Clinical trial NCT03123094
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-05-16; Completion date: 2018-01-04
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the safety and tolerability of spesolimab following administration of single rising intravenous doses and single subcutaneous dose in healthy Japanese male volunteers.

Secondary objective is the exploration of the pharmacokinetics including dose proportionality of spesolimab in healthy Japanese male volunteers.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: Spesolimab intervention 2: Placebo
Intervention descriptions: intervention 1: single dose intervention 2: single dose

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08998695-04
BI Trial No.:
1368-0009
BI Investigational
Product:
BI 655130
Title:
Safety, tolerability and pharmacokinetics of single rising intravenous 
dose and single subcutaneous dose of BI 655130 in healthy Japanese 
male volunteers (double-blind, randomised, placebo-controlled 
design)
Lay title:
This study is done in healthy Japanese volunteers. It looks at how BI 
655130 is taken up in the body and how well it is tolerated.
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol(based on global amendment3))
Version and Date:
Version: 4.0
Date: 01 Aug 2017
Page 1 of 71
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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 655130
Protocol date:
Trial number:
Revision date:
01 Aug 2017
18 Jan 2017
1368-0009
Title of trial:
Safety, tolerability and pharmacokinetics of single rising intravenous dose and single 
subcutaneous dose of BI 655130 in healthy Japanese male volunteers (double-blind, 
randomised, placebo-controlled design)
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability and pharmacokinetics following single rising 
intravenous dose and single subcutaneous does of BI 655130
Methodology:
double-blind, randomised, placebo-controlled within dose group
No. of subjects: 
total entered:
32 Japanese
each treatment:
8 subjects per dose group (6 on active drug and 2 on placebo)
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male Japanese subjects
Age and 45 years
BMI range: ≥18.5 and 25.0 kg/m2
Test product 1:
BI 655130 
) solution for infusion
dose:
Single dose of 
 and 
mg
mode of admin.:
Intravenous as 90 min infusion
Test product 2:
BI 655130 
) solution for injection
dose:
Single dose of 
mode of admin.:
Subcutaneous injection
Comparator product 1: Matching placebo for BI 655130 (
L) solution for infusion
dose:
Not applicable


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 655130
Protocol date:
Trial number:
Revision date:
01 Aug 2017
18 Jan 2017
1368-0009
mode of admin.:
Intravenous as 90 min infusion
Comparator product 2: Matching placebo for BI 655130 (
 solution for injection
dose:
Not applicable
mode of admin.:
Subcutaneous injection
Duration of treatment: One day (single dose) for each treatment
Criteria for 
pharmacokinetics:
(iv) single rising dose group
Secondary endpoints: AUC0-∞, Cmax, CL and Vss
(sc) single dose group
Secondary endpoints: AUC0-∞and Cmax
 
Criteria for 
pharmacodynamics:
Not applicable
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 655130 is the number [N (%)] 
of subjects with drug-related adverse events (AEs).
 
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 655130 will be explored using a regression model. A 95% 
confidence interval (CI) for the slope will be computed.


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FLOW CHART
(iv) Single rising dose group
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKblood
4
 
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs (BP, PR)
Query on adverse events, 
concomitant therapies9
1
-28
to -3
screening1
X
X
X
2
-3 to -
1
-72:00
8:00
ambulatory visit
X11
-1
-12:00
20:00
admission to
trial site
X
1
-2:00
6:00
randomization and 
pre-dose2
X
X
X
X
X
X5
0:00
8:00
drug administration
start of infusion
▲
│
0:30
8:30
│
│
X
1:00
9:00
│
│
X
1:30
9:30
▼
end of infusion12
X
X
X
│
│
X
X5
2:00
10:00
X
X
X
▼
X
3:00
11:00
X
X
4:00
12:00
Lunch6
X
X
X
X5
6:00
14:00
X
X
X
8:00
16:00
X
X
10:00
18:00
Dinner6
12:00
20:00
X
X
X
X
X5
2
24:00
8:00
Breakfast6
X
X
X
X
X
X5
28:00
12:00
Lunch6
32:00
16:00
X
X
34:00
18:00
Dinner6
X
3
48:00
8:00
Discharge from
trial site
(confirmation of 
fitness7)
X
X
X
X
4
72:00
8:00
ambulatory visit
X
X
X
5
96:00
8:00
ambulatory visit
X
X
8
168:00
8:00
ambulatory visit
X
X
X
X
X
15
336:00
8:00
ambulatory visit
X
X


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FLOW CHART (cont.)
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKblood 
4
 
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies9
2
22
504:00
8:00
ambulatory visit
X
X
X
X
X
29
672:00
8:00
ambulatory visit
X
X
X
X
X
36
840:00
8:00
ambulatory visit
X
X
43
1008:00
8:00
ambulatory visit
X
X
57
1344:00
8:00
ambulatory visit
X
X
71
1680:00
8:00
ambulatory visit
X
X
92±2
2184:00
8:00
ambulatory visit
X
X
120±3
2856:00
8:00
ambulatory visit
X
X
3
148±3
3528:00
8:00
EOT10
X13
X
X
X
X
1.
Screening with subject information, informed consent as the first measure, includes physical examination, check of 
vital signs, ECG, safety laboratory (under fasting conditions), drug screening, demographics (including 
determination of body height and weight, smoking and alcohol history), relevant medical history, concomitant 
therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate: blood sampling is to be performed and completed within 30 minutes prior to drug 
administration; all other procedures are to be performed and completed within 2 h prior to drug administration. 
Within 2 hours prior to the planned dosing, planned time -2:00 will be used.
3.
Laboratory tests (safety laboratory) include clinical chemistry, haematology, coagulation and urinalysis; in 
addition at screening: serology (HBV, HCV, HIV, QuantiFERON), and drug screening.
4.
PK sampling times may be adapted based on information obtained during trial conduct.
5.
Local tolerability test inclusive.
6.
If several actions are indicated at the same time point, the intake of meals will be the last action.
7.
Confirmation of fitness includes physical examination.
 
9. 
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.
 
 
11.
Safety laboratory is to be taken within three days prior to study drug administration and can be omitted, if the 
screening examination is performed between Day -5 to Day -3.
12.
First measure after completion of infusion collection of PK sample 


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FLOW CHART
(sc) Single dose group
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKblood
4
 
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs (BP, PR)
Query on adverse events, 
concomitant therapies9
1
-28
to -3
screening1
X
X
X
2
-3 to -1
-72:00
8:00
ambulatory visit
X11
-1
-12:00
20:00
admission to
trial site
X
1
-2:00
6:00
randomisation and 
pre-does2
X
X
X
X
X
X5
0:00
8:00
drug 
administration
▲
0:30
8:30
X
X
│
X
X5
1:00
9:00
│
X
1:30
9:30
X
│
X
2:00
10:00
X
X
X
▼
X
3:00
11:00
X
X
4:00
12:00
Lunch6
X
X
X
X5
6:00
14:00
X
X
X
8:00
16:00
X
X
10:00
18:00
Dinner6
12:00
20:00
X
X
X
X
X5
2
24:00
8:00
Breakfast6
X
X
X
X
X
X5
28:00
12:00
Lunch6
32:00
16:00
X
X
34:00
18:00
Dinner6
X5
3
48:00
8:00
Discharge from
trial site
(confirmation of 
fitness7)
X
X
X
X5
4
72:00
8:00
ambulatory visit
X
X
X5
5
96:00
8:00
ambulatory visit
X
X5
8
168:00
8:00
ambulatory visit
X
X
X
X
X5
15
336:00
8:00
ambulatory visit
X
X5


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FLOW CHART (cont.)
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKblood 
4
 
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
vital signs (BP, PR)
Query on adverse events, 
concomitant therapies9
2
22
504:00
8:00
ambulatory visit
X
X
X
X
X5
29
672:00
8:00
ambulatory visit
X
X
X
X
X5
36
840:00
8:00
ambulatory visit
X
X5
43
1008:00
8:00
ambulatory visit
X
X5
57
1344:00
8:00
ambulatory visit
X
X5
71
1680:00
8:00
ambulatory visit
X
X
92±2
2184:00
8:00
ambulatory visit
X
X
120±3
2856:00
8:00
ambulatory visit
X
X
3
148±3
3528:00
8:00
EOT10
X12
X
X
X
X5
1.
Screening with subject information, informed consent as the first measure, includes physical examination, check of 
vital signs, ECG, safety laboratory (under fasting conditions), drug screening, demographics (including 
determination of body height and weight, smoking and alcohol history), relevant medical history, concomitant 
therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate: blood sampling is to be performed and completed within 30 minutes prior to drug 
administration; all other procedures are to be performed and completed within 2 h prior to drug administration. 
Within 2 hours prior to the planned dosing, planned time -2:00 will be used.
3.
Laboratory tests (safety laboratory) include clinical chemistry, haematology, coagulation and urinalysis; in 
addition at screening: serology (HBV, HCV, HIV, QuantiFERON), and drug screening.
4.
PK sampling times may be adapted based on information obtained during trial conduct.
5.
Local tolerability test inclusive.
6.
If several actions are indicated at the same time point, the intake of meals will be the last action.
7.
Confirmation of fitness includes physical examination.
 
9.
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.
 
 
11.
Safety laboratory is to be taken within three days prior to study drug administration and can be omitted, if the 
screening examination is performed between Day -5 to Day -3. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 19
2.2
TRIAL OBJECTIVES.......................................................................................19
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 23
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................23
3.1.1
Administrative structure of the trial...................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................25
3.3.1
Main diagnosis for study entry............................................................25
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................25
3.3.4
Removal of subjects from therapy or assessments.............................27
3.3.4.1
Removal of individual subjects................................................27
3.3.4.2
Discontinuation of the trial by the sponsor..............................28
3.3.5
Replacement of subjects .......................................................................28
4.
TREATMENTS........................................................................................ 29
4.1
TREATMENTS TO BE ADMINISTERED....................................................29
4.1.1
Identity of BI investigational product and comparator 
products .................................................................................................29
4.1.2
Method of assigning subjects to treatment groups ............................30
4.1.3
Selection of doses in the trial................................................................30
4.1.4
Drug assignment and administration of doses for each subject .......31
4.1.5
Blinding and procedures for unblinding ............................................32
4.1.5.1
Blinding....................................................................................32
4.1.5.2
Procedures for emergency unblinding .....................................32
4.1.6
Packaging, labelling, and re-supply ....................................................32


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4.1.7
Storage conditions.................................................................................33
4.1.8
Drug accountability ..............................................................................33
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................34
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................34
4.2.2
Restrictions............................................................................................34
4.2.2.1
Restrictions regarding concomitant treatment .........................34
4.2.2.2
Restrictions on diet and life style.............................................34
4.3
TREATMENT COMPLIANCE.......................................................................35
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 36
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................36
5.1.1
Endpoints of efficacy.............................................................................36
5.1.2
Assessment of efficacy...........................................................................36
5.2
SAFETY..............................................................................................................36
5.2.1
Endpoints of safety................................................................................36
5.2.2
Assessment of adverse events...............................................................36
5.2.2.1
Definitions of adverse events...................................................36
5.2.2.2
Adverse event collection and reporting ...................................39
5.2.3
Assessment of safety laboratory parameters......................................41
5.2.4
Electrocardiogram................................................................................44
5.2.4.1
12-lead resting ECG.................................................................44
5.2.4.2
Continuous ECG monitoring ...................................................44
5.2.5
Assessment of other safety parameters...............................................44
5.2.5.1
Vital signs ................................................................................44
5.2.5.2
Medical examinations..............................................................45
5.2.5.3
Local tolerability test ...............................................................45
5.3
OTHER...............................................................................................................45
5.3.1
Pharmacogenomic evaluation..............................................................45
5.3.2
Other endpoints.....................................................................................45
5.3.3
Other assessments .................................................................................45
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................45
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................45
5.5.1
Pharmacokinetic endpoints..................................................................46
5.5.1.1
Secondary endpoints................................................................46
5.5.2
Methods of sample collection...............................................................47
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................47
5.5.3
Analytical determinations ....................................................................47
6.
INVESTIGATIONAL PLAN.................................................................. 49


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6.1
VISIT SCHEDULE............................................................................................49
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................50
6.2.1
Screening period....................................................................................50
6.2.2
Treatment period ..................................................................................50
6.2.3
End of trial and follow-up period........................................................50
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 51
7.1
STATISTICAL DESIGN – MODEL ...............................................................51
7.1.1
Objectives...............................................................................................51
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................51
7.3
PLANNED ANALYSES....................................................................................51
7.3.1
Primary analyses...................................................................................51
7.3.2
Secondary analyses ...............................................................................51
7.3.3
Safety analyses.......................................................................................53
7.3.4
Interim analyses ....................................................................................53
7.3.5
Pharmacokinetic analyses ....................................................................53
7.4
HANDLING OF MISSING DATA ..................................................................54
7.4.1
Safety......................................................................................................54
7.4.2
Plasma/urine drug concentration - time profiles ...............................54
7.4.3
Pharmacokinetic parameters...............................................................54
7.5
RANDOMISATION ..........................................................................................54
7.6
DETERMINATION OF SAMPLE SIZE ........................................................55
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 56
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................56
8.2
DATA QUALITY ASSURANCE .....................................................................56
8.3
RECORDS..........................................................................................................57
8.3.1
Source documents .................................................................................57
8.3.2
Direct access to source data and documents.......................................57
8.3.3
Storage of records .................................................................................57
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................57
8.5
STATEMENT OF CONFIDENTIALITY.......................................................58
9.
REFERENCES......................................................................................... 59
9.1
PUBLISHED REFERENCES...........................................................................59
9.2
UNPUBLISHED REFERENCES.....................................................................60
10. APPENDICES .......................................................................................... 61
10.1
CLINICAL EVALUATION OF LIVER INJURY .........................................61
10.1.1 Introduction...........................................................................................61
10.1.2 Procedures .............................................................................................61


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11. DESCRIPTION OF GLOBAL AMENDMENT................................... 63


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ABBREVIATIONS
ADA
ADCC
Anti-drug antibodies
Antibody-dependent cellular cytotoxicity
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine amino transferase
ANCOVA
Analysis of Covariance
API
Active Pharmaceutical Ingredient
AST
Aspartate amino transferase
AUC
Area under the curve
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
%AUCtz-∞
the percentage of AUC0-∞obtained by extrapolation
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CDC
Complement-dependent cytotoxicity
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravenous administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CRO
Clinical Research Organization
CTP
Clinical trial protocol
CTR
CTSU
Clinical trial report
Clinical Trial Supply Unit
DILI
Drug induced liver impairment
DP
Drug product
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme Linked Immunosorbent Assay
EOT
End of trial
FDA
Food and Drug Administration
FIH
First in Human
GCP
Good Clinical Practice


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HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
IB
Investigator’s brochure
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IPV
Important protocol violations
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant in plasma
kDA
Kilodalton
LI
linearity index
LOQ
Limit of Quantification
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mmHg
Millimeters Mercury
MMP
Matrix metalloproteinase
MRD
Multiple Rising Dose
MRT
Mean residence time of the analyte in the body after intravenous 
administration
N
Number
NC
Not calculated
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PBMC
peripheral blood mononuclear cells
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
pM
Picomolar
PR
Pulse rate
PTM
Planned Time
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
REP
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
Residual Effect Period
RR
Respiratory Rate
SAE
Serious adverse event
SOP
Standard Operating Procedure
SRD
Single-rising dose
ss
(at) steady state


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t1/2
Terminal half-life of the analyte in plasma
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TDMAP
Trial Data Management and Analysis Plan
TGF
Transforming growth factor
TMDD
Target mediated drug disposition
TMF
Trial Master File
TSAP
Trial statistical analysis plan
UC
Ulcerative colitis
ULN
Upper limit of normal
USP
United States Pharmacopeia
Vss
Volume of distribution at steady state after intravenous administration
Vz
Volume of distribution during the terminal phase after intravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WBC
White Blood Cells


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 655130
following administration of single rising intravenous doses and single subcutaneous dose in 
healthy Japanese male volunteers.
Secondary objective is the exploration of the pharmacokinetics including dose proportionality 
of BI 655130 in healthy Japanese male volunteers.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The single rising intravenous dose part of the trial is designed as double-blind, randomised, 
and placebo-controlled within parallel dose groups. The single subcutaneous dose part of the 
trial is designed as double blind, randomised, and placebo-controlled.
A total of 32 healthy male subjects is planned to participate in the trial, according to 4 dose
groups comprising 8 subjects per group. Within each dose group 6 subjects will receive the 
active drug and 2 subjects will receive placebo. 
Only single dose is tested within each dose group. The dose groups to be evaluated are 
outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose group
1
2
3
4
Dose
intravenous
subcutaneous
No. of subjects
8
8
8
8
Subjects receiving placebo
2
2
2
2
Subjects receiving active
6
6
6
6
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 14 days between the first drug administration in the previous dose 
group and the first drug administration of the subsequent dose group in single rising dose part. 
(Dose groups 1-3) The decision to proceed to the next dose group will be based upon the 
safety and tolerability 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).
The investigator is allowed to interrupt the further dose escalation in case the safety 
evaluation leads to concerns until alignment with sponsor.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 


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-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial will be conducted at 
 in 
 under the 
supervision of the principal investigator (
).
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany. 
On-site monitoring will be performed under the responsibility of Clinical Operations in BI
Korea.
Safety laboratory tests will be performed by the local laboratory of the trial site or/and at a 
CRO designated by the sponsor.
The analyses of BI 655130 concentrations in plasma and ADAs will be performed at 
. 
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For single rising dose part, the design described in Section 3.1 is viewed favourable under the 
provision not to expose the subjects involved to undue risks since the main study objective is 
to investigate safety and tolerability of BI 655130.
With the rising dose design, double-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to the dose-depending effects as well as time effects, but it has the 
virtue of minimizing subject risk by sequentially studying ascending doses. As time-effects 
are expected to be small relative to the differences between the doses in the broad range 
investigated, unbiased comparisons between treatments can still be expected.
The single subcutaneous part (
 will start at least 1 week after the first drug 
administration of the first dose group (
 of the single-rising intravenous dose part. 
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety and tolerability. Each dose group consists of 8 subjects with 6 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 


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groups treated with placebo. 6 subjects per active treatment group are in general considered 
as sufficient for the exploratory evaluation of pharmacokinetics.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 32 healthy male subjects will enter the study. Subjects will be recruited 
from the volunteers' pool of the trial site. 
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.
A log of all subjects enrolled into the study (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 according to the investigator’s assessment, based on a complete medical 
history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical 
laboratory tests.
2.
Japanese ethnicity, according to the following criteria:
-
born in Japan, have lived outside of Japan <10 years, and have parents and 
grandparents who were all born in Japan
3. Age of 20 to 45 years (incl.)
4. BMI of 18.5 to 25.0 kg/m2 (incl.)
5. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
6. Male subjects who agree to minimize the risk of female partners being pregnant by 
fulfilling any of the following criteria starting from the first administration of trial 
medication and until 30 days after trial completion:
-
Use of adequate contraception, e.g. any of the following methods plus condom:
combined oral contraceptives, intrauterine device
-
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)
-
Surgically sterilised (including hysterectomy) female partner
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator


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2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
7. History of relevant orthostatic hypotension, fainting spells, or blackouts
8. Chronic or relevant acute infections including active tuberculosis, HIV or viral hepatitis; 
QuantiFERON TB test will be performed at screening.
9. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
10. 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)
11. Participation in another trial where an investigational drug has been administered within 5 
half-lives prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug.
13. Administered live vaccine within 6 weeks prior to randomisation or Have plans for 
administration of live vaccines during the study period.
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (consumption of more than 30 g per day)
17. Drug abuse or positive drug screening
18. Blood donation of more than 
 within 30 days prior to administration of trial 
medication or intended donation during the trial
19. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
20. Inability to comply with dietary regimen of trial site
21. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
22. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
23. 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 
For study restrictions, refer to Section 4.2.2.


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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, 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, 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 Section 10.1 of this clinical trial protocol and the 
‘DILI checklist’ provided in the ISF.
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
Infusion reactions should also lead to the removal of an individual subject. However, in mild 
transient cases of infusion reactions (with clinical symptoms such as dizziness, headache, 
nausea) requiring no treatment the clinical investigator may continue [P16-06636]. However, 
the overall infusion time must not exceed 90 minutes.
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). The only exception to this 
rule is when the subject had an AESI and/or SAE that the investigator considers related to the 
screening procedure. If a subject is removed from or withdraws from the trial after 
administration of trial medication, this will be documented and the reason for discontinuation
must be recorded in the CRF. In this case, the data will be included in the CRF/trial database 
and will be reported in the CTR. At the time of discontinuation a complete end of trial 
examination will be performed if possible and the information will be recorded in the CRFs. 
If the discontinuation occurs before the end of the REP (see Section 5.2.2.2), the discontinued 
subject should if possible be questioned for AEs and concomitant therapies at or after the end 
of the REP in order to ascertain collection of AEs and concomitant therapies throughout the 
REP, if not contrary to any consent withdrawal of the subject. These discontinuations will be 
discussed in the CTR.


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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, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported that is
considered to be unacceptable.
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.
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.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured by BI Pharma GmbH & Co. KG. 
4.1.1
Identity of BI investigational product and comparator products
For intravenous administration
The characteristics of the test product are given below:
Substance:
BI 655130
Pharmaceutical formulation: solution for infusion
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
 (per 
vial)
Posology:
1-0-0
Route of administration:
IV infusion
Duration of use:
Single dose 
At the time of use, the IV solution for dosing will be prepared as detailed in the instruction 
given in ISF.
The characteristics of the reference product (placebo) are given below:
Substance:
Pharmaceutical formulation: solution for infusion
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
not applicable
Posology:
1-0-0
Route of administration:
IV infusion
Duration of use:
Single dose 
For subcutaneous administration
The characteristics of the test product are given below:
Substance:
BI 655130
Pharmaceutical formulation: solution for injection
Source:
BI Pharma GmbH & Co. KG, Germany


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Unit strength:
 (per 
vial)
Posology:
1-0-0
Route of administration:
SC injection 
Duration of use:
Single dose (
The characteristics of the reference product (placebo) are given below:
Substance:
Pharmaceutical formulation: solution for injection
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
not applicable
Posology:
1-0-0
Route of administration:
SC injection
Duration of use:
Single dose (
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 
one of the 4 dose groups, the following subjects will be allocated to one of the other dose 
groups. Therefore, the allocation of subjects to dose groups is not influenced by trial 
personnel, but only by the subjects’ temporal availability. As the study includes healthy 
subjects from a homogenous population in each ethnicity, relevant imbalances between the 
dose groups are not expected.
The list of subject and medication numbers will be provided to the trial site in advance. The 
allocation of subjects to study subject numbers will be performed prior to the first 
administration of trial medication. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
Three dose strengths for intravenous administration and one dose strength for subcutaneous 
administration are to be investigated in this trial. These three doses for IV will cover potential 
therapeutic dose ranges and provide a safety margin for future development. The number of 
doses will also allow for evaluation of dose proportionality.
This trial is designed to evaluate the safety, tolerability and pharmacokinetics of BI 655130 in 
Asian healthy young male volunteers using a safe and tolerable dose achieved in previous 
trials.


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4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. Each subject will receive 
one single dose of trial medication. The dose volume for placebo corresponds to the dose 
volume of the respective dose level. For further details concerning timing see Flow Chart.
Detailed instructions for the preparation are provided in ISF.
Table 4.1.4: 1
Final dose of BI 655130 in solution containing active drug
Dose group
Final dose of BI 655130 [
1
(intravenous infusion)
2
(intravenous infusion)
3
(intravenous infusion)
4
subcutaneous injection)
For intravenous administration
The detailed instructions for the dilution of the trial product, the preparation of the infusion 
solution and the volume to be administered is provided in ISF. In all subjects the infusion 
solution will be intravenously administered over 90 minutes approximately between 8:00 and 
10:00 of the respective study day. Start and end time of the infusion will be recorded.
In case of safety concerns, e.g. due to infusion reactions, the investigator or his/her designee 
should stop of the infusion. Further based on 
 medical judgment he/she will provide 
medications such as steroids, etc. as needed.
For administration of the infusion, an intravenous indwelling catheter is placed into an arm 
vein of the subject and will be kept patent with a saline infusion. A second indwelling 
catheter used for collection of blood samples will be placed on the contralateral arm.
The administration of the trial medication on all study days will be done under supervision of 
the investigating physician or a 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. For the purpose of drug 
accountability, the infusion set will be weighed before and after drug administration.
Water is allowed except for 1 hour before start of infusion and 1.5 h after end of infusion.
For subcutaneous administration
Following an overnight fast of at least 10 hours, the medication will be administered. Trial 
drug will be injected subcutaneously in the abdominal region. The skin is sanitized before 
injection. Combi-stopper is removed from syringe containing trial drug. Syringe is connected 
to hypodermic needle for injection. Needle is placed subcutaneously and solution with trial 
drug is injected within 60 seconds. Detailed handling instructions will be provided in the ISF.
For all dose groups standardised meals will be served as outlined in the Flow Chart. Subjects 
will be kept under close medical surveillance until 48 h following drug administration. 
Thereafter subjects will be discharged and further assessments will be conducted in an 
ambulatory fashion. For restrictions with regard to diet see also Section 4.2.2.2. 


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
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. The trial will only be unblinded to the subjects, investigators 
and trial site staffs after locking of the database.Sponsor staffs that have direct interaction 
with the investigator and site staff (e.g. CML and CRA) will not be aware of the treatment 
allocation (i.e. active vs placebo) as well until database lock.
Monitoring on drug accountability should be conducted by unblinded CRA.
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical monitor, data manager, 
statistician, bioanalyst, pharmacokineticist, pharmacometrician as well as dedicated CRO
personnel). The objective of the trial is not expected to be affected.
4.1.5.2
Procedures for emergency unblinding
For blinded trials, the investigator will be supplied with a set of sealed envelopes containing 
the medication codes for each subject according to the randomisation scheme. The envelopes 
will be kept unopened at the trial site until the end of data collection. An envelope may only 
be opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or to assure safety of trial 
participants. If the envelope for a subject is opened, the sponsor must be informed 
immediately. The reason for opening the code break must be documented on the envelope or 
appropriate CRF page along with the date and the initials of the person who broke the code. 
At the close-out visit all envelopes are collected.
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 clinical trial supply containers will be labelled with:

BI trial number

Medication number

Batch 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


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
Use-by date

Investigator
The vials are labelled with reduced requirements.
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. Examples of the labels will be available in the 
ISF.
Re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the study protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre

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 or immediately imminent 
signing of the clinical trial protocol 
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused trial medication must be returned to the sponsor. All used 
medication will be destructed locally by the trial site. Receipt, usage, return and disposal
must be documented on the respective forms in ISF. Account must be given for any 
discrepancies. 
The investigator / pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each subject, and 
the return to the sponsor or alternative disposal of unused or partially used 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 / pharmacist / investigational drug storage manager 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 or


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return to the sponsor, the investigator / pharmacist / investigational drug storage manager 
must verify that no remaining supplies are in the investigator’s possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency 
procedures are to be followed. No additional treatment is planned. However, in case of 
adverse events in need of treatment, the investigator can authorise symptomatic therapy. In
those cases, subjects will be treated as necessary and, if required, kept under supervision at 
the trial site or transferred to a hospital until all medical evaluation results have returned to an 
acceptable level.
4.2.2
Restrictions
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. Standardised meals will be served at the time points 
described in the Flow Chart. On Day 1 for all subjects, no food is allowed for at least 10 h 
before and 1.5 h after administration of the study drug (= end of infusion for intravenous dose 
group).
On all days of drug administration, starting from 1 hour before drug administration until 1.5 h 
after the completion of administration liquid intake is not allowed. Until 24 hours post-dose 
water intake will be within
. Total fluid intake on all 24 hours inhouse days 
is recommended to be at least 1.5 liters and should not exceed 3.5 liters.
Smoking is not allowed during in-house confinement at the trial site. On the ambulatory days 
it is restricted to not more than 10 cigarettes or 3 cigars or 3 pipes per day
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during inhouse confinement. Alcoholic beverages are not 
permitted starting 7 days before the first administration of trial medication until Day 28. 
From Day 29 onwards, alcohol consumption is restricted to 20 g alcohol per day 
corresponding to 0.5 L beer or 0.2 L of white wine per day.
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.


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4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
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 655130 is the number [N (%)] of 
subjects with drug-related AEs.
Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring 

Vital signs (blood pressure, pulse)
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 unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death, 

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity 

is a congenital anomaly/birth defect, 
or 

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered ‘Always Serious’
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 given 
above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system, a remote data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
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:


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
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
marked peak 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 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).


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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 study 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 through the residual effect period (REP), 
until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs. 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.


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
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 relevant SAEs and relevant AESIs of which 
 may 
become aware of.
The residual effect period (REP) for BI 655130, when measurable drug levels or PD effects 
are still likely to be present after the last administration, is not known for this trial. Therefore,
all AEs reported until the end of trial examination (last per protocol contact) will be 
considered on treatment, please see section 7.3.3.
The follow-up period describes the period of time from the last administration of trial 
medication including the REP until the end of trial examination (last per protocol contact).
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 of 
awareness) to the sponsor’s unique entry point (country specific contact details will be 
provided in the ISF). The same timeline applies if follow-up information becomes available. 
In specific occasions the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (if applicable). The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and on the SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.


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If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male
trial participant becomes pregnant. This requires a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designate 
for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is a clinically relevant abnormality in the automatic blood cell count or in 
the urinalysis, respectively, and it is deemed clinically necessary by the investigator.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Automatic WBC differential 
(relative and absolute cell count)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC1
Neutrophils (stabs), eosinophils, basophils, monocytes, 
lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (ALP))
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Serum tryptase1
Hormones2
Thyroid stimulating hormone (TSH)
fT3, fT4
Substrates
Serum glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Protein electrophoresis (Protein EP) (only at screening 
examination)1
Albumin 
Alpha-1-Globulin
Alpha-2-Globulin
Beta-Globulin
Gamma-Globulin 
C-Reactive Protein (CRP) 
Uric acid 
Total cholesterol 
Triglycerides
Electrolytes
Sodium
Potassium
Chloride
Calcium
Inorganic phosphate (IP)


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
Test name 
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment3
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1
Only if automatic differential WBC is abnormal and it is deemed clinically necessary by the investigator
2
Only at screening
3
Only if erythrocytes, leukocytes, nitrite or protein are abnormal in urinalysis and it is deemed clinically necessary 
by the investigator
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. Drug screening will be performed at screening.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Opiates 
Infectious screening (blood)1
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV antibody (qualitative)
QuantiFERON (qualitative)
1
Only at screening
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
at screening, and may be repeated at any time during the study at the discretion of an 
investigator or designate. The results will not be included in the CTR. 
In case of a potential systemic allergic reaction blood samples for determination of serum 
tryptase will be collected 0.5 h, 2 h, 6 h and 24 h after onset of the event.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed by the local 
laboratory of the trial site or/and at a CRO designated by the sponsor.
Laboratory data will be transmitted electronically from the trial site to BI.


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5.2.4
Electrocardiogram
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 
computerised electrocardiograph 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 5 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.
At all time points single ECGs will be recorded. 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). 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. 
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. 
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 12-lead ECG 
recording for at least 15 min before (for baseline assessment) and 2 h following drug
administration.
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) or heart rate (heart rate 
is considered to be equal to pulse rate in healthy volunteers) will be measured by a blood 
pressure monitor at the times indicated in the Flow Chart, after subjects have rested for at 
least 5 min in a supine position. All recordings should be made using the same type of blood 
pressure recording instrument on the same arm if possible.


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5.2.5.2
Medical examinations
At the screening visit, the medical examination will include documentation of subject 
information, informed consent, 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), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination with determination of weight
5.2.5.3
Local tolerability test
Local tolerability will be assessed by the investigator according to ‘swelling’, ‘induration’, 
‘heat’, ‘redness’, ‘pain’, or ‘other findings’.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Not applicable.
5.3.2
Other endpoints
Not applicable.
5.3.3
Other assessments
Not applicable.
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 parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.5 are generally used 
assessments of drug exposure. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be 
documented in the CRFs. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 


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visits as long as the total blood volume taken per subject does not exceed
. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints
IV administration:

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)

CL (total clearance of the analyte in the plasma after intravenous administration)

Vss (Volume of distribution at steady state after intravenous administration)
SC administration:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
 
 
 
 
 
 


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 655130 plasma concentrations, approximately
 of blood will 
be taken from a forearm vein into a K2EDTA (ethylendiaminetetraacetic acid) anticoagulant 
blood-drawing tube at the time points listed in the Flow Chart under plasma PK. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle. Two aliquots of plasma will need to be processed from the blood volume 
collected at each planned time point. The detailed procedure for sample processing and 
handling can be found in the Lab Manual.
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing. However, only data related to the analyte 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 after the final study 
report has been signed.
 
 
 
 
 
 
 
 
 
 
5.5.3
Analytical determinations
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.


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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, observation visit, 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).
The acceptable deviation from the scheduled time for vital signs and ECG will be:

±15 min up to including 12 h

±30 min from 12h up to including 48 h

±60 min from 48 h up to Day 8

±24h from Day 15 up to Day 71

±48h on Day 92

±72h from Day 120 up to the last measurements
The tolerance for pharmacokinetic/ADA/laboratory parameters will be:

±1 min up to including 1 h

±5 min up to including 12 h

±15 min up to including 48 h

±60 min from 48 h up to Day 8

±24h from Day 15 up to Day 71

±48h on Day 92

±72h from Day 120 up to the last measurements
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 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.


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
6.2.2
Treatment period
Study participants will be admitted to the trial site in the evening of Day -1 and kept under 
close medical surveillance for at least 48 h following 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.
Trial medication will be administered as intravenous infusion or subcutaneous injection 
according to each dose group by the investigating physician or 
 designee. Details on 
treatments and procedures of administration are described in Section 4.1.4.
For details on time points and procedures for collection of plasma analysis, refer to Flow 
Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2. 
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial and follow-up period 
For AE assessment, laboratory tests, collection of PK and ADA samples, recording of ECG 
and vital signs, and physical examination during the end of trial period, see Sections 5.2.2 to 
5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
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. Adverse events persisting after trial completion must be 
monitored until they have normalised or have been sufficiently characterised. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 655130 by 
using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in Section 5.2.1. Inferential statistics is not planned (as explained 
in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) of BI 655130. 
Endpoints as specified in 5.5.1 will be analysed by descriptive statistics. AUC0-∞and Cmax for 
intravenous doses will be subjected to analysis of dose proportionality by use of the power 
model. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 4 different dose groups of BI 655130 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
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.
7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). Analyses will be 
performed for parent drug.
Plasma concentration data and parameters of a subject will be included in the statistical PK 


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analysis 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 violation may be:

Incorrect trial medication taken, i.e. the subject received trial medication the subject 
was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

Missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the treated set who provide at 
least one PK parameter that was not excluded according to the description above.
Assessment of dose proportionality
Dose proportionality will be assessed for AUC0-∞and Cmax in intravenous doses.
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints.
The model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate. 
Together with 
and 
, taking natural logarithms converts this model 
to a linear form as follows:
where
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where number of dose groups i = 1, 2, 3, and j = 1, 2, …, N where N is 
the number of subjects per dose group;

intercept parameter;
slope parameter;
logarithm of dose i;
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model.
ij
i
ij
ε
)
X
exp(
)
exp(Y







)
exp(


)
exp(
ε
ij
ij



ij
i
ij
ε
X
β
α
Y




ij
Y
β
i
X
ij
ε


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Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is, 
all subjects who received at least one dose of study drug), will be included in the safety 
evaluation. Safety analyses will be descriptive in nature and will be based on BI standards.
No hypothesis testing is planned.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
Measurements (such as vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the concept of treatment emergent AEs. Therefore, 
measurements planned or AEs recorded prior to first intake of trial medication will be 
assigned to 'screening', those between first trial medication intake until the end of trial visit 
will be assigned to the treatment period, and those after the end of trial examination will be 
assigned to ‘post-study’. These assignments including the corresponding time intervals will 
be defined in detail in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, intensity and causal relationship of AEs will be tabulated by 
treatment, primary 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 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 examination will be assessed with regard to possible changes 
compared to findings before start of treatment.
7.3.4
Interim analyses
A preliminary analysis of available safety, tolerability and/or PK data will be performed in 
order to provide the results for the interaction with regulatory agency.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 655130 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).


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Subjects who are not included in the PKS (refer to Section 7.3.1.) will be reported with their 
individual plasma and individual pharmacokinetic parameters; however, they will not be 
included in descriptive statistics for plasma, 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).
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 analysed), 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 randomised within each dose group in a 3:1 ratio which reflects the ratio of 
subjects receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable. 
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).


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7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 32 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose studies of the present type and in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics [R95-0013].


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
The certificate of the insurance cover is made available to the investigator and the subjects, 
and is stored 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/her 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 authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 


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auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the CTMF.
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 of records
Trial site:
The trial site must retain the source and essential documents (including ISF) for 15 years 
based on the site’s Trial Close-Out Visit date.
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 regulatory reporting obligation and in accordance to the
requirements defined in this CTP.


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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.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P16-06636
Denis Choquette, Rafat Faraawi et al., J Rheumatol 2015;42;1105-1111
R09-2768
Vargas HM, Bass AS, Breidenbach A, Feldman HS, Gintant GA, Harmer AR, 
Heath B, Hoffmann P, Lagrutta A, Leishman D, McMahon N, Mittelstadt S, 
Polonchuk L, Pugsley MK, Salata JJ, Valentin JP. Scientific review and 
recommendations on preclinical cardiovascular safety evaluation of biologics. 
J Pharmacol Toxicol Methods 2008;58(2):72-76.
R13-2269
Sandborn WJ. State-of-the-art: immunosuppression and biologic therapy. Dig 
Dis 2010;28:536-542.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c03320877-02
 Investigator’s Brochure of BI 655130
c03361085-07
 Single-blind, partially randomised, 
placebo-controlled Phase I study to investigate safety, tolerability, 
pharmacokinetics and pharmacodynamics of single rising intravenous doses of 
BI 655130 in healthy male volunteers, 1368.1, 27 Jan 2016.
c09105854-04 Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple 
rising intravenous doses of BI 655130 (double-blind, partially randomised 
within dose groups, placebo-controlled parallel group design) and one single 
intravenous dose of BI 655130 (single-blind, partially randomised, placebo-
controlled) in healthy male subjects, 1368.2, 11 Oct 2016.


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10.
APPENDICES
10.1
CLINICAL EVALUATION OF LIVER INJURY
10.1.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-specified 
AESIs), are to be further evaluated using the following procedures:
10.1.2
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 h. If it is confirmed that ALT and/or AST values ≥3 fold ULN occur in conjunction 
with an elevation of total bilirubin of ≥2 fold ULN, the laboratory parameters listed below 
(clinical chemistry, serology, hormones, haematology) must be determined and made 
available to the investigator and to BI as soon as possible.
In addition, 

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the ‘DILI checklist’ provided in the ISF 

obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the ‘DILI checklist’ provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and 
work place exposure) according to the ‘DILI checklist’ provided in the ISF;
and report these via the CRF.
Clinical chemistry
Alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-
HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody 
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody
Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus 
(IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis (IgG, IgM)
Hormones, tumormarker
TSH
Haematology
Thrombocytes, eosinophils


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
Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology, e.g. bile duct stones or neoplasm.

Initiate close observation of subjects by repeat testing of ALT, AST, and total 
bilirubin (total and direct) at least weekly until the laboratory ALT and/or AST 
abnormalities stabilize or return to normal, then monitor further as specified in the
CTP. Depending on further laboratory changes, additional parameters identified e.g. 
by reflex testing will be followed up based on medical judgement and Good Clinical 
Practices (GCP).


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11.
DESCRIPTION OF GLOBAL AMENDMENT
Number of global amendment
1
Date of CTP revision
17 Feb 2017
EudraCT number
BI Trial number
1368-0009
BI Investigational Product(s)
BI 655130
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising intravenous dose of BI 655130 in healthy 
Japanese male volunteers (double-blind, 
randomised, placebo-controlled design)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Throughout the protocol
2. Throughout the protocol
3. Synopsis
4. Synopsis
5. Synopsis
6. Synopsis
7. Flow Chart
8. Flow Chart
9. Flow Chart
10. Flow Chart
11. Flow Chart
12. Abbreviation
13. Abbreviation
14. Abbreviation
15. Abbreviation
16. Section 1.2
17. Section 2.1
18. Section 2.2


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Number of global amendment
1
19. Section 2.3
20. Section 2.3
21. Section 3.1
22. Section 3.1.1
23. Section 3.2
24. Section 3.3
25. Section 3.3.3
26. Section 4.1.1
27. Section 4.1.2
28. Section 4.1.2
29. Section 4.1.2
30. Section 4.1.3
31. Section 4.1.4
32. Section 4.1.8
33. Section 4.1.8
34. Section 4.2.2.2
35. Section 4.2.2.2
36. Section 5.2.2.2
37. Section 5.2.3
38. Section 5.2.3
39. Section 5.2.5.3
40. Section 5.5.1.1
41. Section 5.5.1.1
42. Section 5.5.1.2
43. Section 6.2.2
44. Section 7.2
45. Section 7.3.4
46. Section 7.6
47. Section 9.2
Description of change
1. 1368.0009 -> 1368-0009
2. Deletion of single subcutaneous dose group in 
title
3. Insert of ‘Lay title’
4. Number of subjects 32 -> 24
5. Deletion of Test product 2 and Comparator 
pruduct 2
6. Deletion of sc dose group in Criteria for PK
7. Deletion of sc dose group
8. Pkplasma -> pkblood
9. Remove '9' on Laboratory/Urinalysis
10. Remove 'Breakfast'
11. Local telerability test inclusite in Note 5
12. Remove bolus in MRT
13. REP: Residual Effect Period
14. RR: Respiratory Rate


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Number of global amendment
1
15. Remove single in Vss
16. Update the result of 1368-0002 in Clinical 
PK/PD studies
17. Update the reference of 1368-0002
18. Deletion of sc dose group
19. Deletion of sc dose group in Drug-related risks 
and safety measures
20. Deletion of continuous ECG monitoring 
interval
21. Deletion of sc dose group
22.
 -> 
23. Deletion of sc dose group
24. Number of subjects 32 -> 24
25. Update the exclusion criteria 13
26. Deletion of sc IMP
27. One of the 8 dose groups -> one of the 3 dose 
groups
28. Add 'As the study includes healthy subjects 
from a homogenous population in each 
ethnicity, relevant imbalances between the dose 
groups are not expected.'
29. Remove 'For this purpose, the subjects will be 
allocated to a study subject number by drawing 
lots. '
30. Deletion of sc dose group
31. Deletion of sc dose group and details of 
infusion bag
32. Disposed locally by the trial site upon written 
authorisation by the clinical monitor -> 
destructed locally by the trial site
33. Disposal of unused products -> disposal of 
unused or partially used products
34. Deletion of 'From breakfast'
35. From Day 28 -> From Day 29
36. Add 'Pregnancy' related paragraph
37. Deletion of 'and at admission to trial site the 
day prior to each treatment.'
38. Deletion of 'and at start of the inhouse period 
(Day -1), '
39. Local tolerability -> Local tolerability test
40. Deletion of sc dose group
41. Deletion of 'apparent' in Vss
42. Deletion of 'total' in MRT
43. Deletion of sc dose group
44. Deletion of sc dose group


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Number of global amendment
1
45. Deletion of 'and/or PK'
46. Number of subjects 32 -> 24
47. Add reference for 1368-0002 trial
Rationale for change
1. Format change of trial name
2. Deletion of SC dose group
3. Update
4. Update due to deletion of SC dose group
5. Update due to deletion of SC dose group
6. Update due to deletion of SC dose group
7. Update due to deletion of SC dose group
8. Correction
9. Correction
10. Update
11. To clarify
12. Correction
13. Correction
14. Correction
15. Correction
16. Update
17. Update
18. Update due to deletion of SC dose group
19. Update due to deletion of SC dose group
20. Correction
21. Update due to deletion of SC dose group
22. To clarify
23. Update due to deletion of SC dose group
24. Update due to deletion of SC dose group
25. To clarify
26. Update due to deletion of SC dose group
27. Correction
28. To clarify
29. Correction
30. Update due to deletion of SC dose group
31. Update due to deletion of SC dose group and 
details are specified in ISF
32. Correction
33. To clarify
34. Correction
35. Correction
36. Update the process for pregnancy
37. Correction
38. Correction
39. To clarify
40. Update due to deletion of SC dose group
41. Correction


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Number of global amendment
1
42. Correction
43. Update due to deletion of SC dose group
44. Update due to deletion of SC dose group
45. Correction
46. Update due to deletion of SC dose group
47. Update of reference


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Number of global amendment
2
Date of CTP revision
24 Feb 2017
EudraCT number
BI Trial number
1368-0009
BI Investigational Product(s)
BI 655130
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising intravenous dose and single subcutaneous dose
of BI 655130 in healthy Japanese male volunteers 
(double-blind, randomised, placebo-controlled 
design)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Thoughout the protocol
2. Synopsis
3. Synopsis
4. Synopsis
5. Flow Chart
6. Section 2.2
7. Section 2.3
8. Section 3.1
9. Section 3.2
10. Section 3.3
11. Section 4.1.1
12. Section 4.1.2
13. Section 4.1.3
14. Section 4.1.4
15. Section 4.1.5.1
16. Section 5.5.1.1
17. Section 5.5.1.2
18. Section 6.2.2
19. Section 7.2
20. Section 7.6


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Number of global amendment
2
Description of change
1. Addition of single subcutaneous dose group in 
title
2. Number of subjects 24 -> 32
3. Addition of Test product 2 and Comparator 
pruduct 2
4. Addition of sc dose group in Criteria for PK
5. Addition of sc dose group
6. Addition of sc dose group
7. Addition of sc dose group in Drug-related risks 
and safety measures
8. Addition of sc dose group
9. Addition of sc dose group
10. Number of subjects 24 -> 32
11. Addition of sc IMP
12. Addition of sc dose group
13. Addition of sc dose group
14. Addition of sc dose group
15. Add the unblinded CRA for drug accountability
16. Addition of sc dose group
17. Addition of sc dose group
18. Addition of sc dose group
19. Addition of sc dose group
20. Number of subjects 24 -> 32
Rationale for change
1. Addition of SC dose group
2. Update due to addition of SC dose group
3. Update due to addition of SC dose group
4. Update due to addition of SC dose group
5. Update due to addition of SC dose group
6. Update due to addition of SC dose group
7. Update due to addition of SC dose group
8. Update due to addition of SC dose group
9. Update due to addition of SC dose group
10. Update due to addition of SC dose group
11. Update due to addition of SC dose group
12. Update due to addition of SC dose group
13. Update due to addition of SC dose group
14. Update due to addition of SC dose group
15. Update due to the difference in color of sc 
formulation between active and placebo
16. Update due to addition of SC dose group
17. Update due to addition of SC dose group
18. Update due to addition of SC dose group
19. Update due to addition of SC dose group
20. Update due to addition of SC dose group


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Number of global amendment
3
Date of CTP revision
01 Aug 2017
EudraCT number
BI Trial number
1368-0009
BI Investigational Product(s)
BI 655130
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising intravenous dose and single subcutaneous dose
of BI 655130 in healthy Japanese male volunteers 
(double-blind, randomised, placebo-controlled 
design)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Section 3.1.1
2. Section 4.1.4
3. Section 5.2.3
4. Section 6.1
Description of change
1. The name for analytic analysis is changed to 
2. Change ‘For administration of the infusion, an 
intravenous indwelling catheter is placed into 
an arm vein of the subject and closed with a 
mandrin.’ ‘For administration of the 
infusion, an intravenous indwelling catheter is 
placed into an arm vein of the subject and will 
be kept patent with a saline infusion.’
3. Add the description for safety laboratory test, 
‘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 designate for 


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Number of global amendment
3
retests.
The parameters that will be determined are 
listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF. 
Manual differential white blood cell count or 
urine sediment examinations will only be 
performed if there is a clinically relevant 
abnormality in the automatic blood cell count or 
in the urinalysis, respectively.’
Change ‘Plasma glucose’ ‘Serum glucose’
Remove ‘microscopic examination if urine 
analysis abnormal’
Change ‘Laboratory data will be transmitted 
electronically from the laboratory to the trial 
site.’ ‘Laboratory data will be transmitted 
electronically from the trial site to BI.’
4. Change ‘The tolerance for pharmacokinetic 
/laboratory parameters will be’ ‘The 
tolerance for pharmacokinetic/ADA/laboratory
parameters will be’
Change ‘±24h from Day 8 up to Day 71’ 
‘±24h from Day 15 up to Day 71’
Rationale for change
1. The analytic laboratory is changed
2. Mandrin is not available in this trial
3. To clarify regarding safety laboratory test
(sample logistics, fasting status, condition for 
urine sediment test)
4. To clarify the time window for sampling


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08998695
4.0
clinical-trial-protocol-revision-03
Safety, tolerability and pharmacokinetics of single rising intravenous dose and single
subcutaneous dose of BI 655130 in healthy Japanese male volunteers (double-blind,
randomised, placebo-controlled design)
Approval-Team Member Medicine
01 Aug 2017 14:22 CEST
Approval-Therapeutic Area 
01 Aug 2017 16:10 CEST
Author-Clinical Monitor
02 Aug 2017 02:04 CEST
Approval-Clinical Pharmacokinetics
02 Aug 2017 03:04 CEST
Author-Trial Statistician
02 Aug 2017 07:42 CEST
Verification-Paper Signature
Completion
02 Aug 2017 07:48 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c15047157-01
BI Trial No.:
1368-0009
Title:
Safety, tolerability and pharmacokinetics of single rising 
intravenous dose and single subcutaneous dose of BI 655130 in 
healthy Japanese male volunteers (double-blind, randomised, 
placebo-controlled design)
Protocol Amendment 3 1368-0009-protocol-amendment-3
[c08998695-03]
Investigational
Product:
BI 655130
Responsible trial 
statistician:
Address:
Phone: 
, Fax: 
Date of statistical 
analysis plan:
01 FEB 2018 SIGNED
Version:
final
Page 1 of 22
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................5
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................6
5.
ENDPOINT(S).......................................................................................................7
5.1
PRIMARY ENDPOINT(S) ..................................................................................7
5.2
SECONDARY ENDPOINT(S) ............................................................................7
5.2.1
Key secondary endpoint(s)...................................................................................7
5.2.2
Secondary endpoint(s) ..........................................................................................7
..............................................................................7
..............................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ............................................................9
6.1 
TREATMENT(S)..................................................................................................9
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................10
6.3
SUBJECT SETS ANALYSED...........................................................................12
.................................................................................................13
6.5
POOLING OF CENTRES .................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........15
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................15
7.3
TREATMENT COMPLIANCE........................................................................16
7.4
PRIMARY ENDPOINT(S) ................................................................................16
7.5
SECONDARY ENDPOINT(S) ..........................................................................16
7.5.1
Key secondary endpoint(s).................................................................................16
7.5.2
(Other) Secondary endpoint(s) ..........................................................................16
............................................................................17
7.7
EXTENT OF EXPOSURE.................................................................................17
7.8
SAFETY ANALYSIS..........................................................................................17
7.8.1
Adverse events.....................................................................................................17
7.8.2
Laboratory data ..................................................................................................18
7.8.3
Vital signs.............................................................................................................18
7.8.4
ECG......................................................................................................................18
7.8.5
Others...................................................................................................................18
8.
REFERENCES....................................................................................................20
..........................................................................21
10.
HISTORY TABLE..............................................................................................22


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LIST OF TABLES
Table 6.1: 1
Treatment Set-up..............................................................................................10
Table 6.2: 1
Important Protocol violations...........................................................................11
Table 6.3: 1
Subject sets analysed........................................................................................13
Table 10: 1
History table .....................................................................................................22


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Ati-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
BMI
Body mass index
CTP
Clinical Trial Protocol
DBL
Dtabase lock
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
PKS
Pharmacokinetic set
PV
Potocol violation
RPM
Report planning meeting
RS
Randomised set
SAE
Serious adverse event
SD
Standard deviation
TS
Treated set
TSAP
Trial statistical analysis plan


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9, the purpose of this document is 
to provide a more technical and detailed elaboration of the principal features of the analysis 
described in the protocol, and to include detailed procedures for executing the statistical 
analysis of the primary and secondary variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 ’Statistical Methods and Determination of 
Sample Size‘. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
SAS® Version 9.4 (or later version) will be used for all analyses.
This initial version of the TSAP is defining important protocol violations in Section 6.2.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There will be no changes in the planned analysis of the study.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
CTP 5.2.1 defines the frequency [N(%)] of subjects with drug-related AEs as primary 
endpoint.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
There are no key secondary endpoints in this trial.
5.2.2
Secondary endpoint(s)
CTP 5.5.1.1 defines the following pharmacokinetic parameters for BI 655130 as secondary 
endpoints:
IV administration:

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)

CL (total clearance of the analyte in the plasma after intravenous administration)

Vss (Volume of distribution at steady state after intravenous administration)
SC administration:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on investigational products, assignments of treatment, and 
selection of doses, please see CTP, Sections 3 and 4.
All subjects on active treatment will be analysed according to their actual treatment group. 
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made).
The following separate study phases will be defined for analyses of adverse events (AEs), 
laboratory tests, and vital signs:

Screening (ranging from 0:00 h on day of informed consent until first administration 
of study drug)

On-treatment (separately for each treatment, ranging from the time of first 
administration of the respective treatment until study termination date )
Displays of AEs, laboratory tests and vital signs will account for the treatments (Table 6.1: 1) 
during on-treatment phase.
A) High-level analysis (for CTR Section 15.3 and Appendix 16.1.9.2.8.2 displays)
In this analysis screening and post-study periods will not be included. In Section 15.3 AE 
tables (but not in Appendix 16.1.9.2.8.2 AE tables), the following totals will be provided in 
addition to the by treatment display:

a total over all active treatments during on-treatment phase, excluding placebo 
("Total BI")

a total over the on-treatment phase and placebo ("Total")
B) Low-level analysis (for Appendix 16.1.9.2.8.1 displays)
Results will be presented separately for the following phases:

Screening

On-treatment (labelled with the name of the study drug administered at the start of the 
on treatment phase)
In Section 16.1.9.2.8.1 AE tables, the following totals will be provided in addition:

a total over all active treatments during on-treatment phase, excluding placebo ("Total 
BI")

a total over all phases ("Total")


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Table 6.1: 1
Treatment Set-up
Treatment
Short label
A BI 655130, 
 iv
 iv
B BI 655130, 
 iv
 iv
C BI 655130,
 iv
 iv
I
Placebo, iv
Placebo
D BI 655130, 
 sc injection
 sc
S Placebo, sc injection
Placebo
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects in the 
database (i.e., treated subjects and subjects with serious AE (SAE) which the investigator 
considered related to the screening procedure). Consistency check listings (for identification 
of violations of time windows) and a list of protocol deviations (e.g. deviations in drug 
administration, in blood sampling times, etc.) will be provided to be discussed at the report 
planning meeting (RPM). At this meeting, it will be decided whether a discrepant data value 
can be used in analyses or whether it must be corrected in the clinical database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation (PV). For definition of important PVs, and for the process of identification of these, 
refer to the Boehringer Ingelheim reference document ‘Protocol Violation Handling 
Definitions’ (1). 
If any important PVs are identified, they are to be summarised into categories and will be 
captured in the RPM minutes via an accompanying Excel spreadsheet (2). The following 
table contains the categories which are considered to be important PVs in this trial. If the data 
show other important PVs, this table will be supplemented accordingly by the time of the 
RPM. If substantial numbers of PVs are reported at the RPM, a decision about summarising 
the PVs in a tabular format will be made. Otherwise, only a PV listing will be provided.
The following Table 6.2: 1 gives the important PVs for this trial.


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Table 6.2: 1
Important Protocol violations
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication administered
C2
Randomisation not followed
C3
Non-compliance
C4
Medication code broken inappropriately
C5
Incorrect administration of trial medication
D
Concomitant medication
D1
Prohibited medication use
E
Missing data
E1
Certain violations of procedures used to measure primary or secondary data
F
Incorrect timing
F1
Certain violations of time schedule used to measure primary or secondary data.


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6.3
SUBJECT SETS ANALYSED

Randomised set (RS):
This subject set includes all randomised subjects, whether treated or not.

Treated set (TS):
This set includes all subjects who were provided with study medication and were 
documented to have taken at least one dose. 
Section 7.3.1 of the CTP:
Plasma concentration data and parameters of a subject will be included in the statistical 
PK analysis 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 violation may be:

Incorrect trial medication administrated, i.e. the subject received at least one dose 
of trial medication the subject was not assigned to

Incorrect dose of trial medication administrated

Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

Missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the treated set who provide 
at least one PK parameter that was not excluded according to the description above.

Pharmacokinetic set (PKS):
The PKS includes all subjects in the treated subjects who provide at least one PK 
parameter that was not excluded according to the description above. 
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to populations will be made at latest at the RPM.
The following table summarises which subject sets will be used for the different analyses.


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Table 6.3: 1
Subject sets analysed
Class of endpoint
RS
TS
PKS
Disposition, exposure
X
Important PVs
X
Primary endpoints 
X
Secondary endpoints and further 
parameters of interest in PK analyses
X
Safety endpoints
X
Demographic/baseline endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects, who discontinued from the trial due to screening failures prior to 
administration of any trial medication, will not be included in the CTR except for those with 
SAEs which the investigator considered related to the screening procedures. The safety data 
of treated subjects who were withdrawn from the trial prematurely will be reported as far as 
available. All withdrawals will be documented and the reason for withdrawal recorded.
Handling of missing data is according to the CTP, Section 7.4. Additionally, handling 
information of missing data is shown as follows:

Missing data and outliers of PK data are handled according to (3).

Missing or incomplete AE dates are imputed according to BI standards (see ’Handling of 
missing and incomplete AE dates‘). (5)


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline values of laboratory data and vital signs for safety analysis will be defined as the 
last values before first drug infusion or administration. 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/database lock (DBL) meeting.


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7.
PLANNED ANALYSIS
In general, a set of descriptive statistics to be displayed for continuous variables in the 
clinical trial report will be as follows:
Non-pharmacokinetic variables:
For End-Of-Text tables, the set of summary statistics is: N, mean, standard deviation (SD), 
min, median, and max.
Tabulation of frequencies for categorical or categorised data will include all possible 
categories and display numbers of observations (subjects) with the percentage relative to the 
respective treatment sequence / regimen. Percentages will be rounded to one decimal place. 
The category ‘missing’ will be displayed if and only if there are actually missing values. 
Percentages will be based on all subjects in the respective subject set whether they have non-
missing values or not.
Pharmacokinetic variables:
The analysis of standard PK parameters will be performed according to (3).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics by group are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medication will be coded 
according to the most recent version of the World Health Organisation – Drug Dictionary.
A respective listing only is planned for this section of the report. The data will be summarised 
in total.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later
than at the RPM/DBLM.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of first administration of this treatment, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).


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7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete administration of the trial medication will be addressed in the RPM and described 
in the CTR.
7.4
PRIMARY ENDPOINT(S)
The analysis will be performed as defined in the CTP, Section 7.3.1.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
There are no key secondary endpoints in this trial.
7.5.2
(Other) Secondary endpoint(s)
The analysis will be performed as defined in the CTP, Section 7.3.2.
Exclusion of PK parameters:
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma concentrations:
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the 
value will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses.
Further details are given in (3, 4).


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7.7
EXTENT OF EXPOSURE
A respective listing only is planned for this section of the report.
7.8
SAFETY ANALYSIS
The analysis will be performed as defined in the CTP. All safety analyses will be performed 
on the TS.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA. The analyses of AEs will be 
descriptive in nature. All analyses of AEs will be based on the number of subjects with AEs 
and not on the number of AEs.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest (AESI))

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
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
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
For further details on summarisation of AEs data, please refer to (5, 6).
According to ICH E3 (7), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious with
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or


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(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a RPM/DBLM. 
An overall summary of AEs will be presented.
The frequency of subjects with AEs will be summarised by group, primary system organ 
class (SOC) and preferred term (PT) (MedDRA levels to be displayed in the tables). 
Separate tables will be provided for subjects with other significant AEs according to ICH E3 
(7), for subjects with drug-related AEs, for subjects with significant non-serious AEs (only if 
these were defined for the project) and for subjects with serious AEs. 
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and PT. The frequency of subjects with SAEs will also be 
summarised.
The SOCs will be sorted by default alphabetically. PTs will be sorted by frequency (within 
system organ class).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (8), descriptive statistics with original values will be provided by group for 
baseline, on-treatment values and for changes from baseline. Clinically relevant findings in 
laboratory data were to be reported as AEs and will be analysed as part of AE analysis. 
Laboratory values will be compared to their reference ranges and frequency tables will be 
provided for the number of subjects within and outside the reference range at baseline and the 
last measurement on treatment. Frequency tables for categorical laboratory values categorised 
by value at baseline and last value on treatment will be shown.
7.8.3
Vital signs
Only descriptive statistics by group and planned visit are planned for this section of the 
report. Clinically relevant findings in vital signs data were to be reported as AEs and will be 
analysed as part of AE analysis.
7.8.4
ECG
ECG data will not be listed but clinically relevant abnormal findings will be reported as AEs.
7.8.5
Others
 
 


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Physical examination 
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1
001-MCS-50-413_RD-01: "Protocol Violation Handling Definitions", current 
version; IDEA for CON.
2
001-MCS-50-413_RD-02: "Important Manual Protocol Violations Spreadsheet", 
current version; IDEA for CON.
3
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON;
4
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", current version; IDEA for CON;
5
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version IDEA for CON;
6
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", Version 5; IDEA for CON.
7
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
8
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
22-MAY-17
None
This is the initial TSAP with necessary 
information for trial conduct.
Final
01-FEB-18
Section 
5, 6 and 
7
Details for analysis are specified.