Conditions: Colitis, Ulcerative
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The primary objective of this trial is to understand the mechanism of action of BI655130 in patients with UC

Secondary objectives are to explore clinical effect, safety and tolerability (including immunogenicity) of BI 655130 treatment

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Spesolimab
Intervention descriptions: intervention 1: 12 weeks treatment

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c10710598-04
EudraCT No.:
EU Trial No:
2017-000100-20
BI Trial No.:
1368-0004
BI Investigational 
Product(s):
BI 655130
Title:
Exploratory Trial to Assess Mechanism of Action, Clinical 
Effect, Safety and Tolerability of 12 Weeks of Treatment with BI 
655130 in Patients with Active Ulcerative Colitis (UC)
Lay Title:
This study tests how BI 655130 works in patients with active 
ulcerative colitis. The study also tests how well BI 655130 is 
tolerated and whether it helps the patients.
Clinical Phase:
IIa
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 3))
Version and Date:
Version: 4.0
Date: 03 Apr 2019
Page 1 of 82
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:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 655130
Protocol date:
13 Feb 2017
Trial number:
1368-0004
Revision date:
03 Apr 2019
Trial site(s):
Multi-centre, multi-national
Clinical phase:
IIa
Objective(s):
The primary objective of this study is to understand the mode of 
action of BI 655130 in patients with active ulcerative colitis (UC)
Methodology:
This is an open-label, single-arm, phase IIa exploratory trial in 
patients with moderately to severely active UC.
The trial includes a screening period, a 12-week treatment period and 
a safety follow-up period of 16 weeks (~5 half-lives of BI 655130,
after the last dose of BI 655130, which is at Week 8).
Patients are required to be on conventional, non-biologic treatment 
for UC, with stable treatment doses throughout the trial. Cf. Section 
4.2.1 for more details.
No. of patients: 
total entered:
10
each treatment:
10 (single-arm)
Diagnosis :
Moderately to severely active ulcerative colitis (UC)
Main criteria for 
inclusion:

18 – 75 years at screening

Body weight ≤ 100 kg (at screening and at Day 1 of treatment)

Diagnosis of UC ≥3 months prior to screening.

Moderately to severely active UC as confirmed by Mayo Score ≥6
(with rectal bleeding ≥ 1 and modified endoscopy score ≥2) and 
elevated CRP or calprotectin at pre-baseline visit

Receiving conventional, non-biologic therapy for UC.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 655130
Protocol date:
13 Feb 2017
Trial number:
1368-0004
Revision date:
03 Apr 2019
Treatment could consist of one of the following:
•
Oral 5-ASA compound, with stable dose for at least 4 weeks
prior to screening
•
6-MP, MTX or AZA, with stable dose for at least 8 weeks 
prior to screening
•
Oral corticosteroids (≤ 20mg/day per day of prednisone or 
equivalent), with stable dose for at least 4 weeks prior to 
screening

Negative colon cancer screening by full colonoscopy with serial 
biopsies (or according to local standard of care) performed and 
documented within the past 12 months prior to screening 
(otherwise to be done at pre-baseline visit)

Patients who are naïve or experienced to TNF antagonists 
(including infliximab, adalimumab, or golimumab) but have not 
failed that treatment due to primary non-response or loss of 
response (previous anti-TNF treatment outcome and reason for 
discontinuation must be documented in source data )
Test product(s):
BI 655130 (infusion solution)
dose:
1200mg every four weeks
mode of 
administration:
i.v.
Duration of treatment:
12 weeks (i.v. infusions at Day 1, Week 4, Week 8)
Primary and Secondary 
Endpoints
Primary endpoint:
The total number of deregulated genes comparing baseline to post-
treatment, analysed by gene expression of mucosal biopsies via RNA 
sequencing, per time point up to week 12. 
Secondary endpoints:

Drug related adverse events

Percent change in CRP from baseline to Week 12 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 655130
Protocol date:
13 Feb 2017
Trial number:
1368-0004
Revision date:
03 Apr 2019

Percent change in faecal calprotectin from baseline to Week 12

Percent change in faecal lactoferrin from baseline to Week 12 

Clinical remission (defined as Mayo score ≤2 points, and all 
subscores ≤1 point) at Week 12
Safety criteria:
Physical examination, vital signs, 12-lead ECG, laboratory tests, 
adverse events, serious adverse events and tolerability
Pharmacokinetic criteria Pharmacokinetic parameters of BI 655130: trough levels (for all 
patients), descriptive statistics and PK parameters as appropriate
Statistical methods:
Descriptive statistics for efficacy endpoints, safety and PK.


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FLOW CHART
Trial periods
Screening
Treatment period
Follow-up
Visit
V1a
(Screening)
V1b
(Pre-baseline)
V2
V3
V4
V5
V6
V7
V8
EoT13
FU1
EoO12
Week
2
4
6
8
10
12
18
28
Day
-35 to -9
-8 to -6
1
4
15
29
43
57
71
85
V7
+70
V7
+141
Visit window (days)
±1
±2
±2
±2
±2
-6 to+1
±5
+5
Informed consent
X
In-/exclusion criteria
X
X
X
Demographics
X
Medical history incl smoking/alcohol
X
Sigmoidoscopy + biopsies1
X2
X3, 14
X
X
X3
X
Mayo score4
XT
XT
XT
XP
XP
XT
XP
XT
XP
XP
Physical exam5
XC
XT
XT
XT
XT
XT
XT
XT
XT
XC
XT
XC
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
X
X
X
Pregnancy test7
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Blood sampling for safety lab tests8 
and infection screening
X
X
X9
X
X
X9
X
X9
X
X
X
X


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Flow chart (cont.)
Trial periods
Screening
Treatment period
Follow-up
Visit
V1a
(Screening)
V1b
(Pre-baseline)
V2
V3
V4
V5
V6
V7
V8
EoT13
FU1
EoO12
Week
2
4
6
8
10
12
18
28
Day
-35 to -9
-8 to -6
1
4
15
29
43
57
71
85
V7
+70
V7
+141
Visit window (days)
±1
±2
±2
±2
±2
-6 to+1
±5
+5
QuantiFERON Test for TB screening
X
Blood sampling for gene expression 
and methylation pattern 
X
X9,14
X
X
X9
X9
X
Blood sampling for PK
X9
X
X
X9
X
X9
X
X
X
X
Blood sampling for ADAs
X9
X9
X9
X
X
X
Stool sampling for faecal BMs
X
X
X
X
X
X
X
X
X
Stool sampling for enteric pathogens
X10
X10
Diary dispensing11
X
BI 655130 i.v. infusion
X
X
X
Trial completion
X13
X13


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1.
Sigmoidoscopy (or colonoscopy at pre-baseline visit, if applicable), should be done prior to study drug administration. At each visit indicated, biopsies will be collected for gene 
expression and for methylation patterns. At Day 1 (pre-dose), at Week 2 and at Week 12, additional biopsies will be taken 
 
. Refer to Section 15 of the ISF for further information on the collection of biopsies.
2.
A documented negative colon cancer screening by full colonoscopy with serial biopsies (or according to local standard of care) is required from the past 12 months prior to screening. 
If this is not available, colon cancer screening has to be conducted at Visit 1b (pre-baseline). In that case, a full colonoscopy will be done instead of the planned sigmoidoscopy at that 
visit. In both cases, biopsies for the evaluation of trial endpoints will be taken. Refer to Section 15 of the ISF for further details.
3.
At study visits with study drug administration, biopsy samples must be obtained prior to start of i.v. infusion. At study visit 2, additional biopsy samples must be obtained at 4 hours 
after start of the study drug infusion.
4.
Mayo score: T=total, P=partial (without endoscopic subscore), a modified Mayo Score excluding physician’s assessment will also be evaluated. Refer to Appendix 10.1.
5.
Physical examination: C=complete, T=targeted. Refer to Section 5.3.1.
6.
At visits with study drug administration (Visits 2, 5 and 7), vital signs will be assessed pre-dose, and at approximately 5 and 120 minutes after end of infusion. Monitor for signs and 
symptoms of hypersensitivity reactions for approximately 2 hours after end of infusion. Refer to Section 5.3.2.
7.
Only applicable for women of childbearing potential. A serum pregnancy test will be performed at screening. Urine pregnancy tests will be performed at all other visits indicated in the 
Flow Chart. In case of a positive urine pregnancy test, a serum pregnancy test will be done. Urine pregnancy testing should be done prior to administration of study drug in case there 
is dosing at study visits. Study drug should only be administered in case of a negative test result.
8.
Includes clinical chemistry, haematology, coagulation and urinalysis assessments. Patient must be fasting for at least 8 hours prior to blood collection (except screening visit). If not 
fasted, mark on laboratory requisition.
9.
At study visits with drug administration, blood samples must be obtained within approximately 2 hours prior to start of i.v. infusion. 
10. Stool sampling will be done during screening period (Visit 1a or visit 1b, or at an unscheduled visit).
11. Diary will be used by the patient for the reporting of bowel movement frequency and rectal bleeding (blood in stool). The information will be used for the calculation of mayo score at 
the visits indicated in the Flow Chart. In addition, background UC medication will be recorded. Refer to Section 6.2.1 for more details.
12. Patients with early treatment discontinuation will complete EoT visit procedures and return for EoO visit 20 weeks (>5 half-lives of BI 655130) after the last dose of BI 655130.
13. Patients who complete regular treatment in study 1368-0004 will be offered to enter a long-term extension trial (1368-0017), which is currently in preparation. These patients can 
switch to trial 1368-0017 at EOT visit, and for these patients, their EoT visit will also be their EoO visit.
14. At Visit 2, a second sigmoidoscopy will be performed at 4 hours after start of the first study drug infusion to collect biopsy samples 4 hours post-dose. Also an additional blood sample
for gene expression and methylation pattern analysis will be collected at 4 hours after start of infusion.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................13
MEDICAL BACKGROUND.............................................................................13
1.1
DRUG PROFILE................................................................................................13
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....17
RATIONALE FOR PERFORMING THE TRIAL.........................................17
2.1
TRIAL OBJECTIVES........................................................................................18
2.2
BENEFIT-RISK ASSESSMENT.......................................................................18
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.1
3.1.1
Administrative structure of the trial .................................................................23
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................24
SELECTION OF TRIAL POPULATION .......................................................24
3.3
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................26
Gastrointestinal Exclusion Criteria.......................................................................26
3.3.3.1
Infectious Disease Exclusion Criteria...................................................................27
3.3.3.2
General Exclusion Criteria....................................................................................27
3.3.3.3
3.3.4
Withdrawal of patients from therapy or assessments .....................................28
Withdrawal from trial treatment ...........................................................................28
3.3.4.1
Withdrawal of consent for trial participation........................................................28
3.3.4.2
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................29
4.
TREATMENTS...................................................................................................30
INVESTIGATIONAL TREATMENTS ...........................................................30
4.1
4.1.1
Identity of the Investigational Medicinal Products..........................................30
4.1.2
Selection of doses in the trial..............................................................................30
4.1.3
Method of assigning patients to treatment groups...........................................31
4.1.4
Drug assignment and administration of doses for each patient......................31
4.1.5
Blinding and procedures for unblinding...........................................................32
Blinding.................................................................................................................32
4.1.5.1
Unblinding and breaking the code ........................................................................32
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................32
4.1.7
Storage conditions...............................................................................................32


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4.1.8
Drug accountability.............................................................................................32
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................33
4.2.1
Other treatments and emergency procedures..................................................33
4.2.2
Restrictions............................................................................................................35
Restrictions on diet and life style..........................................................................37
4.2.2.1
Restrictions regarding women of childbearing potential......................................37
4.2.2.2
TREATMENT COMPLIANCE........................................................................37
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................38
TRIAL ENDPOINTS..........................................................................................38
5.1
5.1.1
Primary Endpoint ...............................................................................................38
5.1.2
Secondary Endpoints..........................................................................................38
ASSESSMENT OF EFFICACY........................................................................39
5.2
ASSESSMENT OF SAFETY.............................................................................39
5.3
5.3.1
Physical examination ..........................................................................................40
5.3.2
Vital Signs............................................................................................................40
5.3.3
Safety laboratory parameters ............................................................................40
5.3.4
Electrocardiogram ..............................................................................................44
5.3.5
Assessment of adverse events.............................................................................44
Definitions of adverse events................................................................................44
5.3.5.1
Adverse event collection and reporting ................................................................47
5.3.5.2
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................49
5.4.1
Assessment of Pharmacokinetics.......................................................................49
5.4.2
Analytical determinations ..................................................................................49
5.4.3
Methods of sample collection .............................................................................50
Plasma sampling for PK analysis..........................................................................50
5.4.3.1
Plasma sampling for ADA assessment .................................................................50
5.4.3.2
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................50
ASSESSMENT OF BIOMARKER(S) ..............................................................50
5.5
5.5.1
RNA sequencing..................................................................................................51
6.
INVESTIGATIONAL PLAN.............................................................................54
VISIT SCHEDULE.............................................................................................54
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................54
6.2
6.2.1
Screening and run-in period(s)..........................................................................54
6.2.2
Treatment period(s)............................................................................................56
6.2.3
Follow Up Period and Trial Completion...........................................................57


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................58
STATISTICAL DESIGN - MODEL.................................................................58
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................58
7.2
PLANNED ANALYSES.....................................................................................58
7.3
7.3.1
Primary endpoint analyses.................................................................................60
7.3.2
Secondary endpoint analyses .............................................................................61
7.3.4
Safety analyses.....................................................................................................62
INTERIM ANALYSES ......................................................................................63
7.4
HANDLING OF MISSING DATA ...................................................................63
7.5
RANDOMISATION ...........................................................................................63
7.6
DETERMINATION OF SAMPLE SIZE .........................................................64
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................65
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................65
DATA QUALITY ASSURANCE ......................................................................65
8.2
RECORDS...........................................................................................................66
8.3
8.3.1
Source documents ...............................................................................................66
8.3.2
Direct access to source data and documents.....................................................67
8.3.3
Storage period of records ...................................................................................67
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................67
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........67
8.5
TRIAL MILESTONES.......................................................................................67
8.6
9.
REFERENCES....................................................................................................69
PUBLISHED REFERENCES............................................................................69
9.1
UNPUBLISHED REFERENCES......................................................................72
9.2
10.
APPENDICES.....................................................................................................73
MAYO SCORE ...................................................................................................73
10.1
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................76


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ABBREVIATIONS
ADA
AE
Anti-drug Antibody
Adverse Event
AESI
Adverse Event of Special Interest
ALT
5-ASA
AST
AUC
Alanine Aminotransferase
5-Aminosalicylate
Aspartate Aminotransferase
Area under the Curve
AZA
Azathioprine
BI
Boehringer Ingelheim
BM
CD
Biomarker
Crohn’s Disease
Cmax
CML
Maximum concentration observed
Local Clinical Monitor 
CRA
Clinical Research Associate
CRO
CRS
CRP
Clinical Research Organisation
Cytokine Release Syndrom
C-Reactive Protein
CTP
Clinical Trial Protocol
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
ECG
eCRF
eDC
Deoxyribonucleic Acid
Electrocardiogram
Electronic Case Report Form
Electronic Data Capture
ELISA
EoO
Enzyme Linked Immunosorbent Assay
End of Observation (End of Trial)
EoT
End of Treatment
EudraCT
European Clinical Trials Database
FcR
Fc Receptor
GCP
Good Clinical Practice
GLP
GMP
GPP
GPV
HBV
HCV
HIV
Good Laboratory Practice
Good Manufacturing Practice
Generalized Pustular Psoriasis
Global Pharmacovigilance
Hepatitis B Virus
Hepatitis C Virus
Human Immunodeficiency Virus
IB
Investigator’s Brochure
IBD
ICH
IEC
Inflammatory Bowel Disease
International Conference on Harmonisation
Independent Ethics Committee
IFNγ
IgE
IgG
IHC
Interferon gamma
Immunoglobulin E
Immunoglobulin G
Immunohistochemistry


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IL-36R
IRB
Interleukin-36 Receptor
Institutional Review Board
ISF
Investigator Site File
i.v.
intravenous
mAb
MedDRA
Monoclonal antibody
Medical Dictionary for Drug Regulatory Activities
MoA
MTX
6-MP
Mode of Action
Methotrexate
6-Mercaptopurine
PBMC
PBO
PD
Peripheral Blood Mononuclear Cells
Placebo
Pharmacodynamics
PK
Pharmacokinetics
PP
PPP
PT
Per Protocol
Palmoplantar pustulosis
Preferred Term
qw
rDNA
RBS
RCTC
REP
Once a week
Ribosomal DNA
Rectal Bleeding Subscore
Rheumatology Common Toxicity Criteria
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RNA
RNAseq
RRBS
SAE
Ribonucleic Acid
RNA sequencing
Reduced Representation Bisulfite sequencing
Serious Adverse Event
SAP
SUSAR
TB
Statistical Analysis Plan
Suspected Unexpected Serious Adverse Reaction
Tuberculosis
TCM
Trial Clinical Monitor
TGF-β
TNF
TSAP
UC
ULN
V
VEGF
w
WBC
WHO
Transforming Growth Factor beta
Tumour Necrosis Factor
Trial Statistical Analysis Plan
Ulcerative Colitis
Upper Limit of Normal
Visit
Vascular Endothelial Growth Factor
Week
White Blood Count
World Health Organization


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Ulcerative Colitis (UC) has an estimated incidence of 24.3 and 19.2 cases per 100,000 
persons per year in Europe and the USA, respectively, resulting in a continuously rising 
prevalence (R15-0886). UC is characterized clinically by abdominal pain, fever, and blood or 
mucosa-containing diarrhea, and pathologically by inflammatory lesions in the 
gastrointestinal mucosa. Inflammatory lesions characteristically occur distal to the terminal 
ileum, and by confinement of lesions to the mucosa and submucosa without transmural 
inflammation. UC typically follows a relapsing and remitting course, and is associated with 
substantial acute and long-term morbidity and increased mortality. The mainstays of drug 
therapy for UC are: orally administered aminosalicylates, glucocorticoids, oral 
immunomodulatory agents azathioprine (AZA) and 6-mercaptopurine (6-MP), and Tumour 
Necrosis Factor (TNF) antagonists. In patients with mild UC, 5-Aminosalicylate (5-ASAs)
are safe and effective for induction and maintenance treatment. Glucocorticoids, 
immunomodulators, TNF antagonists, and more recently vedolizumab, are reserved for 
patients with moderate to severe disease, in whom the primary goals of drug therapy are to 
induce and subsequently to maintain remission from signs and symptoms of active disease.
Current biologic treatment of UC is associated with approximately one third of patients each 
failing with primary or secondary non-response. In addition, treatment may be limited due to 
safety and tolerability issues. Therefore, despite therapeutic progress, there remains a 
significant unmet medical need for new treatment options with an improved safety and 
efficacy profile compared to the current therapeutic standard.
DRUG PROFILE
1.2
BI 655130 is a humanized antagonistic monoclonal Immunoglobulin G (IgG)1 antibody that 
blocks human Interleukin-36 (IL-36R) signalling. Binding of BI 655130 to IL-36R is 
anticipated to prevent the subsequent activation of IL-36R by cognate ligands (IL36 α, β and 
γ) and downstream activation of pro-inflammatory and pro-fibrotic pathways with the aim to 
reduce epithelial cell/ fibroblast/ immune cell-mediated inflammation and interrupt the 
inflammatory response that drives pathogenic cytokine production in inflammatory diseases 
including generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP) and 
inflammatory bowel disease (IBD).
Preclinical studies
BI 655130 binds to human IL-36R with high binding avidity. BI 655130 effectively inhibits 
IL36 ligand-stimulated NF-B activation, IL8 release and IFNγ secretion in human cell 
cultures or Peripheral Blood Mononuclear Cells (PBMC) stimulated with IL36α, IL36β, or 
IL36γ combined with IL12.
Mutations BI 655130`s Fc receptor (FcR) were introduced to abrogate FcR binding activity 
and function. Direct assessment of the impact of these mutations in the IgG1 FcR binding 
sites revealed that the mutations abrogate both antibody-dependent cellular cytotoxicity and 
complement-dependent cytotoxicity effector functions and indicate that BI 655130 will be a 
non-depleting therapy in vivo.


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Toxicology studies
BI 655130 does not bind to IL-36R from common toxicology species. Therefore, meaningful 
toxicity studies of the molecule cannot be performed in any animal species with BI 655130. 
However, hazard identification studies of the mode-of-action (MoA) of IL-36R inhibition 
were performed in mice using a mouse specific anti-IL-36R monoclonal antibody (mAb) (BI 
674304), a mouse IgG2a mAb with rat variable regions. In a 13-week intravenous (i.v.)
toxicity study of BI 674304 in mice, no adverse effects of IL-36R antagonism were seen at a 
dose (50 mg/kg, twice weekly) that was 5 fold higher than the dose that was protective in an 
experimental mouse colonic inflammation model. The in vitro cytokine release and tissue 
cross-reactivity assays demonstrate that the risk of transient cytokine release in humans is 
low and that, as expected, BI 655130 stains epithelium in a variety of tissues. There were no 
signs of local irritation after single, 1 mL injections of the subcutaneous formulation in 
rabbits. 
These preclinical data suggest that BI 655130 can be safely administered to humans for up to 
13 weeks.
Clinical PK/PD studies
BI 655130 or placebo (PBO) was administered to 78 healthy volunteers at single ascending 
IV doses from 0.001 mg/kg to 10 mg/kg body weight (1368.1). Safety and tolerability of all 
tested IV doses was good. There were no drug-related serious adverse events (SAEs).
Adverse events (AEs) categorized as related to treatment were observed in 3/19 (15.8%) 
subjects in the PBO group and in 7/59 (11.9%) subjects treated with BI 655130. The most 
frequent treatment-emergent AEs were nasopharyngitis (BI 655130: 21%; PBO: 15%), 
headache (BI 655130: 9%; PBO: 15%), influenza like illness (BI 655130: 7%; PBO: 10%), 
and diarrhoea (BI 655130: 3%; PBO: 10%). There were two AEs of moderate intensity 
(injection site haematoma, headache), all remaining AEs were of mild intensity. There was no 
apparent relationship between the frequency of AEs and the dose. There were no relevant 
changes compared to PBO for laboratory safety, including clinical chemistry, haematology, 
coagulation parameters, and urinalysis. No clinically relevant changes were observed in 12 
lead ECGs, vital signs, and cardio-monitoring.
Pharmacokinetics (PK) analysis showed that exposure (AUC0-tz and Cmax) to BI 655130 seems 
to increase with increasing dose in a greater than dose-proportional manner from 0.01 to 0.3 
mg/kg while exposure increased with increasing dose in an approximately dose-proportional 
manner from 0.3 to 10 mg/kg. The effective half-life of BI 655130 is approximately 4 weeks 
in the linear dose range. Overall, PK data so far suggests target-mediated drug disposition 
kinetics for BI 655130. The saturation of the non-linear elimination pathway is likely 
occurring after 0.3 mg/kg and BI 655130 seems to exhibit linear kinetics from the next dose-
level onwards. Anti-drug antibodies (ADA) were detected in 8 patients, 3 of those had pre-
existing levels. However, caution should be taken in interpreting the ADA results because the 
drug concentrations in many ADA samples exceeded the drug tolerance level of the ADA 
assay (100 μg/mL). Pharmacodynamic (PD) effects in this first in human Single Rising Dose 
trial (c03320877) were assessed by indirect target engagement of IL-36R by BI 655130 using 
an ex-vivo whole blood stimulation assay. Preliminary analyses indicate
that >94% peripheral IL-36R receptor occupancy is achieved with doses ≥3 mg/kg from 30 
minutes post infusion to Week 10.


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In the multiple rising dose trial (1368.2), BI 655130 or PBO have been administered to 
healthy male volunteers at multiple ascending i.v. doses of 3, 6 and 10 mg/kg given once a 
week (qw) for 4 weeks (i.e. 4 administrations), as well as a single dose cohort of 20 mg/kg. 
All dose groups (8 patients each, 3:1 on active or PBO) have completed dosing and 4 weeks 
of follow-up. Overall, BI 655130 was well tolerated. There were no AEs considered to be 
dose limiting and no SAEs. In all cases the AEs were of mild or moderate intensity. 
Furthermore, there were no clinically relevant abnormalities on treatment with BI 655130 
with respect to safety laboratory, vital signs, or ECGs as assessed by a central reader.
Based on population pharmacokinetic modelling informed by both studies, the exposures of 
BI 655130 in this trial 1368.10 are not predicted to exceed the exposures tested and found 
safe with the highest tested dose regimen in 1368.2 (20 mg/kg qw for 4 weeks). Specifically, 
body weight was included as a covariate in the PK model which accounted for a small portion 
of inter-individual variability in exposure. This model was then used to simulate with 
variability the pharmacokinetic profile for a typical 30 kg individual dosed 1200 mg every 4 
weeks and compared to a 60 kg individual receiving 20 mg/kg weekly as shown in the plot 
below:
Figure 1.2: 1
Population pharmacokinetic modelling comparing the 1200 mg q4w dosing 
regimens of a 30 kg individual in 1368.10 to the 1200 mg qw dosing regimen of a 60 kg 
subject in 1368.2.
The shaded region in the plot represents the 90 % prediction/confidence interval of the 
simulated PK profiles for the respective dosing regimens. As can be seen from the plot, the 
30 kg predictions do not exceed the maximum observed Cmax from the 1368.2 trial for the 
planned 1368.10 trial duration. Additionally, the AUC and Cmax predicted at steady state for 
the 30 kg individual do not exceed the steady state exposures predicted after weekly dosing 


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of 20 mg/kg. Assuming no differences in drug clearance between healthy volunteers and 
patients with UC, for patients with a body weight of 30 kg, the median AUC at steady state is 
predicted to be 2.88 fold lower (35,595 ug/mL*day vs 12,344 ug/mL*day) in the 30 kg 
subject dosed 1200 mg q 4 weeks compared to the 20 mg/kg dosing regimen given weekly. 
Similarly, the median Cmax (log transformed) at steady state is predicted to be lower at 13.58 
ug/L (13.4 – 13.9 (90% CI)) for the 30 kg individual compared to 14.3 ug/L (13.98 – 14.53 
(90% CI)).
Summary
BI 655130 is an anti IL-36R antibody with a high potential to block IL-36R signaling. BI 
655130 has been tested in healthy volunteers with single and multiple doses up to 20 mg/kg 
i.v. (single dose) or 20 mg/kg (multiple doses), which were all safe and well tolerated. In 
addition, IL-36R inhibition shows a favorable nonclinical safety profile. Therefore, BI 
655130 might be a promising drug to treat patients suffering from UC.
For a more detailed description of the BI 655130 profile, please refer to the current 
"Investigator`s Brochure" (c03320877).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
BI 655130 is currently under development for the treatment of UC. Its unique dual mode of 
action (MoA) includes anti-inflammatory effects as well as tissue remodeling effects and thus 
may provide a clear advantage over current drugs and investigational compounds, which 
target inflammatory pathways. The potential BI655130 effects on remodeling may turn into 
increased mucosal healing and reduced stricturing and fistulizing complications of IBD.
The link between IL-36R driven inflammation and epithelial inflammation has led to the 
hypothesis that IL-36R signalling may play an important role in IBDs such as UC:

IL-36R and its ligands are expressed in intestinal biopsies from patients with chronic 
IBD;

IL36-induced genes are upregulated in human intestinal myofibroblasts and correlate
with gene signatures observed in UC and Crohn’s disease (CD) patients;

Human IL-36 ligands in cell culture enhance epithelial intestinal barrier permeability, a 
hallmark of IBD pathogenesis;

IL-36R signalling induces in human intestinal myofibroblasts and macrophages not only 
pro-inflammatory but also tissue remodelling related mediators (e.g., tissue growth factor 
TGF-β, matrix metalloproteinase), which differentiates this mechanism from TNF alpha 
and IL23 pathways;

IL-36R signalling in disease relevant cells such as intestinal myofibroblasts and 
macrophages induce not only pro-inflammatory but also tissue remodelling related 
mediators (e.g., tissue growth factor TGF-β, matrix metalloproteinase)

An antagonist anti-mouse IL-36R antibody ameliorates intestinal inflammation in 
various acute and chronic murine colitis models.
Altogether these findings support a prominent role of IL-36R in driving intestinal 
inflammation.
In the present trial, an exploratory systems biology approach will be used to investigate 
genomic changes in the patient, in response to the cytokine blockade induced by systemic 
(i.v.) exposure to BI 655130.
The collected data from this trial will enable the determination of the mechanism of action of 
BI 655130 and the characterization of pathophysiology events following BI 655130 exposure
in UC patients. 


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In addition, first data on clinical effect, safety and PK of 12 weeks of BI 655130 treatment in 
UC patients will be gained and compared to the BI 655130 exposure achieved with 
equivalent doses in healthy volunteers. These data will help to understand the 
pharmacokinetic characteristics of BI655130 in UC, which may differ from those in healthy 
volunteers and patients with other diseases due to the expected intestinal protein loss 
subsequent to mucosal inflammation and ulceration in the colon. 
These findings will support planning and conduct of later stage proof-of-concept dose-finding 
and pivotal trials.
Furthermore, the collected data may assist in identifying potential biomarkers (BMs) for the
development of targeted therapies and for clinical monitoring of therapeutic effect of 
treatment.
The most recent and more detailed information is available in the current IB (c03320877).
TRIAL OBJECTIVES
2.2
The primary objective of this trial is:

To understand the mechanism of action of BI 655130 in patients with UC
Secondary and further objectives are:

To explore clinical effect, safety and tolerability (including immunogenicity) of BI 
655130 treatment

To identify specific BMs with potential usefulness to predict clinical efficacy or safety 
outcome or to help understand BI 655130’s MoA

To evaluate PK during treatment with BI 655130 in UC as compared to healthy 
volunteers and other disease states (e.g. PPP and GPP)
BENEFIT-RISK ASSESSMENT
2.3
Preclinical profiles of BI 655130 and clinical data from trials in healthy volunteers suggest 
that BI 6555130 is safe and may address an unmet medical need in UC patients by a dual 
bimodal anti-inflammatory and anti-fibrotic mechanism of action (cf. Section 2.1).
No relevant animal species is available for toxicology testing of the highly human specific 
antibody BI 655130. However, preclinical toxicology studies with a mouse surrogate 
antibody have demonstrated the safety of IL-36R inhibition in mice (for details cf. IB 
(c03320877)).
The clinical safety and tolerability profile of BI 655130 has been tested and found favourable 
in male healthy subjects treated with i.v. single doses up to 20mg/kg or multiple doses up to 
20 mg/kg body weight qw for up to 4 weeks: BI 655130 was safe and well tolerated in both 
completed Phase I trials at all dose groups with no reporting of any dose dependent, severe or 
serious AE (for details cf. Section 1.2 and Investigator’s Brochure (IB) (c03320877)). In 
addition, further phase I studies in healthy volunteers (1368.3, 1368.9) and clinical proof-of-
concept studies are ongoing in different indications (1368.11 – GPP; 1368.15 – PPP, 1368.10 
– UC) under regular surveillance by an independent DMC. None of these studies has so far 


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generated any specific safety signal (see IB c03320877). In summary, as of September 2017, 
more than 170 subjects have been exposed to active drug without observation of any dose
limiting safety or tolerability issue.
Importantly, based on population pharmacokinetic modelling informed by1368.1 and 1368.2, 
the exposures of BI 655130 in this trial are predicted to not exceed the exposures tested and 
found safe with the highest tested dose regimen in 1368.2 even in subjects with a body 
weight as low as 30 kg (see section 1.2). As can be seen from the plot in figure 1.2: 1, the
predictions for a 30 kg individual do not exceed the maximum observed Cmax from the 1368.2 
trial for the planned 1368.10 trial duration. However, the expected difference in drug 
clearance between healthy volunteers and patients with UC will further increase the 
differences in exposures between 1368.2 and 1368.10 and thus increase the safety margin. 
Therefore, there is no need to restrict enrolment in patients with a low body weight.
As BI 655130 is a first-in class compound, no clinical patient data of compounds with a 
related MoA have been disclosed. Trial 1368-0004 is the first trial to include evaluations for 
efficacy with BI 655130 in UC patients. Therefore, it is difficult to estimate the chance of a
direct benefit for the individual patient in this phase II trial. However, as remissions under 
induction treatment in active UC can typically be seen after 4-8 weeks of treatment with 
biologics, 12 weeks treatment duration in this trial are expected to be sufficient in principle to 
observe a clinical and/or endoscopic remission, which would represent an individual benefit. 
Also, patients who complete 12 weeks treatment duration will be offered to continue 
treatment in a long-term extension trial.
For patients experiencing treatment failure or relapse after End of Treatment (EoT), four 
approved biologics with two different MoAs will be available for treatment, as all patients are 
naïve to previous biologics treatments. 
In addition to a potential individual benefit, this trial may also contribute to generate a group 
benefit for this and other patient populations, as the main aim of this trial is to investigate the 
mode of mechanism of BI 655130 by collection of various BMs in mucosal biopsies, blood 
and stool. 
Thus, the exposure range expected with the selected dose regimen in study participants will 
be covered by safety data from healthy volunteer studies, even if the subject’s body weight is 
as low as 30 kg. However, these predictions are made based upon comparable exposures 
between healthy volunteers and IBD patients, while in fact lower systemic exposures are 
typically found in UC patients compared to healthy subjects due to higher drug clearance of 
monoclonal antibodies resulting from: (i) intestinal protein loss caused by exsudative 
enteropathy (R16-5741; R16-5706), (ii) higher degree of systemic inflammatory burden 
(R13-3046) and (iii) higher expression of the target molecule (IL-36R) in diseased tissues as
compared to peripheral blood of healthy subjects, which may increase the effect of target-
mediated drug disposition on clearance of BI 655130.
Such lower exposure found with many biologics in IBD patients represents the basis for 
requiring higher doses in IBD compared to other indications (e.g. infliximab, adalimumab, 
ustekinumab) (R13-5226; R15-4915; R16-0692; R16-0573).


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Also, in contrast to new chemical entities, the safety and tolerability profile of biologics is 
generally driven by the downstream effects of target molecule binding, and is not directly 
dose dependent at exposures approaching full receptor occupancy, which has been achieved
for BI 655130 in the healthy volunteer trials. The only exception might be infusion reactions, 
which have not been reported in phase I and will be closely monitored during extended 
monitoring after each study drug administration.
As with any immune modulating agent, BI 655130 has the theoretical potential to impair 
immune function resulting in an increased risk of infection or lymphoma. In line with IL-36 
being a member of the pro-inflammatory IL-1 cytokine family, IL-36 has been shown in vitro
to stimulate various pro-inflammatory cytokines and activate NFB.
The potential risk of immunosuppression will be mitigated by thorough safety measures: (i) 
exclusion of patients with history or increased risk of malignancies or infections; (ii) close 
clinical monitoring for AEs, including Rheumatology Common Toxicity Criteria (RCTC)
criteria for intensity grading as project standard; (iii) selection of sites experienced in 
treatment of IBD patients with biologics; and (iv) implementation of an independent data-
monitoring committee (DMC).
Other risks of participating in this study include risks related to the trial specific procedures 
blood sampling, i.v. infusion of study medication, and sigmoidoscopy (or colonoscopy) with 
biopsy. Blood sampling and i.v. infusions can cause local bruising, inflammation, nerve 
damage and pain. Colonoscopy or sigmoidoscopy with biopsy, although generally well 
tolerated, can be associated with diarrhoea, abdominal pain, perforation, bleeding, effects 
from anaesthetic medications, and infection. Most of the endoscopies in this trial will be 
limited to sigmoidoscopies, which do not require a complete bowel preparation and are better 
tolerated by the patients. Investigators are highly experienced and UC patients are familiar 
with the burden and risks of endoscopies from their own disease history.
Due to its antagonistic effect it is considered highly unlikely that BI 655130 may lead to a 
clinical cytokine release syndrome. In addition, preclinical and clinical phase I evaluation did 
not suggest cytokine release induced by BI 655130. However, occurrence of such a syndrome 
will be carefully monitored for as an AESI. 
Manifestations of local and systemic hypersensitivity reactions are readily detectable, 
transient in nature, and in general manageable with standard medical treatment. Specific 
safety measures will be taken during the trial. Following the i.v. infusion, the patients will be 
monitored for infusion reactions at the site for two hours after infusion.
Although rare, a potential for drug induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.3.5.1.
Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of women of childbearing potential in this 


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study is justified (c03320877). To minimize the risk of unintentional exposure of an embryo 
or fetus to the investigational drug, women of childbearing potential must agree to the 
requirements for pregnancy testing at the visits indicated in the Flow Chart and contraceptive 
methods described in the patient information. Male patients will be asked to use effective 
methods of birth control to prevent their partner from becoming pregnant if she is of 
childbearing potential. Birth control methods must be used for 20 weeks after the last 
infusion (corresponding to five BI 655130 half-lives).
Summary of benefit-risk assessment
Due to the lack of mechanism- or compound-related safety signals and the antagonistic MoA
action of BI 655130 it is considered likely that UC patients will not be exposed to undue risks 
and AEs in relation to the information that is expected to be gained from this trial. 
Considering the medical need of the development of an effective and well tolerated drug for 
the therapy of UC, the benefit of this trial is considered to outweigh the potential risks for 
individual UC patients participating in this trial.
The benefit-risk profile is thus considered appropriate for an experimental therapy at this 
stage of clinical development.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is an open-label, single-arm, phase IIa exploratory trial to assess the genomic and 
epigenetic changes in both the patient and the microbiome, in response to the IL-36 
signalling blockade induced by i.v. treatment with BI 655130 in patients with moderate to 
severe active UC. 10 patients will be investigated.
The trial includes a screening period, a 12-week treatment period and a safety follow-up 
period of 16 weeks. This allows safety monitoring for 20 weeks (~5 half-lives of BI 655130)
after the last dose of BI 655130, which is administered at Week 8.
Patients should be on stable doses of conventional treatment for their disease.
Patients found suitable for trial participation based on in-/exclusion criteria during screening 
period can enter the treatment phase. Administration of 1200mg BI 655130 intravenously
will take place every four weeks (Day 1, Week 4 and Week 8).
A schematic overview of trial design is shown in Figure 3.1: 1.
Figure 3.1: 1 Trial Design
Abbreviations: W0: Week 0, W4: Week 4, W8: Week 8, W12: Week 12, W28: Week 28,     : 
i.v. infusion
During treatment phase, sequential sigmoidoscopies will be conducted to collect biopsies for 
evaluation of endpoint variables. Also, blood and stool samples will be collected at various 
visits, and data will be correlated with the results from biopsies.
Endoscopic as well as histologic evaluations of mucosal biopsies will be performed by a 
central expert who is independent from the investigator.
Patients who terminate study drug early in trial 1368-0004 will complete EoT visit 
procedures and return for an End of Observation (EoO) visit 20 weeks (>5 half-lives of BI 
655130) after the last dose of BI 655130.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Section 6.1 and Section 6.2, 
respectively.


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Patients who complete the full treatment period of study 1368-0004 will be offered to roll 
over into a long-term extension trial (1368-0017).
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at different centres
participating in this multi-centre trial. Tasks and responsibilities are defined in a contract.
A project-independent, partially-external data monitoring committee (DMC), will be
established to assess the progress of the clinical trial, including a safety and
efficacy assessment at specified intervals, and to recommend to the sponsor whether to
continue, modify, or stop the trial due to safety or ethical concerns. Measures will be put in
place to ensure blinding of the project team and all other trial participants. The tasks and
responsibilities of the DMC will be specified in a charter. The DMC will maintain written
records of all its meetings.
Relevant documentation on the participating (principal) investigators and other important
participants, including their curricula vitae, will be filed in Investigator Site File (ISF).
BI has appointed a Trial Clinical Monitor (TCM), 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 (CMLs), Clinical
Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective
local or regional BI-organisation (Operating Unit) in accordance with applicable
regulations and internal SOPs, or by a Clinical Research Organisation (CRO) with which the
responsibilities and tasks will have been agreed and a written contract filed before initiation
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined
according to BI SOPs. A list of responsible persons and relevant local information can be
found in the ISF.
A central laboratory service will be used in this trial. Details will be provided in a Central 
Laboratory Manual, available in Section 10 of the ISF. Central reading of endoscopies and 
central evaluation of histopathology will be done. Details will be provided in Section 15 of 
the ISF.


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DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
This trial is designed as an open-label, single-arm, phase IIa exploratory trial of BI 655130 in 
patients with active UC.
The present trial is of exploratory nature and aims to explore the mechanism of action of the 
1st in class IL-36R inhibitor in UC. The primary aim of the trial is to evaluate changes in 
various genetic and epigenetic markers under conditions of IL-36 pathway inhibition and will 
be compared to the individual baseline values rather than a control group. The comparison 
between two baseline visits will describe the spontaneous variability in expression of the 
target genes and markers. The nature of the regulated genes and BMs will shape the 
subsequent development of BI 655130 in IBD to define potential new endpoints, target 
indications and BMs to identify responder patient populations. In addition, this trial will 
include clinical and endoscopic activity evaluations of BI 655130 which may support 
subsequent trials in achieving clinical proof of concept (PoC) of this potential UC treatment. 
As shown in the recent proof of concept trial with etrolizumab (R17-0373) in a similar UC 
population as the one proposed here with BI 655130, the clinical response and remission rates 
on PBO were very low, probably due to endoscopic screening of patients. Since the patient 
population in this trial will be similar and endoscopic eligibility criteria have to be met as 
well, a potential clinical effect is likely to be caused by treatment rather than representing a 
PBO effect. However, clinical effects are not the primary objective and a clinical PoC study 
will be conducted in a different properly designed trial. Therefore, a control group is not 
required for this mechanistic trial comparing gene and BM expression after treatment with 
baseline, and a single-arm open-label design is appropriate to answer this question.
Since a PoC for BI 655130 is not yet available in UC, the chance of an individual benefit for 
study participants is difficult to estimate, and thus the sample size and treatment duration was 
limited to a minimum to achieve the study objectives. The sample size of 10 treated subjects 
is not based on a power calculation but on coordinating investigator’s experience with regard 
to similar mechanistic studies.
The treatment duration of 12 weeks of BI 655130 was selected to cover a longer induction 
period compared to currently approved biologic treatment and is covered by currently 
available preclinical Good Laboratory Practice (GLP) toxicology studies. 
As clinical remissions under induction treatment in active UC are typically detected after 6-8 
weeks of treatment with biologics, the duration of 12 weeks will allow observation of clinical 
and/or endoscopic remissions, provided BI 655130 is clinically active in UC. It may also 
determine the kinetics of response and optimal duration of induction treatment.
SELECTION OF TRIAL POPULATION
3.3
It is planned that a total of 10 patients will be treated in the current trial. A sufficient number 
of patients will be screened to meet this goal. Recruitment will be competitive. 
Patients who fulfil all the inclusion criteria (Section 3.3.2) and none of the exclusion criteria 
(Section 3.3.3) are eligible for inclusion in the trial. The selection of biologics naïve patients 
will maximize the chance to detect biologic activity not confounded by previous treatments, 
and at the same time offer approved rescue treatment in case of insufficient responses.


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Women of childbearing potential or men able to father a child with a level of acceptable 
contraception, in alignment with the Clinical Trials Facilitation Group guideline on 
“Recommendations related to contraception and pregnancy testing in clinical trials” will be 
allowed to participate, as supported by results from pre-clinical toxicology and teratology 
studies with BI 655130. Please refer to the IB for more details.
A log of all patients enrolled into the trial (i.e., who have signed 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 trial entry
Patients with moderately or severely active UC who have not been satisfactorily controlled
on conventional treatments, are naïve or experienced to TNF antagonist treatment but have 
not failed that treatment due primary non-response or lack of response, and have not received
any other biologic agent in the past.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. 18 – 75 years at screening
2. Body weight ≤ 100 kg (at screening and at Day 1 of treatment)
3. Diagnosis of UC ≥3 months prior to screening.
4. Moderately to severely active UC as confirmed by Mayo Score ≥6 (with rectal 
bleeding ≥ 1 and modified endoscopy score ≥2) and elevated C-Reactive protein 
(CRP) or faecal calprotectin at pre-baseline visit.
5. Receiving conventional, non-biologic therapy for UC.
This therapy could consist of one or more of the following:

Oral 5-ASA compound, with stable dose for at least 4 weeks prior to screening

6-MP, Methotrexate (MTX) or AZA, with stable dose for at least 8 weeks prior to 
screening

Oral corticosteroids (≤ 20mg/day per day of prednisone or equivalent), with stable 
dose for at least 4 weeks prior to screening
6. Negative colon cancer screening by full colonoscopy with serial biopsies (or 
according to local standard of care) performed and documented within the past 12 
months prior to screening (otherwise to be done at pre-baseline visit)
7. Patients who are naïve or experienced to TNF antagonists (including infliximab, 
adalimumab, or golimumab) but have not failed that treatment due to primary non-


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response or loss of response (previous anti-TNF treatment outcome and reason for 
discontinuation must be documented in source data).
8. Women of childbearing potential and men able to father a child must use highly 
effective methods of birth control per International Conference on Harmonisation
(ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly. A list of contraception methods meeting these criteria is 
provided in the patient information.
Note: A woman is considered of childbearing potential, i.e. fertile, following menarche 
and until becoming postmenopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause. 
9. Signed and dated written informed consent in accordance with GCP and local 
legislation prior to admission to the trial
3.3.3
Exclusion criteria
The exclusion criteria are divided into 3 categories: gastrointestinal exclusion criteria, 
infectious disease exclusion criteria, and general exclusion criteria. Patients meeting any of 
the following exclusion criteria are not eligible for trial participation.
Gastrointestinal Exclusion Criteria
3.3.3.1
1. Patients who have previously failed treatment with any TNF antagonist (including 
infliximab, adalimumab, golimumab) due to primary non-response or loss of response
2. Patients who were treated with a TNF antagonist within 8 weeks prior to screening, or 3 
half-lives of agent from screening, whichever is longer
3. Prior use of any other biological treatment in the past (e.g. integrin inhibitors, IL12/23 or 
IL23 inhibitors, any other investigational biological drugs)
4. Extensive colonic resection, subtotal or total colectomy
5. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
6. Patients who must or wish to continue the intake of restricted medications (see Table 
4.2.2: 1) or any drug considered likely to interfere with the safe conduct of the trial
7. Evidence of infection with C. difficile or other intestinal pathogen <30 days prior to 
screening
8. Currently require or are anticipated to require surgical intervention for UC
9. Colonic moderate or severe mucosal dysplasia 


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10. Colonic adenomas (unless properly removed)
11. Primary sclerosing cholangitis
12. Faecal transplant ≤ 6 months before screening
13. Disease limited to the rectum, extending <15 cm past the anal verge (ulcerative proctitis).
Infectious Disease Exclusion Criteria
3.3.3.2
14. Increased risk of infectious complications (e.g., recent pyogenic infection, any congenital 
or acquired immunodeficiency (e.g., HIV), live vaccination within 6 weeks prior to 
screening, past organ or stem cell transplantation)
15. Active or latent tuberculosis (TB) (Note: Patients with a positive QuantiFERON TB test 
are excluded. Patients with suspected false positive or undeterminable QuantiFERON TB 
result may be re-tested.)
16. Any severe infection within 30 days prior to screening, including chronic or acute 
hepatitis B or C infection
General Exclusion Criteria
3.3.3.3
17. Evidence of a current or previous disease, medical condition (including chronic alcohol or 
drug abuse) other than UC, surgical procedure, medical examination finding (including 
vital signs and electrocardiogram (ECG)), or laboratory value at the screening visit 
outside the reference range that in the opinion of the investigator is clinically significant 
and would make the study participant unreliable to adhere to the protocol or to complete 
the trial, compromise the safety of the patient, or compromise the quality of the data
18. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix
19. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to randomization or planned during the trial, e.g., hip replacement
20. Pathological safety lab parameters: haemoglobin <8.5g/dL, total white blood count 
(WBC) <3.500 cells/μl, neutrophils <1.000 cells/μl, thrombocytes <75.000/μl, albumin 
<30g/L, serum creatinine ≥ 2mg/dL, AST >2xULN, ALT>2xULN, total bilirubin > 1.5x 
ULN (patients with Gilbert’s syndrome are not excluded), alkaline phosphatase >3x ULN
21. Currently enrolled in another investigational device or drug study, or less than 30 days or 
5 half-lives, whichever is longer, since ending another investigational device or drug 
study(s), or receiving other investigational treatment(s)
22. Women who are pregnant, nursing, or who plan to become pregnant while in the trial


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23. Known hypersensitivity to any component of BI 655130
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole 
(“withdrawal of consent”) with very different implications, please see Section 3.3.4.1 and
Section 3.3.4.2 below.
Every effort should be made to keep the patients in the trial, at least to collect important trial 
data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to randomization, as well as the 
explanation of the consequences of withdrawal.
The decision to withdraw from trial treatment or from the whole trial as well as the reason 
must be documented in the patient files and Electronic Case Report Form (eCRF).
Withdrawal from trial treatment
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient needs to take concomitant drugs that interfere with the investigational 
product or other trial medication. Please refer to Section 4.2.2 for restricted medication 
during this trial.

The patient requires additional medical therapy or dose increase in patient’s baseline 
medication, as deemed by the investigator, to treat the underlying UC due to disease 
worsening.

The patient can no longer be treated with trial medication for other medical reasons such 
as surgery, AEs, other diseases, or pregnancy.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future.
Exclusion criteria occurring after randomization will not necessarily be a reason for 
withdrawal of a patient. 
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart and Section 6.2.3.
For all patients, the reason for withdrawal from treatment (e.g., adverse event) must be 
recorded in the eCRF. These data will be included in the trial database and reported.
Withdrawal of consent for trial participation
3.3.4.2
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision. This will however mean that no further information may be collected for 
the purpose of the trial and negative implications for the scientific value may be the 
consequence. Furthermore it may mean that further patient follow up on safety cannot occur.


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If a patient wants to withdraw consent, the investigator should explain the difference between
treatment withdrawal and withdrawal of consent for trial participation.
3.3.4.3
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1.
Failure to meet expected enrolment goals overall or at a particular trial site
2.
Emergence of any efficacy/safety information invalidating the earlier positive benefit 
risk-assessment that could significantly affect the continuation of the trial
3.
Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
INVESTIGATIONAL TREATMENTS 
4.1
Multiple doses of BI 655130 will be administered intravenously. BI 655130 will be supplied 
by BI.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Description of test product BI 655130 12 weeks
Substance:
BI 655130
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, 
Germany
Chemical form:
Anti-human IL-36 Receptor mAb
Molecular weight:
146 kDa
Unit strength:
150mg/vial (20mg/mL)
Posology
1200mg at Day 1, at Week 4 and at Week 8
Route of administration:
intravenous infusions
Duration of Use
12 weeks
4.1.2
Selection of doses in the trial
The aim of this small exploratory study is to provide the highest likelihood to study the 
mechanism of BI 655130 in UC analysing various BMs in sequential biopsies. Based on 
other effective anti-cytokine drugs in IBD and pre-clinical assays for IL36 inhibition, a linear 
or logistic rather than a bell-shaped dose-response curve is expected for these BMs. Thus, the 
highest tolerated dose should provide the highest likelihood to achieve this objective. This 
dose is also expected to provide the best chance to induce clinical remissions in UC patients.
The fixed rather than weight-based dose regimen of 1200mg given at weeks 0, 4 and 8 has 
been selected for the following reasons:


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
Early trials of therapeutic monoclonal antibodies often investigate body weight based 
regimens to reduce the inter-subject variability in drug exposure. However, there is 
generally only modest contribution of body weight to overall PK and PD variability of
monoclonal antibodies. Furthermore, monoclonal antibodies are highly target-specific
and offer a relatively large therapeutic window as compared to new chemical entities.
Therefore, most monoclonal antibodies are approved at fixed doses in antibody/target 
excess in order to cover target turnover and maximize efficacy. (R13-4749, R10-6267, 
R13-4753, R13-4750, R13-4754).

Body weight has been included in the current PK model as a covariate indicating 
decreased exposure with increasing body weight.  The current model indicates that body 
weight explains less than 15% of between-subject variability in PK of BI 655130 when 
comparing a model with and without body-weight as a covariate of exposure.

A fixed dose regimen will minimize the potential for dosing errors due to less complex 
dose calculation, study drug preparation and administration as compared with weight 
based dosing. It will also facilitate dose finding and PK-PD analyses due to covering a 
wider weight/exposure range (R10-6267).

This dose regimen is the highest covered by current healthy volunteer PK and safety data
irrespective of body weight.
Currently approved or investigational biologics (e.g. TNFi, vedolizumab, ustekinumab) have 
established 4-8 weeks duration of induction treatment in UC; a longer induction period of 12 
weeks was selected to allow assessment of the response kinetics for BI 655130, which
represents a new and clinically non-validated mode-of-action (MoA). The dosing interval of 
once every 4 weeks is supported by the long half-life of BI 655130 of approximately four 
weeks. The discontinuation of BI 655130 treatment after 12 weeks is supported by preclinical 
GLP toxicology studies with the surrogate antibody and will allow study of the PK and PD
wash-out profile (clinical effect and BM) of BI 655130. 
4.1.3
Method of assigning patients to treatment groups
There is only one treatment group in this trial.
4.1.4
Drug assignment and administration of doses for each patient
In this trial, a dose of 1200mg of BI 655130 will be administered intravenously at Day 1, 
Week 4 and Week 8. The concentration of the application solution in the infusion bag will be
20mg/mL.
Detailed instructions for the preparation of the infusion solution, the volume to be 
administered and the infusion rate are provided in Section 4 of the ISF. 
In case of safety concerns, e.g., due to infusion reactions, it is at the discretion of the 
investigator or his/her designee to adapt the infusion scheme, including but not limited to 
slowing down the infusion rate, stopping of the infusion and provided no further safety 


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concern exists restarting at a slower rate. In any case, the total duration of infusion should not 
exceed 240 minutes (4 hours) provided that the maximum time between the start of 
preparation and completion of administration of the solution to the patient does not exceed 
300 minutes (5 hours). For further instructions on how to proceed in case of an infusion 
reaction, please refer to Section 4.2.1.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
This is an open-label, single-arm trial. Therefore, no blinding will be necessary. 
Unblinding and breaking the code
4.1.5.2
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP).
For details of packaging and the description of the label, refer to Section 4 of the ISF.
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 storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the sponsor must be 
contacted immediately. Refer to the Section 4 of the ISF for contact information.
For further user information and in-use stability, refer to Section 4 of the ISF.
4.1.8
Drug accountability
The Investigator and/or Pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:

Approval of the trial protocol by the ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational 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 (CTP)


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Only authorised personnel as documented in the form “Trial Staff List” may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. The Investigator and/or Pharmacist and/or investigational drug storage 
manager must maintain records of the product’s delivery to the trial site, the inventory at the 
site, the use by each patient, and the return to the sponsor or warehouse / drug distribution 
centre or alternative disposal of unused products. If applicable, the sponsor or warehouse / 
drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates
and the unique code numbers assigned to trial patients. The Investigator / Pharmacist / 
investigational drug storage manager will maintain records that document adequately that the 
patients were provided the doses specified by the CTP and reconcile all investigational 
products received from the sponsor. At the time of return to the sponsor< and/or >appointed 
CRO, the Investigator / Pharmacist / investigational drug storage manager must verify that all 
unused or partially used drug supplies have been returned by the clinical trial staff and that no 
remaining supplies are in the Investigator’s possession.
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Patients in this trial are required to be on conventional, non-biologic treatment for UC.
Conventional treatment may consist of one or more of the following drugs (cf. Section 3.3.2, 
inclusion criteria), which are therefore permitted concomitant medications:

Oral 5-ASA compound, with stable dose for at least 4 weeks prior to screening and 
throughout the trial

6-MP, MTX or AZA, with stable dose for at least 8 weeks prior to screening and 
throughout the trial

Oral corticosteroids (≤ 20mg/day per day of prednisone or equivalent), with stable dose 
for at least 4 weeks prior to screening and throughout the trial. For equivalent doses of 
corticosteroids, please cf. Appendix 10.3.
Dose has to be stable throughout the trial. In the event that a patient experiences an 
intolerable increase of UC, as deemed by the investigator, during the course of the trial, the 
decision whether or not to discontinue treatment (if applicable) and start rescue treatment 
should be taken in the discretion of the investigator and in discussion with the CML. Rescue 
treatment may be any new medication or any increase in dose of a baseline medication.
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (cf. Section 3.3.3) are 
permissible. All concomitant medications should be carefully evaluated by the investigator, 
and the CML should be contacted when there are questions regarding concomitant 
medications.


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Details of all concomitant medication will be recorded in the eCRF, along with the main 
reason for prescription. In addition, all prior treatment for UC within 12 months of Visit 1a 
will be recorded.
Infusion reactions including anaphylactic reactions:
In case of infusion reactions including anaphylactic reactions emerging during or after 
infusion of BI 655130, the investigator should consider in accordance with severity of the 
reaction and local standard of care to

Immediately interrupt the infusion

Treat with systemic anti-histamines and i.v. steroids and in case of a severe allergic
reaction (eg, anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA as detailed in the Lab Manual (Section 10 of 
the ISF).
Based on patient’s clinical course and medical judgment, the infusion may be re-initiated in 
case of mild or moderate infusion reactions (according to RCTC grading in Section 5 of the 
ISF) at lower speed with gradual increase to complete the infusion as detailed in the 
Instructions for Preparation and Handling of BI 655130 in the Investigator Site File.
In any case, the total duration of infusion should not exceed 240 minutes (4 hours) provided 
that the maximum time between the start of preparation and completion of administration of 
the solution to the patient does not exceed 300 minutes (5 hours). 
In case of anaphylactic reaction, the investigator should discontinue treatment with BI
655130.
Cytokine release syndrome (CRS)
This syndrome manifests when a large number of immune cells becomes activated and
releases inflammatory cytokines. It is clinically characterized by fever, chills, rigor and
rash, possibly with nausea, dyspnoea, tachycardia and hypotension.
Potentially life-threatening complications of a cytokine release syndrome include cardiac
dysfunction, respiratory distress syndrome, neurologic toxicity, renal and/or hepatic
failure, and disseminated intravascular coagulation. In case of suspicion of a cytokine
release syndrome, it is recommended to measure IL-6 levels in the local laboratory if the
assay is available.
The investigator should discontinue treatment with BI 655130. Aggressive supportive
care is essential for patients experiencing CRS, with early intervention for hypotension
and treatment of concurrent infections. IL-6 receptor blockade with tocilizumab
remains the mainstay pharmacologic therapy for CRS, though indications for
administration vary among centres. Corticosteroids should be reserved for neurologic
toxicities and CRS not responsive to tocilizumab (R16-5751).


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Opportunistic infections or mycobacterium tuberculosis infections or serious infections
The investigator should discontinue treatment with BI 655130. Treatment of the
infection has to be initiated according to local standard of care.
4.2.2
Restrictions
Restrictions regarding previous and concomitant treatment are summarized in Table 4.2.2: 1.
Table 4.2.2: 1
Restrictions regarding previous and concomitant treatment
Medication or class of medications
Restriction 
Biologics
TNF inhibitors are only allowed in the past, if 
stopped for other reasons than primary non-
response or lack of response 
Other biologics are excluded.
Not allowed from 8 weeks prior to screening or 3 
half-lives of agent from screening, whichever is 
longer, up to the end of the trial.
Cyclosporine, tacrolimus, 
mycophenolate mofetile and other 
immunomodulators not listed below
Not allowed from 8 weeks prior to screening or 5 
half-lives of agent from screening, whichever is 
longer, up to end of the trial
AZA, 6-MP, MTX
Only allowed during the trial, if dose is stable for
at least 8 weeks prior to screening and throughout 
the trial.
For use of any of these drugs as concomitant
medication, refer to Section 4.2.1. 


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Table 4.2.2: 1
Restrictions regarding previous and concomitant treatment (cont.)
5-ASA
Oral administration:
Only allowed during the trial, if dose is stable for 
at least 4 weeks prior to screening and throughout 
the trial.
For use as concomitant medication, refer to 
Section 4.2.1.
Rectal route of administration (5-ASA):
Not allowed from 2 weeks prior to screening up 
to end of the trial
Corticosteroids 
Oral administration:
Only allowed at a dose of 
≤ 20mg/day per day of prednisone or 
equivalent and with stable dose for at least 
4 weeks prior to screening and throughout 
the trial.
For use of oral corticosteroids as concomitant 
medication, refer to Section 4.2.1.
Parenteral administration:
Not allowed from 2 weeks prior to screening up 
to end of the trial
Rectal administration:
Not allowed from 2 weeks prior to screening up 
to end of the trial
NSAID
Chronic use
(Note: occasional use of NSAIDs and 
acetaminophen for headache, arthritis, myalgias, 
menstrual cramps, etc., and daily use of baby or 
low dose (81-162.5mg) aspirin for cardiovascular 
prophylaxis are permitted.)
Probiotics 
Not allowed from 2 weeks prior to screening up 
to end of the trial
Antidiarrheals
Not allowed from screening up to end of the trial 
Life-attenuated vaccines
Not allowed from 6 weeks prior to screening up    
to end of the trial
Antibiotics for IBD
Not allowed from 4 weeks prior to screening up 
to end of the trial


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Restrictions on diet and life style
4.2.2.1
Patient should be fasted for at least 8 hours prior to collection of the safety laboratory 
samples, starting from Visit 2 and as indicated in the Flow Chart.
Restrictions regarding women of childbearing potential 
4.2.2.2
Women of childbearing potential must use the contraception methods as described in the 
patient information.
TREATMENT COMPLIANCE
4.3
Compliance will be assured by administration of all trial medication in the study centre by the 
authorised personnel (e.g., study nurse). The measured plasma concentration will provide 
additional confirmation of compliance.
Subjects who are not compliant (e.g., who do not appear for scheduled visits or violate trial 
restrictions) may be removed from the trial and the eCRF will be completed accordingly (for 
further procedures, please see Section 3.3.4.1).
Any missed dose has to be documented and reported to the CML.


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5.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The total number of deregulated genes comparing baseline to post-treatment, analysed by 
gene expression of mucosal biopsies via RNA sequencing (RNAseq), per time point up to 
week 12.
The total number of deregulated genes per time point will be reported.
Further details on the planned analyses will be given in Section 7.3.
5.1.2
Secondary Endpoints

Drug related AEs

Percent change in CRP from baseline to Week 12 

Percent change in faecal calprotectin from baseline to Week 12 

Percent change in faecal lactoferrin from baseline to Week 12 

Clinical remission at Week 12 based on Mayo Score (Mayo Score ≤2 with all
subscores ≤1)
For a definition of (modified) Mayo Score 
 please 
refer to Appendix 10.1


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ASSESSMENT OF EFFICACY
5.2
The changes in UC activity during the trial will be assessed using the Mayo score (disease 
activity score) 
 as indicated in the Flow Chart. Please 
refer to Appendix 10.1 (Mayo Score)
for further details. 
The change in CRP as well as in faecal calprotectin and faecal lactoferrin during the trial will 
be assessed as a measure for UC activity, as indicated in the Flow Chart. The normal ranges 
will be provided by the lab.
ASSESSMENT OF SAFETY
5.3
The secondary safety endpoint to assess safety and tolerability of BI 655130 is specified as 
drug related AEs.
In general, safety will be assessed descriptively based on:

AEs

SAEs

Clinical laboratory values (haematology, clinical chemistry, coagulation and 
urinalysis)

Physical examination

Vital signs 

12-lead ECG


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5.3.1
Physical examination
A complete physical examination will include general appearance as well as evaluation of all 
organ systems and will be performed by the investigator or a delegated sub-investigator at 
Visit 1a, at EoT visit and at EoO visit. Height (cm) and weight (kg, without shoes) will be 
measured at Visit 1a. Weight will also be measured (prior to dosing, if applicable) at Day 1 of 
treatment, at Week 4 (Visit 5), Week 8 (Visit 7) and EoT Visit.
A targeted physical examination will include evaluation of organ systems associated with 
AE(s) symptoms or laboratory abnormalities and will take place at all other visits.
Preferably, the same individual should perform the physical examinations for a patient during 
the course of the trial. The investigator will evaluate the clinical significance.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
5.3.2
Vital Signs
Vital signs will be assessed at all study visits. Vital signs assessment will include 
temperature, pulse rate, systolic/diastolic blood pressure and respiratory rate. Respiratory 
rate, pulse rate and blood pressure will be measured after the patient has been sitting 
comfortably for at least five minutes. All recordings should be made using the same type of 
blood pressure recording instrument on the same arm if possible.
At visits with study drug administration (Visits 2, 5 and 7) vital signs will be assessed pre-
dose, and additional evaluations will be taken at approximately 5 and 120 minutes after end 
of study drug administration. 
The investigator should evaluate the clinical significance of the results. Clinically abnormal 
findings will be reported as baseline conditions or AEs.
5.3.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.3.3:1. For the sampling time 
points please see the Flow Chart.
Table 5.3.3: 1
Safety laboratory parameters
Functional lab group
Test name
Haematology
Haematocrit (Hct)
Haemoglobin (Hb)
Mean cellular haemoglobin (MCH)
Mean cellular haemoglobin concentration 
(MCHC)
Mean cellular volume (MCV)


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Table 5.3.3: 1
Safety laboratory parameters (cont.)
Reticulocyte count 
Platelet count
Red blood cell (RBC) count / Erythrocytes
White blood cell (WBC) count / Leucocytes
Differential automatic (relative and absolute 
Neutrophils
count)
Eosinophils
Basophils
Monocytes
Lymphocytes
Differential manual (relative and absolute
Neutrophils, Bands
count (if differential automatic is abnormal)
Neutrophils, Polymorphonuclear (PMN)
Eosinophils
Basophils
Monocytes
Lymphocytes
Coagulation
Activated Partial Thromboplastin Time 
(aPTT)
Prothrombin Time (Quick / INR)
Fibrinogen
Enzymes
Alanine Aminotransferase (ALT)
Aspartate Aminotransferase (AST)
Alkaline Phosphatase (AP)
Gamma Glutamyl Transferase (GGT)
Lactic Dehydrogenase (LDH)
Creatine Kinase (CK)
CK-MB (if CK >ULN)
Amylase
Lipase
Electrolytes
Calcium
Sodium
Potassium


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Table 5.3.3: 1
Safety laboratory parameters (cont.)
Bicarbonate
Chloride
Substrates
Creatinine
C-Reactive protein (CRP)
Albumin
Glucose
eGFR (estimated by CKD-EPI formula) 
(only at screening) 
Bilirubin Total
Bilirubin Direct (only if total bilirubin 
outside the normal range)
Bilirubin Indirect (only if total bilirubin 
outside the normal range)
Total Cholesterol, High density Lipoprotein 
(HDL) Cholesterol, Calculated Low Density 
Lipoprotein (LDL) Cholesterol
Triglycerides
Protein, Total
Urea nitrogen
Uric acid
Troponin (only in case of elevated CK)
Protein electrophoresis (only at Visit 1a)
Hormones
Thyroid stimulating hormone (only at Visit 
1a)
fT3 and fT4 (only if TSH is outside normal 
range)
Urinalysis (dipstick)
Urine Glucose
Urine Bilirubin
Urine Ketone
Specific Gravity
Urine RBC / Erythrocytes
Urine WBC / Leucocytes
pH


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Table 5.3.3: 1
Safety laboratory parameters (cont.)
Urine Protein
Urine Urobilinogen
Urine Nitrite
Urine sediment (microscopic examination if 
urine analysis abnormal)
Only positive findings will be reported (e.g., 
the presence of sediment bacteria, casts in 
sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
Infection screening
Hepatitis B Surface Antigen (only at Visit 
1a)
Hepatitis C Antibody (only at Visit 1a)
HIV –and HIV-2 Antibody (only at Visit 
1a)
QuantiFERON®-TB (only at Visit 1a)
Specific gamma-globulin quantification
IgE (only in case of allergic reaction), IgG
Stool sample (for enteric pathogens)
Salmonella (only at Visit 1a)
Shigella (only at Visit 1a)
Yersinia (only at Visit 1a)
Campylobacter (only at Visit 1a)
Vibrio (only at Visit 1)
E. coli O157/H7 (only at Visit 1a)
Clostridium difficile toxin (only at Visit 1a)
Enteric parasites and their ova including 
Cryptosporidia (only at Visit 1a)
Urine pregnancy test (only for female 
patients of childbearing potential) at 
randomization and continued as indicated in 
the Flow Chart
Human Chorionic Gonadotropin in urine
Serum Pregnancy test (only for female 
patients of childbearing potential) at Visit 
1a and if urine pregnancy test is positive
Human Serum Chorionic Gonadotropin
With the exception of urine pregnancy test, all analyses will be performed by a central 
laboratory, the respective reference ranges will be provided in Section 10 of the ISF.
Patients will need to be fasted for all visits (except Visit 1a) as several parameters in the 
safety lab require fastened conditions. 


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Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in Section 10 of the ISF. 
Laboratory results (i.e. all safety laboratory and clinical laboratory data relevant for current 
clinical practice) of the patients will be available in real time to the respective investigator 
(via laboratory reports) and to the sponsor (via the central laboratory website) and selected 
abnormal laboratory alerts will be flagged to the site and sent to sponsor in real time.
Clinically relevant abnormal findings will be reported as baseline conditions or AE’s. A
clinically relevant value may be either in- or outside the reference range. Clinically relevant 
abnormal laboratory test results should be confirmed using an unscheduled visit laboratory kit 
and should be repeated until normalization or stabilization or until an alternative explanation 
has been found. Abnormal laboratory values will be also graded for intensity by using RCTC 
Version 2.0 criteria (R13-3515).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.3.5.1 and the DILI Checklist provided in Section 5 of the 
ISF). The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.
5.3.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart.
ECGs will be recorded after the patients have rested for at least 5 minutes in a supine position 
and will always precede blood sampling to avoid impact of sampling on results. Six limb 
leads, as specified by Einthoven (I, II and III) and Goldberger (aVR, aVL, aVF), and six pre-
cordial leads (V1–V6), according to Wilson, will be used.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle
movements, electrode dislocation).
Additional ECGs may be collected for safety reasons. Clinically relevant, abnormal findings 
will be reported as AEs.
The electronic version, if applicable, or dated and signed printouts of the ECG will be 
regarded as source data and stored in the patient’s medical file.
5.3.5
Assessment of adverse events
Definitions of adverse events
5.3.5.1
Adverse event
An 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.


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Serious adverse event
An 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 or 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in 5.3.5.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI 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 Electronic Data Capture (eDC)
system. These events should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
i.e., AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the 
same timeframe that applies to SAEs, please see above.
The following is considered an AESI:
Infusion reactions including anaphylactic reaction
Any suspicion of severe infusion reaction and of any potential cases of anaphylaxis
should be defined and assessed using the criteria discussed in the statement paper from
Sampson HA (R11-4890).


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Cytokine release syndrome
May manifest when a large number of immune cells becomes activated and releases
inflammatory cytokines. Potentially life-threatening complications include cardiac
dysfunction, respiratory distress syndrome, neurologic toxicity, renal and/or hepatic
failure, and disseminated intravascular coagulation.
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis pneumonia, toxoplasmosa gondii encephalitis,
cryptosporidiosis, microsporidiosis, mycobacterium tuberculosis, mycobacterium
avium, bacterial respiratory disease, bacterial enteric infection, mucocutaneous
candidiasis, invasive mycoses, CMV, EBV, herpes simplex, varicella zoster, human
herpesvirus 8, JC virus infection (adapted from http://aidsinfo.nih.gov/guidelines).
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in Section 5 
of the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of adverse events
The intensity of AE will be classified and recorded in the eCRF according to the RCTC
Version 2.0. For these criteria, please refer to Section 5 of the ISF. 
Causal relationship of adverse events
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.


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
Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days
/ weeks of drug administration; an allergic reaction weeks after discontinuation of 
the drug concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is 
prolonged despite removing the original trigger.

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.
Adverse event collection and reporting
5.3.5.2
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until the individual patient’s end of trial: 
all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only 
report related SAEs and related AESIs of which the investigator may become aware of
by any means of communication, e.g. phone call. Those AEs should however, not be 
reported in the CRF.


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Figure 5.3.5.2: 1
AE reporting
The residual effect period (REP) for BI 655130, i.e., when measurable drug levels or PD 
effects are still likely to be present after the last administration, is 140 days (20 weeks).
Therefore, all AEs reported through the REP will be considered on-treatment, cf. Section 
7.3.4.
As end of REP coincides with EoO visit (last per protocol (PP) visit) in this trial, all AEs 
reported from first dose until end of the trial will be considered on-treatment. 
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in Section 1 of 
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 timelines apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication and any possible interactions between the trial medication
and a Non-Investigational Medicinal Product / Auxiliary Medicinal Product 
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.


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If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’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 patient 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.
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 Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
BI 655130 concentrations will be reported descriptively. The relationship between PK and 
selected endpoints, BMs and AEs may be assessed. Also, ADAs will be measured, as the 
clearance of BI 655130 can potentially be affected by the presence of anti-BI 655130 
antibodies similar to the cases seen in anti- TNFs.
Refer to Flow Chart for the time points of PK and ADA sample collection. Data and exact 
time of drug administration and PK and ADA sampling will be recorded on eCRFs. These 
actual administration and sampling times will be used for determination of PK parameters. 
On visits with study medication dosing, PK and ADA samples should be collected prior to 
administration of study drug.
5.4.2
Analytical determinations
BI 655130 concentrations will be determined by a validated immunoassay.
The presence of ADA to BI 655130 will be assessed via a tiered approach using a validated 
electrochemiluminescence assay (screening, confirmatory, and titration analysis, as 
appropriate). Samples that are confirmed positive may be further characterized using a 
validated neutralizing antibody (Nab) assay.


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5.4.3
Methods of sample collection
Plasma sampling for PK analysis 
5.4.3.1
For quantification of BI 655130 plasma concentrations, blood will be taken from a forearm 
vein into a K2EDTA (ethylendiaminetetraacetic acid) anticoagulant
blood-drawing tube at the time points listed in the Flow Chart under plasma PK. Handling 
procedures can be found in the lab manual (Section 10 of the ISF).
After completion of the trial, the plasma samples may be used for further methodological
investigations, e.g. for stability testing. However, only data related to the analyte will be
generated by these additional investigations. The study samples will be discarded after
completion of the additional investigations but not later than 5 years upon the final study
report has been signed.
Plasma sampling for ADA assessment
5.4.3.2
For ADA assessment, blood will be taken from a forearm vein into a K2EDTA anticoagulant 
blood-drawing tube at the time points listed in the Flow Chart
under plasma ADA. Handling procedures can be found in the lab manual (Section 10 of the 
ISF).
After completion of the trial, the plasma samples may be used for further methodological
investigations, e.g. for stability testing. However, only data related to the ADAs 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.
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
The PK and PD data from this study may be used for an exploratory investigation of PK/PD 
relationship of BI 655130, however, it is not planned to report the results of this investigation 
into the clinical trial report of this study.
ASSESSMENT OF BIOMARKER(S)
5.5
BMs associated with UC and the IL-36 pathway will be assessed in biopsies, peripheral blood 
(including serum and plasma) and stools from patients pre and post treatment with 
BI 655130.
Samples will be collected at time points indicated in the Flow Chart for the analysis of BMs. 
For further information on sample handling, please refer to the lab manual (Section 10 of the 
ISF).


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All the BMs, other than the ones defined as formal endpoints (see Section 5.1.3), may be 
reported in a separate BM report.
5.5.1
RNA sequencing
During visits at time points specified in the Flow Chart, colon biopsies and blood will be 
collected for RNAseq.
Please refer to the ISF for further details on the collection and the processing of the biopsies 
and the handling of the blood samples.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
All patients are to adhere to the visit schedule as specified in the Flow Chart. Each visit data 
(with its window) up to EoT is to be counted from Day 1 (Visit 2). If any of these visits has to 
be rescheduled, subsequent visits should follow the original visit date schedule from Day 1. 
Follow-up visits (after EoT) refer to the last dose administration of BI 655130 at Visit 7 
(Week 8). Additional visits for the purpose of re-testing of laboratory parameters or AE 
monitoring may be included as deemed necessary by the investigator.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
Study procedures to be performed at each visit are listed in the Flow Chart and the respective 
protocol sections. Refer to Section 5 and Section 10 (Appendix) for explanations of 
procedures. Additional details on procedures at selected visits are provided below. 
Measurement of vital signs should precede blood sampling and be assessed pre-dose at all 
dosing visits.
6.2.1
Screening and run-in period(s)
After patients have been informed about the trial, written informed consent in accordance 
with GCP and the local legislation must be obtained prior to performing any study related 
procedures.
Once they have consented, the patient is considered to be enrolled in the trial. The patient 
should be recorded on the subject enrolment log. Patient will be assigned a patient number 
and enrolment must be recorded in the eCRF pages.
Screening visit (Visit 1a):
The Screening visit (Visit 1a) should normally take place no more than 35 days before Visit 2
and be complete no less than 9 days prior to Visit 2. At this visit, information will be 
collected for evaluation of trial eligibility as indicated in the Flow Chart.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding UC) will be reported on the baseline condition eCRF page.
Patients who have a laboratory test value outside the range specified by the inclusion criteria 
may have the test repeated to determine eligibility. The result must be available prior to Visit 
2 (Day 1).


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Demography
Informed consent date, gender, age, race and ethnic origin will be collected in the eCRF page. 
Also, the patient’s smoking and alcohol history will also be assessed. Information concerning 
race/ethnicity will be collected as it has been suggested that there might be race/ethnicity 
variations in the incidence, phenotypic manifestations and outcome of UC. Note: In some 
countries, race may not be collected.
Medical and Surgical History
Information on clinically significant previous and concomitant illnesses, other than UC, or 
any clinically significant signs or symptoms that are present before informed consent, or pre-
existing conditions identified through findings from assessments and examinations done 
during the screening visits will be recorded as medical and surgical history at screening. For 
planned procedures/hospitalisations during the trial, documentation should be completed at 
the time of the screening. Regarding the UC, a detailed history of the disease, including date 
of diagnosis, disease severity, hospitalizations, and extraintestinal manifestations will be 
collected. Also, previous and concomitant treatment for UC will be recorded.
Blood sampling 
Blood samples will be taken for safety lab and infection screening (HIV, HBV, HCV, TBC).
For women of childbearing potential, a serum pregnancy test will be performed. 
Stool sampling
A stool sample will be collected to exclude existence of enteric pathogens. If collection is not 
possible at Visit 1a, stool sample has to be collected at (or prior to) Visit 1 or at an 
unscheduled visit. For further details, please refer to the lab manual (Section 10 of the ISF). 
Patient diary
Patients who are eligible at Visit 1a will receive a patient diary to be used for 
1) daily reporting of stool frequency and rectal bleeding (blood in stool) during the week
prior to visits which include assessment of Mayo score, as well as 
2) confirming regular intake of concomitant UC medication over the whole treatment period. 
Patients will be instructed on the use of the diary during screening and treatment phase. The 
diary will be returned at EoO visit.
Visit 1b:
The Visit 1b should take place no more than 8 days and no less than 6 day prior to Visit 2.
A full colonoscopy with serial mucosal biopsies will be performed at this visit to exclude 
malignancy, if no fully documented procedure is available ≤ 12 months prior to screening. If 
a full colonoscopy is available from the past 12 months prior to Visit 1, a sigmoidoscopy incl.
biopsy will be performed instead. Images will be centrally read by an external independent 
assessor.
Based on the results from sigmoidoscopy (or colonoscopy, if applicable) and clinical 
symptoms of the patient, a baseline Mayo score will be determined. 


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Results from the mucosal biopsies will be used as first baseline value for endpoint parameters.
Refer to Section 15 of the ISF for details.
Blood samples will be collected to evaluate baseline gene expression, methylation pattern, 
immunophenotyping, metabolomics profiling and inflammatory BMs. 
For a detailed description of the trial procedures at Visits 1a and 1b, please refer to the Flow 
Chart.
The time window for Visit 1a and 1b may be extended at the discretion of the CML in 
conjunction with the TCM on a case by case basis or re-screening is performed.
Re-screening will be allowed once.
6.2.2
Treatment period(s)
The treatment period is from Visit 2 to End of Treatment (EoT) Visit.
Study related procedures will be performed as specified in the Flow Chart. 
Pregnancy testing
Urine pregnancy testing for all women of child-bearing potential will be conducted on-site 
approximately every four weeks and must be negative to continue treatment. The pregnancy 
testing should be done prior to study drug administration. A positive urine test must be 
confirmed with a serum pregnancy test.
Blood sampling
Blood sampling (e.g., for safety lab, BMs) should be done prior to study drug administration
and prior to sigmoidoscopy, if applicable. Patients should come in a fasted condition. If a 
patient comes in a non-fasted condition, where a fasting condition is required, the visit should 
be performed, the non-fasted condition documented on the laboratory requisition, and the 
patient reminded about the expected conditions. 
At Visit 2, an additional blood sample for gene expression and methylation pattern will be 
collected at 4 hours after start of i.v. infusion. 
Sigmoidoscopies
Sigmoidoscopies will be done after blood sampling and prior to study drug administration. 
During sigmoidoscopies, biopsies will be taken for endpoint evaluation at time points as 
indicated in the Flow Chart. Please refer to Section 5 of the ISF for further information on the 
collection and the processing of biopsies.
At Visit 2, an additional sigmoidoscopy will be done at 4 hours after start of i.v. infusion to 
collect additional biopsy samples.
PK and ADA sampling
At visits with study drug administration, blood sampling for PK assessments should be done 
within 2 hours prior to study drug administration.


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Clinical monitoring after study drug administration:
The patient will be monitored for infusion reactions at the site for approximately 2 hours after 
end of infusion. At all visits with study drug administration, vital signs will be assessed pre-
dose, and at approximately 5 and 120 minutes after end of infusion.
Unscheduled visits
The patient may be called in for additional unscheduled visits due to safety reason at the 
discretion of the investigator or the sponsor, unless the patient has withdrawn his/her consent. 
The patient may also contact the site due to safety reason for an unscheduled visit. The 
unscheduled visit may include additional collection of blood samples for safety reasons. The 
unscheduled visit may also include additional assessments deemed necessary by the 
investigator such as laboratory samples, ECGs, or other procedures which were missed at a 
previous visit. All unscheduled visits should be described (including the reason for the visit) 
and documented in the medical/source record, and in the eCRF.
Concomitant medication review
Data concerning concomitant medications and procedures will be collected throughout the 
trial, as specified in the Flow Chart. These data will be obtained at scheduled or unscheduled 
trial visits based on information provided in the patient diaries, provided spontaneously by 
the patient or as a result of questioning the patient.
6.2.3
Follow Up Period and Trial Completion
For all patients, termination of trial medication and trial completion must be recorded on the 
corresponding eCRF.
For patients completing the trial regularly, two safety follow-up visits will be scheduled: 10 
weeks (FU1 visit) and 20 weeks (EoO visit) after the last dose of study drug (which is at 
Week 8, Visit 7).
Early treatment discontinuation
Patients who discontinue treatment prior to the regular EoT visit, EoT procedures should be 
completed as soon as possible after termination of study drug. These patients should return to 
the clinic for an EoO visit 20 weeks after their last administered dose of BI 655130. 
Further treatment after the end of the trial
At the end of the trial, patients will be treated for their UC at the discretion of the investigator, 
according to local UC guidelines (e.g. ECCO guideline R17-0243).
Trial completion:
Trial completion is defined as a patient having reached the EoO visit (Week 28).
Patients who complete regular treatment in study 1368-0004 will be offered to enter a long-
term extension trial (1368-0017), which is currently in preparation. These patients can switch 
to trial 1368-0017 at EoT visit, and for these patients, their EoT visit will also be their EoO 
visit.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This trial is designed as an open-label, single-arm, Phase IIa exploratory trial of BI 655130 in 
patients with active moderate or severe UC. For each patient, two pre-treatment blood and 
biopsy samples (pre-baseline at V1b and baseline at Visit 2) will serve as an internal control 
for the change in relevant endpoint variables. Patients should be on stable conventional 
treatment for their disease.
NULL AND ALTERNATIVE HYPOTHESES
7.2
It is not planned to test any statistical hypotheses in a confirmatory sense. Instead, the
endpoints will be described in their entirety and evaluated by descriptive statistical methods.
For efficacy endpoints 95% confidence intervals may be presented in addition. They have to 
be interpreted in the perspective of the exploratory character of the study, i.e. confidence 
intervals are considered as interval estimates for effects.
PLANNED ANALYSES
7.3
Due to the exploratory nature of this trial, all statistical descriptions of clinical results will be 
descriptive and no formal testing for significance of differentiation will be provided.
Gene expression of mucosal biopsies as assessed by RNAseq will be analysed to identify the 
total number of deregulated genes over time. Deregulated genes are those genes that react to 
the drug administration over time (compared to baseline) in a significant manner. 
Quantitative criteria for the selection of deregulated genes are given below in Section 7.3.1
after the required details of the gene expression analyses including pre-processing of raw read 
count values are described.
The gene expression analysis includes initially all genes and all determined read counts. This 
means, if no gene expression values have to be excluded due to technical or other reasons, 
there is one read count value per person, per gene and per time point (pre-baseline, baseline, 
and during treatment period at time points indicated in the Flow Chart).
Based on these raw read count values (refer to Section 5.5.1) the DESeq2 method, one of the 
standard methods to analyse RNAseq data, is used for the gene expression analysis and for 
the identification of deregulated genes. In the following key properties and special 
characteristics of this method with regard to the considered analysis will be delineated. For a 
detailed description of this method and further statistical details please refer to Love et al. 
(R16-5384). 


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Starting with the raw read counts the DESeq2 method models these counts following a 
negative binomial distribution with a certain mean and dispersion parameter. In more detail, 
the read count Kij for gene i in sample j is described by 
K~NB
mean = μ, dispersion = α.
The mean consists of a design specific quantity q scaled by a normalization factor s. The 
basic idea of the DESeq2 method is now to fit a generalized linear model of the negative
binomial family with a logarithmic link. Thereby the quantity q of each gene is described by 
log q = ∑x!β!
!
with design matrix elements x! and coefficients β!
To get interpretable results several pre-processing steps are needed to correct e.g. for 
different sequencing depth. For most of these steps the default approach (option) in the 
DESeq2 software package is used. In detail for the actual study design the following steps are 
conducted: 
-
Genes for which the sum of all counts is less than or equal to 1 are excluded. 
-
Genes with a high pre-treatment variability are excluded from the analysis:
A gene is excluded if it meets the regular criteria (>1.5 fold deregulation, FDR adjusted p 
value <0.01) of being differentially expressed between the two consecutive pre-treatment 
time points. Hereby, the adjusted P-value is based on the Wald test including only the two 
pre-treatment time points (i.e. pre-baseline and baseline).
-
Read Counts are normalized using the median-of-ratios method of Anders and Huber
(R17-0129):
The normalization constants s are considered constant within a sample, i.e. s = s. The 
value s is calculated by 
s = median:$%
&'(
$%)
$%
&   with   K
* = 
∏
K
,
-.

./,.
-
Estimation of the dispersion parameter α:
For each gene, an estimate of the dispersion is found which maximizes the Cox Reid-
adjusted profile likelihood (R17-0128). 
-
Handling of outlier using Cook’s distance (using the default option cooksCutoff = 0.99 in 
the DESeq2 package): Cook’s distance (R17-0126) quantifies how much a single sample 
is influencing the fitted coefficients for a gene, and a large value of Cook’s distance is 
intended to indicate an outlier count. No changes to the default setting are conducted. 
After these pre-processing steps the actual expression analysis can be conducted (see Section 
7.3.1)
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified in the Trial Statistical Analysis Plan (TSAP).


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The patient set for the primary evaluation of gene expression will include all patients who 
completed trial medication and trial through EoT visit and who provide at least one evaluable 
baseline and one evaluable post-baseline biopsy RNA measurement. The patient set for the 
safety analyses will include all patients who received at least one dose during the trial. Details 
on the analysis sets and further analysis sets e.g. for the BM assessments, will be defined in 
the TSAP.
7.3.1
Primary endpoint analyses
For all genes, which are not excluded in the pre-processing step the Wald test (included as the 
default test for significance testing in the DESeq2 package) is conducted to identify whether 
this gene is deregulated or not for a certain time point.
Only one baseline value is included in the model, namely the last value before first drug 
administration, but all post-treatment values. The generalized linear model includes time as 
additional covariable (and also subject as covariable). So every time point is an additional 
design matrix element x! and the model fit leads (for every gene i) to β! estimates for each 
time point. To test changes from baseline the contrasts of these β coefficients (or more 
precisely the difference between post-treatment estimate and baseline) are divided by their 
estimated standard error, resulting in a z-statistic, which is compared to a standard normal 
distribution. Hereby the default option lfcThreshold = 0 is utilized, meaning a null hypothesis 
of no difference.
The Wald test results in a P-value and an FDR adjusted P-value for each gene and each post-
treatment time point. A gene has a small P-value at a certain time point if there is a 
significant difference to the pre-treatment estimate, meaning an adjusted mean value clearly 
lower or higher compared to baseline. The calculation of the FDR adjusted P-value is (by 
default in the DESeq2 package) based on the Benjamini and Hochberg (P05-11198) approach 
(pAdjustMethod = "BH") combined with independent filtering (independentFiltering = TRUE).
The independent filtering is based on the mean of normalized counts as a filtering statistic 
(R17-0127). A threshold on the filter statistic is found which optimizes the number of FDR 
adjusted P-values lower than a significance level of alpha=0.1 (default setting). In doing so, 
genes with very low counts at all time points are excluded and no FDR adjusted P-value is 
reported for these genes.
Beside the FDR adjusted P-value the Wald test calculates for every gene and every time point
the difference in fold change compared to the baseline estimate. To get a conservative and 
stringent approach for the identification of deregulated genes both of these measurements, the 
FDR adjusted P-value based on the Wald test and the fold change, are used to identify 
deregulated genes.
Definition of deregulated genes
A gene is defined as deregulated at time point i if the FDR adjusted P-value of the Wald test 
is below 0.01 and if |fold change (time point i vs. baseline)| ≥ 1.3.
The total number of deregulated genes per time point will be reported.


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Sensitivity analyses for example evaluation of alternative thresholds for the classification of 
genes (deregulated vs. not deregulated) will be provided in the TSAP. In particular if e.g. the 
number of identified deregulated genes is very large a smaller threshold for the FDR adjusted 
P-value might be considered.
7.3.2
Secondary endpoint analyses
The efficacy endpoints, such as percent change in CRP, will be evaluated descriptively, along 
with exact 95% confidence intervals, if feasible. Additionally the original as well as change 
from baseline values for all time points from baseline up to Week 12 will be presented. If the 
data appears to be very skewed then a log transformation and a summary statistic on the log 
scale will also be presented. Summary plots will also be produced if necessary.
The binary efficacy endpoint patient with clinical remission based on Mayo score at Week 12
will be described using patient frequencies and percentages. Exact 95% confidence intervals 
will additionally be provided for the proportion of patients, if feasible. Furthermore shift 
tables from baseline up to Week 12 will be produced for the Mayo score.
Analysis of safety and tolerability is described in Section 7.3.4.


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7.3.4
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.3. All treated patients (that is all 
patients who received at least one dose of the study drug) will be included in the safety 
analysis. In general, safety analyses will be descriptive in nature and will be based on BI 
standards. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment and end of the residual effect period will be 
considered ‘treatment-emergent’. The residual effect period is defined as 140 days after the 
last dose of trial medication. AEs that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’. Drug related AEs, as a secondary 
endpoint of this trial, will be tabulated by system organ class and preferred term (PT) after 
coding according to the current version of the Medical Dictionary for Drug Regulatory 
Activities (MedDRA).
In addition, the frequency, severity, and causal relationship of AEs will be tabulated by 
system organ class and PT after coding according to the current version of the MedDRA.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings.
Vital signs, physical examinations, 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.
For vital signs, the differences from baseline will be evaluated.
Relevant ECG findings will be reported as AEs.


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INTERIM ANALYSES
7.4
In order to ensure the patient’s safety during the trial, a partially external DMC, independent 
of the trial and project teams, will be set-up to review all available safety data as well as 
selected efficacy data at regular intervals following first-patient-in. A DMC Statistical 
Analysis Plan (SAP) which describes the analyses required for assessment by the DMC will 
be produced and finalized prior to first patient screened into the trial. Further details will be 
provided in a DMC charter.
No formal interim analysis is planned. However a first exploratory analysis of BM data (e.g. 
RNAseq and inflammatory BMs) may be performed if the period for recruiting of the entire 
patient population exceeds approximately 6 months. The purpose will be to facilitate further 
substance development and project planning. The results of these evaluations will be 
preliminary and may be subject to change, as these do not involve a formal database lock. No 
interim report will be written. There will be no changes to the design of the trial as a result of 
the performance of this optional exploratory analysis. If performed, the exploratory analysis 
of BM data will be done once the first 50% of the total required number of patients has 
completed 12 weeks of study. Further details of this optional exploratory analysis of BM data 
will be described in the TSAP.
HANDLING OF MISSING DATA
7.5
Every effort should be made to collect complete data at all visits.
With respect to safety evaluations, it is not planned to impute missing values.
No imputations for the primary endpoint and for any missing BM data are planned.
RANDOMISATION
7.6
No randomisation is planned in this trial, as it is an open-label trial with one treatment arm. 
All patients will receive the same treatment. A randomisation list will only be provided for 
logistical reasons with a block size of 1, i.e., a list of consecutive numbers is provided with 
separate number ranges for each site (starting with number 
 
 and so on for the 
different sites).


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DETERMINATION OF SAMPLE SIZE
7.7
In line with the exploratory nature of the trial, 10 patients with active UC will be enrolled.
The planned sample size is not based on a power calculation but on feasibility, coordinating 
investigator’s experience with regard to recruitment and practical considerations.
If patients withdraw early from treatment prior to Week 12, they may be replaced. Up to 4 
patient replacements is considered adequate to ensure that the required number of patients 
provide data through Week 12. 


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor with regard 
to publication of the results of this trial are described in the Investigator contract. As a rule, 
no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF.
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Independent Ethics Committee (IEC) and competent authority 
according to national and international regulations. The same applies for the implementation 
of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient 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 patient-information form retained by the Investigator as 
part of the trial records. A signed copy of the informed consent and any additional patient 
information must be given to each patient.”
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IEC or by regulatory authorities. The quality assurance auditor will have 


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access to all medical records, the Investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms (CRF) for individual patients will be provided by the sponsor. For drug 
accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the eCRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including surgeries, history of UC and concomitant diseases, if 
applicable)

Medication history

AEs and outcome events (onset date (mandatory), and end date (if available))

SAEs (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 


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conducted specific for a protocol) to support inclusion/exclusion criteria does not make
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator/institution will allow on-site trial-related monitoring, audits, Institutional 
Review Board (IRB) / IEC review and regulatory inspections. Direct access must be provided 
to the eCRF and all source documents/data, including progress notes, copies of laboratory 
and medical test results, which must be available at all times for review by the CRA, auditor 
and regulatory inspector (e.g. FDA). The CRA and auditor may review all eCRFs and 
informed consents. The accuracy of the data will be verified by direct comparison with the 
source documents described in Section 8.3.1. The sponsor will also monitor compliance with 
the protocol and ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) 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.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below and in 5.5.1. Patient 
privacy will be ensured by using patient identification code numbers. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook. Treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’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 or delegates, by the IRB / IEC and the regulatory authorities.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”). The “Last Patient Drug Discontinuation” (LPDD) date is defined as 


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the date on which the last patient at an individual trial site ends trial medication (as scheduled 
PP or prematurely). Individual Investigators will be notified of Suspected Unexpected 
Serious Adverse Reactions
(SUSARs) occurring with the trial medication until 6 weeks after LPDD at their site. Early 
termination of the trial is defined as the premature termination of the trial due to any reason 
before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
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Benjamini Y, Hochberg Y, Controlling the false discovery rate: a practical 
and powerful approach to multiple testing. J R Stat Soc 1995; (B) 57 (1), 
289 – 300
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Wang DD, Zhang S, Zhao H, Men AY, Parivar K, Fixed dosing versus 
body size-based dosing of monoclonal antibodies in adult clinical trials. J 
Clin Pharmacol 2009; 49, 1012 – 1024
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Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, 
Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J,
Gruchalla RS, Harlor AD Jr, Hepner DL, Lewis LM, Lieberman PL, 
Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D,
Simons FE, Thomas S, Wood JP, Decker WW. Second symposium on the
definition and management of anaphylaxis: summary report – second
National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol 117 (2), 391 -
397 (2006)
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Ordas I, Mould DR, Feagan BG, Sandborn WJ, Anti-TNF monoclonal 
antibodies in inflammatory bowel disease: pharmacokinetics-based dosing 
paradigms; Clin Pharmacol Ther 2012; 91 (4), 635 – 646
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, Tsuji 
W, Stevens R, Fries J, Witter J, Johnson K, Lassere M, Brooks P,
Standardizing assessment and reporting of adverse effects in rheumatology 
clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0, J 
Rheumatol 2007; 34 (6), 1401 – 1414
R13-4749
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, Tang 
M, Allison DE, Lu D, Zhang Y, Joshi A, Dresser MJ, A guide to rational 
dosing of monoclonal antibodies. Clin Pharmacokinet 2012; 51 (2), 119 –
135
R13-4750
Joos B, Trkola A, Kuster H, Aceto L, Fischer M, Stiegler G, Armbruster C, 
Vcelar B, Katinger H, Guenthard HF, Long-term multiple-dose 
pharmacokinetics of human monoclonal antibodies (MAbs) against human 
immunodeficiency virus type 1 envelope gp120 (MAb 2G12) and gp41 
(MAbs 4E10 and 2F5). Antimicrob Agents Chemother 2006; 50 (5), 1773 –
1779
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Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S, Projecting 
human pharmacokinetics of therapeutic antibodies from nonclinical data: 
what have we learned? MAbs 2011; 3 (1), 61 – 66


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Xin y, Gordon MS, Jin D, Wakshull E, Chen DS, Rosen LS, Munster PN, 
Naumovski L, Bai S, Population pharmacokinetic (PK) analysis supports 
fixed dosing for the humanized monoclonal antibody (huMAb) anti-EGFL7 
(MEGF0444A) administered intravenously in patients with advanced solid 
tumors. 47th Ann Mtg of the American Society of Clinical Oncology 
(ASCO), Chicago, 3 - 7 Jun 2011. J Clin Oncol 2011; 29 (15) (Suppl), 
Abstr 2586
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Brudno JN, Kochenderfer JN, Toxicities of chimeric antigen receptor T 
cells: recognition and management. Blood 127 (26), 3321-3330 (2016)
R13-5226
Remicade 100 mg powder for concentrate for solution for infusion (EPAR -
product information: summary of product characteristics, manufacturer(s) 
of the biological active substance(s) and manufacturer(s) responsible for 
batch release, conditions or restrictions regarding supply and use, other 
conditions and requirements of the marketing authorisation, conditions or 
restrictions with regard to the safe and effective use of the medicinal 
product, labelling and package leaflet, last updated: 06/08/2013),
webpage: ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/ human/000240/WC500050888.pdf (access date: 2 
Feb 2017)
R15-0886
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, 
Benchimol EI, Panaccione R, Ghosh S, Barkema HW, Kaplan GG,
Increasing incidence and prevalence of the inflammatory bowel diseases 
with time, based on systematic review. Gastroenterology 2012; 142 (1), 46 
– 54
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Humira 40 mg/0.8 ml solution for injection for paediatric use, 40 mg 
solution for injection in pre-filled syringe, 40 mg solution for injection in 
pre-filled syringe with needleguard, 40 mg solution for injection in pre-
filled pen, 40 mg solution for injection in pre-filled syringe (summary of 
product characteristics, manufacturer(s) of the biological active substance 
and manufacturer(s) responsible for batch release, conditions or restrictions 
regarding supply and use, other conditions and requirements of the 
marketing authorisation, conditions or restrictions with regard to the safe 
and effective use of the medicinal product, labelling and package leaflet, 
20150728). 
webpage: ec.europa.eu/health/documents/community-register/2015/
20150728132555/anx_132555_en.pdf (access date: 2 Feb 2017)


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R16-0573
Sandborn W, Gasink C, Blank M, Lang Y, Johanns J, Gao LL, Sands B, 
Hanauer S, Feagan B, Targan S, Ghosh S, Villiers W de, Colombel J F, Lee 
S, Desreumaux P, Loftus E, Vermeire S, Rutgeerts P, A multicenter, 
double-blind, placebo-controlled phase3 study of ustekinumab, a human IL-
12/23P40 mAB, in moderate-service Crohn's disease refractory to anti-
TFNalpha: UNITI-1. AIBD 2015; Advances in Inflammatory Bowel 
Diseases National Clinical and Research Conf of the Crohn's and Colitis 
Foundation of America, Orlando, 10 - 12 Dec 2015. Inflamm Bowel Dis 
2016; 22 (Suppl 1), Abstr O-001
R16-0692
Feagan B, Gasink C, Lang Y, Friedman JR, Johanns J, Gao LL, Sands B, 
Hanauer S, Rutgeerts P, Targan S, Ghosh S, Villiers W de, Colombel JF, 
Tulassay Z, Seidler U, Sandborn WJ, A multicenter, double-blind, placebo-
controlled Ph3 study of ustekinumab, a human monoclonal antibody to IL-
12/23P40, in patients with moderately-severely active Crohn's disease who 
are naive or not refractory to anti-TNFa: UNITI-2. 23rd United European 
Gastroenterology Week (UEGW), Barcelona, 24 - 28 Oct 2015, United Eur 
Gastroenterol J (2015); 3 (6), 563 - 564, Abstr OP054-LB4
R16-4416
Schroeder KW, Tremaine WJ, Ilstrup DM, Coated oral 5-aminosalicylic 
acid therapy for mildly to moderately active ulcerative colitis: a randomized 
study. N Engl J Med 317 (26), 1625 - 1629 (1987)
R16-5384
Love MI, Huber W, Anders S, Moderated estimation of fold change and 
dispersion for RNA-seq data with DESeq2. Genome Biol 2014; 15, 550
R16-5706
Brandse JF, Brink GR van den, Wildenberg ME, Kleij D van der, Rispens 
T, Jansen JM, et al, Loss of infliximab into feces is associated with lack of 
response to therapy in patients with severe ulcerative colitis. 
Gastroenterology 2015; 49 (2), 350 – 355
R16-5741
Kapel N, Meillet D, Favennec L, Magne D, Raichvarg D, Gobert JG, 
Evaluation of intestinal clearance and faecal excretion of alpha1-
antiproteinase and immunoglobulins during Crohn's disease and ulcerative 
colitis, Eur J Clin Chem Clin Biochem 1992; 30 (4), 197 - 202
R17-0038
Ulcerative Colitis: Clinical Trial Endpoints. Guidance for Industry. Draft 
Guidance. August 2016; website: 
http://www.fda.gov/downloads/Drugs/Guidances/UCM515143.pdf: (assess 
date: 2 Feb 2017)
R17-0126
Cook RD, Detection of influential observation in linear regression,
Technometrics 1977; 19 (1), 15 – 18
R17-0127
Bourgon R, Gentleman R, Huber W, Independent filtering increases 
detection power for high-throughput experiments, Proc Natl Acad Sci USA 
2010; 107 (21), 9546 – 9551


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R17-0128
McCarthy DJ, Chen Y, Smyth GK, Differential expression analysis of 
multifactor RNA-Seq experiments with respect to biological variation,
Nucleic Acids Res 2012; 40 (10), 4288 – 4297
R17-0129
Anders S, Huber W Differential expression analysis for sequence count 
data. Genome Biol 2010; 11, R106
R17-0243
Dignass A, Van ASsche G, Lindsay JO, Lémann M, Söderholm J, 
Colombel JF, Danese S, D’Hoore A, Gassull M, Gomollón F, Hommes 
DW, Michetti P, O’Morain C, Oresland T, Windsor A, Stange EF, Travis 
SP, European Crohn’s and Colitis Organisation (ECCO), Second European 
evidence-based consensus on the diagnosis and management of ulcerative 
colitis Part 2: Current management, J Crohns Colitis 2010; 4(1) 28-62
R17-0373
Vermeire S, O’Byrne S, Keir M, Williams M, Lu TT, Mansfield JC, Lamb 
CA, Feagan BG, Panes J, Salas A, Baumgart DC, Schreiber S, Dotan I; 
Sandborn WJ, Tew GW, Luca D, Tang MT, Diehl L, Eastham-Andersen J, 
De Hertogh G, Perrier C, Egen JG, Kirby JA, van Assche G,  Rutgeerts P, 
Etrolizumab as induction therapy for ulcerative colitis: a randomized, 
controlled, phase 2 trial 2014; 384: 309-18
UNPUBLISHED REFERENCES
9.2
c03320877
Investigator’s Brochure BI 655130


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10.
APPENDICES
MAYO SCORE
10.1
The Mayo score (R16-4416) is a composite disease activity score consisting of four items or 
subscores: stool frequency (relative to normal), rectal bleeding, physician’s global 
assessment, and endoscopic appearance. As proposed by FDA draft guidance (R17-0038), the 
endoscopic subscore is modified so that a value of 1 does not include friability. The overall 
range of the Mayo score is 0-12 (higher scores being worse) and each subscore has a range of 
0-3 (Table 10.1: 1). At visits without sigmoidoscopy, a partial Mayo score without endoscopy 
subscore will be assessed. The overall range of this partial Mayo score is 0-9.
In addition, based on FDA’s recommendation (R17-0038), a modified Mayo score will be 
assessed, which excludes physician’s assessment. The overall range of the modified Mayo 
score is 0-9.
The scores for stool frequency and rectal bleeding will be calculated as an average of the last
3 non-missing entries (from the patient daily diary) within the week prior to each applicable
visit. If the patient undergoes bowel preparation for endoscopy on any of the days before a
visit, the stool frequency and RBS for that day(s) should be considered missing. In addition, 
the stool frequency and RBS will be considered missing for the day of and the day after all 
endoscopies.
The endoscopic appearance score will be assessed by a central reader, who is independent 
from the investigator.


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Table 10.1: 1
Mayo score (adapted from Schroeder et al, 1987 (R16-4416))
Subscore
Severity
Score
Stool Frequencya
(daily)
Normal number of stools for patient
0
1 to 2 stools more than normal
1
3 to 4 stools more than normal
2
≥5 stools more than normal
3
Rectal Bleedingb
(daily)
No blood seen
0
Streaks of blood with stool
1
Obvious blood with stool
2
Blood alone passes
3
Physician’s Global 
Assessmentc
Normal
0
Mild disease
1
Moderate disease
2
Severe disease
3
Endoscopic 
Appearanced
Normal
0
Mild disease
1
Moderate disease
2
Severe disease
3
a Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency.
b The daily bleeding score represents the most severe bleeding of the day.
c The physician’s assessment acknowledged the three other criteria, the patient’s daily record of abdominal discomfort and 
general sense of well-being, and other observations, such as physical findings and  the patient’s performance status.
d Modified endoscopic appearance: 0 (normal), Mild (erythema, decreased vascular pattern), Moderate (marked 
erythema, loss of vascular pattern, any friability, erosions), Severe (spontaneous bleeding, ulceration).


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
16 Jan 2018
EudraCT number
2017-000100-20
BI Trial number
1368-0004
BI Investigational Product(s)
BI 655130
Title of protocol
Exploratory Trial to Assess Mechanism of Action, 
Clinical Effect, Safety and Tolerability of 12 
Weeks of Treatment with BI 655130 in Patients 
with Active Ulcerative Colitis (UC)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
X
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
Across whole protocol
Description of change
Trial number 1368.4 was changed to 1368-0004
Rationale for change
To implement new format of trial number across 
trial documents for consistency reason
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
The lower body weight limit of 60 kg was deleted. 
Rationale for change
A lower body weight limit is not needed any more.
Section to be changed
FLOW CHART
Description of change
For some visits, total Mayo Score (“T”) was 
replaced by partial Mayo Score (“P”).
Rationale for change
To correct a typographical error.
Section to be changed
FLOW CHART
Description of change
Sigmoidoscopy at 4 hours after the first i.v. 
infusion was deleted. All biopsy samples should be 
obtained prior to IMP administration.


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Rationale for change
To reduce the overall number of sigmoidoscopies 
in this trial. 
Section to be changed
FLOW CHART
Description of change
The time-point of EoO visit was corrected.
Rationale for change
To ensure that EoO visit will take place after the 
end of the residual effect period of the IMP.
Section to be changed
FLOW CHART
Description of change
It was added that patients who completed regular 
treatment in trial 1368-0004 would be offered to 
enter the long-term extension trial 1368-0017. 
Rationale for change
To add option for long-term treatment for patients 
who completed regular treatment.  
Section to be changed
1.2 DRUG PROFILE
Description of change
Information from study 1368.1 and 1368.2 and 
from population pharmacokinetic modelling was 
updated.
Rationale for change
To update safety information on BI 655130 and 
provide rationale why the lower body weight limit 
is not needed anymore.
Section to be changed
2.3 BENEFIT-RISK ASSESSMENT
Description of change
Information from study 1368.1 and 1368.2 and 
from population pharmacokinetic modelling was 
updated.
Rationale for change
To update safety information on BI 655130 and 
provide rationale why the lower body weight limit 
is not needed anymore.
Section to be changed
2.3 BENEFIT-RISK ASSESSMENT
Description of change
It was added that patients who completed 12 weeks 
treatment duration would be offered long-term 
treatment in trial 1368-0017.
Rationale for change
To include the option for long-term treatment for 
patients who completed regular treatment in the 
risk-benefit assessment, as long-term treatment for 
these patients is considered an individual benefit.
Section to be changed
3.1 OVERALL TRIAL DESIGN AND PLAN
Description of change
It was added that patients who complete regular 
treatment can receive long-term treatment in trial 
1368-0017. 
Rationale for change
To update the trial design regarding the option for 
long-term treatment for patients who complete 
regular treatment in trial 1368-0004. 
Section to be changed
3.3.1 Main diagnosis for trial entry
Description of change
The trial population was extended to patients who 
were treated with TNF antagonist(s) previously but 
did not stop that treatment due to primary non-


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response or loss of response
Rationale for change
To update trial population with the aim to facilitate 
recruitment
Section to be changed
3.3.2 Inclusion criteria
Description of change
The lower body weight limit of 60 kg was deleted.  
Rationale for change
A lower body weight limit is not needed any more.
Section to be changed
3.3.2 Inclusion criteria
Description of change
The trial population was extended to patients who 
were treated with TNF antagonist(s) previously but 
who stopped treatment for other reasons than 
primary non- response or lack of response. The 
reason for stopping treatment has to be documented 
in the source data.
Rationale of change
To update trial population with the aim to facilitate 
recruitment.
Section to be changed
3.3.3 Exclusion criteria
Description of change
The trial population was extended to patients who 
were treated with TNF antagonist(s) previously but 
did not stop that treatment due to primary non-
response or loss of response
Rationale for change
To update trial population with the aim to facilitate 
recruitment.
Section to be changed
3.3.3.3 General exclusion criteria
Description of change
Unit for haemoglobin was corrected to g/dL.  
Rationale for change
To correct error.
Section to be changed
3.3.3 Exclusion criteria
Description of change
The numbering of exclusion criteria was changed 
so that it is continuous.
Rationale for change
To update numbering of exclusion criteria so that it 
is consistent with the numbering in the BRAVE 
system.
Section to be changed
4.1.2 Selection of doses in this trial
Description of change
The lower body weight limit of 60kg was deleted.
Rationale for change
A lower body weight limit is not needed anymore.
Section to be changed
Section 4.2.1 Other treatments and emergency 
procedures
Description of change
Further guidance has been added regarding 
infusion reactions, cytokine release syndrome and 
infections.
Rationale for change
To provide guidance to the investigator for infusion 
reactions, cytokine release syndrome and 
infections. 
Section to be changed
Section 4.2.2 Restrictions


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Description of change
The information regarding biologics treatment was 
updated to allow previous TNF antagonist(s)
treatment, if stopped for other reasons than primary 
non- response or lack of response. Also, it was 
added, that the last dose of TNF antagonist(s)
treatment has to be at least 8 weeks or 3 half-lives, 
whichever is longer, from screening.
Rationale for change
To update restrictions regarding the previous use of 
biologics.
Section to be changed
Section 5.3.5.1 Definitions of adverse events 
Description of change
Infusion reactions including anaphylactic reactions, 
cytokine release syndrome and opportunistic and 
mycobacterium tuberculosis infections were added 
to adverse events of special interest (AESIs). 
Rationale for change
To update section on AESIs so that it is consistent 
across the BI 655130 project. 
Section to be changed
Section 6.2.1 Screening and run-in period
Description of change
The information regarding the patient diary was 
changed, as daily reporting of CMs is not included 
in the current diaries, but the patients have to 
confirm regular intake of CMs before each visit. 
Rationale for change
To change description of the diaries to clarify that 
daily reporting of CM intake is not included.
Section to be changed
6.2.3 Follow up period and Trial Completion
Description of change
It was added that patients who complete regular 
treatment can receive long-term treatment in trial 
1368-0017. EoO visit would be on the same day as 
EoT visit. 
Rationale for change
To clarify the time-point of trial completion for 
patients who enter long-term extension trial 1368-
0017. 
Section to be changed
Section 7.3 PLANNED ANALYSES 
Description of change
It was clarified that the set for the primary 
evaluation of gene expression includes all patients 
who completed trial medication and trial 
throughout EOT visit and who provide at least one 
evaluable baseline and one evaluable post-baseline 
biopsy RNA measurement. 
Rationale for change
To clarify description of the patient set for the 
primary evaluation of gene expression.
Section to be changed
Section 7.3.1 Primary endpoint analyses 
Description of change
“log2” was removed.
Rationale for change
To correct an error.
Section to be changed


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Description of change
Rationale for change
Section to be changed
Section 9.1 PUBLISHED REFERENCES
Description of change
To add two additional references. 
Rationale for change
To update Section 9.1 regarding two additional 
references. 
Section to be changed
Section 10.2 MAYO SCORE
Description of change
In Table 10.2: 1, “granularity” was deleted from 
footnote d.
Rationale for change
To correct assessment of modified endoscopic 
response, according to established criteria for 
Mayo Score.
Section to be changed
Section 10.3 EQUIVALENT DOSES OF 
CORTICOSTEROIDS
Description of change
“16-Methylprednisolone” was deleted from the 
table.
Rationale for change
To correct typographical error.
Section to be changed
10.3 EQUIVALENT DOSES OF 
CORTICOSTEROIDS
Description of change
To add equivalent doses of budenoside.
Rationale for change
To update table with information for budesonide.
Number of global amendment
2
Date of CTP revision
18 May 2018
EudraCT number
2017-000100-20
BI Trial number
1368-0004
BI Investigational Product(s)
BI 655130
Title of protocol
Exploratory Trial to Assess Mechanism of Action, 
Clinical Effect, Safety and Tolerability of 12 
Weeks of Treatment with BI 655130 in Patients 
with Active Ulcerative Colitis (UC)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –


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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
FLOW CHART
Description of change
The time-point of FU1 visit was corrected.
Rationale for change
To correct an error.
Section to be changed
FLOW CHART
Description of change
Sigmoidoscopy with biopsy sample collection and 
blood sampling for gene expression and 
methylation pattern analysis at 4 hours after the 
first i.v. infusion was re-included.
Rationale for change
Based on expert PI feedback.
Section to be changed
Section 3.3.3
Description of change
The numbering of the exclusion criteria was 
corrected.
Rational for change
To correct an error.
Section to be changed
Section 6.2.2
Description of change
It was clarified that an additional sigmoidoscopy 
will take place at 4 hours after first i.v. infusion to 
collect biopsy samples. Also, it was clarified that 
an additional blood sample will be collected at 4 
hours after first i.v. infusion for gene expression 
and methylation pattern analysis. 
Rationale for change
Based on expert PI feedback.
Section to be changed
Section 7.3.1
Description of change
A typographical error was corrected.
Rationale for change
To correct an error.
Section to be changed
Section 7.6
Description of change
The description of the number ranges per site was 
updated.
Rationale for change
Additional study sites are planned to be included.
Section to be changed
Section 11
Description of change
The word “biologics” was replaced by “TNF 
antagonist(s)” in the description of changes related
to sections 3.3.1, 3.3.2, 3.3.3 and 4.2.2.


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Rationale for change
To correct an inconsistency.
Number of global amendment
3
Date of CTP revision
03 Apr 2019
EudraCT number
2017-000100-20
BI Trial number
1368-0004
BI Investigational Product(s)
BI 655130
Title of protocol
Exploratory Trial to Assess Mechanism of Action, 
Clinical Effect, Safety and Tolerability of 12 
Weeks of Treatment with BI 655130 in Patients 
with Active Ulcerative Colitis (UC)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Sections to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS,  
Section 3.3.2 Inclusion criteria
Description of change
Inclusion criterion 1: Change upper age limit from 
65 years to 75 years.
Rationale for change
Upper age limit is changed to 75 years in order to 
facilitate recruitment into the study. 75 years as 
upper age limit is also consistent with more 
recently started trials in this project. No safety 
issues detected in program so far (see IB)


 
 
 
 
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Title: 
 
 
 
 
                                                                                                                   
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c10710598
4.0
clinical-trial-protocol-revision-03
Exploratory Trial to Assess Mechanism of Action, Clinical Effect, Safety and
Tolerability of 12 Weeks of Treatment with BI 655130 in Patients with Active
Ulcerative Colitis (UC)
Author-Trial Statistician
04 Apr 2019 16:55 CEST
Author-Trial Clinical
Pharmacokineticist
04 Apr 2019 17:06 CEST
Approval-Team Member Medicine
04 Apr 2019 17:08 CEST
Author-Clinical Trial Leader
04 Apr 2019 17:21 CEST
Approval-Therapeutic Area 
05 Apr 2019 09:43 CEST
Verification-Paper Signature
Completion
05 Apr 2019 10:06 CEST


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 Technical Version Number:
 
 
 
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c10710598
4.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c17032121-03
BI Trial No.:
1368-0004
Title:
Exploratory Trial to Assess Mechanism of Action, Clinical
Effect, Safety and Tolerability of 12 Weeks of Treatment with BI 
655130 in Patients with Active Ulcerative Colitis (UC) including 
Protocol Amendment 3 [c10710598-04]
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone:+
Fax: 
Date of statistical 
analysis plan:
06-DEC-2019 REVISED
Version:
Version 3.0 Revised 
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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.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT .....................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoint .....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
5.2.2.1
Secondary efficacy endpoints ...............................................................................10
5.2.2.2
Secondary safety endpoints...................................................................................10
5.3.3
Further safety criteria ........................................................................................11
5.4.1
Demographic and other baseline characteristics .............................................12
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT  SETS ANALYSED..........................................................................24
6.5
POOLING OF CENTRES .................................................................................25
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................25
6.6.1
Withdrawals ........................................................................................................26
6.6.2
Efficacy data........................................................................................................26
6.6.3
Safety data ...........................................................................................................26
6.6.4
PK data.................................................................................................................27
6.6.6
RNA sequencing data..........................................................................................27
6.6.7
Time since first diagnosis ...................................................................................27
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................28
7.
PLANNED ANALYSIS......................................................................................30
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........31


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7.2
CONCOMITANT DISEASES AND MEDICATION .....................................31
7.3
TREATMENT COMPLIANCE........................................................................32
7.4
PRIMARY ENDPOINTS...................................................................................33
7.5
SECONDARY ENDPOINT ...............................................................................33
7.5.1
Key secondary endpoint .....................................................................................33
7.5.2
Secondary endpoints...........................................................................................33
7.5.2.1
Secondary efficacy endpoints ...............................................................................33
7.7
EXTENT OF EXPOSURE.................................................................................36
7.8
SAFETY ANALYSIS..........................................................................................36
7.8.1
Adverse events.....................................................................................................36
7.8.2
Laboratory data ..................................................................................................38
7.8.3
Vital signs.............................................................................................................39
7.8.4
ECG......................................................................................................................40
7.8.5
Others...................................................................................................................40
7.9
HANDLING OF DMC ANALYSES .................................................................40
8.
REFERENCES....................................................................................................41
10.
HISTORY TABLE..............................................................................................48


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases ...........................................................................14
Table 6.2: 1
Important protocol deviations...........................................................................15
Table 6.3: 1
Patient sets analysed .........................................................................................25
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, biomarker, 
and RNA sequencing measurements to visits for statistical analysis...............28
Table 7.1: 1
Categories for summary of continuous variables .............................................31
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Event Concepts.37
Table 10: 1
History table .....................................................................................................48


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug antibodies
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
5-ASA
5-Aminosalicylate
AST
Aspartate aminotransferase
ATC3
Anatomical-Therapeutic-Chemical classification level 3
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
CARE
Clinical data analysis and reporting environment
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CRP
C-reactive protein
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
ELISA
Enzyme Linked Immunosorbent Assay
EoO
End of Observation 
EoT
End of trial
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials


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Term
Definition / description
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full analysis set
F/U
Follow-up
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IL
Interleukin
IL-36R
Interleukin-36 Receptor
IMP
Investigational medicinal product
iPD
important protocol deviation
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical quality review meeting
MTX
Methotrexate
6-MP
6-Mercaptopurine
NOA
Not analysed
NOR
No valid result
NOS
No sample available
OC
Observed cases
OC-IR
Observed cases including values after rescue medication
OR
Original results
PD
Pharmacodynamic(s)
PG
Pharmacogenomic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PPS
Per protocol set
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
RBS
Rectal Bleeding Subscore
REP
Residual effect period


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Term
Definition / description
RNA
Ribonucleic Acid
RNAseq
RNA sequencing
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SFS
stool 
SI
Système international d’unités
SMQ
Standardised MedDRA query
TGF-β
Transforming Growth Factor beta
TNF
Tumour Necrosis Factor
TS
Treated set
TSAP
Trial statistical analysis plan
UC
Ulcerative Colitis
ULN
Upper limit of normal range
VEGF
Vascular Endothelial Growth Factor


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the CTP and its amendments, 
and to include detailed procedures for executing the statistical analysis of the primary and 
secondary variables and other data.
This TSAP assumes familiarity with the CTP. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, and planning of sample size.
Study data will be stored in a trial database within BRAVE system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
R version 3.1.2 or later (6), Bioconductor version 2.13 or later, and the DESeq-package 
version 3.18.13 or later will be used in the analyses of gene expression data. Genome version 
hg38/GRCh38 will be used in conjunction with Ensembl version 84 or later.
This TSAP describes the analyses of BMs defined as endpoints and planned to be reported in 
the CTR.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The following changes of endpoints (based on Mayo score) were implemented to be 
consistent across trials.
The following renamings were conducted:

The secondary endpoint clinical remission (Mayo Score ≤2 with all
subscores ≤1) will be labelled as total clinical remission

The further endpoint Modified clinical remission (Mayo Score ≤2 AND (A) rectal 
bleeding subscore (RBS) = 0, (B) modified endoscopic subscore ≤1; and (C) stool 
frequency subscore = 0 or =1 and drop ≥ 1 from baseline) will be labelled as clinical 
remission
See Section 9.1 for details on deriving the efficacy endpoint scores at each visit.


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5.
ENDPOINTS
For all endpoints and unless explicitly specified otherwise, Week 10 refers to Visit V8 and 
Week 12 refers to Visit EOT.
For handling of missing data and corresponding sensitivity analyses, see Section 6.6.
5.1
PRIMARY ENDPOINT
The primary endpoint is the total number of deregulated genes comparing baseline to post-
treatment, analysed by gene expression of mucosal biopsies via RNA sequencing, per time 
point up to week 12.
Details on the planned analyses are given in Section 7.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable. No key secondary endpoints have been specified in the CTP.
5.2.2
Secondary endpoints
5.2.2.1
Secondary efficacy endpoints
The following secondary efficacy endpoints will be analysed:

Percent change in CRP from baseline to Week 12

Percent change in faecal calprotectin from baseline to Week 12

Percent change in faecal lactoferrin from baseline to Week 12 

Total clinical remission (defined as Total Mayo score ≤2 points, and all
subscores ≤1 point) at Week 12 (cf. Section 4)
For details on calculating the total Mayo score at each visit, cf. Section 9.1.
5.2.2.2
Secondary safety endpoints 
Secondary endpoint to assess safety and tolerability of BI 655130 is the number [N (%)] of 
patients with drug-related AEs (cf. Section 5.3 of the CTP).


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5.3.3
Further safety criteria
Intensity of adverse events will be assessed by Rheumatology Common Toxicity Criteria 
(RCTC) version 2.0.
Further safety criteria of interest are:

AEs

SAEs


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
Safety laboratory values (haematology, clinical chemistry, coagulation and urinalysis)

Physical examination

Vital signs 

Relevant findings in 12-lead ECG

IgE and ADA (anti-drug antibodies), as detailed in the lab manual
5.4.1
Demographic and other baseline characteristics
Standard demographic data and baseline characteristics are used as recorded in the eCRF.
These include sex, ethnicity, race, age, height, weight, BMI, smoking status. Disease 
characteristics including time since first diagnosis, previous surgery for UC and extra
intestinal manifestations will be collected during screening.
Age [years] will be determined as the difference between year of birth and year of informed 
consent.
BMI will be calculated as weight [kg] / height [m]2 (based on the last available weight 
measurement prior to the first dose of BI 655130). 
Time since first diagnosis [years] will be calculated as the difference between date of first 
diagnosis and date of informed consent, divided by 365.25. For calculation in context of 
incomplete information on the date of first diagnosis, cf. Section 6.6.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on the treatment to be administered, assignment to treatment, and 
selection of dose, cf. Section 4 of the CTP.
All patients will receive intravenous doses of 1200mg of BI 655130 solution for infusion (at 
V2, V5 and V7).
The following study phases are defined:


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Table 6.1: 1
Flow chart of analysis phases 
Study analysis 
phase
Description
Start (included)
End (included)
Screening phase
Screening
Earliest of (Date of informed 
consent, first screening 
procedure) 
Date/time of start of infusion of first 
study drug minus 1 minute.
Treatment phase
& Residual 
effects period 
(REP)
On-treatment 
period
Date/time of start of infusion of 
first study drug (Day 1)
Date of end of infusion of last 
study drug + 140 days at 11:59 p.m.
Follow-up1 phase
Off-treatment 
period
Date of end of infusion of last 
study drug + 141 days at 12:00 
a.m.
Latest of: i) Date of EoO visit (Week 
28 visit); ii) end date on trial 
termination page at 11:59 p.m.
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase will 
not extend beyond the start date of the following phase. 
1 The Follow-up phase only exists if the trial completion date is after the date of end of last infusion + 140 days
CTR Section 15 AE displays will present results for the on-treatment period only. Screening
and follow-up phases will not be included in this analysis.
Treatment groups for the analysis will be labelled as follows:

"Speso 1200 mg IV BI q4w"
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
database (i.e., enrolled patients). Consistency check listings (for identification of violations of 
time windows) and a list of protocol deviations will be provided to be discussed at the 
RPM/DBLM/MQRM. At this meeting, it will be decided whether a discrepant data value can 
be used in analyses or whether it must be queried in the clinical database. Each protocol 
deviation must be assessed to determine whether it is an important Protocol Deviation (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).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM/MQRM minutes via an accompanying Excel spreadsheet. The following 
Table 6.2: 1 contains the categories which are considered to be iPDs in this trial. If the data 
show other iPDs, this table will be supplemented accordingly by the time of the 
RPM/DBLM/MQRM. Not all iPDs will lead to exclusion from analysis sets. iPDs leading to 
exclusion from analysis sets are indicated as such in Table 6.2:1.
iPDs will be summarised and listed for the entered set.


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Table 6.2: 1
Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
Age out of range
LABEL: 
Age beyond 18-65
Inclusion criterion 1
Also check versus derived age 
for patient.
None
A1.02
Body weight out of range
LABEL: 
Body weight larger 100 kg
Inclusion criterion 2
Also check versus reported 
body weight for patient
None
A1.03
Diagnosis of UC <3 months prior to 
screening
LABEL: 
Diagnosis only recent
Inclusion criterion 3
Also check derived time since 
diagnosis for patient
None
A1.04
Moderately to severely active UC not 
confirmed, e.g. Mayo Score ≤6 and/or 
no elevated C-Reactive protein (CRP) or 
faecal calprotectin at pre-baseline visit.
LABEL: 
Disease activity not moderate or severe
Inclusion criterion 4
Also check derived total 
MCS,CRP and faecal 
calprotectin at pre-baseline
Manual check in addition.
CAS
# PV will be detected manually
Source: BI reference document: "Identify and Manage Important Protocol Deviations (iPD)" [001-MCS-40-413] (2).
1 See Section 6.3 for population definitions 


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Table 6.2: 1
Important protocol deviations (continued)
Category / 
Code
Description
Comments
Excluded from1
A1.05
Receiving conventional, non-biologic 
therapy for UC.
Concurrent UC treatments need to be on 
stable doses:
This therapy could consist of one or more of 
the following:

Oral 5-ASA compound, with 
stable dose for at least 4 weeks 
prior to screening

6-MP, Methotrexate (MTX) or 
AZA, with stable dose for at 
least 8 weeks prior to 
screening

Oral corticosteroids               
(≤ 20mg/day per day of 
prednisone or equivalent), with 
stable dose for at least 4 weeks 
prior to screening
LABEL:
Concurrent UC treatment not on stable 
dose
Inclusion criterion 5
CAS
#
A1.06
Negative colon cancer screening within the 
past 12 months prior to screening not 
available
LABEL:
Lack of negative colorectal cancer screening
Inclusion criterion 6
None
A1.07
Patients who are naïve or experienced to 
TNF antagonists (including infliximab, 
adalimumab, or golimumab) but have not 
failed that treatment due to primary non-
response or loss of response 
LABEL:
Patient with previous TNF experience (non-
response or loss of response) 
Inclusion criterion 7
CAS
A1.08
Women of childbearing potential did not 
agree to use effective method of birth 
control; male patients did not agree to use 
condoms 
LABEL:
Contraception methods not used
Inclusion criterion 8
None
# PV will be detected manually
Source: BI reference document: "Identify and Manage Important Protocol Deviations (iPD)" [001-MCS-40-413] (2)
1 See Section 6.3 for population definitions 


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Table 6.2: 1
Important protocol deviations (continued)
Category / 
Code
Description
Comments
Excluded from1
A1.09
Signed and dated written informed consent 
in accordance with GCP and local 
legislation prior to admission to the trial
LABEL:
IC not in accordance with legislation
Inclusion criterion 9–
check for tick box only. 
Further PVs on informed 
consent are defined in 
section B below
All
A2
Exclusion criteria violated 
A2.01
Pregnancy 
LABEL:
Pregnancy
General exclusion 
criterion 6
None
A2.02
Patients who have previously failed 
treatment with any TNF antagonist 
(including infliximab, adalimumab, 
golimumab) due to primary non-response or 
loss of response
LABEL:
Prior failure with any TNF antagonist
Gastrointestinal
exclusion criterion 1
CAS
#
A2.03
Extensive colonic resection, subtotal or total 
colectomy
LABEL:
Extensive colonic resection, or colectomy.
Gastrointestinal 
exclusion criterion 4
None
A2.04
Ileostomy, colostomy, or known fixed 
symptomatic stenosis of the intestine
LABEL:
Ileostomy, colostomy, or stenosis
Gastrointestinal
exclusion criterion 5
None
A2.05
Patients who must or wish to continue the 
intake of restricted medications  (cf. CTP 
Table 4.2.2.1) or any drug considered likely 
to interfere with the safe conduct of the trial
LABEL:
Use of restricted medication
Gastrointestinal 
exclusion criterion 6
CAS
# PV will be detected manually
Source: BI reference document: "Identify and Manage Important Protocol Deviations (iPD)" [001-MCS-40-413] (2)
1 See Section 6.3 for population definitions 


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Table 6.2: 1
Important protocol deviations (continued)
Category / 
Code
Description
Comments
Excluded from1
A2.06
Evidence of infection with C. difficile or 
other intestinal pathogen < 30 days prior to 
screening
LABEL:
Infection with intestinal pathogen
Gastrointestinal 
exclusion criterion 7
CAS
A2.07
Currently require or are anticipated to 
require surgical intervention for UC
LABEL:
Require surgical intervention for UC
Gastrointestinal 
exclusion criterion 8
CAS
A2.08
Colonic mucosal dysplasia (moderate or 
severe) or colonic adenomas
LABEL:
Colonic mucosal dysplasia
Gastrointestinal 
exclusion criterion 9, 10
None
A2.09
Primary sclerosing cholangitis
LABEL:
Primary sclerosing cholangitis
Gastrointestinal 
exclusion criterion 11
None
A2.10
Faecal transplant ≤ 6 months before 
screening
LABEL:
Faecal transplant within 6 months
Gastrointestinal 
exclusion criterion 12
None
A2.11
Disease limited to the rectum, extending 
<15 cm past the anal verge (ulcerative 
proctitis)
LABEL:
Disease limited to the rectum
Gastrointestinal 
exclusion criterion 13
CAS
# PV will be detected manually
Source: BI reference document: "Identify and Manage Important Protocol Deviations (iPD)" [001-MCS-40-413] (2)
1 See Section 6.3 for population definitions 


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Table 6.2: 1
Important protocol deviations (continued)
Category / 
Code
Description
Comments
Excluded from1
A2.12
Relevant infectious disease or  increased 
risk of infectious complications
LABEL:
Increased risk of infectious complications
Infectious Disease 
exclusion criterion 14, 
15, 16
None
A2.13
Evidence of a current or previous disease or 
medical condition other than UC that in the 
opinion of the investigator is clinically 
significant and would make the study 
participant unreliable to adhere to the 
protocol or to complete the trial, 
compromise the safety of the patient, or 
compromise the quality of the data
LABEL:
Current or previous disease leading to 
exclusion
General exclusion 
criterion 15
CAS
A2.14
Active or suspected malignancy or history 
of malignancy within 5 years prior to 
screening visit
LABEL:
Malignancy within last 5 years
General exclusion 
criterion 16
None
A2.15
Major surgery performed within 12 weeks 
prior to randomization or planned during the 
trial
LABEL:
Recent or planned major surgery
General exclusion 
criterion 17
None
A2.16
Pathological safety lab parameters
LABEL:
Pathological safety lab parameters
General exclusion 
criterion 18
None
#
A2.17
Conflicting other investigational treatment 
LABEL:
Conflicting other treatment
General exclusion 
criterion 19
CAS
# PV will be detected manually
Source: BI reference document: "Identify and Manage Important Protocol Deviations (iPD)" [001-MCS-40-413] (2)
1 See Section 6.3 for population definitions 


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Table 6.2: 1
Important protocol deviations (continued)
Category / 
Code
Description
Comments
Excluded from1
A2.18
Known hypersensitivity to any component 
of the IMP
LABEL:
Known hypersensitivity to IMP
General exclusion 
criterion 21
None
A2.19
Patients who were treated with a TNF 
antagonist within 8 weeks prior to 
screening, or 3 half-lives of agent from 
screening, whichever is longer
LABEL:
Recent TNF treatment
Gastrointestinal 
exclusion criterion 2
CAS
#
A2.20
Prior use of any other biological treatment 
in the past (e.g. integrin inhibitors, IL12/23 
or IL23 inhibitors, any other investigational 
biological drugs)
LABEL:
Prior use of any other biologic
Gastrointestinal 
exclusion criterion 3
CAS
#
B
Informed consent
B1
Informed consent not available
LABEL:
IC not available
Based on direct 
assessment, not simply 
the tick box (which is 
A1.08).
Date of informed 
consent missing or no 
signature on patient’s 
“Declaration of 
Informed Consent”
In this case: Patient’s 
data will not be used at 
all.
All
B2
Informed consent too late
LABEL:
IC too late.
Informed consent date 
was after Visit 1
None
# PV will be detected manually
Source: BI reference document: "Identify and Manage Important Protocol Deviations (iPD)" [001-MCS-40-413] (2)
1 See Section 6.3 for population definitions 


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Table 6.2: 1
Important protocol deviations (continued)
Category / 
Code
Description
Comments
Excluded from1
C
Trial medication and randomisation
C1
Incorrect trial medication
C1.01
Study drug medication not taken 
LABEL:
Study drug medication not taken at all
Patient entered but no 
study drug taken
CAS, FAS, SAF
C1.02
Incorrect medication overall 
LABEL:
Incorrect medication 
Patient who fulfills the 
following would be 
considered an iPD:

>= 2 vials 
(300mg) 
deviation from 
planned dose at 
one visit

>= 3 vials 
(450mg)
deviation from 
planned dose 
overall 
CAS
C1.03
Patient skipped an intermediate dose
LABEL:
Patient skipped an intermediate dose.
Patient missing a dose at 
an intermediate visit 
when dose at a later 
scheduled visit has been 
taken.
CAS
C2
Non-compliance
D
Concomitant medication
D1
Previous medication
D1.01
Washout of previous medication too short
LABEL:
Washout too short
Washout period too short 
-See Table 4.2.2: 1 in 
CTP.
CAS
#
# PV will be detected manually
Source: BI reference document: "Identify and Manage Important Protocol Deviations (iPD)" [001-MCS-40-413] (2)
1 See Section 6.3 for population definitions 


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Table 6.2: 1
Important protocol deviations (continued)
Category / 
Code
Description
Comments
Excluded from1
D2
Prohibited medication use
D2.01
Use of restricted medication as per CTP 
Table 4.2.2: 1 on or after Screening or 
during the on-treatment period when not 
provided as a rescue treatment to stabilize a 
worsening disease condition- prior to or up 
to Week 12
LABEL:
Restricted medication prior to week 12
If restricted medication 
is initiated during trial
CAS
#
D2.02
Use of restricted medication as per CTP 
Table 4.2.2: 1 when not provided as a 
rescue treatment to stabilize a worsening 
disease condition – after Week 12
LABEL:
Restricted medication after week 12
If restricted medication 
is initiated during trial
None
#
D3
Change in background medication 
D3.01
Concurrent UC treatments need to be on 
stable doses during treatment:
Any dose change in background medication 
on or after Screening or during the on-
treatment period unless it is due to rescue 
use or adverse event– prior to or up to Week 
12
LABEL:
Concurrent UC treatment not stable prior to 
Week 12 
Medical review
CAS
#
D3.02
Any dose change in background medication
period unless it is due to rescue use or 
adverse event – after Week 12
LABEL:
Concurrent UC treatment not stable after 
Week 12 
Medical review 
None
#
# PV will be detected manually
Source: BI reference document: "Identify and Manage Important Protocol Deviations (iPD)" [001-MCS-40-413] (2)
1 See Section 6.3 for population definitions 


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Table 6.2: 1
Important protocol deviations (continued)
Category / 
Code
Description
Comments
Excluded from1
E
Missing data
None
Missing visits, 
evaluations, and tests 
will be considered 
missing data, not 
protocol deviations
F
Study specific analysis
F1
Other trial specific violation
F1.01
Incomplete diagnosis of ulcerative colitis 
LABEL:
Incomplete diagnosis of UC
Medical review
CAS
#
F2
Certain violations of procedures used to 
measure primary or secondary 
efficacy/biomarker data
F2.01
To be defined at the RPM, if applicable
Manual iPDs which have 
a potentially relevant 
effect on primary or
secondary data
Any exclusion 
will be defined 
at the RPM/
DBLM/ 
MQRM.
#
G
Other safety related violations
G1
Pregnancy test not done for woman of child 
bearing potential
LABEL:
Pregnancy test not done
None
# PV will be detected manually
Source: BI reference document: "Identify and Manage Important Protocol Deviations (iPD)" [001-MCS-40-413] (2)
1 See Section 6.3 for population definitions 


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6.3
SUBJECT SETS ANALYSED
The following analysis sets will be defined for this trial:

Enrolled set (ES)
This patient set includes all patients who signed informed consent. 
It will be used for analyses of patient disposition.

Entered set (ENTS)
This patient set includes all patients who signed informed consent and entered the 
trial. It will be used for analyses of patient disposition.

Safety analysis set (SAF):
This patient set includes all patients in the ENTS who received at least one dose of 
study drug. It will be used for analysis of safety, demographic data, baseline 
characteristics and (certain) biomarkers.

Completers analysis set (CAS):
This patient set includes all patients in the SAF who completed trial medication and 
trial through EOT visit (i.e. a visit date was reported within the time-window of Week 
12 visit; cf. Table 6.7: 1) and who had a baseline and at least one post-baseline 
measurement available for any clinical efficacy endpoint (e.g. Mayo score or Robarts 
histopathology index) or any biomarker endpoint (e.g. gene expression and/or 
inflammatory biomarker) without any iPD flagged for exclusion from the CAS in the 
table above. If a patient has any rescue use on or after Visit 1b but prior to 
administration of first dose of BI 655130 then this patient will also be excluded from 
the CAS. This is the main analysis set for presentation of primary endpoint 

Full analysis set (FAS):
This patient set includes all patients in the SAF who had a baseline and at least one 
post-baseline measurement available for any clinical efficacy endpoint (e.g. Mayo 
score or Robarts histopathology index) or any biomarker endpoint (e.g. gene 
expression or inflammatory biomarker) without any iPD flagged for exclusion from 
the FAS in the table above (cf. Table 6.2: 1). If a patient has any rescue use on or after 
Visit 1b but prior to administration of first dose of BI 655130 then this patient will 
also be excluded from the FAS. This patient set will be used for (sensitivity) analyses 
of efficacy and biomarkers.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at latest at the RPM/DBLM/MQRM. These decisions 
will be documented in the RPM decision log (3).
Table 6.3: 1 illustrates the data sets which are to be used for each category class of endpoints, 
and the approaches used with regard to missing data. For explanation of the different methods 
of handling missing data, cf. Section 6.6.


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Table 6.3: 1
Patient sets analysed
Class of endpoint
ES
ENTS
SAF
CAS
FAS
Disposition
OR
OR
Compliance 
OR
Exposure
OR
iPDs
OR
Demographic/
baseline characteristics
OR
Primary endpoint
OC
OC
Secondary safety endpoint
OR
Secondary (and further) clinical efficacy endpoints
OC
Secondary inflammatory endpoints
OC
Further safety parameters
OR,
OC-IR
i) For explanation of the different approaches with regard to missing data see Section 6.6.
OC = observed cases, OC-IR = observed cases including also values after rescue medication, OR = original results.
Note that the number of patients with available data for an endpoint may differ. For details, 
see section “Handling of missing data”.
6.5
POOLING OF CENTRES
Given the low number of patients per centre and the primarily descriptive nature of the 
statistical analysis, separate analyses by centre are not meaningful and not desirable. All 
patients from all centres will be pooled for statistical analysis.
Listings, sorted by centre, will however be displayed.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
The original results (OR) approach implies the presentation of data exactly as observed (not
using time windows as described in Section 6.7 and not setting values to missing).
OR analysis will be performed on parameters and endpoints that are not affected by patients’ 
rescue medication use (e.g. plasma concentration level of BI 655130), or, if it is not 
meaningful to apply any imputation rule for the replacement of missing values.


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6.6.1
Withdrawals
For all patients, the reason for withdrawal from treatment (e.g., adverse event) must be 
recorded in the eCRF. These data will be included in the trial database and reported.
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.
6.6.2
Efficacy data
For the Mayo and RHI total scores, a missing item or component score will lead to a missing 
total score. However, individual items and subscores may be presented as applicable. It is not 
planned to impute missing data for any efficacy endpoint in this trial. Cf. Section 9.1 for 
details regarding the derivation of (clinical) efficacy endpoints.
Data censoring for rescue medication use
Rescue medication use will be identified on the eCRF. For the purpose of data censoring, the 
following scenarios are considered rescue therapy in this trial:

Any medication taken (even single use) after first dose of BI 655130 and on or before end 
of the on-treatment period which is considered by the investigator to be rescue treatment
(as per tick in the CRF);

Any increase in the dose of background medication for UC after first dose of BI 655130 
and on or before end of the on-treatment period (i.e. Treatment phase plus REP) which is 
considered by the investigator to be rescue treatment (as per tick in the CRF)
The following approach will be used to present the efficacy data: 
Observed cases (OC) approach will include all collected data (based on time windows
as described in Section 6.7), with no imputation performed on the missing data. Such an 
OC approach will exclude all values measured after intake of a rescue medication (i.e. 
such values will be set to missing).
6.6.3
Safety data
With respect to safety evaluations, it is not planned to impute missing values. The only 
exceptions where imputation might be necessary for safety evaluation are AE dates and start 
and stop dates for concomitant medications. Missing or incomplete AE dates are imputed 
according to BI standards (see 001-MCG-156_RD-01 (4)). 
Partial start and stop dates for concomitant medications and historical medication for UC will 
be imputed to enable subsequent calculation (but not for display) by the following "worst 
case" approach:

If the day of the end date is missing, then the end date is set to last day of the month (or to 
the patient's trial completion date, if it is earlier than the last day of the month).

If the day and month of the end date are missing then the end date is set to 31st of 
December of the year (or to the patient's trial completion date, if it is earlier than the 
31st of December of the year).


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
If the day of the start date is missing the start date is set to first day of the month (except 
for rescue medication, where the first dosing day will be used if first dosing happened in 
the same month).

If the day and month of the start date are missing then the start date is set to 1st January of 
the year (except for rescue medication, where the first dosing day/month will be used if 
first dosing happened in the same year).

All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance.
If a concomitant medication or historical medication was ticked to be ongoing, it is expected 
that the end date is missing and will not be imputed for display purposes.
In principle safety data are displayed using the OR approach (meaning the presentation of 
data exactly as observed). However, for safety data that are displayed by time point (or visit) 
of measurement, the following approach will be used:
Observed cases including rescue (OC-IR) approach will include all collected data
(based on time windows as described in Section 6.7), with no imputation performed on 
the missing data and including all values measured after intake of a rescue medication.
6.6.4
PK data
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-36-
472_RD-01) (5). 
6.6.6
RNA sequencing data
The OC approach (cf. Section 6.6.2) will be used to present the RNA sequencing data. 
6.6.7
Time since first diagnosis
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows:


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
If the year of first diagnosis is unknown, time since first diagnosis will be set to missing.

If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th June of that year.

If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Measurements reported with date and time and taken prior to start of administration of trial 
treatment will be considered pre-treatment values. Measurements reported with a date only 
(and no time) and taken on the day of first administration of trial treatment will also be 
considered pre-treatment values. These pre-treatment values will be assigned to visits 
according to the nominal visit number as recorded on the eCRF or as provided by the 
laboratory.
Baseline, unless otherwise specified, is defined as the last measurement collected prior to the 
start of administration of the trial treatment.
Measurements taken after start of administration of trial treatment will be considered on-
treatment values or off-treatment values, based on the definition of the study analysis phases 
in Section 6.1, and will be assigned to visits for statistical analysis, if applicable, as defined 
below.
Analysis of AE data, concomitant medication or non-drug therapies, as well as use of rescue 
medication will not be based on visits. Frequency tables for these data will be using on-
treatment data only. Therefore, no assignment to time windows will be necessary.
All other safety, efficacy and biomarker measurements will be assigned to visits based on 
extended time windows around the planned visit dates, defined relative to the day of first trial 
treatment (which is scheduled for Visit 2). These time windows are defined in Table 6.7: 1.
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, biomarker, 
and RNA sequencing measurements to visits for statistical analysis
Visit 
number
/name
Planned 
day
Time window (Days)
Visit label
Window
(per CTP)
Start 
(per CTP)
End 
(per CTP)
Start 
(extended)
End 
(extended)
V1a
Screening
-35 to -9
n/a
V1b
Screening
-8 to -6
n/a
V2
Baseline
Day 1
+/-0
1A
1A
≤1 A
1 A
V3
Week 1, Day 
4
Day 4
+/-0
4
4
2A
8
V4
Week 2
Day 15
+/- 1
14
16
9
21
V5
Week 4
Day 29
+/- 2
27
31
22
35
V6
Week 6
Day 43
+/- 2
41
45
36
49
V7
Week 8
Day 57
+/- 2
55
59
50
63
V8
Week 10
Day 71
+/- 2
69
73
64
77
EoT
Week 12
Day 85
-6 to +1
79
86
78
99
FU1
Week 18
Day 127
+/- 5
122
132
100
141
EoOB
Week 28
V7
+141daysC
+5
142
Day of last f-
up valueB


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Days are counted relative to the day of treatment, which is defined as Day 1.
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made 
after start of infusion of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be 
assigned to Visit 3. Such data will be listed only.
B Note that measurements assigned to the Week 28/EoO visit may represent follow-up measurements (off-
treatment period; cf. Table 6.1: 1). Both on-treatment and off-treatment data will be included for analysis of this 
visit.
Repeated and unscheduled efficacy, safety and biomarker measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date of measurement.
Only one observation per time window will be selected for statistical analysis at a particular
visit – the value which is closest to the protocol planned visit day will be selected. If there are 
two observations which have the same difference in days to the planned day, but which are 
not measured on the same day, the later value will be selected. If there are two observations 
which are both closest to the planned day and were measured on the same day, the worst 
value will be selected.
Assignment of observations to visits based on time windows will be based on the non-
imputed (observed) data after setting values after rescue medication intake to missing (if 
applicable, i.e. for the "OC" approach defined in Section 6.6.2). Visits which were not 
assigned a value based on time windows will not be imputed in this trial.
For derivation of the last value on treatment, minimum value on treatment, and maximum 
value on treatment, all on-treatment values (whether or not selected in any time window; see 
Table 6.1: 1 for definition of the on-treatment period) will be considered; these will be 
derived for analysis of laboratory and vital signs data. For identification of potentially 
clinically significant abnormal laboratory values, all values (whether or not selected in any 
time window) before the off-treatment period will be considered.
Tables and figures with results of the statistical analysis will only display visits at which the 
respective parameter was planned to be collected according to the CTP.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI standards "Standards for Reporting of 
Clinical Trials and Project Summaries"(10).
A separate DMC SAP which describes the analyses required for assessment by the DMC will 
be produced and handled by the DMC. 
The individual values of all patients will be listed. Listings will generally be sorted by 
country, centre number, patient number and visit (if visit is applicable in the respective 
listing). AE listings will be sorted by 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
Q1
lower quartile
Median 
median
Q3
upper quartile
Max 
maximum
For plasma concentrations and some biomarkers, the following descriptive statistics will 
additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI standards "Standards for Reporting of Clinical Trials and Project Summaries"(10). 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if there actually are missing values. Percentages will be based on 
all patients in the respective patient set whether they have non-missing values or not.
Note that for the analysis of all data in this trial, the primary approach is to report only those 
data that fall within the on-treatment period. However, for selected displays of endpoints 
presented by-visit, additional ouputs which include both on- and off-treatment data will also 
be produced.
Disposition of the patient population participating in the trial will be summarised for the ES 
by presentation of the frequency of patients screened, entered, screened but not entered, 
treated, entered but not treated, who completed planned visit at Week 12, who completed all 


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doses of trial medication as planned, who completed planned observation time, and who were 
prematurely discontinued, by reason. Patients who completed trial through the planned visit at 
Week 12 must not be considered to have discontinued trial at any time prior to the lower 
bound of the Week 12 time window. The vital status of prematurely discontinued patients at 
EoO visit will also be summarised. Disposition will be listed by country.
The frequency of patients with iPDs, also summarised by whether or not the iPD led to 
exclusion from the CAS or FAS, will be presented for the ENTS. 
The frequency of patients in each of the different analysis sets will also be presented.
Unless explicitly specified otherwise baseline, for applicable analyses, refers to the last 
measurement collected prior to the start of administration of the trial treatment.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
Descriptive statistics will be presented for demographic parameters and baseline 
characteristics, based on the FAS.
For the continuous variables described below, the following categories will be defined and 
presented according to the number and percentage of patients in each category:
Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
< 50 years
50 to < 65 years
65 to < 75 years
≥ 75 years
Weight
≤70 kg
>70 to ≤80 kg
>80 to ≤ 90 kg
>90 kg
BMI
< 25 kg/m2
25 to < 30 kg/m2
≥ 30 kg/m2
Time since first diagnosis
≤ 1 year
> 1 to ≤ 5 years
> 5 to ≤ 10 years
> 10 years
7.2
CONCOMITANT DISEASES AND MEDICATION
Analyses of concomitant diseases and medication will be based on the FAS.


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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.
Characteristics of the trial disease, such as the disease diagnosis and the type of extra-
intestinal diagnoses which are present at start of the study, as well as the occurrence of any 
prior surgery for ulcerative colitis will be descriptively summarized. Any changes in the pre-
existing extra-intestinal diagnoses (improved or worsened) as well as the development of 
newly diagnosed extra-intestinal diagnoses will be listed.
A medication will be considered concomitant to treatment, if it

is ongoing at the start of trial treatment or

starts within the on-treatment period (see Section 6.1 for a definition of treatments and 
analysis phases).
Concomitant medication use (excluding rescue medication, historical medication for UC and 
background medication) will be summarised with frequency and percentage of patients by 
preferred name. Summaries will be presented for concomitant medication taken during the on-
treatment period (cf. Section 6.1). 
The frequency and percentage of patients with previous medication for UC treatment will be 
displayed.
The frequency and percentage of patients taking any background medication for UC will be 
tabulated by type of background therapy; any increases or decreases in dose of these 
medications during the on-treatment period will also be displayed.
Rescue medication use (including via background medication dose increase defined for 
purpose of rescue use) on or after Visit 2 and before end of the on-treatment period will be 
summarised separately.
Concomitant use of non-drug therapies will be summarised with frequency and percentage. 
Summaries will be presented for concomitant non-drug therapies taken any time during the 
on-treatment period (cf. Section 6.1).
7.3
TREATMENT COMPLIANCE
Treatment compliance will be summarised overall via total volume infused (as a % of 
planned) for the FAS using descriptive statistics (N, mean, SD, minimum, median, 
maximum). For the patients who discontinued the study treatment prematurely only the visits 
on or before premature discontinuation will be used for the calculation of overall compliance.
The by visit compliance will be listed only. 
The number and percentage of patients with the following overall compliance categories will 
be presented:

"< 80% of planned", 


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
"80 to 120% of planned" and 

"> 120% of planned".
7.4
PRIMARY ENDPOINTS
The pre-processing of the raw read count values will be conducted as described in Section 7.3 
of the CTP. The primary endpoint will be evaluated for the CAS. The analysis will be 
performed as defined in Section 7.3.1 of the CTP. The FDR adjusted P-value based on the 
Wald test and the log2 fold change, are used to identify deregulated genes.
Definition of deregulated genes
A gene is defined as deregulated at time point i if the FDR adjusted P-value of the Wald test 
is below 0.01 and if |fold change (time point i vs. baseline)| ≥ 1.3.
The total number of deregulated genes per (post-baseline) time point (V2, V3, V4, V7 and 
EoT) will be reported. 
The following sensitivity analyses may be conducted:

The number of deregulated genes will be evaluated for the FAS in case this analysis 
set differs (with regard to RNA analyses) from the CAS

In case the number of identified deregulated genes is very large (> 5000 deregulated 
genes at all time points) a smaller threshold for the FDR adjusted P-value will be 
considered

In case the number of identified deregulated genes is empty (or includes less than 50
genes at all time points) the 50 genes with the smallest FDR adjusted P-values will be 
listed per (post-baseline) time point
7.5
SECONDARY ENDPOINT
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified.
7.5.2
Secondary endpoints
7.5.2.1
Secondary efficacy endpoints
The analysis of CRP, FCP and FLFwill be performed as defined in Section 7.3.2 of the CTP
and will be based on theSAF. 
The CRP, FCP and FLF will be descriptively summarized by visit as continuous variables.
For each marker the absolute value and percent change from baseline will be analysed per 
treatment group via

Mean, standard deviation, median, Q1, Q3, normalized IQR (0.7413*IQR), minimum, 
maximum, gMean


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
Error bars for the median with Q1 being the lower end and Q3 the upper end of the 
bars of the respective outcome variable will be calculated for each time point. This 
information will be displayed graphically in conjunction with the median.  

Line plots presenting individual values of the respective outcome variable over time. 
Beside the individual patient lines also a median line will be depicted in all plots for a 
better visual interpretation.
In plots with absolute values reference lines indicating LLOQ and ULOQ may be included. In 
addition lower and upper limit of the normal range, if a normal range is available, will be 
presented.
The analysis of secondary efficacy endpoints will be performed as defined in Section 7.3.2 of 
the CTP and will be based on the FAS. 
Total clincal remission at Week 12 will be assessed based on the proportion of patients with 
Total Mayo score ≤2 points, and all subscores ≤1 point (cf. Section 9.1.1). The proportion of 
patients with total clinical remission will be summarized descriptively by visit, presenting 
patient frequencies and proportions together with exact 95% Wilson score confidence 
intervals.
Additional displays of the patient frequencies and percentages for the individual total Mayo 
scores (resp. partial MCS), as well as for each of the four subscore (SFS, RBS, PGA and 
mESS; cf. Section 9.1.1) will also be produced. Furthermore line plots will be produced 
presenting Mayo score (resp. the Mayo subscores SFS, RBS, PGA and mESS) over time. 


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7.7
EXTENT OF EXPOSURE
The number of subjects who received a dose of trial drug will be tabulated. The duration of 
infusion [in minutes], the amount of treatment received (actual and weight based), as well as 
the volume infused [% of planned] will be listed.
7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the SAF and following BI standards. No 
hypothesis testing is planned.
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 patients with AEs and not on the number of AEs. System organ classes (if 
applicable) will be sorted according to the standard sort order specified by the EMA, preferred 
terms (if applicable) will be sorted by total frequency (within system organ class).
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the start date of the second, later occurrence is the same or one day 
later than the end date of the first occurrence)
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (4). 
The analysis of AEs will be based on the concept of treatment emergent AEs. This means that 
all AEs will be assigned to the screening phase, on-treatment period or off-treatment period 
(i.e. follow-up) as defined in Section 6.1. Since only the start date of an AE is collected
(without start time), any AE occurrence on the same day as first BI 655130 administration 
will be assigned to the on-treatment phase.


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An overall summary of AEs will be presented. This overall summary will include summary 
statistics for the class of other significant AEs (sponsor definition based on ICH E3)
according to ICH E3 (9) and for the class of AESIs.
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
The following is considered an AESI (cf. CTP section 5.3.5.1):

Infusion reactions including anaphylactic reaction

Cytokine release syndrome

Opportunistic and mycobacterium tuberculosis infections

Hepatic injury
The investigator identified AESI will be captured from the eCRF and reported as 
“Investigator reported AESI” table. In addition, user defined adverse event concepts 
(UDAEC) identified through specific search criteria will be reported separately (cf. Table 
7.8.1:1). 
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Event Concepts
Adverse event of special 
interest
Categories
Infusion/Systemic 
hypersensitivity reactions 
including anaphylactic 
reactions
Narrow SMQ “Anaphylactic reaction”
Narrow SMQ “Angioedema”
Narrow SMQ “Hypersensitivity”
Severe infections 
(according to RCTC 
grading)
SOC Infections and infestations of at least severe RCTC 
grade, by HLGT
Opportunistic and 
mycobacterium 
tuberculosis infections
BIcMQ “Infections”: 
Narrow sub-search 8 “Opportunistic infections 
including Tuberculosis related terms”
Tuberculosis related terms
BIcMQ “Infections”: 
Narrow sub-search 8.2 “Tuberculosis related terms”
HLT “Tuberculosis infections”
Malignant tumours
(SMQ “Malignancies” – not for display)
(Sub-SMQ “Malignant or unspecified tumours” – not 
for display)
Narrow Sub-SMQ “Malignant tumours”
  Sub-SMQ “Haematological malignant tumours”
Sub-SMQ “Non-Haematological malignant tumours”


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Based on the specification provided in ICH E3 (9), the sponsor has defined AEs which are to 
be classified as ‘other significant’. For the current trial, these will include those non-serious 
AEs which were reported with ‘action taken = Drug withdrawn’ or ‘action taken = Dose 
reduced’.
The frequency of patients 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 
will be summarised separately. Separate tables will also be provided for patients with SAEs,
drug related SAEs, patients with AESIs, patients with AEs leading to trial discontinuation,
and patients with other significant AEs (as described previously) and User-defined Adverse 
Event Concepts (UDAEC) per SSAP (cf. Table 7.8.1: 1). AEs will also be summarized by 
maximum intensity.
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients 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 patients with 
SAEs will also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of non-serious AEs with an 
incidence of greater than 5 % (in preferred terms) and the frequency of SAEs will be 
summarised.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(8). Note that data from the central Laboratory will be used for all displays described below, 
unless otherwise specified.
For continuous safety laboratory parameters, normalized values will be derived.
Normalisation means transformation to a standard unit and to a standard reference range. The 
process of normalisation, handling of repeat values at the same visit for by-visit displays, as 
well as standard analyses for safety laboratory data are described in the BI guidance for the 
Display and Analysis of Laboratory Data (8). All analyses considering multiple times of the 
ULN (as described below) will be based on standardized and not normalized values. For 
continuous safety laboratory parameters, differences to baseline will be calculated.
Only patients with at least one available post-baseline value will be included in the analysis of 
an individual laboratory parameter. All individual laboratory data will be listed. Values 
outside the reference range will be flagged.
Descriptive statistics of laboratory values over time and for the difference from baseline (see
Section 6.7) will be based upon normalized values and provided by visit(including follow 
up), including summaries of the last value on treatment, the minimum value on treatment and 
maximum value on treatment. Graphical displays via box plots will be produced to present
each continuous laboratory endpoint over time.
Laboratory values will be compared to their reference ranges; shift tables will be provided for 
the number of patients with a specific RCTC grade at baseline versus the grade at the last 


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measurement on treatment, as well as the worst grade on treatment. These analyses will be 
based on normalized laboratory values.
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on normalized converted lab values, i.e. using SI units. These rules will be 
listed in the SDL appendix of the CTR. Frequency tables will summarize the number of 
patients with potentially clinically significant abnormalities. Patients having an abnormal lab 
value at baseline will be presented separately. A separate listing will present potentially 
clinically significant abnormal lab values; for each functional lab group all patient’s lab 
values will be listed, if there exists at least one lab value with clinically significant 
abnormality within the group.
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥ 10xULN, and 
≥ 20xULN will be displayed based on standardized laboratory values. To support analyses of
liver related adverse drug effects, the frequency of patients with AST and/or ALT ≥ 3xULN 
combined with a total bilirubin ≥ 2xULN in a 30 day period after AST/ALT elevation will be 
displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a patient can potentially 
be in both alkaline phosphatase strata in case of multiple AST/ALT and bilirubin elevations). 
The start of the 30 day time span is triggered by each liver enzyme elevation above the 
defined thresholds. This analysis will be based on standardized laboratory values. 
A graphical analysis of the ALT and total bilirubin during the on-treatment period will also be 
performed; the so called eDISH plot. In the graph, for each subject, the peak total bilirubin is 
presented as a fold increase over the ULN against the peak ALT as a fold increase over the 
ULN, on a log10 scale. The measurements displayed for total bilirubin and ALT may, or may 
not, occur on the same date. Two reference lines, 2xULN for total bilirubin and 3xULN for 
ALT, are drawn onto the graph in order to divide the plane into four quadrants. Normal cases 
are in the lower left quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law 
quadrant), while the lower right quadrant is known as the Temple’s corollary range (ALT ≥ 
3xULN and total bilirubin < 2xULN).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate), body temperature, and body weight 
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 by treatment using on-treatment data only, including summaries of and 
will include the last value during on-treatment period, the minimum value during on-treatment
period, and the maximum value during on-treatment period.
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
Others
Immunogenicity
The frequency and percentage of patients with ADAs to BI 655130 will be presented, by visit.
ADA will be analyzed descriptively. A potential effect of ADA on PK and safety may be 
evaluated.
7.9
HANDLING OF DMC ANALYSES
A fully external DMC, independent of the trial and project teams, will be set-up to review all 
available un-blinded safety data as well as selected efficacy data at regular intervals following 
first-patient-in. A separate DMC SAP which describes the analyses required for assessment 
by the DMC will be produced. Further details will be provided in a DMC charter.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Statistical Principles for Clinical Trials, current 
version
2
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3
001-MCS-50-415_RD-03: "Clinical Trial Analysis Decision Log (template with 
annotations)", current version; IDEA for CON
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
R Development Core Team (2013): R: A language and environment for statistical 
computing. R Foundation for Statistical Computing, Vienna, Austria (2013);
website: R-project.org
7
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED
8
KM Asset BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of 
Laboratory Data", 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-0045:"Standards for Reporting of Clinical Trials 
and Project Summaries", current version; KMED


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10.
HISTORY TABLE
Table 10: 1
History table
This is a revised TSAP including the following modifications to the final TSAP
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Initial
19-MAY-17
None
This is the initial TSAP with necessary
information for trial conduct
Final 
16-MAY-18
All
This is the final TSAP
Revised 
(Version 3.0)
06-DEC-19
All
Changes with respect to biomarker 
analyses and changes due to updated 
project standards are implemented.