Pharmacokinetics, Safety and Tolerability of BI 1015550 Following Oral Administration in Male and Female Participants With Different Degrees of Hepatic Impairment (Child-Pugh Classification A and B) Compared With Matched Male and Female Participants With Normal Hepatic Function (an Open-label, Non-randomised, Single-dose, Parallel, Individual-matched Design Trial)
Phase: PHASE1
Conditions: Hepatic Insufficiency
Sponsor: Boehringer Ingelheim



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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
28 Oct 2022
Revision date
30 Mar 2023
BI trial number
1305-0027
Title of trial
Pharmacokinetics, safety and tolerability of BI 1015550 following oral 
administration in male and female participants with different degrees of hepatic 
impairment (Child-Pugh classification A and B) compared with matched male and 
female participants with normal hepatic function (an open-label, non-randomised,
single-dose, parallel, individual-matched design trial)
 Investigator 
Trial site
Clinical phase
I
Trial rationale
In this trial, pharmacokinetics, safety and tolerability of BI 1015550 single oral 
dose in participants with different degrees of hepatic impairment compared to 
individually matched participants with normal hepatic function will be assessed.
Trial objectives
To investigate the effect of mild (Child-Pugh A) and moderate (Child-Pugh B) 
hepatic impairment on the pharmacokinetics, safety and tolerability of BI 1015550
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of BI 1015550
Secondary endpoints: AUC0-! of BI 1015550
Trial design
Open-label, non-randomised, parallel, individual matched design
Number of participants 
total entered
32*
on treatment
∀Group 1: 8 participants with mild hepatic impairment (Child-Pugh A)
∀Group 2: 8 participants with moderate hepatic impairment (Child-Pugh B)
∀Group 3: 8* participants with normal hepatic function individually matched to 
participants of Group 1 **
∀Group 4: 8* participants with normal hepatic function individually matched to 
participants of Group 2**
** Matching criteria: age (± 10 years), gender and weight (± 15%)
* One participant with normal hepatic function may match one participant in one 
or both groups of participants with hepatic impairment. Thus, the total sample size 
may be 24 to 32 participants. Additional participants may be included to ensure 
that the study objectives are reached.

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Diagnosis
Participants with hepatic impairment (Child-Pugh A or B) and participants with 
normal hepatic function (matched controls to the participants with hepatic 
impairment)
Main inclusion criteria
Male/female participants (at least 25% of each gender), age 18 - 79 years 
(inclusive), body mass index (BMI) of 18.5 to 35 kg/m2 (inclusive) with hepatic 
impairment of Child-Pugh A (mild) and B (moderate) classification. 
Male/female participants (at least 25% of each gender) with normal hepatic 
function individually matched to participants with hepatic impairment with respect 
to age, gender, and weight 18-79 years (inclusive), BMI of 18.5 to 35 kg/m2
(inclusive)
Test product
BI 1015550 film-coated tablet
dose
18 mg
mode of 
administration
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
Single dose
Statistical methods
To assess the effect of hepatic impairment on the primary and secondary 
pharmacokinetic endpoints of BI 1015550, the relative bioavailability will be 
estimated by the ratios of the geometric means of the respective pairwise 
comparison of interest, i.e., for each hepatic impairment group vs. the respective 
control group. Additionally, their two-sided 90% confidence intervals (CIs) will 
be provided. This method corresponds to the two one-sided t-test procedure, each 
at a 5% significance level. Since the main focus is on estimation and not testing, a 
formal hypothesis test and associated acceptance range is not specified for any 
comparison of interest. The statistical model will be an analysis of variance 
(ANOVA) on the logarithmic scale including the fixed effect ‘degree of hepatic 
impairment’ and the random effect ‘matched pair’.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
Visit
Day
Planned time (relative to 
drug administration) 
(h:min)
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory 7
PK blood8
Suicidality assessment 12
12-lead ECG 9
Vital signs (BP, PR) 10
Questioning for AEs and 
concomitant therapy 6
1
-21 to 
-2
Screening (SCR) 1
A
x
x
x
2
-1
-24:00
08:00
Admission to trial site 
B 5
x11
x
1
-2:00
06:00
x2
x
x2
x2
x2
0:00
08:00
Drug administration
0:30
08:30
x
0:45
08:45
x
1:00
09:00
x
x
x
x
1:15
09:15
x
1:30
09:30
x
1:45
09:45
x
2:00
10:00
240 mL fluid intake (snack for 
participants with diabetes) 3
x
x
x
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch 3
x
x
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary) 3
x
x
x
x
10:00
18:00
x
11:00
19:00
Dinner 3
12:00
20:00
x
14:00
22:00
x
x
2
24:00
08:00
B
x
x
x
x
36:00
20:00
x
x
3
48:00
08:00
x
x
4
72:00
08:00
Breakfast 3 (voluntary),
discharge from trial site
B
x
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
6
120:00
08:00
Ambulatory visit
x
x
7
144:00
08:00
Ambulatory visit
x
x
x
3
8 to 14
End of study (EoS) examination 4
C
x
x
x
x
1.
Participant must be informed and written informed consent obtained prior to starting any screening procedures. 
Screening procedures include physical examination (including assessment of suicidal ideation and behaviour using the 
C-SSRS questionnaire), check of vital signs, ECG, safety laboratory (including drug screening, alcohol breath test, 
serology, and SARS-CoV-2 PCR test, serum pregnancy test in WOCBP), demographics (including determination of 
body height and weight, smoking status and alcohol history), relevant medical history, concomitant therapy and review 
of inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 2 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination (including 
assessment of suicidal ideation and behaviour using the C-SSRS questionnaire), body weight, vital signs, ECG, safety 
laboratory (including urine pregnancy test in WOCBP), recording of AEs and concomitant therapies. 
5.
In addition: urine drug screening, alcohol breath test, SARS-CoV-2 antigen test, as well as serum pregnancy test in 
WOCBP

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6.
AEs and concomitant therapies will be recorded throughout the trial but will be specifically asked for at the times 
indicated in the Flow Chart above
7.
Letters A, B and C define different sets of safety laboratory examinations (for details refer to Section 5.2.3).
8.
For details of PK blood sampling, refer to Section 5.3.2.
9.
For details of 12-lead ECG, refer to Section 5.2.4.
10. For details of vital signs evaluation, refer to Section 5.2.2.
11. Only assessment of body temperature (if needed due to the current status of the pandemic).
12. For details of suicidality assessment, refer to Section 5.2.5.1.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS AND DEFINITIONS..................................................... 10
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................14
1.2.1
BI 1015550 .............................................................................................14
1.2.1.4
Clinical safety and efficacy......................................................18
1.2.2
Residual Effect Period..........................................................................20
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................20
1.4
BENEFIT - RISK ASSESSMENT ...................................................................21
1.4.1
Benefits...................................................................................................21
1.4.2
Risks .......................................................................................................21
1.4.3
Discussion...............................................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 28
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......28
2.1.1
Main objectives......................................................................................28
2.1.2
Primary endpoints ................................................................................28
2.1.3
Secondary endpoint ..............................................................................28
2.2.2.2
Safety and tolerability..............................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 30
3.1
OVERALL TRIAL DESIGN............................................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for trial entry..............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.2.1
Inclusion criteria applicable to all participants........................33

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3.3.2.2
Inclusion criteria applying only to participants with impaired 
hepatic function........................................................................34
3.3.2.3
Inclusion criteria applying only to participants with normal 
hepatic function........................................................................34
3.3.3
Exclusion criteria ..................................................................................35
3.3.3.1
Exclusion criteria applying to all participants .........................35
3.3.3.2
Exclusion criteria applying only to participants with hepatic 
impairment...............................................................................37
3.3.3.3
Exclusion criteria applying only to participants with normal 
hepatic function........................................................................37
3.3.4
Withdrawal of subjects from treatment or assessments ...................38
3.3.4.1
Withdrawal from trial treatment ..............................................38
3.3.4.2
Withdrawal of consent to trial participation ............................40
3.3.4.3
Discontinuation of the trial by the sponsor..............................40
3.3.5
Replacement of subjects .......................................................................40
4.
TREATMENTS........................................................................................ 41
4.1
INVESTIGATIONAL TREATMENTS ..........................................................41
4.1.1
Identity of the Investigational Medicinal Products ...........................41
4.1.2
Selection of doses in the trial................................................................41
4.1.3
Method of assigning subjects to treatment groups ............................41
4.1.4
Drug assignment and administration of doses for each subject .......42
4.1.5
Blinding and procedures for unblinding ............................................43
4.1.6
Packaging, labelling, and re-supply ....................................................43
4.1.7
Storage conditions.................................................................................43
4.1.8
Drug accountability ..............................................................................43
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................44
4.2.1
Other treatments and emergency procedures....................................44
4.2.2
Restrictions............................................................................................44
4.2.2.1
Restrictions regarding concomitant treatment .........................44
4.2.2.2
Restrictions on diet and life style.............................................45
4.2.2.3
Contraception requirements.....................................................45
4.3
TREATMENT COMPLIANCE.......................................................................45
5.
ASSESSMENTS....................................................................................... 46
5.1
ASSESSMENT OF EFFICACY.......................................................................46
5.2
ASSESSMENT OF SAFETY............................................................................46
5.2.1
Physical examination ............................................................................46
5.2.2
Vital signs...............................................................................................46
5.2.3
Safety laboratory parameters..............................................................46
5.2.4
Electrocardiogram................................................................................50
5.2.5
Other safety assessments......................................................................50
5.2.5.1
Suicidal risk (C-SSRS) ............................................................50

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5.2.6
Assessment of adverse events...............................................................51
5.2.6.1
Definitions of adverse events...................................................51
5.2.6.1.1 Adverse event ............................................................51
5.2.6.1.2 Serious adverse event ................................................51
5.2.6.1.3 AEs considered ‘Always Serious’.............................52
5.2.6.1.4 Adverse events of special interest .............................52
5.2.6.1.5 Intensity (severity) of AEs.........................................54
5.2.6.1.6 Causal relationship of AEs ........................................54
5.2.6.2
Adverse event collection and reporting ...................................55
5.2.6.2.1 AE collection.............................................................55
5.2.6.2.2 AE reporting to the sponsor and timelines ................56
5.2.6.2.3 Pregnancy ..................................................................56
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................56
5.3.1
Assessment of pharmacokinetics .........................................................56
5.3.2
Methods of sample collection...............................................................57
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................57
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................58
5.4
ASSESSMENT OF BIOMARKERS................................................................58
5.5
BIOBANKING ...................................................................................................58
5.6
OTHER ASSESSMENTS .................................................................................58
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................58
6.
INVESTIGATIONAL PLAN.................................................................. 59
6.1
VISIT SCHEDULE............................................................................................59
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................60
6.2.1
Screening period....................................................................................60
6.2.2
Treatment period ..................................................................................60
6.2.3
Follow-up period and trial completion ...............................................60
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 61
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................61
7.2
PLANNED ANALYSES....................................................................................61
7.2.1
General considerations.........................................................................61
7.2.1.1
Analysis sets.............................................................................61
7.2.1.2
Pharmacokinetics.....................................................................61
7.2.2
Primary endpoint analyses...................................................................62
7.2.3
Secondary endpoint analyses ...............................................................63

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7.2.5
Safety analyses.......................................................................................63
7.2.6
Interim analyses ....................................................................................64
7.3
HANDLING OF MISSING DATA ..................................................................64
7.3.1
Safety......................................................................................................64
7.3.2
Pharmacokinetics..................................................................................64
7.4
RANDOMISATION ..........................................................................................64
7.5
DETERMINATION OF SAMPLE SIZE ........................................................65
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 66
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................66
8.2
DATA QUALITY ASSURANCE .....................................................................67
8.3
RECORDS..........................................................................................................67
8.3.1
Source documents .................................................................................67
8.3.2
Direct access to source data and documents.......................................68
8.3.3
Storage period of records.....................................................................68
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................68
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......69
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................69
8.6
TRIAL MILESTONES .....................................................................................69
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................70
9.
REFERENCES......................................................................................... 72
9.1
PUBLISHED REFERENCES...........................................................................72
9.2
UNPUBLISHED REFERENCES.....................................................................73
10. APPENDICES .......................................................................................... 74
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................74
10.2
LISTING RESTRICTED CONCOMITANT MEDICATION......................80
10.2.1 Strong CYP3A4 inhibitors ...................................................................80
10.2.2 Combinations of CYP 3A4 inhibitors .................................................80
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 81
11.1
GLOBAL AMENDMENT 1 .............................................................................81
11.2
GLOBAL AMENDMENT 2 .............................................................................82

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eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EFD
Embryo-foetal development
EoS
End of Study (synonym for End of Trial)
ESR
Erythrocyte Sedimentation Rate
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FEED
Fertility and early embryonic development
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GFR
Glomerular filtration rate
GI
Gastro-intestinal
GLDH
Glutamate dehydrogenase
gMean
Geometric mean
HIV
Human immunodeficiency virus
HR
Heart rate
IB
Investigator’s brochure
iCF
Intended commercial formulation
IEC
Independent Ethics Committee
IME
Important medical event
IPD
Important protocol deviation
IPF
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
LOAEL
Lowest observed adverse effect Level
MACE
Major Adverse Cardiovascular Events
MDA
Methylenedioxyamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NCT 
Number Connection Test
NOAEL
No adverse effect level
NOEL
No observable effect level

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1.2.1.4
Clinical safety and efficacy
BI 1015550 has been investigated in a total of 9 clinical studies: 8 Phase I trials (seven trials 
in healthy subjects and one in patients with IPF), and a proof-of-clinical principle Phase II 
trial in patients with IPF. Overall, 146 healthy volunteers and 107 patients with IPF have 
been exposed to BI 1015550.
BI 1015550 was well tolerated following single dose administration up to 48 mg in healthy 
volunteers and following multiple administrations up to 18 mg bid over a treatment period of 
up to 12 weeks in patients.
Clinical safety
In healthy subjects, seven clinical studies have been completed with BI 1015550. Overall, 
BI 1015550, up to a 48 mg single-dose and 12 mg bid multiple-dose appeared to show 

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1.2.2
Residual Effect Period
The REP of BI 101550 
. This is the period after the last dose during which 
measurable drug levels and/or pharmacodynamic effects are still likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
This exploratory trial is designed to investigate the effect of mild (Child-Pugh A) and 
moderate (Child-Pugh B) hepatic impairment on the pharmacokinetics, safety and tolerability 
of BI 1015550. The data obtained in this trial will provide a basis for the treatment of patients 
suffering from IPF and other forms of progressive pulmonary fibrosis with hepatic 
impairment, as well as a potential dose adaptation for this category of patients. The design of 
this trial follows the FDA guideline for Industry “Pharmacokinetics in Patients with Impaired 
Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling” [R05-
0337] and the EMA “Guideline on the evaluation of the pharmacokinetics of medicinal 
products in patients with impaired hepatic function” [R05-0340].

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For ethical and safety reasons, also the low prevalence of severe hepatic impaired patients in 
target population, patients with severely impaired hepatic function (Child-Pugh C) will not be 
enrolled in this trial.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for participants with 
impaired hepatic function and participants with normal hepatic function. Their participation, 
however, is of major importance for the development of BI 1015550.
1.4.2
Risks
Participants are exposed to risks of trial procedures and risks related to the exposure to the 
trial medication. An overview of trial-related risks is given in Table 1.4.2: 1.
To date, no side effects have been identified for BI 1015550. Potential side effects of 
BI 1015550 will be under continuous evaluation during clinical development. Vasculitis and 
foetal loss are considered as important potential risk based only on non-clinical findings. The 
risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs and from preclinical and clinical data of 
compounds with a comparable mode of action. For AEs reported during clinical trials with 
BI 1015550 please refer to Section 1.2.1.

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Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or 
known risks of 
clinical relevance 
Summary of data, rationale for the risk
Mitigation strategy
Investigational Medicinal Product: BI 1015550

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of this study is to investigate the effect of mild (Child-Pugh A, score 
5-6) and moderate (Child-Pugh B, score 7-9) hepatic impairment on the PK of BI 1015550.
2.1.2
Primary endpoints
The following PK parameters will be determined for BI 1015550:
∀
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point)
∀
Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following PK parameter will be determined for BI 1015550:
∀
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)

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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 1015550 will be assessed based on:
∀
AEs (including clinically relevant findings from the physical examination)
∀
Safety laboratory tests
∀
Assessment of suicidal ideation and behaviour (C-SSRS)
∀
12-lead ECG
∀
Vital signs (blood pressure, pulse rate)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as a non-randomised, single-dose, open-label, parallel, individual
matched design in order to investigate PK of BI 1015550, as well as safety and tolerability of 
BI 1015550 in male and female participants with mild (Child-Pugh A) and moderate (Child-
Pugh B) hepatic impairment compared to individually matched control participants. The 
treatment will be one 18 mg tablet administered to trial participants in the fasting state. For 
details, refer to Section 4.1.
∀
Group 1: 8 participants with mild hepatic impairment (Child-Pugh A)
∀
Group 2: 8 participants with moderate hepatic impairment (Child-Pugh B)
∀
Group 3: 8 participants with normal hepatic function individually matched to 
participants of Group 1
∀
Group 4: up to 8 participants with normal hepatic function individually matched to 
participants of Group 2
One participant with normal hepatic function may match one participant in one or both 
groups of participants with hepatic impairment.
The matching criteria of the participants with normal hepatic function to the participants with 
hepatic impairment:
∀
Age (± 10 years) 
∀
Gender 
∀
Weight (± 15%) 
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
Recruitment will start with Group 1. After 4 participants in Group 1 have been treated, 
relevant safety data (i.e., AEs, medically relevant abnormalities in vital signs, ECG, and 
safety laboratory up to Day 4) will be reviewed by the Principal Investigator (or an authorised 
deputy) and the Clinical Trial Leader (or an authorised deputy). If these data do not raise 
safety concerns, treatment of participants of Group 2 may be started. Participants of Group 3 
and 4 may be recruited in parallel to Groups 1 and 2. See also Section 4.1.3 for dosing in 
subcohorts.
Definition of trial start and end are given in Section 8.6.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The defined single-dose individual-matched comparison is deemed appropriate to meet the 
objectives of the study. There was no indication of a deviation from dose proportionality of 
either Cmax or AUC, both after single administration as well as at steady state following twice 
daily dosing. For the purpose of evaluating hepatic impairment on the exposure of 
BI 1015550, the single dose design is sufficient since the multiple dose PK of BI 1015550 

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can be predicted by the single dose PK and the major metabolite is inactive. The single dose 
of 18 mg of BI 1015550 selected in this trial is the currently expected therapeutic dose in a 
twice daily (bid) regimen and has been considered safe for the trial populations and sufficient 
for the planned PK evaluations.
The resulting group sizes (see Section 7.5) are considered to be sufficient for the exploratory 
evaluation of PK. The assignment of matched control participants with normal hepatic 
function is a useful method to control for other factors which may influence the PK of 
BI 1015550 in a hepatic impaired population. The open-label treatment is not expected to 
bias results, since the main study endpoints are derived from measurement of plasma 
concentrations of the analyte.
The study design is in accordance with the guidance on PK in patients with impaired hepatic 
function [R05-0337]; this requires applying a single dose administration regimen to patients 
fulfilling the Child-Pugh A or B criteria and was deemed appropriate for the present trial. 
As discussed in Section 1.3, participants with severely impaired hepatic function (Child-Pugh 
C) will not be enrolled in this trial for ethical and safety reasons.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 8 male or female participants with mild hepatic impairment (Child-Pugh A, 
Group 1) and 8 male or female participants with moderate hepatic impairment (Child-Pugh B, 
Group 2) and up to 16 individually matched participants with normal hepatic function (Group 
3, 4) will enter the trial. Each group will consist of at least 25% of each sex. 
Participants will be recruited from the volunteers' pool of the trial site. In addition, 
participants with hepatic impairment will be recruited in cooperation with different 
hepatology centres who primarily diagnose the underlying medical condition leading to 
chronic hepatic impairment.
Participants with hepatic impairment will be assigned to one of the hepatic impairment 
groups (mild or moderate), according to Child-Pugh score (see Table 3.3: 1 and 3.3: 2). The 
hepatic function assessment and assignment to the hepatic impairment groups will be 
conducted by the investigators at the screening examination. 

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Table 3.3: 1
Child-Pugh scoring
Measure
1 Point
2 Points
3 Points
Total Bilirubin, μmol/L (mg/dL)
< 34 (< 2)
34 - 50 (2 - 3)
> 50 (> 3)
Serum albumin, g/dL
> 3.5
2.8 - 3.5
< 2.8
Prothrombin time, prolongation (s)
/ or INR
< 4.0
< 1.7
4.0 - 6.0
1.7 - 2.3
> 6.0
> 2.3
Ascites
None
Mild 
(or suppressed 
with 
medication)
Moderate to 
severe (or 
refractory)
Hepatic encephalopathy
None
Grade I–II
Grade III–IV
Table 3.3: 2
Child-Pugh scoring interpretation
Total Points
Hepatic Impairment Class
5–6
Child-Pugh A (mild hepatic impairment)
7–9
Child-Pugh B (moderate hepatic impairment)
10–15
Child-Pugh C (severe hepatic impairment)
Encephalopathy Grading System:
∀Grade 0: normal consciousness, personality, neurological examination,
electroencephalogram
∀Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting,
5 cps waves
∀Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic
waves
∀Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity,
slower waves
∀Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta
activity
Number Connection Test (NCT):
The exclusion of a possible hepatic encephalopathy will be performed using the Number
Connection Test (NCT). This test measures cognitive motor abilities. In the NCT, subjects
have to connect numbers printed on paper consecutively from 1 to 25, as quickly as possible.

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Errors are not enumerated, but subjects are instructed to return to the preceding correct 
number and then carry on. The test score is the time the subject needs to perform the test,
including the time needed to correct the errors. A low score indicates a good performance. If 
the time needed exceeds 80 seconds, subjects will be excluded from the study. In addition, an 
experienced physician may assess hepatic encephalopathy by performing a standard 
neurological examination, which includes handwriting and common amnestic testing.
Participants with normal hepatic function will be matched individually by gender, age (within 
±10 years) and weight (within ±15%) to the participants with hepatic impairment. One 
participant with normal hepatic function may match one participant in one or both groups of 
participants with hepatic impairment.
Please refer to Section 4.1.3 regarding the method of assigning participants to hepatic 
function groups.
A log of all participants 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 investigational 
drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in participants with mild or moderate hepatic impairment and 
matched control participants with normal hepatic function.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
3.3.2.1
Inclusion criteria applicable to all participants
Participants will only be included in the trial if they meet the following criteria:
1. Male or female participants
2. Age 18-79 years (inclusive)
3. BMI of 18.5 to 35 kg/m2 (inclusive)
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
5. Male participants are not required to use contraception
6. Women of childbearing potential are allowed to participate provided they use a highly 
effective contraception from at least 30 days before the administration of trial 
medication until 7 days after trial completion. 
Of note, oral hormonal contraceptives are not considered as highly effective in this 
study due to the potential CYP3A induction by BI 1015550. Therefore, the following 

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methods of contraception are considered adequate for female participants of 
childbearing potential:
-
Use of combined (oestrogen and progestogen containing) hormonal 
contraception that prevents ovulation (oral, intravaginal or transdermal), plus 
condom
-
Use of progestogen-only hormonal contraception that inhibits ovulation (only 
injectables or implants), plus condom
-
Use of intrauterine device or intrauterine hormone-releasing system
-
Sexually abstinent
-
A vasectomised sexual partner who received medical assessment of the 
surgical success (documented absence of sperm) and provided that partner is 
the sole sexual partner of the trial participant.
Female participants are not considered to be of childbearing potential if they are 
either surgically sterilised (including hysterectomy) or postmenopausal, defined as 
no menses for 1 year without an alternative medical cause (in questionable cases a 
blood sample with levels of FSH above 40 U/L and oestradiol below 30 ng/L is 
confirmatory).
3.3.2.2
Inclusion criteria applying only to participants with impaired hepatic function
In addition to the inclusion criteria given in Section 3.3.2.1, participants with impaired 
hepatic function must fulfil the following criteria:
7. Hepatic impairment classified as Child-Pugh A (score 5-6 points) or Child-Pugh B 
(score 7-9 points)
8. Absence of clinically significant abnormalities, as based on a complete medical 
history including a full physical examination, vital signs (BP, PR), 12-lead ECG, and 
clinical laboratory tests at both screening and admission to trial site, with the 
exception of findings that in the opinion of the investigator are consistent with the 
participant’s hepatic impairment.
9. Medication and/or treatment regimens must have been stable (i.e., no dose 
adjustments) for at least 4 weeks prior to the screening period and should be kept 
stable until study completion. 
Fluctuating treatment regimens may be considered for inclusion on a case-by-case 
basis if the underlying disease is under control in the opinion of the investigator and 
must be agreed to by both the investigator and the sponsor’s medical monitor.
3.3.2.3
Inclusion criteria applying only to participants with normal hepatic function
In addition to the inclusion criteria given in Section 3.3.2.1, participants with normal hepatic 
function must fulfil the following criteria: 

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10. Individually matched to participants with hepatic impairment according to sex, age, 
and weight
11. Absence of clinically significant abnormalities identified by a detailed medical 
history, full physical examination, vital signs and 12-lead ECG at both screening and 
admission to trial site
12. Absence of clinically significant abnormalities identified by a laboratory test at 
screening visit
3.3.3
Exclusion criteria
3.3.3.1
Exclusion criteria applying to all participants
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
2. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the PK of the trial medication (except appendectomy or simple hernia repair)
3. Diseases of the CNS (including but not limited to any kind of seizures or stroke), and 
other relevant neurological or psychiatric disorders (including but not limited to major 
depressive disorder)
4. History of relevant orthostatic hypotension, fainting spells, or blackouts
5. Relevant chronic or acute infections
6. Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal cell carcinoma of the skin
or squamous cell carcinoma in situ of the skin or in situ carcinoma of uterine cervix
7. History of relevant allergy or hypersensitivity (including allergy to the trial 
medication or its excipients) 
8. Use of drugs within 30 days (or 5 of its half-lives, whichever is longer) of planned
administration of trial medication that might reasonably influence the results of the 
trial (including drugs that cause QT/QTc interval prolongation)
9. Intake of an investigational drug in another clinical trial within 60 days (for multiple 
dose studies) / within 30 days (for single dose studies) or 5 half-lives (whichever is 
longer) of planned administration of investigational drug in the current trial, or 
concurrent participation in another clinical trial in which investigational drug is 
administered

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10. Intake of strong CYP3A inhibitors, e.g., amprenavir, indinavir, nelfinavir, ritonavir, 
itraconazole or ketoconazole within 30 days or 5 half-life times (whichever is longer) 
to administration of trial medication. 
11. Smoker (more than 15 cigarettes or 5 cigars or 5 pipes per day)
12. Inability to refrain from smoking on specified trial days
13. Alcohol abuse (consumption of more than 10 g per day for females and 20 g per day
for males)
14. Drug abuse or positive drug screening
15. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
16. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
17. Inability to comply with the dietary regimen of the trial site
18. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
19. Subject is assessed as unsuitable for inclusion by the investigator, for instance,
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study 
20. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
21. For female participants: Lactation, pregnancy or positive pregnancy test, or plans to 
become pregnant during the trial or within 7 days after trial completion
22. Active vasculitis, unstable or uncontrolled within 8 weeks prior to Visit 1 or during 
the screening period.
23. History of vasculitis
24. Relevant immunodeficiency
25. Patients with active TB at Visit 1 or medical history of incompletely treated TB.
26. Any suicidal behaviour in the past 2 years (i.e., actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour).
27. Any suicidal ideation of type 4 or 5 on the C-SSRS in the past 3 months or at Visit 1 
and/or Visit 2 predose (i.e., active suicidal thought with method and intent but without 
specific plan; or active suicidal thought with method, intent and plan).

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28. Cardiovascular diseases, any of the following:
a. Severe hypertension within 3 months of Visit 1
b. Myocardial infarction, stroke or transient ischaemic attack within 6 months of 
Visit 1
c. Unstable cardiac angina within 6 months of Visit 1
29. Chronic kidney disease with eGFR less than 60 ml/min/1.73m2 at Visit 1 (CKD-EPI 
formula or Japanese version of CKD-EPI for Japanese patients) 
3.3.3.2
Exclusion criteria applying only to participants with hepatic impairment
In addition to the exclusion criteria listed in Section 3.3.3.1, participants with hepatic 
impairment fulfilling any of the following criteria will not be included into the trial:
30. A marked prolongation of QT/QTc interval (such as QTcF intervals that are 
repeatedly greater than 480 ms in males or repeatedly greater than 500 ms in females) 
or any other relevant ECG finding at screening 
31. Repeated measurement of systolic blood pressure outside the range of 90 to 
170 mmHg, diastolic blood pressure outside the range of 50 to 100 mmHg, or pulse 
rate outside the range of 50 to 90 bpm
32. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance, except for laboratory values outside the reference range due to 
underlying disease
33. Thrombocytes < 40.000 10E9/L
34. Gastrointestinal bleeding within 3 months of Visit 1
35. Encephalopathy > grade II or the time needed for the Number Connection Test 
exceeds 80 seconds
36. Oesophageal varices > stage 2
37. Severe ascites
3.3.3.3
Exclusion criteria applying only to participants with normal hepatic function
In addition to the exclusion criteria listed in Section 3.3.3.1, participants with normal hepatic 
function fulfilling any of the following criteria will not be included into the trial:
38. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator

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39. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males or repeatedly greater than 470 ms in females) or any 
other relevant ECG finding at screening
40. Repeated measurement of systolic blood pressure outside the range of 90 to 140 
mmHg (for participants older than 60 years: 90 to 150 mmHg), diastolic blood 
pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 
90 bpm
41. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance
42. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Participants may withdraw or may be removed from trial treatment or may withdraw consent 
to trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below.
If a participant is removed from or withdraws from the trial prior to the administration of trial 
medication, the data of this participant will not be entered in the CRF and will not be reported 
in the CTR.
If a participant is removed from or withdraws from the trial after the administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete EoS examination should be performed. If the 
discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.2), the 
discontinued participant should, if possible, be questioned for AEs and concomitant therapies 
at or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the participant.
3.3.4.1
Withdrawal from trial treatment
An individual participant will be withdrawn from trial treatment if:
∀
The participant wants to withdraw from trial treatment. The participant will be asked to 
explain the reasons but has the right to refuse to answer
∀
The participant has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 
participant cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future.

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∀
The participant needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
∀
The participant can no longer receive trial treatment for medical reasons (such as 
pregnancy, surgery, AEs, or diseases)
∀
Participants with normal hepatic function: The participant has an elevation of AST and/or 
ALT ≥3-fold ULN and an elevation of total bilirubin ≥2-fold ULN (measured in the same 
blood sample) and/or needs to be followed up according to the DILI checklist provided in 
the ISF
Participants with impaired hepatic function: Elevation of AST and/or ALT of at least 3-
fold together with an increase in total bilirubin of at least 2-fold compared to screening 
values
∀
The patient exhibits suicidality, in the clinical judgement of the investigator or according 
to the following criteria:
o
any suicidal behaviour (i.e., actual attempt, interrupted attempt, aborted attempt, 
or preparatory acts or behaviour)
o
any suicidal ideation of type 4 or 5 in the C-SSRS (i.e., active suicidal thought 
with intent but without specific plan, or active suicidal thought with plan and 
intent)
∀
If any of the following AEs is reported, the treatment has to be discontinued: 
-
Severe or serious infections, opportunistic or mycobacterium tuberculosis infections
-
Malignancies 
-
Vasculitis
Of note, depending on the current status of the COVID-19 pandemic, all participants with 
confirmed SARS CoV-2 infection will be handled in accordance with local guidance and 
SOPs meaning that any confirmed SARS CoV-2 infection during the conduct of the trial will 
lead to discontinuation of the participant (refer to Section 1.4.2).
In addition to these criteria, the investigator may discontinue participants at any time based 
on his or her clinical judgement.
If it is known that a participant becomes pregnant during the trial, she is to be removed from 
the trial. The participant is to be followed until she has given birth or until the end of the 
pregnancy. The participant’s data are to be collected until the end of the trial (last visit of last 
participant) and reported in the CTR. For reporting of pregnancy and associated events, refer 
to Section 5.2.6.2.3.
If new efficacy or safety information becomes available, BI will review the benefit-risk-
assessment and, if needed, pause or discontinue the trial treatment for all participants or take 
any other appropriate action to guarantee the safety of the trial participants.

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3.3.4.2
Withdrawal of consent to trial participation
Participants may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a participant wants to withdraw consent, the investigator should be 
involved in the discussion with the participant and explain the options for continued follow-
up after trial discontinuation
3.3.4.3
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial at any time for any of the following reasons (if 
reasons 4 and/or 5 are met, the trial should be discontinued immediately):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. The sponsor decides to discontinue the further development of the investigational 
products
3. Deviation from GCP, or the CTP, or the contract with BI impairing the 
appropriate conduct of the trial
4. New toxicological findings, SAEs, or any safety information invalidating the 
earlier positive benefit-risk-assessment (see Section 3.3.4.1)
5. More than 50% of the participants show drug-related and clinically relevant AEs
of moderate or severe intensity, or if more than two participants have drug-related 
severe non-serious AEs, or if at least one drug-related SAE is reported
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 2 participants do not complete the trial in any trial group (including 
participants non-evaluable for PK), additional participants may be treated in this respective 
trial group, i.e., ‘replaced‘, if considered necessary to reach the objective of the trial. 
Participants who withdraw or are withdrawn from assessments because of a drug-related 
adverse event will not be replaced. The Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many participants will 
be replaced. The total number of replacements may not exceed 1/3 of the total number of 
evaluable participants anticipated to complete the trial. A ‘replacement’ participant will be 
assigned a unique trial participant number, and will be assigned to the same treatment as the 
participant he or she replaces. The ‘replacement’ participant does not have to have the same 
gender he/she replaces, but the distribution of at least 25% of each gender per group has to be 
adhered to.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 1015550
Pharmaceutical formulation: Film-coated tablets (iCF formulation)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
18 mg
Posology:
1-0-0
Mode of administration:
Oral
4.1.2
Selection of doses in the trial
The dose of 18 mg of BI 1015550 selected for this trial is the expected therapeutic dose that 
is used in clinical drug development (see Section 1.2).
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment investigated in this trial. The participants with hepatic 
impairment and the matching participants with normal hepatic function will be assigned to 
treatment groups according to the Child-Pugh classification and as control groups as outlined 
in Table 4.1.3: 1.

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Table 4.1.3: 1
Trial treatment groups
Treatment Groups
Child-Pugh 
classification
Child-Pugh 
score 
(points)
Number of 
participants
Group 1 (mild hepatic impairment)
A
5-6
8
Group 2 (moderate hepatic impairment)
B
7-9
8
Group 3 (matching participants with 
normal hepatic function individually
matched to participants of Group 1)
-
-
8
Group 4 (matching participants with 
normal hepatic function individually 
matched to participants of Group 2)
-
-
8*
* if a participant of Group 3 is matching by age (± 10 years), gender, and weight (± 15%) to participant of Group 
2, this participant will also be considered in Group 4 (i.e., one participant with normal hepatic function may 
match one participant in one or both groups of participants with hepatic impairment). Hence, the sample size of 
participants to be treated for the composition of Groups 3 and 4 may be below 16. 
Once a participant number has been assigned, it cannot be reassigned to any other participant.
Dosing will start with 4 participants of Group 1. Participants in this subcohort may be treated 
on the same calendar day. After review of safety data (see Section 3.1) and decision to 
continue, all participants may be treated in one cohort, i.e., all participants may receive 
treatment on the same calendar day. In case this is not feasible (e.g., due to logistical or 
recruitment reasons), the groups may be split into several cohorts as required. For discussion 
of trial-associated risks and safety measures, see Section 1.4).
4.1.4
Drug assignment and administration of doses for each subject
This is a non-randomised, open-label, individual-matched parallel design trial. All 
participants will receive the same active treatment. The treatment to be evaluated is 
summarised in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T (Test)
BI 1015550
Film-coated 
tablet
18 mg
1 tablet (18 mg) single dose for 1 day
18 mg
Administration of trial medication will be performed after participants have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. The investigator (or 
authorised designee) will administer the trial medication as an oral dose together with about 
240 mL of water to participants who are in a sitting/standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 

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and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
Participants will be kept under close medical surveillance until 72 h after drug administration. 
During the first 4 h after drug administration, participants are not allowed to lie down (i.e., no 
declination of the upper body of more than 45 degrees from upright posture), except for 
examinations and assessments.
4.1.5
Blinding and procedures for unblinding
This non-randomised open-label Phase I trial will be handled in an open fashion throughout. 
There will be only one treatment, so the treatment assignment will be available to all involved 
parties.
4.1.6
Packaging, labelling, and re-supply
The IMPs will be provided by BI. They will be packaged and labelled in accordance with the 
principles of GMP. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the participant information form. The EudraCT number is indicated on 
the title page of this protocol as well as on the participant information and informed consent 
forms. 
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Research Associate (as provided in the list of contacts) is to be contacted 
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor 
when the following requirements are fulfilled:
∀
Approval of the CTP by the IRB / ethics committee
∀
Availability of a signed and dated clinical trial contract between the sponsor or 
delegate and the investigational site
∀
Approval/notification of the regulatory authority, e.g. competent authority
∀
Availability of the curriculum vitae of the Principal Investigator
∀
Availability of a signed and dated CTP

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Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial participants. Investigational drugs are not allowed to be used 
outside of this CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each participant, and the disposal of unused products.
These records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, 
and the unique code numbers assigned to the investigational medicinal product and trial 
participants. The investigator or designee will maintain records that document adequately that 
the participants were provided the doses specified by the CTP and reconcile all 
investigational medicinal products received from the sponsor. At the time of disposal of 
remaining trial medication, the investigator or designee must verify that no remaining 
supplies are in the investigator’s possession. 
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if AE require treatment, the investigator can authorise symptomatic 
therapy. In those cases, participants will be treated as necessary and, if required, kept under 
supervision at the trial site or transferred to a hospital until all results of medical evaluations 
are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed for participants with normal hepatic function,
except for hormonal contraceptives or ovary hormone replacement. In participants with 
hepatic impairment, contraceptives as well as concomitant medication for treatment of the 
hepatic or other concomitant diseases are allowed.
Strong CYP3A inhibitors are restricted medication in all trial participants due to potential 
drug-drug interactions (see Appendix 10.2). See also Section 3.3.3 for excluded medication. 
If necessary, short-term use of ibuprofen or acetylsalicylic acid is acceptable for symptomatic 
treatment of AEs. 
All concomitant or rescue therapies will be recorded (including time of intake on trial days) 
on the appropriate pages of the CRF.

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4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the participants will be instructed not to consume any foods 
or drinks other than those provided by the staff. Standardised meals will be served at the 
times indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake. Only 
participants with diabetes will receive a snack at 2 h post dose, if necessary.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
participants). From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements are not permitted from 7 days before the administration of trial 
medication until after the last PK sample is collected. 
Products containing St. John's wort (Hypericum perforatum) are not permitted from 30 days 
before the administration of trial medication until after the last PK sample is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before until 24 h after administration of trial 
medication.
Smoking is not allowed from 10 h before until 8 h after administration of trial medication.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the administration of trial medication until the EoS examination.
4.2.2.3
Contraception requirements
If WOCBP are included in the trial, adequate contraception is to be maintained throughout 
the course of the trial (see Section 3.3.2 for the definition of adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Participants who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. 
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination. 
At the EoS examination, it will include review of vital signs, 12-lead ECG, laboratory tests, 
and a physical examination including determination of body weight.
5.2.2
Vital signs
Systolic and diastolic blood pressures as well as pulse rate or HR (HR is considered to be 
equal to pulse rate) will be measured by a blood pressure monitor (Dinamap Pro 100, 
) at the times indicated in the Flow Chart, after 
participants have rested for at least 5 min in a supine position. All recordings should be made 
using the same type of blood pressure recording instrument on the same arm, if possible.
Body temperature will be monitored as part of vital signs assessment if still needed due to the 
current status of the pandemic. Body temperature will not be entered into the eCRF.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the participants have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. 
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential WBC count or urine sediment examinations will only be performed if 
there is an abnormality in the automatic blood cell count or in the urinalysis, respectively. 

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.; 
Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – Quick
Prothrombin time – INR (International Normalisation Ratio)
Fibrinogen
X
X
X
X
X
X
X
--
X
X
X
--
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine 
Free T4 – Thyroxine 
FSH (if applicable)
X
X
X
X
--
--
--
--
--
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant)
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Electrolytes
Sodium
Potassium
Chloride
Calcium
Magnesium
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal in 
urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2 on Days -1, 2 and 4 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (EoS examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in WOCBP will be performed at screening, prior to 
treatment, and as part of the EoS examination. Drug screening will be performed at screening 
and prior to treatment.

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5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
at the times provided in the Flow Chart. 
To achieve a stable HR at rest and to assure high quality recordings, the site personnel will be 
instructed to assure a relaxed and quiet environment, so that all participants are at complete 
rest.
All ECGs will be recorded for a 10 sec duration after participants have rested for at least 5 
min in a supine position. ECG assessment will always precede all other trial procedures 
scheduled for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System 
. Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven. 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the participant will be removed 
from the trial and will receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety assessments
5.2.5.1
Suicidal risk (C-SSRS)
Prospective monitoring will be conducted throughout this trial using C-SSRS.
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation. It does
not give a global score but provides some categorical and some severity information
specifically for behaviour and ideation.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be
administered at the screening visit (using the ‘screening/baseline’ version) with the aim to
exclude participant’s suicidal ideation type 4 to 5 within the preceding 3 months or at Visit 1 
or any suicidal behaviour in the past 2 years. The lifetime history of suicidal ideation and
behaviour will also be recorded.
After Visit 1, the assessment ‘since last visit’ will be performed at each clinic visit (‘since last
visit’ version).
Appendix 10.1 provides details how the C-SSRS will be assessed.
C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.2.

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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 CRF and BI SAE form (if applicable):
∀
Worsening of the underlying disease or of other pre-existing conditions 
∀
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
SAE reporting in case of suicidal risk assessed by the C-SSRS
All C-SSRS reports of suicidal ideation type 4 and 5 and all reports of suicidal behaviour 
must be reported as separate SAEs by the investigator.
For ‘self-injurious behaviour, no suicidal intent’ (type 11) standard AE/SAE reporting rules 
are to be applied.
For each negative report (Suicidal ideation type 1, 2, or 3) after the start of the trial, the 
investigator is to decide based on clinical judgement whether it represents an AE as defined 
in the CTP, and if it is considered an AE then it must be reported accordingly.
Adverse event report for diarrhoea events
In case of events of diarrhoea the following definitions should be followed:
∀
Diarrhoea is defined ≥3 loose/liquid stools per day (WHO definition)
∀
Diarrhoea episode = 2 diarrhoea episodes are separated by at least 7 days without any
diarrhoea
5.2.6.1.2
Serious adverse event
An SAE is defined as any AE which fulfils at least one of the following criteria:
∀
Results in death 

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∀
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 
upon 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 
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the EMA 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, an electronic data 
capture system which allows the entry of trial data at the trial site. 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 must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
5.2.6.1.4
Adverse events of special interest
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see Section 5.2.6.2.2.
The following are considered as AESIs:
∀
Potential severe DILI
A potential severe DILI that requires follow-up is defined by the following alterations 
of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN

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These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
∀
Vasculitis events
In this CTP, vasculitis is defined as any event term included in the MedDRA SMQ Vasculitis 
(broad). This includes clinical and pathological features related to primary or secondary 
vasculitis syndromes and involving any type, size, and location of blood vessels. 
The investigator should monitor for any signs and symptoms of vasculitis at all times and 
specifically as part of the AE questioning. 
In case of (suspected) events of vasculitis, further work-up and management as outlined in 
Section 4.2.1 has to be followed, including biopsy, appropriate imaging/angiography, 
laboratory measures (e.g. ESR, additional lab sample for immunological and further 
inflammation markers).
∀
Serious infections, opportunistic or mycobacterium tuberculosis infections. 
These include Pneumocystis jirovecii, BK virus disease including polyomavirus-
associated nephropathy (PVAN), Cytomegalovirus (CMV), post-transplant 
lymphoproliferative disorder (Epstein–Barr virus [EBV]), progressive multifocal 
leucoencephalopathy, bartonellosis (disseminated only), blastomycosis, 
toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), 
candidiasis (invasive or pharyngeal), cryptococcosis, other invasive fungi 
(mucormycosis (zygomycosis, rhizopus, mucor, lichtheimia), 
Scedosporium/Pseudallescheria boydii, fusarium), legionellosis, Listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), HBV reactivation, herpes simplex 
(invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, Penicillium marneffei, Sporothrix 
schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), Trypanosoma cruzi infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), HCV progression [R17-2617]

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5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Infections classified as ‘severe’ are considered as AESIs, see Section 5.2.6.1.4.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug 
∀
The event is known to be caused by or attributed to the drug class
∀
A plausible time to onset of the event relative to the time of drug exposure
∀
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)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
∀
Continuation of the event, taking into account the pharmacological properties of the 
compound (e.g. after 5 half-lives). Of note, this criterion may not be applicable to 
events whose time course is prolonged despite removing the original trigger
∀
There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned

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5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be 
made using non-specific questions such as ‘How do you feel?’. Specific questions will be 
asked wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
∀
From signing the informed consent onwards until an individual participant’s end of 
trial (EoS visit): 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.
∀
After the individual participant’s EoS: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs 
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.

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5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 24 h 
of becoming aware of the event, the country specific reporting process will be provided in the 
ISF. The same timeline applies if follow-up information becomes available. On specific 
occasions, the Investigator could inform the sponsor upfront via telephone. This does not 
replace the requirement to complete and send the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after the individual participant’s EoS, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. 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 participant has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 h) by means of Part 
A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of PK, blood samples will be collected at the time points indicated in the 
Flow Chart. The actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters. 

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5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 1015550 and 
 concentrations in plasma, 2.7 mL 
of blood will be drawn from an antecubital or forearm vein into a K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C within 1 h after blood draw. Two plasma 
aliquots will be obtained and stored in polypropylene tubes. The first aliquot should contain 
at least 0.5 mL of plasma. The remaining plasma will be transferred into a second 
polypropylene tube. The process from blood collection until transfer of plasma aliquots into 
the freezer should be completed within 2 h, with interim storage of blood samples and 
aliquots at room temperature. The time each aliquot was placed in the freezer will be 
documented. Until transfer on dry ice to the analytical laboratory, the aliquots will be stored 
upright at approximately -20°C or below at the trial site. The second aliquot will be 
transferred to the analytical laboratory after the bioanalyst has acknowledged safe arrival of 
the first aliquot. At the analytical laboratory, the plasma samples will be stored at 
approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After analysis, the plasma samples may be used for further methodological investigations
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. However, only data related to the analyte and/or 
its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.

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5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between PK and pharmacodynamic parameters is planned for 
this trial.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor participants’ safety and to determine PK parameters in an 
appropriate way. The scheduled measurements will allow monitoring of changes in vital
signs, standard laboratory values, suicidal risk, and ECG parameters that might occur as a 
result of administration of trial medication. The safety assessments are standard, are accepted 
for evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The PK parameters and measurements outlined in Section 5.3 are generally 
used for the assessments of drug exposure.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, ECG, and laboratory tests will be ± 30 min during the inhouse period, and 
± 2 h for ambulatory visits.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the procedures due to its inconvenience to the subject and possible influence on physiological
parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of PK parameters.
To allow for a streamlined operational conduct of trials at trial site, the following flexibility 
as regards time-windows for PK sampling times will be allowed: 
∀
Predose: within 2 h prior to drug administration
∀
Postdose:
-
From dosing until 2 h: ± 2 min; 
-
>2 h until 4 h: ± 5 min; 
-
>4 h until 72 h: ± 15 min; 
-
>72:00: ± 60 min
If a participant misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.

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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all participants will provide written informed 
consent in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.
6.2.2
Treatment period
On Day -1 of the treatment period, trial participants will be admitted to the trial site. They 
will be kept under close medical surveillance for at least 72 h following drug administration 
on Day 1. The participants will then be allowed to leave the trial site on Day 4 after formal 
assessment and confirmation of their fitness. On all other trial days, participants will come to 
the trial site for ambulatory visits.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this CTP and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining participant’s written informed consent until the EoS
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Participants who discontinue prematurely should undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained. 

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
To assess the effect of hepatic impairment on the PK of BI 1015550, the relative 
bioavailability will be estimated by the ratios of the geometric means of the respective 
pairwise comparison of interest for the primary and secondary endpoints, i.e., for each 
hepatic impairment group vs. the respective control group. Additionally, their two-sided 90% 
confidence intervals (CIs) will be provided. This method corresponds to the two one-sided t-
test procedure, each at the 5% significance level. Since the main focus is on estimation and 
not testing, a formal hypothesis test and associated acceptance range is not specified.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:
∀
Treated set (TS): The treated set includes all participants who were treated with one 
dose of trial drug. The treated set will be used for safety analyses.
∀Pharmacokinetic parameter analysis set (PKS): This set includes all participants in the 
treated set (TS) who provide at least one primary or secondary PK endpoint and who 
were not excluded due to a protocol deviation relevant to the evaluation of PK or due 
to PK non-evaluability (as specified in the following subsection ‘Pharmacokinetics’).
Thus, a participant will be included in the PKS, even if he/she contributes only one of 
the main PK parameter value to the statistical assessment. Descriptive and model-
based analyses of PK parameters will be based on the PKS.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be suggested in the iPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the iPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The PK parameters listed in Section 2.1 and 2.2.2 for drug BI 1015550 
 
will be calculated according to the relevant BI internal procedures. 
Plasma concentration data and parameters of a participant will be included in the statistical 
PK analyses if they are not flagged for exclusion due to a protocol deviation relevant to the 
evaluation of PK (to be decided no later than in the Report Planning Meeting) or due to PK 
non-evaluability (as revealed during data analysis, based on the criteria specified below). 
Exclusion of a participant’s data will be documented in the CTR.

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Important protocol deviations may be
∀
Incorrect trial medication taken, i.e., the participant received at least one dose of trial
medication the participant was not assigned to
∀
Incorrect dose of trial medication taken
∀
Use of restricted medications
Plasma concentrations and/or parameters of a participants will be considered as non-
evaluable, if for example
∀
The participant experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the participants
experiencing emesis), 
∀
A predose concentration is >5% Cmax value of that participant
∀
Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a participant which are flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses. 
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. Concentrations used in the PK calculations 
will be in the same format provided in the bioanalytical report, (that is, to the same number of 
decimal places provided in the bioanalytical report). 
7.2.2
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
the effect ‘degree of hepatic impairment’ as a fixed effect and ‘matched pair’ as random 
effect. The model is described by the following equation:
ykm = % + ∃k + sm + ekm, where
ykm = logarithm of response measured on participant m with degree of impairment k,
% = the overall mean,
∃k = the effect of the kth degree of impairment, k = 1 for no impairment (control) and
          k = 2, 3 for Child-Pugh class A and B, respectively,
sm = the effect of the mth matched pair, m=1, …, 8,
ekm = the random error associated with the kth degree of hepatic impairment for 
          matched pair m 
         where ekm is assumed to be independent and identically normally distributed.
The model described above will be fitted separately for the two hepatic impaired groups, i.e.,
one model for the participants with moderate hepatic impairment and their matched controls,
and one model for the participants with mild hepatic impairment and their matched controls.

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For evaluation of each primary endpoint, the difference between the expected means for
log(∃k)-log(∃1), for k>1, will be estimated by the difference in the corresponding adjusted
means (Least Squares Means). Additionally, their two-sided 90% CIs will be calculated based 
on the residual error from the ANOVA and quantiles from the t-distribution. These quantities 
will then be back-transformed to the original scale to provide the point estimate and 90% CIs 
for each endpoint.
In addition to the model-based approach, all parameters will be calculated and analysed 
descriptively.
7.2.3
Secondary endpoint analyses
The secondary endpoint (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures and will be assessed statistically using the same methods as described 
for the primary endpoints.
7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
participants (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses 
will be descriptive in nature and based on BI standards. No hypothesis testing is planned.
Hepatic function groups will be compared in a descriptive way. Tabulations of 
frequencies/proportions will be used to evaluate categorical (qualitative) data, and tabulations 
of descriptive statistics will be used to analyse continuous (quantitative) data.
Measurements (such as vital signs or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to intake of trial medication will be assigned 
to the screening period, those between intake of trial medication and end of REP (see 
Section 1.2.2) will be assigned to the treatment period. Events occurring after the REP but 
prior to EoS examination date will be assigned to ’follow-up’. These assignments including 
the corresponding time intervals will be defined in detail in the TSAP. Note that AEs 
occurring after the last per protocol contact but entered before database lock of the trial will 
be reported to Pharmacovigilance only and will not be captured in the trial database.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately. 

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C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.2 and will be 
summarized as such. Results of the C-SSRS will be provided as listing.
Previous and concomitant therapies will be presented per group without consideration of time 
intervals and treatment periods.
In general, unless otherwise specified in the TSAP, the last non-missing measurement 
prior to study treatment will be used as baseline for safety variables.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No formal interim analysis is planned for this trial. 
A preliminary, exploratory analyses of all available or specific data (e.g. safety, PK) may be 
performed prior to final database lock to inform other activities during the development of 
BI 1015550. In case of preliminary assessment of PK data, the PK parameters will be 
calculated according to the relevant BI internal procedure. In contrast to the final PK 
calculations, the preliminary analysis will be based on planned sampling times rather than on 
actual times, regardless of whether actual times were within the time windows. Therefore, 
minor deviations may occur between preliminary and final results. The possible preliminary 
PK analysis will provide individual and gMean concentration profiles and summary statistics 
of PK parameters per group. No inferential statistical preliminary analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures. 
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.4
RANDOMISATION
The trial will not be randomised, thus this section is not applicable.

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7.5
DETERMINATION OF SAMPLE SIZE
It is planned to include a maximum of 32 participants in the trial: 8 participants with mild 
hepatic impairment (Child-Pugh A), 8 participants with moderate hepatic impairment (Child-
Pugh B) and up to 16 matched control participants with normal hepatic function will be 
treated. Note, one participant with normal hepatic function may match a participant in only 
one or in both groups with hepatic impaired participants. The matching criteria are described 
in Section 3.1.
The planned sample size is not based on a power calculation but is considered as sufficient to 
detect major differences between the different groups of participants with hepatic impairment 
and the respective control group with participants with normal hepatic function. Furthermore, 
a sample size of 8 participants in each hepatic impairment and control group is considered 
sufficient for hepatic impairment trials [R05-0337].

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC and other relevant regulations. Investigators and site staff must adhere to these 
principles. Deviation from the protocol, the principles of ICH GCP or applicable regulations 
will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol 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 are described in the investigator contract. As a general 
rule, no trial results should be published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT 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 a subject’s participation in the trial, written informed consent must be obtained from 
each subject 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 subject-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each participant.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject 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.

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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial participant that 
include all observations and other data pertinent to the investigation. Source data as well as 
reported data should follow the ‘ALCOA principles’ and be attributable, legible, 
contemporaneous, original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the participant may not be sufficient to confirm eligibility for 
the trial and the investigator may need to request previous medical histories and evidence of 
any diagnostic tests. In this case, the investigator must make at least one documented attempt 
to retrieve previous medical records. If this fails, a verbal history from the participant, 
documented in their medical records, would be acceptable.
Before providing any copy of participants’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., participant’s name, initials, address, phone 
number, and social security number) have properly been removed or redacted to ensure 
participant confidentiality.
If the participant is not compliant with the protocol, any corrective action (e.g. re-training) 
must be documented in the subject file.
For the CRF, data must be derived from source documents, for example:
∀
Subject identification: gender, year of birth (in accordance with local laws and 
regulations)

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∀
Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)
∀
Dates of subject’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
AEs and outcome events (onset date [mandatory], and end date [if available])
∀
SAEs (onset date [mandatory], and end date [if available])
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)
∀
ECG results (original or copies of printouts)
∀
Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)
∀
Prior to allocation of a subject 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 subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.

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8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject 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 subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’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, storage and 
future use of biological samples and clinical data, in particular
∀
Sample and data usage have to be in accordance with the informed consent
∀
The BI internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.
∀
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
∀
A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage
∀
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
∀
Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.

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The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
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 subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
under the supervision of the Principal Investigator.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial 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 local Clinical Trial Mangers
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites
The trial medication will be provided by the 
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
Analyses of BI 1015550 and BI 764333 concentrations in plasma will be performed at 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI, or a contract research 
organisation appointed 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.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P15-07539
Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT 
clinical practice guideline: treatment of idiopathic pulmonary fibrosis: an 
update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 
2015; 192(2): e3-e19.
P17-10582
Flaherty KR, Brown KK, Wells AU, et al. Design of the PF-ILD trial: a 
double-blind, randomised, placebo-controlled phase III trial of nintedanib 
in patients with progressive fibrosing interstitial lung disease. BMJ Open 
Respir Res 2017; 4: e000212.
P18-04729
Wells AU, Brown KK, Flaherty KR, et al. IPF Consensus Working Group. 
What's in a name? That which we call IPF, by any other name would act 
the same. Eur Respir J 2018; 51:1800692.
P18-06345
Sisson TH, Christensen PJ, Muraki Y, et al. Phosphodiesterase 4 inhibition 
reduces lung fibrosis following targeted type II alveolar epithelial cell 
injury. Physiol Rep 2018; 6(12): e13753.
P19-01738
Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases: 
knowns and unknowns. Eur Respir Rev 2019; 28:180100.
P20-01299
Wong AW, Ryerson CJ, Guler SA. Progression of fibrosing interstitial 
lung disease. Respir Res 2020; 21(1):32.
P22-03204
Raghu G, Remy-Jardin M, Richeldi L, et al. American Thoracic Society, 
European Respiratory Society, Japanese Respiratory Society, Asociacion 
Latinoamericana de Torax. Idiopathic pulmonary fibrosis (an update) and 
progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT 
clinical practice guideline. Am J Respir Crit Care Med 2022;205(9):e18-
e47
R05-0337
United States Food and Drug Administration (FDA). Guidance for 
Industry “Pharmacokinetics in Patients with Impaired Hepatic Function: 
Study Design, Data Analysis, and Impact on Dosing and Labeling”. May 
2003.
R05-0340
European Medicines Agency (EMA): Guideline on the evaluation of the 
pharmacokinetics of medicinal products in patients with impaired hepatic 
function. CPMP/EWP/2339/02. 17 Feb 2005
R17-2617
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen 
P, et al. Opportunistic infections and biologic therapies in immune-
mediated inflammatory diseases: consensus recommendations for 
infection reporting during clinical trials and postmarketing surveillance. 
Ann Rheum Dis 2015;74
R19-0854
Kolb M, Vasakova M. The natural history of progressive fibrosing 
interstitial lung diseases. Respir Res 2019; 20(1):57.

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9.2
UNPUBLISHED REFERENCES
c02094779
Investigator's Brochure BI 1015550 for 
1305.P3, current version.
c02191718
Safety, tolerability and pharmacokinetics of multiple rising oral doses of 
BI 1015550 powder for oral solution in healthy male volunteers q.d. or bid 
for 14 days (a randomised, double-blind, placebo-controlled within dose 
groups Phase I trial). 1305.0002.
c20307414
Relative bioavailability of BI 1015550 following oral administration under 
fed and fasted conditions in healthy male subjects. 1305-0020.
c22991937
Safety, tolerability and pharmacokinetics of single and multiple rising oral 
doses of BI 1015550 in healthy subjects. 1305-0011.
c24902949
Relative bioavailability of a single oral dose of BI 1015550 when 
administered alone or in combination with multiple oral doses of 
itraconazole in healthy male subjects. 1305-0015.
c25085412
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of 
BI 1015550 in patients with idiopathic pulmonary fibrosis (IPF) on no 
background anti-fibrotic therapy. 1305-0012.
c36151567
A Phase I, open-label, non-randomized, single-dose, single-arm, single-
period study to investigate the metabolism and pharmacokinetics of [C 14]-
labelled BI 1015550 after oral administration in healthy male subjects. 
1305-0016.
c37065416
A randomised, double-blind, placebo-controlled parallel group study in IPF 
patients over 12 weeks evaluating efficacy, safety and tolerability of 
BI 1015550 taken orally. 1305-0013.
c39775503
 Assessment of requirement for male contraception. Memo. 09 
June 2022
n00201897
In vitro determination of BI 1015550 protein binding in human and animal 
plasma and in human serum albumin and α1-acid glycoprotein solutions. 
(DM-11-1046).
n00201905
In vitro blood cell partitioning of 14C-BI 1015550 in rat, Göttingen 
minipig, and human blood. (DM-11-1045).
n00261666
BI 1015550: Metabolite profiling in plasma after multiple oral 
administration to healthy volunteers and metabolite exposure determination 
in human and the relevant toxicity species.
n00290709
A fertility and early embryonic development to implantation study of 
BI 1015550 by oral gavage in male and female rats. CRL study no. 
9001829, BI no. 21R070.

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10.2
LISTING RESTRICTED CONCOMITANT MEDICATION
10.2.1
Strong CYP3A4 inhibitors
∀
boceprevir
∀
ceritinib
∀
clarithromycin
∀
cobicistat
∀
conivaptan
∀
diltiazem
∀
idelalisib 
∀
indinavir
∀
itraconazole
∀
ketoconazole oral administration
∀
LCL161
∀
mifepristone
∀
mibefradil
∀
nefazodone
∀
nelfinafir
∀
posaconazole
∀
ribociclib
∀
ritonavir
∀
saquinavir
∀
telaprevir
∀
telithromycin
∀
troleandomycin
∀
VIEKIRA PAK2
∀
voriconazole
10.2.2
Combinations of CYP 3A4 inhibitors
∀
danoprevir/ritonavir
∀
elvitegravir/ritonavir
∀
indinavir/ritonavir
∀
lopinavir/ritonavir
∀
paritaprevir/ritonavir/ombitasvir/dasbuvir
∀
saquinavir/ritonavir
∀
tipranavir/ritonavir

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
14 Dec 2022
EudraCT number
EU number
2022-002811-45
BI Trial number
1305-0027
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
Pharmacokinetics, safety and tolerability of BI 
1015550 following oral administration in male and 
female participants with different degrees of hepatic 
impairment (Child-Pugh classification A and B) 
compared with matched male and female 
participants with normal hepatic function (an open-
label, non-randomised, single-dose, parallel, 
individual-matched design trial)
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1. Synopsis and Section 3.3.2 Inclusion 
Criteria
2. Section 3.3.3 Exclusion Criteria
3. Section 10.1 Columbia Suicide Severity 
Rating Scale
Description of change
1. Inclusion Criteria no. 2 Age changed to 18-
79 years inclusive
2. Exclusion Criteria no. 21: For female 
participants: Lactation, pregnancy or 
positive pregnancy test, or plans to become 
pregnant during the trial or within 7 instead 
of 30 days after trial completion
3. Change of screenshot for C-SSRS 
Baseline/Screening Version
Rationale for change
1. BfArM Request
2. Inconsistency between Inclusion Criteria no. 
2 and Exclusion Criteria no. 21
3. Incorrect screenshot for Baseline/Screening 
Version used

 
 
 
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