Relative Bioavailability Comparison of BI 1015550 as the Intended Commercial Formulation (iCF) Versus Trial Formulation 2 and iCF With and Without Food Following Oral Administration in Healthy Subjects (an Open-label, Randomised, Single-dose, Three-way Crossover Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-11 (7.0) / Saved on: 22 Jun 2021
Clinical Trial Protocol
TITLE PAGE
Document Number:
c37740081-01
EudraCT No.
2021-006890-44
BI Trial No.
1305-0028
BI Investigational
Medicinal Product
BI 1015550
Title
Relative bioavailability comparison of BI 1015550 as the 
intended commercial formulation (iCF) versus trial 
formulation 2 and iCF with and without food following oral 
administration in healthy subjects (an open-label, randomised, 
single-dose, three-way crossover trial)
Lay Title
A study in healthy people to compare 2 different formulations 
of BI 1015550 taken with or without food
Clinical Phase
I
Clinical Trial Leader
Phone: 
, Fax: 
Principal Investigator
Phone: 
 Fax: 
Current Version, Date
Version 1.0, 17 May 2022
Original Protocol Date
17 May 2022
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© 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
17 May 2022
Revision date
Not applicable
BI trial number
1305-0028
Title of trial
Relative bioavailability comparison of BI 1015550 as the intended commercial 
formulation (iCF) versus trial formulation 2 and iCF with and without food 
following oral administration in healthy subjects (an open-label, randomised, 
single-dose, three-way crossover trial)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
This trial is conducted to bridge pharmacokinetic and safety data between trial 
formulation 2 (TF2) and the intended Commercial Formulation (iCF) of 
BI 1015550, and to evaluate a potential food effect on the iCF to support further 
clinical development of BI 1015550.
Trial objectives
To investigate the
-
relative bioavailability of BI 1015550 iCF compared with TF2
-
effect of food on the pharmacokinetics of BI 1015550 iCF
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of BI 1015550
Secondary endpoint: AUC0-of BI 1015550
Trial design
Randomised, open-label, single-dose, three-way crossover design
Number of subjects 
total entered
24
on each treatment
24
Diagnosis
Not applicable
Main inclusion criteria
Healthy male/female subjects, age of 18 to 55 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive)

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Test product
BI 1015550 intended commercial formulation (iCF), 18 mg film-coated tablets: (T)
dose
18 mg (1x 18 mg)
mode of 
administration
Oral with 240 mL of water after an overnight fast of at least 10 h (T1)
and 
Oral  with 240 mL of water after a high-calorie breakfast (T2)
Reference product
BI 1015550 Trial Formulation 2 (TF2), 6 mg film-coated tablets (R)
dose
18 mg (3 x 6 mg)
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
Three single doses (treatment R = fasted, treatment T1= fasted, treatment T2 = fed) 
separated by a washout phase of at least 7 days
Statistical methods
Relative bioavailability of iCF will be estimated by the ratios of the geometric 
means (T1/R) for the primary and secondary endpoints. The effect of food on iCF 
will be estimated by the ratio of the geometric means (T2/T1) for the primary and 
secondary endpoints. 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. 
The statistical model will be an analysis of variance (ANOVA) on the logarithmic 
scale including effects for sequence, subjects nested within sequences, period and 
treatment. CIs will be calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
Period
Visit
Day
Planned time (relative to 
drug administration)  [h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to
-1
Screening (SCR)1
xA
x
x
1/2/3 (three identical periods separated by a wash-out of 
at least 7 days
2/3/4
-1
-12:00
20:00
Admission to trial site8
x5,8
x8
1
-1:00
07:00
Allocation to treatment2 (visit 2 only)
x2,B
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast
(treatment T2 only)
0:00
08:00
Drug administration
0:30
08:30
x
0:45
08:45
x
1:00
09:00
x
1:15
09:15
x
1:30
09:30
x
1:45
09:45
x
2:00
10:00
240 mL fluid intake
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
6:00
14:00
x
8:00
16:00
x
10:00
18:00
Dinner
12:00
20:00
x
x 
2
24:00
08:00
Breakfast3 (voluntary),
discharge from trial site
xB
x
x
x
x
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
x
x
5
96:00
08:00
Ambulatory visit
x
x
6
120:00
08:00
Ambulatory visit
xB
x
x
7
144:00
08:00
Ambulatory visit
x
x
FU
5
8 to 14
End of study (EoS) examination4
xC
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening and 
pregnancy test in women), demographics (including determination of body height and weight, smoking status and 
alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
Pharmacogenetic samples will be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 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, vital signs, ECG, 
safety laboratory (including pregnancy test in women), recording of AEs and concomitant therapies, body weight.
5.
Only urine drug screening and alcohol breath test as well as pregnancy test in women will be done at this time
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 (see Section 5.2.3)
8. 
The time is an approximate. The procedure is to be completed no later than 10 hours prior to drug administration.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS AND DEFINITIONS........................................................9
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................12
1.2.1
Residual Effect Period of BI 1015550..................................................12
1.2.2
BI 1015550 .............................................................................................12
1.2.3
Clinical Experience with other PDE4 inhibitors................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................16
1.4
BENEFIT - RISK ASSESSMENT ...................................................................17
1.4.1
Benefits...................................................................................................17
1.4.2
Risks .......................................................................................................17
1.4.3
Discussion...............................................................................................21
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......22
2.1.1
Main objectives......................................................................................22
2.1.2
Primary endpoints ................................................................................22
2.1.3
Secondary endpoint ..............................................................................22
2.2.2.2
Safety and tolerability..............................................................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 24
3.1
OVERALL TRIAL DESIGN............................................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................25
3.3
SELECTION OF TRIAL POPULATION ......................................................25
3.3.1
Main diagnosis for trial entry..............................................................25
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................26
3.3.4
Withdrawal of subjects from treatment or assessments ...................27
3.3.4.1
Withdrawal from trial treatment ..............................................28
3.3.4.2
Withdrawal of consent to trial participation ............................29
3.3.4.3
Discontinuation of the trial by the sponsor..............................29

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3.3.5
Replacement of subjects .......................................................................29
4.
TREATMENTS........................................................................................ 30
4.1
INVESTIGATIONAL TREATMENTS ..........................................................30
4.1.1
Identity of the Investigational Medicinal Products ...........................30
4.1.2
Selection of doses in the trial................................................................30
4.1.3
Method of assigning subjects to treatment groups ............................30
4.1.4
Drug assignment and administration of doses for each subject .......31
4.1.5
Blinding and procedures for unblinding ............................................32
4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................33
4.1.8
Drug accountability ..............................................................................33
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................34
4.2.1
Other treatments and emergency procedures....................................34
4.2.2
Restrictions............................................................................................34
4.2.2.1
Restrictions regarding concomitant treatment .........................34
4.2.2.2
Restrictions on diet and life style.............................................34
4.2.2.3
Contraception requirements.....................................................35
4.3
TREATMENT COMPLIANCE.......................................................................35
5.
ASSESSMENTS....................................................................................... 36
5.1
ASSESSMENT OF EFFICACY.......................................................................36
5.2
ASSESSMENT OF SAFETY............................................................................36
5.2.1
Physical examination ............................................................................36
5.2.2
Vital signs...............................................................................................36
5.2.3
Safety laboratory parameters..............................................................36
5.2.4
Electrocardiogram................................................................................39
5.2.5
Other safety parameters.......................................................................39
5.2.6
Assessment of adverse events...............................................................40
5.2.6.1
Definitions of adverse events...................................................40
5.2.6.1.1 Adverse event ............................................................40
5.2.6.1.2 Serious adverse event ................................................40
5.2.6.1.3 AEs considered ‘Always Serious’.............................41
5.2.6.1.4 Adverse events of special interest .............................41
5.2.6.1.5 Intensity (severity) of AEs.........................................42
5.2.6.1.6 Causal relationship of AEs ........................................42
5.2.6.2
Adverse event collection and reporting ...................................43
5.2.6.2.1 AE collection.............................................................43
5.2.6.2.2 AE reporting to the sponsor and timelines ................44
5.2.6.2.3 Pregnancy ..................................................................44
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................45
5.3.1
Assessment of pharmacokinetics .........................................................45
5.3.2
Methods of sample collection...............................................................45

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5.3.2.1
Blood sampling for pharmacokinetic analysis.........................45
5.4
ASSESSMENT OF BIOMARKERS................................................................46
5.5
BIOBANKING ...................................................................................................46
5.6
OTHER ASSESSMENTS .................................................................................46
5.6.1
Pharmacogenomic evaluation..............................................................46
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................47
6.
INVESTIGATIONAL PLAN.................................................................. 48
6.1
VISIT SCHEDULE............................................................................................48
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................48
6.2.1
Screening period....................................................................................48
6.2.2
Treatment periods.................................................................................48
6.2.3
Follow-up period and trial completion ...............................................49
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 50
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................50
7.2
PLANNED ANALYSES....................................................................................50
7.2.1
General considerations.........................................................................50
7.2.1.1
Analysis sets.............................................................................50
7.2.1.2
Pharmacokinetics.....................................................................50
7.2.2
Primary endpoint analyses...................................................................51
7.2.3
Secondary endpoint analyses ...............................................................52
7.2.5
Safety analyses.......................................................................................52
7.2.6
Interim analyses ....................................................................................53
7.3
HANDLING OF MISSING DATA ..................................................................53
7.3.1
Safety......................................................................................................53
7.3.2
Pharmacokinetics..................................................................................54
7.4
RANDOMISATION ..........................................................................................54
7.5
DETERMINATION OF SAMPLE SIZE ........................................................54
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 56
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................56
8.2
DATA QUALITY ASSURANCE .....................................................................57
8.3
RECORDS..........................................................................................................57
8.3.1
Source documents .................................................................................57

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8.3.2
Direct access to source data and documents.......................................58
8.3.3
Storage period of records.....................................................................59
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................59
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......59
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................59
8.6
TRIAL MILESTONES .....................................................................................60
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................60
9.
REFERENCES......................................................................................... 62
9.1
PUBLISHED REFERENCES...........................................................................62
9.2
UNPUBLISHED REFERENCES.....................................................................63
10. APPENDICES .......................................................................................... 65
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 66

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ABBREVIATIONS AND DEFINITIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALAT
Alanin-Aminotransferase
ANOVA
Analysis of variance
ATS
American Thoracic Society
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
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
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
cAMP
Cyclic adenosine monophosphate
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
Cmax
Maximum measured concentration of the analyte in plasma
COPD
Chronic obstructive pulmonary disease
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoS
End of Study (synonym for End of Trial)
ERS
European Respiratory Society
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in one second 

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FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
iCF
Intended Commercial Formulation
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
IPD
Important protocol deviation
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
JRS
Japanese Respiratory Society
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple Rising Dose
PCR
Polymerase chain reaction
PDE4B
Preferential inhibitor of the phosphodiesterase
PE
Polyethylene
PF-ILDs
Progressive fibrosing interstitital lung diseases
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single rising dose

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SUSAR
Suspected unexpected serious adverse reaction
T
Test product or treatment
TEAE
Treatment-Emergent Adverse Event
TF2
Trial Formulation 2
TMF
Trial master file
TNF-α
Tumornekrosefaktor-α
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal

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1.
INTRODUCTION
BI 1015550, a preferential inhibitor of the phosphodiesterase 4B (PDE4B) isoenzyme which 
hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), is being developed by 
Boehringer Ingelheim (BI) for the treatment of progressive fibrosing interstitital lung diseases 
(PF-ILDs), including idiopathic pulmonary fibrosis (IPF).
1.1
MEDICAL BACKGROUND
IPF and other PF-ILDs share common pathophysiologic characteristics; alveolar epithelial 
cell injury and subsequent dysregulated repair, characterized by excessive deposition of 
extracellular matrix and loss of normal parenchymal architecture and lung function (P11-
07084). In IPF, fibroblasts exhibit unregulated proliferation and differentiate into 
myofibroblasts. The latter is considered the hallmark cell in the development and 
establishment of lung fibrosis (P12-03241). Several growth factors are implicated in the 
proliferation, migration and transdifferentiation of the fibroblast and myofibroblast pool in 
pulmonary fibrosis.
As of date, nintedanib and pirfenidone are the only drugs registered for the treatment of IPF 
and recommended in the recent ATS/ERS/JRS/ALAT Clinical Practice Guideline for the 
Treatment of Idiopathic Pulmonary Fibrosis [R18-2794]. Nintedanib is also approved in the 
U.S., the European Union and many other countries for the treatment of other fibrosing ILDs 
with progressive phenotype. Despite the availability of these drugs, the medical need remains 
high in these devastating diseases.
1.2
DRUG PROFILE
1.2.1
Residual Effect Period of BI 1015550
The Residual Effect Period (REP) of BI 1015550 is 7 days. This is the period after the last 
dose with measurable drug levels and / or pharmacodynamic effects still likely to be present.
1.2.2
BI 1015550
BI 1015550 is a potent inhibitor of human PDE4 B, showing mean half-maximal inhibition 
(IC50) at 10 nM with a nine-fold selectivity over phosphodiesterase 4D (PDE4 D) (mean IC50
91 nM) without relevant known interaction with other targets, (78 receptors and 42 enzymes 
tested at the very high concentration of 10,000 nM). In-vitro anti-inflammatory activity has 
been confirmed for TNF-α (IC50: 12 nM) and IL-2 release (IC50: 5 nM) from purified human 
peripheral blood mononuclear cells respectively.
Key pharmacokinetic characteristics
The pharmacokinetic (PK) of BI 1015550 was linear over all dose groups tested in single-
rising dose (SRD) and multiple-rising dose (MRD) studies. 
After oral administration, BI 1015550 was rapidly absorbed with peak plasma concentrations 
occurring at a median tmax of 1.38 to 3.92-hour post-dose. 
The gMean terminal elimination half-life was round 25 h. 

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After single and multiple oral doses BI 1015550 exposure (Cmax and AUC0-∞) appeared to 
increase dose proportionally. Steady state of BI 1015550 and its metabolites was achieved by 
Day 6 of bid administration.
Accumulation ratio based on AUC and Cmax values amounted up to 1.87-fold. 
Administration of single dose of 24 mg BI 1015550 Tablet formulation 1 (TF1) with food did 
not change the exposure to BI 1015550 to a clinically relevant extent. 
In the human ADME (mass balance) study, the total recovery of [14C]BI 1015550-related 
material was on average 95.0% of the administered dose with 58.0% excreted in faeces and 
36.4% excreted in urine where 11.9% was excreted unchanged as parent compound 
(c36151567).
Drug drug interactions
BI 1015550 is mainly metabolized by CYP3A with minor contributions from Uridine 
Diphosphoglucuronosyl Transferase.
Administration of BI 1015550 together with a strong CYP3A4 inhibitor increased AUC of BI 
1015550 2.2-fold and Cmax 1.3-fold (c24902949).
Based on in-vitro evaluation, BI 1015550 has the potential to induce CYP3A4.
Data from non-clinical studies
The toxicity profile for BI 1015550 has been assessed in safety pharmacology studies, genetic 
toxicology studies, and repeat dose studies in the rat, minipig, and monkeys of up to 26, 39, 
and 13 weeks, respectively. 
Vasculopathy and mortality secondary to vasculopathy are the primary findings defining the 
no adverse effect level (NOAEL) and lowest observed adverse effect Level (LOAEL) in the 
rat and minipig, respectively. 
In contrast, vascular changes were not observed in a 13-week monkey study at 30 mg/kg/day, 
supporting the decreased sensitivity of primates to PDE4i-induced vascular changes. 
Vasculopathy is a well characterized class-effect pathology associated with PDE4 inhibitors 
[R10-1559] and has not been demonstrated in humans administered marketed PDE4i 
apremilast and roflumilast
In addition, a fertility and early embryonic development (rat) and embryo-fetal development 
toxicity studies (rat and rabbit) were conducted. Decreased mating, fertility, and pregnancy 
indices were observed in male and female rats at a dose level that also level caused evidence 
of severe toxicity in both sexes. In rats but not in rabbits foetal loss was increased. 
Teratogenicity and fetotoxicity was not observed. In long-term toxicity studies in rats (26-
weeks), minipig and monkeys (13-weeks) there was no microscopic evidence of changes in 
female reproductive organs or on male spermatogenesis. 
For more details, please refer to the current Investigator’s Brochure (IB) (c02094779).
Data from clinical studies
Seven Phase I clinical studies have been completed in healthy volunteers in which 146 
subjects received BI 1015550.
Up to 48 mg single dose and 12 mg bid multiple dose showed acceptable safety and 
tolerability. The most common treatment emergent AEs (TEAEs) were nervous system 
events, particularly headache and gastrointestinal (GI) events, mainly diarrhoea and 

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abdominal pain. These events were mostly of mild intensity. 
In the MRD trial (1305-0002), one subject (after multiple dose of 6 mg bid) experienced 
postprandial pain,  constipation, lower abdominal pain, lower left quadrant abdominal pain,  
and increased CRP in blood. These events were classified as drug-related. They were of mild 
intensity, with the exception of CRP increase which was of moderate intensity and led to 
discontinuation of the subject (c02191718).
A trend towards weight loss in subjects treated with either 6 mg or 12 mg BI 1015550 bid 
over 11 days has been observed in study 1305-0011 (c22991937). 
No severe, serious, fatal events or suspected unexpected serious adverse reactions (SUSARs) 
have been reported in healthy volunteers.
Two clinical trials have been completed in patients with IPF: 
A Phase 1c study of BI 1015550 at 18 mg twice daily in patients with IPF not on background 
antifibrotic therapy showed similar PK to healthy volunteers along with an acceptable safety 
and tolerability profile. A total of 10 patients were treated with BI 1015550 18 mg bid and 
5 patients were treated with placebo.
The most frequently reported AEs by system organ class were gastrointestinal disorders. 
Gastrointestinal disorders were more frequent in the BI 1015550 group (8 patients, 80%) than 
in the placebo group (2 patients, 40%). On preferred term level, diarrhoea and flatulence were
the most frequently reported gastrointestinal disorders; they occurred with similar incidences 
in both treatment groups (diarrhoea: 40% each in BI 1015550 and Placebo group, flatulence: 
30% in BI 1015550, 20% in placebo group). SAEs were reported for 1 patient (anal fistula 
and anal incontinence) that were related to a long-lasting pre-existing condition and 
subsequent elective surgery. No fatal events were reported (c25085412).
Treatment with BI 1015550 at 18 mg twice daily in a Phase II proof-of-concept trial 
preserved lung function in patients with IPF over a period of 12 weeks, either as a 
monotherapy or on top of approved antifibrotic standard of care (nintedanib or pirfenidone). 
BI 1015550 showed acceptable safety and tolerability in the overall study population and in 
the subgroups of patients without or with background antifibrotic treatment.
In this trial 97 patients were exposed to BI 1015550 and 50 patients to placebo. The most 
frequently reported AEs were gastrointestinal disorders (32.0% in the BI 1015550 group, 
24.0% in the placebo group). Diarrhea was the most common AE, with a higher frequency in 
the BI 1015550 group (23.7%) than in the placebo group (12.0%) and diarrhea was also the 
most common event leading to treatment discontinuation (3 patients, all in the BI 1015550 
group and all on background treatment with nintedanib). However, the majority of diarrhea 
events were mild in intensity.
AEs leading to discontinuation of trial treatment were only observed in the BI 1015550 
treatment group. Apart from the mentioned 3 patients with diarrhoea and 2 patients with 
Covid-19, all events occurred in single patients without any pattern or cluster.
Serious adverse events were reported in 10.0% of patients in the placebo group and 6.2% of 
patients in the BI 1015550 treatment group. There were two events with fatal outcome in the 
BI 1015550 treatment group, one patient with Covid-19 pneumonia and one patient with 
suspected IPF exacerbation and suspected vasculitis (the diagnosis of vasculitis could not be 

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confirmed by the sponsor nor the independent external data monitoring committee). Risk 
factors were present in both fatal events.
There were no clinically relevant changes in vital signs (including body weight) and/or ECG
parameters (including QTc) observed. No changes in the Columbia Suicidal Severity Rating 
Scale (C-SSRS) and no AEs of suicidal ideation or behaviour were reported during trial 
treatment (c37065416).
For a more detailed description of the BI 1015550 profile, please refer to the current 
Investigator’s Brochure (IB) (c02094779).
1.2.3
Clinical Experience with other PDE4 inhibitors
Selective PDE4 inhibitors have been approved for chronic obstructive pulmonary disease 
(COPD) with chronic bronchitis and a history of exacerbations (roflumilast), and for 
moderate to severe plaque psoriasis and active psoriatic arthritis (apremilast). 
Roflumilast has been tested in Phase III studies for asthma and apremilast in Phase III studies 
for active Behcet’s disease. No PDE4 inhibitor has been tested in IPF, yet.
Cilomilast
Cilomilast was the first selective PDE4 inhibitor developed for the maintenance of lung
function (forced expiratory volume in one second (FEV1)) in patients with COPD but failed
to demonstrate efficacy to support approval of the drug. Cilomilast nonclinical findings  
include mesenteric arteritis in rats. In the clinical program the frequency of GI AEs was high.
Fecal occult blood testing was benign with unremarkable colonoscopy findings in the few
patients with blood in the stool. Lack of approval was based on inadequate evidence of
efficacy rather than any safety concern (P06-08316).
Roflumilast
Only one PDE4 inhibitor, roflumilast (Daxas® in EU, Daliresp® in US), has received
marketing authorization by regulatory agencies for a respiratory indication, COPD.
More than 5,000 patients with COPD were included in the “COPD Safety Pool” of the large
roflumilast clinical development program. The most frequently reported AEs associated with
the treatment with roflumilast were diarrhoea, weight loss, nausea, abdominal pain and
headache followed by insomnia, dizziness and decreased appetite.
The most common AEs leading to withdrawal in approximately 14% of the patients treated 
with roflumilast were nausea, diarrhoea and headache. The rate of withdrawal due to AEs 
among patients receiving placebo was 9%. 

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The mechanism of weight loss, which was observed in approximately 7% of the patients 
receiving roflumilast, is not fully understood (R10-1555). 
Clinical manifestation of mesenteric vasculitis was not reported in these clinical studies. The 
SPCs of Daxas®/Daliresp®, recommend the close monitoring of patient’s body weight and 
its cautious use in patients with previous or existing psychiatric symptoms or if concomitant 
treatment with other medicinal products, which are likely to cause psychiatric events, is 
intended. The above events were not observed with cilomilast, hence not clearly defined as 
class effects.
Apremilast
One PDE4 inhibitor for treatment of active psoriatic arthritis (Otezla®) has been approved by
the FDA on March 2014, in September 2014 for moderate to severe plaque psoriasis and in
July 2019 for the treatment of oral ulcers associated with Behçet’s disease.
Otezla® has been evaluated in 1493 patients with active psoriatic arthritis in three 
randomised placebo-controlled studies (R17-1427). 
The most common adverse reactions were diarrhoea, headache and nausea, followed by 
vomiting, upper respiratory tract infection, nasopharyngitis and abdominal pain. 
The most common adverse reactions leading to discontinuation were diarrhoea (1.8%), 
nausea (1.8%) and headache (1.2%).
The proportion of patients with psoriatic arthritis who discontinued treatment due to any 
adverse reaction was 4.6% for patients taking Otezla® 30 mg twice daily and 1.2% for 
placebo-treated patients.
The product information of Otezla® recommends the close monitoring of patient’s body
weight and its cautious use in patients with history of depression and/or suicidal thoughts or
behaviour (R14-1795).
BI 137882
One previous selective inhibitor of PDE4 B, BI 137882 has been tested in 40 healthy
volunteers [U10-3777] at Boehringer Ingelheim. Most frequently reported drug-related AEs 
were oropharyngeal pain and headache. The oropharyngeal pain was considered to be related 
to the solution for reconstitution. Most AEs were mild in intensity. AEs of moderate intensity 
were reported in 5 patients; most frequent was headache. A fatal event, not considered related 
to study medication, occurred in a 25 year old volunteer 8 days following administration of a 
single dose. The cause of death was myocarditis, in retrospect considered pre-existing with an 
additional finding of pre-existing Hashimoto thyroiditis [U11-2788].
1.3
RATIONALE FOR PERFORMING THE TRIAL
This trial is conducted to bridge pharmacokinetic and safety data between trial formulation 2 
(TF2) and the intended Commercial Formulation (iCF) of BI 1015550, and to evaluate a 
potential food effect on the iCF to support further clinical development of BI 1015550.

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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 1015550.
1.4.2
Risks
Subjects 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.
There are no identified risks for BI 1015550, based on the toxicology program or any clinical 
trials conducted for this product to date. Vasculitis and foetal loss are considered as important 
potential risk based only on nonclinical findings (see Section 1.2.1).
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 (see Section 1.2.3). For adverse events 
reported during clinical trials with BI 1015550 please refer to Section 1.2.1.
Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or 
known risks of 
clinical relevance 
for this trial
Summary of data, rationale for the risk
Mitigation strategy
Investigational Medicinal Product BI 1015550: compound and class specific (see section 1.2.1 and 1.2.3)
Pharmacokinetic 
interaction with 
strong CYP3A4 
inhibitors
CYP450 3A4 is regarded as the major enzyme responsible 
for BI 1015550 metabolism in human hepatocytes and 
predicted to contribute to ~70% of its hepatic metabolism.
In a drug drug interaction trial, the strong CYP 3A4 inhibitor 
(itraconazole) increased the exposure to BI 1015550 by 1.3-
fold (Cmax) and 2.2-fold AUC.
Potent CYP3A inhibitors 
are restricted medication.
Vasculitis
Vasculopathy is an established preclinical toxicity of PDE4 
inhibitors.
Vasculitis has been shown in both the rats and minipigs 
following oral administration of BI 1015550 but not in a 13-
week study in monkeys.
Vasculitis is listed as an important potential risk in the risk 
management plan (RMP) for the marketed PDE4- inhibitor 
apremilast. 
In marketed PDE4 inhibitors, vasculitis has not been 
identified as an adverse drug reaction in humans
Close clinical monitoring 
for AEs of vasculitis
Treatment interruption in 
case of any vasculitis 
adverse event. Restart only 
if not BI 1015550 related 
and considered acceptable 
by the investigator

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Reproductive 
toxicity
No teratogenicity was seen in 2 species in preclinical studies 
and exposure with BI 1015550 via the semen is expected to 
be very low.
In rats, male and female fertility was potentially reduced.
Long-term toxicity studies with BI 1015550 data in rat and 
monkey, showed no microscopic evidence of changes in 
female reproductive organs or male spermatogenesis. 
For another PDE4 inhibitor with comparable preclinical 
findings (class-effect), clinical data showed no effect on 
male fertility and sperm in humans. 
Fetal loss was increased was increased in female rats treated 
with BI 1015550.  
Efficacy of oral hormonal contraceptives can be impacted by 
potential BI 1015550 related CYP3A induction
Women of childbearing 
potential need to use a 
highly effective method of 
contraception. Of note oral 
hormonal contraceptives 
are not considered a highly 
effective method due to 
potential drug interactions.
Thorough counselling of 
women of childbearing 
potential about appropriate 
contraceptive measures
Repeated pregnancy testing
Discontinuation of trial in 
case of pregnancy
Weight decrease 
in underweight 
subjects (BMI < 
18.5 kg/m2)
For the marketed PDE4-inhibitors apremilast and roflumilast 
weight loss in underweight subjects is an identified 
important risk.
Presumably caused by increased energy expenditure and 
causing predominately loss of body fat
Inclusion of subjects with 
BMI> 18.5 only is routine 
inclusion criterion in 
Phase I
With a single dose 
administration the risk is 
considered to be very low.
Psychiatric 
disorders:
Depression and 
anxiety
Suicidality
For the marketed PDE4i depression is listed as side effect 
and they are associated with increased risk of depression 
with some patients reporting suicidal ideation and attempts 
and also reported cases of completed suicide.
In IPF patients treated with 18 mg BI 1015550 bid for up to 
12 weeks, no on-treatment events of suicidal ideation or 
behaviour and no events of depression or anxiety were 
reported
The risk after single dose 
administration in Phase I 
(done on site) is considered 
low and will be addressed 
by careful close clinical 
monitoring for AEs and 
increased awareness by the 
investigator for signs and 
symptoms of depression 
and anxiety as well as for 
signs and symptoms of 
suicidal ideation and 
behaviour
Only healthy subjects with 
no relevant medical history 
including psychiatric 
disorders will be enrolled.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Severe and 
serious infections 
Inhibition of the immune response due to the anti-
inflammatory mode of action of BI 1015550 potentially 
increases the risk of severe and serious infections.
Serious infections were balanced between placebo and 
BI 1015550 in Phase II trial
Nasopharyngitis was more frequently reported under 
treatment with BI 1015550 in Phase Ic/II but not in Phase I 
trials and the numbers were very small
Screening procedures for 
infections are defined for 
this trial. Subjects with any 
relevant chronic or acute 
infections are excluded 
from the trial. 
Treatment of infections 
should be initiated 
promptly according to 
standards of care.
Treatment interruption in 
case of severe acute 
infection until the subject 
has recovered based on the 
investigator’s medical 
judgement
Major Adverse 
Cardiovascular 
Events (MACE) 
and
tachyarrhythmia
Important potential risk for marketed PDE4 inhibitor 
apremilast
In preclinical studies with BI 1015550 no adverse 
cardiovascular findings detected
In clinical trials with BI 1015550 no relevant findings were 
observed
These risks will be 
addressed by careful safety 
monitoring and safety 
measures such as
close clinical monitoring 
for AEs;
regular monitoring of vital 
signs and ECG 
assessments.
Malignancies
Inhibition of the immune response with an 
immunomodulatory drug may potentially impair immune 
defences and thus theoretically decrease immune defence 
against malignancies.
Subjects with a recent 
history of malignancy 
within 5 years will be 
excluded from 
participation in this trial.
In case of occurrence of 
malignant neoplasm other 
than appropriately treated 
basal cell carcinoma or 
squamous cell carcinoma 
of the skin or in situ 
carcinoma of uterine 
cervix, the investigator 
should discontinue trial 
treatment 
Diagnostics and treatment 
have to be initiated 
according to local standard 
of care.
Gastrointestinal
disorders (e.g.
diarrhoea, nausea, 
vomiting, 
abdominal pain)
Vomiting and diarrhea are important dose-limiting side 
effects of marketed oral PDE-4 inhibitors. 
In Phase II (BI 1015550):
diarrhoea was the most frequently reported AE.
Increased awareness of 
symptoms.
Careful monitoring of 
hydration in subjects with 
diarrhoea recommended.
Symptomatic treatment if 
required

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
General safety topics
Drug-induced 
liver injury (DILI)
Rare but severe event, standard topic of interest for products 
in development thus under constant surveillance by sponsors 
and regulators.
Timely detection, 
evaluation, and follow-up 
of laboratory alterations in 
selected liver laboratory 
parameters to ensure 
subjects´ safety. Increased 
awareness and expedited 
reporting (AESI).
Trial procedures
Blood Sampling
As with all blood sampling, there is a risk of mild pain, local 
irritation, or bruising (a black or blue mark) at the puncture 
site. Furthermore, there is a small risk of light-headedness 
and/or fainting. In rare cases, the puncture site can also 
become infected or nerves may be damaged, inducing long-
lasting abnormal sensations (paraesthesia), impaired 
sensation of touch and persistent pain.
These risks will be 
addressed by careful safety 
monitoring and risk 
mitigation measures such 
as
close clinical monitoring 
for AEs;
selection of experienced 
sites and site staff 
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Risk assessment and risk mitigation measures in SARS-CoV-2 pandemic situation
Based on the pharmacological mechanism and existing non-clinical and clinical data, there is
no indication that treatment with BI 1015550 may increase the risk of infection including
SARS-CoV-2 infection.
The investigator will take the totality of information related to each single healthy volunteer 
and the local COVID-19 situation into consideration when performing the individual benefit-
risk assessment on a case-by-case basis. 
Considering all aspects, the investigator will decide upon each subject’s (continued) 
participation in the trial
Risk mitigation:

A risk management plan has been set up at the clinical site that details specific 
precautionary measures (e.g. hygienic rules, wearing of face masks, physical 
distancing), which will be filed in the ISF. These measures were implemented per 
local requirements in Baden-Württemberg and recommendation by the Robert Koch 
Institute. The local requirements may be subject to change and the trial procedures 
will be adapted accordingly, if applicable

AEs will be closely monitored and guidance pertaining to treatment and management 
of acute infections occurring during the trial will be provided 

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
Trial participants will be screened for SARS-CoV-2, e.g. via polymerase chain 
reaction (PCR) test, prior to screening (see also exclusion criterion #24) and at various 
time points during the trial 

In case SARS-CoV-2 infection is suspected in a subject during trial participation, 
PCR testing will be initiated without delay to enable the investigator to take decisions 
about the next steps (e.g. according to Section 3.3.4.1)

Any subject with suspected or diagnosed COVID-19 will be referred to health care 
professionals in charge to receive treatment according to standard of care
SARS-CoV-2 vaccination
Due to BI 1015550’s modulating effect on the immune system, the immune response elicited
by active vaccination may potentially be reduced. However, no non-clinical and/or clinical
data are available for BI 1015550 or the approved PDE4 inhibitors that show an adverse
effect of PDE4 inhibition on active vaccination, including COVID-19 vaccination. Hence, it
is not known whether the modulatory effect of BI 1015550 on the immune system translates
into clinical significance.
It is recommended to the investigators to take the totality of information, related to each
single patient and the local COVID-19 situation, into consideration when performing the
individual benefit-risk assessment on a case-by-case basis.
Trial participants need to be counselled that due to BI 1015550’s mode of action the
protection induced by any kind of active vaccination may be potentially reduced. The
decision on COVID-19 vaccination of a BI trial participant must be taken based on an
individual benefit-risk assessment by the investigator after thorough discussion with the
subject. This assessment should consider the approved labels of the respective vaccine.
The package insert for available COVID-19 vaccines or therapeutics should be carefully 
reviewed.
1.4.3
Discussion
The nature of the target and the mechanism of action of BI 1015550 is well understood.  
Based on its mode of action, BI 1015550 is hypothesized to have complementary activity to 
current therapies in IPF.
In the context of the unmet medical need and anticipated benefit of BI 1015550, the benefit 
risk evaluation of the compound, based upon the available preclinical and clinical 
information, is favourable.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of BI 1015550 iCF 
compared with TF2 and the effect of food on the pharmacokinetics of BI 1015550 iCF
following oral administration.
2.1.2
Primary endpoints
The following pharmacokinetic 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 pharmacokinetic 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:  

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Body weight

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as a randomised, open-label, single-dose, three-way crossover 
trial in healthy male and female subjects in order to compare the test treatment 1 (T1) to the
reference treatment (R) and to compare test treatment 2 (T2) to test treatment 1 (T1).
The treatments will be 
-
one 18 mg BI 1015550 film-coated tablet of the intended commercial formulation 
administered to subjects in the fasting state (T1) 
-
one 18 mg BI 1015550 film-coated tablet of the intended commercial formulation 
administered to subjects in fed state (T2) 
-
three 6 mg film-coated tablets of trial formulation 2 (TF2) administered to subjects in 
the fasting state (R).
The subjects will be randomly allocated to the 3 treatment sequences. There will be a 
washout period of at least 7 days between the treatments (referring to day 1). In each 
treatment period (1, 2, 3), the subject is planned to receive 1 single dose of medication (R, 
T1,T2). see Figure 3.1.:1.
Figure 3.1: 1
Trial design
For details, refer to Section 4.1.
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.
At least 7 days
R
T1
T1
R
R
T2
T1
T2
T2
Treatment period
1
2
3
Treatment
sequence
1
2
3
At least 7 days

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his/her own control, the comparison between treatments is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 healthy male and female subjects will enter the trial. They will be 
recruited from the volunteers' pool of the trial site.
A log of all subjects 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 healthy subjects.
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
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male or female subjects according to the assessment of the investigator, as 
based on a complete medical history including a physical examination, vital signs 
(BP, PR), 12-lead ECG, and clinical laboratory tests.
2. Age of 18 to 55 years (inclusive) 
3. BMI of 18.5 to 29.9 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. Either male subject, or female subject who meet any of the following criteria from 30 
days before drug administration until 7 days after trial completion:
-
Use of non-oral hormonal contraception associated with inhibition of ovulation:
intravaginal or transdermal combinations of estrogen and progestogen or
injectable or implantable progestogen
-
Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

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-
Sexually abstinent, i.e. complete abstinence from male-female sex when this is in line 
with the preferred and usual lifestyle of the study participant. 
Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods; 
declaration of abstinence for the duration of exposure to study drug; and withdrawal 
are not acceptable.
-
Vasectomised sexual partner with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate, provided that partner is the sole sexual partner of 
the study participant
-
Surgically sterilised (including hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, bilateral tubal occlusion)
-
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 estradiol 
below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 
140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse 
rate outside the range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or simple hernia 
repair)
7. Diseases of the central nervous system (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 or history of suicide attempts)
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections
10. 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
11. History of relevant allergy or hypersensitivity (including allergy to the trial 
medication or its excipients) 
12. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc 
interval prolongation)

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13. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation 
in another clinical trial in which investigational drug is administered
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day
for males)
17. Drug abuse or positive drug screening
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
19. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. 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
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
23. 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 
24. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
25. For female subjects: Positive pregnancy test
26. For female subjects: Lactation, pregnancy, or plans to become pregnant during the 
trial or within 7 days after trial completion. 
27. History of vasculitis
28. Known relevant immunodeficiency
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects 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 subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).
If a subject is removed from or withdraws from the trial after the first 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 end-of-trial examination should be performed.

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If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.2), the 
discontinued subject 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 subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer
2. The subject 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 
subject cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy,
surgery, adverse events (AEs), or diseases)
5. The subject 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
6. If the following adverse events are reported, the treatment has to be interrupted or 
discontinued:
-
Severe or serious infections, opportunistic or mycobacterium tuberculosis infections:
No further trial medication should be administered until the active infection has 
resolved. Treatment with BI 1015550 may be restarted when the subject has recovered 
according to investigator’s assessment.
-
Malignancies:
In case of occurrence of malignant neoplasm other than appropriately treated basal 
cell carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine 
cervix, the investigator should discontinue treatment with BI 1015550. 
-
Vasculitis:
The occurrence of any vasculitis adverse event requires treatment interruption. Restart 
only if not BI 1015550 related and considered acceptable by the investigator
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.6.2.3.

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If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim 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 impairing the appropriate conduct of the trial
4. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1)
5. More than 50% of the subjects show drug-related and clinically relevant adverse events of 
moderate or severe intensity, or if at least one drug-related serious adverse event is 
reported.
3.3.5
Replacement of subjects
In case more than 3 subjects do not complete the trial (including subjects non- evaluable for 
PK), subjects may be replaced if considered necessary to reach the objective of the trial.
Subjects who withdraw or are withdrawn from treatment or 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 subjects will be 
replaced. The total number of replacements may not exceed 1/3 of the total number of 
evaluable subjects anticipated to complete the trial. A replacement subject will be assigned a 
unique trial subject number, and will be assigned to the same treatment sequence as the 
subject he or she replaces.

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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 (T) are given below:
Substance:
BI 1015550
Pharmaceutical formulation: Film-coated tablets, iCF
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
18 mg
Posology:
1-0-0
Mode of administration:
Oral
The characteristics of the reference product (R) are given below:
Substance:
BI 1015550
Pharmaceutical formulation: film-coated tablets, TF2
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
6 mg
Posology:
3-0-0
Mode of administration:
Oral
Excipients of TF2 include lactose monohydrate, microcrystalline cellulose, croscarmellose 
sodium, magnesium stearate, film-coating mixture red.
Excipients of iCF include hydroxypropylcellulose, lactose, microcrystalline cellulose type 
101, croscarmellose sodium, magnesium stearate, ready to use film-coating dry mixture 
(Opadry ® pink).
4.1.2
Selection of doses in the trial
The dose selected for this trial is the standard clinical dose (see Section 1.2).
4.1.3
Method of assigning subjects to treatment groups
The randomisation scheme will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
scheme will be allocated to the subjects by drawing lots. Subjects are then assigned to a 
treatment sequence according to the randomisation scheme.
Once a subject number has been assigned, it cannot be reassigned to any other subject.

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All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the 
group may be split into several cohorts as required. Treatment of all subjects on the same 
calendar day is acceptable considering the trial-associated risks and safety measures, see 
Section 1.4.2).
The randomisation procedure is described in Section 7.4.
4.1.4
Drug assignment and administration of doses for each subject
This is a 3-way crossover trial. All subjects will receive the 3 treatments in randomised order. 
The treatments to be evaluated are summarised in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit 
strength
Dosage
Metabolic 
state
Total dose
T1 (Test 1)
BI 1015550
iCF
18 mg
1 film-coated tablet, 
single dose
Fasted
18 mg
T2 (Test 2)
BI 1015550
iCF
18 mg
1 film-coated tablet, 
single dose
Fed
18 mg
R (Reference)
BI 1015550
TF2
6 mg
3 film-coated tablets, 
single dose
Fasted
18 mg
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a 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, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
Administration of trial medication in two treatment periods (T1 and R) will be performed 
after subjects have fasted overnight; fasting is to start no later than 10 h before the scheduled 
dosing. Furthermore, subjects in these periods will continue to fast 4 additional hours after 
the dose administration. 
In one treatment period (T2), the subjects will start to consume a high-fat, high-calorie meal 
30 min before drug administration. The subjects must completely consume the meal prior to 
drug intake. The composition of the standard high-fat, high-calorie meal is detailed in 
Table 4.1.4: 2; this meal is in compliance with the FDA guidance ‘Food-Effect 
Bioavailability and Fed Bioequivalence Studies’ [R03-2269]. For restrictions with regard to 
diet, see Section 4.2.2.2.

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Table 4.1.4: 2
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (whole content) for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 
Subjects will be kept under close medical surveillance until 24 h after drug administration. 
During the first 4 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture).
The treatments will be separated by a wash-out phase of at least 7 days.
4.1.5
Blinding and procedures for unblinding
The table below summarizes the masking/blinding level of individual functions, roles and 
responsibilities involved in the trial. 
Table 4.1.5: 1
Blinding level of individual functions
Role/function
Timing of Unblinding / receiving access to the treatment information 
(including rationale)
Subject/Participant
This open label trial will provide the subject treatment information as 
soon as treatment has been assigned.
Investigator/Site Staff
The randomization scheme will be provided to the trial site prior to 
randomization for preparation of medication.
Sponsor trial team 
and data
Unblinded as requested.
Bioanalytical Staff
As requested for analysis of bioanalytical samples.
Persons directly involved in bioanalyses of PK samples will be blinded 
to trial treatments.
Pharmacokineticist/
Pharmacometrician
As requested for analysis
Unblinded Pharmacist/ 
Pharmacy staff
Prior to first subject entered.

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During the time a role/function is blinded according to the table above, the randomisation 
schemes and medication kit lists (i.e. the treatment information) are kept restricted by the 
global Randomization Team per Sponsor SOP.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP). 
For details of packing and the description of the label, refer to the ISF.
The name, address and telephone number of the trial site are provided in the subject 
information form. The EudraCT number is indicated on the title page of this protocol as well 
as on the subject information and informed consent forms.
Packaging and labelling will be performed in such a way that reserve samples as per 
21CFR230 are available for storage by the investigational site and that the trial materials can 
be chosen in a random way by the Investigator.
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 clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
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 subject, and the disposal of unused products. These 

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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 subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
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 adverse events require treatment, the investigator can authorise 
symptomatic therapy. 
In those cases, subjects will be treated as necessary (following local standard of care) 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. In particular strong CYP3A inhibitors and 
oral hormonal contraceptives are restricted medication due to potential drug-drug 
interactions. 
Ibuprofen may be used as an analgesic. All concomitant or rescue therapies will be recorded 
(including time of intake on trial days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects 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.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 2), the water administered with the drug, and an additional 
240 mL of water at 2 h and 4 h post-dose (mandatory for all subjects). 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 and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 3 days before the first administration of trial medication until after the last PK 
sample of each trial period is collected.

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Poppy-seeds containing foods should not be consumed within 3 days before each admission 
to trial site, in order to avoid false-positive results in the drug screen.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed while admitted to the trial site (i.e. during in-house stay).
Smoking is not allowed during in-house confinement.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
4.2.2.3
Contraception requirements
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course (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.
Subjects 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, 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 end of trial 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 (BP) as well as pulse rate (PR) or heart rate (heart rate 
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 subjects 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.
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 subjects have fasted for at least 9 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 white blood cell 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 Normalization Ratio)
X
X
X 
--
--
--
--
--
--
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
X
X
X
X
X
X
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2, 3 and 4 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 5 (end of trial examination)

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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine HGB (qual)
Urine leukocyte esterase (qual)
Urine pH
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, 3 and 4 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 5 (end of trial 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 women will be performed at screening, prior to 
each treatment period, and as part of the end of trial examination. Drug screening will be 
performed at screening and prior to each treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
(At screening only)
Hepatitis A antibodies (qualitative)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)

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To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. AlcoTrue® M, 
 will be performed prior to each treatment period, and 
may be repeated at any time during the trial at the discretion of an investigator or designee. 
The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at
 with the exception of 
drug screening and pregnancy tests. These tests will be performed at the trial site using 
M-10/14-PDT Surestep Multiline test and HCG-K20 test, respectively, or comparable test 
systems. In case of positive drug screen, confirmatory test may be done at 
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4). 
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 heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects 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 subject 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 parameters
Not applicable.

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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 adverse event (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.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse

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5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, 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 adverse events of special interest (AESI) relates to any specific AE that has been
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 
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
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 
eDC. 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.

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
Vasculitis events
In this trial protocol vasculitis is defined as any event term included in the 
Standardized MedDRA Query “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. A list of terms is provided in 
the ISF. 

Severe infections, serious infections, opportunistic or mycobacterium tuberculosis 
infections
The opportunistic infections include pneumocystis jirovecii, Human Polyoma-1 virus 
disease including polyomavirus-associated nephropathy, Cytomegalie Virus, post-
transplant lymphoproliferative disorder (Epstein-Barr-Virus), 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), 
Hepatitis C progression (R17-2617).
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 judgment 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.

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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

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
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.

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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 subject’s end of trial
(the End of Study (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 subject’s end of trial: 
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.
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 hours 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 subject’s end of trial, 
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 subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. 

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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 pharmacokinetics, 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. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 1015550 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an 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 g to 4000 g and at about 4 to 8 °C. 
Two plasma aliquots will be obtained and stored in polypropylene tubes. The first aliquot 
should contain at least 0.5 mL of plasma. The process from blood collection until transfer of 
plasma aliquots into the freezer should be completed within 120 min, 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) will be generated by these additional investigations. 

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The trial samples will be discarded after completion of the additional investigations but not 
later than 5 years after the CTR is archived.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
5.6.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
obtained at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the CTR. However, the data may be part of the CTR, if necessary.

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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, 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 pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used 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 3 h-period prior to the 
trial drug administration.
Up to 48:00 h after drug administration (planned time), the acceptable deviation from the 
scheduled time for vital signs, ECG, and laboratory tests will be ± 60 min, if not stated 
otherwise in the Flow Chart. 
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 pharmacokinetic parameters.
For logistical reasons, i.e. to provide more flexibility for ambulatory visits, a time window of 
± 120 min will be allowed for all procedures beyond planned time of 48 hours after drug 
administration. Otherwise no time window is defined for PK sampling.
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, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
If a subject 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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects 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 5.2.4.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.6).
6.2.2
Treatment periods
Each subject is expected to participate in 3 treatment periods (Days -1, 1-7 in each period). At 
least 7 days will separate drug administrations in the first, second, and third treatment period.

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On the evening of Day -1 of each treatment period, trial participants will be admitted to the 
trial site and kept under close medical surveillance for at least 24 h following drug 
administration. The subjects will then be allowed to leave the trial site after formal 
assessment and confirmation of their fitness. On all other trial days, subjects will be treated in 
an ambulatory fashion.
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 protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial
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, body weight, and 
physical examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period 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
The relative bioavailability of BI 1015550 iCF compared with TF2 will be estimated by the 
ratios of the geometric means (T1/R). The effect of food on BI 1015550 iCF will be 
estimated by the ratio of the geometric means (T2/T1). Additionally, their corresponding 2-
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 subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period 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 pharmacokinetic 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 subject will be included in the statistical 
pharmacokinetic (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 subject’s data will be documented in the CTR.

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Important protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Incorrect intake of meal prior to drug administration in treatment periods under fed
condition

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A BI 1015550 predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic 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
The primary endpoints (refer to Section 2.1.2) will be calculated according to the relevant BI 
internal procedures.
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 
effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment  
k in period j,
= the overall mean,

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i = the ith sequence effect, i = 1, 2, 3
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., 6
j = the jth period effect, j = 1, 2, 3
k = the kth treatment effect, k = 1, 2, 3
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (T1/R or T2/T1) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T1)-log(R) and for 
log(T2)-log(T1) will be estimated by the difference in the corresponding adjusted means 
(Least Squares Means). Additionally their two-sided 90% confidence intervals 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.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects.
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 
subjects (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.

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For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments 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 ECG, 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 first intake of trial medication will be 
assigned to the screening period, those between first trial medication intake and end of REP 
(see Section 1.2.2) will be assigned to the treatment period. Events occurring after the REP 
but prior to next intake or end of trial termination date will be assigned to ’follow-up’. In case 
of two or more treatments, the follow-up will be summarized according to the previous 
treatment. 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 will be reported to Pharmacovigilance only and will not be captured in 
the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
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. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as possibly clinically significant values 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 interim analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.

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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
Subjects will be randomised to one of the 3 treatment sequences (refer to Figure 3.1: 1) in a 
1:1:1 ratio. The block size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation scheme will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation scheme will contain additional blocks to allow for subject replacement 
(refer to Section 3.3.5).
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 24 subjects in the trial. A minimum of 18 evaluable subjects
are needed because this sample size is considered sufficient to achieve the aims of this 
exploratory trial. With this sample size, the following precision in estimating the ratio of 
geometric means (T1/R or T2/T1) can be expected with 95% probability. Precision is defined 
as the ratio of upper CI limit to the relative BA estimate. Note that the precision is 
independent of the actual ratio of geometric means.
The observed intra-individual coefficient of variation (gCV) for BI 101550 in a previous trial 
(1305-0015 [c24902949]) was roughly 13.6% for Cmax and 15.9% for AUC0-∞. The observed 
intra-individual coefficient of variation (gCV) for BI 101550 in a previous trial of food effect 
(1305-0020 [c20307414]) was roughly 16.0% for Cmax and 5.9% for AUC0-∞.   
For various assumptions around the gCV of 10%-25% , Table 7.5: 1 provides an overview of 
the achievable precision for estimating the ratio of geometric means (T1/R or T2/T1). For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios of geometric means.

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Table 7.5: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T1/R or T2/T1) for different gCVs in a 3x3 crossover trial 
(N=18 evaluable subjects)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
10
1.07
80
74.77
85.6
10
1.07
100
93.46
107
10
1.07
125
116.82
133.75
10
1.07
150
140.19
160.5
15
1.11
80
72.3
88.52
15
1.11
100
90.38
110.65
15
1.11
125
112.97
138.31
15
1.11
150
135.56
165.97
20
1.14
80
69.94
91.5
20
1.14
100
87.43
114.38
20
1.14
125
109.29
142.97
20
1.14
150
131.14
171.57
25
1.18
80
67.69
94.54
25
1.18
100
84.62
118.18
25
1.18
125
105.77
147.72
25
1.18
150
126.93
177.27
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit,  = exp(ln(θ) ± ω),
with θ being the ratio (T1/R or T2/T1) on original scale and ω the distance from the estimate 
θ to either confidence interval limit on the log-scale, which was obtained from the achievable 
precision on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 4.0.1.

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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 Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. 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 Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional 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 subject or the 
subject’s legally accepted representative.
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.

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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the 
 Phase I unit – the 
validated ClinBaseTM system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system,
ClinBaseTM serves as database. Instead of being entered into CRFs, selected data are directly 
entered into the ClinBaseTM system.
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 subject 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 subject 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 subject, documented 
in their medical records, would be acceptable.

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Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject 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: sex, year of birth (in accordance with local laws and 
regulations)

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)

Meal documentation

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.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
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. 

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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 must retain the source and essential documents (including ISF) according to the 
local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND 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

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
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 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the 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 the
 
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. The investigators will have access to the BI web portal Clinergize to access 
documents provided by the sponsor.
BI has appointed a Clinical Trial Leader (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 

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Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).
Analyses of BI 1015550 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 according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P06-08316
Giembycz MA, An update and appraisal of the cilomilast phase III clinical 
development programme for chronic obstructive pulmonary disease. Br J 
Clin Pharmacol; 2006; 62(2); 138-152.
P11-07084
An official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary 
Fibrosis: Evidence-based Guidelines for Diagnosis and Management. 
Am J Respir Crit Care Med 2011, 183:6, 788-824.
P12-03241
King TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. 
Lancet 2011. 378: 1949-1961
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER) 
2002:1-9.
R10-1555
Daxas (roflumilast) in chronic obstructive pulmonary disease, NDA 22-
522, FDA Advisory Committee briefing document presented to: 
Pulmonary-Allergy Drugs Advisory Committee (briefing book, April 7, 
2010).http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMate
rials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/ucm207376.htm 
(access date: 23 November 2010) ; Jersey City: Forest Research Institute; 
2010.
R10-1559
Giembycz MA. Life after PDE4: overcoming adverse events with dual 
specificity phosphodiesterase inhibitors. Curr Opin Pharmacol 2005;
5:238-244.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R14-1795
Otezla (apremilast) tablets, for oral use (Celgene) (U.S. prescribing 
information, revised: 3/2014).
R17-0915
Roflumilast 500 mcg tablets (Forest Research Institute):
pharmacology/toxicology NDA/BLA review and evaluation, application 
number: 022522Orig1s000. Source: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s0
00PharmR.pdf (access date: 13 March 2017) ; Department of Health and 
Human Services, Public Health Service, Food and Drug Administration, 
Center for Drug Evaluation and Research; 2011.
R17-0919
Otezla (apremilast) (Celgene): pharmacology/toxicology NDA/BLA 
review and evaluation, application number: 205437Orig1s000. Source: 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205437Orig1s0
00PharmR.pdf (access date: 13 March 2017) ; Department of Health and 
Human Services, Public Health Service, Food and Drug Administration, 
Center for Drug Evaluation and Research; 2014.

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R17-1427
Otezla 10 mg, 20 mg, 30 mg film-coated tablets, Otezla 30 mg film-coated 
tablets (Celgene) (summary for product characteristics, manufacturer 
responsible for batch release, conditions or restrictions regarding supply 
and use, other conditions and requirements of the marketing authorisation, 
conditions or restrictions with regard to the safe and effective use of the 
medicinal product, labelling and package leaflet (first published 
16/02/2015). Source: https://ec.europa.eu/health/documents/community-
register/2015/20150115130395/anx _130395_en.pdf (access date: 19 April 
2017); 2015.
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; 2107-2116.
R18-2794
Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, 
et al, American Thoracic Society, European Respiratory Society, Japanese 
Respiratory Society, Latin American Thoracic Society.
Diagnosis of idiopathic pulmonary fibrosis: an official 
ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care 
Med 2018; 198(5); e44-e68.
R94 1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992
9.2
UNPUBLISHED REFERENCES
c02094779
BI 1015550 - Investigator’s Brochure, 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). 1305.2.
c20307414
 Relative bioavailability of 
BI 1015550 following oral administration under fed and fasted conditions 
in healthy male subjects. Clinical Trial Report, 13 December 2017.
c22991937
 Safety, tolerability, and 
pharmacokinetics of single (Part 1) and multiple rising oral doses (Part 2) 
of BI 1015550 in healthy male subjects. Clinical Trial Report.
15 November 2018.
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.
Clinical Trial Report, 15 March 2019

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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.
U10-3777
BI 137882 – Investigator’s Brochure, 11 February 2011
U11-2788
, Safety, tolerability and pharmacokinetics of single rising 
doses of BI 137882 in healthy male volunteers (A randomised, single-
blind, placebo–controlled Phase I study. Clinical Trial Report 28 
December 2011

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10.
APPENDICES
Not applicable.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c37740081
1.0
clinical-trial-protocol-version-01
Relative bioavailability comparison of BI 1015550 as the intended commercial
formulation (iCF) versus trial
Author-Clinical Trial Leader
18 May 2022 08:24 CEST
Verification-Paper Signature
Completion
18 May 2022 08:30 CEST
Author-Trial Statistician
18 May 2022 10:22 CEST
Approval-Clinical Program 
18 May 2022 21:29 CEST

Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c37740081
1.0