Safety, Tolerability, and Pharmacokinetics of Single (Part 1) and Multiple Rising Oral Doses (Part 2) of BI 1015550 in Healthy Male Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c15772185-03
EudraCT No.:
BI Trial No.:
2017-002003-10
1305-0011
BI Investigational
Product:
BI 1015550
Title:
Safety, tolerability, and pharmacokinetics of single (Part 1) and 
multiple rising oral doses (Part 2) of BI 1015550 in healthy male 
subjects
Lay Title:
This study tests how healthy men tolerate different doses of BI 
1015550. The study also tests how BI 1015550 is taken up by the 
body.
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax: 
Principal Investigator:
Phone:
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 28 August 2017
Page 1 of 103
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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BI Trial No.: 1305-0011
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Trial Protocol
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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:
28 August 2017
18 May 2017
1305-0011
Title of trial:
Safety, tolerability, and pharmacokinetics of single (Part 1) and multiple rising 
oral doses (Part 2) of BI 1015550 in healthy male subjects 
Principal 
Investigator:
 
Trial site:
Phone: 
Fax: 
Clinical phase:
I
Objectives:
To investigate safety, tolerability, and pharmacokinetics following single and
multiple rising doses of BI 1015550
Methodology:
Part 1: 
Single-blind, partially randomized within dose groups, placebo-controlled, 
parallel-group design
Part 2: 
Double-blind, partially randomized within dose groups, placebo-controlled, 
parallel-group design
No. of subjects: 
total entered:
N= 42
each treatment: Part 1: 18 (9 per dose group: 6 on active drug and 3 on placebo)
Part 2: 24* (12 per dose group: 8 on active drug and 4 on placebo)
*Subjects in Part 2 are only to be dosed after completion of dosing in Part 1. 

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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:
28 August 2017
18 May 2017
1305-0011
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 45 years, body mass index (BMI) of 18.5 
to 29.9 kg/m2
Test product:
BI 1015550 as tablet formulation (TF 1 containing 6 mg BI 1015550)
dose:
Part 1: 36 mg, 48 mg 
Part 2: 6 mg b.i.d., 12 mg b.i.d.
mode of admin.: Part 1: Oral with 240 mL of water after an overnight fast of at least 10 h
Part 2: Oral with 240 mL of water after a moderate fat meal 
Reference products: Matching placebo as tablet formulation
dose:
Not applicable
mode of admin.: Part 1: Oral with 240 mL of water after an overnight fast of at least 10 h
Part 2: Oral with 240 mL of water after a moderate fat meal
Duration of 
treatment:
Part 1: Single dose
Part 2: Subjects will be treated for 14 days and will receive a single morning 
dose on Day 1, followed by a 11 day treatment (i.e., 6 mg b.i.d., 12 
mg b.i.d. or matching placebo on Days 3 to 13), and a single morning 
dose on Day 14.

Boehringer Ingelheim
28 Aug 2017
BI Trial No.: 1305-0011
c15772185-03
Trial Protocol
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
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:
28 August 2017
18 May 2017
1305-0011
Criteria for 
pharmacokinetics:
Part 1: 
Secondary endpoints:
AUC0-∞and Cmax
 
Part 2: 
Secondary endpoints:
After the first dose:
AUCτ,1 and Cmax
After the last dose:
AUCτ,ss and Cmax,ss
Accumulation ratios:
RA,AUC, RA,Cmax,
       
 
                                       
                                       
                                                            
       

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BI Trial No.: 1305-0011
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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:
28 August 2017
18 May 2017
1305-0011
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 1015550 is the number 
[N (%)] of subjects with drug-related AEs.
Further criteria of interest:
Treatment emergent AEs (TEAEs) including clinically relevant findings from 
the physical examination, safety laboratory tests 
, 12-lead 
electrocardiogram (ECG), continuous ECG monitoring (only Part 1), vital 
signs (blood pressure [BP], pulse rate [PR], respiratory rate [RR], aural body 
temperature), body weight (only Part 2), and 
 
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
 
 

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FLOW CHARTS
PART 1: SRD 
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 signs8,12
12-lead ECG12
Surveillance (continuous ECG-monitoring)
In-house
PK blood
9
 
 
Adverse event questioning7
1
-14 to 
-2
Screening 
examination1
x
x
x3
x
2
-3 to 
-1
-72:00
08:00
Ambulatory visit
x11
x
-1
-12:00
20:00
Admission
x11
x
1
-2:00
06:00
Randomization
x17
x14
x14,19
┬
x14,15
x
0:00
08:00
Drug administration
┬
│
x
0:15
08:15
│
│
x
0:30
08:30
x
x3
│
│
x
x
0:45
08:45
│
│
x
1:00
09:00
x
x3
│
│
x
x
1:15
09:15
│
│
x
1:30
09:30
x
x3
│
│
x
x
2:00
10:00
240 mL fluid intake 10
x
x3
│
│
x
x
2:30
10:30
│
│
x
3:00
11:00
│
│
x
x
4:00
12:00
Lunch10
x
x
x3
┴
│
x
x
6:00
14:00
│
x
8:00
16:00
Snack (voluntary) 10
x
x3
│
x
x
10:00
18:00
x
x3
│
11:00
19:00
Dinner10
│
12:00
20:00
│
x
x
2
24:00
08:00
Discharge5
x
x
x3
┴
x18
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x3
x
x
4
72:00
08:00
Ambulatory visit
x
x
x3
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
6
120:00
08:00
Ambulatory visit
x
x
x
x
x
3
8 to 9
End of trial 
x
x
x
x

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examination4
1.
Screening (14 to 2 days before drug administration) including subject information, informed consent, check of inclusion/exclusion 
criteria, physical examination, laboratory 
 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 (Triple-ECG) will be recorded 
4.
End-of-study-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.
9.
PK blood sampling times may be adapted based on information obtained during trial conduct (e.g. preliminary PK) including addition 
of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject.
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 2 h prior to drug administration.
 
17. Only urinalysis
19. 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.

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PART 2: MRD
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory / 
Urinalysis
 
PK blood
9
 
12-lead ECG12
Vital signs 8,12 
In-house
Adverse event questioning 7
1
-21 
to -
2
Screening 
examination1
x
x3
x
x
2
-1
-24:00
08:00
Admission13
x11
┬
x
1
-2:00 –
0:00
6:00 –
08:00
Randomisation14,15
x20
x15,16
x15,22
x15
│
│
x15
-0:30
07:30
Breakfast17 
│
0:00
08:00
Drug administration
│
x
0:15
08:15
x
│
0:30
08:30
x
│
0:45
08:45
x
│
1:00
09:00
x
x3
x
│
x
1:15
09:15
x
│
1:30
09:30
x
│
2:00
10:00
240 mL fluid intake10
x
x3
x
│
x
3:00
11:00
x
│
4:00
12:00
240 mL fluid intake, 
lunch10
x
x3
x
│
│
x
6:00
14:00
x
│
8:00
16:00
Snack (voluntary)10
x
│
10:00
18:00
│
11:00
19:00
Dinner10
│
12:00
20:00
x
x3
x
│
x
2
24:00
08:00
x
x
x3
x
│
x
34:00
18:00
x
│
x
3
47:00
07:00
│
47:30
07:30
Breakfast17
│
47:55
07:55
x
│
48:00
08:00
Drug Administration
│
x
59:30
19:30
Dinner17
│
60:00
20:00
Drug Administration
│
x
4
71:00
07:00
│
71:30
07:30
Breakfast17
│
71:55
07:55
x
│

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Visit
Day
Planned time (relative to first 
drug administration 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory / Urinalysis
 
 
PK blood
9
 
12-lead ECG12
Vital signs 8,12 
In-house
Adverse event questioning 7
2
4
72:00
08:00
Drug Administration
│
x
83:30
19:30
Dinner17
│
84:00
20:00
Drug Administration
│
x
5
95:30
07:30
Breakfast17
x15
x3,15
x15
│
96:00
08:00
Drug administration
│
x
107:30
19:30
Dinner17
│
108:00
20:00
Drug Administration
│
x
6
119:00
07:00
│
119:30
07:30
Breakfast17
│
120:00
08:00
Drug administration
│
x
131:30
19:30
Dinner17
│
132:00
20:00
Drug Administration
│
x
7
143:30
07:30
Breakfast17
x15,23
│
144:00
08:00
Drug administration
│
x
155:30
19:30
Dinner17
│
156:00
20:00
Drug Administration
│
x
8
167:00
07:00
│
167:30
07:30
Breakfast17
│
167:55
07:55
x
│
168:00
08:00
Drug administration
│
x
179:30
19:30
Dinner17
│
180:00
20:00
Drug Administration
│
x
9
191:30
07:30
Breakfast17
x15
x15
x15
│
192:00
08:00
Drug administration
│
x
203:30
19:30
Dinner17
│
204:00
20:00
Drug Administration
│
x
10
215:00
07:00
│
215:30
07:30
Breakfast17
│
216:00
08:00
Drug administration
│
x
227:30
19:30
Dinner17
│
228:00
20:00
Drug Administration
│
x
11
239:30
07:30
Breakfast17
│
239:55
07:55
x
│
240:00
08:00
Drug administration
│
x
251:30
19:30
Dinner17
│
252:00
20:00
Drug Administration
│
x
12
263:00
07:00
x15,23
│
263:30
07:30
Breakfast17
│

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Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory / 
Urinalysis
 
 
PK blood
9
 
12-lead ECG12
Vital signs 8,12 
In-house
Adverse event questioning 7
2
12
263:55
07:55
x
│
264:00
08:00
Drug administration
│
x
275:30
19:30
Dinner17
│
276:00
20:00
Drug administration
│
x
13
287:30
07:30
Breakfast17
│
287:55
07:55
x
│
288:00
08:00
Drug administration
│
x
299:30
19:30
Dinner17
│
300:00
20:00
Drug Administration
│
x
14
311:00
07:00
x15
x3,15
x15
│
311:30
07:30
Breakfast17
│
311:55
07:55
x
│
312:00
08:00
Drug Administration
│
x
312:15
08:15
x
│
312:30
08:30
x
│
312:45
08:45
x
│
313:00
09:00
x
x3
x
│
x
313:15
09:15
x
│
313:30
09:30
x
│
314:00
10:00
240 mL fluid intake10
x
x3
x
│
x
315:00
11:00
x
│
316:00
12:00
240 mL fluid intake, 
lunch10
x
x3
x
│
│
x
318:00
14:00
x
│
320:00
16:00
Snack (voluntary)10
x
│
322:00
18:00
│
x
323:00
19:00
Dinner10
│
324:00
20:00
x
x3
x
│
15
336:00
08:00
x
x3
x
│
x
346:00
18:00
x
│
x
16
360:00
08:00
Discharge 5,13
x
x
x3
x
┴
x
17
384:00
08:00
Ambulatory visit
x
x3
x
x
18
408:00
08:00
Ambulatory visit
x
x
x
x
19
432:00
08:00
Ambulatory visit
x
x
x
x
20
456:00
08:00
Ambulatory visit
x
x
x
x
21
480:00
08:00
Ambulatory visit
x
x
x
x
22
504:00
08:00
Ambulatory visit
x
x
x
23
528:00
08:00
Ambulatory visit
x
x
x
24
552:00
08:00
Ambulatory visit
x
x
x
25
576:00
08:00
Ambulatory visit
x
x
x
3
26-
28
End of trial 
examination4
x
x
x
x

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1.
Screening (within 21 to 2 days before first drug administration) including subject information, informed consent, demographics 
including height and weight, smoking and alcohol history, relevant medical history and prior medications, check of inclusion/exclusion 
criteria, vital signs (BP, PR, respiratory rate, body temperature), 12-lead ECG, clinical laboratory (hematology, clinical chemistry, 
urinalysis, fecal occult blood and fecal calprotectin testing), drug and virus screening, alcohol breath test, 
and a 
physical examination
 
 
3.
Three 12-lead ECGs (Triple-ECG) will be recorded 
4.
End-of-study-examination to be performed within 1 to 3 days after last PK sampling; including physical examination, vital signs, ECG, 
laboratory, concomitant therapy, AE review and 
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, respiratory rate
9.
PK blood sampling times may be adapted based on information obtained during trial conduct (e.g. preliminary PK) including addition 
of samples and visits as long as the total blood volume taken does not exceed 500 mL per subject.
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 12-lead ECG after 10 minutes of rest in supine position
13. Measurement of body weight on admission and prior discharge
14. On day 1 of visit 2 prior first trial drug administration only
15. The time is approximate; the respective procedure is to be performed and completed within 2 h prior to drug administration and prior to 
predose meal intake.
17. Moderate fat breakfast and moderate fat dinner i.e 400-500 kcal with fat content of approx. 150 kcal, respectively, starting 30 min. prior 
to drug administration and has to be consumed completely within 25 minutes.
20. Only urinalysis
 
 
22. 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.
23. Abbreviated safety laboratory (for details refer to Section 5.2.3)

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHARTS.................................................................................................6
TABLE OF CONTENTS ................................................................................ 12
ABBREVIATIONS.......................................................................................... 16
1.
INTRODUCTION.................................................................................... 19
1.1
MEDICAL BACKGROUND............................................................................19
1.2
DRUG PROFILE...............................................................................................19
1.2.1
Nonclinical Pharmacology....................................................................19
1.2.2
Safety pharmacology ............................................................................20
1.2.4
Nonclinical pharmacokinetics..............................................................23
1.2.5
Clinical experience in humans.............................................................23
1.2.5.1
Clinical safety ..........................................................................23
1.2.5.1.1 Single-Rising Dose study (1305.1)............................24
1.2.5.1.2 Multiple-Rising Dose study (1305.2)........................24
1.2.5.1.3 Clinical experience with other PDE4 inhibitors........26
1.2.6
Drug product.........................................................................................28
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 29
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................29
 
2.2
TRIAL OBJECTIVES.......................................................................................32
2.3
BENEFIT - RISK ASSESSMENT ...................................................................33
2.3.1
Procedure-related risks ........................................................................33
2.3.2
Drug-related risks and safety measures..............................................33
2.3.3
Safety measures.....................................................................................35
2.3.4
Overall assessment................................................................................36
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 38
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................38
3.1.1
Administrative structure of the trial...................................................40

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................41
3.3
SELECTION OF TRIAL POPULATION ......................................................42
3.3.1
Main diagnosis for study entry............................................................42
3.3.2
Inclusion criteria...................................................................................42
3.3.3
Exclusion criteria ..................................................................................43
3.3.4
Removal of subjects from therapy or assessments.............................44
3.3.4.1
Removal of individual subjects................................................44
3.3.4.2
Discontinuation of the trial by the sponsor..............................45
3.3.5
Replacement of subjects .......................................................................46
4.
TREATMENTS........................................................................................ 46
4.1
TREATMENTS TO BE ADMINISTERED....................................................46
4.1.1
Identity of BI investigational product and reference products ........46
4.1.2
Method of assigning subjects to treatment groups ............................47
4.1.3
Selection of doses in the trial................................................................48
4.1.4
Drug assignment and administration of doses for each subject .......48
4.1.5
Blinding and procedures for unblinding ............................................50
4.1.5.1
Blinding50
4.1.5.2
Procedures for emergency unblinding .....................................51
4.1.6
Packaging, labelling, and re-supply ....................................................51
4.1.7
Storage conditions.................................................................................52
4.1.8
Drug accountability ..............................................................................52
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................52
4.2.1
Other treatments and emergency procedures....................................52
4.2.2
Restrictions............................................................................................53
4.2.2.1
Restrictions regarding concomitant treatment .........................53
4.2.2.2
Restrictions on diet and life style.............................................53
4.3
TREATMENT COMPLIANCE.......................................................................54
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 55
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................55
5.1.1
Endpoints of efficacy.............................................................................55
5.1.2
Assessment of efficacy...........................................................................55
5.2
SAFETY..............................................................................................................55
5.2.1
Endpoints of safety................................................................................55
5.2.2
Assessment of adverse events...............................................................55
5.2.2.1
Definitions of adverse events...................................................55
5.2.2.2
Adverse event collection and reporting ...................................59
5.2.3
Assessment of safety laboratory parameters......................................61
5.2.4
Electrocardiogram................................................................................64
5.2.4.1
12-lead resting ECG.................................................................64

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5.2.5
Assessment of other safety parameters...............................................66
5.2.5.1
Vital signs ................................................................................66
5.2.5.2
Medical examinations..............................................................66
5.3
OTHER...............................................................................................................67
5.3.1.1
Methods and timing of sample collection................................67
5.3.1.2
Analytical determinations........................................................67
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................68
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................68
5.5.1
Pharmacokinetic endpoints..................................................................68
5.5.1.1
Primary endpoints....................................................................68
5.5.1.2
Secondary endpoints................................................................68
5.5.2
Methods of sample collection...............................................................70
5.5.2.1
Plasma sampling for pharmacokinetic analysis of BI 1015550
70
 
5.5.3
Analytical determinations ....................................................................73
5.5.3.1
Analytical determination of drug plasma concentration..........73
 
5.6
BIOMARKER....................................................................................................74
5.7
PHARMACOKINETIC - PHARMACODYNAMIC BIOMARKER
RELATIONSHIP...............................................................................................75
6.
INVESTIGATIONAL PLAN.................................................................. 76
6.1
VISIT SCHEDULE............................................................................................76
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................76
6.2.1
Screening period....................................................................................76
6.2.2
Treatment period ..................................................................................77
6.2.3
End of trial period.................................................................................78
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 79
7.1
STATISTICAL DESIGN – MODEL ...............................................................79

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7.1.1
Objectives...............................................................................................79
7.1.2
Endpoints...............................................................................................79
7.1.3
Model......................................................................................................79
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................79
7.3
PLANNED ANALYSES....................................................................................79
7.3.1
Primary analyses...................................................................................80
7.3.2
Secondary analyses ...............................................................................80
7.3.3
Safety analyses.......................................................................................82
7.3.5
Pharmacokinetic analyses ....................................................................84
7.4
HANDLING OF MISSING DATA ..................................................................85
7.4.1
Safety......................................................................................................85
7.4.2
Plasma/urine drug concentration - time profiles ...............................85
7.4.3
Pharmacokinetic parameters...............................................................85
7.5
RANDOMISATION ..........................................................................................85
7.6
DETERMINATION OF SAMPLE SIZE ........................................................86
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 87
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................87
8.2
DATA QUALITY ASSURANCE .....................................................................87
8.3
RECORDS..........................................................................................................88
8.3.1
Source documents .................................................................................88
8.3.2
Direct access to source data and documents.......................................88
8.3.3
Storage period of records.....................................................................88
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................88
8.5
STATEMENT OF CONFIDENTIALITY.......................................................89
8.6
COMPLETION OF TRIAL..............................................................................89
9.
REFERENCES......................................................................................... 90
9.1
PUBLISHED REFERENCES...........................................................................90
9.2
UNPUBLISHED REFERENCES.....................................................................92
10. APPENDICES .......................................................................................... 94
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 100

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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
 
AUCτ,1
Area under the concentration-time curve of the analyte in plasma over an 
uniform dosing interval τ after the first dose
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma over the
dosing interval at steady state
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
Maximum measured concentration of the analyte in plasma
COPD
Chronic Obstructive Pulmonary Disease
 
CRF
Case report form
CRO
Contract Research Organization
C-SSRS
Columbia Suicidal Severity Rating
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

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eCRF
electronic Case report form
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
FDA
Food and Drug Administration
 
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
GMP
Good manufacturing practice
HPLC-MS/MS
High performance liquid chromatography with tandem mass spectrometry
HR
Heart rate
IB
Investigator’s brochure
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IFP
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
MedDRA
Medical Dictionary for Regulatory Activities
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)
PDE
Phosphodiesterase
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set

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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)
RA, AUC
Accumulation ratio of the analyte in plasma after multiple dose 
administration over a uniform dosing interval τ, expressed as ratio of AUC 
at steady state and after single dose
RA, Cmax
Accumulation ratio of the analyte in plasma after multiple dose 
administration over a uniform dosing interval τ, expressed as ratio of Cmax
at steady state and after single dose
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SD
Standard Deviation
SmPC
Summary of Product Characteristics
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
 

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1.
INTRODUCTION
BI 1015550 is a selective inhibitor of the Phosphodiesterase 4 B (PDE4 B) with broad anti-
inflammatory and anti-fibrotic activities. It is under development for the treatment of 
 This integrated clinical trial is an extension of the 
previously performed single and multiple rising dose trials 1305.1 and 1305.2 [U13-1792-01
and c02191718-02] to investigate safety, tolerability and pharmacokinetics of single and 
multiple rising doses of BI 1015550 beyond the ones already investigated.
1.1
MEDICAL BACKGROUND
 
 
 
 
 
For further information please refer to the Investigator’s Brochure [c02094779-02].
1.2
DRUG PROFILE
1.2.1
Nonclinical Pharmacology
 
 
 
 

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For details on nonclinical pharmacology refer to the nonclinical pharmacology section in the
IB [c02094779-02].
1.2.2
Safety pharmacology
 
 
 
 
 
 
 
For further details on safety pharmacology refer to the IB [c02094779-02].
 
 
 
 
 
 

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1.2.4
Nonclinical pharmacokinetics
 
 
 
 
 
 
 
 
 
 
 
 
 
For further information please refer to the IB [c02094779-02].
1.2.5
Clinical experience in humans
1.2.5.1
Clinical safety
Two clinical trials have been completed with BI 1015550 in healthy male volunteers:

a single rising dose First-in-Men (FIM) trial (1305.1) [U13-1792-01]

a multiple rising dose trial (1305.2) [c02191718-02]

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1.2.5.1.1
Single-Rising Dose study (1305.1)
BI 1015550 (0.02 mg, 0.06 mg, 0.2 mg, 0.6 mg, 2 mg, 4 mg, 8 mg, 16 mg and 24 mg dose 
levels) has been tested in 70 healthy male subjects who completed a partially randomised, 
placebo-controlled within dose groups, partially single-blinded, 2 cohorts with first cohort 
with defined treatment sequence (active-placebo-active-active), nine dose groups FIM study.  
Sixteen subjects received placebo and 54 received BI 1015550.
A total of 41 treatment emergent adverse events (TEAEs) were reported by 27 (39%) 
subjects. Five of these subjects (31%) received placebo. The most frequent TEAEs occurred 
within the CNS and GI organ classes. In total, 27 out of 70 subjects (38.6%) reported at least 
1 TEAE during the treatment period of the trial. Twenty-two subjects were reported with AEs 
following administration of BI 1015550. In each dose group between 1 and 3 subjects 
reported at least 1 TEAE. Five subjects reported TEAEs following the administration of 
placebo. There was no correlation of the administered drug-dose and the number of subjects 
reporting at least 1 TEAE. Most subjects reported TEAEs of mild intensity (23 of the 27 
subjects). Four of the subjects (including one subjects on placebo) reported moderate TEAEs 
(headache: 1 subject in the 0.2 mg group and 1 subject in the 4 mg group, nausea, vomiting, 
fatigue and headache: 1 subject in the 8 mg groups). All subjects were reported to have
recovered from TEAEs by the end-of-study examination. 
Nine subjects (12.9%) reported TEAEs that were considered drug-related by the investigator, 
most of them of mild-intensity: A total of 3 subjects were reported with drug-related diarrhea
(all mild), 2 subjects with abdominal pain (mild), 2 subjects with headache (mild), and 1 
subject each with nausea, vomiting, fatigue (all moderate), and oral herpes (mild).
There were no SUSARs, nor any significant (based upon ICH E3), severe, serious or fatal
AEs. No subject was discontinued due to AEs.
In addition, no clinically relevant laboratory, vital signs and ECG changes were observed 
following administration of single doses of BI 1015550.
Global tolerability was assessed as good for all 70 subjects entered.
In summary, single doses from 0.02 mg up to 24 mg BI 1015550 were well tolerated by 
healthy male subjects. There were no notable differences between the dose groups with 
respect to safety and tolerability.
Further details can be found in IB [c02094779-02].
1.2.5.1.2
Multiple-Rising Dose study (1305.2)
BI 1015550 (1 mg and 6 mg b.i.d. for two weeks) has been tested in 24 healthy male subjects
who completed two out of four planned dose levels in a randomized, double-blind, placebo-
controlled within dose groups trial. Six subjects received placebo and 18 received BI 
1015550. Dose escalation was stopped after the 2nd dose group as per protocol; interim PK 

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evaluation predicted that exposure in the 3rd dose group would exceed a pre-defined exposure 
limit (based on the NOAEL exposure of the 4-week rat repeat-dose toxicity study). 
A total of 10 TEAEs were reported by 6 (25%) subjects, 1 subject (16.7%) in the placebo 
group, 4 subjects (44.4%) in the 1 mg group and 1 subject (11.1%) in the 6 mg group.
The most frequent TEAEs, all of mild intensity, occurred within the CNS and GI organ
classes. TEAEs involving the CNS included headache reported by 1 subject on placebo and 1
subject on BI 1015550. GI TEAEs occurred in 3 subjects treated with BI 1015550 including
mild diarrhea, abdominal pain and aphtous stomatitis in two subjects (1 mg b.i.d.) and mild
constipation and abdominal pain in one subject (6 mg b.i.d.). No GI TEAE occurred in the 
placebo group.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
There were no TEAEs of severe intensity, SUSARS, severe, serious or fatal AEs.
Two subjects were discontinued, one for personal reasons in the 1 mg b.i.d. group and one
due to TEAEs in the 6 mg b.i.d. group (see above).
In conclusion, BI 1015550 was well tolerated with headache in both groups (Placebo and BI 
1015550) and abdominal pain in the BI 1015550 treated group being the most frequent
TEAEs. There was no apparent association between increasing dose and GI TEAEs.

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1.2.5.1.3
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.
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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1.2.6
Drug product
 
 
For a more detailed description of the BI 1015550 profile please refer to the current 
Investigator’s Brochure [c02094779-02].

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
 
 
The planned trial 1305-0011 will investigate safety, tolerability and pharmacokinetics of BI 
1015550 and thereby provide essential information for a clinical development of BI 1015550 
 As this trial is an extension of the previously conducted single rising 
dose First-in-Man trial 1305.1 [U13-1792-01] and multiple rising dose trial 1305.2 
[c02191718-02], an integrated clinical trial protocol has been chosen combining 2 parts:
Part 1: single rising dose part (SRD)
Part 2: multiple rising dose part (MRD)
 
 
 
 
 
 
 
 
 
 

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2.2
TRIAL OBJECTIVES
Objectives in this integrated trial vary between trial parts. A description of all 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. 
Part 1 (SRD):
The primary objective of this trial part is to investigate the safety and tolerability of BI 
1015550 in healthy male subjects following oral administration of single rising doses of 36 
mg and 48 mg.
Secondary objectives are the exploration of the pharmacokinetics of BI 1015550 after single 
dosing.
Part 2 (MRD):
In Part 2, the primary objective is to investigate the safety and tolerability of BI 1015550 in 
healthy male subjects following oral administration of multiple rising doses of 6 mg b.i.d. and 
12 mg b.i.d..

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Secondary objectives are the exploration of the pharmacokinetics of BI 1015550 after 
multiple dosing.
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 
 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.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 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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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.

A maximum acceptable human exposure has been defined based on toxicity findings.
Dose escalation within Part 1 (SRD) and Part 2 (MRD) is guided by measurements of 
BI 1015550 (free Cmax and free AUC0-∞). The exposure in the next higher dose group 
in both parts will be estimated based on preliminary data of the preceding dose 
groups. The next higher dose level will only be administered if estimated gMean 
values for free Cmax and free AUC0-∞do not exceed the maximum acceptable human 
exposure (see Section 2.1.2; Section 7.3.4 and Section 3.3.4.2).

For safety reasons, each dose group in Part 1 and Part 2 will be split into 2 cohorts:
Part 1:
Each dose group of 9 subjects (6 on active and 3 on placebo) will be divided into two
cohorts. The first cohort will consist of 3 subjects who will be dosed in a fixed 
sequence fashion (active-placebo-active). Drug administration will be separated by at
least 55 min between the first three subjects. This design ensures that between first 
and second active dose of each dose level there is a time interval of at least 110 min.
 
 
 
 If BI 
1015550 is safe and well tolerated during in the first cohort, the remaining subjects of 
the respective dose level (i.e. second cohort) could be dosed as close as 30 minutes 
apart.

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Part 2:
Each dose group of 12 subjects (8 on active and 4 on placebo) will be divided into two 
cohorts. The first cohort will consist of 3 (2 on active and 1 one placebo) subjects, the 
second of 9 subjects (6 on active, 3 on placebo).

For each dose level, the two cohorts will be separated by a pre-defined time interval:
Part 1:
at least 48 hours (between 1st subject of each cohort), 
 
Part 2:
Dose group 6 mg b.i.d.:
at least 48 hours (between 1st subjects of each cohort)
Dose group 12 mg b.i.d.:
at least 72 hours (between 1st subjects of each cohort)
 

A documented Safety Review meeting takes place prior to each dose escalation. Dose
escalation is only permitted if there are no safety concerns and if none of the 
prespecified stopping criteria are met. The minimum time interval between last dosing 
in the first cohort of 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.

After completion of Part 1 (SRD) a documented Safety Review meeting has to be 
performed before proceeding to Part 2. No subject in Part 2 may be dosed before the 
last subject in Part 1 has been dosed and the drug was considered safe and well-
tolerated. This Safety Review meeting is based on safety and tolerability criteria of 
Part 1 without PK data of the 48 mg single dose group as this is no further dose 
escalation step. Further, based on the available human PK data of this dose it is 
unlikely that the maximum acceptable human exposure will be exceeded with 6 mg 
b.i.d. However, for the safety review meeting between dose group 1 and 2 of Part 2, 
PK data of Part 1 have to be available to ensure that expected exposure (Cmax and 
AUC0-24) after multiple dosing of 12 mg b.i.d. is covered by exposures reached after 
single dosing before [R17-1541].

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 (in 
Part 1) and additional repeated single and triple 12-lead ECGs in Part 1 and 2

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

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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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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
Part 1:
This single-rising dose part of the trial is designed as single-blind, partially randomized, and 
placebo-controlled within parallel dose groups.
A total of 18 healthy male subjects is planned to participate in Part 1 of the trial, according to 
2 sequential groups comprising 9 subjects per group. However, additional subjects may be 
entered to allow testing of additional doses on the basis of experience gained during the trial 
conduct (e.g. preliminary PK data), provided the planned and approved highest dose will not 
be exceeded. Thus, the actual number of subjects entered may exceed 18, but will not exceed 
27 subjects entered. Such changes may be implemented via non-substantial CTP 
Amendments.
Within each dose group, 6 subjects will receive the active drug and 3 will receive placebo. 
Only one dose is tested within each dose group. Each dose group will consist of 2 cohorts 
which will be treated subsequently for safety reasons.
The design is partially randomized, i.e. the first block of one dose group will be treated 
according to a fixed sequence (Active-Placebo-Active) the other block will be randomized.
The dose groups to be evaluated in Part 1 are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1A
1B
Dose (mg)
36
48
Number of subjects
9
9
Subjects receiving placebo
3
3
Subjects receiving active drug
6
6
Part 2:
The second part, the multiple-rising dose part, is designed as double-blind, partially 
randomized, and placebo-controlled within parallel dose groups.
A total of 24 healthy male subjects is planned to participate in this part of the trial, according 
to 2 sequential groups comprising 12 subjects per group. However, additional subjects may 
be entered to allow testing of additional doses on the basis of experience gained during the 
trial conduct (e.g. preliminary PK data), provided the planned and approved highest dose will 
not be exceeded (for details please see end of this Section). 
Within each dose group of Part 2, 8 subjects will receive the active drug and 4 will receive 
placebo. Only one dose is tested within each dose group. Each dose group will consist of 2 
cohorts which will be treated subsequently for safety reasons.

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The design is partially randomized, i.e. the first block of one dose group will be treated 
according to a fixed sequence (Active-Placebo-Active) and the other block will be 
randomized.
The dose groups to be evaluated are outlined in Table 3.1: 2 below.
Table 3.1: 2
Dose groups
Dose Group
2A
2B
Daily dose (mg)
12 mg
24 mg
Dose regimen
6 mg b.i.d.
12 mg b.i.d.
Posology Day 1 and 14
1-0-0
1-0-0
Posology Day 3 to 13
1-0-1
1-0-1
Number of subjects
12
12
Subjects receiving placebo
4
4
Subjects receiving active drug
8
8
In Part 1 and 2, the two dose groups (Part 1: 1A and 1B, and Part 2: 2A and 2B) 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 (i.e. Part 1: dose group 
1A (36 mg SD); Part 2: dose group 2A (6 mg b.i.d.)) and the first drug administration of the 
subsequent dose group (i.e. Part 1: dose group 1B (48 mg SD); Part 2: dose group 2B (12 mg 
b.i.d.). The decision to proceed to the next dose group will be based upon the safety, 
tolerability and pharmacokinetic data of the preceding dose groups. 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).
A documented Safety Review must take place prior to each dose escalation in Part 1 and 2. 
Furthermore, unscheduled safety review meeting can be requested anytime for any reasonable 
cause by the Principal Investigator (or an authorized deputy) or the sponsor of the study, e.g. 
because of any unforeseen adverse events, etc. Dose escalation will only be permitted if no 
safety concerns exist in the opinion of the Principal Investigator (or an authorized deputy) 
and the trial clinical monitor (or an authorized deputy).
The minimum data set for review consists of the following data:

AEs in the current and preceding dose groups (including clinically relevant findings 
from ancillary safety testing listed below) (Note: AEs may be ongoing at the time of 
Safety Reviews and AE information may be subject to change prior to Database Lock)

Results from 12-lead EGG and AEs, i.e. abnormal findings judged clinically relevant 
by the Investigator, from continuous ECG monitoring (only in Part 1) in the current 
and preceding dose groups

Vital signs in the current and preceding dose groups

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
Clinical laboratory tests in the current and preceding dose groups including fecal
occult blood and fecal calprotectin testing and urinalysis

Preliminary PK data of the preceding dose groups for selected time points, i.e of DG 
1A before proceeding to DG 1B and of DG 1A, DG 1B and DG 2A before proceeding 
to DG 2B (Section 7.3.4). 

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorized deputy) and the trial clinical monitor (or an authorized deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 
face-to-face or by video/telephone conference. The trial clinical monitor is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (or an authorized deputy) and filed in the ISF and TMF.
The investigator and/or the sponsor should stop dose escalation in case the safety evaluation 
leads to concerns that would not allow higher dosing.
Additional dose groups in Part 1 and 2
The investigator (after consultation with the sponsor) is allowed to alter the scheduled dose 
levels (e.g. add low and/or intermediate dose levels) within the approved dose range on the 
basis of experience gained during the study. This may include PK data suggesting an exposure 
close or just above predefined thresholds or initial safety signals with open causality (not dose 
limiting), provided the planned and approved highest dose is not exceeded. In this case, the 
total number of subjects in this trial might increase. 
Thus, for Part 1 the actual number of subjects entered may exceed 18, but will not exceed 27 
subjects entered. For Part 2 the number of subjects entered may increase but will not exceed 
36. Such changes may be implemented via non-substantial CTP Amendments.
The dosing of such an additional dose group will follow the same dosing regimen as 
described for the planned dose groups of this trial part, including same time intervals between 
cohorts and dose groups (ref. to Section 2.3.3). 
An overview of all relevant trial activities is provided in the Flow Charts. For visit schedules 
and details of trial procedures at selected visits, refer to Section 6.1 and Section 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,

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
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 at
 
under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
The analyses of BI 1015550 concentrations in plasma and urine will be performed at
 
 
 
Biomarker analyses will be performed by 
The digitally recorded 12-lead ECGs will be sent to a specialized contract research 
organization
) for evaluation.
On-site monitoring will be performed by BI or a contract research organization appointed by 
BI.
Data management and statistical evaluation will be done by BI or by a suitable contract 
research organization (CRO) under the responsibility of BI and according to BI SOPs.
Tasks and functions assigned in order to organize, 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.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The design described in Section 3.1 is viewed favorable 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, single-blind (Part 1) and double-blind (Part 2) 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 

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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 and tolerability. 
For Part 1, each dose group consists of 9 subjects with 6 on active treatment and 3 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. 
In Part 2, each dose group will consist of 12 subjects with 8 on active treatment and 4 on 
placebo. The placebo control group includes all subjects of all dose groups treated with 
placebo. 8 subjects per active treatment group are in general considered as sufficient for the 
exploratory evaluation of pharmacokinetics. After the first dose (single dose segment), a 
drug-free time to calculate AUC0-∞is included before the second dose (first dose of the 
multiple dose segment) is administered. This will allow for appropriate calculation of the 
pharmacokinetic parameters after a single dose administration and for comparison with 
pharmacokinetic parameters at steady state. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 42 healthy male subjects (18 in Part 1, 24 in Part 2) will enter the study. The 
actual number of subjects entered may exceed the total of 42 if additional intermediate doses 
will be tested (see Section 3.1). 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, 12-lead ECG, 
and clinical laboratory tests 
2. Age of 18 to 45 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)

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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 vital signs 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 55 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease 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)
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
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 than 20 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
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 

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23. Male subjects who do not agree to minimize the risk of female partners becoming 
pregnant from the first dosing day until two 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 with
spermicide, 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
3.3.4.1
Removal of individual subjects
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.
 
 
 

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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 first 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.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, dose escalation will be terminated if more 
than 50% of the subjects of one dose group show drug-related and clinically relevant 
adverse events of moderate or severe intensity, and the trial will be terminated 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.
 
 
 
 
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 
 replaces.
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 reference products
Part 1 (SRD)
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 1A: 6-0-0
Dose group 1B: 8-0-0
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 1A: 6-0-0 
Dose group 1B: 8-0-0
Route of administration:
p.o.
Duration of use:
Single dose 

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Part 2 (MRD)
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 2A: 1-0-0 (day 1 and 14), 1-0-1 (day 3 - 13)
Dose group 2B: 2-0-0 (day 1 and 14), 2-0-2 (day 3 - 13)
Route of administration:
p.o.
Duration of use:
2 day single dose (day 1 and 14) and 11 days b.i.d. dosing
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 2A: 1-0-0 (day 1 and 14), 1-0-1 (day 3 - 13)
Dose group 2B: 2-0-0 (day 1 and 14), 2-0-2 (day 3 - 13)
Route of administration:
p.o.
Duration of use:
2 day single dose (day 1 and 14) and 11 days b.i.d. dosing
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and 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 the 2 dose cohorts (2 cohorts per dose group) the following subjects will be allocated to 
one of the other dose cohorts. Therefore, the allocation of subjects to dose cohorts or groups
is not influenced by trial personnel, but only by the subjects’ temporal availability. As the 
study includes healthy subjects from a homogenous population, relevant imbalances between 
the dose groups are not expected. 
For Part 1, the randomization list with study subject numbers and allocated treatments and for 
Part 2, 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 the method 'first come first served'. Once a subject number has been 
assigned, it cannot be reassigned to any other subject.
The randomization procedure is described in Section 7.5.

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4.1.3
Selection of doses in the trial
Trial 1305-0011 is an extension of the previous single and multiple rising dose trials (1305.1 
and 1305.2) and proceeds with dose escalation. The doses selected cover the expected sub-
therapeutic as well as the estimated therapeutic range including a safety window. For safety 
margins and further details on dose selection see Section 2.1.1 and Section 2.1.2.
4.1.4
Drug assignment and administration of doses for each subject
Part 1 (SRD)
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
Substance
Pharmaceutical
form
Unit strength
Number of units 
per administration
Total 
daily dose
1A
BI 1015550
Tablet
6 mg
6 tablets as single dose 
36 mg
1B
BI 1015550
Tablet
6 mg
8 tablets as single dose 
48 mg
1A-1B
Placebo1
Tablet
--
identical to active treatment
--
1Subjects receiving placebo are equally distributed across dose groups 
The trial medication will be administered to the subjects, while in a standing position, as an 
oral dose together with about 240 mL of water under supervision of the investigating 
physician or an authorized 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 
Subjects will be kept under close medical surveillance until at least 24 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.
Additional doses
Additional subjects may be entered to allow testing of additional doses on the basis of the 
experience gained during the conduct of the trial (e.g. preliminary PK data), provided that the 
planned and approved highest dose will not be exceeded (see Section 3.1). Such changes may 
be implemented via non-substantial CTP amendments.
Part 2 (MRD)
The treatments to be evaluated are outlined in Table 4.1.4: 2 below. The number of units for 
placebo corresponds to the number of units of the respective dose level.

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Table 4.1.4: 2
BI 1015550 and placebo treatments, oral administration
Dose
Substance
Pharmaceutical 
form
Unit 
strength
Number of units 
per administration
Total daily dose
2A
BI 1015550
Tablet
6 mg
1 tablet as single dose on Day 1 + 14, 
1 tablet in the morning and evening on 
Days 3-13
6 mg (Day 1+14)
12 mg (Day 3-13)
2B
BI 1015550
Tablet
6 mg
2 tablets as single dose on Day 1 + 14, 
2 tablets in the morning and evening 
on Days 3-13
12 mg (Day 1+14)
24 mg (Day 3-13)
2A-2B
Placebo1
Tablet
--
identical to active treatment
--
1 Subjects receiving placebo are equally distributed across dose groups 
This trial part will be divided into two segments (single dose and multiple doses). During the 
single dose segment (Days 1 to 2) subjects will receive one single dose of BI 1015550 (or 
placebo) on Day 1. The multiple dose segment starts on Day 3 and subjects will receive a 
dose of 6 mg (dose group 2A) or 12 mg (dose group 2B) of BI 1015550 (or placebo) twice
daily (in the morning and in the evening at about 12 hours after the morning dose) for 11 days 
(Days 3 to 13) and a single dose of 6 mg (dose group 2A) or 12 mg (dose group 2B) of BI 
1015550 (or placebo) in the morning of Day 14.
The trial medication will be administered to the subjects, while in a standing position, as an 
oral dose together with about 240 mL of water under supervision of the investigating 
physician or an authorized 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.
After an overnight fast of at least 10 hours, a standard moderate-fat breakfast and a moderate-
fat dinner, respectively, will be served 30 minutes before drug administration. The meal
should be in compliance with recommendations provided by EMA [R17-1541], i.e. the meal 
should contain approximately 400-500 kcal with fat contributing to ca. 150 kcal. The meals
must be completely consumed within 25 minutes or less; however the medication should be 
taken 30 minutes after start of the meal.
To ensure a dosing interval of 12 h from Day 3 to Day 14, the administration of trial 
medication should take place at the same time every morning and evening (no evening 
administration on Day 14).
Subjects will be kept under close medical surveillance until 48 h following the last drug 
administration on Day 14. During the first 2 h after drug administration, they are not allowed 
to lie down (i.e. no declination of the upper body of more than 45 degrees from upright 
posture except for medical examination or medical reasons), or to sleep. 
For further restrictions with regard to diet see Section 4.2.2.2.

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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Regarding the sponsor, the database of this trial (both parts) 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.
In Part 2 only, access to the randomization schedule is restricted to unblinded pharmacists at
the trial site. Access to the codes will be controlled and documented by a signed 
confidentiality statement, which will be stored in the TMF. Persons directly involved in the 
clinical conduct of the trial will not have access to the treatment allocation prior to database 
lock.
At the ECG laboratory all staff will be blinded with respect to treatment. Within the ECG 
laboratory, the staff involved with interval measurements and assessments will also be 
blinded with regard to the recording date and time as well as time points of the ECGs. Semi-
automatic interval measurements for a given subject will be performed in 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 interim / preliminary PK analysis. He or she will confirm in writing 
that the codes will be treated confidentially.
Further, the Human Pharmacology Centre (HPC) deputy of the sponsor will receive the 
randomization codes prior to official unblinding, so that in case of emergency the HPC 
physician on duty can perform emergency unblinding. HPC deputy will confirm in writing 
that the codes will be treated confidentially.
In addition, the drug metabolism scientist will receive the randomization codes prior to 
official unblinding to perform metabolites in safety testing analysis (MIST). He or she will 
confirm in writing that the codes will be treated confidentially.
Part 1 (SRD)
The treatments administered (active or placebo) will be single-blind (blinded to subjects 
only). However, the current dose level will be known to the subjects. 
Part 2 (MRD) 
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). According to the rising dose design, the current dose level will be known 
to subjects and investigators.

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4.1.5.2
Procedures for emergency unblinding
Part 1 (SRD) 
As this part of the trial will be conducted single-blind, the treatment information will be 
known to the investigator. Therefore, no emergency envelopes will be provided.
Part 2 (MRD)
For the double-blinded part of this trial, the investigator will be supplied with a set of sealed 
envelopes containing the medication codes for each subject according to the randomization
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.
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. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. 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 (only in Part 2)

Batch number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
A re-supply after Part 1 is planned.

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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 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 authorized 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 will be disposed locally by the trial site upon 
written authorization by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. 
These 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 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 disposal, the investigator 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 
authorize 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.

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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
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.
 
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardized 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 in all parts 
of the trial. Further restrictions apply for the different parts:
Part 1 (SRD)
From 1 hour before drug intake until 4 hours post-dose liquid intake is restricted to the fluid 
administered with the drug and 240 mL of water at 2 hours and 4 hours post-dose (mandatory 
for all subjects). From 4 hours post-dose until 24 hours post-dose water intake is restricted to
3000 mL. Standardized meals will be served at 4, 8, 11 and 24 hours following drug 
administration. 
During the days of urine collection, total fluid intake should be at least 1.5 liters and should 
not exceed 3.5 liters.
Part 2 (MRD)
On PK profile days (i.e., Day 1 and Day 14) liquid intake is restricted from 1 hour before
administration until lunch with exception to the fluid administered with the breakfast and the 
drug and 240 mL of water at 2 and 4 hours post-dose (mandatory for all subjects). From 
lunch until 24 hours post-dose water intake is restricted to 3000 mL. On all other days, fluid 
intake is restricted from 1h before administration until 2h post-dose with the exception of the 
fluid administered with the meals and the drug. On PK profile days (i.e., Day 1 and Day 14), 
standardized meals will be served at 4, 8, and 11 hours following drug administration.
Both parts
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.

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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 center 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 AEs.
Further criteria of interest:

TEAEs (including clinically relevant findings from the physical examination)

Safety laboratory tests, including 
 
urinalysis

12-lead ECG

Abnormal findings in the continuous ECG monitoring if rated as AE (only Part 1)

Vital signs (blood pressure, pulse rate, respiratory rate, aural body temperature) and 
body weight (only Part 2)
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
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 unfavorable 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:

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
results in death, 

is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalization or 

requires prolongation of existing hospitalization,

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 jeopardize 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 hospitalization or 
development of dependency or abuse. 
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 eDC system. These events should 
always be reported as SAEs as described above.

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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. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs in this trial:

Hepatic injury, as 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
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients 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 
analyzed, 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.
With the exception of DILI, no AESIs have been defined for this trial.
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 etiologies 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).

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
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.

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 trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AEs 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 

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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.
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 but prior to the last 
per protocol contact 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 
eCRF 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 the BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

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
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.
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.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject subject has been 
enrolled in the clinical trial and has taken trial medication, the investigator must report any 
drug exposure during pregnancy in a trial participant immediately (within 24 hours) by means 
of Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male
trial participant becomes pregnant. This requires 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 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 Table 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, 
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
D4
EOT
Hematology5
Hematocrit
Hemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Erythrocyte sedimentation rate (ESG)
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
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
x
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Glutamate dehydrogenase (GLDH)
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
Hormones
Thyroid stimulating hormone (TSH)
fT3, fT4
x
x
--
--
--
--
--
--
--
--
x
x
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct + indirect bilirubin
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
D4
EOT
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
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
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
x
x
x
x
x
x
x
x
x
x
x
x
x
x 
x
x
x
x
-
-
-
-
-
-
-
-
-
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x 
x
x
x
x
x
x
x
x
x
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are 
abnormal in urine)
Only positive findings will be reported (for 
instance, the presence of sediment 
bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1
A: Days -3 to -1
2
B: post-dose on Day 1 (Part 1 (SRD) only)
3
C: Days 2, 4, 6 (Part 1 (SRD)), days 2, 5, 9, 14, 16, 20, 24 (Part 2 (MRD) 
4
D: abbreviated safety lab Days 7 and 12 (Part 2 (MRD)) only
5
In addition to the parameters listed above MCV,MCH and MCHC will be reported by the lab, as due to technical reasons 
only a complete blood count can be analyzed 
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 each treatment period.

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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/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 antibody/HIV-1 p24-antigen (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed at screening and prior to each 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 Table 5.2.3: 2 will be performed at 
Medizinisches Versorgungszentrum Dr. Klein Dr. Schmitt & Partner, Kaiserslautern, 
Germany with the exception of the urinalysis stix and drug screening tests. These tests will be 
performed at the trial site using Combur9 Test and AccuSign® DOA 10 test, respectively.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerized electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the time points given in the Flow Chart.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for a 10-sec duration after the subjects 
have rested for at least 10 min in a supine position. The site personnel will be instructed to 
assure a relaxed and quiet environment so that all subjects are at complete rest during the 
recordings. ECG assessment will always precede all other study procedures of the same time 
point (except blood drawing from an intravenous cannula which is already in place) to avoid 
impact of sampling on the ECG quality.
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.

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ECGs will be recorded as single ECGs or as triple ECGs (three single ECGs recorded within 
180 sec) as indicated in the Flow Chart.
All locally printed ECGs will be evaluated by the investigator or a designee.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation). For time points with triple ECGs, all three single ECGs 
will be repeated. For the repeats due to quality reasons, only the repeated ECG recordings 
will be sent to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths. 
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 ECG machines or their 
manual corrections by the investigators will be used. In doubtful cases, ECGs may be sent 
upfront for centralized evaluation (see below). 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. 
A post-study centralized evaluation of all 12-lead ECGs recorded after Days 1 (Part 1 and 2) 
and Days 14 (Part 2 only) 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.

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Assessed ECGs will comply with the ICH E14 guidance document and supplements 
[R05-2311], [R13-0801], [R13-4095] as well as the FDA requirements for annotated digital 
ECGs [R09-4830].
 
 
 
 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure device (Dinamap, GE Medical Systems, Freiburg, Germany) 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 oral body temperature as well as 
body weight (only Part 2) will be monitored.
Body temperature will be determined in the ear at the time points indicated in the Flow Chart
using electronic thermometers (Thermoscan, Welch Allyn GmbH, Hechingen, Germany).
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 5 minutes. 
Recording of the values will be done at the time points indicated in the Flow Chart.
5.2.5.2
Medical examinations
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, 
respiratory rate), 12-lead ECG, laboratory tests including fecal occult blood and fecal
calprotectin testing, suicidality assessment (C-SSRS, only Part 2) and a physical examination. 
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, suicidality assessment (C-SSRS, only Part 2) and a physical examination with 
determination of weight.
 
 

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5.3
OTHER
 
 
 
 
 
 
 
5.3.1.1
Methods and timing of sample collection
One blood sample of at most 10 mL will be taken from an arm vein in a PAXgene blood 
DNA drawing tube prior to the first study drug administration (Visit 2, Day 1). The blood 
sample has to be stored at a temperature of approximately -20°C or below. Once frozen, 
thawing of the samples should be avoided.
Frozen blood samples should be shipped on dry ice to:
5.3.1.2
Analytical determinations
Genomic DNA will be extracted from blood samples according to standard molecular 
genetics methods and analyzed by DMET analysis or other standard genotyping technologies.

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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. The biomarkers and measurements outlined in 
Section 5.6 are of exploratory nature only. 
 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs.
Times and periods for sampling of PK as well as metabolism analysis may be adapted during 
the trial based on information obtained during trial conduct (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken per subject 
does not exceed 500 mL. Such changes would be implemented via non-substantial CTP 
Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters for BI 1015550 will be determined if feasible:
5.5.1.1
Primary endpoints 

Not applicable
5.5.1.2
Secondary endpoints
Part 1 (SRD)

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)
Part 2 (MRD) 
After the first dose:

AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a uniform 
dosing interval τ after administration of the first dose)

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
Cmax (maximum measured concentration of the analyte in plasma)
After the last dose:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady state over 
a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over a 
uniform dosing interval τ)
Accumulation ratios:

RA,Cmax (accumulation ratio based on Cmax,ss)

RA,AUC (accumulation ratio based on AUC0-τ)
 
 
 
 
 
 
 
 
 

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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis of BI 1015550
For quantification of analyte plasma concentrations, 2.7 mL of blood will be taken from an 
antecubital or forearm vein into a K3-EDTA (tripotassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will be 

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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 
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) including anti-drug 
antibodies (if applicable) 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
5.5.3.1
Analytical determination of drug plasma concentration
Concentrations of BI 1015550 in plasma from subjects will be determined by a validated 
HPLC-MS/MS assay (high performance 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 

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Pharma GmbH & Co. KG, Biberach, Germany at a suitable contract research organization 
(CRO).
 
 
 
5.6
BIOMARKER
 
 
 
 
 
 
 
 
 
 

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5.7
PHARMACOKINETIC - PHARMACODYNAMIC BIOMARKER 
RELATIONSHIP
The direct relationship between pharmacokinetic concentrations and biomarker parameters 
will be explored by a scatter plot. Further analysis might be performed, if deemed reasonable.

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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 2 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
The acceptable deviation on profile days from the scheduled time for vital signs and ECG 
will be -10 min and for laboratory tests will be ± 30 min for the first 4 h after trial drug 
administration and ± 30 min thereafter.
Fecal occult blood and calprotectin testing will be done as indicated and described in the 
Flow Chart. 
The tolerance for drug administration will be ± 1 min on Days 1 and 14, ± 10 min on all other 
treatment days.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 12-
lead ECG recordings have to be done first. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological
parameters.
For planned individual plasma concentration sampling times and urine collection intervals 
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 
 
 urinalysis), ECG, vital signs, and physical examination,
 
(only Part 2) refer to Section 5.2.3 to Section 5.2.5.

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6.2.2
Treatment period
Part 1 (SRD)
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.
Study participants will be admitted to the trial site in the evening of Day -1 and kept under 
close medical surveillance for at least 24 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 and urine samples 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.
Part 2 (MRD)
Each subject will receive a single dose of BI 1015550 or placebo on Day 1 and then daily 
multiple doses of BI 1015550 of the respective dose strength or placebo for 11 days from Day 
3 onwards as described in Section 4.1.
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.
Study participants will be admitted to the trial site in the morning of Day -1 and kept under 
close medical surveillance for at least 48 h following the last 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 samples 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.

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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 Section 5.2.2 to Section 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained. 
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 objectives in this integrated trial vary between trial parts and are described in 
Section 2.2.
7.1.2
Endpoints
Safety and tolerability will be determined on the basis of the parameters specified in 
Section 5.2.1. Pharmacokinetics and 
 will be explored based on 
endpoints and parameters specified in Section 5.5.1 and Section 5.6.1.
7.1.3
Model
The statistical models used for the assessments of 
 
 are described in Section 7.3.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 4 different dose groups in 2 trial parts (SRD, MRD) 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.
The statistical analysis will be based on the following analysis sets.

Entered set (ES): This subject set includes all entered and randomized subjects, 
whether treated or not. 

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
Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the subjects received.

Pharmacokinetic set (PKS): 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 below. 
Plasma and urine concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol 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 and urine 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.
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.
 

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7.3.3
Safety analyses
Safety will be assessed for the endpoints and parameters of interest listed in Section 5.2.1. 
Safety analyses will be done based on the treated set (refer to Section 7.3) and 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 for Part 1 and 2
in the safety evaluation will consist of all placebo treated subjects in the respective trial part, 
regardless of the dose group in which they were treated. For trial Parts 1 and 2, 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 analyze continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’. 
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 will be 
assigned to the treatment period, and all AEs occurring between the end of REP and trial 
termination date will be assigned to ’follow-up’. These assignments including the 
corresponding time intervals will be defined in detail in the TSAP. Please note that AEs 
occurring after the last per protocol contact but entered before database lock will be reported 

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to drug safety only and will not be captured in the trial database. 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.
The ECG variables QT, HR, QTcF, QTcB, PR, QRS, and RR obtained from the centralized
evaluation of 12-lead ECG recordings from Part 1 and 2 will be the basis for the derivation of 
quantitative and categorical ECG endpoints. These endpoints and their analyses will be 
described in the TSAP.
 
 
 
 
 
 
 
 

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7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1015550 will be 
calculated according to the BI SOP ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472] using validated software 
programs (preferably Phoenix WinNonlin®).
Subjects who are not included in the PKS (refer to Section 7.3) will be reported with their 
individual plasma / urine concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma / urine concentrations, 
pharmacokinetic parameters or other statistical assessment.
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. This rule will only be applied for derivation 
of PK parameters after single dose.
 
 
 

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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/urine 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 analyzed), BLQ (below the lower limit of quantification), or NOP (no peak 
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 partially-randomized within each dose group. For each dose group the first 
block will be treated according to fixed sequence (active-placebo-active), the remaining block 
will be randomized in a 2:1 ratio, which reflects the ratio of subjects receiving active drug to 
placebo.
The sponsor will arrange for the randomization as well as packaging and labelling of trial 
medication. The randomization 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 randomization list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).

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7.6
DETERMINATION OF SAMPLE SIZE
A total of 42 subjects shall be included into this trial.
Part 1 (SRD)
It is planned to include a total of 18 subjects into this part of the trial. The planned sample 
size is not based on a power calculation. The size of 9 subjects per dose group (6 on active 
treatment, and 3 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] and enables a balanced analysis of subjects on 
verum and on different doses of BI 1015550.
Part 2 (MRD)
In this part, it is planned to include a total of 24 subjects. The planned sample size is not 
based on a power calculation. The size of 12 subjects per dose group (8 on active treatment, 
and 4 on placebo) is commonly used in multiple-rising dose studies of the present type and is 
in general considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics [R95-0013] and enables a balanced analysis of subjects on verum and on 
different doses of BI 1015550.
Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 42, but will not exceed 54 subjects entered.

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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 Harmonized Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
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 finalization of the 
CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and 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 or her medical records may be examined by authorized
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 and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
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, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.

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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.
R05-2311
ICH E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonised 
tripartite guideline, recommended for adoption at step 4 of the ICH process 
on 12 May 2005 by the ICH Steering Committee). www.emea.eu.int 
2005:1-14.
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.
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/
Pulmonary-AllergyDrugsAdvisoryCommittee/ucm207376.htm (access 
date: 23 November 2010); Jersey City: Forest Research Institute; 2010.
R10-1559
Giembycz MA. Life after PDE4: overcoming adverse events with dual-
specificity phosphodiesterase inhibitors. Curr Opin Pharmacol 2005;5:238-
244.
 

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R13-0801
E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs - Questions and 
Answers (R1). October 2012. 
website.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/ucm323656.htm
R13-4095
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): ICH guideline E14 - questions and answers: step 
5 (May 2012, EMA/CHMP/ICH/310133/2008). 
website.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2009/09/WC500002878.pdf
R14-1795
Otezla (apremilast) tablets, for oral use (Celgene) (U.S. prescribing 
information, revised: 3/2014). 2014
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/2011/022522Orig1s000Ph
armR.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/2014/205437Orig1s000Ph
armR.pdf (access date: 13 March 2017) ; Department of Health and Human 
Services, Public Health Service, Food and Drug Administration, Center for 
Drug Evaluation and Research (2014)

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R17-1427
Otezla 10 mg, 20 mg, 30 mg film-coated tablets, Otezla 30 mg film-coated 
tablets (Celgene) (summary for product characteristics, manufacturer 
responsible for batch release, conditions or restrictions regarding supply 
and use, other conditions and requirements of the marketing authorisation, 
conditions or restrictions with regard to the safe and effective use of the 
medicinal product, labelling and package leaflet (first published 
16/02/2015). 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). 
website.medicines.org.uk/emc/print-document?documentId=29793 (access 
date: 2 May 2017); 2017.
R17-1541
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on strategies to identify and mitigate 
risks for first-in-human and early clinical trials with investigational 
medicinal products: draft (10 November 2016, 
EMEA/CHMP/SWP/28367/07 rev. 1). 
website.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2016/1 1/WC500216158.pdf (access date: 3 May 2017) ; London: European 
Medicines Agency (EMA); 2016.
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-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
001-MCG-312
Biomarker Assessments on Trial Level. 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

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c02094779-02
 
 Investigator's Brochure BI 1015550 for Idiopathic Pulmonary 
Fibrosis. 12 May 2017
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
PH12-2006
 Trial Form I Development Report for BI 1015550 BS. 10 Aug 
2012

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10.
APPENDICES

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Boehringer Ingelheim
28 Aug 2017
BI Trial No.: 1305-0011
c15772185-03
Trial Protocol
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
03 July 2017
EudraCT number
2017-002003-10
BI Trial number
1305-0011
BI Investigational Product(s)
BI 1015550
Title of protocol
Safety, tolerability, and pharmacokinetics of single 
(Part 1) and multiple rising oral doses (Part 2) of 
BI 1015550 in healthy male subjects
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
1. Flow Chart, Part 2 (MRD)
2. Section 3.3.4.2 Discontinuation of the trial by 
the sponsor
3. Section 4.1.6: Packaging, labelling, and re-
supply 
Description of change
1. Flow Chart, Part 2 (MRD), p 8+10:
Minor modifications in the Flow chart (PK 
urine) to be consistent with the foot notes 
2. Section 3.3.4.2, p 46:
Clarification that the trial will be stopped in 
case one subject experience a drug-related 
SAE
3. Section 4.1.6, p 52:
A re-supply with IMP is needed due to 
organizational issues with the updated LTAFs 

Boehringer Ingelheim
28 Aug 2017
BI Trial No.: 1305-0011
c15772185-03
Trial Protocol
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
1
Rationale for change
Based on the feedback by BfArM and Ethics 
Committee, the respective recommendation was 
included into a revised protocol. In context with 
this adaptation a few remaining inconsistencies 
were also corrected and the requirement of a re-
supply was added.

Boehringer Ingelheim
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BI Trial No.: 1305-0011
c15772185-03
Trial Protocol
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
2
Date of CTP revision
28 August 2017
EudraCT number
2017-002003-10
BI Trial number
1305-0011
BI Investigational Product(s)
BI 1015550
Title of protocol
Safety, tolerability, and pharmacokinetics of single 
(Part 1) and multiple rising oral doses (Part 2) of 
BI 1015550 in healthy male subjects
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
1. Flow Chart, Part 1, p. 6
2. Flow Chart, Part 2, p. 10
3. Table 5.2.3.1, p. 62/63
4. Section 5.2.4.1, p. 65
5. Section 5.5.2.1, p. 71
6. Section 6.1, p. 76
Description of change
1.
Typo corrected (visit 3 instead of visit 4)
2. Missing visit number 3 added, inconsistency 
regarding urine collection start between 
footnote (312:00) and Flow Chart corrected
3. In addition to the parameters listed in the table 
MCV, MCH and MCHC will be reported by 
the lab, as due to technical reasons only a 
complete blood count can be analyzed
4. Clarification of wording regarding timepoints 
of ECG analysis
5. Clarification that “after completion of the trial” 
refers to completion of the bioanalysis of BI 
1015550 as described in the protocol. Left-over 

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BI Trial No.: 1305-0011
c15772185-03
Trial Protocol
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Number of global amendment
2
samples may only be used for further analysis 
after the predefined bioanalysis of the sample 
has been completed.
6. Correction of an inconsistency between Flow 
Chart and section 6.1: “before” trial medication 
corresponds to a 2 h-period.
Rationale for change
Clarification that analysis of left-over plasma 
samples may only be done after the samples was 
analyzed for BI 1015550 as predefined in the 
protocol. 
In addition some minor inconsistencies were 
corrected and clarified.

 
 
 
 
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clinical-trial-protocol-revision-02
Safety, tolerability, and pharmacokinetics of single (Part 1) and multiple rising oral
doses (Part 2) of BI 1015550 in healthy male subjects
Approval-Trial Clinical Monitor
28 Aug 2017 12:59 CEST
Author-Trial Statistician
28 Aug 2017 13:02 CEST
Approval-Therapeutic Area 
28 Aug 2017 13:55 CEST
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29 Aug 2017 05:00 CEST
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29 Aug 2017 14:55 CEST
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