR monitoring should continue between the EoT / ED visit and the EoS visit.
6.2.3
Follow-Up (End of Study) and trial completion
An EoS visit should be scheduled 4 weeks after an EoT and / or ED visit (refer to the Flow 
Chart and Section 3.3.4); participation in the trial is over once this visit has been completed; 
completion must be recorded on the corresponding eCRF.
When an EoS visit is performed after an ED visit, the assessments performed at the EoS visit 
should be in accordance with the Flow Chart, with the following exceptions:

  
Trial completion is defined as a patient who completes the EoS visit within the specified time 
window and who has not discontinued trial medication prematurely.  Following an EoS visit, 
the patient will return to standard medical care.  


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
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 in comparison to placebo, however it is not planned to test a 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they 
will be described and evaluated by descriptive statistical methods.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The analyses will be performed based on the following analysis sets:
Enrolled set (ES) – this analysis set includes all patients having signed informed consent 
and who were eligible for inclusion into the trial. The ES will be used for analyses of 
patient disposition
Randomised set (RS) – this analysis set includes all enrolled patients that were 
randomised to the trial medication. The RS will be used for demographic and baseline 
disease characteristics presentation
Treated set (TS) – the treated set includes all patients who were 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 randomised patients who received 
at least one dose of trial medication and have a baseline measurement for the primary 
endpoint recorded. The FAS will be used for the efficacy analyses
Further analysis sets will be defined in the TSAP, if needed.
Efficacy analyses will be performed based on the planned treatment (i.e. the treatment 
assignment at randomisation).  Safety analyses will be based on the actual treatment received 
at the randomisation visit.  
Unless otherwise stated, baseline is defined as the latest measurement before the first trial 
medication intake.


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7.2.2
Handling of intercurrent events
The expected intercurrent events of interest in this trial are:
use of the following restricted concomitant therapy:
o
NO-sGC-cGMP pathway activating therapies like NO-donors (e.g. glyceryl trinitrate, 
isosorbide di- or mono-nitrate, molsidomine), PDE-5-inhibitors (e.g. sildenafil, 
tadalafil, and vardenafil), non-specific PDE inhibitors such as dipyridamole and 
theophylline, or sGC-stimulators (e.g. riociguat)  
new onset of / dose change in existing NSBB / carvedilol concomitant therapy
occurrence of a decompensation event
All intercurrent events will be handled according to the hypothetical approach as defined in 
ICH E9 (R1), to perform treatment comparison as if all patients took randomised treatment.  
Each analysis will reference the strategy for handling intercurrent events that it will be 
estimating. The estimand for each main analysis in this CTP 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 blinded 
review and will be documented in the TSAP.
7.2.3
Primary objective analyses
For the primary endpoint (refer to Section 2.1.2), a restricted maximum likelihood (REML) 
based approach using a mixed model with repeated measurements (MMRM) will be used to 
obtain adjusted means for the treatment effects. The analysis will include the fixed, 
categorical effects of treatment at each visit, use of NSBBs or carvedilol (yes / no) at baseline 


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(refer to Sections 3.1 and 3.2), and the fixed continuous effects of baseline HVPG at each 
visit. Visit will be treated as the repeated measure with unstructured covariance structure to 
model the within-patient measurements. The Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom and adjust standard errors.  The analysis will only 
be used for estimation of treatment effects without performing statistical tests. The analysis 
will be based on the FAS. Patients will be analysed according to the stratum to which they 
belong (regardless of any mis-assignment to treatment based on identification of the wrong 
stratum), as such an error occurs before randomisation and is therefore consistent with 
regulatory guidance. Procedures to follow if the analysis fails to converge will be described 
in the TSAP.
7.2.4
Secondary objective analyses
Unless otherwise stated, only descriptive statistics will be presented for the secondary 
endpoints defined in Section 2.1.3.
7.2.6
Safety analyses
Safety analyses will be descriptive in nature and follow BI standards, including (but not 
limited to): AEs, SAEs and AESI.  AEs will be coded using the Medical Dictionary for Drug 
Regulatory Activities (MedDRA).  Standard BI summary tables and listings will be produced.
All AEs with an onset between start of treatment and end of the REP (refer to Section 1.2.1)
will be assigned to the on-treatment period for evaluation.
Safety analyses will be done by “treatment at onset” principle.  All treated patients will be 
included in the safety analysis (TS). In general, safety analyses will be descriptive in nature 
and will be based on BI standards. No hypothesis testing is planned.


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Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs, i.e. all 
AEs occurring between start of treatment and end of the REP. AEs that start before first trial 
medication intake and deteriorate under treatment will also be considered as ‘treatment-
emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of the MedDRA at DBL.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range, as well as values defined as clinically relevant, will be summarised. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.2.8
Interim analyses
An interim anlaysis is planned after the first 60 patients (20 per treatment group) have 
completed the first 8 weeks of treatment and the HVPG procedure.  All available data at this 
stage will be analysed in the same way as is planned for the final analysis with the only 
exception of the primary endpoint and one of the secondary endpoints.  The primary endpoint 
will not be analysed since the focus is the week 8 time point for the interim analysis.  If 
applicable, the secondary endpoint defined as “percentage change in HVPG from baseline 
(measured in mmHg) after 8 weeks of treatment” will be analysed using an analysis of 
covariance (ANCOVA) model with treatment and baseline HVPG.  This model will only be 
used to estimate treatment effects, no comparison via statistical testing will be performed.
The extent of the safety analyses will be to ensure that the trial is being conducted safely.
The interim analysis will be performed by an independent statistics and programming team 
within BI.  The results of the interim analysis will be used internally and individuals involved 
in the conduct of the trial will not be made aware of the results. There will be no changes of 
the design of the trial because of this interim analysis and no stopping rules apply.  For this 
interim analysis an interim analysis SAP and an interim analysis logistics plan will be 
developed, including a list with individuals and roles who will have access to unblinding 
information.


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An external DMC will be implemented, with tasks and administrative details as briefly 
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; the DMC will be informed about the results 
of the interim analysis.   
7.3
HANDLING OF MISSING DATA
For the interim analysis, the missing HVPG data at week 8 will not be imputed.
For the primary endpoint, the mixed effect model will handle missing data based on a 
likelihood method under the “missing at random” assumption. No imputation of missing data 
is planned for the remaining endpoints.  
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 the two dose 
groups of active BI 685509.  Patients will be randomised in blocks to one of the three 
treatment groups in a 1:1:1 ratio.  The randomisation will be stratified by use (or not) of 
NSBBs or carvedilol (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 randomise 78 patients in total in this trial: 26 patients per treatment group 
(placebo, low dose and high dose of BI 685509) [R21-1984, R21-1945].
In a positive scenario, it was assumed that the mean reduction from baseline HVPG at week 
24 would be: 0%, 23%, and 25% for placebo, low, and high dose of BI 685509, respectively 
(with a standard deviation of 27.5% in each group and a correlation coefficient of 0.2 
between the two BI 685509 dose groups).  With the sample size of 78 in total (26 per 
treatment group), there is 94.95% probability to observe a difference of at least 15% points 
HVPG reduction from baseline between at least one dose group of BI 685509 and placebo.  
In a negative scenario, this probability is 10.41%, assuming the mean HVPG reduction from 
baseline would be 0%, 3%, and 4%, respectively (with a standard deviation of 27.5% in each 
group). Probabilities of achieving an assumed treatment effect within different scenarios are 
presented in Table 7.5: 1 (R21-1984, R21-1945).


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Table 7.5: 1
Scenarios of probabilities of achieving the assumed treatment effect
Scenario No. 
Final analysis
(n=26 per treatment group)
Assumption of mean reduction in HVPG from baseline 
to week 24
(BI 685509 
 BID / BI 685509 
 BID / placebo)
Probability that the 
treatment effect1 is ≥15%
Positive scenario
1
23%/21%/0% (SD=27.5%)
91.45%
2
23%/21%/0% (SD=33.0%)
88.62%
3
25%/23%/0% (SD=27.5%)
94.95%
4
25%/23%/0% (SD=33.0%)
92.52%
Negative scenario
5
4%/3%/0% (SD=27.5%)
10.41%
6
4%/3%/0% (SD=33.0%)
16.23%
1
Treatment effect defined as difference in mean reduction from baseline to week 24 in HVPG between active treatments and placebo
The calculations were peformed 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 IRB / IEC and 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 patient protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, Supplier 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
eCRFs for individual patients will be provided by the Sponsor. Refer to 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 


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evidence of any diagnostic tests. In this case, the Investigator must make at least one 
documented attempt to retrieve previous medical records. If this fails, a verbal history from 
the patient, documented in their medical records, would be acceptable.
Copies of source documents necessary for e.g. HVPG central evaluation and hepatic injury 
adjudication will be provided to external Suppliers. Before sending or uploading those 
copies, the Investigator must ensure that all patient identifiers (e.g. patient’s name, initials, 
address, phone number, social security number etc.) have been properly removed or redacted 
from any copy of the patients’ source documents.
If the patient is not compliant with the CTP, any corrective action e.g. re-training must be 
documented in the patient file.
For the eCRF, data must be derived from source documents, for example:

patient identification: sex, year of birth (in accordance with local laws and regulations)

patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

dates of patient’s visits, including dispensing of trial medication

medical history (including trial indication and concomitant diseases, if applicable)

medication history

AEs and AESIs (onset date [mandatory], and end date [if available]), including those 
identified from measurements within the home BP and HR monitoring equipment

SAEs (onset date [mandatory], and end date [if available])

concomitant therapy (start date [where required], dose / frequency [where required], 
changes)

originals or copies of laboratory results and other imaging or testing results (e.g. 
gastroscopy, HVPG, ultrasound and 
, 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 eCRF and all source 


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documents / data, including progress notes, copies of laboratory and medical test results,
which must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all eCRFs and informed consents. The accuracy of the data 
will be verified by direct comparison with the source documents described in Section 8.3.1.
The Sponsor or delegate will also monitor compliance with the CTP and GCP.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war; refer to 
Section 6), site access may be restricted thus limiting the ability to perform standard site 
monitoring activities on site such as on-site source data review and source data verification. 
Therefore, some of these activities may be performed remotely or replaced by centralised 
monitoring to the extent possible, based on a documented risk assessment and in alignment 
with local regulations.
8.3.3
Storage period of records
Trial 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 PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the World Health 
Organisation GCP handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare
data generated at the site as a result of the trial need to be available for inspection on 
request by the participating physicians, the Sponsor’s representatives, by the IRB / IEC 
and the regulatory authorities
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular:


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sample and data usage has to be in accordance with the separate biobanking informed 
consent
the BI-internal facilities storing biological samples from clinical trial participants, as well 
as the external banking facility, are qualified for the storage of biological samples 
collected in clinical trials
an appropriate sample and data management system, including audit trail for clinical data 
and samples to identify and destroy such samples according to the informed consent is in 
place
a fit for purpose documentation (
 ensures 
compliant usage

samples and / or data may be transferred to third parties and other countries as specified in 
the biobanking informed consent
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
medication (as scheduled per CTP or prematurely). Individual Investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this CTP.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
Sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / CA in each participating EU member state will be notified about the trial
milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The Sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by BI.


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A Coordinating Investigator will be responsible to coordinate Investigators at the different 
sites participating in this trial. Tasks and responsibilities will be defined in a contract. 
Data Monitoring Committee:
A DMC will be established. Members of the DMC will be independent of BI, and will 
include physicians experienced in the treatment of the disease under investigation, and a 
statistician.  The DMC will evaluate safety data, and receive efficacy data, results of interim 
analyses, significant safety concerns, and decisions from hepatic injury adjudication for 
evaluation. While DMC members may be unblinded, measures will be 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.  All evaluations will be performed in a blinded fashion.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.  The Investigators will have access to the BI web portal
Clinergize to access documents provided by the Sponsor.
BI has appointed a Clinical Trial Leader responsible for coordinating all required activities, in 
order to:
manage the trial in accordance with applicable regulations and internal SOPs
direct the clinical trial team in the preparation, conduct and reporting of the trial
ensure appropriate training and information of Clinical Trial Managers, CRAs and 
Investigators of participating countries
In the participating countries the trial will be performed by the respective local or regional 
BI-organisation (Operating Unit) in accordance with applicable regulations and BI SOPs, or 
by a CRO based on a contract. The CRO will perform project management, clinical field 
monitoring, medical monitoring, and reporting.
Data Management and statistical evaluation will be done by BI according to BI SOPs.


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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 
 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
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
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
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
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
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
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
R20-4181
Hari A, Nair HK, Gottardi A de, Baumgartner I, Dufour JF, Berzigotti A.  
Diagnostic hepatic haemodynamic 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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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
R20-4089
Chan Y, Pranke S, Rashidi F, Nosib S, Worobetz L.  Safety profile of liver 
FibroScan in patients with cardiac pacemakers or implantable cardioverter-
defibrillators.  Can J Gastroenterol Hepatol 2017; 2017; 7298032
R21-0296
Krystallis C, Masterton GS, Hayes PC, Plevris JN.  Update of endoscopy in 
liver disease: more than just treating varices.  World J Gastroenterol 
2012;18(5):401-411
R20-4090
Reiberger T, Puespoek A, Schoder M, Baumann-Durchschein F, Bucsics T, 
Datz C, et al.  Austrian consensus guidelines on the management and 
treatment of portal hypertension (Billroth III).  Wien Klin Wochenschr 
2017;129(Suppl 3):S135-158
R20-1204
Mandorfer M, Kozbial K, Schwabl P, Chromy D, Semmler G, Staettermay 
AF, et al.  Changes in hepatic venous pressure gradient predict hepatic 
decompensation in patients who achieved sustained virologic response to 
interferon-free therapy. Hepatology 2020;71(3);1023-1036
R20-4092
Groszmann RJ, Garcia-Tsao G, Bosch J, Grace D, Burroughs AK, Planas R, 
et al, Portal Hypertension Collaborative Group.  Beta-blockers to prevent
gastroesophageal varices in patients with cirrhosis.  N Engl J Med 
2005;353(21);2254-2261
R20-4093
Merkel C, Marin R, Angeli P, Zanella P, Felder M, Bernardinello E, et al, 
Gruppo Triveneto per l'Ipertensione Portale.  A placebo-controlled clinical 
trial of nadolol in the prophylaxis of growth of small esophageal varices in 
cirrhosis.  Gastroenterology 2004;127(2);476-484
R20-4091
Mandorfer M, Hernandez-Gea V, Reiberger T, Garcia-Pagan JC. 
Hepatic venous pressure gradient response in non-selective beta-blocker 
treatment - is it worth measuring? Curr Hepatol Rep 2019;18;174-186
P09-12413
Guidance for industry: drug-induced liver injury: premarketing clinical 
evaluation (July 2009).  Silver Spring: U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER);2009


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R18-1357
U.S. Department of Health and Human Services.  Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: November 27, 
2017).
https://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
R07-1314
Brooks R, EuroQol Group.  EuroQol: the current state of play.  Health 
Policy 1996;37:53-72
R12-1920
Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, Bonsel G, 
Badia X.  Development and preliminary testing of the new five-level 
version of EQ-5D (EQ-5D-5L).  Qual Life Res 2011;20:1727-1736
R17-3267
Reenen M van, Janssen B.  EQ-5D-5L user guide: basic information on 
how to use the EQ-5D-5L instrument (version 2.1, April 2015).  
https://euroqol.org/wp-content/uploads/2016/09/EQ-5D-
5L_UserGuide_2015.pdf (access date: 25 September 2017);
Rotterdam:EuroQol Research Foundation; 2015
R17-0283
Younossi ZM, Guyatt G, Kiwi M, Boparai N, King D.  Development of a 
disease specific questionnaire to measure health related quality of life in 
patients with chronic liver disease.  Gut 1999;45:295-300
R21-1984
Gupta V, Rawat R, Shalimar, Saraya A.  Carvedilol versus propranolol 
effect on hepatic venous pressure gradient at 1 month in patients with index 
variceal bleed: RCT. Hepatol Int 2017;11:181-187
R21-1945
Garcia-Tsao G, Fuchs M, Shiffman M, Borg BB, Pyrsopoulos N, Shetty K, 
et al.  Emricasan (IND-6556) lowers portal pressure in patients with 
compensated cirrhosis and severe portal hypertension.  Hepatology 
2019;69(2);717-728  
R18-3281
Murray KF, Carithers RL.  AASLD practice guidelines: evaluation of the 
patient for liver transplantation.  Hepatology 2005;41(6):1407-1432
R20-3280
Abraldes JG, Garcia-Tsao G.  The design of clinical trials in portal 
hypertension.  Semin Liver Dis; 2017;37(1);73-84.
R23-3868
Villanueva C, Aracil C, Colomo A, Hernandez-Gea V, Lopez-Balaguer JM, 
Alvarez-Urturi C, et al.  Acute hemodynamic response to beta-blockers and 
prediction of long-term outcome in primary prophylaxis of variceal 
bleeding. Gastroenterology 2009;137(1):119-128


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9.2
UNPUBLISHED REFERENCES
c02778238
Investigator’s Brochure.  BI 685509.  Current version 
c35011958
TMCP List of Analyses for BI 685509 (1366.P1/P2)
n00260803
Soluble guanylate cyclase activator BI 685509 in rats with biliary cirrhosis 
(BDL) and portal hypertension
n00261471-01
Prediction of BI 685509 pharmacokinetics and therapeutic dose in human in 
non-alcoholic steatohepatitis (NASH). 25 May 2018


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10.
APPENDICES


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


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


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


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
11.1
GLOBAL AMENDMENT 1
Date of Amendment
15 Jul 2021
EudraCT No.
EU Trial No.
2021-001285-38
BI Trial No.
1366-0021
BI Investigational 
Medicinal Product
BI 685509
Title of protocol
Randomised, double-blind, placebo-controlled and parallel 
group trial to investigate the effects of two doses (up-titration 
to a fixed dose regimen) of oral BI 685509 on portal 
hypertension after 24 weeks treatment in patients with 
clinically significant portal hypertension (CSPH) in 
compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Addition of exclusion criteria to align with adjustment to 
Section 3.3.3 Exclusion criteria #2 (see below)
Rationale for change
See rationale for Section 3.3.3 EX#2 below
Section to be changed
Abbreviations and Definitions
Description of change
New abbreviation (A1At) added due to addition of exclusion 
criteria #2 to Section 3.3.3 Exclusion criteria (see below)
Rationale for change
See rationale for Section 3.3.3 EX#2 below
Section to be changed
Section 1.4.2 Risks
Description of change
The last two sentences underneath Table 1.4.2: 2 have been 
adjusted to align with the adjustment to Section 3.3.3 
Exclusion criteria #19 (see below).  The text in bold is new.  
Rationale for change
See rationale for Section 3.3.3 EX#19 below
Section to be changed
Section 3.3.3 Exclusion criteria (EX#2)
Description of change
New exclusion criteria #2 added:
“History of other forms of chronic liver disease (e.g. non-
alcoholic steatohepatitis [NASH], Hepatitis B virus [HBV], 
untreated HCV, autoimmune liver disease, primary biliary 


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sclerosis, primary sclerosing cholangitis, Wilson’s disease, 
haemachromatosis, alpha-1 antitrypsin [A1At] deficiency)”  
Rationale for change
Omitted in error from original protocol.  This criteria is 
required so that the trial population consists only of patients 
with alcohol-related liver disease 
Section to be changed
Section 3.3.3 Exclusion criteria (EX#19)
Description of change
Wording of exclusion criteria #19 adjusted to include the bold 
text shown below: “Contraindication to any of the trial 
assessments (e.g. poor patient co-operation for gastroscopy, 
Rationale for change


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Section to be changed
Table 7.5: 1 Scenarios of probabilities of achieving the 
assumed treatment effect
Description of change
Footnote 1 of the table has been adjusted to include the text 
“Treatment effect defined as combined difference in mean 
reduction from ….” in front of the existing footnote
Rationale for change
Administrative correction
Section to be changed
Section 8.3.1 Source documents
Description of change
The inverted comma has been removed from after the word 
“trial” in the bullet “completion of patient’s participation in the 
trial …”
Rationale for change
Administrative correction
11.2
GLOBAL AMENDMENT 2
Date of Amendment
21 Sep 2021
EudraCT No.
EU Trial No.
2021-001285-38
BI Trial No.
1366-0021
BI Investigational 
Medicinal Product
BI 685509
Title of protocol
Randomised, double-blind, placebo-controlled and parallel 
group trial to investigate the effects of two doses (up-titration 
to a fixed dose regimen) of oral BI 685509 on portal 
hypertension after 24 weeks treatment in patients with 
clinically significant portal hypertension (CSPH) in 
compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Flow Chart
Description of change
i)
Footnote label 23 added to the rows for vital signs and 
resting 12-lead ECG
ii)
Footnote label 22 added to the row for physical 
examination
iii)
“x” added to Visits 3, 4, 6 and 8-10 in the row for 
resting 12-lead ECG
iv)
Footnote 2 updated with the following bold words 
“Visit 2 = randomisation / Day 1 of trial medication.  
All assessments at this visit (excluding post-dose vital 
signs and ECGs, 
 


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v)
Footnote 3 updated with the following new sentence: 
“The last dose of trial medication will be administered 
in the evening of the day before the EoT visit” and the 
following bold words “… during an ED visit and the 
EoS visit that follows it”
vi)
Footnote 7 (sentence 1 and 2) updated with the 
following bold words “Measurement of vital signs
should precede the 12-lead ECG, and measurement 
of the 12-lead ECG should precede blood sampling and 
intake of trial medication at visits where a single 
ECG is required.  The 12-lead ECG should be 
performed after the patient has rested for at least 5 
minutes in a supine position.”  
vii)
Footnote 22 has been added “The physical examination 
at Visit 1a should include an assessment of the clinical 
criteria for Child-Turcotte-Pugh classification (refer to 
Appendix 10.3)”
viii)
Footnote 23 has been added “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
 
(refer to Sections 
5.2.2, 5.2.4 and 5.3)”
Rationale for change
i)
See rationale for Section 1.2.3 below
ii)
Clarification
iii)
See rationale for Section 1.2.3 below
iv)
See rationale for Section 1.2.3 below
v)
Clarification
vi)
See rationale for Section 1.2.3 below
vii)
Clarification
viii)
See rationale for Section 1.2.3 below
Section to be changed
Abbreviations and Definitions
Description of change
New abbreviations added for BPM, CI, ECG, HERG
BRPM revised to RPM
Rationale for change
To align with other changes made via this global amendment
Section to be changed
1.2.3 Data from clinical studies
Description of change
i)
In the first sentence of the third paragraph, the number 
of patients in Trial 1366-0020 was changed from 48 to 
49, and number of patients with cirrhosis Child-
Turcotte-Pugh B was changed from 24 to 25


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ii)
The following next text has been added to the end of the 
section: 
“Summary of recent data from Trial 1366-0020:
Based on recent data from Trial 1366-0020, an effect of 
BI 685509 on the predicted placebo-corrected change 
from baseline QTcF (∆∆QTcF) was seen.  As 
mentioned above, this trial included patients with 
cirrhosis Child-Pugh stage A (24 patients) and B (25 
patients).  Dosing regimens up to 
BID (i.e. the 
same as the highest dose group in this trial) were used.  
In both patient groups, there was a dose dependent 
increase of ∆∆QTcF up to 13.7 ms, with the upper 90% 
CI > 20 ms.  In one patient group (Child Pugh B) this 
was concomitant with a change of the predicted 
placebo-corrected change from baseline heart rate 
(∆∆HR) of > 10 beats per minute (bpm), but not in the 
other patient group.  No such effect was seen in healthy 
Caucasian volunteers for dosing regimens used in Trial 
1366-0010.  In healthy Asian volunteers (Trial 1366-
0013), at a dose regimen relevant for this trial (i.e. 
starting dose of 
 BID up to a final dose of 
 
BID), increase of ∆∆QTcF was seen up to 11.7 ms with 
90% CI < 20 ms, concomitant with an increase of 
∆∆HR of nearly 10 bpm.  
BI 685509 has no effect on the human ether-a-go-go 
related gene (hERG) channel at doses used in this 
clinical trial, and no effect on QT-interval or T-wave 
morphology was seen in conscious animal studies (for 
further details refer to the current Investigator’s 
Brochure (IB) [c02778238]).”
Rationale for change
i)
Administrative correction
ii)
Based on the change described above, as a 
precautionary measure, until further investigations about 
the potential effect of BI 685509 on the QT-interval are 
conducted, exclusion and discontinuation criteria have 
been added, as has more frequent ECG monitoring and 
restricted concomitant therapies have been introduced to 
protect trial patients from a potential QT-prolongation 
effect of BI 685509.
Section to be changed
1.3 Rationale for Performing the Trial
Description of change
The words “or genetic” have been removed from the last 
sentence in this section:
“If the patient agrees, banked samples may be used for future 
biomarker research and drug development projects, e.g. to 


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identify patients that are more likely to benefit from a 
treatment or experience an AE, or to gain a mechanistic or 
genetic understanding of drug effects and thereby better match 
patients with therapies.”
Rationale for change
There is no genetic element to the biobanking planned in this 
trial (biobanking of plasma and serum)
Section to be changed
Table 1.4.2: 1 Overview of risk – investigational medicinal 
product (BI 685509)
Description of change
New row added to the table for potential QT-interval 
prolongation, together with a reference to Section 1.2.3 and 
the following new text for the mitigation strategy:
“Patients with long QT / QTcF-interval, patients with a family 
history of long QT syndrome, or those using concomitant 
therapies known to increase the risk of Torsade de Points will 
be excluded from the trial (refer to Sections 3.3.3 and 4.2.2.1).
ECGs will be performed at each visit in the randomised 
treatment period of the trial, and trial medication will be 
discontinued in the event of a prolonged QT / QTcF-interval
(refer to Section 3.3.4.1).”
Rationale for change
See rationale for Section 1.2.3
Section to be changed
3.3.3 Exclusion criteria
Description of change
i)
Wording of EX #3 adjusted to include the bold text 
shown below: 
“Has received curative anti-viral therapy with direct-
acting anti-virals within the last 2 years for HCV, or, if 
such treatment was > 2 years ago with a and there is 
no sustained virological response (SVR) at screening 
(Visit 1a), or, must take curative anti-viral therapy 
with direct-acting anti-virals throughout the trial
(refer to Section 4.2.2.1)”
ii)
New EX #18 added:
“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 at screening (Visit 1a) 
or planned initiation of such therapies during the trial 
(refer to Section 4.2.2.1)”
Rationale for change
i)
Criteria re-worded to clarify that patients treated with
direct-acting anti-virals > 2 years ago are excluded from 
the trial if there is no SVR, and that the use of such 
treatment is prohibited throughout the trial
ii)
See rationale for Section 1.2.3


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Section to be changed
3.3.4.1 Discontinuation of trial medication
Description of change
New discontinuation criteria added:

“patients with a QT or QTcF interval > 500 ms, or an 
increase of QT or QTcF of > 60 ms from the value at Visit 
2 / randomisation (baseline). Such cases must be reported 
as AEs”
Rationale for change
See rationale for Section 1.2.3
Section to be changed
4.1.4 Drug assignment and administration of doses for each 
patient
Description of change
New sentence added at the end of the first paragraph:
“The last dose of trial medication will be administered in the 
evening of the day before the EoT visit.”  
Rationale for change
Clarification
Section to be changed
4.2.2.1 Restrictions regarding concomitant treatment
Description of change
New paragraph inserted as follows:
“In addition, intake of concomitant therapies with a known 
risk of Torsade de Pointes must not be co-administered with 
BI 685509 (also refer to Table 1.4.2: 1).  These restrictions 
apply from screening (Visit 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.”
Rationale for change
See rationale for Section 1.2.3
Section to be changed
5.1.1 Hepatic venous pressure gradient
Description of change
2nd paragraph, the word “laboratory” has been deleted from 
the phrase “HVPG laboratory manual” and the words in bold 
have been added to the sentence below:
“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.”
Rationale for change
Clarification


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Section to be changed
5.2.2 Vital signs / home blood pressure and heart rate 
monitoring
Description of change
The words in bold have been added to the sentence below:
“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.”
The following new sentence has been added to the end of the 
section:
“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).”  
Rationale for change
Clarification
See rationale for Section 1.2.3
Section to be changed
Table 5.2.3: 1 Safety laboratory tests
Description of change
i)
Reticulocytes adjusted so it is a required test rather than 
reflex in case of anaemia; footnote labels re-numbered
as original footnote 1 removed
ii)
Footnote 10 re-worded to align with re-worded EX #3:
“Reflex in case of positive HCV antibody and / or HCV 
infection that has been treated in the past”
Rationale for change
i)
To avoid cancellation of reticulocyte results due to short 
sample stability; a parameter that is important in the 
trial population
ii)
See rationale for Section 3.3.3. Exclusion criteria
Section to be changed
5.2.4 Electrocardiogram
Description of change
The words in bold have been added to the sentence below, and 
two new sentences have been added as a new paragraph:
“The 12-lead ECGs will be recorded at the time points 
specified in the Flow Chart; the ECGs should be performed 
after the measurement of vital signs, prior to blood 
sampling and intake of trial medication (at visits where 
only a single ECG is required), and recorded after the 
patient has rested for at least 5 minutes in a supine position.”  
“During the dose-titration period (i.e. when up-titration is 
occurring) and at the subsequent visit, 12-lead ECGs will also 


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be performed approximately 1 hour and 2 hours after intake of 
trial medication. 
”
The following three sentences have also been added at the end 
of the section:
“ECG abnormalities will be carefully assessed by the 
Investigator or delegate, and if trial discontinuation criteria are 
met (refer to Section 3.3.4.1), the patient will be discontinued 
from the trial.”  
“Copies of ECGs will be sent to a central ECG Supplier for 
storage purposes.  This will enable a subsequent centralised 
and independent re-evaluation if necessary.”
Rationale for change
See rationale for Section 1.2.3
Section to be changed
6.2 Details of Trial Procedures at Selected Visits
Description of change
The words in bold have been added to the two sentences 
below:
“Exceptions to this are post-dose vital signs and ECGs, 
“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).”
A new bullet point has been added to the list of assessments 
that can be performed at the patient’s home:

“resting 12-lead ECG (using a portable ECG machine)”
Rationale for change
See rationale for Section 1.2.3
Section to be changed
6.2.2 Treatment period
Description of change
The words in bold have been added to the sentence below:
“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,
The following new sentence has been added at the end of 
paragraph 1:
“The last dose of trial medication will be administered in the 
evening of the day before the EoT visit.”  
Rationale for change
See rationale for Section 1.2.3
Clarification


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11.3
GLOBAL AMENDMENT 3
Date of Amendment
07 Jul 2022
EudraCT No.
EU Trial No.
2021-001285-38
BI Trial No.
1366-0021


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BI Investigational 
Medicinal Product
BI 685509
Title of protocol
Randomised, double-blind, placebo-controlled and parallel 
group trial to investigate the effects of two doses (up-titration 
to a fixed dose regimen) of oral BI 685509 on portal 
hypertension after 24 weeks treatment in patients with 
clinically significant portal hypertension (CSPH) in 
compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
1.2.1 Key characteristics of BI 685509
Description of change
Drug interaction section: added a potential of a drug-drug 
interaction with CYP2C8 substrates 
Rationale for change
Updated information based on the current version of the BI 
685509 Investigator’s Brochure
Section to be changed
1.2.3 Data from clinical studies
Description of change
Summary of recent data from 1366-0020 section: correction of 
a typographical error in the patient group, trial number, and 
dosing regimen.  Information updated about Trials 1366-0003 
and 1366-0013
Rationale for change
Correction and clarification 
Section to be changed
1.4.2: 1 Overview of risks – investigational medicinal product 
(BI 685509)
Description of change
In the row “Risks related to DDI”, risk updated to include 
CYP2C8 substrates 
Rationale for change
See rationale for Section 1.2.1
Section to be changed
4.2.2.1.1 Close monitoring for AEs based on concomitant 
therapy
Description of change
Updated to include close monitoring for AEs based on 
concomitant therapy that is metabolised by CYP2C8
Rationale for change
See rationale for Section 1.2.1
Section to be changed
7.3 Handling of Missing Data
Description of change
Update of the imputation method for different analyses
Rationale for change
To clarify the imputation strategies for missing data
11.4
GLOBAL AMENDMENT 4
Date of Amendment
16 Aug 2022
EudraCT No.
2021-001285-38


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EU Trial No.
BI Trial No.
1366-0021
BI Investigational 
Medicinal Product
BI 685509
Title of protocol
Randomised, double-blind, placebo-controlled and parallel 
group trial to investigate the effects of two doses (up-titration 
to a fixed dose regimen) of oral BI 685509 on portal 
hypertension after 24 weeks treatment in patients with 
clinically significant portal hypertension (CSPH) in 
compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Adjustment to one inclusion criteria and one exclusion criteria
to align with adjustments to Sections 3.3.2 Inclusion criteria 
#6 and 3.3.3 Exclusion criteria #4 (see below)
Rationale for change
See rationale for Sections 3.3.2 IN#6 and 3.3.3 EX#4 below
Section to be changed
Section 3.3.2 Inclusion criteria
Description of change
Wording of inclusion criteria #6 adjusted to include the bold
and strikethrough text shown below:
“Abstinence from significant alcohol misuse / abuse for a
minimum of 26 months prior to screening (Visit 1a), and the 
ability which, based on Investigator judgement, to abstain 
from alcohol can be maintained throughout the trial (both 
evaluated based on Investigator judgement)”
Rationale for change
Based on recruitment difficulties experienced by initiated 
sites, the requirement for complete abstinence from alcohol 
prior to the first trial visit has been changed to allow screening 
of patients without any significant alcohol misuse / abuse (in 
the opinion of the Investigator).  The timeframe has also been 
reduced from 6 months to 2 months.  Patients will still be 
expected to abstain from alcohol during the trial as previously 
defined in Section 4.2.2.2 since excessive alcohol 
consumption could lead to hypotension when taken 
concomitantly with BI 685509.
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
Wording of exclusion criteria #4 adjusted to include the bold 
text shown below:
“ARLD without adequate treatment (e.g. lifestyle 
modification) or with ongoing pathological drinking 
behaviour (misuse / abuse based on Investigator 
judgement)”


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Rationale for change
To align with the change described for Section 3.3.2 Inclusion 
criteria above.
Section to be changed
Section 11.3 Global Amendment 3
Description of change
In the rows describing changes for Sections 1.4. 2: 1 and 
4.2.2.1.1, the words “See rationale for Section 1.2.3” was 
changed to “See rationale for Section 1.2.1”
Rationale for change
Correction (and described in Protocol Administrative Letter of 
13-Jul-22)
11.5
GLOBAL AMENDMENT 5
Date of Amendment
14 Dec 2022
EudraCT No.
EU Trial No.
2021-001285-38
BI Trial No.
1366-0021
BI Investigational 
Medicinal Product
BI 685509
Title of protocol
Randomised, double-blind, placebo-controlled and parallel 
group trial to investigate the effects of two doses (up-titration 
to a fixed dose regimen) of oral BI 685509 on portal 
hypertension after 24 weeks treatment in patients with 
clinically significant portal hypertension (CSPH) in 
compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Adjustment to total number of patients randomised, number of 
patients per treatment group and two inclusion criteria to align 
with adjustments elsewhere in this global amendment (see 
below)
Rationale for change
See rationale for Sections 7.5 and 3.3.2
Section to be changed
Flow Chart
Description of change
i)
“Week” and “Day” adjusted for screening period
ii) Time window for screening period removed and replaced 
with a reference to footnote 1
iii) Footnote 1 adjusted with the bold and strikethrough text 
shown below:
“The screening period consists of 3 visits (Visits 1a/b/c).  
These visits should ideally be completed within a period of 4 
weeks, but a maximum 3-4 of 6 weeks (-2842 days, window 


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+ 7 days, range -21 to -28) will be permitted.  There is no 
minimum duration. A patient can …..”
Rationale for change
To assist sites with scheduling difficulties for the required 
screening assessments, the permitted duration of the screening 
period has been increased by 2 weeks
Section to be changed
Abbreviations and Definitions
Description of change
New abbreviation added for SSc
Rationale for change
To align with other changes made via this global amendment
Section to be changed
Section 1.2 Drug Profile
Description of change
Systemic sclerosis (SSc) added as a third intended indication 
for BI 685509
Rationale for change
Updated information based on the current version of the BI 
685509 Investigator’s Brochure
Section to be changed
Table 1.4.2: 2 Overview of risks - procedures
Description of change
In the row “Risks associated with assignment to the placebo 
group”, the mitigation strategy has been adjusted (from 50 to 
35) with the number of randomised patients who will be 
assigned to the placebo treatment group
Rationale for change
To align with other changes made via this global amendment
Section to be changed
Section 3.1 Overall Trial Design
Description of change
i)
Screening period duration adjusted from 4 to 6 weeks
ii) Total number of patients randomised adjusted from 150 to 
105
Rationale for change
i)
See rationale for Flow Chart above
ii) See rationale for Section 7.5 Determination of Sample 
Size below
Section to be changed
Figure 3.1: 1 Trial Design Schematic
Description of change
i)
Screening period during adjusted from 4 to 6 weeks
ii) Total number of patients randomised adjusted from 150 to 
105, and number of patients per treatment group adjusted 
from 50 to 35
Rationale for change
i)
See rationale for Flow Chart above
ii) See rationale for Section 7.5 Determination of Sample 
Size below
Section to be changed
Section 3.3 Selection of Trial Population
Description of change
i)
Total number of patients randomised adjusted from 150 to 
105
ii) Number of patients anticipated to be randomised at each 
site adjusted from 2-3 to 2


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Rationale for change
i)
See rationale for Section 7.5 Determination of Sample 
Size below 
ii) To align with other changes made via this global 
amendment
Section to be changed
Section 3.3.2 Inclusion criteria
Description of change
i)
Wording of inclusion criteria #3 adjusted to include the 
bold and strikethrough text shown below:
“Clinical signs of CSPH as described by either one of the 
points below.  Each trial patient must have a gastroscopy 
during the screening period (Visit 1b) or within 36 months 
prior to screening (Visit 1b).  For further details refer to 
Section 5.2.5.2

documented endoscopic proof of oesophageal varices 
and / or gastric varices at screening (Visit 1b) or 
within 36 months prior to screening (Visit 1b)

documented endoscopic-treated oesophageal varices
as preventative treatment”  
ii) Wording of inclusion criteria #9 adjusted to include the 
bold and strikethrough text shown below:
“If receiving treatment with NSBBs or carvedilol must be on a 
stable dose for at least 31 months prior to screening (Visit 1b), 
with no planned dose change throughout the trial”  
Rationale for change
i)
To ease recruitment difficulties by permitting the use of a 
historical gastroscopy over a longer period of time prior to 
screening, due to the invasive nature of this procedure
ii) To ease recruitment difficulties by reducing the amount of 
time that a stable dose of NSBBs or carvedilol is required 
prior to screening
Section to be changed
Section 4.2.2.1 Restrictions regarding concomitant treatment
Description of change
4th paragraph adjusted to align with other changes made via 
this global amendment in relation to the stability of NSBBs or 
carvedilol prior to screening
Rationale for change
See rationale for Section 3.3.2
Section to be changed
Section 5.1.1 Hepatic venous pressure gradient
Description of change
The following sentence has been added to the 4th paragraph:
“If an alternative time of day (i.e. not in the morning, see 
above) has been chosen for treatment period HVPGs, the 
morning dose of trial medication can be taken prior to the 
procedure.”  
Rationale for change
Clarification


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Section to be changed
Section 5.2.5.1 Ultrasound (liver and spleen)
Description of change
ii) The words “at screening (Visit 1b or 1c)” have been 
removed from the last sentence of the penultimate 
paragraph
Rationale for change
ii) Correction, since the liver and spleen parameters 
mentioned are measured each time an ultrasound is 
performed, and not just at the screening visit 
Section to be changed
Section 5.2.5.2 Gastroscopy
Description of change
i)
Wording adjusted in the 2nd paragraph with the bold and 
strikethrough text shown below:
“The gastroscopy can be skipped if both of the conditions
below areis met.  In all other cases, a gastroscopy is required 
at Visit 1b, and documentary evidence must be available (e.g. 
source data) following the procedure to confirm the presence 
of oesophageal / gastric varices.
(i) a patient has had this procedure in the previous 36
months to Visit 1b (and there is documentary evidence 
[e.g. source data such as a referral letter etc.] available 
to confirm the presence of oesophageal / gastric 
varices)
(ii) there has been no change in the treatment of the PH 
since the gastroscopy was performed (i.e. the 
“treatment” has been monitoring alone)6”
ii) Footnote 6 has been deleted
Rationale for change
i)
See rationale for Section 3.3.2
ii) To ease recruitment difficulties, if therapy with NSBBs / 
carvedilol was initiated after a historical gastroscopy, the 
requirement for a further gastroscopy to confirm the 
persistence of varices has been removed 
Section to be changed
Section 6.2.1 Screening period (Visits 1a to 1c)


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Description of change
Wording adjusted for the screening period duration and 
permitted time window to reflect adjustments to the Flow 
Chart 
Rationale for change
To align with other changes made via this global amendment 
(see rationale for Flow Chart)
Section to be changed
Section 7.5 Determination of Sample Size
Description of change
Total number of patients updated to 105 with 35 patients per 
treatment group, and the corresponding probabilities of 
achieving the assumed treatment effects (a difference of at 
least 20% points HVPG reduction from baseline between at 
least one dose group of BI 685509 and placebo) in the final 
analysis were updated.  The correlation coefficient of the 
mean reduction of HVPG from baseline at week 24 in two BI 
685509 dose groups was added.
Rationale for change
To increase the trial efficiency while preserving the 
probability to observe a difference of at least 20% points 
HVPG reduction from baseline between at least one dose 
group of BI 685509 and placebo under a positive scenario.  
11.6
GLOBAL AMENDMENT 6
Date of Amendment
02 Nov 2023
EudraCT No.
EU Trial No.
2021-001285-38
BI Trial No.
1366-0021
BI Investigational 
Medicinal Product
BI 685509
Title of protocol
Randomised, double-blind, placebo-controlled and parallel 
group trial to investigate the effects of two doses (up-titration 
to a fixed dose regimen) of oral BI 685509 on portal 
hypertension after 24 weeks treatment in patients with 
clinically significant portal hypertension (CSPH) in 
compensated cirrhosis
Global Amendment due to urgent safety reasons
Global Amendment
x
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
i. Adjustment to total number of patients randomised and 
the corresponding number of patients per treatment group
ii. Main exclusion criteria: “primary biliary sclerosis” 
replaced by “primary biliary cholangitis”
Rationale for change
i. See rationale for Section 7.5 Determination of Sample 
Size below
ii. Correction / clarification


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Section to be changed
Table 1.4.2: 2 Overview of risks - procedures
Description of change
In the row “Risks associated with assignment to the placebo 
group”, the mitigation strategy has been adjusted (from 35 to 
26) with the number of randomised patients who will be 
assigned to the placebo treatment group
Rationale for change
To align with other changes made via this global amendment
Section to be changed
Section 3.1 Overall Trial Design
Description of change
Total number of patients randomised adjusted from 105 to 78
Rationale for change
See rationale for Section 7.5 Determination of Sample Size 
below
Section to be changed
Figure 3.1: 1 Trial Design Schematic
Description of change
Total number of patients randomised adjusted from 105 to 78, 
and number of patients per treatment group adjusted from 35 
to 26
Rationale for change
See rationale for Section 7.5 Determination of Sample Size 
below
Section to be changed
Section 3.3 Selection of Trial Population
Description of change
Total number of patients randomised adjusted from 105 to 78
Rationale for change
See rationale for Section 7.5 Determination of Sample Size 
below 
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
Exclusion criteria no. 2 adjusted as shown below:
2.
History of other forms of chronic liver disease (e.g. non-
alcoholic steatohepatitis [NASH], Hepatitis B virus 
[HBV], untreated HCV, autoimmune liver disease, 
primary biliary sclerosischolangitis, primary sclerosing 
cholangitis, Wilson’s disease, haemachromatosis, alpha-1 
antitrypsin [A1At] deficiency)  
Rationale for change
Refer to rationale for Clinical Trial Protocol Synopsis
Section to be changed
Table 5.2.3: 1 Safety laboratory tests
Description of change
The text in bold has been added to footnotes 10 and 11:
10 Reflex in case of positive HCV antibody and / or HCV 
infection that has been treated in the past.  Per central 
laboratory assay, if HCV RNA is < 15 IU / ml at 
screening (Visit 1a), eligibility criteria are met
11 Reflex in case of positive HBV core antibody and negative 
HBV surface antigen.  Per central laboratory assay, if 
HBV DNA is < 20 IU / ml at screening (Visit 1a), 
eligibility criteria are met


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Rationale for change
Clarification for interpretation of HCV RNA and HBV DNA 
reflex results
Section to be changed
Section 7.5 Determination of Sample Size
Description of change
Total number of patients updated to 78 with 26 patients per 
treatment group, and the corresponding probabilities of 
achieving the assumed treatment effects (a difference of at 
least 15% points HVPG reduction from baseline between at 
least one dose group of BI 685509 and placebo) in the final 
analysis were updated. 
Software version for calculations also updated.
Rationale for change
A smaller sample size is required to observe a difference of at 
least 15% points HVPG reduction from baseline between at 
least one dose group of BI 685509 and placebo under a 
positive scenario.  20% HVPG reduction was chosen due to 
academic guidelines on clinical development for portal 
hypertension at start of development in 2018. More recent 
data has shown, that already a 10% reduction of portal 
pressure has a positive effect on outcomes (R20-1204, R23-
3868, R20-3280), therefore, it was decided to reduce the 
threshold to 15% HVPG reduction.
Section to be changed
Section 9.1 Published References
Description of change
Two references added as shown below:
R20-3280
Abraldes JG, Garcia-Tsao G.  The design of 
clinical trials in portal hypertension.  Semin Liver Dis; 
2017;37(1);73-84.
R23-3868
Villanueva C, Aracil C, Colomo A, Hernandez-
Gea V, Lopez-Balaguer JM, Alvarez-Urturi C, et al.  Acute
hemodynamic response to beta-blockers and prediction of 
long-term outcome in primary prophylaxis of variceal 
bleeding. Gastroenterology 2009;137(1):119-128
Rationale for change
References added in support of the “rationale for the change”
provided above for Section 7.5.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34798591
7.0
clinical-trial-protocol-07
Randomised, double-blind, placebo-controlled and parallel group trial to investigate
the effects of two doses (up-titration to a fixed dose regimen) of oral BI 685509 on
portal hypertension after 24 weeks treatment in patients with clinically significant
portal hypertension (CSPH) in compensated cirrhosis
Approval-Clinical Trial Leader
02 Nov 2023 16:03 CET
Approval-Team Member Medicine
02 Nov 2023 16:21 CET
Approval-Biostatistics
03 Nov 2023 03:22 CET
Verification-Paper Signature
Completion
06 Nov 2023 08:37 CET


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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34798591
7.0

SAP_001.pdf: 
ABCD
BI-VQD-12681-S-G_50-415_AD-01 (5.0)
TRIAL STATISTICAL ANALYSIS PLAN
TITLE PAGE
Document No.:
c44563547-01
BI Trial No.:
1366-0021
Title:
Randomised, double-blind, placebo-controlled and parallel group
trial to investigate the effects of two doses (up-titration to a fixed
dose regimen) of oral BI 685509 on portal hypertension after 24
weeks treatment in patients with clinically significant portal
hypertension (CSPH) in compensated cirrhosis
  Including Protocol Revision 6 [c34798591-07]
Investigational
Product:
Avenciguat
Responsible trial 
statistician:
Tel.:
Fax: 
Date of statistical 
analysis plan:
12 July 2024
Version:
1.0
Page 1 of 34
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS..........................................................................................................8
5.1
PRIMARY ENDPOINT........................................................................................8
5.2
SECONDARY ENDPOINTS ...............................................................................8
5.2.1
Key secondary endpoints ......................................................................................8
5.2.2
Secondary endpoints .............................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................................12
6.1
TREATMENT .....................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
INTERCURRENT EVENTS..............................................................................14
6.4
SUBJECT SETS ANALYSED ...........................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................16
6.6.1
Efficacy data ........................................................................................................16
6.6.2
Safety data............................................................................................................16
6.6.3
Missing dates and times ......................................................................................16
6.6.6
Time since first diagnosis....................................................................................17
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS...................17
7.
PLANNED ANALYSIS ......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........21
7.2
CONCOMITANT DISEASES AND MEDICATION......................................22
7.3
TREATMENT COMPLIANCE ........................................................................23
7.4
PRIMARY OBJECTIVE ANALYSIS ..............................................................23
7.4.1
Main analysis .......................................................................................................23


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7.5
SECONDARY OBJECTIVE ANALYSIS ........................................................24
7.5.1
Key secondary objective analysis.......................................................................24
7.5.2
Secondary objective analysis..............................................................................24
7.7
EXTENT OF EXPOSURE .................................................................................26
7.8
SAFETY ANALYSIS..........................................................................................26
7.8.1
Adverse Events ....................................................................................................26
7.8.1.1 Assignment of AEs to treatment ..................................................................................27
7.8.1.2 Analysis of other significant AEs.................................................................................27
7.8.1.3 AE summaries ..............................................................................................................27
7.8.1.4 AEs of special interest (AESIs)....................................................................................28
7.8.1.5 User-defined adverse event category (UDAEC)..........................................................28
7.8.2
Laboratory data...................................................................................................29
7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG ......................................................................................................................31
7.8.5
Ultrasound............................................................................................................31
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............31
9.
REFERENCES ....................................................................................................32
11.
HISTORY TABLE..............................................................................................34


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases ...........................................................................13
Table 6.4: 1
Subject sets analysed ........................................................................................15
Table 6.7:1     Endpoint specific follow-up period for the assignment to treatment phase......18
Table 6.7:2
Time windows for assignment of measurements to visits for statistical 
analysis .............................................................................................................19
Table 7.1: 1
Categories for summary of continuous variables .............................................22
Table 7.5.2:1 Categories for decompensation events .............................................................25
Table 7.8.1.5: 1
Definition of continuous UDAEC............................................................28
Table 11: 1
History table .....................................................................................................34


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AC
AE
Adjudication Committee
Adverse Event
AESI
Adverse Event of Special Interest
ALQ
Above Limit of Quantification
ALT
Alanine transaminase
ANCOVA
Analysis of Covariance
AST
Aspartate transaminase
ATC
Anatomical-Therapeutic-Chemical classification
BIcMQ
BI-customized MedDRA query
BLQ
Below Limit of Quantification
BMI
Body mass index
BMS
Biomarker Set
CI
Confidence Interval
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DILI
Drug-Induced Liver Injury
DMC
Data Monitoring Committee
DBP
Diastolic blood pressure
DV
Protocol Deviation
ECG
Electrocardiogram
EDMS 
Electronic Document Management System
EoS
End of Study (corresponds with End of Trial)
EoT
End of Treatment
FAS
Full Analysis Set
FHVP
Free hepatic venous pressure


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Term
Definition / description
HE
Hepatic Encephalopathy
HVPG
Hepatic Venous Pressure Gradient
ICE
Intercurrent Event
ICH
International Council on Harmonization
IPD
Important protocol deviation
TSAP
Trial Statistical Analysis Plan
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM 
Mixed Model with Repeated Measurements
NSBB 
Non-Selective Beta-Blocker
PD
Protocol deviation
PEth
Phosphatidylethanol
PK
Pharmacokinetic
PT
Preferred term
REP
Residual effect period
RPM
Report planning meeting
RS
Randomized Set
SBP
Systolic blood pressure
SAE
Serious Adverse Event
SD
Standard deviation
SDL
Subject data listing
SMQ
Standardized MedDRA query
SOC
System Organ Class
TMF
Trial Master File
TOC
Table of contents
TS
Treated Set
ULN
Upper Limit of Normal
ULOQ
Upper limit of quantification
VH
Variceal Haemorrhage
WHVP
Wedged Hepatic Venous Pressure


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


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4. CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There are no changes in this TSAP compared to the statistical methods described in the CTP.
5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is defined as the percentage change from baseline in HVPG after 24 
weeks of treatment. 
The average wedged hepatic venous pressure (WHVP) and the average free hepatic venous 
pressure (FHVP) will be calculated based on the triplicate measurements.
Either the average FHVP 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 average FHVP, then: 
                     HVPG (mmHg)=average WHVP (mmHg) – PFHVP (mmHg);
if the average FHVP is considered to be more reliable than the recorded PFHVP, then:
HVPG (mmHg)=average WHVP (mmHg) – average FHVP (mmHg).
The quality of the HVPG will be categorized in to optimal, sub-optimal and not evaluable 
based on the judgement of the central reader. A frequency table of the number and percent of 
HVPG tracings (measured at baseline, week 8 and week 24) belonging to different quality
categories will be provided.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Since there are no key secondary endpoints specified in the CTP, this section is not
applicable.
5.2.2
Secondary endpoints
The following secondary endpoints will be analysed:
•
Percentage change in HVPG from baseline (measured in mmHg) after 8 weeks of
treatment.


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•
Response defined as > 10% reduction from baseline HVPG (measured in mmHg) after 
8 weeks of treatment. Number and percentage of patients with response will be 
presented.
•
Response defined as > 10% reduction from baseline HVPG (measured in mmHg) after 
24 weeks of treatment. Number and percentage of patients with response will be 
presented.
•
Occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on 
Investigator judgement, during the first 8 weeks of treatment period. Number and 
percentage of patients with these events will be presented.
•
Occurrence of CTCAE grade 3 (or higher) hypotension or syncope based on 
Investigator judgement, during the 24-week treatment period. Number and percentage 
of patients with these events will be presented.
•
Occurrence of discontinuation due to hypotension or syncope during the first 8 weeks 
of the treatment period. Number and percentages of patients with those events will be 
presented.
•
Occurrence of discontinuation due to hypotension or syncope during the 24-week
treatment period. Number and percentages of patients with those events will be 
presented.
•
Occurrence of one or more decompensation events (i.e., ascites, VH, and/or overt HE) 
during the 24-week treatment period. Number and percentages of patients with those 
events will be presented.


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


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Table 6.1: 1
Flow chart of analysis phases
Label
Interval
Start date
End date
Screening 
Screening
Date of informed consent
Date of first
administration of
double-blind study
medication - 1
Placebo/
Avenciguat 2mg/
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. Follow-up phase might not be displayed, e.g., if 
the patient’s trial termination date is within 7 days after last administration of study drug.
For efficacy analyses of HVPG, data up to REP+1 (8 days) after last treatment intake will be 
considered as on-treatment, because an HVPG measurement at EOT is permitted within 7 
days after scheduled EOT (i.e., REP+1 day after last dose) as stated in Section 5.1.1 of the 
CTP.
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to
treatment groups, i.e., patients will be analysed in the treatment group they were randomized
to.
AEs with an onset during the time of the incorrect study treatment will be listed separately.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Protocol deviations (PD) 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 PD could generate exclusion from analysis sets will be taken during
the study and finalized at the last report planning meeting (RPM), i.e., before unblinding.
Non-important COVID-19 related PDs will only be listed.


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6.3
INTERCURRENT EVENTS
The expected intercurrent events (ICEs) of interest in this trial are:

Use of the following restricted concomitant therapy:
-
NO-sGC-cGMP pathway activating therapies like NO-donors (e.g. glyceryl
trinitrate, isosorbide di- or mono-nitrate, molsidomine), PDE-5-inhibitors (e.g.
sildenafil, tadalafil, and vardenafil), non-specific PDE inhibitors such as dipyridamole 
and theophylline, or sGC-stimulators (e.g., riociguat)

New onset of / dose change in existing NSBB / carvedilol, 

Occurrence of a decompensation event

Premature discontinuation of assigned trial medication.
The identified ICEs based on medical review will be confirmed before the DBL.
As a primary estimand, the Hypothetical strategy will be used for handling these
intercurrent events for primary objective as a main analysis as if all the intercurrent events had 
not happened.  
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).

Screened set (SCR) – this analysis set includes all patients having signed informed 
consent. The SCR will be used for analyses of patient disposition.


The discussion on all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at latest at the DBLM.


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In Table 6.4:1 the subject sets which are to be used for each class of endpoint are illustrated.
Table 6.4: 1
Subject sets analysed
Subject set
Class of endpoint
SCR
RS
TS
FAS
Disposition
X
Primary endpoint
X
Secondary efficacy and 
X
Secondary and further 
safety endpoints
(including liver 
decompensation) & 
treatment exposure
X
Demographic/baseline 
endpoints
X
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 randomised 
treatment group. In the case of stratification error at randomisation, the subjects will 
be analysed according to the stratum to which they actually belong (regardless of any 
mis-assignment to treatment based on identification of the wrong stratum from IRT), 
as such an error occurs before randomization and is therefore consistent with 
regulatory guidance. 
Then, for safety analyses, the following will be used in addition:
-
If a patient is planned to receive avenciguat (i.e., randomised to either avenciguat 2 mg 
BID or avenciguat 3 mg BID), then patients will be reported under the planned
treatment from the randomization 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 


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avenciguat kits at any visit. If the patient was administered at least one kit of 
avenciguat during the treatment period, then the patient will be assigned to a relevant 
avenciguat dose treatment group (either avenciguat
BID or avenciguat
BID, depending on the kit administered).
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.
6.6.3
Missing dates and times
Missing or incomplete AE dates are imputed according to Boehringer Ingelheim standards
(2).
If the date of first drug administration is missing but the patient was randomized, the date of
the first drug administration will be set to the date of randomization. If the date of first
administration is partially missing with the month and year present, the day will be set to the
date of randomization if randomisation was in the same month. If randomization 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.


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All other cases need to be assessed by the trial team on an individual basis, using above points 
as guidance.
6.6.6
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 be 
calculated as if diagnosed on the 15th of that month.
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 randomized study medication.
Measurements taken prior to the first intake of randomized 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 6.1:1 below and will be assigned to the randomized study 
medication for efficacy analyses and to the first study medication taken for 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 Endpoint 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 
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. 
On-treatment efficacy, safety 
 measurements will be assigned to visits based on 
the extended time windows around the planned visit dates, defined relative to the day of first 
trial medication intake (see Table 6.7:2). 
For the analyses of the secondary and further safety endpoints at week 8, the actual V7 date + 
X days (X=3 or 7 days for safety laboratory and AE respectively) will be used for the analysis 
time windows.


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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)
*
EndA
(extended)
*
V1
Screening
-42
+7
-∞
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
Day 57
±3
54
60
51
71
V8
Week 12
Day 85
±5
80
90
72
99
V9
Week 16
Day 113
±5
108
118
100
127
V10
Week 20
Day 141
±5
136
146
128
155
V11
Week 24/
EoT
Day 169
±5
164
174
156
Study
medication 
stop
date + X#  days
Off-treatment
V12
Week 28/
EoS
Day 197
±5
192
202
Study
medication 
stop
date + X#
days +1
Day of last 
follow-up 
value
A In case of premature discontinuation of the study medication, an early EoT visit has to be performed within 7 days of 
medication stop date. If such an EoT Visit falls into the time window of a previous visit, measurements will be assigned to 
this previous visit and the visit value will be determined as described above. In this case, the time window for the visit that 
includes the early EoT visit will end X days after the study medication stop date, including Day X. Patients will then be asked 
to continue in the study according to the visit schedule. Off-treatment measurements will be assigned to visits in the same 
manner. 
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 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 


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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 randomization will be based on nominal visits and time windowing will not be
applied. For these time points, data from the scheduled visit will always be selected if they are 
collected correctly. Unscheduled visits will only be considered if no correct data from the
scheduled visit is available. If no correct data from a scheduled visit is available and multiple
unscheduled correct values are available for a visit, the first correct value will be selected.
7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
Clinical Trials and Project Summaries" (3).
Disposition of the patient population participating in the trial will be summarized by the 
presentation of the frequency of patients screened, randomized, screened but not randomized, 
randomised and treated, randomized but not treated, who completed the treatment period as 
planned, who were prematurely discontinued study treatment by reason, who is still ongoing 
in the study, who completed the observational period as planned, who prematurely 
discontinued study participation, and who completed Week 8 visit (V7). 
A frequency of patients with iPDs will be presented by treatment group for treated set. The 
frequency of patients in different analysis sets will also be presented for each treatment group. 
The iPDs per patient will be listed indicating whether the iPD led to exclusion from patient 
sets analysed.
For in-text tables presenting descriptive analysis of the endpoints and other variables (in 
original scale), the set of summary statistics is: N (number of patients with non-missing 
values), mean, standard deviation (SD).
For end-of-text tables, the set of summary statistics is: 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" (3). 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as percentage (%) relative to the 
respective treatment group. Percentages will be based on all patients in the respective patient 
set whether they have non-missing values or not. Percentages will be rounded to one decimal 
place. The category missing will be displayed if and only if there are actual missing values. 


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section.
Descriptive statistics for demographic parameters and baseline characteristics will be 
presented based on the RS. A separate listing will be provided for gastroscopy data.
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
≤ 30
> 30 to ≤ 45
> 45 to ≤ 60
> 60 to ≤ 90
> 90
Time since first diagnosis of cirrhosis
(years)
≤ 1
> 1 to ≤ 5
> 5 to ≤ 10
> 10
Baseline HVPG
(mmHg)
≤ 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 Organization – Drug Dictionary (WHO-DD).
A medication will be considered concomitant to treatment if it:


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
is ongoing at the start of trial medication intake.

starts within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
Concomitant medication use will be summarized 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:

“Yes”,

“No” and，

“Missing”.
7.4
PRIMARY OBJECTIVE ANALYSIS
7.4.1
Main analysis
The primary endpoint will be analysed through a MMRM model in combination with the 
primary estimand of handling ICEs (see Section 6.3). The FAS will be used for the analysis: 
the patient set includes all patients who had at least one evaluable baseline HVPG 
measurement. The missing data will not be imputed. Instead, the MMRM will handle missing 
data based on a likelihood method under the “missing at random” assumption.
For the MMRM model, treatment at each visit, use of NSBBs or carvedilol (yes / no) at 
baseline, and baseline HVPG at each visit will be used as covariates. Refer to Section 7.2.3 of 
the CTP for a detailed description of the statistical analysis for the percentage change from 
baseline in HVPG after 24 weeks of trial treatment.
The adjusted estimate of mean percentage change from baseline in HVPG at 24 weeks and its 
standard error will be obtained from MMRM for the placebo and treatment groups. The 95% 
CI will be provided for adjusted mean effect of each treatment group as well as the 
comparison with placebo.
SAS code for the MMRM model will be based on the following structure:
PROC MIXED DATA=alldat cl method=reml; 
CLASS visit trt subject;
MODEL chg = base*visit visit*trt stra / ddfm=kr s CL; REPEATED visit / subject= 
subject type=un r rcorr;


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LSMEANS visit*trt /pdiff=all om cl alpha=0.05 slice=visit;
RUN;
7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
This section is not applicable as no key secondary endpoints have been specified in the
protocol.
7.5.2
Secondary objective analysis
The secondary endpoints for this study are described in CTP Section 2.1.3.
For the secondary endpoint of percentage change in HVPG after 8 weeks of treatment, the 
analysis of covariance (ANCOVA) will be used. The analysis will be performed on the FAS 
with treatment assignment as randomized and include on-treatment HVPG only. If a patient 
misses the Week 8 visit, the missing data will not be imputed. 
This model will include treatment and use (or not) of NSBBs or carvedilol as fixed 
classification effects and baseline HVPG as a linear covariate. The random error is assumed to 
be normally distributed with mean 0 and variance σ². The analysis will only be used for 
estimation of treatment effects without performing statistical tests.
For other secondary endpoints, only descriptive statistics will be presented. 


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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
Definition
Ascites
PT - ‘Ascites’
PT - ‘Bacterascites’ 
PT - ‘Haemorrhagic ascites’
Variceal haemorrhage
PT - ‘Oesophageal varices haemorrhage’
PT - ‘Oesophageal haemorrhage’
PT - ‘Bleeding varicose vein’
HLT – ‘Gastric and oesophageal haemorrhages’
HLT – ‘Non-site-specific gastrointestinal haemorrhages’
Hepatic encephalopathy
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 (in years) that all patients pooled together were on treatment. A separate
listing will be created for patients who switched treatment at any time (i.e., down-titration)
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, >8 to 12 weeks, >12 to 18 weeks, >18 to 24 weeks, >24 weeks.
No temporary treatment interruption period will be reported.
7.8
SAFETY ANALYSIS
AEs reported to be related to study procedures will be based on the enrolled set and listed. All 
the other safety analyses will be performed based on the TS following BI standards.
7.8.1 Adverse Events
AEs will be coded with the most recent version of MedDRA coding dictionary. Patients will 
be analysed according to the actual treatment received.
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 (randomization 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. For this purpose, AE data will be 
combined in a 2-step procedure into AE records.
In the first step, AE occurrences, i.e., AE entries on the CRF, will be collapsed into AE
episodes if all of the following apply:

The same MedDRA lowest level term was reported for the occurrences.

The occurrences were time-overlapping or time-adjacent (time-adjacency of 2
occurrences is given if the second occurrence started on the same day or on the day
after the end of the first occurrence. 

Treatment did not change between the onset of the occurrences OR treatment changed
between the onset of the occurrences, but no deterioration was observed for the later
occurrence.


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In a second step, AE episodes will be condensed into AE records provided that the episodes
were reported with the same term on the respective MedDRA level and that the episodes are
assigned to the same treatment. 
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 until 7 days (residual effect period –
REP) after last drug intake will be assigned to the on-treatment period. All AEs occurring 
before first drug intake will be assigned to ‘screening’ and all AEs occurring after last drug 
intake + REP of 7 days will be assigned to ‘follow-up’ (for listings only). For details on the 
treatment definition, see Section 6.1. 
If only the start date of an AE is collected (without the start time), any AE occurrence on the 
same day as the first avenciguat administration will be assigned to the on-treatment phase. 
Drug-related AEs which will be presented as actual treatment taken at each given timepoint.
AEs and serious adverse events (SAEs) assigned to the following phases: screening, each 
treatment group (placebo, avenciguat 2 mg and avenciguat 3 mg), 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 summarized according to ICH E3 criterion (5).
Thus, AEs classified as 'other significant' will include those non-serious adverse events with
‘action taken = discontinuation’ or ‘action taken = dose reduced’. 
7.8.1.3 AE summaries
An overall summary of AEs will be presented.
The frequency of patients with AEs will be summarized by treatment, primary SOC and PT. 
AEs which were defined as secondary endpoints will be summarized separately. AEs will also 
be reported by intensity according to the maximum Common Terminology Criteria for 
Adverse Events (CTCAE). Separate tables will be provided for patients with other significant 
AEs according to ICH E3 (5), adverse events of special interest (AESI), for patients with 
serious adverse events, for patients with AEs leading to dose reduction, for patients with AEs 
leading to discontinuation, and for patients with drug-related AEs.
The SOC will be sorted alphabetically, PTs will be sorted by frequency (within SOC).
Customized sorting orders may also be used based on trial needs, e.g., SOC sorted by
frequency.
For further details on summarization of AE data, please refer to “Handling of missing and 
incomplete AE dates” (2) and “Analysis and Presentation of Adverse Event data from Clinical 
Trials” (6). 


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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 randomization 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).
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. 


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Analysis on hypotension based on baseline BP and the lowest BP during the episode will be 
carried out. Criteria for significant (vs. non-significant) hypotensive episode are:
-
Baseline SBP <=140: decrease *
+,-./ 0# 12345 /6- -74.+1- – 9:.-4- 0#
9:.-4- 0#
; ≥30%;
-
Baseline SBP >140: decrease *
+,-./ 0# 12345 /6- -74.+1- – 9:.-4- 0#
9:.-4- 0#
; ≥40%;
-
Or lowest SBP during the episode <90.
-
Baseline DBP <=70: *
+,-./ A0# 12345 /6- -74.+1- – 9:.-4- A0#
9:.-4- A0#
; ≥30%;
-
Baseline DBP > 70: *
+,-./ A0# 12345 /6- -74.+1- – 9:.-4- A0#
9:.-4- 0#
; ≥40%;
-
Or lowest DBP during the episode <50.
-
Lowest mean arterial pressure (MAP = 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
7.8.2
Laboratory data
The analyses of laboratory parameters will be descriptive in nature and will be based on BI 
standards (7). Note that data from the central laboratory will be used for all displays described 
below, unless otherwise specified.
For continuous safety laboratory parameters standardized and normalized values will be
derived as well as the differences to baseline. Normalisation means transformation to a 
standard unit and to a standard reference range. The process of normalisation, handling of 
repeat values at the same visit for by-visit displays, as well as standard analyses for safety 
laboratory data are described in the BI guidance for “Handling, Display and Analysis of 
Laboratory Data” (7). All analyses considering multiple times of the ULN (as described 
below) will be based on standardised and not normalised values. 
Laboratory parameters will be shown in conventional units. Where conventional units differ
from SI units, analyses will be repeated on SI units in the appendix.
Laboratory values will be compared to their reference ranges and frequency tables will be
provided for the number of patients within and outside the reference range at baseline (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.
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.


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The following lab parameters will also be presented graphically:

Haematocrit

Haemoglobin

RBC count / erythrocytes

WBC / leukocytes

Platelet count / thrombocytes

Reticulocytes

INR

ALT

Alkaline phosphatase

AST

Bilirubin (total)

Albumin

gamma-GT

eGFR
To support analyses of liver related adverse drug effects, the frequency of patients with AST 
and/or ALT ≥ 3xULN combined with the total bilirubin ≥ 2xULN in a 30-day period after 
AST/ALT elevation will be displayed, stratified by alkaline phosphatase < 2xULN and ≥ 
2xULN (a patient can potentially be in both alkaline phosphatase strata in case of multiple 
AST/ALT and bilirubin elevations). The start of the 30-day time span is triggered by each 
liver enzyme elevation above defined thresholds. This analysis will be based on standardised 
laboratory values.
A graphical analysis of the ALT and total bilirubin during the on-treatment period will also be 
performed; the so called eDISH plot. In the graph, for each subject, the peak total bilirubin is 
presented as a fold increase over the ULN against the peak ALT as a fold increase over the 
ULN, on a log 10 scale. The measurements displayed 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 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 analysed 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 during treatment period and post-treatment 
period (pre-dose, 1 hour, 2 hours) and for the difference from baseline and pre-dose (see 
Section 6.7) will be provided by treatment Figures for change from baseline and change from 
pre-dose for both on-treatment visit and post-treatment visit will be provided as well.


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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.
7.8.5 Ultrasound
Descriptive analysis of change from baseline of portal vein diameter at week 8 and week 24
will be provided. A listing of all the collected data from the ultrasound CRF page for each 
patient will be reported.
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION
The treatment information will be released to unblind the trial database after the last patient 
has completed their EoS/Follow-up visit and all data has been entered and cleaned as defined 
in the “Data Ready to be Unblinded and/or Final Trial Closure Notification” (RUN) form.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline
Topic E9; Note for Guidance on Statistical Principles for Clinical Trials, current
version
2.
BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE dates”, current
version; KMED.
3.
KM Asset BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and 
Project Summaries", current version, KMED.
4.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses
performed within Clinical Pharmacokinetics/Pharmacodynamics”, current
version; KMED.
5.
CPMP/ICH/137/95: “Structure and content of clinical study reports”, ICH Guideline
Topic E3; Note for Guidance on Structure and Content of Clinical Study Reports,
current version.
6.
KM Asset BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse Event 
data from Clinical Trials”, current version, KMED.
7.
KM Asset BI-KMED-BDS-HTG-0042: " Handling, Display and Analysis of Laboratory 
Data", current version; KMED


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11. HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
12-July-24
None
This is the final TSAP