Safety, Tolerability and Pharmacokinetics of Single Rising Oral Doses of BI 1015550 in Healthy Japanese Male Subjects (Double-blind, Randomised, Placebo-controlled, Parallel Group Design)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

Clinical Trial Protocol
TITLE PAGE
Document Number:
c19450453-02
BI Trial No.:
1305-0017
BI Investigational
Product:
BI 1015550
Title:
Safety, tolerability and pharmacokinetics of single rising oral doses of 
BI 1015550 in healthy Japanese male subjects (double-blind, 
randomised, placebo-controlled, parallel group design)
Lay Title:
This study is done in healthy Japanese volunteers. It looks at how 
different doses of BI 1015550 are taken up in the body and how well 
they are tolerated.
Clinical Phase:
I
Trial Clinical Monitor:
Tel: 
Fax: 
Principal Investigator:
Phone:
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment1))
Version and Date:
Version: 2.0
Date: 1 May 2018
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1015550
Protocol date:
Trial number:
Revision date:
1 May 2018
22 Mar 2018
1305-0017
Title of trial:
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 1015550 in 
healthy Japanese male subjects (double-blind, randomised, placebo-controlled, 
parallel group design)
Principal Investigator:
Trial site(s):
Clinical phase:
I
Objectives:
To investigate safety, tolerability and pharmacokinetics following single rising doses 
of BI 1015550
Methodology:
Double-blind randomised within dose groups, placebo-controlled, parallel-group 
design 
No. of subjects: 
total entered:
24 Japanese
each treatment:
8 per dose group (6 on active drug and 2 on placebo)
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy Japanese male subjects
Age and 45 years
BMI range: ≥18.5 and 25.0 kg/m2
Test product:
BI 1015550 as tablet formulation (TF 1 containing 6 mg BI 1015550)
dose:
Single dose of 12 mg, 24 mg and 36 mg 
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
Comparator product:
Matching placebo as tablet formulation
dose:
Not applicable
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment: Single dose
Criteria for
pharmacokinetics:
The following pharmacokinetic parameters of BI 1015550 will be calculated.
Secondary endpoints: 
AUC0-∞and Cmax
 
 

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1015550
Protocol date:
Trial number:
Revision date:
1 May 2018
22 Mar 2018
1305-0017
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 1015550 is the number [N 
(%)] of subjects with drug-related adverse events.
Further criteria of interest:
Treatment emergent AEs (TEAEs) including clinically relevant findings from the 
physical examination, safety laboratory tests (including testing for fecal occult blood 
and fecal calprotectin, urinalysis for hematuria), 12-lead electrocardiogram (ECG), 
continuous ECG monitoring, vital signs (blood pressure [BP], pulse rate [PR], 
respiratory rate [RR], body temperature).
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
 

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FLOW CHART
Visit
Day
Planned time (relative to drug 
administration [h:min]
Approximate clock time  of actual day 
[h:min]
Event and comment
Safety laboratory/Urinalysis
Vital signs 8,12
12-lead ECG12
Continuous ECG monitoring
PK blood 
 
Questioning for AEs and concomitant 
therapy 7
1
-28
to -1
Screening 
examination1
x
x
x3
2
-3 to 
-1
-72:00
9:00
Ambulatory visit
x11
x
-1
-12:00
21:00
Admission
x11
x
1
-3:00
6 :00
Randomization
x14,
17
x14
x3,14,
18
x14
x
0:00
9:00
Drug administration
┬
x
0:15
9:15
│
x
x
0:30
9:30
x
x3
│
x
x
0:45
9:45
│
x
x
1:00
10:00
x
x3
│
x
x
1:15
10:15
│
x
x
1:30
10:30
x
x3
│
x
x
2:00
11:00
240 mL fluid intake10
x
x3
│
x
x
3:00
12:00
│
x
x
4:00
13:00
Lunch10
x
x
x3
┴
x
x
6:00
15:00
x
x
8:00
17:00
Snack (voluntary)10
x
x3
x
x
10:00
19:00
x
x3
x
11:00
20:00
Dinner
x
12:00
21:00
x
x 
2
24:00
9:00
Breakfast10
x19
x
x3
x
x
28:00
13:00
Lunch
34:00
19:00
x
x
35:00
20:00
Dinner
3
48:00
9:00
Breaskfast10
x
x3
x
x
52:00
13:00
Lunch
59:00
20:00
Dinner
4
72:00
9:00
Discharge5
x19
x
x3
x
x
5
96:00
9:00
Ambulatory visit20
x
x
x
x
6
120:00
9:00
Ambulatory visit20
x19
x
x
x
x
3
8 to 
9
End of trial (EOT) 
examination4
x
x
x
x

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1.
Screening (28 to 1 days before drug administration) including subject information, informed consent, check of 
inclusion/exclusion criteria, physical examination, laboratory including fecal occult blood and fecal calprotectin testing, 
vital signs, ECG, demographics including body weight and height, drug and virus screening, alcohol breath test, medical 
history and concomitant therapy (cf. Section 6.2.1).
 
3.
Three 12-lead ECGs (triplicate ECG) will be recorded.
4.
End-of-trial examination to be performed within 2-3 days after last PK sampling; including physical examination, vital 
signs, ECG, laboratory, concomitant therapy, AE review.
5.
Discharge by the investigator or 
 designee after confirmation of fitness of the subject
7. 
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
8. 
Blood pressure (BP), pulse rate (PR), body temperature, and respiratory rate (RR).
 
10. If several actions are indicated at the same time point, the intake of meals/fluid will be the last action.
11. Drug screen and alcohol breath test will be performed on admission. Safety laboratory to be taken and to be medically 
evaluated within 3 days prior to administration of study drug; this safety laboratory can be omitted, if the screening 
examination is performed on Days -3, -2 or -1.
12. Blood pressure (BP), pulse rate (PR), respiratory rate and ECG after 10 minutes lying in supine position
 
14. The time is approximate; the respective procedure is to be performed and completed within 3 h prior to drug 
administration.
 
17. Only urinalysis
18. At baseline (i.e. Day 1, prior to drug administration) 3 triplicate ECGs are recorded within approximately one hour. The 
recordings should be separated by at least 15 minutes.
19. Urinalysis on Days 2, 4, and 6 to be performed within ±3 hours from planned time
20. Procedures on Days 5 and 6 to be performed within ±3 hours from planned time

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.2
DRUG PROFILE...............................................................................................13
1.2.5.1.4 Clinical experience with other PDE4 inhibitors ....................................21
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 25
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................25
2.2
TRIAL OBJECTIVES.......................................................................................26
2.3
BENEFIT - RISK ASSESSMENT ...................................................................26
2.3.1
Procedure-related risks ........................................................................26
2.3.2
Drug-related risks and safety measures..............................................27
2.3.3
Safety measures.....................................................................................29
2.3.4
Overall assessment................................................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 31
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................31
3.1.1
Administrative structure of the trial...................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................33
3.3
SELECTION OF TRIAL POPULATION ......................................................33

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3.3.1
Main diagnosis for study entry............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................34
3.3.4
Removal of subjects from therapy or assessments.............................35
Removal of individual subjects................................................35
3.3.4.1
Discontinuation of the trial by the sponsor..............................36
3.3.4.2
3.3.5
Replacement of subjects .......................................................................37
4.
TREATMENTS........................................................................................ 38
4.1
TREATMENTS TO BE ADMINISTERED....................................................38
4.1.1
Identity of BI investigational product and comparator product......38
4.1.2
Method of assigning subjects to treatment groups ............................38
4.1.3
Selection of doses in the trial................................................................39
4.1.4
Drug assignment and administration of doses for each subject .......39
4.1.5
Blinding and procedures for unblinding ............................................40
Blinding....................................................................................40
4.1.5.1
Procedures for emergency unblinding .....................................40
4.1.5.2
4.1.6
Packaging, labelling, and re-supply ....................................................41
4.1.7
Storage conditions.................................................................................41
4.1.8
Drug accountability ..............................................................................41
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................42
4.2.1
Other treatments and emergency procedures....................................42
4.2.2
Restrictions............................................................................................42
Restrictions regarding concomitant treatment .........................42
4.2.2.1
Restrictions on diet and life style.............................................42
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................43
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 44
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................44
5.1.1
Endpoints of efficacy.............................................................................44
5.1.2
Assessment of efficacy...........................................................................44
5.2
SAFETY..............................................................................................................44
5.2.1
Endpoints of safety................................................................................44
5.2.2
Assessment of adverse events...............................................................44
Definitions of adverse events...................................................44
5.2.2.1
Adverse event collection and reporting ...................................47
5.2.2.2
5.2.3
Assessment of safety laboratory parameters......................................49
5.2.4
Electrocardiogram................................................................................52
12-lead resting ECG.................................................................52
5.2.4.1
Continuous ECG monitoring ...................................................54
5.2.4.2
5.2.5
Assessment of other safety parameters...............................................54
Vital signs ................................................................................54
5.2.5.1
Medical examinations..............................................................54
5.2.5.2

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5.4
APPROPRIATENESS OF MEASUREMENTS.............................................55
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................55
5.5.1
Pharmacokinetic endpoints..................................................................55
Primary endpoints....................................................................55
5.5.1.1
Secondary endpoints................................................................55
5.5.1.2
5.5.2
Methods of sample collection...............................................................56
Plasma sampling for pharmacokinetic analysis of BI 
5.5.2.1
1015550....................................................................................56
5.5.3
Analytical determinations ....................................................................58
Analytical determination of drug plasma concentration..........58
5.5.3.1
 
6.
INVESTIGATIONAL PLAN.................................................................. 60
6.1
VISIT SCHEDULE............................................................................................60
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................60
6.2.1
Screening period....................................................................................60
6.2.2
Treatment period ..................................................................................61
6.2.3
End of trial period.................................................................................61
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 62
7.1
STATISTICAL DESIGN – MODEL ...............................................................62
7.1.1
Objectives...............................................................................................62
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................62
7.3
PLANNED ANALYSES....................................................................................62
7.3.1
Primary analyses...................................................................................62
7.3.2
Secondary analyses ...............................................................................62
7.3.3
Safety analyses.......................................................................................64
7.3.4
Preliminary pharmacokinetic analyses...............................................65
7.3.5
Pharmacokinetic analyses ....................................................................65

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7.4
HANDLING OF MISSING DATA ..................................................................66
7.4.1
Safety......................................................................................................66
7.4.2
Plasma
 drug concentration - time profiles ...............................66
7.4.3
Pharmacokinetic parameters...............................................................67
7.5
RANDOMISATION ..........................................................................................67
7.6
DETERMINATION OF SAMPLE SIZE ........................................................67
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 68
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................68
8.2
DATA QUALITY ASSURANCE .....................................................................68
8.3
RECORDS..........................................................................................................69
8.3.1
Source documents .................................................................................69
8.3.2
Direct access to source data and documents.......................................69
8.3.3
Storage period of records.....................................................................69
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................69
8.5
STATEMENT OF CONFIDENTIALITY.......................................................70
8.6
COMPLETION OF TRIAL..............................................................................70
8.7
PROTOCOL VIOLATIONS ............................................................................70
8.8
COMPENSATION AVAILABLE TO THE SUBJECT IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................70
9.
REFERENCES......................................................................................... 71
9.1
PUBLISHED REFERENCES...........................................................................71
9.2
UNPUBLISHED REFERENCES.....................................................................73
10. APPENDICES .......................................................................................... 74
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 75

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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
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
BI
Boehringer Ingelheim
b.i.d.
Bis in die, twice daily
BLQ
Below the limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
 
Cmax
CNS
Maximum measured concentration of the analyte in plasma
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case report form
CRO
Contract Research Organization
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P
DDI
Drug drug interaction
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
electronic Case report form
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
F
Absolute bioavailability
FDA
Food and Drug Administration
 
GCP
Good Clinical Practice

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gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
HIV
HR
Human immunodeficiency virus
Heart rate
IB
Investigator’s brochure
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in safety testing
MRD
Multiple-rising dose
MTD
Maximum tolerated dose
nM
Nanomolar
NOA
Not analysed
NOAEL
No observed adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
q.d.
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
 
 

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REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SD
Standard Deviation
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE(s)
Treatment emergent adverse event(s)
TMF
Trial master file
 
TDMAP
Trial Data Management and Analysis Plan
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WBC
 
White Blood Cells

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1.
INTRODUCTION
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2
DRUG PROFILE
 
 
 
 
 
 
 
 

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1.2.5.1.4
Clinical experience with other PDE4 inhibitors
Selective PDE4 inhibitors have been approved for 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.

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Cilomilast 
Cilomilast was the first selective PDE4 inhibitor developed for the maintenance of lung 
function (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 gastrointestinal 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 
This PDE4 inhibitor (Daxas® in EU, Daliresp® in US) got approved for treatment of COPD. 
More than 5,000 patients with COPD were included in the “COPD Safety Pool”. The most 
frequently reported AEs associated with roflumilast treatment were gastrointestinal events 
(diarrhea, weight loss, nausea, abdominal pain) and headache followed by insomnia, 
dizziness and decreased appetite.
There was an increased incidence of neuropsychiatric adverse reactions such as insomnia, 
anxiety, nervousness and depression; in rare instances suicidal ideation behavior (including 
completed suicide). Atrial fibrillation as SAE was reported more often in patients treated with 
roflumilast. Among the AEs leading to death, cardiac arrest was reported in a higher number 
of patients who received roflumilast [R10-1555]. Clinical manifestation of mesenteric 
vasculitis, an adverse effect that has been a concern with PDE4 inhibition in general, was not 
reported in these clinical studies.
Apremilast
One PDE4 inhibitor for treatment of active psoriatic arthritis (Otezla®) has been approved by
the FDA for moderate to severe plaque psoriasis. Otezla® has been evaluated in 1493 patients 
with active psoriatic arthritis in three randomized placebo-controlled studies ([R17-1427] 
Access date 29, March 2017.). The most common adverse reactions were diarrhea, headache 
and nausea, followed by vomiting, upper respiratory tract infection, nasopharyngitis and 
abdominal pain. 
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 
behavior [R14-1795].
 
 
 
 
 
 
 
 

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
 
 
The objective of this trial 1305-0017 is to investigate safety, tolerability and
pharmacokinetics of BI 1015550 and thereby provide essential information for a clinical 
development of BI 1015550 as a treatment for IPF. 
 
 
 
 
 
In this study, safety, tolerability and pharmacokinetics of BI 1015550 will be assessed in
healthy male volunteers to define a safe and tolerable dose for use in Japanese subjects.
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 1015550 in 
healthy male subjects following oral administration of single rising doses of 12 mg, 24 mg, 
and 36 mg.
Secondary objectives are the exploration of the pharmacokinetics (PK) 
 
after single dosing.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of BI 1015550 
as a treatment for IPF. The subjects are exposed to the risks of the study procedures and the 
risks related to the exposure to the trial medication.
2.3.1
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
ECG electrodes may cause local and typically transient skin reactions.

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The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (400 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
2.3.2
Drug-related risks and safety measures
BI 1015550 is considered a low risk compound for the purpose of this trial:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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In this trial a single dose of 12 mg, 24 mg and 36 mg BI 1015550 will be administered that 
has been investigated and well tolerated in humans before.  
2.3.3
Safety measures
The following precautionary measures will be taken in this study in order to minimize the 
risk for healthy volunteers:

Careful dose selection as described in Section 2.1.

Dose escalation is only permitted if there are no safety concerns and if none of the 
pre-specified stopping criteria are met. The minimum time interval between last 
dosing in a given dose group and the first dosing in the next higher dose group is 7 
days. For details see Section 3.1 and Section 3.3.4.2.

Safety laboratory examinations including surrogate markers of 
inflammation/vasculitis will be performed as described above

A thorough ECG and heart rate monitoring including continuous ECG measurement 
over 4 hours post dose to cover the anticipated period of highest drug exposure and 
additional repeated single and triple 12-lead ECGs

During in-house confinement the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events.

Subjects have to use adequate contraception as detailed in Section 3.3.3.
2.3.4
Overall assessment 
BI 1015550 is a PDE4 inhibitor that has been safely administered to humans before. 
The currently available toxicology data suggest that BI 1015550 can be safely administered
to men and women of non-childbearing potential for up to13 weeks. Considering the good 
tolerability of BI 1015550 in two previous clinical trials, the well characterized target 
structure and its mode of action and taking into account the safety measures described above, 
participation in this trial does not represent an undue risk to healthy subjects.

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Vasculopathy is the main concerns related to PDE4 inhibitors. Although vasculitis has not 
been observed in humans with the marketed PDE4 inhibitors close monitoring of surrogate 
markers of intestinal inflammation will be performed. Further the investigator will pay 
special attention of any signs of mood changes.
IPF is a devastating disease with significant associated morbidity and mortality and limited 
treatment options. BI 1015550 as a selective PDE4 B inhibitor has the potential to offer 
improved efficacy and/or tolerability as add-on to registered anti-fibrotics or as a mono 
therapy in IPF. Considering the medical need for a better treatment of IPF the sponsor feels 
that the benefit of this trial outweighs the potential risks and justifies exposure of healthy 
volunteers.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single-rising dose trial is designed as double-blind, randomised, and placebo-controlled 
within parallel dose groups. (Figure 3.1:1)
Figure 3.1:1 Study Design Overview
Within each dose group, 6 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group. 
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
Dose (mg)
12
24
36
Number of subjects
8
8
8
Subjects receiving placebo
2
2
2
Subjects receiving active drug
6
6
6
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 7 days between the last drug administration in the previous dose 
group and the first drug administration of the subsequent dose group. The next dose will only 
be given if, in the opinion of the investigator, no safety concerns arose in the preceding dose 
group (i.e. no dose-limiting events occurred) and if none of the pre-specified trial-specific 
stopping criteria were met (refer to Section 3.3.4.2). The decision to proceed to the 36 mg
dose group will be based upon the safety, tolerability, pharmacokinetic of the preceding dose 
groups.

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The investigator and/or the sponsor should stop dose escalation in case the safety evaluation 
leads to concerns that would not allow higher dosing.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany.
The trial will be conducted 
in 
 under the supervision of 
the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site or/and at a 
CRO designated by the sponsor.
The analyses of BI 1015550
 
 will be performed at a suitable contract research organization (CRO) under 
the responsibility of the Department of Drug Metabolism and Pharmacokinetics, BI Pharma 
GmbH & Co. KG, Biberach, Germany. 
 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation.
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 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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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 1015550.
With the rising dose design, double-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to the dose-depending effects as well as time effects, but it has the 
virtue of minimizing subject risk by sequentially studying ascending doses. As time-effects 
are expected to be small relative to the differences between the doses in the broad range 
investigated, unbiased comparisons between treatments can still be expected.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety, tolerability and pharmacodynamic effects. Each dose group consists 
of 8 subjects with 6 on active treatment, and 2 on placebo. The placebo control group 
includes all subjects of all dose groups treated with placebo. 6 subjects per active treatment 
group are in general considered as sufficient for the exploratory evaluation of 
pharmacokinetics. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 healthy male subjects will enter the study. Subjects will be recruited 
from the volunteers' pool of the trial site. 
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2. Age of 20 to 45 years (incl.) at screening.
3. BMI of 18.5 to 25.0 kg/m2 (incl.) at screening.

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4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
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) is deviating from 
normal and judged 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 50 to 90 bpm at screening
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance at screening
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and 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 mood disorders and any history of suicidality
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections including viral hepatitis, human immunodeficiency 
virus (HIV) and/or syphilis. (Subject with positive Hepatitis B core antibody will not 
allowed to participate in this trial)
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on trial days
15. Alcohol abuse (consumption of more 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site

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20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
23. Male subjects who do not agree to minimize the risk of female partners becoming 
pregnant from the first dosing day until three months after the study completion. 
Acceptable methods of contraception comprises barrier contraception and a medically 
accepted contraceptive method for the female partner (intra-uterine device or hormonal 
contraceptive since at least two months)
In addition, the following trial-specific exclusion criteria apply:
 
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
Removal of individual subjects
3.3.4.1
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
4. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg) or of clinically relevant changes in ECG requiring intervention as well as 
unexplained liver enzyme elevations at any time during the trial.
5. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with 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.
1305.11

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In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if 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.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
5. Dose escalation will be stopped as soon as at least 2 subjects at one dose level on active 
drug showed relevant individual QT prolongation, i.e. a QTc increase of greater 60 ms 
from baseline in connection with absolute QT or QTc greater than 500 ms, which has 
been confirmed by a repeat ECG recording.
6. Dose escalation will be stopped, if the predicted gMean Cmax or AUC of 36 mg dose 
group is above the experienced gMean exposure of the 48 mg single dose in 1305.11
 Prediction will be done after 24 mg 
dose group based on preliminary pharmacokinetics results of preceding dose groups as 
specified in Section 7.3.4.

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The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number, and will 
be assigned to the same treatment as the subject he replaces.

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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are given below:
Substance:
BI 1015550
Pharmaceutical formulation: Tablet formulation 1 (TF1)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
6 mg
Posology:
Dose group 1: 2-0-0
Dose group 2: 4-0-0
Dose group 3: 6-0-0
Route of administration:
p.o.
Duration of use:
Single dose
The characteristics of the reference product (placebo) are given below:
Substance:
Placebo matching in size and weight to 6 mg tablet
Pharmaceutical formulation: Tablet formulation
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
Dose group 1: 2-0-0
Dose group 2: 4-0-0
Dose group 3: 6-0-0
Route of administration:
p.o.
Duration of use:
Single dose
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be informed about the planned visit dates. The 
subjects willing to participate will be recruited to dose groups according to their temporal 
availability. As soon as enough subjects have been allocated to 1 of 3 dose groups, the 
following subjects will be allocated to one of the other dose group. Therefore, the allocation 
of subjects to dose group is not influenced by trial personnel, but only by the subjects’ 

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temporal availability. As the study includes healthy subjects from a homogenous population, 
relevant imbalances between the dose groups are not expected. 
The list of subject and medication numbers will be provided to the trial site in advance. The
allocation of subjects to study subject numbers will be performed prior to the first 
administration of trial medication. For this purpose, the subjects will be allocated to a study 
subject number by drawing lots. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
Three dose groups are to be investigated in this trial.
 
 
This trial is designed to evaluate the safety, tolerability, and pharmacokinetics of BI 1015550
in Japanese healthy young male volunteers. A safe and tolerable dose achieved in previous 
trials is used as a reference for the dose selection in this trial.
 
 
Furthermore, there will be 
preliminary PK analysis of dose groups 1 and 2 to decide whether dose group 3 is warranted.
For safety margins and further details on dose selection see Section 2.1.1.
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of units for 
placebo corresponds to the number of units of the respective dose level.
Table 4.1.4: 1
BI 1015550 and placebo treatments, oral administration
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Number of units 
per administration
Total dose
1
BI 1015550
Tablet
6 mg
2 tablets as single dose
12 mg
2
BI 1015550
Tablet
6 mg
4 tablets as single  dose
24 mg
3
BI 1015550
Tablet
6 mg
6 tablets as single dose
36 mg
1-3
Placebo*
Tablet
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
The trial medication will be administered to the subjects, while in a sitting position, as an oral 
dose together with about 240 mL of water under supervision of the investigating physician or 
an authorised designee. The so-called four-eye principle (two-person rule) should be applied 
for administration of trial medication and – if applicable – its preparation (e.g. reconstitution), 
if correct dosage cannot be ensured otherwise. Administration will be performed following an 
overnight fast, which is to start no later than 10 h before the scheduled dosing.

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Subjects will be kept under close medical surveillance until at least 72 h following drug 
administration. During the first 4 hours after drug administration subjects will be confined to 
bed with a bed inclination angle of at least 45 degrees unless lower or supine positioning is 
required for trial-related measurements (e.g. recording of 12-lead ECG) or medical reasons 
(e.g., adverse events). 
For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
The trial is designed double-blind with regard to the subjects and the investigators (as well as 
the research staff at the trial site) in order to eliminate observer or performance bias. This 
means avoiding systematic differences in assessments regarding the subject’s treatment 
(active or placebo). Persons directly involved in the clinical conduct of the trial will not have 
access to the treatment allocation prior to database lock.
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical monitor, data manager, 
statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug metabolism scientist, 
as well as dedicated CRO personnel). The objective of the trial is not 
expected to be affected.
Within the central ECG lab, the staff involved with interval measurements will be blinded 
with respect to the treatment and also with regard to the recording date and time as well as 
planned time points of the ECGs. The interval measurements for a given subject will be 
performed in a random and blinded sequence by a single technician.
In addition, the trial bioanalyst will receive the randomization codes prior to official 
unblinding to perform the preliminary PK analysis. He or she will confirm in writing that the 
codes will be treated confidentially.
Procedures for emergency unblinding
4.1.5.2
For blinded trials, the investigator will be supplied with a set of sealed envelopes containing 
the medication codes for each subject according to the randomisation scheme. The envelopes 
will be kept unopened at the trial site until the end of data collection. An envelope may only 
be opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or to assure safety of trial 
participants. If the envelope for a subject is opened, the sponsor must be informed 
immediately. The reason for opening the code break must be documented on the envelope or 
appropriate CRF page along with the date and the initials of the person who broke the code. 
At the close-out visit all envelopes are collected.

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4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
The clinical trial supply consists of containers holding the trial medication which are labelled
with trial identification. Containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Subject or medication number

Batch number 
Examples of the labels will be available in the ISF.
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 according to the recommended (labelled) storage conditions. Where 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 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator, pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication must be returned to sponsor. Receipt, usage and 

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return must be documented on the respective forms. Account must be given for any 
discrepancies. 
The investigator or pharmacist must maintain records of the product’s delivery to the trial 
site, the inventory at the site, the use by each subject, and the return to the sponsor of unused 
products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator or pharmacist will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP, and that reconcile all investigational products 
received from the sponsor. At the time of return to the sponsor, the investigator or pharmacist 
must verify that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
 
Restrictions on diet and life style
4.2.2.2
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until 4 hours post-dose liquid intake is restricted to the fluid
administered with the drug and an additional 240 mL of water served at 2 h (mandatory for 
all subjects). From 4 hours post-dose until 24 hours post-dose water intake is restricted to 
3000 mL. During the days of urine collection, total fluid intake should be at least 1.5 litres 
and should not exceed 3.5 litres.

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Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the first administration of trial medication until after the last 
PK sample of each study period is collected.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed 24 hours preceding the administration of study medication and 
until the end of plasma pharmacokinetic sampling of the respective visit.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion 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.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 1015550 is the number [N (%)] of 
subjects with drug-related adverse events.
Further criteria of interest:

TEAEs (including clinically relevant findings from the physical examination)

Safety laboratory tests, including fecal occult blood and fecal calprotectin testing and 
urinalysis

12-lead ECG

Abnormal findings in the Continuous ECG monitoring if rated as AE

Vital signs (blood pressure, pulse rate, respiratory rate and body temperature)
5.2.2
Assessment of adverse events
Definitions of adverse events
5.2.2.1
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 or not considered related to the medicinal product.
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, 

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
is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, 
or 

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. 
The following events will be handled as ‘deemed serious for any other reason’. AEs which 
possibly lead to disability will be reported as SAEs.
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.2.2, subsections ‘AE collection’ and ‘AE reporting to sponsor and 
timelines’. 
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further 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 RDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see section 5.2.2.2.
The following are considered as AESIs:

Hepatic injury:
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or

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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 ISF. 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure 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.
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
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

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 diminished).
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.

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
Additional arguments amongst those stated before, like 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 study drug treatment continues or remains 
unchanged. 
Adverse event collection and reporting
5.2.2.2
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 as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful 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, and intensity of the event as 
well as 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: 
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 or trial database 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 AEs but 
should only report related SAEs and related AESIs of which the investigator 
may become aware of by any means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.

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The REP for BI 1015550, when measurable drug levels or PD effects are still likely to be 
present, is defined as 
after the last administration of BI 1015550. Therefore, all AEs 
which occurred through the treatment phase and throughout the REP will be considered as on 
treatment; please see Section 7.3.3. Events which occurred after the REP will be considered 
as follow-up events.
AE reporting to 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 via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax 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.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication. The following should also be recorded as an (S)AE in the 
CRF and on the 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 CRF only.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.

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Pregnancy
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of 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 
Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (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 Trials 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.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests.
The parameters that will be determined are listed in Table 5.2.3:1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count will only be performed if there is an abnormality 
in the automatic blood cell count, i.e. if automatic count is not feasible or differential WBC is 
abnormal (i.e. pathological or atypical cells) and clinically relevant in the opinion of the 
investigator. 
In case the urinalysis is positive for erythrocytes, leukocytes, nitrite or protein and clinically 
relevant in the opinion of the investigator, microscopic examination of the urine sediment 
will be performed. Positive findings of the urine sediment examination will be monitored and 
if needed based on the medical judgment of the investigator an urologist may be consulted.
 
 
 
 

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
SCR
A1
B2
C3
EOT
Hematology
Hematocrit
Hemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Erythrocyte sedimentation rate (ESR)
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Automatic WBC 
differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, 
monocytes, lymphocytes
x
x
x
x
x
Manual differential 
WBC (if automatic count is 
not feasible or differential 
WBC is abnormal and 
clinically relevant in the 
opinion of the investigator)
Polymorphnuclear neutrophils (segs), 
band neutrophils (stabs), eosinophils, 
basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time 
(aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK); CK-MB only if 
CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hormones
Thyroid stimulating hormone (TSH)
fT3, fT4
x
x
--
--
--
--
--
--
x
x
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
high sensitivity C-Reactive Protein 
(hsCRP) 
Uric acid 
Total cholesterol 
Triglycerides
Albumin 
x
x
x
x
x
x
x
x
x
x
--
x
x
x
x
x
x 
x
x
x
--
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Electrolytes
Sodium
Potassium
Calcium
Chloride
Inorganic phosphate
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis (Stix)4
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
x
x
x
x
x
x
x
x
x
x 
-
-
-
-
-
x
x
x
x
x
x
x
x
x
x

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Functional lab group
Test name 
SCR
A1
B2
C3
EOT
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
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 and 
clinically relevant in the 
opinion of the investigator)
Only positive findings will be reported 
(for instance, the presence of sediment 
bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1
A: Days -3 to -1
2
B: post-dose on Day 1
3
C: Days 2, 4, 6
4
Urinalysis will be done at pre-dose on Day 1 
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which 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 drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antigen and/or antibody (qualitative)
Syphilis test (RPR, TP antibody method)
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
at screening and prior to treatment period, and may be repeated at any time during the study 
at the discretion of an investigator or designee. The results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3:1 and 5.2.3: 2 will be performed at by the local 
laboratory of the trial site or/and at a CRO designated by the sponsor.
Laboratory data will be transmitted electronically from the trial site to BI.

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5.2.4
Electrocardiogram
12-lead resting ECG
5.2.4.1
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (MAC 800 ECG machines, GE Healthcare) at the time 
points given in the Flow Chart. 
Electrode placement will be performed according to the method of Wilson, Goldberger and 
Einthoven modified by Mason and Likar (hips and shoulders instead of ankles and wrists). 
Precise electrode placement will be marked with an indelible mark on the skin to allow 
reproducible placement throughout the study.
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 10 seconds duration after subjects have rested for at least 10
min in a supine position. ECG recording will always precede all other study procedures 
scheduled for the same time (except for blood drawing from an intravenous cannula that is 
already in place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For time points with triple ECGs, all three single 
ECGs will be repeated. The repeat ECGs are assigned to the respective scheduled time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database. 
Storing
All ECGs will be stored electronically on the Muse Cardiology Information System (GE 
Medical Systems, Freiburg, Germany).
Data transfer
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).

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Evaluation
a) Central ECG lab
A post-study centralized evaluation of all 12-lead ECGs recorded after Days 1 up to 
72 h after drug administration will be performed by an independent ECG laboratory. 
This analysis will include the determination of cardiac axis as assessed by the ECG 
machine’s algorithm as well as the intervals RR, PR, QRS and QT measured semi-
automatically. With the exception of the first triple ECG (used as baseline before the 
first drug administration), only the first of the three replicate ECG at a single 
assessment time will be evaluated. The remaining second and third replicate ECG will 
be stored for additional analyses if required, e.g. by authorities at a later time point. 
HR and QTc (QT interval corrected for HR, e.g. QTcF and QTcB) will be determined 
in house (see TSAP for details).
Abnormalities detected during centralized ECG evaluation will not necessarily qualify 
as AE. All interval measurements in one subject will be performed on the same lead. 
The intervals will be measured from four cardiac cycles (beats) in lead II. If lead II 
shows a flat T wave or is not measurable for any reason, lead V5 will be used, or if 
that lead is not measurable, then lead I will be used. The lead actually used will be 
reported in the CTR.
For blinding arrangements see Section 4.1.5.1. No more than two different blinded 
readers will evaluate all ECGs of the study. For quality assurance and control of the 
measurements, all ECGs of a subject will be subsequently reviewed by the ECG 
technician supervisor or his/her designee with respect to the overall variance of the 
measured intervals, in order to detect accidentally switching of leads and/or false 
subject assignments of the ECGs. After the quality control the fiducial point markings 
will be reviewed by the cardiologist assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 
computerised ECG system or their manual corrections by the investigators will be 
used. In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data 
transfer) for cardiologic assessment by the central lab. In this case, these centrally 
measured results would overrule any other results obtained.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities 
will be monitored carefully and, if necessary, the subject will be removed from the 
trial and will receive the appropriate medical treatment. 

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Continuous ECG monitoring
5.2.4.2
Cardiac rhythm (including heart rate) will be monitored by means of continuous 3-lead ECG 
recording for at least 15 min before drug administration (for baseline assessment) and for 4 h 
following drug administration. This continuous ECG monitoring supports the early detection 
of adverse events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the 
trial site. Beyond this clinical evaluation at the trial site, no further data collection or analyses 
are performed based on continuous ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial 
database. Abnormal findings during continuous ECG recording will be recorded as AEs if 
judged clinically relevant by the Investigator.
5.2.5
Assessment of other safety parameters
Vital signs
5.2.5.1
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor at the times indicated in the Flow Chart, after subjects have rested for 
at least 10 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.
Further, respiratory rate [RR] and body temperature will be monitored. Body temperature will 
be determined at the time points indicated in the Flow Chart using electronic thermometers 
(Name of device at site). Respiratory rate will be counted by trained study personal by 
observing the chest movements over a period of one minute after the subject has rested in the 
supine position for 10 minutes. Recording of the values will be done at the time points 
indicated in the Flow Chart.
Medical examinations
5.2.5.2
At screening, the medical examination will include demographics including 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, body temperature 
and respiratory rate), 12-lead ECG, laboratory tests including fecal occult blood and fecal 
calprotectin testings 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.
 
 
 
 

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5.4
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 and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values including surrogate markers 
for gastrointestinal vasculitis, 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 5.5 are 
generally used assessments of drug exposure. 
 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters for BI 1015550 will be determined if feasible:
Primary endpoints
5.5.1.1

Not applicable
Secondary endpoints
5.5.1.2

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)

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5.5.2
Methods of sample collection
Plasma sampling for pharmacokinetic analysis of BI 1015550
5.5.2.1
For quantification of analyte plasma concentrations,3 mL of blood will be taken from an 
antecubital or forearm vein into an EDTA (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 about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Centrifugation will be started within 45 min after blood 
withdrawal (with interim storage of blood samples in ice water or on ice). Two plasma 
aliquots will be obtained and stored in polypropylene tubes. The first aliquot should contain 
at least 0.5 mL plasma. Plasma aliquots will be frozen within 2 hours after blood withdrawal 
(interim storage of plasma at room temperature or in ice/water or on ice). For each aliquot the 
time when the sample was placed in the freezer will be documented. Until transfer on dry ice 
to the analytical laboratory, the aliquots will be stored upright at about -20°C or below at the 
trial site. The second aliquot will be transferred to the analytical laboratory after the 

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bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory the 
plasma samples will be stored at about -20°C or below until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as “PK”, matrix 
and aliquot number (e.g. 1 or 2/back-up) may also be provided. 
After bioanalysis of BI 1015550, left-over  plasma samples may be used for further 
methodological investigations, e.g. for stability testing and/or, assessment of metabolites. 
However, only data related to the analyte and/or its metabolite(s) will be generated by these 
additional investigations. The study samples will be discarded after completion of the 
additional investigations but not later than 5 years upon the final study report has been 
signed.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.5.3
Analytical determinations
Analytical determination of drug plasma concentration
5.5.3.1
Concentrations of BI 1015550 in plasma from subjects will be determined by a validated LC-
MS/MS assay (liquid chromatography, tandem mass spectrometry). The bioanalyst will be 
unblinded during sample analysis. The analysis will be performed under the responsibility of 
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, 
Biberach, Germany at a suitable contract research organization (CRO).
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 end of trial examination are given 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 (including blank values for PK 
The acceptable deviation on profile days from the scheduled time for vital signs and ECG 
will be -15 min and for laboratory tests will be ± 30 min for the first 4 h after trial drug 
administration and ± 30 min thereafter.
 will be done as indicated and described in the
Flow Chart. 
The tolerance for drug administration will be ± 1 min on Days 1.
If several activities are scheduled at the same time point in the flowchart, ECG should be the 
first and meal the last activity. Furthermore, if several measurements including venipuncture 
are scheduled for the same time, venipuncture should be the last of the measurements due to 
its inconvenience to the subject and possible influence on physiological parameters.
For planned individual plasma concentration sampling times and 
 
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 determination of 
pharmacokinetic parameter.
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.
Relevant time violations will be identified and their handling discussed no later than at the 
(Blinded) Report Planning Meeting (cf. Section 7.4).
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening, 
 
and urinalysis), ECG, vital signs, and physical 
examination, refer to Section 5.2.3 to 5.2.5. 

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6.2.2
Treatment period
Each subject will receive one dose of the respective trial medication (BI 1015550 or placebo) 
at Visit 2. Trial medication will be taken orally by each subject under direct supervision of 
the investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
Participants will be admitted to the trial site in the evening of Day -1 and kept under close 
medical surveillance for at least 72 h following the drug administration. The subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their fitness 
by the investigator or 
 designee. On all other study days, the study will be performed in an 
ambulatory fashion.
For details on time points and procedures for collection of plasma 
 for PK 
analysis, refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2. 
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 1015550
by using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in Section 5.2.1. Inferential statistics is not planned (as explained 
in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) of BI 1015550. 
Endpoints as specified in Sections 5.5.1 and 5.6.1 will be analysed by descriptive statistics. 
Secondary endpoints as defined in Section 5.5.1.2 will be subjected to analysis of dose 
proportionality by use of the power model.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 3 different dose groups of BI 1015550 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.
7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). Analyses will be 
performed for parent drug. Plasma 
 concentration data and parameters of a subject 

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will be included in the statistical pharmacokinetic (PK) analyses if they are not flagged for 
exclusion due to a protocol violation 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.
Relevant protocol violations 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

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),

Missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one PK parameter that was not excluded according to the description above.
 
 


 
 
 
 

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7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is, 
all subjects who received at least one dose of study drug), will be included in the safety 
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘randomised treatment’. 
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 planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent 
AEs(TEAEs)).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake and end of REP (see
Section 5.2.2.2) will be assigned to the treatment period. Events after the residual effect 
period but prior to end of trial examination will be summarized as ‘post-treatment’, those 
after the end of trial examination will be assigned to ‘post-study’. These assignments 
including the corresponding time intervals will be defined in detail in the TSAP. 

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Additionally, further treatment intervals (analyzing treatments) may be defined 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 post-study 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 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the ECG variables QT, HR, QTcF, QTcB, PR, QRS, RR, and further derived ECG 
parameters. The derivation of the quantitative and qualitative ECG parameters and their 
analyses will be described in the TSAP.
7.3.4
Preliminary pharmacokinetic analyses
A preliminary analysis of PK parameters of dose groups 1 and 2 (AUC0-∞and Cmax of BI 
1015550), provided as individual values and geometric means of all subjects, will be 
performed before proceeding to dose level 3. 
Data from the above mentioned dose levels will be sufficient as long as PK data up to 48h 
after drug administration from at least 4 subjects on active treatment are available.
In contrast to the final PK calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times. Therefore, minor deviations of preliminary and 
final results may occur. The preliminary analysis will provide summary statistics of 
individual PK parameters without subject identification. The preliminary results will be 
distributed to the investigator and the trial team. 
Depending on the results of available preliminary PK analyses, the tolerability and safety of 
the compound, and changes of dosing schedule (e.g. additional intermediate doses) additional 
PK preliminary analysis may be performed based on the request of the TCM, the investigator, 
or Trial Clinical Pharmacokineticist. No formal preliminary PK report will be written.
No inferential statistical interim analysis is planned. However, after each dose group the 
investigator (or 
 deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data already obtained has been performed.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1015550 will be 
calculated using validated software (preferably Phoenix WinNonlin®) according to the BI 

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SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3) will be reported with their 
individual plasma
 concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma
 concentrations, 
pharmacokinetic parameters or other statistical assessment. Descriptive evaluations of PK 
parameters are based on 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).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
 
 
 
 
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma
 drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 

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detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
Subjects will be randomised within each dose group in a 3:1 ratio, which reflects the ratio of 
subjects receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 24 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics [R95-0013].

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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs and the Japanese GCP regulations 
(Ministry of Health and Welfare Ordinance No. 28, March 27, 1997).
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
Insurance Coverage: The terms and conditions of the insurance coverage are made available 
to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND 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 are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his personal trial-related data will be used by Boehringer 
Ingelheim in accordance with the local data protection law. The level of disclosure must also 
be explained to the subject.
The subject must be informed that his medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 

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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.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source documents and essential documents for a period defined 
by the Japanese GCP regulation and trial site’s contract with the sponsor.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.

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8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated 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.
8.6
COMPLETION OF TRIAL
When the trial is completed, the investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
sponsor of the completion in writing.
8.7
PROTOCOL VIOLATIONS
The investigator or sub-investigator should record all CTP violations. The investigator should 
provide and submit the sponsor and the head of the trial site the records of violations 
infringing the Japanese GCP or violations to eliminate an immediate hazard to trial subjects 
and for other medically inevitable reasons.
8.8
COMPENSATION AVAILABLE TO THE SUBJECT IN THE EVENT OF 
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract signed by the trial site.

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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.
 
 
 
 
 
R95-0013 Broom C. Design of first-administration studies in healthy man. Early Phase Drug 
Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan Press: London, 1990, 
206 213.
R06-1037 Guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. U.S. Department of 
Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER); 2005.
R07-4722 Guidance for industry: E14 clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center for 
Biologics Evaluation and Research (CBER) (2005)
R09-4830   Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
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). 
website.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulm
onary-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.
R11-2587 Ley B, Collard HR, King TE. Clinical course and prediction of survival in 
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183:431-440.
 
 

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R14-1795 Otezla (apremilast) tablets, for oral use (Celgene) (U.S. prescribing information, 
revised: 3/2014). 2014
R16-0366 E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs: questions & answers (R3) 
(current version dated 10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficac
y/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2015) ; Geneva: 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
R17-0158 Korkmaz S, Maupoil V, Sobry C, et al. An increased regional blood flow 
precedes mesenteric inflammation in rats treated by a phosphodiesterase 4 
inhibitor. Tox Sci 2009; 107(1):298-305.
R17-0915 Roflumilast 500 mcg tablets (Forest Research Institute): 
pharmacology/toxicology NDA/BLA review and evaluation, application number: 
022522Orig1s000. 
website.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000PharmR.
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)
R17-0916 Losco PE, Evans EE, Barat SA, et al. The toxicity of SCH 351591, a novel 
phosphodiesterase-4 inhibitor, in cynomolgus monkeys. Toxicol Pathol 2004; 
32:295-308.
R17-0919 Otezla (apremilast) (Celgene): pharmacology/toxicology NDA/BLA review and 
evaluation, application number: 205437Orig1s000.
website.accessdata.fda.gov/drugsatfda_docs/nda/2014/205437Orig1s000PharmR.
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)
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). 
website.ec.europa.eu/health/documents/community-register/2015/20 
150115130395/anx_130395_en.pdf (access date: 19 April 2017); 2015.
R17-1539 Otezla 30mg tablets (Celgene) (summary of product characteristics updated 05-
Jan-2017). website.medicines.org.uk/emc/print-document?documentId=29792 
(access date: 2 May 2017); 2017.
R17-1540 Otezla 10mg, 20mg, 30mg treatment initiation pack (Celgene) (summary of 
product characteristics updated 05-Jan-2017). 

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website.medicines.org.uk/emc/print-document?documentId=29793 (access date: 
2 May 2017); 2017.
R17-1542 Daxas 500 micrograms film-coated tablets (AstraZeneca) (summary of product 
characteristics updated 06-Dec-2016). website.medicines.org.uk/emc/print-
document?documentId=23416 (access date: 2 May 2017); 2016.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics. Current version
U10-3777-01
 Investigator Brochure BI 137882 BS. 11 Feb 2011
U11-2788-01
 Safety, tolerability and pharmacokinetics of single rising oral 
doses of BI 137882 in healthy male volunteers (A randomised, single-blind, 
placebo-controlled phase I study). 1306.1. 28 Dec 2011
U13-1792-01
. Safety, tolerability and 
pharmacokinetics of single rising oral doses of BI 1015550 in healthy male 
volunteers (a partially randomised, single-blinded, placebo-controlled Phase I 
study). 1305.1. 21 Jun 2013
c02094779-03
 
 Investigator's Brochure BI 1015550 for Idiopathic Pulmonary 
Fibrosis. 22 Feb 2018
c02191718-02
. Safety, tolerability and 
pharmacokinetics of multiple rising oral doses of BI 1015550 powder for oral 
solution in healthy male volunteers q.d. or b.i.d. for 14 days (a randomised, 
double-blind, placebo-controlled within dose groups Phase I trial). 1305.2. 15 
Apr 2014
c15772185-02
. Safety, tolerability, and pharmacokinetics of single (Part
1) and multiple rising oral doses (Part 2) of BI 1015550 in healthy male
subjects. 1305.11. 03 July 2017
c17549115-01
. Relative bioavailability of BI 1015550
following oral administration under fed and fasted conditions in healthy
male subjects. 1305-0020. 11 Jul 2017.

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10.
APPENDICES
Not applicable.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
1 May 2018
EudraCT number
BI Trial number
1305-0017
BI Investigational Product(s)
BI 1015550
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1015550 in healthy 
Japanese male subjects (double-blind, 
randomised, placebo-controlled, parallel group 
design)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title page
Description of change
Information of Trial Clinical Monitor (TCM)
Changed the information from ‘
 
 Phone: +
Fax: +
 to ‘
 
.
 
 
Tel: 
Fax:
’
Rationale for change
Affiliation of TCM is changed

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Number of global amendment
1
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
Exclusion Criteria #9
Added the sentence in ‘including viral hepatitis, 
human immunodeficiency virus (HIV) and/or 
syphilis (Subject with positive Hepatiits B core 
antibody will not be allowed to participate in this 
trial.)’
Rationale for change
To address PMDA requirement
Section to be changed
Section 3.3.3 Exclusion criteria
Description of change
Exclusion Criteria #23
Changed the contraception periods from two 
months to three months
Rationale for change
To address PMDA requirement

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c19450453
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clinical-trial-protocol-version-02
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 1015550 in
healthy Japanese male subjects (double-blind, randomised, placebo-controlled,
parallel group design)
Author-Trial Clinical Monitor
02 May 2018 13:14 CEST
Approval-Therapeutic Area 
02 May 2018 13:15 CEST
Author-Trial Statistician
07 May 2018 01:08 CEST
Author-Trial Clinical
Pharmacokineticist
08 May 2018 01:52 CEST
Approval-Team Member Medicine
09 May 2018 13:30 CEST
Verification-Paper Signature
Completion
09 May 2018 13:34 CEST

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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
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