Clinical trial NCT03617835
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2018-08-16; Completion date: 2019-06-03
Enrollment: 48 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the relative bioavailability of BI 655130 administered as two subcutaneous injections in the left and right periumbilical region compared to a single subcutaneous periumbilical injection of BI 655130.

The secondary objective is to investigate the relative bioavailability of a single subcutaneous injection of BI 655130 into the thigh compared to a single subcutaneous periumbilical injection of BI 655130.

Detailed description:

Arms: arm 1: Single low dose of BI 655130 administered as one single subcutaneous injection (given as 1 x 2 milliliter (mL)) in the periumbilical region following an overnight fast of at least 10 hours. arm 2: Single low dose of BI 655130 administered as two single subcutaneous injections (given as 2 x 1 milliliter (mL)) in the periumbilical region (left and right) following an overnight fast of at least 10 hours. arm 3: Single low dose of BI 655130 administered as one single subcutaneous injection (given as 1 x 2 milliliter (mL)) in the thigh region following an overnight fast of at least 10 hours. arm 4: Single high dose of BI 655130 administered as two single subcutaneous injections (given as 2 x 2 milliliter (mL)) in the periumbilical region (left and right) following an overnight fast of at least 10 hours.
Interventions: intervention 1: R - Low dose of BI 655130 intervention 2: T1 - Low dose of BI 655130 intervention 3: T2 - Low dose of BI 655130 intervention 4: T3 - High dose of BI 655130
Intervention descriptions: intervention 1: Single low dose of BI 655130 administered as one single subcutaneous injection (given as 1 x 2 milliliter (mL)) in the periumbilical region following an overnight fast of at least 10 hours. intervention 2: Single low dose of BI 655130 administered as two single subcutaneous injections (given as 2 x 1 milliliter (mL)) in the periumbilical region (left and right) following an overnight fast of at least 10 hours. intervention 3: Single low dose of BI 655130 administered as one single subcutaneous injection (given as 1 x 2 milliliter (mL)) in the thigh region following an overnight fast of at least 10 hours. intervention 4: Single high dose of BI 655130 administered as two single subcutaneous injections (given as 2 x 2 milliliter (mL)) in the periumbilical region (left and right) following an overnight fast of at least 10 hours.

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c21745299-03
EudraCT No.:
BI Trial No.:
2018-001074-18
1368-0029
BI Investigational
Product:
BI 655130
Title:
Relative bioavailability, safety, and tolerability following 
subcutaneous injection of different doses of BI 655130 and different 
injection sites in healthy male and female subjects (a single dose, 
mono-centric, open-label study in matched-group design).
Lay Title:
A study in healthy people to measure the amount of BI 655130 in the 
blood after injecting different doses into different parts of the body
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version 3.0
Date: 07 January 2019
Page 1 of 63
Proprietary confidential information
© 2019 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:
07 January 2019
25 June 2018
1368-0029
Title of trial:
Relative bioavailability, safety, and tolerability following subcutaneous 
injection of different doses of BI 655130 and different injection sites in 
healthy male and female subjects (a single dose, mono-centric, open-label 
study in matched-group design).
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
-
To investigate the relative bioavailability of 
 BI 655130 
administered as two subcutaneous injections of 
 in the left 
and right periumbilical region compared to a single subcutaneous 
periumbilical injection of 
 BI 655130 
-
To investigate the relative bioavailability of a single subcutaneous 
injection of 
BI 655130 into the thigh compared to a single 
subcutaneous periumbilical injection of 
 BI 655130
-
To investigate safety, tolerability, and pharmacokinetics of 
 BI 
655130 administered as two subcutaneous injections of 
in 
the left and right periumbilical region.
Methodology:
Single dose, open-label in matched-group design
No. of subjects: 
total entered:
48
each treatment:
12
Diagnosis:
Healthy subjects assigned to Dose Group 2 
 left and right 
periumbilical SC injection, 
 of BI 655130), Dose group 3 
 
left and right periumbilical SC injection, 
 of BI 655130) and Dose 
Group 4 
 SC injection in the thigh, 
 of BI 655130) will be 
matched for gender and body weight (± 10%) to subjects assigned to Dose 
Group 1 
 periumbilical SC injection, 
 of BI 655130).


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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:
07 January 2019
25 June 2018
1368-0029
Main criteria
for inclusion:
Healthy male and female subjects, age of 18 to 50 years, body mass index 
(BMI) of 19.0 to 29.9 kg/m2
Test treatment:
BI 655130 
 solution for injection 
dose:
mode of admin.:
Subcutaneous (SC) injection:
-
Two single injections of 
 periumbilical left and right (Dose Group 2)
-
Two single injections of
 periumbilical left and right (Dose Group 3)
-
One single injection of 
 into the thigh (Dose Group 4)
Reference treatment:
BI 655130 
 solution for injection 
dose:
mode of admin.:
One single subcutaneous (SC) injection of 
 periumbilical (Dose Group 1)
Duration of treatment: One day (single dose) for each treatment
Criteria for
pharmacokinetics:
Primary endpoints: AUC0-tz and Cmax
Secondary endpoints: AUC0-
Further parameters of interest as appropriate.
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, local tolerability, safety laboratory tests, 12-lead 
electrocardiogram (ECG), vital signs (blood pressure [BP], pulse rate [PR]).
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’, and ‘matched pair’. 
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
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
12-lead ECG
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies9
Query regarding local 
tolerability5
1
-28
to -3
Screening1
X12
X
X
-5
Ambulatory visit
X11
2
-1
-12:00
20:00
Admission to
trial site
X8
X
1
-2:00
6:00
X2
X2, 12
X2
X2
X2
X
0:00
8:00
Drug 
administration
0:30
8:30
X
X
1:00
9:00
X
2:00
10:00
Light breakfast6
X
X
3:00
11:00
X
4:00
12:00
Lunch6
X
X
X
X
6:00
14:00
X
8:00
16:00
Snack (voluntary)6
X
X
10:00
18:00
Dinner6
12:00
20:00
X
X
X
X
X
2
24:00
8:00
Breakfast6
X
X
X
X
X
28:00
12:00
Lunch6
32:00
16:00
Snack (voluntary)6
X
34:00
18:00
Dinner6
X
X
3
48:00
8:00
Breakfast6
discharge from
trial site
(confirmation of 
fitness7)
X
X
X
X
X
X
4
72:00
8:00
Ambulatory visit
X
X
X
5
96:00
8:00
Ambulatory visit
X
X
X
6
120:00
8:00
Ambulatory visit
X
X
X
7
144:00
8:00
Ambulatory visit
X
X
X
8
168:00
8:00
Ambulatory visit
X
X
X
X
X
X
15
336:00
8:00
Ambulatory visit
X
X
X
X


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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), drug screening, alcohol breath test, 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 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.
8. 
Only drug screening and alcohol breath test.
9.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time 
points indicated in the Flow Chart above.
10.
EoTrial (End of trial examination) includes physical examination, body weight, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. EoTrial must not be performed before last PK
 
 sampling. 
11.
Safety laboratory is to be taken within five days prior to study drug administration and can be omitted if the
screening examination is performed between Day -5 and Day -3.
12.
At these time points, a pregnancy test will be done.
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
12-lead ECG
vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies9
Query regarding local 
tolerability5
2
22
504:00
8:00
Ambulatory visit
X
X
X
X
29
672:00
8:00
Ambulatory visit
X
X
X
X
X
X
36
840:00
8:00
Ambulatory visit
X
X
43
1008:00
8:00
Ambulatory visit
X
X
57 ±3
1344:00
8:00
Ambulatory visit
X
X
X
71 ±3
1680:00
8:00
Ambulatory visit
X
X
92 ±3
2184:00
8:00
Ambulatory visit
X
X12
X
X
120 ±3
2856:00
8:00
Ambulatory visit
X
X
148 ±3
3528:00
8:00
Ambulatory visit
X
X
3
176 ±3 
4200:00
8:00
EoTrial10
X
X12
X
X
X
X


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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.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Nonclinical pharmacology....................................................................13
1.2.2
Safety pharmacology ............................................................................13
1.2.3
Toxicology..............................................................................................13
1.2.4
Nonclinical pharmacokinetics..............................................................14
1.2.5
Clinical experience................................................................................14
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 19
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................19
2.2
TRIAL OBJECTIVES.......................................................................................19
2.3
BENEFIT - RISK ASSESSMENT ...................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 22
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................22
3.1.1
Administrative structure of the trial...................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................24
3.3.1
Main diagnosis for study entry............................................................24
3.3.2
Inclusion criteria...................................................................................24
3.3.3
Exclusion criteria ..................................................................................25
3.3.4
Removal of subjects from therapy or assessments.............................26
3.3.4.1
Removal of individual subjects................................................26
3.3.4.2
Discontinuation of the trial by the sponsor..............................27
3.3.5
Replacement of subjects .......................................................................28
4.
TREATMENTS........................................................................................ 29
4.1
TREATMENTS TO BE ADMINISTERED....................................................29
4.1.1
Identity of BI investigational product.................................................29
4.1.2
Method of assigning subjects to treatment groups ............................29
4.1.3
Selection of doses in the trial................................................................29
4.1.4
Drug assignment and administration of doses for each subject .......30


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4.1.5
Blinding and procedures for unblinding ............................................30
4.1.6
Packaging, labelling, and re-supply ....................................................30
4.1.7
Storage conditions.................................................................................31
4.1.8
Drug accountability ..............................................................................31
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................32
4.2.1
Other treatments and emergency procedures....................................32
4.2.2
Restrictions............................................................................................32
4.2.2.1
Restrictions regarding concomitant treatment .........................32
4.2.2.2
Restrictions on diet and life style.............................................32
4.3
TREATMENT COMPLIANCE.......................................................................33
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 34
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................34
5.1.1
Endpoints of efficacy.............................................................................34
5.1.2
Assessment of efficacy...........................................................................34
5.2
SAFETY..............................................................................................................34
5.2.1
Endpoints of safety................................................................................34
5.2.2
Assessment of adverse events...............................................................34
5.2.2.1
Definitions of adverse events...................................................34
5.2.2.2
Adverse event collection and reporting ...................................37
5.2.3
Assessment of safety laboratory parameters......................................38
5.2.4
Electrocardiogram................................................................................41
5.2.5
Assessment of other safety parameters...............................................41
5.2.5.1
Vital signs ................................................................................41
5.2.5.2
Medical examinations..............................................................41
5.2.5.3
Local tolerability......................................................................42
5.3
OTHER...............................................................................................................42
5.3.1
Pharmacogenomic evaluation..............................................................42
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................42
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................42
5.5.1
Pharmacokinetic endpoints..................................................................42
5.5.1.1
Primary endpoints....................................................................42
5.5.1.2
Secondary endpoint..................................................................42
5.5.1.3
Further parameters of interest..................................................43
5.5.2
Methods of sample collection...............................................................43
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................43
5.5.3
Analytical determinations ....................................................................44
5.5.3.1
Analytical determination of BI 655130 plasma concentration 44
6.
INVESTIGATIONAL PLAN.................................................................. 45


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6.1
VISIT SCHEDULE............................................................................................45
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................45
6.2.1
Screening period....................................................................................45
6.2.2
Treatment period ..................................................................................45
6.2.3
End of trial period.................................................................................46
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 47
7.1
STATISTICAL DESIGN – MODEL ...............................................................47
7.1.1
Objectives...............................................................................................47
7.1.2
Endpoints...............................................................................................47
7.1.3
Model......................................................................................................47
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................48
7.3
PLANNED ANALYSES....................................................................................48
7.3.1
Primary analyses...................................................................................48
7.3.2
Secondary analyses ...............................................................................49
7.3.3
Safety analyses.......................................................................................49
7.3.4
Interim analyses ....................................................................................50
7.3.5
Pharmacokinetic analyses ....................................................................50
7.4
HANDLING OF MISSING DATA ..................................................................51
7.4.1
Safety......................................................................................................51
7.4.2
Plasma drug concentration - time profiles..........................................51
7.4.3
Pharmacokinetic parameters...............................................................51
7.5
RANDOMISATION ..........................................................................................51
7.6
DETERMINATION OF SAMPLE SIZE ........................................................51
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 53
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................53
8.2
DATA QUALITY ASSURANCE .....................................................................53
8.3
RECORDS..........................................................................................................54
8.3.1
Source documents .................................................................................54
8.3.2
Direct access to source data and documents.......................................54
8.3.3
Storage period of records.....................................................................54
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................54
8.5
STATEMENT OF CONFIDENTIALITY.......................................................55
8.6
COMPLETION OF TRIAL..............................................................................55
9.
REFERENCES......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56
9.2
UNPUBLISHED REFERENCES.....................................................................57
10. APPENDICES .......................................................................................... 58


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10.1
PREPARATION AND HANDLING OF BI 655130 SOLUTION FOR 
INJECTION 
.................................................................................58
10.1.1 Preparation Instructions 
 SC (Dose group 1,  injection 
left or right periumbilical)....................................................................58
10.1.2 Preparation Instructions 
 SC dose (Dose Group 2, 
injection left and right periumbilical).................................................59
10.1.3 Preparation Instructions 
 SC dose (Dose group 3, 
injection left and right periumbilical).................................................60
10.1.4 Preparation Instructions 
 SC dose (Dose group 4, 
injection in the thigh)............................................................................61
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 62


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ABBREVIATIONS
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
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
%AUCtz-∞
The percentage of AUC0-∞obtained by extrapolation
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CD
Crohn’s Disease
CI
Confidence interval
CL
confidence limits
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Coefficient of variation
DILI
Drug induced liver impairment
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EoTrial
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
HIV
Human Immunodeficiency Virus
IB
Investigator’s brochure
IBD
Inflammatory bowel diseases
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IL36R
Interleukin 36 receptor
IRB
Institutional Review Board


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ISF
Investigator site file
ITE
Indirect target engagement
IV
Intravenous
KO
Knock out
LOQ
Limit of Quantification
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MIP
Macrophage inflammatory protein
MRD
Multiple rising dose
MRT
Mean residence time of the analyte in the body after SC administration
N
Number
NC
Not calculated
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
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
SAE
Serious adverse event
SOP
Standard Operating Procedure
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TDMAP
Trial Data Management and Analysis Plan
TGF
Transforming growth factor
TMDD
Target mediated drug disposition
TMF
Trial Master File
TSAP
Trial statistical analysis plan
UC
Ulcerative colitis
ULN
Upper limit of normal
Vz
Volume of distribution during the terminal phase after intravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WBC
White Blood Cells


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36 
receptor (IL36R) signalling. Binding of BI 655130 to IL36R is anticipated to prevent the 
subsequent activation of IL36R by cognate ligands (IL36 α, β and γ) and downstream 
activation of pro-inflammatory and pro-fibrotic pathways in inflammatory skin and bowel 
diseases such as generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), and 
inflammatory bowel disease (IBD).
Genetic human studies established a strong link between IL36R signalling and skin 
inflammation, as demonstrated by the occurrence of GPP in patients with a loss of function
mutation in IL36Rα,the gene encoding the endogenous inhibitor of IL36R, which resulted in 
uncontrolled IL36R signalling [R14-5158, R15-1421]. Mutations in other genes linked to the 
IL36 pathway such as CARD14 also lead to GPP [R16-0929]. IL36R signalling drives skin 
inflammation in several animal models, further supporting the strong link between IL36R 
biology and skin disorders based on human genetics [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 [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 signalling may play an important role in IBD. 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 patients with Crohn’s 
disease (CD). Human IL36 ligands enhanced intestinal barrier permeability, a hallmark of 
IBD pathogenesis, in primary human intestinal epithelial cells co-cultured with intestinal 
myofibroblasts. The link between IL36R signalling and IBD was further strengthened by 
demonstrating that antagonist anti-mouse IL36R antibodies ameliorated intestinal 
inflammation in both acute and chronic 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 (UC) and CD 
patients. Finally, IL36R signalling in disease relevant cells, such as intestinal myofibroblasts 
and macrophages, induces both pro-inflammatory (e.g. IL-1b, IL-8, TNF-α) and tissue 
remodelling related mediators (e.g. TGF-β, MMPs).
Altogether, these findings support a prominent role for IL36R in driving skin and intestinal 
inflammation and support anti-human IL36R antibody BI 655130 as a therapeutic agent for 
epithelial-mediated inflammatory diseases such as GPP, PPP, and IBD.
GPP is characterised by systemic inflammation of the skin and internal organs [R15-1421; 
R16-0933]. Acute GPP is difficult to treat and no approved or standard of care therapy is 


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available in the US/EU. Current treatment options aiming to control acute GPP and maintain 
response are cyclosporine, acitretin, and methotrexate [R16-0933]. Secukinumab, Infliximab, 
Brodalumab, and Ixekizumab have been approved for GPP exclusively in Japan based on 
small local uncontrolled studies. Treatment is commonly not effective in suppressing acute 
flares during induction and recurrences emerge frequently.
PPP is a form of chronic Pustular Psoriasis characterized by sterile pustules limited to palms 
and soles [R16-0927]. No approved or effective treatment is available.
Both UC and CD are characterised by abdominal pain, fever, bloody diarrhoea, and 
inflammatory lesions in the gastrointestinal mucosa. Current treatment options include 
aminosalicylates, glucocorticoid therapy, azathioprine, 6-mercaptopurine, and biologics 
(blocking TNF or integrin α4β7). 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 progress, there remains a 
significant unmet medical need for new treatment options with an improved safety and 
efficacy profile compared with the current therapeutic standard.
1.2
DRUG PROFILE
1.2.1
Nonclinical pharmacology
BI 655130 is a humanized monoclonal antibody (mAb) of the IgG1 isotype that is directed 
against human IL36R. It is derived from a mouse antibody 81B4 (BI 674308) cloned into a 
human IgG1 Kappa backbone. The mAb uses an IgG1 that has two mutations in the Fc region 
(Leu234Ala and Leu235Ala) to reduce FcγR and complement binding. In addition, to reduce 
charge heterogeneity, the C-terminal lysine residue of the heavy chain is deleted.
For a more detailed description of the BI 655130 profile please refer to the current
Investigator’s Brochure (IB) [c03320877-04].
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 [c03320877-04].
1.2.3
Toxicology
As BI 655130 does not demonstrate adequate pharmacological activity in common 
toxicology species, a surrogate antibody (BI 674304) specific for mouse IL36R was 
developed and used for toxicology assessments. The toxicology package includes 4, 13 and 
26-week toxicity studies and reproductive/developmental toxicity studies with BI 674304 in 
mice. In addition, the toxicology package includes a 2-week toxicity study in mice with 
BI 655130 and local tolerance, in vitro cytokine release, and tissue cross-reactivity studies.


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1.2.4
Nonclinical pharmacokinetics
The pharmacokinetics (PK) of BI 655130 was studied in cynomolgus monkeys. In mice, 
pharmacokinetic studies were performed with the mouse-specific anti-IL36R antibody, 
BI 674304 [c03320877-04].
1.2.5
Clinical experience
In Phase I, BI 655130 has been evaluated in three clinical trials: a first-in-human (FIH) SRD 
trial [c09985235-01], an MRD trial [c09105854-05], and a recently completed relative 
bioavailability study exploring the pharmacokinetics as well as safety and tolerability of a 
newly developed SC formulation (1368-0003, [c10896574-01].
FIH-Study (Trial 1368.1)
The FIH (first-in-human) trial [c09985235-01] explored safety, tolerability, 
pharmacokinetics, and pharmacodynamics of intravenously administered BI 655130 in 
healthy male subjects. Subjects received single ascending IV doses of 
 up 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.
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 diarrhea 
(BI 655130: 2/58 subjects [3.4%]; placebo: 2/20 subjects [10.0%]).
There were two AEs of moderate intensity, both considered not related to the study drug, 
(injection site hematoma and 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. Deaths, serious AEs, and 
protocol-specified AEs of special interest were not reported in this trial. No clinically relevant 
changes were observed in 12 lead ECGs, vital signs, physical exams, and cardio-monitoring.
MRD study (Trial 1368.2)
Trial 1368.2 [c09105854-05] explored the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising intravenous doses of BI. 
In total, 40 subjects entered this trial and were treated. The study consisted of a multiple dose 
part with four dose groups 
 and a single dose arm 
 A total of 32 subjects were assigned to the MRD part. In each of the 4 dose 
groups 6 subjects received BI 655130 and 2 subjects received placebo. Additional 8 subjects 
entered the SD part of the trial with 6 subjects assigned to BI 655130 and 2 subjects assigned 
to placebo [c18789185-01].
Overall, a total of 3 subjects did not complete the planned observation time according to the 
CTP. One subject of the placebo group of the MRD part of the trial withdrew consent after 
having received all 4 planned doses. Two subjects of the 
 MD BI 655130 treatment 
group discontinued treatment because of AEs: 1 subject after having received 1 dose of 


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BI 655130 and the other subject after having received 3 doses of 
 BI 
655130 (infusion of the third dose was stopped after 8 min). 
The frequency of subjects with at least 1 drug-related treatment-emergent AE was similar for 
the MD placebo group and the MD BI 655130 treatment groups (ranging from 16.7% to 
66.7%), and no dose-dependency was observed. The drug related AE with the highest 
incidence was headache, which was reported in 5 of 6 subjects in the 
 group. 
Additionally, gastrointestinal disorders (abdominal discomfort, diarrhoea, and nausea) 
appeared to occur more often in subjects who received BI 655130 than in subjects who 
received placebo. Infusion related reaction, decreased appetite, and anxiety were only 
observed in the 
 MD BI 655130 treatment group. In total, 2 out of the 24 subjects 
(8.3%) who received multiple doses of BI 655130 were reported with AEs leading to
discontinuation of trial drug, 1 subject with mild pyrexia after the first infusion and 1 subject 
with mild and transient infusion related reactions during the third infusion. One subject of the 
placebo group of the MRD part of the trial withdrew consent after having received all 4 
planned doses.
Deaths, serious AEs, and protocol-specified AEs of special interest were not reported in this 
trial. No relevant changes were observed in safety laboratory tests, vital signs, and ECGs. For 
further details, please refer to the final study report [c18789185-01].
Trial 1368-0003
This study explored the pharmacokinetics as well as safety and tolerability of an SC
formulation of BI 655130 at 2 different dose strengths of 
 and 
 
in an open-label, sequential group design. Furthermore, the relative bioavailability of the 
 SC dose was compared with one single 
 IV dose of BI 655130 in an open-
label, matched group design.
The study included a total of 36 healthy male and female subjects with 12 subjects per 
treatment group. 
Based on preliminary data the SC formulation is considered to be well tolerated, the 
standardised assessment of injection pain, redness, induration, swelling, heat, or other 
findings did not reveal any noteworthy changes. There were three subjects with a transient 
occurrence of redness and one subject with a swelling at injection site 30 minutes after the SC 
injection. No further local tolerability findings were reported, in particular no injection pain 
and no induration at injection site during an observation period of up to 6 months.
Regarding systemic AEs, there were no AEs of severe intensity. Deaths, serious AEs, and 
protocol-specified AEs of special interest were not reported in this trial. No relevant changes 
were observed in safety laboratory tests, vital signs, and ECGs. The clinical part of the study 
has been completed. The study report is under preparation (final safety tables available, 
[c18789185-01]).
Pharmacokinetics
The PK parameters of BI 655130 after a single IV infusion from Trial 1368.1 are shown in 
Table 1.2.5:1. BI 655130 plasma levels were first detected at a dose level of 
 


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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. 
Table 1.2.5:1
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)
0.998 (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)


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In the MRD Trial 1368.2, PK data are consistent with the preceding single dose study as 
shown in Table 1.2.5:2. 
Table 1.2.5:2
Geometric mean (geometric CV %) PK parameters of BI655130 in 
study 1368.2 after multiple dosing  
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)
298 (9.26)
451 (7.96)
604 (4.77)
760 (4.21)
Cmax (µg/mL)
77.9 (19.4)
101 (11.4)
117 (14.8)
141 (4.33)
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)
552 (10.4)
895 (4.45)
1140 (5.11)
1390 (4.63)
Cmax (µg/mL)
130 (8.48)
185 (9.31)
223 (6.64)
253 (8.70)
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)
923 (17.3)
1610 (18.0)
2090 (16.9)
2500 (16.7)
Cmax (µg/mL)
229 (22.9)
310 (21.9)
444 (34.1)
467 (21.4)
Dose
N=5
[Day 1] 0-168 h
N=5
[Day 8] 168-336 h
N=4
[Day 15] 336-504 h
N=4
[Day 22] 504-600 h
AUC0-t (µg·day/mL)
1770 (12.5)
2900 (7.52)
3950 (16.1)
4660 (12.9)
Cmax (µg/mL)
422 (18.5)
646 (10.7)
780 (17.1)
826 (15.8)
Exposure of both dose groups is in the linear dose range. The geometric mean t1/2 values 
after dose 4 were similar across dose groups and ranged from 26.5 to 33.5 days with no dose 
dependency.
Table 1.2.5:3 summarizes PK data of the recent completed clinical study 1368.3 conducted 
according to a parallel (matched) group design. Bioavailability of the 
 SC injection 
was calculated to be about 50% and of the 
 SC injection 70% using the 
 IV 
group as reference.


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Table 1.2.5:3
Geometric mean (geometric CV %) PK parameters of BI655130 in 
study 1368.3 after a single dose  
Dose
 
N=11
[SC]
N=12
[SC]
N=11
[IV]
AUC0-inf  
(µg·day/mL)
574 (40.1)
1600 (29.5)
2280 (16.0)
Cmax
(µg/mL)
12.2 (44.5)
33.4 (32.7)
114 (18.0)
Tmax
1
(day)
0.3 - 14
7.0
4 - 21
6.0
0.02-0.3
0.13
t½
(day)
20.6 (26.7)
25.6 (23.5)
27.1 (17.1)
                                 1min – max, median
The geometric mean t1/2 values after subcutaneous administration ranged from 20.6
 
 to 25.6 
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 
 dose groups as compared 
to placebo. This demonstrates that BI 655130 is on-target for the time points analyzed.
Residual Effect Period
The Residual Effect Period (REP) of BI 655130 is up to 16 weeks. This is the period after the 
last dose with measurable drug levels and/or pharmacodynamic effects still likely to be 
present.
For a more detailed description of the BI 655130 profile please refer to the current
Investigator’s Brochure (IB) [c03320877-04].


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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 II development.
In Phase I studies BI 655130 was mainly administered as intravenous infusion. However, the 
subcutaneous injection route is considered to be required to enable in upcoming therapeutic 
studies the self-administration of BI 655130 by patients. For this reason a subcutaneous 
injection formulation is undergoing clinical development.
Recently, the clinical part of a Phase 1 study (Study 1368-0003) has been completed 
exploring the characteristics of a subcutaneous formulation of BI 655130 with particular 
focus on relative bioavailability compared to an intravenous formulation. A further objective 
was the assessment of local tolerability. In this study, the relative bioavailability of a single 
SC injection containing 
of BI 655130 
was in a range of about 50% while 
relative bioavailability increased to 70% for a single SC injection of 
 of BI 655130 
 
 
To further elucidate the origin of the observed potentially dose dependent increasing 
bioavailability, the current study will compare the pharmacokinetics (PK) of a single SC 
injection of 
 of BI 655130 with the PK of two SC injections of 
 
of BI 655130 
This design will investigate the impact of local factors at the SC 
injection site on the overall exposure of BI 655130 which may contribute to the lower 
bioavailability observed in the preceding clinical study.
The current study will also investigate the impact on relative bioavailability regarding the site 
of injection (abdomen and thigh) to enable the switch of injection site if needed.
To widen the SC dose range the current study will also investigate a subcutaneous dose of 
 of BI 655130 corresponding to two single periumbilical SC injections of 
 (i.e. 
total injection volume 
 
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the relative bioavailability of 
 
BI 655130 administered as two subcutaneous injections of
 in the left and right 
periumbilical region compared to a single subcutaneous periumbilical injection of 
 
BI 655130 
The secondary objective is to investigate the relative bioavailability of a single subcutaneous 
injection of 
 BI 655130 into the thigh compared to a single subcutaneous 
periumbilical injection of 
 BI 655130. 
A further objective is to investigate safety, tolerability, and pharmacokinetics of 
 BI 
655130 administered as two subcutaneous injections of 
 in the left and right 
periumbilical region.


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A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to optimize treatment regimen of 
the subcutaneous formulation for potential use as maintenance therapy in patients. The 
subjects are exposed to the risks of the study procedures and the risks related to the exposure 
to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to veinipuncture 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
The toxicology package conducted in mice with a mouse-specific antibody (BI 674304)
includes 4, 13 and 26-week toxicity studies and reproductive/developmental toxicity studies 
without any findings which would preclude clinical studies in humans (see IB 
[c03320877-04]).
The clinical safety and tolerability profile of BI 655130 was comparable to placebo in male 
subjects following once weekly intravenous doses of up to
 body weight
administered over 4 weeks. There were no deaths or other serious adverse events. 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.
Recently the clinical part of an initial with a subcutaneous formulation has been completed. 
The maximum tested SC dose was
 of BI 655130 (
 injection volume). The 
study did not reveal systemic or local AEs which would preclude further clinical studies with 
the SC formulation. The observed exposure at 
 following SC injection was about 6
fold lower compared to the maximum exposure in completed clinical studies with an IV 
infusion of up to 
 of BI 655130. Therefore even the planned maximum SC dose of 
 of BI 655130 is not expected to exceed exposure limits already tested in humans.
Based on studies in healthy subjects, 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:


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
The study will start with Dose Group 1 and 2 (periumbilical SC dose of 
 of 
BI 655130). Provided no dose limiting AEs occurred as 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 up to Day 10
(see Section 3.1), the study will pursue with Dose Group 3 (periumbilical SC dose of
 of BI 655130) and Dose Group 4 (SC dose of 
 of BI 655130 in the 
thigh). Dose Group 3 will be divided into 2 cohorts. In the first week, 6 subjects will 
be treated. There will be an interval of at least 1 week after start of dosing in the first 
cohort before start of dosing of the second cohort of Dose Group 3.

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.

Monitoring of ECG, vital signs, and extensive safety laboratory testing (Table 5.2.3:1)
is conducted throughout the study.

After dosing, the subjects will stay at the site for at least 48 hours.

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 for both expected and unexpected adverse events.
Currently there are no data available to suggest interactions of BI 655130 [c03320877-04].
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 laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.2.1, adverse events of special interest.
Based on the preclinical and 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 IBD and GPP, the benefit of this trial is considered 
to outweigh the potential 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 relative bioavailability, safety, and tolerability following a
subcutaneous (SC) injection of BI 655130 at different dose strengths, injection volumes, and 
injection sites: 
-
One SC injection of 
 periumbilical (Dose Group 1)
-
Two SC injections of 
each periumbilical left and right (Dose Group 2)
-
Two SC injections of 
each periumbilical left and right (Dose Group 3) 
-
One SC injection of 
 in the thigh (Dose Group 4)
The total dose in Dose Group 1, 2, and 4 is 
 of BI 655130 and the total dose in Dose 
Group 3 is 
 of BI 655130.
The study will be conducted in a single-dose, open-label, matched-group design. The 
exposure in Dose Group 1 will be used as reference to assess the relative bioavailability of 
Dose groups 2 - 4. For details refer to Section 4.1.
The study will start with Dose Group 1 and 2. After completion of treatment of the first two 
dose groups, the study will continue with Dose Group 3 and 4. 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).
The Dose Group 3 will follow a staggered administration with treatment of 6 subjects (cohort 
A) in the first week and the remaining subjects (cohort B) from Week 2. 
A documented Safety Review of Dose Group 1 and 2 at least 10 days after last dosing in 
Dose Group 2 must take place prior to continue the study with Dose Groups 3 and 4. 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. Continuation of the study 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 8 evaluable subjects in
each of the Dose Group 1 and 2 are required to decide about continuation with the remaining 
dose groups.
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)

Vital signs 

Clinical laboratory tests 

Check of criteria for stopping subject treatment as per Section 3.3.4.1


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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 
face-to-face or by video/telephone conference. The trial clinical monitor or a delegate 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 
 
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.
The plasma analyses of BI 655130 
 concentrations will be performed at 
 
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The study will be conducted according to a single-dose, open-label design with matched
groups.
The resulting group sizes (see Section 7.6) are considered to be sufficient for the exploratory
evaluation of pharmacokinetics. The assignment of matched healthy volunteers is a useful
method to control for other factors which may influence the pharmacokinetics of BI 1467335
in a renal impaired population.
The open-label treatment is not expected to bias results, since the primary endpoints are
derived from measurement of plasma concentrations of the analytes provided by a
bioanalytical laboratory. It is also considered sufficiently accurate as the trial observations are
objective (PK, laboratory) and over-reporting of AEs is unlikely.
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 tolerability of BI 655130 has already
been evaluated up to 
 MRD, resulting in a far higher exposure compared to the 
expected exposure of the current study.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 48 healthy male and female subjects (12 in each dose group) will enter the 
study. They will be recruited from the volunteers' pool of the trial site. Healthy subjects 
assigned to Dose Groups 2 - 4 will be matched on an individual level for gender and body 
weight (± 10%) to subjects assigned to Dose Group 1 
 periumbilical injection).
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 19.0 to 29.9 kg/m2 (incl.) 


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4. Signed and dated written informed consent prior to admission to the study in accordance 
with ICH-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 IU/L 
and estradiol below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) 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 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
7. History of relevant orthostatic hypotension, fainting spells, or blackouts
8. Chronic or relevant acute infections
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)


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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 up to 4 weeks after administration
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 
Female subjects will not be allowed to participate if any of the following applies:
22. Positive pregnancy test, pregnancy or plans to become pregnant up to study completion
23. Lactation
In addition, the following trial-specific exclusion criterion applies:
24. Previous use of the trial medication
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
This study is a single dose study, therefore removal of subjects from study medication after 
dosing is not applicable. 
An individual subject is to be removed from further assessments 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 from further assessments. This may include 
cases of sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP 


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>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.
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 administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (i.e., 16 weeks, see Section 1.2.5), 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 overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported that is 
considered to be unacceptable
2. The expected enrolment goals 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


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5. Further dosing will be stopped if at least 2 subjects in one dose group 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. Replacement of subjects should always be done in mutual agreement with the 
principal investigator. A replacement subject will be assigned a unique study subject number, 
and will be assigned to the same treatment and matching criteria as the subject he or she 
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 
The characteristics of the 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 or thigh)
Duration of use:
Single dose
At the time of use, the 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 
Dose Group 1, matching subjects will be allocated to the other dose groups. Therefore, the 
allocation of subjects to dose groups is not influenced by trial personnel, but only by the 
subjects’ temporal availability. As the study includes healthy subjects from a homogenous 
population matched for gender and body weight, relevant imbalances between the dose 
groups are not expected.
The allocation of subjects will be performed prior to the administration of trial medication. 
Once a subject number has been assigned to a treatment group, it cannot be reassigned to any 
other treatment group.
4.1.3
Selection of doses in the trial
The dose of 
 of BI 655130 selected for this trial has been selected to correspond to the 
potential dose for maintenance treatment in clinical trials in patients. The highest dose tested 
in this trial 
 of BI 655130) will be included to widen the SC dose range.


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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 solutions are provided in the ISF. 
Table 4.1.4: 1
Dosage and treatment schedule
Dose 
Group
Total 
dose
Route of 
administration
Concentration 
of application 
solution
Application volume
Injection site
1
SC
Periumbilical
2
SC
Periumbilical (left and right)
3
SC
Periumbilical (left and right
4
SC
Thigh
Following an overnight fast of at least 10 hours, the medication will be administered. Trial 
drug will be injected subcutaneously in the abdominal region or into the thigh. 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.
4.1.5
Blinding and procedures for unblinding
No blinding will be performed. 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. Emergency envelopes will not be provided, since 
the treatments of all subjects are known in this open-label trial.
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


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
Storage conditions

Use-by date

Batch number

Investigator

Subject number
The vials are labelled with reduced requirements.
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms.
Examples of the labels will be available in the ISF.
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 


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received from the sponsor. At the time of disposal, the investigator / pharmacist must verify 
that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
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 2 h 
after administration of the study drug.
From 1 h before until 2 h after SC injection, fluid intake is not allowed.
Smoking is not allowed during in-house confinement at the trial site.
Alcoholic beverages are not permitted starting 7 days before the administration of trial 
medication until Day 15. From Day 15 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.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during the in-house confinement.
Poppy-seed containing products are not allowed starting 2 days before screening and 2 days 
before admission to trial site (Day -1) to avoid false positive drug screening results.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the administration of trial medication up to 4 weeks after administration.
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

Vital signs (blood pressure, pulse rate)

Local tolerability
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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions

Chances 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.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 

is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation  

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse.
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since 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, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
The term adverse event of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.2.2.
The AESI in this trial is hepatic injury, as defined by the following alterations of hepatic 
laboratory parameters:


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
an elevation of AST (aspartate transaminase) and/or ALT (alanine aminotransferase) 
≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN measured in 
the same blood sample, or 

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure that these parameters 
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)


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
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
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 any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.


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AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for the initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B)
as well as non-trial specific information and consent for the pregnant partner.
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. 


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
Haematology
Haematocrit 
Haemoglobin 
Red Blood Cell count (RBC)
Reticulocytes count
White Blood Cells count (WBC)
Platelet Count
Automatic WBC differential 
(relative and absolute count possible)
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 (International 
Normalization Ratio)
Enzymes
AST [Aspartate transaminase] /GOT, SGOT
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase (GGT)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [CK-MB, only if CK is elevated]
Lactate Dehydrogenase (LDH)
Serum tryptase1
Hormones1
Thyroid Stimulating Hormone (TSH)
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total
Bilirubin, Direct
Bilirubin, Indirect
Protein, Total
Protein electrophoresis 1
Albumin 
Alpha-1-Globulin
Alpha-2-Globulin
Beta-Globulin
Gamma-Globulin
C-Reactive Protein (CRP)
Uric Acid 
Cholesterol, total
Triglyceride
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
BI test name [comment/abbreviation]
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
Urine sediment (microscopic
examination if urine analysis abnormal)
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, on Day 92, 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 (qual)
Hepatitis B core antibody (qual)
Hepatitis C antibodies (qual)
HIV-1 and HIV-2 antibody (qual)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Dräger 
Alcotest® 6510 and Alcotest® 510, Belgium) will be performed at screening and on 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.


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The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed 
 
 with the exception of the drug screening and pregnancy 
tests. These tests will be performed at the trial site using 'Alere Triage TOX Drug Screen' and 
Alere® –HCG urine, respectively.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a
computerised electrocardiograph (e.g. MAC 5500, GE Healthcare) at the time points given in 
the Flow Chart.
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 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.
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. 
5.2.5
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 (e.g. 
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 (including drug screen and pregnancy test), and a physical examination. The 
end of trial examination will include review of vital signs, 12-lead ECG, laboratory tests, 
recording of AEs and concomitant therapy and a physical examination with determination of 
weight.


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5.2.5.3
Local tolerability
Local tolerability will be assessed as specified in the Flow Chart by the investigator 
according to ‘swelling’, ‘induration’, ‘heat’, ‘redness’, ‘pain’, or ‘other findings’.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
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 parameters in an appropriate 
way. The scheduled measurements will allow monitoring of changes in vital signs, standard 
laboratory values, and ECG parameters that might occur as a result of administration of trial 
medication. The safety assessments are standard, are accepted for evaluation of safety and 
tolerability of an 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:


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
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
5.5.1.3
Further parameters of interest
The following additional endpoints will be evaluated for BI 655130:
Further pharmacokinetic parameters might be calculated as appropriate.
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 K2-EDTA (dipotassium 
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 K2-EDTA-anticoagulated blood samples will be mixed gently and placed on ice until 
centrifugation for about 10 min 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 min 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 -70°C or below at the clinical site until shipment to the 
analytical laboratory. 


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The plasma samples may be used for further methodological investigations (e.g. for stability 
testing), however, only data related to the analyte will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the final study report has been signed.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 655130 plasma concentration
BI 655130 concentrations in plasma will be determined by a validated immunoassay.


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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. 
The acceptable deviation from the scheduled time for vital signs, ECG and safety laboratory
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 15

± 72h from >Day 15 up to the last assessments
If scheduled in the Flow Chart at the same time as a meal, meal will be only provided after 
completion of the concomitant procedures. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, vital signs and 12-lead ECG recordings have to 
be done first and venipuncture should be the last of the measurements due to its 
inconvenience to the subject and possible influence on physiological parameters.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
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 


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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.
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, 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 prematurely the study before the end of the planned treatment 
period (i.e., Day 176 ±3) 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 trial objectives are stated in Section 2.2.
For the purpose of defining reference and test treatments, the following terminology will be 
used. The reference treatment (R) will refer to dose group 1, test treatment 1 (T1) refers to 
dose group 2, test treatment 2 (T2) refers to dose group 4 and test treatment 3 (T3) refers to 
dose group 3. 
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 analysis of primary and secondary endpoints will be an 
ANOVA (analysis of variance) model on the logarithmic scale. This model will include 
effects accounting for the following sources of variation: ‘treatment’ and ‘matched pair’. For 
each matched pair in the study a pair number will be assigned for analysis purpose. The 
resulting variable ‘matched pair’ will be considered as random effect.
The model is described by the following equation:
ykjm = + k + pj + eijkm, where
ykjm = logarithm of response (endpoint) measured on subject m in pair j receiving 
treatment k
= the overall mean,
k = the kth treatment effect, k=1,..,4,
pj = the jth matched pair effect,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.


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where pj ~ N(0,	
) i.i.d., eijk ~ N(0, 	
 ) i.i.d. and pj, eijk are independent random variables (note 
that the indices ‘B’ and ‘W’ correspond to ‘between’ pairs and ’within’ pairs variability, 
respectively).
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of the different dose groups 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 the Report Planning
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the clinical trial
report.
Relevant protocol violations may be:

Incorrect trial medication taken, that is, the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example:

The subject experiences emesis that occurred at or before 2 times median tmax of the 
respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis)

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve


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The following analysis sets will be defined for this trial:

Treated set (TS):
This subject set includes all subjects from the RS who were documented to have 
received one dose of study drug. This is the full analysis set population in the sense of 
ICH-E9

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the 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/she contributes only one PK 
parameter value for one period to the statistical assessment
Point estimates of the ratios of the geometric means (test/reference) for the primary and 
secondary endpoints (see Sections 5.5.1.1 and 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 (Least Squares Means), and a two-sided 90% confidence interval based on the 
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.
The comparisons of interest will be T1 vs. R, T2 vs. R, and T3 vs. R. Further comparisons
may be investigated if appropriate (e.g. T1 vs. T2) and will be described in the TSAP.
7.3.2
Secondary analyses
The same statistical model as stated in Section 7.1.3 will be repeated for the primary and 
secondary endpoints but with all sources of variation considered as fixed effects.
Additionally, the pharmacokinetic parameters listed in Section 5.5.1.3 will be calculated and 
analysed descriptively, if feasible.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is,
all subjects who received at least one dose of study drug), will be included in the safety
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
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.


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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 first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until end of the residual 
effect period (see Section 1.2.5) will be assigned to the treatment period. Events after the 
residual effect period but prior to next intake or end of trial examination will be summarized 
as ‘follow-up’. The follow-up will be summarised according to previous treatment. These 
assignments including the corresponding time intervals will be defined in detail in the TSAP. 
AEs occurring after the last per-protocol contact but entered before database lock will be 
reported to drug safety only and will not be captured in the trial database.
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.
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.
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 drug BI 655130 will be calculated 
according to the relevant SOP of the Sponsor [001-MCS-36-472].
Individual plasma concentration data and the pharmacokinetic parameters will be tabulated,
graphically displayed and summarized by descriptive statistics. The analysis of PK endpoints 
will be based on PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).


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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 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
The study will not be randomised as individually matched subjects will be used. Thus, this 
section is not applicable.
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 4*12 = 48 subjects in the trial, because this sample size is 
considered sufficient to achieve the aims of this exploratory trial. With this sample size, the 
following precision in estimating the ratio of geometric means (test/reference) can be 
expected with 95% probability. Precision is defined as the ratio of upper CI limit to the 
relative BA estimate. Note that the precision is independent of the actual ratio of geometric 
means.


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The observed inter-individual geometric coefficient of variation (gCV) in a previous trial 
(1368.3) was roughly 30% for Cmax and for AUC. For various assumptions on the gCV, 
Table 7.6: 1 provides an overview of the precision for estimating the ratio of geometric 
means (test/reference). For illustrative purposes, the expected 90% confidence intervals are 
displayed for different values of the ratios T/R of geometric means.
Table 7.6: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a parallel trial (for one comparison 
based on 2 arms)
gCV [%]
Precision 
upper CL / 
relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
25
1.24
90
72.64
111.51
25
1.24
100
80.71
123.90
25
1.24
110
88.78
136.29
30
1.29
90
69.70
116.21
30
1.29
100
77.45
129.12
30
1.29
110
85.19
142.03
35
1.34
90
66.95
120.99
35
1.34
100
74.38
134.44
35
1.34
110
81.82
147.88
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The 90% confidence interval limits in the table were derived by
CI limit, = 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 Julious [R11-5230, Chapter 8] using R 
Version 3.4.2.


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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/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 


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auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the 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
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
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 201; 365(7):620-628.
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.
R16-0927
Waal AC de, Kerkhof PCM van de; Pustulosis palmoplantaris is a disease 
distinct from psoriasis; J Dermatol Treat 22 (2), 102 - 105 (2011)
R16-0929
Berki DM, Liu L, Choon SE, Burden AD, Griffiths CEM, Navarini AA,
Tan ES, Irvine AD, Ranki A, Ogo T, Petrol G, Mahil SK, Duckworth M,
Allen MH, Vito P, Trembath RC, McGrath J, Smith CH, Capon F, Barker
JN; Activating CARD14 mutations are associated with generalized pustular 
psoriasis but rarely account for familial recurrence in psoriasis
R16-0933
Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF; 
Clinical profile, morbidity, and outcome of adult-onset generalized pustular 
psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, 
Malaysia; Int J Dermatol 53, 676 - 684 (2014)


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c03320877-04
 Investigator´s Brochure BI 655130 for IL36R antibody in 
Ulcerative Colitis, Palmoplantar Pustulosis and Pustular Psoriasis. 10 Oct 
2017
c09105854-05
, Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising intravenous doses of BI 655130 
(double-blind, partially randomised within dose groups, placebo-controlled 
parallel group design) and one single intravenous dose of BI 655130
(single-blind, partially randomised, placebo-controlled) in healthy male 
subjects, 1368.2, 02 Aug 2017
c09985235-01
Single-blind, partially 
randomised, placebo-controlled Phase I study to investigate safety, 
tolerability, pharmacokinetics and pharmacodynamics of single rising 
intravenous doses of BI 655130 in healthy male volunteers, 1368.1, 07 Apr 
2017 
c10896574-01
 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). 1368.3. 08 Mar 2017 
c18789185-01
 Safety, tolerability, pharmacokinetics 
and pharmacodynamics of multiple rising intravenous doses of BI 655130 
(double-blind, partially randomised within dose groups, placebo-controlled 
parallel group design) and one single intravenous dose of BI 655130 
(singleblind, partially randomised, placebo-controlled) in healthy male 
subjects. 1368.2. 29 May 2018 


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10.
APPENDICES
10.1
PREPARATION AND HANDLING OF BI 655130 SOLUTION FOR 
INJECTION 
10.1.1
Preparation Instructions 
 SC (Dose group 1,  injection left or right 
periumbilical)
Necessary materials: 
2 Vials BI 655130 Solution for Injection 
Consumables: 
 sterile syringe (material: polypropylene) - e.g. B. Braun Injekt Solo 
(article no: 4606027) 
 1½” needle (material: stainless steel/ polypropylene) – e.g. B. Braun 
(article no: 4657527)
 ½” needle for injection (material: stainless steel/ polypropylene) – e.g. BD 
(article no: 305770)
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 
syringe closure (e.g. B.Braun Combi-Stopper).
7.
Attach a sterile 
 ½” needle to the syringe, adjust the volume to 
 and 
gently inject the complete content of the syringe at the left or right periumbilical 
region.


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10.1.2
Preparation Instructions 
 SC dose (Dose Group 2, injection left and
right periumbilical)
Necessary materials: 
2 Vials BI 655130 Solution for Injection 
Consumables: 
1 x 
 sterile syringe (material: polypropylene) - e.g. B. Braun Injekt F 
(article no: 9166017V) 
2 x 
 1½” needle (material: stainless steel/ polypropylene) – e.g. B. Braun 
(article no 4657527)
2 x 
 ½” needle for injection (material: stainless steel/ polypropylene) – e.g. BD 
(article no: 305770)
1. Take a vial filled with 
 of 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 
syringe closure (e.g. B.Braun Combi-Stopper).
6. Attach a sterile 
 ½” needle to the 
 syringe, adjust the volume to 
 
(=syringe 1).
7. Repeat steps 1 to 6 with the second vial to prepare a second, separate syringe ready 
for injection (=syringe 2).
8. Gently inject the complete content of the first syringe containing 
 solution for 
injection at the left or right periumbilical region.
9. Gently inject the complete content of the second syringe containing 
 solution for 
injection periumbilical contralateral to the injection site of the first injection.


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10.1.3
Preparation Instructions 
 SC dose (Dose group 3, injection left and
right periumbilical)
Necessary materials: 
4 Vials BI 655130 Solution for Injection 
Consumables: 
 sterile syringe (material: polypropylene) - e.g. B. Braun Injekt Solo 
(article no: 4606027) 
 1½”needle (material: stainless steel/ polypropylene) – e.g. B. Braun 
(article no 4657527)
 ½” needle for injection (material: stainless steel/ polypropylene) – e.g. BD 
(article no: 305770)
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 
syringe closure (e.g. B.Braun Combi-Stopper).
7.
Attach a sterile 
 ½” needle to the syringe, adjust the volume to 
 (=syringe 
1)
8.
Repeat steps 1 to 7 with the second vial to prepare a second, separate syringe 
ready for injection (=syringe 2).
9.
Gently inject the complete content of the first syringe containing 
 solution for 
injection at the left or right periumbilical region .
10.
Gently inject the complete content of the second syringe containing 
 solution 
for injection periumbilical contralateral to the injection site of the first injection.


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10.1.4
Preparation Instructions 
 SC dose (Dose group 4, injection in the 
thigh)
Necessary materials: 
2 Vials BI 655130 Solution for Injection 
Consumables: 
 sterile syringe (material: polypropylene) - 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: 305770)
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 
syringe closure (e.g. B.Braun Combi-Stopper).
7.
Attach a sterile 
 needle to the syringe, adjust the volume to 
 and 
gently inject the complete content of the syringe in the left or right thigh.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
20 September 2018
EudraCT number
2018-001074-18
BI Trial number
1368-0029
BI Investigational Product(s)
BI 655130
Title of protocol
Relative bioavailability, safety, and tolerability 
following subcutaneous injection of different 
doses of BI 655130 and different injection sites in 
healthy male and female subjects (a single dose, 
mono-centric, open-label study in matched-group 
design).
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
5.5.2 Methods of sample collection
Description of change
Temperature for storage of clinical samples was 
changed to -70°C.
Rationale for change
Update on storage temperature.


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Number of global amendment
2
Date of CTP revision
07 Jan 2019
EudraCT number
2018-001074-18
BI Trial number
1368-0029
BI Investigational Product(s)
BI 655130
Title of protocol
Relative bioavailability, safety, and tolerability 
following subcutaneous injection of different 
doses of BI 655130 and different injection sites in 
healthy male and female subjects (a single dose, 
mono-centric, open-label study in matched-group 
design).
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.2.5 
Clinical experience
3.3.4,1 Removal of individual subjects
Description of change
Residual effect period (REP) changed from 176±3 
to 16 weeks.
Rationale for change
Residual effect period in ongoing patient studies 
16 weeks, change was required to assure 
consistency across clinical studies with BI 
655130.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21745299
3.0
clinical-trial-protocol-revision-02
Relative bioavailability, safety, and tolerability following subcutaneous injection of
different doses of BI 655130 and different injection sites in healthy male and female
subjects (a single dose, mono-centric, open-label study in matched-group design).
Author-Clinical Trial Leader
07 Jan 2019 13:49 CET
Author-Trial Clinical
Pharmacokineticist
07 Jan 2019 14:53 CET
Approval-Therapeutic Area 
07 Jan 2019 15:46 CET
Verification-Paper Signature
Completion
08 Jan 2019 12:51 CET
Approval-Team Member Medicine
08 Jan 2019 18:24 CET
Author-Trial Statistician
08 Jan 2019 19:52 CET


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21745299
3.0


001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c21745299-03
EudraCT No.:
BI Trial No.:
2018-001074-18
1368-0029
BI Investigational
Product:
BI 655130
Title:
Relative bioavailability, safety, and tolerability following 
subcutaneous injection of different doses of BI 655130 and different 
injection sites in healthy male and female subjects (a single dose, 
mono-centric, open-label study in matched-group design).
Lay Title:
A study in healthy people to measure the amount of BI 655130 in the 
blood after injecting different doses into different parts of the body
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version 3.0
Date: 07 January 2019
Page 1 of 63
Proprietary confidential information
© 2019 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:
07 January 2019
25 June 2018
1368-0029
Title of trial:
Relative bioavailability, safety, and tolerability following subcutaneous 
injection of different doses of BI 655130 and different injection sites in 
healthy male and female subjects (a single dose, mono-centric, open-label 
study in matched-group design).
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
-
To investigate the relative bioavailability of 
 BI 655130 
administered as two subcutaneous injections of 
 in the left 
and right periumbilical region compared to a single subcutaneous 
periumbilical injection of 
 BI 655130 
-
To investigate the relative bioavailability of a single subcutaneous 
injection of 
BI 655130 into the thigh compared to a single 
subcutaneous periumbilical injection of 
 BI 655130
-
To investigate safety, tolerability, and pharmacokinetics of 
 BI 
655130 administered as two subcutaneous injections of 
in 
the left and right periumbilical region.
Methodology:
Single dose, open-label in matched-group design
No. of subjects: 
total entered:
48
each treatment:
12
Diagnosis:
Healthy subjects assigned to Dose Group 2 
 left and right 
periumbilical SC injection, 
 of BI 655130), Dose group 3 
 
left and right periumbilical SC injection, 
 of BI 655130) and Dose 
Group 4 
 SC injection in the thigh, 
 of BI 655130) will be 
matched for gender and body weight (± 10%) to subjects assigned to Dose 
Group 1 
, periumbilical SC injection, 
 of BI 655130).


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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:
07 January 2019
25 June 2018
1368-0029
Main criteria
for inclusion:
Healthy male and female subjects, age of 18 to 50 years, body mass index 
(BMI) of 19.0 to 29.9 kg/m2
Test treatment:
BI 655130 
 solution for injection 
dose:
mode of admin.:
Subcutaneous (SC) injection:
-
Two single injections of 
 periumbilical left and right (Dose Group 2)
-
Two single injections of
 periumbilical left and right (Dose Group 3)
-
One single injection of 
 into the thigh (Dose Group 4)
Reference treatment:
BI 655130 
 solution for injection 
dose:
mode of admin.:
One single subcutaneous (SC) injection of 
 periumbilical (Dose Group 1)
Duration of treatment: One day (single dose) for each treatment
Criteria for
pharmacokinetics:
Primary endpoints: AUC0-tz and Cmax
Secondary endpoints: AUC0-
Further parameters of interest as appropriate.
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, local tolerability, safety laboratory tests, 12-lead 
electrocardiogram (ECG), vital signs (blood pressure [BP], pulse rate [PR]).
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’, and ‘matched pair’. 
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
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma
4
Plasma ADA
Laboratory/
Urinalysis 3
12-lead ECG
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies9
Query regarding local 
tolerability5
1
-28
to -3
Screening1
X12
X
X
-5
Ambulatory visit
X11
2
-1
-12:00
20:00
Admission to
trial site
X8
X
1
-2:00
6:00
X2
X2
X2, 12
X2
X2
X2
X
0:00
8:00
Drug 
administration
0:30
8:30
X
X
1:00
9:00
X
2:00
10:00
Light breakfast6
X
X
3:00
11:00
X
4:00
12:00
Lunch6
X
X
X
X
6:00
14:00
X
8:00
16:00
Snack (voluntary)6
X
X
10:00
18:00
Dinner6
12:00
20:00
X
X
X
X
X
2
24:00
8:00
Breakfast6
X
X
X
X
X
28:00
12:00
Lunch6
32:00
16:00
Snack (voluntary)6
X
34:00
18:00
Dinner6
X
X
3
48:00
8:00
Breakfast6
discharge from
trial site
(confirmation of 
fitness7)
X
X
X
X
X
X
4
72:00
8:00
Ambulatory visit
X
X
X
5
96:00
8:00
Ambulatory visit
X
X
X
6
120:00
8:00
Ambulatory visit
X
X
X
7
144:00
8:00
Ambulatory visit
X
X
X
8
168:00
8:00
Ambulatory visit
X
X
X
X
X
X
15
336:00
8:00
Ambulatory visit
X
X
X
X
X


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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), drug screening, alcohol breath test, 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 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.
8. 
Only drug screening and alcohol breath test.
9.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time 
points indicated in the Flow Chart above.
10.
EoTrial (End of trial examination) includes physical examination, body weight, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. EoTrial must not be performed before last PK and ADA sampling. 
11.
Safety laboratory is to be taken within five days prior to study drug administration and can be omitted if the
screening examination is performed between Day -5 and Day -3.
12.
At these time points, a pregnancy test will be done.
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKblood 
4
Plasma ADA
Laboratory/
Urinalysis 3
12-lead ECG
vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies9
Query regarding local 
tolerability5
2
22
504:00
8:00
Ambulatory visit
X
X
X
X
29
672:00
8:00
Ambulatory visit
X
X
X
X
X
X
X
36
840:00
8:00
Ambulatory visit
X
X
43
1008:00
8:00
Ambulatory visit
X
X
X
57 ±3
1344:00
8:00
Ambulatory visit
X
X
X
X
71 ±3
1680:00
8:00
Ambulatory visit
X
X
X
92 ±3
2184:00
8:00
Ambulatory visit
X
X
X12
X
X
120 ±3
2856:00
8:00
Ambulatory visit
X
X
X
148 ±3
3528:00
8:00
Ambulatory visit
X
X
X
3
176 ±3 
4200:00
8:00
EoTrial10
X
X
X12
X
X
X
X


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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.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Nonclinical pharmacology....................................................................13
1.2.2
Safety pharmacology ............................................................................13
1.2.3
Toxicology..............................................................................................13
1.2.4
Nonclinical pharmacokinetics..............................................................14
1.2.5
Clinical experience................................................................................14
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 19
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................19
2.2
TRIAL OBJECTIVES.......................................................................................19
2.3
BENEFIT - RISK ASSESSMENT ...................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 22
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................22
3.1.1
Administrative structure of the trial...................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................24
3.3.1
Main diagnosis for study entry............................................................24
3.3.2
Inclusion criteria...................................................................................24
3.3.3
Exclusion criteria ..................................................................................25
3.3.4
Removal of subjects from therapy or assessments.............................26
3.3.4.1
Removal of individual subjects................................................26
3.3.4.2
Discontinuation of the trial by the sponsor..............................27
3.3.5
Replacement of subjects .......................................................................28
4.
TREATMENTS........................................................................................ 29
4.1
TREATMENTS TO BE ADMINISTERED....................................................29
4.1.1
Identity of BI investigational product.................................................29
4.1.2
Method of assigning subjects to treatment groups ............................29
4.1.3
Selection of doses in the trial................................................................29
4.1.4
Drug assignment and administration of doses for each subject .......30


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4.1.5
Blinding and procedures for unblinding ............................................30
4.1.6
Packaging, labelling, and re-supply ....................................................30
4.1.7
Storage conditions.................................................................................31
4.1.8
Drug accountability ..............................................................................31
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................32
4.2.1
Other treatments and emergency procedures....................................32
4.2.2
Restrictions............................................................................................32
4.2.2.1
Restrictions regarding concomitant treatment .........................32
4.2.2.2
Restrictions on diet and life style.............................................32
4.3
TREATMENT COMPLIANCE.......................................................................33
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 34
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................34
5.1.1
Endpoints of efficacy.............................................................................34
5.1.2
Assessment of efficacy...........................................................................34
5.2
SAFETY..............................................................................................................34
5.2.1
Endpoints of safety................................................................................34
5.2.2
Assessment of adverse events...............................................................34
5.2.2.1
Definitions of adverse events...................................................34
5.2.2.2
Adverse event collection and reporting ...................................37
5.2.3
Assessment of safety laboratory parameters......................................38
5.2.4
Electrocardiogram................................................................................41
5.2.5
Assessment of other safety parameters...............................................41
5.2.5.1
Vital signs ................................................................................41
5.2.5.2
Medical examinations..............................................................41
5.2.5.3
Local tolerability......................................................................42
5.3
OTHER...............................................................................................................42
5.3.1
Pharmacogenomic evaluation..............................................................42
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................42
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................42
5.5.1
Pharmacokinetic endpoints..................................................................42
5.5.1.1
Primary endpoints....................................................................42
5.5.1.2
Secondary endpoint..................................................................42
5.5.2
Methods of sample collection...............................................................43
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................43
5.5.2.2
Plasma sampling for ADA assessment ....................................44
5.5.3
Analytical determinations ....................................................................44
5.5.3.1
Analytical determination of BI 655130 plasma concentration 44
5.5.3.2
Analytical determination of ADA to BI 655130......................44
6.
INVESTIGATIONAL PLAN.................................................................. 45


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6.1
VISIT SCHEDULE............................................................................................45
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................45
6.2.1
Screening period....................................................................................45
6.2.2
Treatment period ..................................................................................45
6.2.3
End of trial period.................................................................................46
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 47
7.1
STATISTICAL DESIGN – MODEL ...............................................................47
7.1.1
Objectives...............................................................................................47
7.1.2
Endpoints...............................................................................................47
7.1.3
Model......................................................................................................47
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................48
7.3
PLANNED ANALYSES....................................................................................48
7.3.1
Primary analyses...................................................................................48
7.3.3
Safety analyses.......................................................................................49
7.3.4
Interim analyses ....................................................................................50
7.3.5
Pharmacokinetic analyses ....................................................................50
7.4
HANDLING OF MISSING DATA ..................................................................51
7.4.1
Safety......................................................................................................51
7.4.2
Plasma drug concentration - time profiles..........................................51
7.4.3
Pharmacokinetic parameters...............................................................51
7.5
RANDOMISATION ..........................................................................................51
7.6
DETERMINATION OF SAMPLE SIZE ........................................................51
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 53
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................53
8.2
DATA QUALITY ASSURANCE .....................................................................53
8.3
RECORDS..........................................................................................................54
8.3.1
Source documents .................................................................................54
8.3.2
Direct access to source data and documents.......................................54
8.3.3
Storage period of records.....................................................................54
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................54
8.5
STATEMENT OF CONFIDENTIALITY.......................................................55
8.6
COMPLETION OF TRIAL..............................................................................55
9.
REFERENCES......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56
9.2
UNPUBLISHED REFERENCES.....................................................................57
10. APPENDICES .......................................................................................... 58


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10.1
PREPARATION AND HANDLING OF BI 655130 SOLUTION FOR 
INJECTION 
.................................................................................58
10.1.1 Preparation Instructions 
 SC (Dose group 1,  injection 
left or right periumbilical)....................................................................58
10.1.2 Preparation Instructions 
 SC dose (Dose Group 2, 
injection left and right periumbilical).................................................59
10.1.3 Preparation Instructions
 SC dose (Dose group 3, 
injection left and right periumbilical).................................................60
10.1.4 Preparation Instructions 
 SC dose (Dose group 4, 
injection in the thigh)............................................................................61
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 62


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ABBREVIATIONS
ADA
Anti-drug antibodies
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
CA
Competent authority
CD
Crohn’s Disease
CI
Confidence interval
CL
confidence limits
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Coefficient of variation
DILI
Drug induced liver impairment
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EoTrial
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
HIV
Human Immunodeficiency Virus
IB
Investigator’s brochure
IBD
Inflammatory bowel diseases
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IL36R
Interleukin 36 receptor
IRB
Institutional Review Board


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ISF
Investigator site file
ITE
Indirect target engagement
IV
Intravenous
KO
Knock out
LOQ
Limit of Quantification
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MIP
Macrophage inflammatory protein
MRD
Multiple rising dose
N
Number
NC
Not calculated
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
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
SAE
Serious adverse event
SOP
Standard Operating Procedure
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
Vz
Volume of distribution during the terminal phase after intravascular 
administration
WBC
White Blood Cells


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36 
receptor (IL36R) signalling. Binding of BI 655130 to IL36R is anticipated to prevent the 
subsequent activation of IL36R by cognate ligands (IL36 α, β and γ) and downstream 
activation of pro-inflammatory and pro-fibrotic pathways in inflammatory skin and bowel 
diseases such as generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), and 
inflammatory bowel disease (IBD).
Genetic human studies established a strong link between IL36R signalling and skin 
inflammation, as demonstrated by the occurrence of GPP in patients with a loss of function
mutation in IL36Rα,the gene encoding the endogenous inhibitor of IL36R, which resulted in 
uncontrolled IL36R signalling [R14-5158, R15-1421]. Mutations in other genes linked to the 
IL36 pathway such as CARD14 also lead to GPP [R16-0929]. IL36R signalling drives skin 
inflammation in several animal models, further supporting the strong link between IL36R 
biology and skin disorders based on human genetics [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 [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 signalling may play an important role in IBD. 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 patients with Crohn’s 
disease (CD). Human IL36 ligands enhanced intestinal barrier permeability, a hallmark of 
IBD pathogenesis, in primary human intestinal epithelial cells co-cultured with intestinal 
myofibroblasts. The link between IL36R signalling and IBD was further strengthened by 
demonstrating that antagonist anti-mouse IL36R antibodies ameliorated intestinal 
inflammation in both acute and chronic 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 (UC) and CD 
patients. Finally, IL36R signalling in disease relevant cells, such as intestinal myofibroblasts 
and macrophages, induces both pro-inflammatory (e.g. IL-1b, IL-8, TNF-α) and tissue 
remodelling related mediators (e.g. TGF-β, MMPs).
Altogether, these findings support a prominent role for IL36R in driving skin and intestinal 
inflammation and support anti-human IL36R antibody BI 655130 as a therapeutic agent for 
epithelial-mediated inflammatory diseases such as GPP, PPP, and IBD.
GPP is characterised by systemic inflammation of the skin and internal organs [R15-1421; 
R16-0933]. Acute GPP is difficult to treat and no approved or standard of care therapy is 


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available in the US/EU. Current treatment options aiming to control acute GPP and maintain 
response are cyclosporine, acitretin, and methotrexate [R16-0933]. Secukinumab, Infliximab, 
Brodalumab, and Ixekizumab have been approved for GPP exclusively in Japan based on 
small local uncontrolled studies. Treatment is commonly not effective in suppressing acute 
flares during induction and recurrences emerge frequently.
PPP is a form of chronic Pustular Psoriasis characterized by sterile pustules limited to palms 
and soles [R16-0927]. No approved or effective treatment is available.
Both UC and CD are characterised by abdominal pain, fever, bloody diarrhoea, and 
inflammatory lesions in the gastrointestinal mucosa. Current treatment options include 
aminosalicylates, glucocorticoid therapy, azathioprine, 6-mercaptopurine, and biologics 
(blocking TNF or integrin α4β7). 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 progress, there remains a 
significant unmet medical need for new treatment options with an improved safety and 
efficacy profile compared with the current therapeutic standard.
1.2
DRUG PROFILE
1.2.1
Nonclinical pharmacology
BI 655130 is a humanized monoclonal antibody (mAb) of the IgG1 isotype that is directed 
against human IL36R. It is derived from a mouse antibody 81B4 (BI 674308) cloned into a 
human IgG1 Kappa backbone. The mAb uses an IgG1 that has two mutations in the Fc region 
(Leu234Ala and Leu235Ala) to reduce FcγR and complement binding. In addition, to reduce 
charge heterogeneity, the C-terminal lysine residue of the heavy chain is deleted.
For a more detailed description of the BI 655130 profile please refer to the current
Investigator’s Brochure (IB) [c03320877-04].
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 [c03320877-04].
1.2.3
Toxicology
As BI 655130 does not demonstrate adequate pharmacological activity in common 
toxicology species, a surrogate antibody (BI 674304) specific for mouse IL36R was 
developed and used for toxicology assessments. The toxicology package includes 4, 13 and 
26-week toxicity studies and reproductive/developmental toxicity studies with BI 674304 in 
mice. In addition, the toxicology package includes a 2-week toxicity study in mice with 
BI 655130 and local tolerance, in vitro cytokine release, and tissue cross-reactivity studies.


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1.2.4
Nonclinical pharmacokinetics
The pharmacokinetics (PK) of BI 655130 was studied in cynomolgus monkeys. In mice, 
pharmacokinetic studies were performed with the mouse-specific anti-IL36R antibody, 
BI 674304 [c03320877-04].
1.2.5
Clinical experience
In Phase I, BI 655130 has been evaluated in three clinical trials: a first-in-human (FIH) SRD 
trial [c09985235-01], an MRD trial [c09105854-05], and a recently completed relative 
bioavailability study exploring the pharmacokinetics as well as safety and tolerability of a 
newly developed SC formulation (1368-0003, [c10896574-01].
FIH-Study (Trial 1368.1)
The FIH (first-in-human) trial [c09985235-01] explored safety, tolerability, 
pharmacokinetics, and pharmacodynamics of intravenously administered BI 655130 in 
healthy male subjects. Subjects received single ascending IV doses of 
 up 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.
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 diarrhea 
(BI 655130: 2/58 subjects [3.4%]; placebo: 2/20 subjects [10.0%]).
There were two AEs of moderate intensity, both considered not related to the study drug, 
(injection site hematoma and 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. Deaths, serious AEs, and 
protocol-specified AEs of special interest were not reported in this trial. No clinically relevant 
changes were observed in 12 lead ECGs, vital signs, physical exams, and cardio-monitoring.
MRD study (Trial 1368.2)
Trial 1368.2 [c09105854-05] explored the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising intravenous doses of BI. 
In total, 40 subjects entered this trial and were treated. The study consisted of a multiple dose 
part with four dose groups 
 and a single dose arm 
 A total of 32 subjects were assigned to the MRD part. In each of the 4 dose 
groups 6 subjects received BI 655130 and 2 subjects received placebo. Additional 8 subjects 
entered the SD part of the trial with 6 subjects assigned to BI 655130 and 2 subjects assigned 
to placebo [c18789185-01].
Overall, a total of 3 subjects did not complete the planned observation time according to the 
CTP. One subject of the placebo group of the MRD part of the trial withdrew consent after 
having received all 4 planned doses. Two subjects of the 
 MD BI 655130 treatment 
group discontinued treatment because of AEs: 1 subject after having received 1 dose of 


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BI 655130 and the other subject after having received 3 doses of 
 BI 
655130 (infusion of the third dose was stopped after 8 min). 
The frequency of subjects with at least 1 drug-related treatment-emergent AE was similar for 
the MD placebo group and the MD BI 655130 treatment groups (ranging from 16.7% to 
66.7%), and no dose-dependency was observed. The drug related AE with the highest 
incidence was headache, which was reported in 5 of 6 subjects in the 
 group. 
Additionally, gastrointestinal disorders (abdominal discomfort, diarrhoea, and nausea) 
appeared to occur more often in subjects who received BI 655130 than in subjects who 
received placebo. Infusion related reaction, decreased appetite, and anxiety were only 
observed in the 
 MD BI 655130 treatment group. In total, 2 out of the 24 subjects 
(8.3%) who received multiple doses of BI 655130 were reported with AEs leading to
discontinuation of trial drug, 1 subject with mild pyrexia after the first infusion and 1 subject 
with mild and transient infusion related reactions during the third infusion. One subject of the 
placebo group of the MRD part of the trial withdrew consent after having received all 4 
planned doses.
Deaths, serious AEs, and protocol-specified AEs of special interest were not reported in this 
trial. No relevant changes were observed in safety laboratory tests, vital signs, and ECGs. For 
further details, please refer to the final study report [c18789185-01].
Trial 1368-0003
This study explored the pharmacokinetics as well as safety and tolerability of an SC
formulation of BI 655130 at 2 different dose strengths of 
 
in an open-label, sequential group design. Furthermore, the relative bioavailability of the 
 SC dose was compared with one single 
 IV dose of BI 655130 in an open-
label, matched group design.
The study included a total of 36 healthy male and female subjects with 12 subjects per 
treatment group. 
Based on preliminary data the SC formulation is considered to be well tolerated, the 
standardised assessment of injection pain, redness, induration, swelling, heat, or other 
findings did not reveal any noteworthy changes. There were three subjects with a transient 
occurrence of redness and one subject with a swelling at injection site 30 minutes after the SC 
injection. No further local tolerability findings were reported, in particular no injection pain 
and no induration at injection site during an observation period of up to 6 months.
Regarding systemic AEs, there were no AEs of severe intensity. Deaths, serious AEs, and 
protocol-specified AEs of special interest were not reported in this trial. No relevant changes 
were observed in safety laboratory tests, vital signs, and ECGs. The clinical part of the study 
has been completed. The study report is under preparation (final safety tables available, 
[c18789185-01]).
Pharmacokinetics
The PK parameters of BI 655130 after a single IV infusion from Trial 1368.1 are shown in 
Table 1.2.5:1. BI 655130 plasma levels were first detected at a dose level of 
 


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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. 
Table 1.2.5:1
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)
0.998 (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)


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In the MRD Trial 1368.2, PK data are consistent with the preceding single dose study as 
shown in Table 1.2.5:2. 
Table 1.2.5:2
Geometric mean (geometric CV %) PK parameters of BI655130 in 
study 1368.2 after multiple dosing  
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)
298 (9.26)
451 (7.96)
604 (4.77)
760 (4.21)
Cmax (µg/mL)
77.9 (19.4)
101 (11.4)
117 (14.8)
141 (4.33)
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)
552 (10.4)
895 (4.45)
1140 (5.11)
1390 (4.63)
Cmax (µg/mL)
130 (8.48)
185 (9.31)
223 (6.64)
253 (8.70)
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)
923 (17.3)
1610 (18.0)
2090 (16.9)
2500 (16.7)
Cmax (µg/mL)
229 (22.9)
310 (21.9)
444 (34.1)
467 (21.4)
Dose
N=5
[Day 1] 0-168 h
N=5
[Day 8] 168-336 h
N=4
[Day 15] 336-504 h
N=4
[Day 22] 504-600 h
AUC0-t (µg·day/mL)
1770 (12.5)
2900 (7.52)
3950 (16.1)
4660 (12.9)
Cmax (µg/mL)
422 (18.5)
646 (10.7)
780 (17.1)
826 (15.8)
Exposure of both dose groups is in the linear dose range. The geometric mean t1/2 values 
after dose 4 were similar across dose groups and ranged from 26.5 to 33.5 days with no dose 
dependency.
Table 1.2.5:3 summarizes PK data of the recent completed clinical study 1368.3 conducted 
according to a parallel (matched) group design. Bioavailability of the 
 SC injection 
was calculated to be about 50% and of the 
 SC injection 70% using the 
 IV 
group as reference.


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Table 1.2.5:3
Geometric mean (geometric CV %) PK parameters of BI655130 in 
study 1368.3 after a single dose  
Dose
 
N=11
[SC]
N=12
[SC]
N=11
[IV]
AUC0-inf  
(µg·day/mL)
574 (40.1)
1600 (29.5)
2280 (16.0)
Cmax
(µg/mL)
12.2 (44.5)
33.4 (32.7)
114 (18.0)
Tmax
1
(day)
0.3 - 14
7.0
4 - 21
6.0
0.02-0.3
0.13
t½
(day)
20.6 (26.7)
25.6 (23.5)
27.1 (17.1)
                                 1min – max, median
The geometric mean t1/2 values after subcutaneous administration ranged from 20.6 
 
SC) to 25.6 
 SC).
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 
 dose groups as compared 
to placebo. This demonstrates that BI 655130 is on-target for the time points analyzed.
Residual Effect Period
The Residual Effect Period (REP) of BI 655130 is up to 16 weeks. This is the period after the 
last dose with measurable drug levels and/or pharmacodynamic effects still likely to be 
present.
For a more detailed description of the BI 655130 profile please refer to the current
Investigator’s Brochure (IB) [c03320877-04].


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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 II development.
In Phase I studies BI 655130 was mainly administered as intravenous infusion. However, the 
subcutaneous injection route is considered to be required to enable in upcoming therapeutic 
studies the self-administration of BI 655130 by patients. For this reason a subcutaneous 
injection formulation is undergoing clinical development.
Recently, the clinical part of a Phase 1 study (Study 1368-0003) has been completed 
exploring the characteristics of a subcutaneous formulation of BI 655130 with particular 
focus on relative bioavailability compared to an intravenous formulation. A further objective 
was the assessment of local tolerability. In this study, the relative bioavailability of a single 
SC injection containing 
of BI 655130 
was in a range of about 50% while 
relative bioavailability increased to 70% for a single SC injection of 
 of BI 655130 
 
 
To further elucidate the origin of the observed potentially dose dependent increasing 
bioavailability, the current study will compare the pharmacokinetics (PK) of a single SC 
injection of 
 of BI 655130 with the PK of two SC injections of 
 
of BI 655130 
This design will investigate the impact of local factors at the SC 
injection site on the overall exposure of BI 655130 which may contribute to the lower 
bioavailability observed in the preceding clinical study.
The current study will also investigate the impact on relative bioavailability regarding the site 
of injection (abdomen and thigh) to enable the switch of injection site if needed.
To widen the SC dose range the current study will also investigate a subcutaneous dose of 
 of BI 655130 corresponding to two single periumbilical SC injections of 
 (i.e. 
total injection volume 
 
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the relative bioavailability of 
 
BI 655130 administered as two subcutaneous injections of 
 in the left and right 
periumbilical region compared to a single subcutaneous periumbilical injection of 
 
BI 655130 
The secondary objective is to investigate the relative bioavailability of a single subcutaneous 
injection of 
 BI 655130 into the thigh compared to a single subcutaneous 
periumbilical injection of
 BI 655130. 
A further objective is to investigate safety, tolerability, and pharmacokinetics of 
 BI 
655130 administered as two subcutaneous injections of
 in the left and right 
periumbilical region.


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A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to optimize treatment regimen of 
the subcutaneous formulation for potential use as maintenance therapy in patients. The 
subjects are exposed to the risks of the study procedures and the risks related to the exposure 
to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to veinipuncture 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
The toxicology package conducted in mice with a mouse-specific antibody (BI 674304)
includes 4, 13 and 26-week toxicity studies and reproductive/developmental toxicity studies 
without any findings which would preclude clinical studies in humans (see IB 
[c03320877-04]).
The clinical safety and tolerability profile of BI 655130 was comparable to placebo in male 
subjects following once weekly intravenous doses of up to
 body weight
administered over 4 weeks. There were no deaths or other serious adverse events. 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.
Recently the clinical part of an initial with a subcutaneous formulation has been completed. 
The maximum tested SC dose was
 of BI 655130 
 injection volume). The 
study did not reveal systemic or local AEs which would preclude further clinical studies with 
the SC formulation. The observed exposure at 
 following SC injection was about 6
fold lower compared to the maximum exposure in completed clinical studies with an IV 
infusion of up to 
 of BI 655130. Therefore even the planned maximum SC dose of 
 of BI 655130 is not expected to exceed exposure limits already tested in humans.
Based on studies in healthy subjects, 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:


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
The study will start with Dose Group 1 and 2 (periumbilical SC dose of 
 of 
BI 655130). Provided no dose limiting AEs occurred as 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 up to Day 10
(see Section 3.1), the study will pursue with Dose Group 3 (periumbilical SC dose of
 of BI 655130) and Dose Group 4 (SC dose of 
 of BI 655130 in the 
thigh). Dose Group 3 will be divided into 2 cohorts. In the first week, 6 subjects will 
be treated. There will be an interval of at least 1 week after start of dosing in the first 
cohort before start of dosing of the second cohort of Dose Group 3.

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.

Monitoring of ECG, vital signs, and extensive safety laboratory testing (Table 5.2.3:1)
is conducted throughout the study.

After dosing, the subjects will stay at the site for at least 48 hours.

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 for both expected and unexpected adverse events.
Currently there are no data available to suggest interactions of BI 655130 [c03320877-04].
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 laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.2.1, adverse events of special interest.
Based on the preclinical and 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 IBD and GPP, the benefit of this trial is considered 
to outweigh the potential 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 relative bioavailability, safety, and tolerability following a
subcutaneous (SC) injection of BI 655130 at different dose strengths, injection volumes, and 
injection sites: 
-
One SC injection of 
 periumbilical (Dose Group 1)
-
Two SC injections of 
each periumbilical left and right (Dose Group 2)
-
Two SC injections of 
each periumbilical left and right (Dose Group 3) 
-
One SC injection of 
 in the thigh (Dose Group 4)
The total dose in Dose Group 1, 2, and 4 is 
 of BI 655130 and the total dose in Dose 
Group 3 is 
 of BI 655130.
The study will be conducted in a single-dose, open-label, matched-group design. The 
exposure in Dose Group 1 will be used as reference to assess the relative bioavailability of 
Dose groups 2 - 4. For details refer to Section 4.1.
The study will start with Dose Group 1 and 2. After completion of treatment of the first two 
dose groups, the study will continue with Dose Group 3 and 4. 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).
The Dose Group 3 will follow a staggered administration with treatment of 6 subjects (cohort 
A) in the first week and the remaining subjects (cohort B) from Week 2. 
A documented Safety Review of Dose Group 1 and 2 at least 10 days after last dosing in 
Dose Group 2 must take place prior to continue the study with Dose Groups 3 and 4. 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. Continuation of the study 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 8 evaluable subjects in
each of the Dose Group 1 and 2 are required to decide about continuation with the remaining 
dose groups.
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)

Vital signs 

Clinical laboratory tests 

Check of criteria for stopping subject treatment as per Section 3.3.4.1


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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 
face-to-face or by video/telephone conference. The trial clinical monitor or a delegate 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 CPU Antwerpen of 
 
 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 ZNA Klinisch Laboratorium, Lindendreef 1, 
2020 Antwerpen, Belgium.
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.
The plasma analyses of BI 655130 and ADA concentrations will be performed at 
 
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The study will be conducted according to a single-dose, open-label design with matched
groups.
The resulting group sizes (see Section 7.6) are considered to be sufficient for the exploratory
evaluation of pharmacokinetics. The assignment of matched healthy volunteers is a useful
method to control for other factors which may influence the pharmacokinetics of BI 1467335
in a renal impaired population.
The open-label treatment is not expected to bias results, since the primary endpoints are
derived from measurement of plasma concentrations of the analytes provided by a
bioanalytical laboratory. It is also considered sufficiently accurate as the trial observations are
objective (PK, laboratory) and over-reporting of AEs is unlikely.
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 tolerability of BI 655130 has already
been evaluated up to 
 MRD, resulting in a far higher exposure compared to the 
expected exposure of the current study.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 48 healthy male and female subjects (12 in each dose group) will enter the 
study. They will be recruited from the volunteers' pool of the trial site. Healthy subjects 
assigned to Dose Groups 2 - 4 will be matched on an individual level for gender and body 
weight (± 10%) to subjects assigned to Dose Group 1 
, periumbilical injection).
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 19.0 to 29.9 kg/m2 (incl.) 


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4. Signed and dated written informed consent prior to admission to the study in accordance 
with ICH-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 IU/L 
and estradiol below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) 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 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
7. History of relevant orthostatic hypotension, fainting spells, or blackouts
8. Chronic or relevant acute infections
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)


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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 up to 4 weeks after administration
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 
Female subjects will not be allowed to participate if any of the following applies:
22. Positive pregnancy test, pregnancy or plans to become pregnant up to study completion
23. Lactation
In addition, the following trial-specific exclusion criterion applies:
24. Previous use of the trial medication
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
This study is a single dose study, therefore removal of subjects from study medication after 
dosing is not applicable. 
An individual subject is to be removed from further assessments 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 from further assessments. This may include 
cases of sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP 


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>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.
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 administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (i.e., 16 weeks, see Section 1.2.5), 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 overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported that is 
considered to be unacceptable
2. The expected enrolment goals 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


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5. Further dosing will be stopped if at least 2 subjects in one dose group 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. Replacement of subjects should always be done in mutual agreement with the 
principal investigator. A replacement subject will be assigned a unique study subject number, 
and will be assigned to the same treatment and matching criteria as the subject he or she 
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 
The characteristics of the 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 or thigh)
Duration of use:
Single dose
At the time of use, the 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 
Dose Group 1, matching subjects will be allocated to the other dose groups. Therefore, the 
allocation of subjects to dose groups is not influenced by trial personnel, but only by the 
subjects’ temporal availability. As the study includes healthy subjects from a homogenous 
population matched for gender and body weight, relevant imbalances between the dose 
groups are not expected.
The allocation of subjects will be performed prior to the administration of trial medication. 
Once a subject number has been assigned to a treatment group, it cannot be reassigned to any 
other treatment group.
4.1.3
Selection of doses in the trial
The dose of 
 of BI 655130 selected for this trial has been selected to correspond to the 
potential dose for maintenance treatment in clinical trials in patients. The highest dose tested 
in this trial 
 of BI 655130) will be included to widen the SC dose range.


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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 solutions are provided in the ISF. 
Table 4.1.4: 1
Dosage and treatment schedule
Dose 
Group
Total 
dose
Route of 
administration
Concentration 
of application 
solution
Application volume
Injection site
1
SC
Periumbilical
2
SC
Periumbilical (left and right)
3
SC
Periumbilical (left and right
4
SC
Thigh
Following an overnight fast of at least 10 hours, the medication will be administered. Trial 
drug will be injected subcutaneously in the abdominal region or into the thigh. 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.
4.1.5
Blinding and procedures for unblinding
No blinding will be performed. 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. Emergency envelopes will not be provided, since 
the treatments of all subjects are known in this open-label trial.
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


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
Storage conditions

Use-by date

Batch number

Investigator

Subject number
The vials are labelled with reduced requirements.
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms.
Examples of the labels will be available in the ISF.
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 


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received from the sponsor. At the time of disposal, the investigator / pharmacist must verify 
that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
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 2 h 
after administration of the study drug.
From 1 h before until 2 h after SC injection, fluid intake is not allowed.
Smoking is not allowed during in-house confinement at the trial site.
Alcoholic beverages are not permitted starting 7 days before the administration of trial 
medication until Day 15. From Day 15 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.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during the in-house confinement.
Poppy-seed containing products are not allowed starting 2 days before screening and 2 days 
before admission to trial site (Day -1) to avoid false positive drug screening results.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the administration of trial medication up to 4 weeks after administration.
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

Vital signs (blood pressure, pulse rate)

Local tolerability
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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions

Chances 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.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 

is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation  

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse.
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since 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, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
The term adverse event of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.2.2.
The AESI in this trial is hepatic injury, as defined by the following alterations of hepatic 
laboratory parameters:


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
an elevation of AST (aspartate transaminase) and/or ALT (alanine aminotransferase) 
≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN measured in 
the same blood sample, or 

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure that these parameters 
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)


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
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
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 any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.


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AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for the initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B)
as well as non-trial specific information and consent for the pregnant partner.
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. 


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
Haematology
Haematocrit 
Haemoglobin 
Red Blood Cell count (RBC)
Reticulocytes count
White Blood Cells count (WBC)
Platelet Count
Automatic WBC differential 
(relative and absolute count possible)
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 (International 
Normalization Ratio)
Enzymes
AST [Aspartate transaminase] /GOT, SGOT
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase (GGT)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [CK-MB, only if CK is elevated]
Lactate Dehydrogenase (LDH)
Serum tryptase1
Hormones1
Thyroid Stimulating Hormone (TSH)
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total
Bilirubin, Direct
Bilirubin, Indirect
Protein, Total
Protein electrophoresis 1
Albumin 
Alpha-1-Globulin
Alpha-2-Globulin
Beta-Globulin
Gamma-Globulin
C-Reactive Protein (CRP)
Uric Acid 
Cholesterol, total
Triglyceride
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
BI test name [comment/abbreviation]
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
Urine sediment (microscopic
examination if urine analysis abnormal)
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, on Day 92, 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 (qual)
Hepatitis B core antibody (qual)
Hepatitis C antibodies (qual)
HIV-1 and HIV-2 antibody (qual)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Dräger 
Alcotest® 6510 and Alcotest® 510, Belgium) will be performed at screening and on 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.


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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 
tests. These tests will be performed at the trial site using 'Alere Triage TOX Drug Screen' and 
Alere® –HCG urine, respectively.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a
computerised electrocardiograph (e.g. MAC 5500, GE Healthcare) at the time points given in 
the Flow Chart.
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 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.
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. 
5.2.5
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 (e.g. 
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 (including drug screen and pregnancy test), and a physical examination. The 
end of trial examination will include review of vital signs, 12-lead ECG, laboratory tests, 
recording of AEs and concomitant therapy and a physical examination with determination of 
weight.


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5.2.5.3
Local tolerability
Local tolerability will be assessed as specified in the Flow Chart by the investigator 
according to ‘swelling’, ‘induration’, ‘heat’, ‘redness’, ‘pain’, or ‘other findings’.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
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 parameters in an appropriate 
way. The scheduled measurements will allow monitoring of changes in vital signs, standard 
laboratory values, and ECG parameters that might occur as a result of administration of trial 
medication. The safety assessments are standard, are accepted for evaluation of safety and 
tolerability of an 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:


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
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
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 K2-EDTA (dipotassium 
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 K2-EDTA-anticoagulated blood samples will be mixed gently and placed on ice until 
centrifugation for about 10 min 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 min 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 -70°C or below at the clinical site until shipment to the 
analytical laboratory. 


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The plasma samples may be used for further methodological investigations (e.g. for stability 
testing), however, only data related to the analyte will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the final study report has been signed.
5.5.2.2
Plasma sampling for ADA assessment
For ADA assessment, approximately 
 of blood will be taken from a forearm vein into 
a K2-EDTA anticoagulant blood-drawing tube at the time points listed in the Flow Chart
under “Plasma ADA”. 
The K2-EDTA -anticoagulated blood samples will be mixed gently and placed on ice until 
centrifugation for about 10 min 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 min after withdrawal. Two aliquots of EDTA plasma samples will be obtained 
in two labelled polypropylene cryotubes (label to include: BI trial number, subject number, 
visit, PTM, aliquot #1 or #2, plasma, and ADA). The two aliquots should contain 
approximately 
 of plasma each. The plasma samples will be stored in a freezer at 
about -70°C or below at the clinical site until shipment on dry ice to the analytical laboratory. 
Both aliquots will be shipped (in separate shipments with dry ice sufficient for 3 days transit) 
to the analytical laboratory for assessment of potential ADA to BI 655130. Once received at 
the analytical laboratory, both aliquots will be stored in a freezer at about -70°C or below.
The plasma samples may be used for further methodological investigations (e.g. for stability 
testing), however, only data related to the anti-drug antibodies will be generated by these 
additional investigations. The study samples will be discarded after completion of the 
additional investigations but not later than 5 years upon the final study report has been 
signed.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 655130 plasma concentration
BI 655130 concentrations in plasma will be determined by a validated immunoassay.
5.5.3.2
Analytical determination of ADA to BI 655130
The presence of ADA to BI 655130 will be assessed via their detection using a validated 
immunoassay in a tiered approach (screening, confirmatory, and titration analysis as 
appropriate).


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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. 
The acceptable deviation from the scheduled time for vital signs, ECG and safety laboratory
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 15

± 72h from >Day 15 up to the last assessments
If scheduled in the Flow Chart at the same time as a meal, meal will be only provided after 
completion of the concomitant procedures. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, vital signs and 12-lead ECG recordings have to 
be done first and venipuncture should be the last of the measurements due to its 
inconvenience to the subject and possible influence on physiological parameters.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
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 


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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.
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, 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 prematurely the study before the end of the planned treatment 
period (i.e., Day 176 ±3) 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 trial objectives are stated in Section 2.2.
For the purpose of defining reference and test treatments, the following terminology will be 
used. The reference treatment (R) will refer to dose group 1, test treatment 1 (T1) refers to 
dose group 2, test treatment 2 (T2) refers to dose group 4 and test treatment 3 (T3) refers to 
dose group 3. 
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 analysis of primary and secondary endpoints will be an 
ANOVA (analysis of variance) model on the logarithmic scale. This model will include 
effects accounting for the following sources of variation: ‘treatment’ and ‘matched pair’. For 
each matched pair in the study a pair number will be assigned for analysis purpose. The 
resulting variable ‘matched pair’ will be considered as random effect.
The model is described by the following equation:
ykjm = + k + pj + eijkm, where
ykjm = logarithm of response (endpoint) measured on subject m in pair j receiving 
treatment k
= the overall mean,
k = the kth treatment effect, k=1,..,4,
pj = the jth matched pair effect,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.


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where pj ~ N(0,	
) i.i.d., eijk ~ N(0, 	
 ) i.i.d. and pj, eijk are independent random variables (note 
that the indices ‘B’ and ‘W’ correspond to ‘between’ pairs and ’within’ pairs variability, 
respectively).
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of the different dose groups 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 the Report Planning
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the clinical trial
report.
Relevant protocol violations may be:

Incorrect trial medication taken, that is, the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example:

The subject experiences emesis that occurred at or before 2 times median tmax of the 
respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis)

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve


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The following analysis sets will be defined for this trial:

Treated set (TS):
This subject set includes all subjects from the RS who were documented to have 
received one dose of study drug. This is the full analysis set population in the sense of 
ICH-E9

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the 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/she contributes only one PK 
parameter value for one period to the statistical assessment
Point estimates of the ratios of the geometric means (test/reference) for the primary and 
secondary endpoints (see Sections 5.5.1.1 and 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 (Least Squares Means), and a two-sided 90% confidence interval based on the 
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.
The comparisons of interest will be T1 vs. R, T2 vs. R, and T3 vs. R.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is,
all subjects who received at least one dose of study drug), will be included in the safety
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
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.


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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 first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until end of the residual 
effect period (see Section 1.2.5) will be assigned to the treatment period. Events after the 
residual effect period but prior to next intake or end of trial examination will be summarized 
as ‘follow-up’. The follow-up will be summarised according to previous treatment. These 
assignments including the corresponding time intervals will be defined in detail in the TSAP. 
AEs occurring after the last per-protocol contact but entered before database lock will be 
reported to drug safety only and will not be captured in the trial database.
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.
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.
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 drug BI 655130 will be calculated 
according to the relevant SOP of the Sponsor [001-MCS-36-472].
Individual plasma concentration data and the pharmacokinetic parameters will be tabulated,
graphically displayed and summarized by descriptive statistics. The analysis of PK endpoints 
will be based on PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).


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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 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
The study will not be randomised as individually matched subjects will be used. Thus, this 
section is not applicable.
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 4*12 = 48 subjects in the trial, because this sample size is 
considered sufficient to achieve the aims of this exploratory trial. With this sample size, the 
following precision in estimating the ratio of geometric means (test/reference) can be 
expected with 95% probability. Precision is defined as the ratio of upper CI limit to the 
relative BA estimate. Note that the precision is independent of the actual ratio of geometric 
means.


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The observed inter-individual geometric coefficient of variation (gCV) in a previous trial 
(1368.3) was roughly 30% for Cmax and for AUC. For various assumptions on the gCV, 
Table 7.6: 1 provides an overview of the precision for estimating the ratio of geometric 
means (test/reference). For illustrative purposes, the expected 90% confidence intervals are 
displayed for different values of the ratios T/R of geometric means.
Table 7.6: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a parallel trial (for one comparison 
based on 2 arms)
gCV [%]
Precision 
upper CL / 
relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
25
1.24
90
72.64
111.51
25
1.24
100
80.71
123.90
25
1.24
110
88.78
136.29
30
1.29
90
69.70
116.21
30
1.29
100
77.45
129.12
30
1.29
110
85.19
142.03
35
1.34
90
66.95
120.99
35
1.34
100
74.38
134.44
35
1.34
110
81.82
147.88
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The 90% confidence interval limits in the table were derived by
CI limit, = 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 Julious [R11-5230, Chapter 8] using R 
Version 3.4.2.


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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/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 


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auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the 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
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
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 201; 365(7):620-628.
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.
R16-0927
Waal AC de, Kerkhof PCM van de; Pustulosis palmoplantaris is a disease 
distinct from psoriasis; J Dermatol Treat 22 (2), 102 - 105 (2011)
R16-0929
Berki DM, Liu L, Choon SE, Burden AD, Griffiths CEM, Navarini AA,
Tan ES, Irvine AD, Ranki A, Ogo T, Petrol G, Mahil SK, Duckworth M,
Allen MH, Vito P, Trembath RC, McGrath J, Smith CH, Capon F, Barker
JN; Activating CARD14 mutations are associated with generalized pustular 
psoriasis but rarely account for familial recurrence in psoriasis
R16-0933
Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF; 
Clinical profile, morbidity, and outcome of adult-onset generalized pustular 
psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, 
Malaysia; Int J Dermatol 53, 676 - 684 (2014)


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c03320877-04
 Investigator´s Brochure BI 655130 for IL36R antibody in 
Ulcerative Colitis, Palmoplantar Pustulosis and Pustular Psoriasis. 10 Oct 
2017
c09105854-05
, Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising intravenous doses of BI 655130 
(double-blind, partially randomised within dose groups, placebo-controlled 
parallel group design) and one single intravenous dose of BI 655130
(single-blind, partially randomised, placebo-controlled) in healthy male 
subjects, 1368.2, 02 Aug 2017
c09985235-01
Single-blind, partially 
randomised, placebo-controlled Phase I study to investigate safety, 
tolerability, pharmacokinetics and pharmacodynamics of single rising 
intravenous doses of BI 655130 in healthy male volunteers, 1368.1, 07 Apr 
2017 
c10896574-01
 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). 1368.3. 08 Mar 2017 
c18789185-01
 Safety, tolerability, pharmacokinetics 
and pharmacodynamics of multiple rising intravenous doses of BI 655130 
(double-blind, partially randomised within dose groups, placebo-controlled 
parallel group design) and one single intravenous dose of BI 655130 
(singleblind, partially randomised, placebo-controlled) in healthy male 
subjects. 1368.2. 29 May 2018 


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10.
APPENDICES
10.1
PREPARATION AND HANDLING OF BI 655130 SOLUTION FOR 
INJECTION 
10.1.1
Preparation Instructions 
 SC (Dose group 1,  injection left or right 
periumbilical)
Necessary materials: 
2 Vials BI 655130 Solution for Injection 
Consumables: 
 sterile syringe (material: polypropylene) - e.g. B. Braun Injekt Solo 
(article no: 4606027) 
 1½” needle (material: stainless steel/ polypropylene) – e.g. B. Braun 
(article no: 4657527)
 ½” needle for injection (material: stainless steel/ polypropylene) – e.g. BD 
(article no: 305770)
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 
syringe closure (e.g. B.Braun Combi-Stopper).
7.
Attach a sterile 27G ½” needle to the syringe, adjust the volume to 
 and 
gently inject the complete content of the syringe at the left or right periumbilical 
region.


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10.1.2
Preparation Instructions 
 SC dose (Dose Group 2, injection left and
right periumbilical)
Necessary materials: 
2 Vials BI 655130 Solution for Injection 
Consumables: 
 sterile syringe (material: polypropylene) - e.g. B. Braun Injekt F 
(article no: 9166017V) 
 1½” needle (material: stainless steel/ polypropylene) – e.g. B. Braun 
(article no 4657527)
 ½” needle for injection (material: stainless steel/ polypropylene) – e.g. BD 
(article no: 305770)
1. Take a vial filled with 
 of 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 
syringe closure (e.g. B.Braun Combi-Stopper).
6. Attach a sterile 
 needle to the 
 syringe, adjust the volume to 
 
7. Repeat steps 1 to 6 with the second vial to prepare a second, separate syringe ready 
for injection 
8. Gently inject the complete content of the first syringe containing 
 solution for 
injection at the left or right periumbilical region.
9. Gently inject the complete content of the second syringe containing 
 solution for 
injection periumbilical contralateral to the injection site of the first injection.


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10.1.3
Preparation Instructions 
 SC dose (Dose group 3, injection left and
right periumbilical)
Necessary materials: 
4 Vials BI 655130 Solution for Injection 
Consumables: 
 sterile syringe (material: polypropylene) - e.g. B. Braun Injekt Solo 
(article no: 4606027) 
 1½”needle (material: stainless steel/ polypropylene) – e.g. B. Braun 
(article no 4657527)
 ½” needle for injection (material: stainless steel/ polypropylene) – e.g. BD 
(article no: 305770)
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 
 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 
syringe closure (e.g. B.Braun Combi-Stopper).
7.
Attach a sterile 
 needle to the syringe, adjust the volume to 
 (=syringe 
1)
8.
Repeat steps 1 to 7 with the second vial to prepare a second, separate syringe 
ready for injection (=syringe 2).
9.
Gently inject the complete content of the first syringe containing 
 solution for 
injection at the left or right periumbilical region .
10.
Gently inject the complete content of the second syringe containing 
 solution 
for injection periumbilical contralateral to the injection site of the first injection.


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10.1.4
Preparation Instructions 
 SC dose (Dose group 4, injection in the 
thigh)
Necessary materials: 
2 Vials BI 655130 Solution for Injection 
Consumables: 
 sterile syringe (material: polypropylene) - e.g. B. Braun Injekt Solo 
(article no: 4606027) 
 1½”needle (material: stainless steel/ polypropylene) – e.g. B. Braun 
(article no 4657527)
 ½” needle for injection (material: stainless steel/ polypropylene) – e.g. BD 
(article no: 305770)
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 
syringe closure (e.g. B.Braun Combi-Stopper).
7.
Attach a sterile 
 needle to the syringe, adjust the volume to 
 and 
gently inject the complete content of the syringe in the left or right thigh.


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Trial Protocol
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001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
20 September 2018
EudraCT number
2018-001074-18
BI Trial number
1368-0029
BI Investigational Product(s)
BI 655130
Title of protocol
Relative bioavailability, safety, and tolerability 
following subcutaneous injection of different 
doses of BI 655130 and different injection sites in 
healthy male and female subjects (a single dose, 
mono-centric, open-label study in matched-group 
design).
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
5.5.2 Methods of sample collection
Description of change
Temperature for storage of clinical samples was 
changed to -70°C.
Rationale for change
Update on storage temperature.


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Number of global amendment
2
Date of CTP revision
07 Jan 2019
EudraCT number
2018-001074-18
BI Trial number
1368-0029
BI Investigational Product(s)
BI 655130
Title of protocol
Relative bioavailability, safety, and tolerability 
following subcutaneous injection of different 
doses of BI 655130 and different injection sites in 
healthy male and female subjects (a single dose, 
mono-centric, open-label study in matched-group 
design).
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.2.5 
Clinical experience
3.3.4,1 Removal of individual subjects
Description of change
Residual effect period (REP) changed from 176±3 
to 16 weeks.
Rationale for change
Residual effect period in ongoing patient studies 
16 weeks, change was required to assure 
consistency across clinical studies with BI 
655130.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21745299
3.0
clinical-trial-protocol-revision-02
Relative bioavailability, safety, and tolerability following subcutaneous injection of
different doses of BI 655130 and different injection sites in healthy male and female
subjects (a single dose, mono-centric, open-label study in matched-group design).
Author-Clinical Trial Leader
07 Jan 2019 13:49 CET
Author-Trial Clinical
Pharmacokineticist
07 Jan 2019 14:53 CET
Approval-Therapeutic Area 
07 Jan 2019 15:46 CET
Verification-Paper Signature
Completion
08 Jan 2019 12:51 CET
Approval-Team Member Medicine
08 Jan 2019 18:24 CET
Author-Trial Statistician
08 Jan 2019 19:52 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21745299
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c27982603-01
BI Trial No.:
1368-0029
Title:
Relative bioavailability, safety, and tolerability following
subcutaneous injection of different doses of BI 655130 and 
different injection sites in healthy male and female subjects (a 
single dose, mono-centric, open-label study in matched-group 
design).
Including Protocol Amendment 2 [c21745299-03]
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone: 
Fax: 
Date of statistical 
analysis plan:
14 JUN 2019 SIGNED 
Version:
Final
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2019 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 ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
5.4
OTHER VARIABLES..........................................................................................9
5.4.3
Safety parameters ...............................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................13
......................................................................................................14
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........16
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINT .....................................................................................17
7.5
SECONDARY ENDPOINTS.............................................................................18
7.5.1
Key secondary endpoint .....................................................................................18
7.5.2
Secondary endpoints...........................................................................................18
7.6
FURTHER ENDPOINTS...................................................................................18
7.6.1
Safety parameters ...............................................................................................18
7.7
EXTENT OF EXPOSURE.................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse events.....................................................................................................19
7.8.2
Laboratory data ..................................................................................................20
7.8.3
Vital signs.............................................................................................................20


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7.8.4
ECG......................................................................................................................21
7.8.5
Local tolerability .................................................................................................21
7.8.6
Others...................................................................................................................21
8.
REFERENCES....................................................................................................22
...............................................................................23
10.
HISTORY TABLE..............................................................................................24


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LIST OF TABLES
Table 6.1: 1
Dosage and treatment schedule ........................................................................11
Table 6.1: 2
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data, local tolerability and vital signs..............................................12
Table 6.2: 1
Important protocol deviations...........................................................................13
Table 6.3: 1
Subject sets analysed ........................................................................................14
Table 10: 1
History table .....................................................................................................24


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
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
AUC0-∞
Area under the concentration-time curve of the analyte over the time 
interval from 0 extrapolated to infinity
BLQ
Below the lower limit of quantification
BMI
Body mass index
BI
Boehringer Ingelheim
BP
Blood pressure
CARE
Clinical data analysis and reporting environment
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
eCRF
Electronic case report form
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important protocol deviation
IQRMP
Integrated quality and risk management plan
LLT
Lower level term
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetics


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Term
Definition / description
PKS
Pharmacokinetic parameter analysis set
PR
Pulse rate
Q1
Lower Quartile
Q3
Upper Quartile
RAGe
Report appendix generator
RPM
Report Planning Meeting
SD
Standard Deviation
TS
Treated set
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 revised 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 and its amendment. 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 Medidata Rave 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; RAGe
system 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.
CTP Section 7.3.1 states that the TS includes all subjects from the “RS” who were 
documented to have received one dose of study drug. “RS” was not explained, but in this 
context certainly refers to a randomized set. Since there is no randomization in this trial, it is 
clear that there is no randomized set and this must be a typo in the CTP and that the CTP 
actually intends the TS to include all subjects who were documented to have received one 
dose of study drug. The TS was defined in this TSAP accordingly, and this was considered to 
be in accordance with the intention of the CTP (despite of the typo).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
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 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)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoint
Secondary endpoint is AUC0-∞in plasma for BI 655130.
5.4
OTHER VARIABLES


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5.4.3
Safety parameters
Further safety parameters of interest will be used as defined in Section 5.2.1 of the CTP:
CTP:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

Vital signs (blood pressure, pulse rate)

Local tolerability
Local tolerability will be assessed as absence or presence of "swelling", "induration", "heat", 
"redness", "pain", or "other findings".
Abnormal findings in 12-lead ECG will be reported as baseline conditions (at screening) or as 
AEs (during the trial) if judged clinically relevant by the investigator.


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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.
All subjects were planned to be treated with a single dose of BI 655130 injected 
subcutaneously in the abdominal region or into the thigh. See Table 6.1: 1 for details on the 
treatment schedule.
Table 6.1: 1
Dosage and treatment schedule
Dose Group
Total dose
Concentration of 
solution
Application volume
Injection site
1 (reference 
treatment R)
Periumbilical
2 (test 
treatment T1)
Periumbilical (left and right)
3 (test 
treatment T3)
Periumbilical (left and right)
4 (test 
treatment T2)
Thigh
The analysis phases specified in Table 6.1: 2 will be defined for each subject for use in the 
statistical analysis of AEs, safety laboratory data, local tolerability and vital signs.


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Table 6.1: 2
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data, local tolerability and vital signs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
BI pmbl,
 BI pmbl (l+r),
 BI pmbl (l+r),
 BI thigh
respectively
Date/time of 
administration of study 
drug
Date/time of administration of
Study drug + 113 * 24 h (i.e., 
REP of  112 days (16 weeks) 
+ 1 day) 
or
0:00 AM on day after subject's 
trial completion or 
discontinuation date
whatever comes first
Follow-up1
F/U
 BI pmbl,
F/U 
 BI pmbl (l+r),
F/U 
 BI pmbl (l+r),
F/U 
 BI thigh
respectively
Date/time of  
administration of
study drug + 113 * 24 h 
(i.e., REP of  112 days (16 
weeks) + 1 day)
0:00 AM on day after subject's 
trial completion or 
discontinuation date
1 If the trial completion or discontinuation date is earlier than 113 days after date of administration of study drug, the follow-
up phase does not exist for the respective subject.
CTR Section 15.3.1, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only. Appendix 16.1.13.1.8.1 will present results for 
the screening, on-treatment and follow-up phase.
In CTR Section 15.3.1 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 
16.1.13.1.8.3 AE tables), the following totals will be provided in addition:

"Total on-trt", defined as the total number of subjects with AEs over all on-treatment 
phases 
Additionally, the following total will be provided in CTR Section 16.1.13.1.8.1 AE tables:

"Total", defined as the total number of subjects with AEs over all study phases (incl. 
screening, on-treatment, and follow-up)
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the RPM. At this meeting, it will be decided whether a 
discrepant data value can be used in analyses or whether it must be corrected in the clinical 
database. Each protocol deviation must be assessed to determine whether it is an IPD. For 
definition of IPDs, and for the process of identification of these, refer to the BI reference 
document "Identify and Manage Important Protocol Deviations (iPD)" (2).


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If any IPDs are identified, they are to be summarised into categories and will be captured in 
the domain “DV” of the database via an Excel spreadsheet (3). Categories which are 
considered to be IPDs in this trial are defined in the following table, along with the 
information which kind of IPDs could potentially lead to exclusion from which analysis set. 
The decision on exclusion of subjects from analysis sets will be made at the latest at the RPM, 
after discussion of exceptional cases and implications for analyses, and will be documented in 
the decision log. If the data show other IPDs, this table will be supplemented accordingly by 
the time of the RPM.
IPDs will be summarised and listed.
Table 6.2: 1
Important protocol deviations
Category 
/ Code
Description
Excluded from which analysis set
A
Entrance criteria not met
A1
Inclusion criteria violated
PKS
A2
Exclusion criteria violated
PKS
B
Informed consent
B1
Informed consent not available
Treated set
B2
Informed consent too late
None
C
Trial medication and 
randomisation
C1
Incorrect trial medication taken
PKS
C2
Incorrect administration of trial 
medication
PKS
C3
Incorrect dose of trial medication 
administered
PKS
D
Concomitant medication
D1
Concomitant medication with the 
potential to affect the assessment of 
the trial medication
PKS
G
Other trial specific important 
deviations
G1
Certain deviations from procedures 
used to measure primary PK data
PKS
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:


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
Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH-E9 (1). It will be used for 
analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one primary or 
secondary PK parameter that was not excluded because of IPDs relevant to the 
statistical evaluation of PK endpoints, or because of non-evaluability, as described in 
Section 7.3.1 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. These decisions will be documented in the decision log.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
IPDs
X
Demographic/baseline characteristics
X
Safety parameters
X
Primary PK endpoints
X
Secondary PK endpoint
X
Further PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to administration of any 
study drug will not be reported in the CTR.
Data of treated subjects who failed to complete the study (dropouts or withdrawals) will be 
reported in the CTR as far as their data are available. All withdrawals will be documented and 
the reason for withdrawal recorded in the CTR.
CTP Section 7.4.1: With respect to safety evaluations, it is not planned to impute missing 
values.


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The only exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (4) [001-MCG-
156_RD-01].
Missing data and outliers of PK data are handled according to BI standards (5) [001-MCS-36-
472_RD-01]. CTP Section 7.4.2: 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 Section 7.4.3: 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
The last non-missing value determined prior to the study drug administration will be defined 
as baseline. 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM.


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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" (6).
The individual values of all subjects will be listed, sorted by treatment group, subject number
and visit. AE listings will be sorted by assigned treatment (see Section 7.8.1 below for 
details). 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
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of 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 group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actually missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. These will be based on the 
TS.


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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.
Only descriptive statistics are planned for this section of the report.
A medication will be considered concomitant to a dose group, if it

is ongoing at the time of administration of this treatment, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a definition 
of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint (cf. Section 5.4.2). Any 
deviations from complete intake will be addressed in the RPM (cf. Section 6.2) and described 
in the CTR.
7.4
PRIMARY ENDPOINT
Analysis of relative bioavailability of the primary endpoints will be performed as defined in 
Sections 7.1.3 and 7.3.1 of the CTP.
The statistical model for the primary analysis defined in the CTP Section 7.1.3 is an analysis 
of variance (ANOVA) model on the logarithmic scale. For each matched pair a pair number 
will be assigned and included in the model as random effect.
The following comparisons will be analysed: T1/R, T2/R and T3/R.
CTP Section 7.3.1: Further comparisons may be investigated if appropriate (e.g. T1 vs. T2)
[…].
A sensitivity analysis will be performed with matched pair as fixed effect. 
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'.


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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. Excluded concentration itself will be listed in the CTR
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (5) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (7).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the CTP.
7.5.2
Secondary endpoints
The secondary PK endpoint will be analysed in the same way as the primary endpoints. A 
sensitivity analysis will also be performed with matched pair as fixed effect.
The endpoint will also be assessed descriptively. The analysis of standard PK parameters is 
performed according to BI standards (5) [001-MCS-36-472_RD-01].
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.
7.6
FURTHER ENDPOINTS
7.6.1
Safety parameters
Safety parameters will be analysed as described in Section 7.8 of this TSAP.
7.7
EXTENT OF EXPOSURE
Treatment exposure will only be listed by subject and date and time of drug administration.


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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 electronic case report form (eCRF) will be 
collapsed into one AE event provided that all of the following applies:

All AE attributes are identical (LLT, 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).
For further details on summarization of AE data, please refer to "Analysis and presentation of 
adverse event data from Clinical Trials" (8) and "Handling of missing and incomplete AE 
dates" (4). 
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, treatment or follow-up phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 2.
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 (9) and for the class of 
AESIs.
CTP Section 5.2.2.1: The AESI in this trial is hepatic injury, as defined by the following 
alterations of hepatic laboratory parameters:
o
an elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) ≥3-
fold ULN combined with an elevation of total bilirubin ≥2-fold ULN measured in the 
same blood sample, or
o
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 system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 


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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)). AEs 
will also be summarized by maximum intensity.
The system organ classes will be sorted by total frequency, preferred terms will be sorted by 
total frequency (within system organ class).
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 system organ class 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.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standard
"Display and Analysis of Laboratory Data" (10).
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 on the eCRF or at the RPM 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 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) and will be analysed as such.
7.8.3
Vital signs
The analysis of vital signs 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 at end of trial examination will be listed, including its change from baseline.
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.


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7.8.4
ECG
Abnormal findings in 12-lead 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
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 on-
treatment time points, cf. Section 6.1) as well as by time point.
7.8.6
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 findings will be 
prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9; 
Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical Trials, 
current version
2
001-MCS-40-413_1.0: "Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3
"Template Domain DV", current version; Section "Resources and Key User Emails" on
ICBI homepage
4
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; KMED
5
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON
6
KM Asset BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
7
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD Data 
Files", current version; IDEA for CON
8
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event Data 
from Clinical Trials", current version; KMED
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
10 KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED


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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
14-JUN-2019
None
This is the final TSAP without any 
modification


TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c27982603-01
BI Trial No.:
1368-0029
Title:
Relative bioavailability, safety, and tolerability following
subcutaneous injection of different doses of BI 655130 and 
different injection sites in healthy male and female subjects (a 
single dose, mono-centric, open-label study in matched-group 
design).
Including Protocol Amendment 2 [c21745299-03]
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone: 
Fax: 
Date of statistical 
analysis plan:
14 JUN 2019 SIGNED 
Version:
Final
Page 1 of 24
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2019 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 ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
.....................................9
.....................................9
.....................................9
.....................................9
.....................................9
...................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................13
......................................................................................................14
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........16
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINT .....................................................................................17
7.5
SECONDARY ENDPOINTS.............................................................................18
7.5.1
Key secondary endpoint .....................................................................................18
7.5.2
Secondary endpoints...........................................................................................18
..................................................................18
..................................................................18
..................................................................18
7.7
EXTENT OF EXPOSURE.................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse events.....................................................................................................19
7.8.2
Laboratory data ..................................................................................................20
7.8.3
Vital signs.............................................................................................................20


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7.8.4
ECG......................................................................................................................21
7.8.5
Local tolerability .................................................................................................21
7.8.6
Others...................................................................................................................21
8.
REFERENCES....................................................................................................22
...............................................................................23
10.
HISTORY TABLE..............................................................................................24


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LIST OF TABLES
Table 6.1: 1
Dosage and treatment schedule ........................................................................11
Table 6.1: 2
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data, local tolerability and vital signs..............................................12
Table 6.2: 1
Important protocol deviations...........................................................................13
Table 6.3: 1
Subject sets analysed ........................................................................................14
Table 10: 1
History table .....................................................................................................24


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
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
AUC0-∞
Area under the concentration-time curve of the analyte over the time 
interval from 0 extrapolated to infinity
BLQ
Below the lower limit of quantification
BMI
Body mass index
BI
Boehringer Ingelheim
BP
Blood pressure
CARE
Clinical data analysis and reporting environment
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
eCRF
Electronic case report form
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important protocol deviation
IQRMP
Integrated quality and risk management plan
LLT
Lower level term
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetics


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Term
Definition / description
PKS
Pharmacokinetic parameter analysis set
PR
Pulse rate
Q1
Lower Quartile
Q3
Upper Quartile
RAGe
Report appendix generator
RPM
Report Planning Meeting
SD
Standard Deviation
TS
Treated set
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 revised 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 and its amendment. 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 Medidata Rave 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; RAGe
system 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.
CTP Section 7.3.1 states that the TS includes all subjects from the “RS” who were 
documented to have received one dose of study drug. “RS” was not explained, but in this 
context certainly refers to a randomized set. Since there is no randomization in this trial, it is 
clear that there is no randomized set and this must be a typo in the CTP and that the CTP 
actually intends the TS to include all subjects who were documented to have received one 
dose of study drug. The TS was defined in this TSAP accordingly, and this was considered to 
be in accordance with the intention of the CTP (despite of the typo).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
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 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)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoint
Secondary endpoint is AUC0-∞in plasma for BI 655130.


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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.
All subjects were planned to be treated with a single dose of BI 655130 injected 
subcutaneously in the abdominal region or into the thigh. See Table 6.1: 1 for details on the 
treatment schedule.
Table 6.1: 1
Dosage and treatment schedule
Dose Group
Total dose
Concentration of 
solution
Application volume
Injection site
1 (reference 
treatment R)
Periumbilical
2 (test 
treatment T1)
Periumbilical (left and right)
3 (test 
treatment T3)
Periumbilical (left and right)
4 (test 
treatment T2)
Thigh
The analysis phases specified in Table 6.1: 2 will be defined for each subject for use in the 
statistical analysis of AEs, safety laboratory data, local tolerability and vital signs.


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Table 6.1: 2
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data, local tolerability and vital signs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
BI pmbl,
 BI pmbl (l+r),
 BI pmbl (l+r),
 BI thigh
respectively
Date/time of 
administration of study 
drug
Date/time of administration of
Study drug + 113 * 24 h (i.e., 
REP of  112 days (16 weeks) 
+ 1 day) 
or
0:00 AM on day after subject's 
trial completion or 
discontinuation date
whatever comes first
Follow-up1
F/U
 BI pmbl,
F/U 
 BI pmbl (l+r),
F/U 
 BI pmbl (l+r),
F/U 
 BI thigh
respectively
Date/time of  
administration of
study drug + 113 * 24 h 
(i.e., REP of  112 days (16 
weeks) + 1 day)
0:00 AM on day after subject's 
trial completion or 
discontinuation date
1 If the trial completion or discontinuation date is earlier than 113 days after date of administration of study drug, the follow-
up phase does not exist for the respective subject.
CTR Section 15.3.1, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only. Appendix 16.1.13.1.8.1 will present results for 
the screening, on-treatment and follow-up phase.
In CTR Section 15.3.1 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 
16.1.13.1.8.3 AE tables), the following totals will be provided in addition:

"Total on-trt", defined as the total number of subjects with AEs over all on-treatment 
phases 
Additionally, the following total will be provided in CTR Section 16.1.13.1.8.1 AE tables:

"Total", defined as the total number of subjects with AEs over all study phases (incl. 
screening, on-treatment, and follow-up)
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the RPM. At this meeting, it will be decided whether a 
discrepant data value can be used in analyses or whether it must be corrected in the clinical 
database. Each protocol deviation must be assessed to determine whether it is an IPD. For 
definition of IPDs, and for the process of identification of these, refer to the BI reference 
document "Identify and Manage Important Protocol Deviations (iPD)" (2).


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If any IPDs are identified, they are to be summarised into categories and will be captured in 
the domain “DV” of the database via an Excel spreadsheet (3). Categories which are 
considered to be IPDs in this trial are defined in the following table, along with the 
information which kind of IPDs could potentially lead to exclusion from which analysis set. 
The decision on exclusion of subjects from analysis sets will be made at the latest at the RPM, 
after discussion of exceptional cases and implications for analyses, and will be documented in 
the decision log. If the data show other IPDs, this table will be supplemented accordingly by 
the time of the RPM.
IPDs will be summarised and listed.
Table 6.2: 1
Important protocol deviations
Category 
/ Code
Description
Excluded from which analysis set
A
Entrance criteria not met
A1
Inclusion criteria violated
PKS
A2
Exclusion criteria violated
PKS
B
Informed consent
B1
Informed consent not available
Treated set
B2
Informed consent too late
None
C
Trial medication and 
randomisation
C1
Incorrect trial medication taken
PKS
C2
Incorrect administration of trial 
medication
PKS
C3
Incorrect dose of trial medication 
administered
PKS
D
Concomitant medication
D1
Concomitant medication with the 
potential to affect the assessment of 
the trial medication
PKS
G
Other trial specific important 
deviations
G1
Certain deviations from procedures 
used to measure primary PK data
PKS
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:


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
Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH-E9 (1). It will be used for 
analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one primary or 
secondary PK parameter that was not excluded because of IPDs relevant to the 
statistical evaluation of PK endpoints, or because of non-evaluability, as described in 
Section 7.3.1 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. These decisions will be documented in the decision log.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
IPDs
X
Demographic/baseline characteristics
X
Safety parameters
X
Primary PK endpoints
X
Secondary PK endpoint
X
Further PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to administration of any 
study drug will not be reported in the CTR.
Data of treated subjects who failed to complete the study (dropouts or withdrawals) will be 
reported in the CTR as far as their data are available. All withdrawals will be documented and 
the reason for withdrawal recorded in the CTR.
CTP Section 7.4.1: With respect to safety evaluations, it is not planned to impute missing 
values.


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The only exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (4) [001-MCG-
156_RD-01].
Missing data and outliers of PK data are handled according to BI standards (5) [001-MCS-36-
472_RD-01]. CTP Section 7.4.2: 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 Section 7.4.3: 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
The last non-missing value determined prior to the study drug administration will be defined 
as baseline. 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM.


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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" (6).
The individual values of all subjects will be listed, sorted by treatment group, subject number
and visit. AE listings will be sorted by assigned treatment (see Section 7.8.1 below for 
details). 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
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of 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 group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actually missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. These will be based on the 
TS.


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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.
Only descriptive statistics are planned for this section of the report.
A medication will be considered concomitant to a dose group, if it

is ongoing at the time of administration of this treatment, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a definition 
of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint (cf. Section 5.4.2). Any 
deviations from complete intake will be addressed in the RPM (cf. Section 6.2) and described 
in the CTR.
7.4
PRIMARY ENDPOINT
Analysis of relative bioavailability of the primary endpoints will be performed as defined in 
Sections 7.1.3 and 7.3.1 of the CTP.
The statistical model for the primary analysis defined in the CTP Section 7.1.3 is an analysis 
of variance (ANOVA) model on the logarithmic scale. For each matched pair a pair number 
will be assigned and included in the model as random effect.
The following comparisons will be analysed: T1/R, T2/R and T3/R.
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'.


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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. Excluded concentration itself will be listed in the CTR
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (5) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (7).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the CTP.
7.5.2
Secondary endpoints
The secondary PK endpoint will be analysed in the same way as the primary endpoints.
 
The endpoint will also be assessed descriptively. The analysis of standard PK parameters is 
performed according to BI standards (5) [001-MCS-36-472_RD-01].
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.
7.7
EXTENT OF EXPOSURE
Treatment exposure will only be listed by subject and date and time of drug administration.


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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 electronic case report form (eCRF) will be 
collapsed into one AE event provided that all of the following applies:

All AE attributes are identical (LLT, 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).
For further details on summarization of AE data, please refer to "Analysis and presentation of 
adverse event data from Clinical Trials" (8) and "Handling of missing and incomplete AE 
dates" (4). 
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, treatment or follow-up phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 2.
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 (9) and for the class of 
AESIs.
CTP Section 5.2.2.1: The AESI in this trial is hepatic injury, as defined by the following 
alterations of hepatic laboratory parameters:
o
an elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) ≥3-
fold ULN combined with an elevation of total bilirubin ≥2-fold ULN measured in the 
same blood sample, or
o
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 system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 


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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)). AEs 
will also be summarized by maximum intensity.
The system organ classes will be sorted by total frequency, preferred terms will be sorted by 
total frequency (within system organ class).
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 system organ class 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.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standard
"Display and Analysis of Laboratory Data" (10).
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 on the eCRF or at the RPM 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 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) and will be analysed as such.
7.8.3
Vital signs
The analysis of vital signs 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 at end of trial examination will be listed, including its change from baseline.
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.


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7.8.4
ECG
Abnormal findings in 12-lead 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
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 on-
treatment time points, cf. Section 6.1) as well as by time point.
7.8.6
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 findings will be 
prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9; 
Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical Trials, 
current version
2
001-MCS-40-413_1.0: "Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3
"Template Domain DV", current version; Section "Resources and Key User Emails" on
ICBI homepage
4
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; KMED
5
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON
6
KM Asset BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
7
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD Data 
Files", current version; IDEA for CON
8
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse Event Data 
from Clinical Trials", current version; KMED
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
10 KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED


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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
14-JUN-2019
None
This is the final TSAP without any 
modification