Clinical trial NCT03100903
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-04-24; Completion date: 2018-01-10
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the relative bioavailability of BI 655130 following subcutaneous administration (Test, T) compared to BI 655130 following intravenous infusion (Reference, R).

The secondary objective is the evaluation and comparison of several pharmacokinetic parameters between all tested treatments.

Detailed description:

Arms: arm 1: Subject received single low dose BI 655130 solution as subcutaneous (SC) injection on day 1. arm 2: Subject received single high dose BI 655130 solution as subcutaneous (SC) injection on day 1. arm 3: Subject received single high dose BI 655130 solution as 30 minutes intravenous (IV) infusion on day 1.
Interventions: intervention 1: BI 655130
Intervention descriptions: intervention 1: single dose

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c10896574-01
EudraCT No.:
BI Trial No.:
2016-004557-32
1368-0003
BI Investigational
Product:
BI 655130
Title:
Safety, tolerability, and pharmacokinetics of two dose strengths of a 
single subcutaneous dose of BI 655130 and one single intravenous 
dose of BI 655130 in healthy male and female subjects (open-label, 
parallel group design)
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:
Principal Investigator:
Phone:
Fax:
Status:
Final Protocol
Version and Date:
Version: 1.0
Date: 08 March 2017
Page 1 of 68
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:
Not applicable
08 March 2017
1368-0003
Title of trial:
Safety, tolerability, and pharmacokinetics of two dose strengths of a single 
subcutaneous dose of BI 655130 and one single intravenous dose of BI 655130 in 
healthy male and female subjects (open-label, parallel group design)
Principal 
Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability, and pharmacokinetics of two dose strengths of a 
single subcutaneous injection of BI 655130 and relative bioavailability of one 
strength of the subcutaneous formulation compared to an intravenous dose
Methodology:
Open-label, partially randomised design
No. of subjects: 
total entered:
36
each treatment:
12
Diagnosis:
Healthy subjects assigned to the intravenous dose will be matched for gender and 
body weight (± 10%) to subjects receiving the 
 subcutaneous dose
Main criteria
for inclusion:
Healthy male and female subjects, age of 18 to 50 years, body mass index (BMI) of 
18.5 to 29.9 kg/m2
Test product:
BI 655130
solution for injection 
dose:
and
[Test]
mode of admin.:
Subcutaneous (SC) injection (periumbilical)
Comparator 
product:
BI 655130 
 solution for infusion [Reference]
dose:
mode of admin.:
Intravenous (IV) as 30 min infusion
Duration of 
treatment:
One day (single dose) for each treatment


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BI Trial No.: 1368-0003
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Trial Protocol
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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:
Not applicable
08 March 2017
1368-0003
Criteria for
pharmacokinetics:
Primary endpoints: AUC0-tz and Cmax
Secondary endpoints: AUC0-  
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, local tolerability, safety laboratory tests, 12-lead electrocardiogram 
(ECG), continuous ECG monitoring, vital signs (blood pressure [BP], pulse rate
[PR]) and oral body temperature
Statistical methods:
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to 
the two one-sided t-tests procedure, each at the 5% significance level. Since the 
main focus is on estimation and not testing, an acceptance range was not specified. 
The statistical model will be an ANOVA on the logarithmic scale including effects 
for ‘treatment’. CIs will be calculated based on the residual error from ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Single dose of BI 655130 as 
 SC, 
 SC or single IV infusion of 
 of 
BI 655130 (subjects will receive only one dose)
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma
4
Laboratory/
Urinalysis 3
Body Temperature
Body Weight
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies11
1
-28
to -3
screening1
X
X
X
X
2
-2
-48:00
8:00
ambulatory visit
X13
2
-1
-12:00
20:00
admission to
trial site
X10
X
1
-2:00
6:30
X2
X2,9
X2
X2
X2
X2,5
0:00
8:00
drug administration
start of infusion
or SC injection
▲
│
0:30
8:30
▼
end of infusion14
X
X
X
│
X
X5
1:00
9:00
│
X
1:30
9:30
X
│
│
X
2:00
10:00
light breakfast6
X
X
X
▼
X
2:30
10:30
3:00
11:00
X
X
4:00
12:00
Lunch6
X
X9
X
X5
6:00
14:00
X
X
X
8:00
16:00
snack (voluntary)6
X
X
10:00
18:00
Dinner6
12:00
20:00
X
X
X
X
X5
2
24:00
8:00
Breakfast6
X
X9
X
X
X
X5
28:00
12:00
Lunch6
32:00
16:00
snack (voluntary)6
X
X
34:00
18:00
Dinner6
X5
3
48:00
8:00
Breakfast6
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
6
120:00
8:00
ambulatory visit
X
X5
7
144:00
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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1.
Screening with subject information, informed consent as the first measure, includes physical examination, check of 
vital signs, ECG, safety laboratory (under fasting conditions), pregnancy test, 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; procedures are to be performed and completed within 3 h prior to drug administration. 
Within 3 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), and drug screening.
4.
PK sampling times may be adapted based on information obtained during trial conduct.
5.
Standardized assessment of local tolerability only for subcutaneous injection using the criteria swelling, induration, 
heat, redness, pain or other findings. 
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. 
At baseline, cytokine (IL1, IL6, TNF-and IFNsamples will be collected together with safety lab. Additional 
cytokine samples IL1, IL6, TNF-and IFNwill be collected at 4 h and 24 h post-dose. Cytokine samples are 
only to be analysed from an individual subject in case of specific adverse events in this subject that are suggestive 
for a cytokine release. At 4 h and 24 h post-dose no safety lab needs to be taken.
10.
Only drug screening and alcohol breath test.
11.
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.
12.
EOT (End of trial examination) includes physical examination, body weight, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. EOT to be performed not before last PK and ADA sampling. 
13.
Safety laboratory is to be taken within two days prior to study drug administration and can be omitted if the
screening examination is performed between Day -5 and Day -3.
14.
First measure after completion of infusion is the collection of PK sample
15.
In case plasma levels still exceed LOQ additional PK samples may be collected beyond Day 176 ±3.
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
Body Weight
12-lead ECG
ECG monitoring
vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies11
2
22
504:00
8:00
ambulatory visit
X
X
X
X
X
29
672:00
8:00
ambulatory visit
X
X
X
X
X5
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
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
148 ±3
3528:00
8:00
ambulatory visit
X
3
176 ±3 
4200:00
8:00
EOT12
X15
X
X
X
X
X
X5


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................14
1.2.1
Nonclinical pharmacology....................................................................14
1.2.2
Safety pharmacology ............................................................................15
1.2.3
Toxicology..............................................................................................15
1.2.4
Nonclinical pharmacokinetics..............................................................16
1.2.5
Clinical experience................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 21
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................21
2.2
TRIAL OBJECTIVES.......................................................................................21
2.3
BENEFIT - RISK ASSESSMENT ...................................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 25
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................25
3.1.1
Administrative structure of the trial...................................................26
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................26
3.3
SELECTION OF TRIAL POPULATION ......................................................27
3.3.1
Main diagnosis for study entry............................................................27
3.3.2
Inclusion criteria...................................................................................27
3.3.3
Exclusion criteria ..................................................................................28
3.3.4
Removal of subjects from therapy or assessments.............................29
3.3.4.1
Removal of individual subjects................................................29
3.3.4.2
Discontinuation of the trial by the sponsor..............................30
3.3.5
Replacement of subjects .......................................................................30
4.
TREATMENTS........................................................................................ 31
4.1
TREATMENTS TO BE ADMINISTERED....................................................31
4.1.1
Identity of BI investigational product and comparator product......31
4.1.2
Method of assigning subjects to treatment groups ............................31
4.1.3
Selection of doses in the trial................................................................32
4.1.4
Drug assignment and administration of doses for each subject .......32
4.1.5
Blinding and procedures for unblinding ............................................33


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4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................34
4.1.8
Drug accountability ..............................................................................34
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................35
4.2.1
Other treatments and emergency procedures....................................35
4.2.2
Restrictions............................................................................................35
4.2.2.1
Restrictions regarding concomitant treatment .........................35
4.2.2.2
Restrictions on diet and life style.............................................35
4.3
TREATMENT COMPLIANCE.......................................................................36
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 37
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................37
5.1.1
Endpoints of efficacy.............................................................................37
5.1.2
Assessment of efficacy...........................................................................37
5.2
SAFETY..............................................................................................................37
5.2.1
Endpoints of safety................................................................................37
5.2.2
Assessment of adverse events...............................................................37
5.2.2.1
Definitions of adverse events...................................................37
5.2.2.2
Adverse event collection and reporting ...................................40
5.2.3
Assessment of safety laboratory parameters......................................42
5.2.4
Electrocardiogram................................................................................45
5.2.4.1
12-lead resting ECG................................................................45
5.2.4.2
Continuous ECG monitoring and oxygen monitoring.............45
5.2.5
Assessment of other safety parameters...............................................46
5.2.5.1
Vital signs ................................................................................46
5.2.5.2
Medical examinations..............................................................46
5.2.5.3
Local tolerability......................................................................46
5.2.5.4
Oral body temperature .............................................................46
5.3
OTHER...............................................................................................................46
5.3.1
Pharmacogenomic evaluation..............................................................46
5.3.2
Other endpoints.....................................................................................46
5.3.3 Other assessments .................................................................................46
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................46
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................47
5.5.1
Pharmacokinetic endpoints..................................................................47
5.5.1.1
Primary endpoints....................................................................47
5.5.1.2
Secondary endpoint..................................................................47
5.5.2
Methods of sample collection...............................................................48
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................48


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5.5.3
Analytical determinations ....................................................................49
5.5.3.1
Analytical determination of BI 655130 plasma concentration 49
6.
INVESTIGATIONAL PLAN.................................................................. 50
6.1
VISIT SCHEDULE............................................................................................50
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 period.................................................................................51
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 52
7.1
STATISTICAL DESIGN – MODEL ...............................................................52
7.1.1
Objectives...............................................................................................52
7.1.2
Endpoints...............................................................................................52
7.1.3
Model......................................................................................................52
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................53
7.3
PLANNED ANALYSES....................................................................................53
7.3.1
Primary analyses...................................................................................53
7.3.2
Secondary analyses ...............................................................................54
7.3.3
Safety analyses.......................................................................................54
7.3.4
Interim analyses ....................................................................................55
7.3.5
Pharmacokinetic analyses ....................................................................55
7.4
HANDLING OF MISSING DATA ..................................................................55
7.4.1
Safety......................................................................................................55
7.4.2
Plasma drug concentration - time profiles..........................................55
7.4.3
Pharmacokinetic parameters...............................................................55
7.5
DETERMINATION OF SAMPLE SIZE ........................................................56
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 57
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................57
8.2
DATA QUALITY ASSURANCE .....................................................................57
8.3
RECORDS..........................................................................................................58
8.3.1
Source documents .................................................................................58
8.3.2
Direct access to source data and documents.......................................58
8.3.3
Storage period of records.....................................................................58
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................58
8.5
STATEMENT OF CONFIDENTIALITY.......................................................59
8.6
COMPLETION OF TRIAL..............................................................................59
9.
REFERENCES......................................................................................... 60


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9.1
PUBLISHED REFERENCES...........................................................................60
10. APPENDICES .......................................................................................... 62
10.1
CLINICAL EVALUATION OF LIVER INJURY .........................................62
10.1.1 Introduction...........................................................................................62
10.1.2 Procedures .............................................................................................62
10.2
PREPARATION AND HANDLING OF BI 655130 SOLUTION FOR 
INFUSION 
 AND BI 655130 SOLUTION FOR INJECTION 
.........................................................................................................64
10.2.1 Preparation Instructions for BI 655130 
 dose 
(concentration 
.......................................................................64
10.2.2 Infusion instructions.............................................................................65
10.2.3 Preparation Instructions 
 SC dose ...........................................66
10.2.4 Preparation Instructions 
 SC Dose..........................................67
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 68


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ABBREVIATIONS
5-ASA
5-aminosalicylic acid
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine amino transferase
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
 
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
b.w.
Body weight
CA
Competent authority
CD
Crohn’s Disease
CI
Confidence interval
 
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CRO
Clinical Research Organization
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Coefficient of variation
DILI
Drug induced liver impairment
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
GMP
Good Manufacturing Practice
GPP
Generalized pustular psoriasis
HBV
Hepatitis B virus
HCV
Hepatitis C virus


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HIV
Human Immunodeficiency Virus
IB
Investigator’s brochure
IBD
Inflammatory bowel diseases
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IFN
Interferon
IL36R
Interleukin 36 receptor
IPF
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
ITE
Indirect target engagement
IV
Intravenous
KO
Knock out
LLOQ
Lower Limit of Quantification
LOQ
Limit of Quantification
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MIP
Macrophage inflammatory protein
MMP
Matrix metalloproteinase
MRD
Multiple rising dose
 
N
Number
NC
Not calculated
NF-B
Nuclear factor kappa-light-chain-enhancer of activated B cells
NOA
Not analysed
NOAEL
No observed adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PBMC
Peripheral blood mononuclear cells
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Subject set for the evaluation of PK endpoints
PPP
Palmoplantar pustulosis
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
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual effect period
RPM
Report Planning Meeting
RR
Riva Rocci
SAE
Serious adverse event


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SCR
Screening
SOP
Standard Operating Procedure
SSc
systemic sclerosis
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
WBC
White Blood Cells


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody blocking IL36α, IL36β,
and IL36γ by binding to IL36R. The IL36 pathway has been associated with the pathogenesis 
of several inflammatory diseases including generalized pustular psoriasis (GPP) and psoriasis 
vulgaris. Emerging preclinical data suggest that IL36R is a potential target for the treatment 
of inflammatory bowel diseases.
Genetic human studies have established a strong link between IL36R signaling and skin
inflammation as demonstrated by the occurrence of generalized pustular psoriasis in patients 
with a loss of function mutation in IL36Rthe gene encoding the endogenous inhibitor of 
IL36R, which resulted in uncontrolled IL36R signaling [R15-1421]; [R14-5158] .
IL36R has been discovered as a target for psoriasis based on (I) the abundant expression of
all three stimulating ligands in human psoriatic lesional skin as reviewed by Towne and Sims 
[R14-4037], (II) IL36α overexpression in murine keratinocytes inducing a psoriatic-like 
phenotype [R15-1432], (III) IL36R KO mice protecting against Imiquimod-induced skin 
inflammation [R15-1447] and (IV) IL36R blockade ameliorating skin inflammation in a 
transplanted psoriatic skin model [R15-1399].
The link between IL36R-driven inflammation and epithelial inflammation has led to the
hypothesis that IL36R signaling may play an important role in inflammatory bowel diseases.
This hypothesis was tested using a series of in vitro and in vivo assays. Immunostaining
studies demonstrated that both IL36R and its ligands are expressed in intestinal biopsies from
Crohn’s disease patients. Human IL36 ligands enhance intestinal barrier permeability, a
hallmark of IBD pathogenesis, in primary human intestinal epithelial cells co-cultured with 
intestinal myofibroblasts. The link between IL36R signaling and IBD was further strengthen 
by demonstrating that antagonist anti-mouse IL36R antibodies ameliorated intestinal 
inflammation in both acute chemically induced and chronic T cell driven murine colitis 
models. 
The therapeutic rational for an IL36R antagonist in IBD is further based on the correlation of 
a set of IL36-induced genes upregulated in primary human intestinal myofibroblasts, a 
disease relevant cell type, with gene signatures observed in ulcerative colitis and Crohn´s 
disease patients. Finally, IL36R signaling in disease relevant cells, such as intestinal 
myofibroblasts and macrophages, induces both pro-inflammatory and tissue remodeling 
related mediators (e.g. TGF-β, MMPs), which differentiates this mechanism from TNF-and 
IL23 pathways.
Altogether, these findings support a prominent role for IL36R in driving intestinal 
inflammation and position anti-human IL36R antibody BI 655130 as a first in class 
therapeutic for IBD and other epithelial-mediated inflammation such as systemic sclerosis 
(SSc) or idiopathic pulmonary fibrosis (IPF). The therapeutic effect on GPP and PPP is also 
under evaluation; detailed background is provided in the IB [c03320877-02].


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Crohn’s Disease (CD) is a chronic relapsing, remitting inflammatory disease of the 
gastrointestinal tract characterised by abdominal pain, fever, and bloody or mucus-containing 
diarrhoea [R13-2231]. The mainstay of treatment for moderate to severe CD has been with
glucocorticoid therapy, azathioprine, or 6-mercaptopurine [R13-2269]. More recently, 
biologics consisting of monoclonal antibodies directed at cytokines, thought to mediate the 
pathology, have been used extensively for this indication.
Ulcerative colitis (UC) has an estimated incidence of 1.2 to 20.3 cases per 100,000 persons 
per year, and a prevalence of 7.6 to 246.0 cases per 100,000 per year [R15-1343]. Like CD, 
UC is characterised clinically by abdominal pain, fever, and bloody or mucus-containing 
diarrhoea, and pathologically by inflammatory lesions in the gastrointestinal mucosa. UC 
differs from CD by the distribution of lesions, which in UC characteristically occur distal to 
the terminal ileum, and by the confinement of lesions to the mucosa and submucosa without 
transmural inflammation. Similar to CD, UC typically follows a relapsing and remitting 
course, and is associated with substantial acute and long-term morbidity and increased 
mortality. The mainstays of drug therapy for UC are the orally administered aminosalicylates, 
glucocorticoids, the oral immunomodulatory agents azathioprine and 6-mercaptopurine, and 
the biologic TNF antagonists. In patients with mild UC, 5-ASAs are a safe and effective
therapy. Glucocorticoids, immunomodulators, TNF antagonists, and more recently 
vedolizumab, an integrin α4β7 blocker, are reserved for patients with moderate to severe 
disease, in whom the primary goals of drug therapy are to induce and subsequently to 
maintain remission from signs and symptoms of active disease.
Treatment of CD and UC is associated with a significant number of patients with primary and 
secondary non-response. In addition, treatment may be limited due to safety and tolerability 
issues. Therefore, despite therapeutic progress, there remains a significant unmet medical 
need for new treatment options with an improved safety and efficacy profile compared to the 
current therapeutic standard.
1.2
DRUG PROFILE
1.2.1
Nonclinical pharmacology
BI 655130 is a humanized monoclonal IgG1 antibody (mAb) against human IL36R. To
minimize Fc effector functions, leucines at position 234 and 235 of the heavy chain were
mutated to alanine. The BI 655130 molecule is a heterodimer with a molecular weight of
approximately 146 kDa. Each heterodimer is composed of a heavy chain (449 amino acids)
and a light chain (215 amino acids). The four polypeptide chains of the antibody are linked
together by disulphide bonds. Each heavy polypeptide chain contains one consensus sequence 
for N-linked glycosylation. BI 655130 blocks IL36α-, IL36 β- and IL36 γ-induced signaling 
by binding to the IL36 receptor.
The functional inhibition of IL36-stimulated NF-B activation by BI 655130 was tested with
all three potent stimulating IL36R ligands on several human cell types, notably HT29 and
NCI/ADR-RES transformed epithelial cells, primary human keratinocytes, primary human
dermal fibroblasts, and primary human intestinal myofibroblasts. All cell types showed IC90
values of inhibition by BI 655130 in a consistent range of 0.7 to 3.7 nM. BI 655130 also


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inhibits IL8 release with identical potency in human NCI/ADR-RES cells, keratinocytes, and 
intestinal myofibroblasts.
BI 655130 was also evaluated in a primary human peripheral blood mononuclear cells 
(PBMC) assay. Isolated human PBMC stimulated with IL36α, IL36β, or IL36γ show a 
synergistic induction of IFNγ secretion when combined with IL12, as exemplified for IL36β 
(please see IB, c03320877-02). Similar findings were observed in mouse splenocytes where
murine IL36 plus IL12 induced a synergistic production of IFN-γ (please see IB, 
c03320877-02), suggesting that the pathways utilized by IL36 to drive inflammatory cytokine 
production are conserved between mouse and human systems. These effects can be blocked
by BI 655130 and BI 674304 in human and mouse assays, respectively (please see IB, 
c03320877-02). Of note, BI 655130 alone does not stimulate cytokine production in human
PBMC, indicating that BI 655130 has a low potential to cause cytokine release. Neither the
addition of BI 655130 directly to whole blood or pre-bound to plastic (to mimic the effects of
mAb crosslinking) resulted in specific cytokine release.
For a more detailed description of the BI 655130 profile please refer to the current
Investigator’s Brochure (IB) [c03320877-02].
1.2.2
Safety pharmacology
Specific safety pharmacology studies have not been conducted with BI 655130 as it is not 
pharmacologically active in common toxicology species. Instead, studies were performed 
with BI 674304, the mouse specific anti-IL36R monoclonal antibody and used as a surrogate 
for BI 655130 (please see also Section 1.2.3). There were no clinical signs of toxicity in mice 
after the 13-week administration [c03320877-02].
1.2.3
Toxicology
As BI 655130 does not demonstrate sufficient cross-reactivity to IL36R from common 
toxicology species, including non-human primates, in vivo toxicity studies were not 
conducted. Instead, the potential adverse effects of IL36R antagonism were assessed in 
toxicity studies in mice using a mouse specific anti-IL36R monoclonal antibody (BI 674304).  
In addition, a human tissue cross-reactivity study and an in vitro cytokine release assay have 
been conducted with the clinical candidate BI 655130. Finally, the local tolerance of 
subcutaneous injections of BI 655130 has been evaluated in rabbits.
In a 13-week intravenous toxicity study of BI 674304 in mice, no adverse effects of IL36R 
antagonism were seen at a dose (
, twice weekly) that was 5-fold higher than the 
dose that was protective in an experimental mouse colonic inflammation model. In addition, 
in an embryo-fetal toxicity study, there was no evidence of effects on fetal growth or 
dysmorphogenesis (teratogenicity) in mice after administration of 
/dose of 
BI 674304 during gestation. The in vitro cytokine release and tissue cross-reactivity assays 
demonstrate that the risk of transient cytokine release in humans is low and that, as expected, 
BI 655130 stains epithelium in a variety of tissues. There were no signs of local irritation 
after single, 
 injections of the subcutaneous formulation in rabbits. These preclinical 
data suggest that BI 655130 can be safely administered to humans for up to 13 weeks.


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For a more detailed description of the BI 655130 profile please refer to the current
Investigator’s Brochure (IB) [c03320877-02].
1.2.4
Nonclinical pharmacokinetics
The pharmacokinetics of BI 655130 was studied in cynomolgus monkeys. In mice, 
pharmacokinetic studies were performed with the mouse-specific anti-IL36R antibody, 
BI 674304 [c03320877-02].
1.2.5
Clinical experience
BI 655130 has been evaluated in two clinical trials: a first-in-human (FIH) SRD trial (1368.1, 
completed) and a MRD trial (1368.2, on-going).
The FIH (first-in-human) trial [c09985235-01] was conducted according to a single-blind,
partially randomised, single rising dose and placebo-controlled (within dose groups) 
design.The study explored safety, tolerability, pharmacokinetics, and pharmacodynamics of
intravenously administered BI 655130 in healthy male subjects. Subjects received single 
ascending IV doses of
, to
 body weight or placebo. Overall, the study 
included 78 male subjects with 58 subjects treated with BI 655130 and 20 subjects treated 
with placebo.
Trial 1368.2 [c09105854-04] explored the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising intravenous doses of BI 655130 in a double-blind, 
partially randomised within dose groups, placebo-controlled, parallel group design and of one 
single intravenous dose of BI 655130 in a single-blind, partially randomised, placebo-
controlled design. A total of 32 healthy male subjects were randomised to 4 sequential groups 
comprising 8 subjects per group. The study consisted of a multiple dose part with three dose 
groups 
and 
 and a single dose arm 
 Within each 
dose group, 6 subjects received the active drug and 2 received placebo. Subjects assigned to 
the multiple dose part received single intravenous doses within 4 weeks (on Day 1, Day 8, 
Day 15, and Day 22). The study is still ongoing, though treatment of all four dose groups has 
been completed.
Safety and tolerability
In the FIH study [c09985235-01], 49 of 78 subjects (62.8%) reported at least 1 treatment-
emergent AE (TEAE). This included 36 of 58 subjects (62.1%) following administration of 
BI 655130 and 13 of 20 subjects (65.0%) following administration of placebo. There was no 
apparent relationship between the frequency of AEs and the dose. AEs categorised as related 
to treatment were observed in 3/20 (15.0%) subjects in the placebo group and in 8/58 (13.8%) 
subjects treated with BI 655130.
Treatment-emergent AEs were reported most frequently in the system organ classes 
'infections and infestations' (BI 655130: 14/58 subjects [24.1%]; placebo: 3/20 subjects 
[15.0%]), 'general disorders and administration site conditions' (BI 655130: 9/58 subjects 


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[15.5%]; placebo: 2/20 subjects [10.0%]), 'gastrointestinal disorders' (BI 655130: 7/58 
subjects [12.1%]; placebo: 4/20 subjects [20.0%]), 'musculoskeletal and connective tissue 
disorders' (BI 655130: 5/58 subjects [8.6%]; placebo: 3/20 subjects [15.0%]), and 'nervous 
system disorders' (BI 655130: 5/58 subjects [8.6%]; placebo: 3/20 subjects [15.0%]).
At preferred term level, the most frequently reported treatment-emergent AEs were 
nasopharyngitis (BI 655130: 12/58 subjects [20.7%]; placebo: 3/20 subjects [15.0%]), 
headache (BI 655130: 5/58 subjects [8.6%]; placebo: 3/20 subjects [15.0%]), influenza like
illness (BI 655130: 4/58 subjects [6.9%]; placebo: 2/20 subjects [10.0%]), and diarrhoea 
(BI 655130: 2/58 subjects [3.4%]; placebo: 2/20 subjects [10.0%]).
There were two AEs of moderate intensity, both considered non related to the study drug, 
(injection site hematoma, headache); all remaining AEs were of mild intensity. 
There were no relevant changes compared to placebo for laboratory safety, including clinical 
chemistry, hematology, coagulation parameters, and urinalysis. No clinically relevant 
changes were observed in 12 lead ECGs, vital signs, physical exams and cardio-monitoring.
Based on a preliminary evaluation of Trial 1368.2, 27 of 32 subjects (84.4%) reported at least 
1 TEAE. The frequency of subjects with AEs was similar in subjects treated with
BI 655130 (range 66.7% to 100%) and placebo (87.5%). AEs categorised as related to 
treatment were observed in 11 of the 32 subjects (34.4%) overall (BI 655130 groups: 16.7% 
to 66.7%; placebo: 25.0%); Table 1.2.5: 1. 
Table 1.2.5: 1
Frequency [N (%)] of subjects with related adverse events by 
treatment and preferred term (Trial 1368.2)
Placebo
MD*
MD*
MD*
SD**
Number of subjects (%)
8 (100.0)
6 (100.0)
6 (100.0)
6 (100.0)
6 (100.0)
Total with related AEs
2 (25.0)
1 (16.7)
4 (66.7)
2 (33.3)
2 (33.3)
Abdominal discomfort
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Diarrhoea
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Nausea
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
Injection site reaction
1 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Fatigue
1 (12.5)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
Malaise
0 (0.0)
1 (16.7)
0 (0.0)
0 (0.0)
0 (0.0)
Headache
0 (0.0)
0 (0.0)
2 (33.3)
1 (16.7)
1 (16.7)
Dermatitis acneiform
0 (0.0)
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
Rash macular
0 (0.0)
0 (0.0)
1 (16.7)
0 (0.0)
1 (16.7)
* 
Multiple dose 
** 
Single dose


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Treatment-emergent AEs were reported most frequently in the system organ class 'general 
disorders and administration site conditions' (overall: 20/32 subjects [62.5%], BI 655130 
groups: 50.0% to 66.7%, placebo: 75.0%). At preferred term level, the most frequently 
reported treatment-emergent AEs were injection site erythema (overall: 9/32 subjects 
[28.1%], BI 655130 groups: 0.0% to 50.0%, placebo: 25.0%), nasopharyngitis (overall: 
7/32 subjects [21.9%], BI 655130 groups: 16.7% to 33.3%, placebo: 12.5%), and headache
(overall: 7/32 subjects [21.9%], BI 655130 groups: 16.7% to 33.3%, placebo: 12.5%).
BI 655130 was well tolerated in Trial 1368.2. There were no AEs considered to be dose 
limiting, no dose dependency, and no SAEs. All subjects completed the treatment per 
protocol. In all cases, the AEs were of mild intensity and resolved without further measures.
Based on the preliminary evaluation, there were no clinically relevant abnormalities on 
treatment with BI 655130 with respect to safety laboratory, ECG, and vital signs.
Pharmacokinetics
Trial 1368.1 PK parameters of BI 655130 after a single IV infusion are shown in 
Table 1.2.5:2. BI 655130 levels were first detected at a dose level of 
. AUC0-inf
results should be considered for informational purposes only given the high %_AUC of 
extrapolated values (>50%) for the 
 dose groups. Exposure in terms of AUC0-
tz and Cmax of BI 655130 increased with increasing dose in a greater than dose-proportional 
manner from 
 and in a dose-proportional manner from 
 
. In the higher dose groups with apparent linear PK characteristics 
 
the half-life (t1/2) of BI 655130 was in the range of 20.4 to 33.9 days. However, because of 
the relatively short sampling time, these values should be considered an estimate only.
Overall, PK data suggest target-mediated drug disposition (TMDD) kinetics for 
BI 655130. 


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Table 1.2.5: 2
Geometric mean (geometric CV%) PK parameters of BI 655130 after
a single IV infusion (Trial 1368.1)
Dose Group#
#1
#2
#3
#4
#5A
#5
Dose
N=6
N=6
N=4
N=6
N=3
N=5
AUC0-tz
[μg·day/mL]
NC
NC
0.00652 (121)
2.08 (29.0)
9.57 (5.90)
25.1 (15.5)
AUC0-inf
[μg·day/mL]
NC
NC
0.0234 (125)
2.35 (23.9)
13.0 (6.59)
27.7 (16.6)
Cmax [µg/mL]
NC
NC
0.0228 (33.5)
0.413 
(21.2)0.413 
(21.2)
0.998 (15.7)
(15.7)
1.96 (11.9)
Dose Group#
#6
#7
#8
#9
#10
Dose
N=4
N=6
N=6
N=6
N=4
AUC0-tz
[μg·day/mL]
113 (5.86)
420 (13.3)
1050 (7.26)
2610 (11.7)
4130 (12.1)
AUC0-inf
[μg·day/mL]
127 (6.05)
563 (26.2)
1260 (6.81)
3380 (15.6)
5080 (18.9)
Cmax [µg/mL]
6.63 (3.28)
20.3 (13.6)
60.6 (7.17)
153 (12.7)
235 (2.79)
In the MRD Trial 1368.2, preliminary PK data up to 5 weeks are available for the  and 
 dose groups (Table 1.2.5: 3). Exposure of both dose groups is in the linear dose 
range; PK evaluation of the remaining dose groups is on-going. 
Table 1.2.5: 3
Preliminary geometric mean (geometric CV%) PK parameters of 
BI 655130 after multiple IV dosing on Days 1, 8, 15, and 22
(Trial 1368.2)
Dose
N=6
[Day 1]
0-168 h
N=6
[Day 8]
168-336 h
N=6
[Day 15]
336-504 h
N=6
[Day 22]
504-672 h
AUC0-t
(µg·day/mL)
311 (10.5)
563 (6.3)
742 (7.1)
865 (8.8)
Cmax
(µg/mL)
72.2 (22.0)
107 (5.9)
132 (7.2)
156 (8.2)
Dose
N=6
[Day 1]
0-168 h
N=6
[Day 8]
168-336 h
N=6
[Day 15]
336-504 h
N=6
[Day 22]
504-600 h
AUC0-t
(µg·day/mL)
652 (5.1)
919 (4.6)
1540 (5.8)
1080 (5.6)
Cmax
(µg/mL)
140 (11.3)
183 (7.0)
277 (6.1)
323 (7.3)


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Pharmacodynamics
Pharmacodynamic effects in Trials 1368.1 (SRD) and 1368.2 (MRD) were assessed by
indirect target engagement (ITE) of IL36R by BI 55130 using an ex-vivo whole blood
stimulation assay. Whole blood was taken before and after treatment of subjects with BI
655130 or placebo and stimulated with IL36γ ligand. After preparation of plasma, the
resulting production of macrophage inflammatory protein (MIP)-1β was quantified via an
immunoassay as an exploratory biomarker. MIP-1β levels are expected to inversely correlate
with the level of IL36R engagement by BI 655130.
In the single rising dose trial (1368.1), doses of 
 and above showed percent inhibition 
of MIP-1β of at least 94% as compared to baseline during the entire time course up to 1680 h. 
Furthermore, in the interim analysis of ITE  in the multiple rising dose trial (1368.2) for dose 
groups evaluated so far, the inhibition of MIP-1β was at least 91% as compared to baseline 
during the entire time course up to 672 h for 
 and 
 dose groups as compared 
to placebo. This demonstrates that BI 655130 is on-target for the time points analyzed.
For a more detailed description of the BI 655130 profile please refer to the current
Investigator’s Brochure (IB) [c03320877-02].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
BI 655130 is in development for the treatment of GPP, PPP, CD, and UC. BI 655130 is 
currently in Phase I development.
Recently, a FIH trial has been completed (see Section 1.2.5) that explored safety, tolerability, 
pharmacokinetics, and pharmacodynamics of BI 655130 following IV infusions of single 
rising doses of 
 up to 
 body weight in a healthy male population. 
BI 655130 was safe and well tolerated. A second Phase I trial investigating multiple 
intravenous doses is ongoing (Trial 1368.2, c09105854-04).
BI 655130 was administered as intravenous infusion in the initial Phase I studies; however, a 
subcutaneous injection formulation is planned for upcoming studies to support self-
administration by the patient. The current study is designed to examine the characteristics of 
the newly developed subcutaneous formulation with particular focus on relative 
bioavailability compared to an intravenous formulation and local tolerability.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the relative bioavailability of 
 of 
BI 655130 following subcutaneous administration (Test, T) compared to 
 of 
BI 655130 following intravenous infusion (Reference, R).
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between all tested treatments
 BI 655130 SC, 
 BI 655130 SC, and 
 BI 655130 IV).
The assessment of safety and tolerability, including the standardised assessment of local 
tolerability, will be an additional objective of this trial.
A description of the endpoints to be determined, and the observations along with specific 
information on how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to investigate a newly developed 
subcutaneous formulation which is considered crucial for long-term studies in patients. The 
subjects are exposed to the risks of the study procedures and the risks related to the exposure 
to the trial medication.


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Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. The same applies for further blood sampling and subcutaneous administration of 
study drug. In rare cases a nerve might be injured while inserting the venous catheter/ 
cannula, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation 
 No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
BI 655130 does not bind to IL36R from common toxicology species. Therefore, the mouse 
reactive mAb, BI 674304, was used to characterize the potential effects of IL36R antagonism 
in vitro and in vivo. The decision to conduct toxicity studies with a mouse reactive 
monoclonal antibody was based on the ICH S6 (R1) guidance and took into account the 
sequence homology and in vitro binding and activity assays. Binding/biologic activity is
insufficient in common toxicology species to adequately evaluate the potential toxicities 
related to IL36R antagonism with BI 655130. It is anticipated that the degree of biologic 
activity is more important for assessing potential toxicity related to exaggerated 
pharmacology than binding affinity. 
The clinical safety and tolerability profile of intravenous single doses of BI 655130 was
comparable to placebo in male subjects with intravenous single doses up to 
 body 
weight. There were no withdrawals for adverse events or abnormal laboratory values. There 
were no deaths or other serious adverse events. The adverse events reported had no apparent 
dose or exposure relationship. There were no dose or exposure related abnormalities in safety 
laboratory parameters and no safety or tolerability concerns that would preclude further 
clinical development of BI 655130.
Nonclinical studies support repeat-dose clinical trials of up to 13 weeks duration. In a 
13-week intravenous toxicity study of BI 674304 in mice, no adverse effects of IL36R 
antagonism was seen at a dose 
 twice weekly) that was 5-fold higher than the dose 
that was protective in an experimental mouse colonic inflammation model. 
For the first trial with the new subcutaneous formulation, a maximum dose of 
 
 injection volume) was selected. This dose is significantly lower than the maximum 
tested intravenous single dose of 
 in the previous single rising dose study and 
considered to be safe (see Section 1.2.5). The same is true for the other planned doses of 
 SC and 
 IV.


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Based on the preceding FIH study, no specific drug-related risks are anticipated. 
Nevertheless, the following safety measures are/will be applied in this study in order to 
minimize the risk for the healthy subjects:

Careful dose selection based on data from the completed FIH study; the exposure of 
any dose of BI 655130 in the current study is projected to be below the highest 
exposure observed in the FIH study

For safety reasons, the study will start with the lowest SC dose of 
 of 
BI 655130. The dose group will be divided into 2 cohorts: on the first study day, 
6 subjects will be treated, with an interval between the injections of at least 15 min. 
The second cohort will be treated at least 48 h apart. There will be an interval of at 
least 1 week after the first dosing in the 
 SC dose group before the start of the 
 SC or IV dose groups in a randomised sequence (in one week 6 subjects on 
IV and 6 subjects on SC and in the following week again 6 + 6) Nomore than 2 
subjects should simultaneously receive an infusion. At any time during the ongoing 
study, further dosing will be stopped in case of safety and tolerability concerns based 
on the criteria defined in Section 3.1

Dose escalation will be shallow (2-fold dose escalation step). In addition, a time 
interval of at least 7 days will be maintained between the first dosing of 
 of 
BI 655130 SC and the first dosing of 
 of BI 655130 SC or IV. An interval of 
one week between the dose groups is expected to cover the period of highest risk / 
peak effect. The decision to proceed to the next dose will be based upon the safety 
and tolerability of the preceding dose. The next dose will only be given if no safety 
concerns arise in the previous dose group (i.e. no dose-limiting events occur) and if 
none of the pre-specified trial-specific stopping criteria are met (see Section 3.3).

The dose will only be escalated if previously approved by the Principal Investigator 
(or an authorised deputy) and the trial clinical monitor (or an authorised deputy) after 
in-depth analysis of all available safety data (see Section 3.1)

Monitoring of ECG and vital signs is incorporated, with continuous ECG monitoring 
over 1.5 hour post dose after each drug administration, the anticipated period of 
highest drug exposure. As an additional measure, repeated single 12-lead ECGs are 
scheduled in the further course of the study. The rationale for the intensified ECG 
monitoring is not an expected increased risk of BI 655130 mediated effects on cardiac 
repolarization 

Extensive safety laboratory testing will be performed (Table 5.2.3:1)

After each dosing, the subjects will stay at the site for at least 48 hours following drug 
administration

While admitted to the trial site, the subjects will be under close medical observation 
and thoroughly monitored for both expected and unexpected adverse events

With IV administration, treatment with BI 655130 can be immediately discontinued,
should any safety concern arise (please refer to Section 4.1.4)

BI 655130 will be administered in a hospital setting and subjects will be under close 
medical observation during their hospitalisation (see Section 6.2), as well as after their 
discharge and until the end of observation period. Safety will be closely monitored 
during site visits
Currently there are no data available to suggest interactions of BI 655130 [c03320877-02].


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Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of alterations in selected liver laboratory parameters to ensure subjects´ safety.
As an antagonist of IL36R, BI 655130 affects a target of the immune system that is
ubiquitously expressed. Due to the antagonistic effect, it is considered unlikely that 
BI 655130 may lead to an amplification of an effect that might not be sufficiently controlled 
by a physiologic feedback mechanism. In addition, preclinical investigations and the 
completed FIH trial did not suggest cytokine release induced by BI 655130.  
Based on the preclinical and initial clinical information for BI 655130, healthy subjects are 
not expected to be exposed to undue risks and adverse events in relation to the information 
expected from this trial. Considering the medical need for the development of an effective 
and well tolerated drug for the therapy of inflammatory bowel disease (and GPP flares), the 
benefit of this trial is considered to outweigh the potential minimal risks and justifies the 
exposure of healthy subjects.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This study will explore the safety, tolerability, and pharmacokinetics of a newly developed
SC formulation of BI 655130 at two different dose strengths of 
 and
 
 in an open-label, sequential group design. Furthermore, the relative bioavailability of
the 
 SC dose (Test) will be compared with one single 
 IV dose of BI 655130 
(Reference) in an open-label, , parallel group design). For details refer to Section 4.1. Each 
participating subject will receive only one dose. Subjects assigned to the 
 IV dose will 
be matched for gender and body weight (± 10%) to subjects receiving the 
 SC dose.
The study will start with the lowest SC dose of 
 of BI 655130. The dose group will be 
divided into 2 cohorts: on the first study day, 6 subjects will be treated, with an interval 
between the injections of at least 15 min. The second cohort will be treated at least 48 h apart. 
There will be an interval of at least 1 week after the first dosing in the 
 SC dose group 
before the start of the 
 SC or IV dose groups in a randomised sequence (in one week 
6 subjects on IV and 6 subjects on SC and in the following week again 6 + 6). No more than 
2 subjects should simultaneously receive an IV infusion. At any time during the ongoing 
study, further dosing will be stopped in case of safety and tolerability concerns based on the 
pre-specified trial-specific stopping criteria (Section 3.3.4.2).
A documented Safety Review must take place prior to dose escalation to 
 
Furthermore, an unscheduled safety review meeting can be requested anytime for any 
reasonable cause by the Principal Investigator (or an authorised deputy) or the sponsor of the 
study, e.g. because of any unforeseen adverse events. Dose escalation will only be permitted 
if no safety concerns exist in the opinion of the Principal Investigator (or an authorised 
deputy) and the trial clinical monitor (or an authorised deputy). In addition, at least 
6 evaluable subjects per dose level are required to decide about dose escalation to the 
dose level.
The minimum data set for review consists of the following data:

AEs (including clinically relevant findings from ancillary safety testing listed below) 
(Note: AEs may be ongoing at the time of Safety Reviews and AE information may 
be subject to change prior to Database Lock)

Results from 12-lead ECG and continuous ECG monitoring 

Vital signs 

Clinical laboratory tests 

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the trial clinical monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 


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face-to-face or by video/telephone conference. The trial clinical monitor is responsible for 
organisation and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (or an authorised deputy) and filed in the ISF and TMF.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial will be conducted at the
 
 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. 
Safety laboratory tests will be performed by 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs or a 
contract research organisation appointed by BI.
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 GROUP
The trial will be conducted open-label. Blinding is not possible because the treatments are 
distinguishable. The open-label treatment is not expected to bias results, since the relative 
bioavailability endpoints are derived from measurement of plasma concentrations of the 
analyte.
For safety reasons, the trial will be conducted in a fixed sequence; a time interval of at least 
7 days will be maintained between the first dosing of 
 of BI 655130 SC and the first 
dosing of 
 of BI 655130 SC or IV.


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No placebo group is included because the study is open-label with a focus on PK. Local 
tolerability is an additional objective  and will remain  relevant in case of dose limiting local 
AEs, whether placebo controlled or not. The systemic AEs have been evaluated up to 
 MRD, a far higher dose than planned for the current study.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 36 healthy male and female subjects (12 subjects per treatment group) will 
enter the study. They will be recruited from the volunteers' pool of the trial site. Healthy 
subjects of the IV dose group will be matched for gender and body weight (± 10%) to 
subjects of the 
 SC dose group.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male or female subjects 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. Age of 18 to 50 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5.
Male subjects, or female subjects who meet any of the following criteria starting from at 
least 30 days before 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: 
implants, injectables, combined oral or vaginal contraceptives, intrauterine device
-
Sexually abstinent
-
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) 
-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in 
questionable cases a blood sample with simultaneous levels of FSH above 40 U/L and 
estradiol below 30 ng/L is confirmatory)


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3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
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
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 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
12. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
13. Inability to refrain from smoking on specified trial days
14. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for 
males)
15. Drug abuse or positive drug screening
16. Blood donation of  more than 
 within 30 days prior to administration of trial 
medication or intended donation during the trial
17. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
18. Inability to comply with dietary regimen of trial site
19. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or 
any other relevant ECG finding at screening
20. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
21. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 


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Female subjects will not be allowed to participate if any of the following applies:
22. Positive pregnancy test, pregnancy or plans to become pregnant within 30 days after 
study completion
23. Lactation 
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as pregnancy, 
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 
marked peak aminotransferase (ALT and/or AST) elevations ≥10-fold ULN and/or needs 
to be followed up according to 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 could 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 pause the infusion or continue 
with a reduced infusion rate as described for other therapeutic proteins [P16-06636]. 
However, the overall infusion time (including time of discontinuation) must not exceed 
45 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). If a subject is removed 


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from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
If it is known that a subject becomes pregnant during the trial, the subject has to be removed 
from the trial. The subject is to be followed until she has given birth or until the end of 
pregnancy. The subject’s data are to be collected until the end of the trial (last visit of last 
subject) and reported in the CTR. For reporting of pregnancy and all related events refer to 
Section 5.2.2.2.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
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 are not met
3. Violation of GCP, or the CTP, or the contract with BI by the 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 if at least 2 subjects at one dose level show 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 he replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured by BI Pharma GmbH & Co. KG. The 
BI 655130 molecule is a heterodimer with a molecular weight of approximately 146 kDa. 
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are given below:
Substance:
BI 655130
Pharmaceutical formulation: Solution for injection
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Daily doses:
Posology:
1-0-0
Route of administration:
SC injection (periumbilical)
Duration of use:
Single dose
The characteristics of the reference product are given below:
Substance:
BI 655130
Pharmaceutical formulation: Solution for infusion
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Daily dose:
Posology:
1-0-0
Route of administration:
IV infusion
Duration of use:
Single dose 
At the time of use, the IV and SC solutions for dosing will be prepared as detailed in the 
instruction given in the ISF.
4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects have been allocated to 
1 of the 6 dose cohorts (2 cohorts per dose group), the following subjects will be allocated to 
one of the other dose cohorts. Therefore, the allocation of subjects to dose cohorts is not 


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influenced by trial personnel, but only by the subjects’ temporal availability. As the study 
includes healthy subjects from a homogenous population, relevant imbalances between the 
dose groups are not expected.
The list with study subject numbers and allocated treatments will be provided to the trial site 
in advance. The allocation of subjects to study subject numbers will be performed prior to the 
first administration of trial medication. For this purpose, the subjects will be allocated to a 
study subject number by drawing lots. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
The subject number procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
The doses selected for this trial are based on data from Study 1368.1 (see Section 1.2.5) and 
correspond to potential doses used in upcoming clinical trials in patients.
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are as outlined in Table 4.1.4: 1. Each subject will receive one
single dose of trial medication. For further details concerning timing, see the Flow Chart.
Detailed instructions for the preparation of the SC injection and IV infusion solutions are 
provided in the ISF. 
Table 4.1.4: 1
BI 655130 treatments  
Total dose
Route of administration
Concentration of application solution 
Application volume 
SC
SC
IV
Subcutaneous injection
Following an overnight fast of at least 10 hours, the medication will be administered. Trial 
drug will be injected subcutaneously within 60 seconds in the abdominal region. Detailed 
handling instructions will be provided in the ISF. Subjects will be kept under close medical
surveillance until 48 hours following drug administration. For restrictions with regard to diet,
see Section 4.2.2.2.
Intravenous infusion
Following an overnight fast of at least 10 hours, the medication will be administered. The 
infusion solution will be administered intravenously over 30 minutes. Start and time of the 
infusion will be recorded. Detailed handling instructions for the infusion will be provided in 
the ISF.
In case of safety concerns, e.g. due to infusion reactions, it is at the discretion of the 
investigator or his/her designee to adapt the infusion scheme, including but not limited 
slowing down the infusion rate, stopping of the infusion and, provided no further safety 


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concern exist, restarting at a slower rate. Further, based on his/her medical judgment the 
investigator 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 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, if correct dosage 
cannot be ensured otherwise. For the purpose of drug accountability, the infusion set will be 
weighed before and after drug administration.
Subjects will be kept under close medical surveillance until 48 h following drug 
administration. For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
No blinding will be performed because the treatments are distinguishable from each other. 
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct, 
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the Annex 13/EU GMP 
Guideline will be provided on the containers. The clinical trial supply containers will be
labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Batch number

Investigator
The vials are labelled with reduced requirements.


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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.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel as documented in the form ‘Site Delegation Log’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator / pharmacist must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator / pharmacist will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP, and that reconcile all investigational products 
received from the sponsor. At the time of disposal, the investigator / pharmacist must verify 
that no remaining supplies are in the investigator’s possession.


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4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
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 except for hormonal contraceptives or ovary 
hormone replacement. 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, no food is allowed for at least 10 h before and 1.5 h 
after administration of the study drug (= end of infusion).
From 1 h before until 1.5 h after study drug administration, fluid intake is not allowed. From 
breakfast until 24 hours post-dose, water intake will be within 
 to 
. Total fluid 
intake on 24-hour in-house days is recommended to be at least 
 and should not 
exceed 
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during the in-house confinement. Alcoholic beverages are not 
permitted starting 7 days before the administration of trial medication until Day 28. From 
Day 28 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 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.
If female subjects of child bearing potential are included, adequate contraception is to be 
maintained throughout the course of the trial (see Section 3.3.2 for adequate measures).


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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
Safety and tolerability of the investigational drug will be assessed based on: 

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring

Vital signs (blood pressure, pulse rate)

Local tolerability

Oral body temperature
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3). 
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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 


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
is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, 
or 

is  deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.2.2, subsections ‘AEs collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The AESI in this trial is hepatic injury, as defined by the following alterations of hepatic 
laboratory parameters:

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 

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN


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These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be assessed based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge,
confounding factors such as concomitant medication, concomitant diseases and relevant
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger


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
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged 
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report related SAEs and related AESIs of which the investigator 
may become aware of by an means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.


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The REP for BI 655130, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known at this early stage of development. 
Therefore, all AEs reported until the end of trial examination will be considered on treatment; 
please see Section 7.3.3.
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 BI SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.


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Pregnancy
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 B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE
form must be completed in addition.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis,
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
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 WBC (if automatic
differential WBC is abnormal)
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 (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB 
Lactate dehydrogenase (LDH)
Serum tryptase1
Hormones1
Thyroid stimulating hormone (TSH)
fT3, fT4
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Protein electrophoresis (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


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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 sediment (microscopic
examination if urine analysis abnormal)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1
Only at screening
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy test and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
treatment, and as part of the end of trial examination. Drug screening will be performed at 
screening and at admission to the trial site the day prior to treatment.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Opiates 
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Dräger Alcotest® 
6510 and Alcotest® 5510, Belgium) will be performed at screening and at the start of the 
in-house period (Day -1) and may be repeated at any time during the study at the discretion of 
an investigator or designee. The results will not be included in the CTR.
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 Table 5.2.3: 1 and 5.2.3: 2 will be performed ZNA Klinisch 
Laboratorium, Antwerpen, Belgium with the exception of the drug screening and pregnancy 


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tests. These tests will be performed at the trial site using 'Alere Triage TOX Drug Screen' and 
MAHSAN® –HCG rapid test or equivalent, respectively.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
Samples for cytokine analysis (cytokines IL1, IL6, TNF-and IFNwill be collected at 
baseline, 4h, and 24h postdose. The cytokine samples will be only analysed in case of 
specific adverse events suggestive for cytokine release.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a
computerised electrocardiograph (MAC 5500, GE Healthcare) 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.
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) and the repeated ECG will be used for analysis.
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 and oxygen monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 2-lead ECG 
recording for at least 15 min before (for baseline assessment) and 2 h following the start of 
IV infusion or SC injection using the Dräger Telemetry monitoring system, Infinity M300. 
Oxygen saturation will be monitored by pulse oximetry using either Type NT1 handheld 
pulse oximeter from Newtech or Oxytrue A from Bluepoint Medical.


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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) will be measured by a blood pressure monitor (Welch 
Allyn 530TP and 530TO devices) at the times indicated in the Flow Chart, after subjects have 
rested for at least 5 min in a supine position. All recordings should be made using the same 
type of blood pressure recording instrument on the same arm if possible.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 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
Local tolerability will be assessed by the investigator according to ‘swelling’, ‘induration’, 
‘heat’, ‘redness’, ‘pain’, or ‘other findings’.
5.2.5.4
Oral body temperature
Oral body temperature will be measured at the times indicated in the Flow Chart using a 
standard device.
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 


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administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an IV and SC administered drug, and are widely used 
in clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 
are generally used assessments of drug exposure.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs.
Exact time points of plasma sampling will be derived from the electronic data capturing 
system LabPas and documented in the CRFs by the medical personnel or sent as electronic 
files to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be determined for BI 655130:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.5.1.2
Secondary endpoint
The following secondary endpoint will be evaluated for BI 655130:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
 


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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 an antecubital or forearm vein into a K2EDTA (ethylenediaminetetraacetic 
acid) anticoagulant blood drawing tube at the times indicated 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.
The K2EDTA-anticoagulated blood samples will be mixed gently and placed on ice until 
centrifugation for about 10 minutes at about 2000 g to 4000 g and at approximately 4°C. The 
blood should be centrifuged to produce plasma as soon as possible after collection, but not 
later than 30 minutes after withdrawal. Two aliquots of EDTA plasma sample will be 
obtained in two labelled polypropylene cryotubes. At a minimum, the sample tube labels 
should list the following information: BI trial number, subject number, visit, PTM, aliquot #1 
or #2, plasma, and PK.
The two aliquots should contain approximately 
 of plasma each. The plasma samples 
will be stored in a freezer at about -20°C or below at the clinical site until shipment to the 
analytical laboratory. 
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


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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 655130 plasma concentration
BI 655130 concentrations will be determined by a validated Enzyme Linked Immunosorbent 
Assay (ELISA).
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK). 
The acceptable deviation 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

±120 min from 48 h up to Day 8

±48h from Day 9 up to Day 14

±72h from >Day 14 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 the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will 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. On all other study days, the study will be performed in an ambulatory fashion.


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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 samples for PK analysis, 
refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2 
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period
For AE assessment, laboratory tests, collection of PK 
 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. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the relative bioavailability of 
 of 
BI 655130 following subcutaneous administration (Test, T) compared to 
 of 
BI 655130 following intravenous infusion (Reference, R). This will be evaluated statistically 
by use of an appropriate linear model.
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between all tested treatments. The secondary objective will be assessed by 
descriptive statistics.
The assessment of safety and tolerability is an additional objective of this trial, and will be 
evaluated by descriptive statistics.
7.1.2
Endpoints
Relative bioavailability is to be determined on the basis of the primary and secondary 
pharmacokinetic endpoints (see Section 5.5.1).
Safety and tolerability will be determined on the basis of the parameters specified in 
Section 5.2.1.
7.1.3
Model
The statistical model used for the inter-individual comparison of the primary and secondary 
endpoints following SC versus IV administration of 
 of BI 655130 will be an ANOVA 
(analysis of variance) model on the logarithmic scale, accounting for the treatment group as a 
source of variation. The effect ‘treatment group’ will be considered as fixed. The model is 
described by the following equation:
yij = + τi+eij, where
yij = logarithm of response (endpoint, see Section 7.1.3) measured on subject j 
receiving treatment i
= overall treatment mean,
τi: effect of treatment i
eij = the random error associated with the subject j who received treatment ,
where eij ∼N(0,σ2) where σ2is the total variability


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7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 655130 following SC compared to IV administration will be 
estimated by the ratios of the geometric means (test/reference) for the primary and secondary
PK endpoints. Additionally, their two-sided 90% confidence intervals (CIs) will be provided. 
This method corresponds to the two one-sided t-tests procedure, each at the 5% significance 
level. Since the main focus is on estimation and not testing, an acceptance range was not 
specified, that is, no hypothesis will be tested.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The pharmacokinetic endpoints listed in 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).
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
violation relevant to the evaluation of PK (to be decided no later than in 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.
A PK concentration or parameter will be considered as non-evaluable if, for example, the 
subject did not receive the complete assigned infusion or injection volume.
Relevant protocol violations may be

Study drug not administered or wrong trial drug administered

Incorrect dose of trial medication taken

Missed/missing PK samples at important phases of PK disposition curve
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one primary or secondary PK parameter that was not excluded according to 
the description above. Thus, a subject will be included in the PKS, even if he contributes only 
one PK parameter value to the statistical assessment.
Relative bioavailability will be estimated by the ratios of the geometric means (test/reference) 
for the primary and secondary endpoints (see 5.5.1.1, 5.5.1.2), and their two-sided 90% 
confidence intervals (CIs) will be provided.
To this end, the PK endpoints will be log transformed (natural logarithm) prior to fitting the 
ANOVA model (cf. Section 7.1.3). For each endpoint, the difference between the expected 
means for log(T)-log(R) will be estimated by the difference in the corresponding adjusted 
means (LeastSquares Means), and a two-sided 90% confidence interval based on the 


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t-distribution will be computed. These quantities will then be back-transformed to the original 
scale to provide the point estimate and 90% CIs for each endpoint.
7.3.2
Secondary analyses
The secondary parameter (refer to Section 5.5.1) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will statistically be assessed using the same 
methods as described for the primary endpoints.
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 one dose of study drug), will be included in the safety analysis. 
Safety analyses will be descriptive in nature and will be based on BI standards. No hypothesis 
testing is planned.
The analyses will be done by ‘treatment at onset’.
Treatments will be compared 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 ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to administration of trial medication 
will be assigned to 'screening', those between trial medication administration 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.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and post-study intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated. Measurements taken immediately 
prior to drug administration on Day 1 will be considered as baseline values.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
Relevant ECG findings will be reported as AEs.


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7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for BI 655130 will be calculated 
according to the relevant SOP of the Sponsor (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma concentrations and individual pharmacokinetic parameters; however, they 
will not be included in descriptive statistics for plasma concentrations, pharmacokinetic 
parameters, or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure 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 


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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
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 36 subjects in the trial (12 subjects per treatment group) 
because this sample size is considered sufficient to achieve the aims of this exploratory trial. 
With this sample size, the following precision of the ratio of geometric means (test/reference)
can be expected. Precision is defined as the ratio of upper to lower confidence interval limit.
Note that the precision is independent of the actual ratio of geometric means. Table 7.5: 1
provides an overview on the achievable precision for estimating the ratio of geometric means 
(test/reference) covering the range of gCVs estimated for the PK endpoints from the results 
obtained from the first-in-human SRD study for BI 655130. For illustrative purposes, the 
expected 90% confidence intervals with 95% coverage probability are displayed for different 
values of geometric means ratios T/R in the parallel design.
Table 7.5.1
Expected two-sided 90% confidence intervals for different gCVs and 
ratios T/R (N=12)
gCV
Precision
90% CI for respective gMean ratio (T/R)
80%
100%
125%
150%
200%
15.6%
1.31
(69.90, 
91.56)
(87.37, 
114.45)
(109.22, 
143.06)
(131.06, 
171.68)
(174.75, 
228.90)
12.7%
1.25
(71.66, 
89.31)
(89.57,
111.64)
(111.97,
139.55)
(134.36,
167.46)
(179.15,
223.28)
7.17%
1.13
(75.17, 
85.15)
(93.96,
106.43)
(117.45,
133.04)
(140.94,
159.65)
(187.91,
212.86)
The expected 90% confidence interval limits in the table were derived by
CI limitupper, lower = exp(ln(θ) ± ω)
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either
confidence interval limit on the log-scale, which was obtained from the achievable precision
on the original scale.
The calculation was performed as described by [R12-0972] using R Version 3.0.3.


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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.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his personal trial-related data will be used by Boehringer 
Ingelheim in accordance with the local data protection law. The level of disclosure must also 
be explained to the subject.
The subject must be informed that his medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 


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


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8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC / competent authority in each participating EU member state needs to be notified
about the end of the trial (last subject / subject out, unless specified differently in 
Section 6.2.3 of the CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P16-06636
Denis Choquette, Rafat Faraawi et al., J Rheumatol 2015;42;1105-1111.
R12-0972
Kupper LL, Hafner KB. How appropriate are popular sample size 
formuulas? Am Stat 1989; 43(2):101-105.
R13-2231
Baumgart DC, Sandborn WJ. Crohn's disease. Lancet 2012;380:1590-1605.
R13-2269
Sandborn WJ. State-of-the-art: immunosuppression and biologic therapy. 
Dig Dis 2010;28:536-542.
R14-4037
Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, 
Sims JE. Interleukin-36 (IL-36) ligands require processing for full agonist 
(IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity. 
J Biol Chem 2011;286(49):42594-42602.
R14-5158
Marrakchi S, et al. Interleukin-36-receptor antagonist deficiency and 
generalized pustular psoriasis. N Engl J Med 2011;365(7):620-628.
R15-1343
Loftus EV. Clinical epidemiology of inflammatory bowel disease: 
incidence, prevalence, and environmental influences. Gastroenterology 
2004;126(6):1504-1517.
R15-1399
Blumberg H, Dinh H, Dean C, Trueblood ES, Beiley K, Shows D, 
Bhagavathula N, Aslam MN, Varani J, Towne JE, Sims JE. IL-1RL2 and 
its ligands contribute to the cytokine network in psoriasis. J Immunol 
2010;185(7):4354-4362.
R15-1421
Onouofriadis A, Simpson MA, Pink AE, Meglio P di, Smith CH, 
Pullabhatla V, Knight J, Spain SL, Nestle FO, Burden AD, Capon F, 
Trembath RC, Barker JN. Mutations in IL36RN/IL1F5 are associated with 
the severe episodic inflammatory skin disease known as generalized 
pustular psoriasis. Am J Hum Genet 2011;89(3):432-437.
R15-1432
Blumberg H, Dinh H, Trueblood ES, Pretorius J, Kugler D, Weng N, 
Kanaly ST, Towne JE, Willis CR, Kuechle MK, Sims JE, Peschon JJ. 
Opposing activities of two novel members of the IL-1 ligand family 
regulate skin inflammation. J Exp Med 2007;204(11):2603-2614.
R15-1447
Tortola L, Rosenwald E, Abel B, Blumberg H, Schaefer M, Coyle AJ, 
Renauld JC, Werner S, Kisielow J, Kopf M. Psoriasiform dermatitis is 
driven by IL-36-mediated DC-keratinocyte crosstalk. J Clin Invest 
2012;122(11):3965-3976.
 


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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, tumor marker
TSH


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Haematology
Thrombocytes, eosinophils

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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10.2
PREPARATION AND HANDLING OF BI 655130 SOLUTION FOR 
INFUSION 
 AND BI 655130 SOLUTION FOR INJECTION 
10.2.1
Preparation Instructions for BI 655130 
 dose (concentration 
Necessary Materials:
Drug Product and Dilution Media:
3 vials BI 655130 Solution for Infusion 
 (correlates to 
 BI 655130)
1 bottle 0.9% sodium chloride solution (e.g. 
 B.Braun, 401734)
Consumables:
1 x Blunt Fill needle 18 G (material: stainless steel/ Polypropylene - e.g. BD, 305180)
 syringe (material: Polycarbonate/ Polypropylene – e.g. BD, 309628)
 syringe (material: Polypropylene - e.g. BD, 300912)
 syringe (material: Polypropylene - e.g. BD, 300629) 
 syringe (material: Polypropylene - e.g. Omnifix B.Braun, 4617509F) 
7 x syringe closure (material: Polyethylene - e.g. Combi-Stopper B.Braun, 4495101)
4 x Spike (material: Polyolefine - e.g. Mini-Spike, 0.45 µm Air Filter B.Braun, 4550242)
Empty EVA (Ethylene vinyl acetate) infusion bag: 
e.g. Freka Mix Monolayer (Fresenius-Kabi, F2859061)
In case that a material is not available it can be replaced by a one which is comparable 
with regard to qualitative composition and dimension.
Preparation overview:
Dilution: 
 of BI 655130 Solution for Infusion 
 0.9% sodium 
chloride 
 BI 655130 (in infusion bag)
1)
Put a Mini-Spike on a bottle containing 
 0.9% sodium chloride solution
2)
Attach a 
 syringe to the Mini-Spike, withdraw 
 of the 0.9% sodium 
chloride Solution and disconnect the filled syringe. Close it with a Combi-Stopper. 
3)
Attach a 
 syringe to the Mini-Spike, withdraw 
 of the 0.9% sodium 
chloride Solution and disconnect the filled syringe. Close it with a Combi-Stopper. 
4)
Attach a 
 syringe to the Mini- Spike, withdraw 
 of the sodium chloride 
Solution and disconnect the filled syringe. Close it with a Combi-Stopper.
5)
Put a Mini-Spike on each of two vials containing BI 655130 Solution for Infusion 
 and connect one 
 syringe to the Mini-Spike.
6)
Withdraw 
 of BI 655130 Solution for Infusion 
 from each of the two 
so the total volume in the syringe is 
 BI 655130). 


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7)
Disconnect the syringe and lock the syringe with a Combi-Stopper. 
8)
Put a Mini-Spike on the third vial containing BI 655130 Solution for Infusion 
 and connect one 
 syringe to the Mini-Spike.
9)
Withdraw 
 of BI 655130 Solution for Infusion 
 from the vial (= 140 
mg BI 655130) 
10) Disconnect the syringe and lock the syringe with a Combi-Stopper.
11) Attach a 1 mL syringe to the Mini-Spike, withdraw 
 of the BI 655130 Solution 
for Infusion 
 from the vial
 BI 655130) and disconnect the filled 
syringe. Close it with a Combi-Stopper. 
12) Lock the fill port of the empty infusion bag close to the bag. Open the injection port 
of the bag.
13) Remove the Combi-Stopper from the syringe obtained in step 6, attach an 18 G needle 
and transfer the complete contents of the syringe into the infusion bag via the 
injection port. 
14) Disconnect the empty syringe from the needle and close the needle using a Combi-
Stopper. Keep bag in an upright position to prevent leakage
15) Connect consecutively the second syringe containing BI 655130 Solution for Infusion 
(step 9) to the needle of the infusion bag containing BI 655130 Solution for Infusion
 and transfer the content of the syringes completely into the infusion bag. 
Disconnect the empty syringe.
16) Connect the third syringe containing BI 655130 Solution for Infusion (step 11) to the 
needle of the infusion bag containing BI 655130 Solution for Infusion
 and 
transfer the content of the syringes completely into the infusion bag. Disconnect the 
empty syringe.
17) Connect consecutively the syringes containing 0.9% sodium chloride solution (step 
2,3 and 4) to the needle of the infusion bag containing BI 655130 Solution for 
Infusion 
and transfer the contents of the syringes completely into the 
infusion bag. Disconnect the empty syringe.
18) Remove the needle and mix solution in the bag by gently kneading and turning it. 
10.2.2
Infusion instructions
In all patients, the infusion solution may be intravenously administered over a period of 
1 hour. Infusion time can be extended up to 4 hours provided that the maximum time between 
the preparation and completion of administration of the solution to the patient does not 
exceed the 4 hours. 


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10.2.3
Preparation Instructions 
 SC dose 
Necessary materials: 
1 Vial BI 655130 Solution for Injection 
Consumables: 
 sterile polypropylene syringe  - e.g. B. Braun Injekt F (article no: 9166017V) 
1 x 21G 1½”needle  (material: stainless steel/ polypropylene) – e.g. B. Braun  (article no 
4657527)
1 x 30G ½” needle for injection (material: stainless steel/ polypropylene) – e.g. BD (article 
no: 304000)
1. Take a vial filled with 
 of BI 655130 Solution for Injection 
to BI 
655130 Solution for Injection 
 out of the refrigerator and let it reach room 
temperature for 30 minutes. 
2. Gently invert the vial five times to homogenize prior to use. Check the vial content for 
visible particles. The solution should be colorless to slightly brownish-yellow and clear 
to slightly opalescent. If discoloration or visual particles are seen discard the vial. 
3. Remove the protective cap from the vial.
4. Using appropriate aseptic technique, insert a sterile 21G needle through the center of 
the stopper and withdraw the complete content of the vial. using a sterile 
 
syringe
5. In case the medication will not be injected immediately close the syringe with a 
Combi-Stopper.
6. Attach a sterile 30G ½” needle to the 
syringe, adjust the volume to 
 and 
gently inject the complete content of the syringe.


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10.2.4
Preparation Instructions 
 SC Dose
Necessary materials: 
2 Vials BI655130 Solution for Injection 
Consumables: 
 sterile polypropylene syringe   - e.g. B. Braun Injekt Solo (article no: 4606027) 
needle (material: stainless steel/ polypropylene) – e.g. B. Braun (article no 
4657527)
 needle for injection (material: stainless steel/ polypropylene) –
e.g. BD (article no: 304000)
1.
Take two vials filled with 
 of BI 655130 Solution for Injection 
 
out of the refrigerator and let it reach room temperature for 30 minutes. 
2.
Take the first vial and gently invert the vial five times to homogenize prior to use. 
Check the vial content for visible particles. The solution should be colorless to 
slightly brownish-yellow and clear to slightly opalescent. If discoloration or visual 
particles are seen discard the vial. 
3.
Remove the protective cap from this vial.
4.
Using appropriate aseptic technique, insert a sterile 21G needle through the center 
of the stopper and withdraw the complete content of this vial using a sterile 
 
syringe.
5.
Repeat steps 1 to 4 with the second vial using the 
 syringe already filled with 
6.
In case the medication will not be injected immediately close the syringe with a 
Combi-Stopper.
7.
Attach a sterile 
 needle to the syringe, adjust the volume to 
and 
gently inject the complete content of the syringe.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
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
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c10896574
1.0
clinical-trial-protocol
Safety, tolerability, and pharmacokinetics of two dose strengths of a single
subcutaneous dose of BI 655130 and one single intravenous dose of BI 655130 in
healthy male and female subjects (open-label, parallel group design)
Author-Trial Clinical Monitor
08 Mar 2017 10:14 CET
Author-Trial Statistician
08 Mar 2017 10:23 CET
Author-Trial Clinical
Pharmacokineticist
08 Mar 2017 15:28 CET
Approval-Therapeutic Area 
09 Mar 2017 14:13 CET
Verification-Paper Signature
Completion
13 Mar 2017 11:39 CET
Approval-Team Member Medicine
13 Mar 2017 12:11 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c10896574
1.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c21342784-01
BI Trial No.:
1368.3
Title:
Safety, tolerability, and pharmacokinetics of two dose strengths of 
a single subcutaneous dose of BI 655130 and one single 
intravenous dose of BI 655130 in healthy male and female subjects 
(open-label, parallel group design).
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
 
Phone: 
Fax:
Phone: 
Fax: 
Date of statistical 
analysis plan:
06 FEB 2018    SIGNED
Version:
Final
Page 1 of 24
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2018 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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINT .................................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
5.3
FURTHER ENDPOINTS.....................................................................................9
5.3.2
Safety parameters .................................................................................................9
5.4
OTHER VARIABLES........................................................................................10
5.4.1
Demographic and other baseline characteristics .............................................10
5.4.2
Treatment compliance and treatment exposure ..............................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................13
6.4
SUBGROUPS ......................................................................................................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 ENDPOINTS...................................................................................16
7.5
SECONDARY ENDPOINT ...............................................................................17
7.5.1
Key secondary endpoint .....................................................................................17
7.5.2
Secondary endpoint.............................................................................................17
.....................................................................18
.....................................................................18
.....................................................................18
.....................................................................18
.....................................................................18
7.7
EXTENT OF EXPOSURE.................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................18
7.8.1
Adverse events.....................................................................................................18


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7.8.2
Laboratory data ..................................................................................................20
7.8.3
Vital signs.............................................................................................................20
7.8.4
ECG......................................................................................................................20
7.8.5
Others...................................................................................................................20
7.8.6
Local tolerability .................................................................................................21
8.
REFERENCES....................................................................................................22
...............................................................................23
10.
HISTORY TABLE..............................................................................................24


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data and vital signs..........................................................................11
Table 6.2: 1
Important protocol violations...........................................................................12
Table 6.3: 1
Subject sets analysed........................................................................................13
Table 10: 1
History table .....................................................................................................24


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADPC
Proper name of the analysis dataset containing PK concentrations per time-
point or per time-interval
ADPP
Proper name of the analysis dataset containing calculated PK parameters
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
CARE
Clinical data analysis and reporting environment
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
ECG
Electrocardiogram
eCRF
Electronic case report form
ER
Exploratory reference treatment
EudraCT
European union drug regulating authorities clinical trials
gCV
Geometric coefficient of variation


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Term
Definition / description
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPV
Important protocol violation
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed
NOR
No valid result
NOS
No sample available
on-trt
on-treatment
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
PV
Protocol Violation
Q1
Lower Quartile
Q3
Upper Quartile
R
Reference treatment
RAGe
Report appendix generator
RPM
Report Planning Meeting
SAE
Serious adverse event
SD
Standard Deviation
SDL
Subject data listing
SOC
System Organ Class
T
Test treatment
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the CTP, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP. 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.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version 6.3, Certara
USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the CTP.
 
 
 
 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints are PK endpoints as defined in Section 5.5.1.1 of the CTP:

AUC0-tz (area under the concentration-time curve of BI 655130 in plasma over the time 
interval from 0 to the last quantifiable data point) 

Cmax (maximum measured concentration of BI 655130 in plasma)
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoint
Secondary endpoint is AUC0-∞(area under the concentration-time curve of BI 655130 in 
plasma over the time interval from 0 extrapolated to infinity).
5.3
FURTHER ENDPOINTS
5.3.2
Safety parameters
CTP:
Safety and tolerability of the investigational drug will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring

Vital signs (blood pressure, pulse rate)

Local tolerability

Oral body temperature
Local tolerability will be assessed as absence or presence of "swelling", "induration", "heat", 
"redness", "pain", or "other findings".


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5.4
OTHER VARIABLES
5.4.1
Demographic and other baseline characteristics
CTP: At screening, the medical examination will include demographics including height and 
body weight, smoking and alcohol history, relevant medical history and concomitant therapy
[…].
Age [years] will be determined as the difference between year of birth and year of informed 
consent.
BMI will be calculated as weight [kg] / (0.01 * height [cm])2.
5.4.2
Treatment compliance and treatment exposure
Treatment compliance will not be analysed as a specific endpoint, cf. Section 4.3 of the CTP.
Treatment exposure is defined as the total dose of BI 655130 per subject.
Additionally, the duration of infusion per subject is calculated for the treatment group of 
subjects who receive BI 655130 intravenously.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignments of dose groups, 
and selection of doses, cf. Section 4 of the CTP.
Subjects were planned to be treated either with one single dose of

as subcutaneous (SC) injection (exploratory reference treatment (ER)) 
or

 as intravenous (IV) infusion (reference treatment (R))
or

 as SC injection (test treatment (T)).
For statistical analysis of AEs, safety laboratory data and vital signs, the following analysis 
phases are defined for each subject:
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data and vital signs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of administration 
of study drug
On-treatment
 BI SC, or
 BI IV or
 BI SC,
respectively
Date/time of administration 
of study drug
0:00 AM on day after 
subject's trial termination 
date
CTR Section 15, Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 AE displays will present 
results for the on-treatment phase only.
In CTR Section 15 AE tables (but not in Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 
AE tables), the following total will be provided in addition:

"Total on-trt BI", defined as the total over all on-treatment phases involving BI 655130
CTR Appendix 16.1.9.2.8.1 displays will present results for the screening and on-treatment 
phases.
Additionally to the totals defined above, the following total will be provided in CTR Section 
16.1.9.2.8.1 AE tables:

"Total ", defined as the total over all study phases (incl. screening and on-treatment).


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More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Consistency check listings (for identification of violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration) will be provided to be discussed 
at the RPM/DBLM. At this meeting, each protocol deviation must be assessed to determine 
whether it is an IPV. For definition of IPVs, and for the process of identification of these, 
refer to the BI reference document "Protocol Violation Handling Definitions" (2).
If any IPVs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet (3). The following table 
contains the categories which are considered to be IPVs in this trial. If the data show other 
IPVs, this table will be supplemented accordingly by the time of the RPM/DBLM.
IPVs will be summarised and listed.
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 taken
C3
Non-compliance
C5
Incorrect intake of trial medication
D
Concomitant medication
D1
Concomitant medication with the potential to affect the assessment of the trial medication
E
Missing data
None1
G
Other trial specific important violations
G1
Certain violations of procedures used to measure primary PK data
Violations C1, C2, C5 and G1 can only be detected at the trial site.
1 Missing visits, evaluations, and tests will be considered missing data, not PVs
Source: BI reference document "Protocol Violation Handling Definitions" [001-MCS-50-413_RD-01] (2).


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6.3
SUBJECT SETS ANALYSED
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received study drug. 

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects of the TS who provide at least one observation 
for at least one primary or secondary PK endpoint without important PVs with respect 
to the statistical evaluation of PK endpoints, as defined in Section 7.3.1 and 
Section 7.3.2 of the CTP.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
IPVs
X
Demographic/baseline endpoints
X
Other safety parameters
X
PK endpoints
X
6.4
SUBGROUPS
A subgroup analysis is not planned.
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
CTP: If a subject is removed from or withdraws from the trial prior to first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) or 
trial database and will not be reported in the clinical trial report (CTR). If a subject is 
removed from or withdraws from the trial after first administration of trial medication, this 
will be documented and the reason for discontinuation must be recorded in the CRF. In this 
case, the data will be included in the CRF/trial database and will be reported in the CTR. 


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CTP: With respect to safety evaluations, it is not planned to impute missing values.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5). CTP: 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).
CTP: 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.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For safety measurements baseline is defined as the last measurement before study drug 
administration.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (001-MCG-159) (10).
The individual values of all subjects will be listed. Listings will generally be sorted by 
treatment group, subject number and visit (if visit is applicable in the respective listing). AE 
listings will be sorted by assigned analysis phase (see Table 6.1: 1 for a definition of analysis 
phases). The listings will be contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if there actually are missing values. Percentages will be based 
on all subjects in the respective subject set whether they have non-missing values or not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.


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Only descriptive statistics are planned for this section of the CTR.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of administration of the respective treatment or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint, but will be assessed for the 
treatment group receiving BI 655130 intravenously based on the duration of infusions 
(descriptive statistics of duration) and dose per infusion (descriptive statistics of the 
administered dose per infusion). Any deviations from complete intake will be addressed in 
the RPM/DBLM (cf. Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
Analysis of relative BA of primary endpoints AUC0-tz and Cmax of BI 655130 in plasma will
be performed as defined in Sections 7.1.3 and 7.3.1 of the CTP.
The statistical model for the primary analysis (comparison of subcutaneous versus 
intravenous administration of 
 of BI 655130) is an ANOVA model on the logarithmic 
scale including an effect for "treatment group" as defined in Sections 7.1.3 and 7.3.1 of the 
CTP.
 
 
 
 
 
 
 
 


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Primary PK endpoints will also be assessed descriptively. The analysis of standard PK 
parameters is performed according to BI standards (5) [001-MCS-36-472_RD-01].
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 001-MCS-36-472_RD-01 "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies" (5) and 001-MCS-36-472_RD-03 
"Description of Analytical Transfer Files and PK/PD Data Files" (6).
7.5
SECONDARY ENDPOINT
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoint
The secondary PK endpoint AUC0-∞will be analysed in the same way as described for the 
primary PK endpoint.
Descriptive analyses of the secondary PK endpoint will be performed according to BI 
standards (5) [001-MCS-36-472_RD-01].


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See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.
7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR, see also Section 7.3.
7.8
SAFETY ANALYSIS
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, 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)


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For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trial" (7) [001-MCG-156] and "Handling of missing and 
incomplete AE dates" (4) [001-MCG-156_RD-01]. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to the screening phase or on-treatment phase as defined in 
Section 6.1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 and for the class of 
AESIs.
CTP: The AESI in this trial is hepatic injury, as defined by the following alterations of 
hepatic laboratory parameters:

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

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (9), AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs, subjects 
with AESIs and subjects with other significant AEs (according to ICH E3 (9)). The frequency 
of subjects with AEs and the frequency of subjects with AEs considered by the investigator to 
be drug related will also be summarised by maximum intensity, primary SOC and preferred 
term.
The SOCs and preferred terms within SOCs will be sorted by descending frequency overall 
treatment groups.
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 preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (8). If possible, analyses will be based on original values. If multiple reference 
ranges apply for a parameter (e.g. due to different age groups), analyses will be based on 
normalised values, which means transforming to a standard unit and a standard reference 
range.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM/DBLM at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. Standard 
or project-specific rules for flagging clinically significant values in an automated manner will 
not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate, body temperature) will be descriptive 
in nature. Descriptive statistics of vital signs over time and for the difference from baseline 
(see Section 6.7) will be provided.
Body weight will only be listed.
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
Abnormal findings in ECG will be reported as baseline conditions (at screening) or as AEs 
(during the trial) if judged clinically relevant by the investigator, and will be analysed as such.
No separate listing or analysis of ECG data will be prepared.
7.8.5
Others
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 will be prepared.
Matching pairs for subjects included in the 
 BI SC and 
 BI IV treatment group 
will be summarized in a table and a listing displaying the matching criteria.


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7.8.6
Local tolerability
Local tolerability (absence or presence of "swelling", "induration", "heat", "redness", "pain", 
or "other findings") will be summarized with counts and percentages overall (i.e. over all 
time points) as well as by time point.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
 
 
 
 
 
 
 
9
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
 


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
06-FEB-18
(
), 
(
)
None
This is the final TSAP without any 
modification