Clinical trial NCT03123120
Conditions: Colitis, Ulcerative
Sponsor: Boehringer Ingelheim
Start date: 2017-06-07; Completion date: 2020-09-16
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this trial are safety and efficacy (proof-of-concept) of induction of mucosal healing by BI 655130 add-on therapy in patients with mild or moderate ulcerative colitis and persisting endoscopic activity despite pre-existing TNFi treatment.

This trial will explore safety and efficacy of a dose of BI 655130 that was modelled to achieve the similar exposures as the highest exposures tested and found safe and tolerable in preceding single and multiple dose studies in healthy subjects, as add-on to pre-existing TNFi (Tumor necrosis factor inhibitor) treatment. Secondary and further objectives include assessment of the pharmacokinetic (PK) profile of BI 655130 and early exploration of specific biomarkers with potential usefulness to predict clinical efficacy or safety outcome or help understand BI 655130's mode of action.

Detailed description:

Arms: arm 1: 1200 milligrams (mg) of Spesolimab (BI 655130) were administered every 4 weeks (q4w) via intravenous infusion over 12 weeks of treatment (3 injections of Spesolimab 1200 mg in total during the 12 weeks: at Week 0, 4, and 8 respectively). arm 2: Matching placebo was administered via intravenous infusion over 12 weeks of treatment.
Interventions: intervention 1: Spesolimab intervention 2: Placebo
Intervention descriptions: intervention 1: 12 weeks treatment intervention 2: 12 weeks treatment

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c11253289-04
EudraCT No.:
EU Trial No:
2016-004572-21
BI Trial No.:
1368.10
BI Investigational 
Product(s):
BI 655130
Title:
Proof-of-concept study of BI 655130 add-on treatment in 
patients with mild-to-moderately active ulcerative colitis 
during TNF inhibitor therapy 
Lay Title:
A study in patients with mild or moderate ulcerative colitis who 
take a TNF inhibitor. The study investigates whether bowel 
inflammation improves when patients take BI 655130 in 
addition to their current therapy.
Clinical Phase:
IIa
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
Phone: 
Status:
Final Protocol (Revised Protocol (based on global 
amendment 3))
Version and Date:
4.0
Date: 04 Mar 2019
Page 1 of 102
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:
N/A
Name of active ingredient:
BI 655130
Protocol date:
14 Feb 2017
Trial number:
1368.10
Revision date:
04 Mar 2019
Title of trial:
Proof-of-concept study of BI 655130 add-on treatment in patients 
with mild-to-moderately active ulcerative colitis during TNF 
inhibitor therapy
Coordinating
Investigator
Phone: 
Trial site(s):
Multi-centre, multi-national
Clinical phase:
IIa
Objective(s):
Safety and efficacy (proof-of concept) of BI 655130 add-on 
treatment to achieve mucosal healing in patients with mild-to-
moderately active ulcerative colitis on TNF inhibitor therapy 
Methodology:
Randomised, parallel-group, placebo-controlled, double-blind
No. of patients: 
total entered:
Approximately 30 patients


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Name of company:
Boehringer Ingelheim 
Name of finished product:
N/A
Name of active ingredient:
BI 655130
Protocol date:
14 Feb 2017
Trial number:
1368.10
Revision date:
04 Mar 2019
each treatment:
20 patients BI 655130, 10 patients placebo
Diagnosis :
Patients with mild-to-moderately active ulcerative colitis on TNF
inhibitor therapy 
Main criteria
for inclusion:
1. 18-75 years at screening (at Visit 1 and 2)
2. Body weight ≤120 kg (at Visit 1 and 2)
3. Diagnosis of ulcerative colitis ≥5 months prior to screening by 
clinical and endoscopic evidence and corroborated by a 
histopathology report
4. Currently receiving TNFi treatment with either:
-
infliximab (INF) with doses (i.e. dose and dosing interval)
unchanged for ≥4 months prior to randomisation and 
detectable drug trough level in blood, OR
-
adalimumab or golimumab with doses (i.e. dose and 
dosing interval) unchanged for ≥2 months prior to 
randomisation and detectable drug trough level in blood.
(Patients may or may not have received up to 2 different prior 
TNFi treatments.)
5. Mild or moderate disease activity, defined as: 
Total Mayo Score (MCS) (≤10), with
-
modified endoscopic subscore (mESS) ≥2, AND
-
disease extending 5 cm or more from anal verge
6. If patients receive concurrent UC treatments, these need to be on 
stable doses as below: 


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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
N/A
Name of active ingredient:
BI 655130
Protocol date:
14 Feb 2017
Trial number:
1368.10
Revision date:
04 Mar 2019
-
Oral 5-ASA compounds, provided that dose has been 
stable for the 4 weeks prior to screening, and/or
-
Oral corticosteroids (≤10 mg per day of prednisone or 
equivalent), provided that dose has been stable for the 4 
weeks prior to screening, and/or
-
Azathioprine, 6-mercaptopurin or methotrexate, provided 
that dose has been stable for the 8 weeks prior to
screening.
-
Probiotics (e.g. S. boulardii) provided that dose has been 
stable for the 2 weeks prior to screening
-
Antidiarrheals (e.g. loperamide, diphenoxylate with 
atropine) for control of chronic diarrhea
7. Patients with extensive colitis of >10 years duration or family 
history of colorectal cancer or personal history of increased 
colorectal cancer risk must have had an negative colorectal cancer 
screening within <1 year prior to screening (otherwise to be done 
during screening colonoscopy).
Test product(s):
BI 655130
dose:
1200 mg at Weeks 0, 4 and 8
mode of 
administration:
i.v.
Comparator products:
Placebo
dose:
Placebo at Weeks 0, 4 and 8


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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
N/A
Name of active ingredient:
BI 655130
Protocol date:
14 Feb 2017
Trial number:
1368.10
Revision date:
04 Mar 2019
mode of 
administration:
i.v.
Duration of treatment:
12 weeks 
Endpoints
Primary endpoint:

Mucosal healing (MCS mESS ≤1) at Week 12
Secondary endpoints:

Treatment emerging adverse events

Clinical remission based on Mayo score (total MCS ≤2 points, 
and all subscores ≤1 point) at Week 12

Histological remission (Robarts (RHI) score ≤6) at Week 12
Safety criteria:
Physical examination, vital signs, 12-lead ECG, laboratory tests, 
adverse events, serious adverse events and tolerability. The 
intensity grading of AEs and abnormal laboratory values will be 
performed according to Rheumatology Common Toxicity Criteria 
(RCTC) Version 2.0.
Statistical methods:
The evaluation of endoscopic activity at Week 12 is the primary 
objective in this trial and is described using the proportion of 
patients with mucosal healing at this time-point.
Randomisation will be stratified based on concomitant use (yes, no) 
of infliximab. The unadjusted absolute risk difference versus 
placebo will be calculated simply as the difference in the observed 
proportion of responses between BI 655130 and placebo, for the 
FAS. A 95% Newcombe confidence interval around this difference 
will be provided. The influence of the stratification variable on the 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
N/A
Name of active ingredient:
BI 655130
Protocol date:
14 Feb 2017
Trial number:
1368.10
Revision date:
04 Mar 2019
primary endpoint will be characterized in exploratory analyses.
Safety will be summarized descriptively.


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FLOW CHART
Trial periods
Screening
Treatment
Follow-up
Visit
V1a1
V1b1
V22
V3
V4
V5
EOT
FU1
FU2
FU3
EOS
Week
-5 to -1
-4 to -1
0
2
4
8
12
16
22
28
36
Day
-35 to -8
- 28 to -6
1
15
29
57
85
113
155
197
253
Visit window  (days)
N.A.
N.A.
0
±2
±3
±3
±4
±4
±4
±4
±4
Informed consent
X
In-/exclusion criteria
X
X
X
Demographics
X
Smoking/alcohol
X
Medical history
X
Prior therapies
X
Ulcerative colitis history
X
Sigmoidoscopy or colonoscopy  + biopsy3,4
X
Sigmoidoscopy + biopsy4,5
X
X
Physical exam (incl. vital signs)6
XC
XT
XT
XT
XT
XC
XC
XT
XT
XT
XC
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
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Total Mayo score8
X
X
X
Partial Mayo score8
X
X
X
X
X
X
X
X
X
X


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Trial periods
Screening
Treatment
Follow-up
Visit
V1a1
V1b1
V22
V3
V4
V5
EOT
FU1
FU2
FU3
EOS
Week
-5 to -1
-4 to -1
0
2
4
8
12
16
22
28
36
Day
-35 to -8
- 28 to -6
1
15
29
57
85
113
155
197
253
Visit window  (days)
N.A.
N.A.
0
±2
±3
±3
±4
±4
±4
±4
±4
Safety laboratory tests9
X
X
X
X
X
X
X
X
X
X
HBV-DNA monitoring9
X
X
Infections screening  (Hep B, Hep C, HIV)
X
QuantiFERON-TB test
X
Blood sampling for TNFi level10
X10
X10
X10
Blood sampling for PK11
X
X
X
X
X
X
X
X
X
Blood sampling for ADAs11
X
X
X
X
X
X
X
X
Blood sampling for biomarkers11
X
X
X
X
X
Blood sampling for immune cell 
11
X
X
X
Blood sampling for gene expression 
11
X
X
X
Optional blood sampling for DNA banking
X
Stool sampling for biomarkers
X12
X12
X
X
X
X
X
X
X
X
X
Stool sampling for enteric pathogens 
X12
X12
IBDQ13
X
X
X
X
EQ-5D(-5L)13
X
X
X
X
Diary dispensing14
X
Diary review
X
X
X
X
X
X
X
X
X
X
Study drug administration
X2,15
X15
X15
Study completion
X


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Footnotes:
1. Visit 1b should be at least 1 day after Visit 1a.
2. First study drug administration will be administered during mid-cycle of background TNFi dosing.
3. In general, a flexible sigmoidoscopy will be performed during screening period. A full colonoscopy must only be done, if a colonoscopy has not been done in past 3 years in order to 
assess disease extent and (if applicable per local guidelines) to exclude cancer.
4. Two sets of mucosal biopsies will be taken; 1 set for gene expression analyses and 1 set for histopathology/IHC analyses at each visit indicated. At visits with study drug administration
this should to be done prior to the study drug infusion. Colonoscopy and sigmoidoscopy images will be centrally read by an external independent assessor(s); management of images will 
be performed by an external vendor.
5. Sigmoidoscopies will be performed at Week 8 and Week 12. A sigmoidoscopy must be performed if a flare of UC occurs during follow up period. This can be performed within an 
extra un-scheduled visit.
6. Physical examination: C=complete, T=targeted. Refer to Section 5.3.1. In addition, at Visits 2, 4 and 5 vital signs will be assessed at approximately 5 and 120 minutes after end of study 
drug administration. Monitor for signs and symptoms of hypersensitivity reactions for approximately 2 hours after all doses of study drug.
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. Total Mayo score includes endoscopy. Partial Mayo score excludes endoscopy.
9. Includes clinical chemistry, haematology, coagulation and urinalysis assessments. At visits with study drug administration safety laboratory tests and HBV (hepatitis B virus)-DNA 
monitoring should to be done prior to the study drug infusion.
10. TNFi trough level will be done during screening period (V1a or V1b, or at a unscheduled visit) under consideration of the individual dosing schedule of the respective TNFi; if 
screening Visit 1a does not occur ≤24 hours before the next scheduled TNFi application, Visit 1b should be timed accordingly to allow endoscopy and TNFi trough level to be performed 
at the same visit; eligibility will be determined based on the real trough level collected at maximum 1 day before the next scheduled TNFi application. TNFi drug level will be done at 
EOT visit. Only if possible, this should be done as a trough level.
11.
At study visits with study drug administration, pre-dose PK/ADA and biomarkers/flow cytometry samples and gene expression samples will be obtained within 2 hours prior to start 
of i.v. infusion.
12. Stool sampling will be done during screening period (V1a or V1b, or at an unscheduled visit).
13. Inflammatory Bowel Disease Questionnaire (IBDQ) and EQ-5D(-5L), a questionnaire developed by EuroQoL group, must be completed by the patient on his/her own in a pre-
specified order in a quiet area/room before any other visit assessments or treatments and, if possible, before any interaction with the investigator or other members of the study team. Refer 
to Section 6.2
14. A diary will be used by the patient for the daily reporting of bowel movement frequency and rectal bleeding (blood in stool). This information will be used for the calculation of Mayo 
score at the visits as indicated in the Flow Chart. In addition, background medication will be recorded by patients in diary provided and assessed by study staff. Refer to Section 6.2.1.
15. Patients who terminate study drug early should be encouraged to follow all study procedures per the Flow Chart until at least Week 12, but not receive any more study drug at the 
respective visits. These patients do have the option to do EOS visit earlier, i.e. 20 weeks after last study drug administration. Until then they should follow the Flow Chart. Patients 
refusing to return to the study site should at least provide safety information and the MCS subscores by phone at the respective visits. 


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................7
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....20
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................20
2.2
TRIAL OBJECTIVES........................................................................................21
2.3
BENEFIT - RISK ASSESSMENT.....................................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................26
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................26
3.1.1
Administrative structure of the trial .................................................................27
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................28
3.3
SELECTION OF TRIAL POPULATION .......................................................29
3.3.1
Main diagnosis for trial entry ............................................................................30
3.3.2
Inclusion criteria .................................................................................................30
3.3.3
Exclusion criteria ................................................................................................31
3.3.4
Removal of patients from therapy or assessments...........................................32
3.3.4.1
Withdrawal from trial treatment ...........................................................................33
3.3.4.2
Withdrawal of consent for trial participation........................................................33
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................34
4.
TREATMENTS...................................................................................................35
4.1
INVESTIGATIONAL TREATMENTS ...........................................................35
4.1.1
Identity of the Investigational Medicinal Products..........................................35
4.1.2
Selection of doses in the trial..............................................................................36
4.1.3
Method of assigning patients to treatment groups...........................................37
4.1.4
Drug assignment and administration of doses for each patient......................37
4.1.5
Blinding and procedures for unblinding...........................................................38
4.1.5.1
Blinding.................................................................................................................38
4.1.5.2
Unblinding and breaking the code ........................................................................38
4.1.6
Packaging, labelling, and re-supply...................................................................38
4.1.7
Storage conditions...............................................................................................39
4.1.8
Drug accountability.............................................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................40


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4.2.1
Other treatments and emergency procedures..................................................40
4.2.2
Restrictions ..........................................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment ......................................................41
4.2.2.2
Restrictions regarding women of childbearing potential......................................42
4.3
TREATMENT COMPLIANCE........................................................................43
5.
VARIABLES AND THEIR ASSESSMENT ....................................................44
5.1
TRIAL ENDPOINTS..........................................................................................44
5.1.1
Primary Endpoint(s)...........................................................................................44
5.1.2
Secondary Endpoint(s) .......................................................................................44
5.2
ASSESSMENT OF EFFICACY........................................................................45
5.3
ASSESSMENT OF SAFETY.............................................................................45
5.3.1
Physical examination ..........................................................................................46
5.3.2
Vital Signs............................................................................................................46
5.3.3
Safety laboratory parameters ............................................................................46
5.3.4
Electrocardiogram ..............................................................................................50
5.3.5
Other safety parameters.....................................................................................50
5.3.6
Assessment of adverse events.............................................................................50
5.3.6.1
Definitions of AEs ................................................................................................50
5.3.6.2
Adverse event collection and reporting ................................................................54
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................56
5.4.1
Assessment of Pharmacokinetics.......................................................................56
5.4.2
Methods of sample collection .............................................................................56
5.4.3
Analytical determinations ..................................................................................56
5.4.3.1
Analytical determination of BI 655130 plasma concentration .............................56
5.4.3.2
Assessment of ADA to BI 655130........................................................................56
5.4.4
Pharmacokinetic – pharmacodynamic relationship........................................56
5.5
ASSESSMENT OF BIOMARKER(S) ..............................................................57
5.5.1
Biochemical and cellular biomarkers................................................................57
5.5.2
Pharmacogenomic biomarkers..........................................................................58
5.5.3
Methods of sample collection .............................................................................58
5.5.4
Analytical determinations ..................................................................................58
5.5.5
Biobanking...........................................................................................................59
5.6
OTHER ASSESSMENTS...................................................................................59
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................60
6.
INVESTIGATIONAL PLAN.............................................................................61
6.1
VISIT SCHEDULE.............................................................................................61
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................61
6.2.1
Screening and run-in period(s)..........................................................................61
6.2.2
Treatment period(s)............................................................................................63
6.2.3
Follow Up Period and Trial Completion...........................................................65
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................66


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7.1
STATISTICAL DESIGN - MODEL.................................................................66
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................66
7.3
PLANNED ANALYSES.....................................................................................66
7.3.1
Primary endpoint analyses.................................................................................67
7.3.2
Secondary endpoint analyses .............................................................................68
7.3.4
Safety analyses.....................................................................................................68
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................69
7.3.6
Biomarker analysis .............................................................................................69
7.3.6.1
Analysis of cellular and biochemical biomarkers.................................................70
7.3.6.2
Pharmacogenomic analyses ..................................................................................70
7.4
INTERIM ANALYSES ......................................................................................70
7.5
HANDLING OF MISSING DATA ...................................................................71
7.6
RANDOMISATION ...........................................................................................72
7.7
DETERMINATION OF SAMPLE SIZE .........................................................72
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................74
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................74
8.2
DATA QUALITY ASSURANCE ......................................................................75
8.3
RECORDS...........................................................................................................75
8.3.1
Source documents ...............................................................................................75
8.3.2
Direct access to source data and documents.....................................................77
8.3.3
Storage period of records ...................................................................................77
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................77
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........77
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................78
8.6
TRIAL MILESTONES.......................................................................................78
9.
REFERENCES....................................................................................................80
9.1
PUBLISHED REFERENCES............................................................................80
9.2
UNPUBLISHED REFERENCES......................................................................83
10.
APPENDICES.....................................................................................................84
10.1
DEFINITIONS OF CLINICAL RESPONSE/REMISSION...........................84
10.2
MAYO SCORING SYSTEM FOR THE ASSESSMENT OF 
ULCERATIVE COLITIS ACTIVITY .............................................................85
10.3
HISTOLOGIC ACTIVITY SCORE.................................................................87
10.4
EQUIVALENT DOSES OF CORTICOSTEROIDS.......................................88
10.5
PATIENT REPORTED OUTCOMES .............................................................89
10.5.1
Inflammatory Bowel Disease Questionnaire (IBDQ) ......................................89
10.5.2
EQ-5D-5L.............................................................................................................89
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................90


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ABBREVIATIONS
ADA
Anti-drug antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
AMP
Auxiliary Medicinal Product
ALT
Alanine Aminotransferase
5-ASA
5-aminosalicylic acid
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BMS
BioMarker Set
CA
Competent Authority
CD
Crohn's disease
Cmax
Maximal Concentration
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CRP
C-Reactive Protein
CRS
Cytokine Release Syndrome
CRO
Contract Research Organisation
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic Acid
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ELISA
Enzyme Linked Immunosorbent Assay
EMA
European Medicines Agency
EOS
End of Study
EOT
End of Treatment
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
ePRO
Electronic Patient Reported Outcome
EQ-5D(-5L)
Questionnaire developed by EuroQoL Group
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FCP
Faecal Calprotectin
FcR
Fc Receptor
FDA
Food and Drug Administration
FIH
First in Human
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GPP
Generalized Pustular Psoriasis
Hep
Hepatitis
HIV
Human Immunodeficiency Virus


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IB
Investigator’s Brochure
IBD
Inflammatory Bowel Disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN-
Interferon gamma
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IHC
Immunohistochemistry
i.m.
intramuscular
IL-36R
Interleukin-36 Receptor
INF
Infliximab
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITE
Indirect Target Engagement
ITT
Intention-To-Treat
i.v.
intravenous
kDa
Kilodalton
LPDD
Last Patient Drug Discontinuation
MCID
Minimal Clinically Important Difference
MCS
Mayo Score
MedDRA
Medical Dictionary for Drug Regulatory Activities
mESS
Modified endoscopic subscore
MMRM
Mixed Model Repeated Measures
MoA
Mode of Action
N
Number
NCE
New chemical entity
NF-B
Nuclear factor kappa-light-chain-enhancer of activated B cells
NIMP
Non-Investigational Medicinal Product
NRI
No Response Imputation
OPU
Operative Unit
PBMC
Peripheral blood mononuclear cells
PBO
Placebo
PCR
Polymerase Chain Reaction
PD
Pharmacodynamics
PGA
Physician Global Assessment
PK
Pharmacokinetics
p.o.
per os (oral)
PoCC
Proof of Clinical Concept
PPP
Palmoplantar Psoriasis
PPS
Per Protocol Set
PRO
Patient Reported Outcome
q.d.
quaque die (once a day)
RBS
Rectal Bleeding Subscore
RCTC
Rheumatology Common Toxicity Criteria


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REML
Restricted Maximum Likehood
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RHI
Robarts Histopathology Index
RNA
Ribonucleic Acid
qw
Weekly (once a week)
SAE
Serious Adverse Event
SAF
Safety Set
SAP
Statistical Analysis Plan
s.c.
Subcutaneous
SFS
Stool Frequency Score
SOP
Standard Operation Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
Tuberculosis
TCM
Trial Clinical Monitor
TGF-ß
Transforming Growth Factor beta
t.i.d.
ter in die (3 times a day)
TNF
Tumor necrosis factor
TNFi
Tumor necrosis factor inhibitor
TSAP
Trial Statistical Analysis Plan
UC
Ulcerative Colitis
ULN
Upper Limit of Normal
V
Visit
VAS
Visual Analog Scale
VEGF
Vascular Endothelial Growth Factor
w
Week
WBC
White Blood Count
WHO
World Health Organization
WOCBP
Women of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
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 and 6-mercaptopurine, and TNFinhibitors (TNFi). In 
patients with mild UC, 5-ASAs are safe and effective for induction and maintenance 
treatment. Glucocorticoids, immunomodulators, TNFi , 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 of 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.
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody blocking IL-36α, IL-36β 
and IL-36γ binding to IL-36R. The IL-36 pathway has been associated with the pathogenesis 
of several inflammatory diseases including inflammatory bowel diseases, pustular psoriasis 
and psoriasis vulgaris. Emerging preclinical data suggest that IL-36R is a potential target for 
the treatment of inflammatory bowel diseases, such as ulcerative colitis.
1.2
DRUG PROFILE
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL-36R 
signaling. Binding of BI 655130 to IL-36R is anticipated to prevent the subsequent activation 
of IL-36R by cognate ligands (IL-36 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).


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Preclinical studies
BI 655130 binds to human IL-36R with high binding avidity. BI 655130 effectively inhibits 
IL-36 ligand-stimulated NF-B activation, IL-8 release and IFN-γ secretion in human cell 
cultures or PBMC stimulated with IL-36α, IL-36β, or IL-36γ combined with IL-12.
Mutations BI 655130`s Fc receptor 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.
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 (BI 
674304), a mouse IgG2a monoclonal antibody with rat variable regions. In a 13-week 
intravenous 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 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 
i.v. doses from 0.001 mg/kg to 10 mg/kg body weight (1368.1). Safety and tolerability of all 
tested i.v. doses was good. There were no drug-related SAEs. AEs categorized as related to 
treatment were observed in 3/19 (15.8%) subjects in the placebo 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 placebo 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. 


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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 effects in this FIH Single Rising Dose trial (c03320877)
were assessed by indirect target engagement (ITE) 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 10 
week.
In the multiple rising dose trial (1368.2), BI 655130 or placebo have been administered to 
healthy male volunteers at multiple ascending i.v. doses of 3, 6 and 10 mg/kg given 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:


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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 
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 ulcerative colitis.
For 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
2.1
RATIONALE FOR PERFORMING THE TRIAL
BI 655130 is currently under development for the treatment of ulcerative colitis (UC). Its 
unique dual modes of action 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 only. The potential BI 655130 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 inflammatory bowel diseases 
such as UC:

IL-36R and its ligands are expressed in intestinal biopsies from patients with chronic 
IBD;

IL-36-induced genes are upregulated in human intestinal myofibroblasts and correlate
with gene signatures observed in ulcerative colitis 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 IL-23 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. 
While these findings support a prominent role of IL-36R in driving intestinal inflammation, 
in vitro studies have demonstrated synergy of IL-36 and TNF in inducing pro-inflammatory 
cytokine stimulation and disease activity markers such as calprotectin. In addition, IL-36 
regulated genes have been found upregulated in UC patients non-responsive to infliximab. 
These findings suggest a synergistic role of both cytokines in the pathogenesis of ulcerative 
colitis and provide a scientific rationale for inhibiting both, TNFi and IL-36 simultaneously in 
patients with UC. 


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Therefore, it is hypothesized that in patients with mild or moderate UC but persisting 
endoscopic activity on treatment with TNFi, a quite frequent outcome of TNFi treatment in 
patients with initially moderate or severe UC, short-term add-on treatment with the IL-36 
inhibitor BI 655130 may induce mucosal healing, which may be maintained by continued 
treatment with the TNFi after withdrawing the IL-36 inhibitor BI 655130. This concept will 
be tested in the present trial.
In addition, data on clinical effect, safety and pharmacokinetics 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 understand the PK 
characteristics of BI 655130 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.
The most recent and more detailed information is available in the current IB (c03320877).
2.2
TRIAL OBJECTIVES
The objectives of this trial are safety and efficacy (proof-of-concept) of induction of mucosal 
healing by BI 655130 add-on therapy in patients with mild or moderate ulcerative colitis and 
persisting endoscopic activity despite pre-existing TNFi treatment.
This trial will explore safety and efficacy of a dose of BI 655130 that was modelled to 
achieve the similar exposures as the highest exposures tested and found safe and tolerable in 
preceding single and multiple dose studies in healthy subjects, as add-on to pre-existing TNFi
treatment. Secondary and further objectives include assessment of the pharmacokinetic (PK) 
profile of BI 655130 and early exploration of specific biomarkers with potential usefulness to 
predict clinical efficacy or safety outcome or help understand BI 655130`s mode of action.
2.3
BENEFIT - RISK ASSESSMENT
Potential Benefits
Preclinical profiles of BI 655130 and clinical data from healthy volunteer trials suggest that 
BI 655130 is safe and may address an unmet medical need in UC patients by a dual anti-
inflammatory and anti-fibrotic mechanism of action (cf. Section 2.1). In-vitro studies have 
demonstrated synergistic effects of IL-36 and TNF in inducing pro-inflammatory responses. 
Thus, combined inhibition of both cytokines may act synergistically to induce deep and 
durable remission in UC patients (cf. section 1.2, and IB (c03320877)). The requirement of 
stable TNFi dosing and detectable blood levels will ensure proper TNFi dosing. 


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
An individual benefit may arise for patients who achieve mucosal healing. Persistent 
endoscopic activity is associated with rectal bleeding and other symptom compromising 
patient`s quality of life (R16-4637), while its absence is associated with improved clinical 
outcomes (reductions in immunosuppressive treatments, hospitalisations, colectomy and 
colorectal cancer (R16-0572). In this study, the combination treatment aims to induce
mucosal healing, while continued treatment with the partially effective TNFi aims to 
maintain mucosal healing. For patients relapsing after BI 655130 termination, approved 
drugs are available as rescue treatment, including TNFi or the integrin inhibitor 
vedolizumab.

Under the assumption of a positive exposure/response relationship, the highest safe and 
tolerable dose schedule is expected to provide the best chance to induce remissions and 
achieve a positive proof-of-clinical-concept (PoCC). If the study achieves a positive 
PoCC, this study will be followed up by detailed phase II exploration of various lower 
dose levels. 

In case of a study outcome demonstrating insufficient clinical activity in presence of 
adequate drug exposure (comparable to exposures effective in other indications), the 
evaluation of pathway engagement and disease modification genes and biomarkers will 
guide additional studies of BI 655130 in other patient populations with UC or CD. Thus, 
apart from potentially providing a benefit to individual patients, participation in this study 
may contribute to generate a group benefit for this or other patient populations.
Potential Risks
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 to impair 
immune function may be increased by combining this compound with a TNFi. However, BI 
655130 has been tested and found safe in healthy volunteer studies, and the risk of combining 
it with TNFi will be mitigated by thorough safety measures.

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 (IB
(c03320877), Section 5.1.2). 

The clinical safety and tolerability profile of BI 655130 has been tested and found 
favourable in male healthy subjects treated with i.v. multiple doses up to 20 mg/kg body 
weight once weekly for 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 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; 1368.4 – UC; 1368.10 - UC) under 
regular surveillance by an independent DMC. None of these studies has so far generated 
any specific safety signal (see IB c03320877). In summary, as of September 2017, more 


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than 170 subjects have been exposed to active drug without a 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. On the other hand an increased body weight might have negative impact
on the compound`s efficacy. However, such an effect will be limited based on the minor 
impact of body weight on PK variability, and the fact that the 1200 mg dose corresponds 
to a dose of ≥10 mg/kg for patients <120 kg, where any dose of ≥3 mg/kg has provided 
maximum indirect target engagement and biological activity in healthy subjects (cf. 
section 1.2). Therefore, there is no need to limit enrolment to certain body weights.

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 weighed 
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:
-
intestinal protein loss caused by exudative enteropathy (R16-5741; R16-5706) 
-
higher degree of systemic inflammatory burden (R13-3046)
-
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).

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 
as AE of special interest (AESI).

The safety risk of the TNFi combination will be mitigated by the pre-selection of patients 
who respond to and tolerate their current TNFi. Moreover, production of IL-1b, a key 
cytokine in native and adaptive immune response, is stimulated through many other 


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signals beyond IL-36R activation, which will remain intact. However, as a worst case 
scenario of IL-1b inhibition, a previous clinical trial has assessed the triple combination 
of the IL-1R inhibitor anakinra (approved for Rheumatoid Arthritis (R16-4481), with the 
TNFi ethanercept and methotrexate. Though this study demonstrated an increased risk of 
serious infections (7.4% vs 0% on placebo/methotrexate), such treatment was considered 
manageable and there were no fatalities (R16-4413). In contrast, the physiological 
relevance of the in-vitro finding of partial IL-1b inhibition following IL-36 inhibition is 
unclear.

Patients randomised to placebo will not be exposed to undue risks, since they will 
continue to receive the standard of care for patients with such mild or moderate disease, a 
situation where the TNFi is usually continued without modification until the patient 
relapses.

Finally, the theoretical risk of profound 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 and the definition of lymphomas, opportunistic or severe infections as adverse 
events of special interest (AESI), allowing accelerated investigation and reporting; (iii) 
selection of sites experienced in treatment of IBD patients with biologics; and (iv) 
implementation of an independent data-monitoring committee (DMC).
Other risks are those related to blood sampling and intravenous infusion of study medication. 
Colonoscopy or sigmoidoscopy with biopsy, although generally well tolerated, can be 
associated with complications. Therefore, endoscopies will in most patients be limited to 
flexible sigmoidoscopies, which do not require complete bowel preparation and are safer and 
better tolerated. A screening colonoscopy will only be required if a colonoscopy has not been 
done in past 3 years in order to assess disease extent or to exclude cancer if applicable in 
accordance with local guidelines (P14-15417). The investigation of endoscopic endpoints is 
requested by FDA and EMA as key part of efficacy assessment. The number of three 
sigmoidoscopies per patient (up to a maximum of four sigmoidoscopies or one colonoscopy 
plus three sigmoidoscopies in patients requiring colonoscopy and experiencing a flare) over a 
36 week time frame is acceptable to patients, considering that the safety risks are limited, 
investigators are highly experienced and that UC patients are usually familiar with the burden 
and risks of endoscopies from their own disease history. The risks are outweighed by the 
benefit of developing a new drug in this severe disease. 
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.


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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 5.3.6.1.
Summary of benefit-risk assessment
Due to the lack of mechanism- or compound-related safety signals and the antagonistic mode 
of action of BI 655130 it is considered likely that UC patients will not be exposed to undue 
risks and adverse events 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
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-centre, multi-national, randomised, parallel-group, multiple-doses, placebo-
controlled, double-blind Phase IIa study. Approximately 30 eligible patients with mild to 
moderate UC and persisting endoscopic activity will be randomised at 2:1 ratio, stratified 
based on concurrent infliximab use, into treatment arm (approximately 20 patients) versus 
placebo (approximately 10 patients) shown in Figure 3.1: 1.
Overall treatment duration is 12 weeks with additional 24 weeks follow-up. However, the 
timing of start of treatment (V2) during mid cycle of the TNFi dosing cycle, and primary 
endpoint assessment at Week 12 are driven by the notation of spontaneous disease activity 
fluctuations in patients in TNFi. This will reduce the confounding effect of such fluctuations. 
Patients will receive BI 655130/placebo as described in Figure 3.1: 1. The overall dosing 
schedule will be the same in all treatment arms in order to keep the blind, this is further 
described in Section 4.1.4. The first dose of study drug will be administered at mid-cycle of 
background TNFi dosing.
The analysis of the efficacy and safety data collected up to Week 12 will be performed when 
the last patient completes the Week 12 visit, which will include the primary endpoint. The 
final analysis of the entire trial data collected through Week 36 will be performed once all 
patients have completed the last scheduled trial visit.
Individual patient participation is concluded when the patient has completed the last planned 
visit. The “last-patient-last-visit-primary-endpoint” is the last scheduled primary endpoint 
visit at Week 12 completed by the last patient. The end of the trial is defined as “last patient 
out”, i.e. last scheduled visit completed by last patient.


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Figure 3.1: 1 Trial design
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, fully-external data-monitoring committee (DMC), will be established 
to assess the progress of the clinical trial, including an unblinded 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 ISF.


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Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), 
Clinical Research Associates (CRAs), and 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, OPU) in accordance with applicable 
regulations and internal SOPs, or by a Contract 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 and an IRT vendor will be used in this trial. Details will be 
provided in IRT Manual and Central Laboratory Manual, available in ISF. Central reading of 
endoscopies and central evaluation of histopathology will be done. Details will be provided in 
ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A randomised, double-blind and placebo controlled trial was considered most appropriate to 
demonstrate a first PoCC and safety of BI 655130 as add-on to a TNFi treatment in patients 
with ulcerative colitis. 
The selection of target patients with mild or moderate disease and persistent endoscopic 
activity during TNFi treatment was based on the high unmet need in such patients, where 
persistent mucosal inflammation is associated with an increased risk of disease progression,
cancer and other complications. This population is rather abundantly available at IBD referral 
centres and there are no established drugs for this condition, nor are these patients addressed 
by other clinical trials. Having failed previous TNFi treatments in the past will not confound 
the mechanistic studies in tissue and blood based on emerging internal biomarker data and 
will thus be lifted as an exclusion criterion.
The concept of BI 655130 add-on to continued TNFi treatment is based on the expectation of 
synergistic anti-inflammatory activity and the hypothesis of an additional tissue remodelling 
activity of BI 655130, which should translate into increased rates of clinical remission 
including mucosal healing (cf. section 2.1). Also, the continuation of the pre-existing TNFi is 
expected to maintain remission beyond the duration of BI 655130 treatment. To explore this 


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effect, the follow-up period will be extended until 24 weeks after the end of treatment, to 
capture differences in relapse rates between both arms. This extended follow-up period will 
also enable studies of wash-out PK to enhance the understanding of differences between UC 
patients and subjects with other diseases, e.g. by intestinal protein losing enteropathy or 
differences in target mediated drug disposition.
Treatment start (Visit 2, randomisation) has to be scheduled to occur during the mid of the 
patient`s individual TNFi dosing cycle (i.e. Week 4 after last dose for INF patients, Week 1 
after last dose for adalimumab patients, Week 2 after last dose for golimumab patients – to be 
adapted accordingly if actual TNFi dosing deviates from the standard dosing intervals) to 
minimize the confounding effect of spontaneous disease fluctuations on the outcome.
The treatment duration of 12 weeks with BI 655130 was selected to cover a longer induction 
period compared to currently approved biologic treatments and is covered by currently
available preclinical 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 to observe mucosal healing and/or clinical remissions, 
provided BI 655130 is clinically active in UC. It will also determine the kinetics of response 
and optimal duration of induction treatment. After the end of BI 655130, patients will stay on 
their TNFi as maintenance therapy and be observed for the occurrence of relapses. In case of 
disease worsening during BI 655130 treatment or endoscopically confirmed relapse after the 
end of treatment, patients will receive standard treatment (switch to treatment with a systemic 
steroid, conventional immune modulator or a different approved TNFi or the integrin 
inhibitor vedolizumab) under consideration of the patient`s previous treatment history per the 
investigator`s discretion. Due to exclusion of patients previously exposed to vedolizumab 
therapy, patients entered in this trial will have a rescue treatment option with this drug.
Therefore, a limited combination treatment with BI 655130 of 12 weeks, followed by TNFi 
maintenance treatment is justified.
The placebo control group is required to explore both the primary efficacy endpoint and the 
safety profile of BI 655130 add-on in patients with UC on background treatment with TNFi
in this yet unstudied patient population. An active comparator for such a treatment situation is 
neither established nor approved.
Thus, this trial design is considered adequate to achieve the objectives outlined above.
3.3
SELECTION OF TRIAL POPULATION
A total of approximately 30 patients will be randomised in this trial. A sufficient number of 
patients will be screened to meet this randomised goal. Patients will be recruited at 
approximately 20 sites in multiple countries. The planned number of patients per site is 1 – 2. 
Recruitment will be competitive.
Women of childbearing potential (WOCBP) 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 


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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
Mild-to-moderately active ulcerative colitis on TNF inhibitor therapy
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, males or females (at Visit 1 and 2)
2. Body weight ≤120 kg (at Visit 1 and 2)
3. Diagnosis of ulcerative colitis ≥5 months prior to screening by clinical and endoscopic 
evidence and corroborated by a histopathology report
4. Currently receiving TNFi treatment with either:
-
infliximab (INF) with doses (i.e. dose and dosing interval) unchanged for ≥4 
months prior to randomisation and detectable drug trough levels in blood, OR
-
adalimumab or golimumab with doses (i.e. dose and dosing interval) unchanged 
for ≥2 months prior to randomisation and detectable drug trough level in blood.
(Patients may or may not have received up to 2 different prior TNFi treatments).
5. Mild or moderate disease activity, defined as: 
Total Mayo Score (MCS) (≤10), with
-
modified endoscopic subscore (mESS) ≥2, AND
-
disease extending 5 cm or more from anal verge
6. If patients receive concurrent UC treatments, these need to be on stable doses as below:
-
Oral 5-ASA compounds, provided that dose has been stable for the 4 weeks prior 
to screening, and/or
-
Oral corticosteroids (≤10 mg per day of prednisone or equivalent), provided that 
dose has been stable for the 4 weeks prior to screening,  and/or 
-
Azathioprine, 6-mercaptopurin or methotrexate, provided that dose has been 
stable for the 8 weeks prior to screening.


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-
Probiotics (e.g. S. boulardii) provided that dose has been stable for the 2 weeks 
prior to screening
-
Antidiarrheals (e.g. loperamide, diphenoxylate with atropine) for control of 
chronic diarrhea
7. Patients with extensive colitis of >10 years duration or family history of colorectal cancer 
or personal history of increased colorectal cancer risk must have had an negative 
colorectal cancer screening within <1 year prior to screening (otherwise to be done during 
screening colonoscopy).
8. Women of childbearing potential (WOCBP) must use highly effective methods of birth 
control per 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 (WOCBP), 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
Gastrointestinal Exclusion Criteria
1. Extensive colonic resection, subtotal or total colectomy
2. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
3. Prior use of more than two different TNF inhibitors or vedolizumab
4. Any treatment limiting safety or tolerability issue of the concurrent TNF inhibitor
5. Concurrent treatment with rectal 5-ASA compounds, parenteral or rectal corticosteroids 
(incl. budesonide) within  2 weeks, any investigational drug within 12 weeks or 5 half-
lives, whatever is longer, or any prior dose of natalizumab or rituximab prior to screening
6. Patients who must or wish to continue the intake of restricted medications (see section 
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 <28 days prior to 
screening
8. Currently require or are anticipated to require surgical intervention for UC
9. Colonic moderate or severe mucosal dysplasia 
10. Colonic adenomas (unless properly removed)


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11. Primary sclerosing cholangitis
12. Faecal transplant ≤6 months before screening
Infectious Disease Exclusion Criteria
13. 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)
14. Active or latent TB (Patients with positive QuantiFERON TB test are excluded. Patients 
with suspected false positive or undeterminable QuantiFERON TB result may be re-
tested) 
15. Any severe infection <30 days prior to screening, including chronic or acute hepatitis B 
or C infection
General Exclusion Criteria
16. 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 
17. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to randomisation or planned during the study, e.g. hip replacement.
18. Pathological safety lab parameters: haemoglobin <8.5 g/dL, total white blood count 
(WBC) <3500 cells/µl, neutrophils <1000 cells/µl, thrombocytes <75.000/µl, albumin 
<30 g/l, creatinine ≥2 mg/dL, aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >2 x ULN, total bilirubin >1.5 x ULN (patients with Gilbert’s 
syndrome are not excluded).
19. Currently  enrolled in another investigational device or drug study, or less than 12 weeks
(or 5 half-lives, whichever is greater) since ending another investigational device or drug 
study(s), or receiving other investigational treatment(s)
20. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
21. Evidence of a current or previous disease, medical condition (including chronic alcohol or 
drug abuse) other than ulcerative colitis, 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 
3.3.4
Removal 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 Sections 3.3.4.1 and 
3.3.4.2 below.


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Every effort should be made to keep the randomised patients in the trial: if possible on 
treatment, or 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 randomisation, 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 eCRF.
3.3.4.1
Withdrawal from trial treatment
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.

If, in the investigator’s opinion, the patient requires additional medical therapy or dose 
increase in patient`s baseline medication to treat the underlying UC due to disease 
worsening or a flare (cf. section 4.2.1) the study drug must be discontinued, while the 
patient should be further followed-up in the trial as outlined below.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, 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.
Given the patient’s agreement, the patient will undergo the procedures for the remaining 
scheduled visits and follow up as outlined in the Flow Chart. Should the patient not agree to 
continue the remaining trial visits as scheduled after the premature treatment discontinuation, 
all efforts should be made to bring in the patient to the primary endpoint visit at Week 12, 
and/or to the End of Residual Effect period at 20 weeks after the last dose of trial medication.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the eCRF. These data will be included in the trial database and reported.
3.3.4.2
Withdrawal of consent for trial participation
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
Boehringer Ingelheim 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 CTP, or the contract disturbing 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
4.1
INVESTIGATIONAL TREATMENTS 
Multiple doses of BI 655130 and placebo to match BI 655130 will be administered 
intravenously. All products will be supplied by Boehringer Ingelheim.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Description of test product BI 655130
Substance:
BI 655130
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Chemical form:
Anti-human IL-36 Receptor mAb
Molecular weight:
146 kDa
Unit strength:
BI 655130 150 mg/vial (20 mg/mL)
Route of administration:
Intravenous infusions
Posology:
1200 mg at Week 0, 4 and 8
Duration of use:
12 weeks
Table 4.1.1: 2
Description of test product placebo to BI 655130
Substance:
Placebo to BI 655130
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Chemical form:
Not applicable
Molecular weight:
Not applicable
Unit strength:
Not applicable
Route of administration:
Intravenous infusions
Posology:
Weeks 0, 4 and 8
Duration of use:
12 weeks


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4.1.2
Selection of doses in the trial
The aim of this small exploratory study is to achieve PoCC for a new MoA in UC. Based on 
other effective anti-cytokine drugs in IBD and pre-clinical assays for IL-36 inhibition, a 
linear or logistic rather than a bell-shaped dose-response curve is expected. Thus, the highest 
tolerated dose should provide the highest likelihood to achieve this objective. Whether lower 
doses will be sufficient to achieve maximum efficacy will be subject of subsequent studies.
The primary endpoint of mucosal healing is well established in the scientific literature (R16-
0172), accepted by regulatory agencies (EMA (R17-0441) and FDA (R17-0038) guidances),
objective and responsive if read by an independent blinded central reader (R17-0435) and 
clinically meaningful in that its relevance for long-term clinical outcome of UC is well
accepted (R16-0572). Therefore it is suited to demonstrate PoCC for a new compound in a 
small study.
The fixed rather than weight-based dose regimen of 1200 mg given at Weeks 0, 4 and 8 has 
been selected for the following reasons:
-
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 pharmacokinetic (PK) and 
pharmacodynamics (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 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 


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PK and PD wash-out profile (clinical effect and biomarker) of BI 655130. It is justified to 
stop BI 655130 since patients stay on maintenance treatment with their original TNFi.
4.1.3
Method of assigning patients to treatment groups
During Visit 2, eligible patients will be randomised to receive treatment in a 2:1 ratio (BI
655130 : placebo) and stratified by concomitant use of infliximab according to a 
randomisation plan. The assignment will occur in a blinded fashion via Interactive Response 
Technology (IRT).
Randomised patients who did not receive study drug due to early discontinuation or due to a 
skipped visit will be replaced.
Details regarding the use of the IRT are described in the site-user manual available in the ISF.
4.1.4
Drug assignment and administration of doses for each patient
In this trial, a dose of 1200 mg 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 
20 mg/mL. 
Detailed instructions for the preparation of the infusion solution, the volume to be 
administered and the infusion rate are provided in the ISF.
In case of safety concerns, e.g., due to infusion reactions, it is in the discretion of the 
investigator or his/her designee to adapt the infusion scheme, including but not limited to 
slowing down the infusion rate, interrupting the infusion and - provided no further safety 
concern exists - restarting at a slower rate. Further, based on his medical judgement he/she 
will provide medications such as steroids, etc., as needed (cf. section 4.2.1 for handling of 
infusion reactions). Detailed instructions for handling of infusion reactions are also provided 
in the ISF.
For administration of the infusion, an intravenous indwelling catheter is placed into an arm 
vein of the subject and closed with a mandarin. 
The administration of the trial medication on all applicable study days will be done under 
supervision of the investigating physician or a designee at the site. If available, a pharmacist 
should prepare the study medication. The so-called four eye principle (two-person rule) 
should be applied for preparation (e.g. choosing the correct vials with the correct medication
number) and administration of trial medication. .
Dose modifications or adjustments are not permitted. In exceptional cases of missed or 
delayed visits, study drug of the following visit should not be administered within 14 days of 
the prior dose. There should be at least 14 days between two consecutive study drug 
administrations.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients and investigators involved in trial conduct will remain blinded with regard to the 
randomised treatment assignments until after the final trial database lock. The randomisation 
code will be kept secret by Clinical Trial Support up to the final database lock. For the 
primary analysis which is to be performed at Week 12 once all randomised patients have 
completed the Week 12 visit, the blind status of trial personnel through the remainder of the
trial will be clarified in a logistics plan which is to be finalized prior to the unblind for the 
Week 12 analysis. Please refer to Section 7.4 for further details.
The randomisation codes will be provided to bioanalytics prior to last patient out to allow for 
the exclusion from the analyses of pharmacokinetic (PK) samples taken from placebo 
patients. Bioanalytics will not disclose the randomisation code or the results of their 
measurements until the trial is officially unblinded.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator / pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate eCRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’ s 
Pharmacovigilance group to access the randomisation code for individual patients during trial 
conduct. The access to the code will only be given to authorised Pharmacovigilance 
representatives and will not be shared further. 
Formal treatment unblinding will be performed prior to each DMC meeting as a prerequisite 
for generation of the applicable DMC summaries required, and subsequent to database lock 
for the Week 12 final analysis, as well as subsequent to the final trial database lock. 
Treatment will be officially unblinded once the final trial database lock has been performed. 
Procedures to protect the integrity of the trial including the blind of patients, investigators, 
and study personnel through the final trial database lock will be implemented and are further 
described in section 7.4.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by Boehringer Ingelheim Pharma GmbH & Co. 
KG, Biberach, Germany.
The investigational product consists of a carton holding a single vial of the trial medication. 
The required information according to the Annex 13/EU GMP Guideline is provided on the 
vial and carton. Each carton will have a unique medication number.


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The investigational product will be packaged and labelled in accordance with the principles 
of Good Manufacturing Practice (GMP). Re-supply to the sites will be managed via an IRT 
system, which will also monitor expiry dates of supplies available at the sites.
For examples of the labels, refer to the ISF.
4.1.7
Storage conditions
Investigational Medicinal Product (IMP) 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 ISF.
Trial medication must be securely stored, e.g. in a locked refrigerator or at a pharmacy. The 
medication may only be dispensed to trial patients according to the CTP by authorized 
personnel as documented in the trial staff list.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee.

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the 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

Availability of the proof of a medical license for the principal investigator 
Only authorized personnel as documented in the form ‘Trial Staff List’ may administer 
medication to trial patients. The trial medication must be administered in the manner 
specified in the CTP. All unused trial medication must be returned to the sponsor. All used 
and partially used medication must be destroyed locally by the trial site. Receipt, usage and 
return or disposal must be documented on the respective forms. Account must be given for 
any discrepancies.
The investigator / pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor. 


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These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and 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, the investigator / pharmacist / investigational drug storage manager must verify that 
all unused drug supplies have been returned by the clinical trial staff and all used or partially 
used supplies have been destroyed by the trial site, and that no remaining supplies are in the 
investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
If the patient requires additional medical therapy or dose increase of baseline UC medication 
to treat the underlying UC due to disease worsening or a disease flare (increase in partial 
MCS score by ≥2 points from nadir, confirmed at a second subsequent visit AND by an 
increase by ≥1 point from nadir in the modified Endoscopic Subscore (mESS)), the study 
drug must be discontinued and patients may receive other treatment for active disease. Such 
patients will be considered as treatment failures in the ITT analysis.
If disease activity cannot be treated adequately prior to Week 12 without the use of the 
medication prohibited by the protocol or changes in the doses of allowed medication (above), 
the patient must be discontinued from study drug according to Section 6.
Treatment options for identified AE of special interest:
Infusion reactions

In case of infusion reactions emerging during or after infusion of study drug, 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 intravenous steroids

Based on patient`s clinical course and medical judgment, the infusion may be re-initiated 
in case of mild or moderate reactions (according to RCTC grading in ISF) at lower speed 
with gradual increase to complete the infusion as detailed in the Instructions for 
Preparation and Handling of BI 655130/placebo in the Investigator Site File.


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Opportunistic, severe or serious infections, TB infection 

The investigator should discontinue treatment with BI 655130 and consider interruption 
of the TNFi. Treatment of the infection has to be initiated according to local standard of 
care.
Lymphoma 

The investigator should discontinue treatment with BI 655130 and consider interruption 
of the TNFi. Diagnostics and treatment has to be initiated according to local standard of 
care.
Cytokine release syndrome (CRS)

This syndrome manifests when a large numbers 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 and consider interruption 
of the TNFi. 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 centers. Corticosteroids should be reserved for
neurologic toxicities and CRS not responsive to tocilizumab (R16-5751). 
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Any concomitant therapies should be limited to those essential for the non-gastrointestinal 
care of the patient. All concomitant medications and the reason(s) for use will be documented 
throughout the course of the study.
Following concomitant UC therapies are allowed to be continued during the study without 
dose modifications: any dose modification or de-novo initiation of any of these restricted 
medications will be considered a rescue treatment.

Oral 5-ASA, stable dose for 4 weeks prior to screening and during study

Oral corticosteroids (≤10 mg per day of prednisone or equivalent), stable dose for 4 
weeks prior to screening and during study


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
Azathioprine, 6-mercaptopurin or methotrexate, stable dose for 8 weeks prior to screening
and during study

Probiotics (e.g. S. boulardii), stable dose for 2 weeks prior to screening and during study

Antidiarrheals (e.g. loperamide, diphenoxylate with atropine) for control of chronic 
diarrhea; stable doses are encouraged
Restrictions regarding previous and concomitant treatment are summarized in Table 4.2.2.1: 
1.
Table 4.2.2.1: 1
Restricted medications
Medications or class of medications
Restriction duration
Investigational products
12 weeks or 5 half-lives, whichever is 
greater, prior to screening and during study
Vedolizumab, natalizumab, rituximab, other 
than current TNFi
Not allowed neither before nor during study
Cyclosporine, tacrolimus, mycophenolate 
mofetile and other immunomodulators
8 weeks prior to screening or 5 half-lives, 
whichever is greater, prior to screening and 
during study
5-ASA compounds
Rectal 5-ASA compounds 2 weeks prior to 
screening and during study
Corticosteroids 
Parental (s.c., i.m., or i.v.) or rectal 
corticosteroids:
2 weeks prior to screening and during the 
study
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 [81-162.5 mg] 
aspirin for cardiovascular prophylaxis are 
permitted.)
Live vaccines
6 weeks prior to screening and during study
Antibiotics for IBD 
4 weeks prior to screening and during study 
4.2.2.2
Restrictions regarding women of childbearing potential 
Women of childbearing potential and men able to father a child must use the contraception 
methods described in the patient information.


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4.3
TREATMENT COMPLIANCE
Study medication will be administered in accordance with the protocol by authorised study 
personnel (e.g. study nurse). The measured plasma concentrations will provide additional 
information about compliance.
Any missed dose has to be documented and reported to the CML.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint(s)

Mucosal healing (MCS mESS ≤1) at Week 12
5.1.2
Secondary Endpoint(s)

Treatment emerging adverse events

Histological remission (Robarts (RHI) score ≤6) at Week 12

Clinical remission based on Mayo score (total MCS ≤2 points, and all subscores ≤1 point) 
at Week 12

Modified clinical remission based on Mayo score (total modified MCS ≤2 and: RBS =0, 
SFS =0 or 1 and drop ≥1 from baseline, AND mESS ≤1) at Week 12


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5.2
ASSESSMENT OF EFFICACY
Mucosal healing will be assessed by endoscopy. Mucosal healing will be defined as a Mayo 
modified endoscopic appearance subscore ≤1.
The changes in UC activity during the trial will be assessed at visits including endoscopies 
using the total Mayo score (disease activity score) including the PGA (physician global 
assessment) and modified ESS (any degree of friability defines a score of at least 2) scores 
and the Robarts histopathology index (histologic activity score). mESS and Robarts histology 
index will be read by a central reader. At all visits not including endoscopic assessment, the 
partial MCS (partial MCS; all subscores except mESS) will be recorded to assess clinical 
disease activity. Please refer to Appendix 10.2 (Mayo Score/modified Mayo score) and to 
Appendix 10.3 (Robarts histopathology index) for further details. 
5.3
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:

Adverse events

Serious adverse events (SAEs)

Clinical laboratory values (haematology, clinical chemistry, coagulation and urinalysis)

Intensity of adverse events will be assessed by Rheumatology Common Toxicity Criteria 
(RCTC) version 2.0 (refer to ISF for details)

Physical examination

Vital signs

12-lead ECG


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5.3.1
Physical examination
Complete and target physical examinations will be performed at visits as described in the 
Flow Chart.
Complete physical examination will include vital sign assessment and general appearance as 
well as evaluation of all organ systems. Targeted physical examination will include vital sign 
assessment and evaluation of organ systems associated with AE(s) symptoms or laboratory 
abnormalities.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
5.3.2
Vital Signs
Vital signs evaluations will be performed at visits as shown in the Flow Chart. This includes 
temperature, pulse rate, systolic/diastolic blood pressure and respiratory rate. Respiratory 
rate, pulse rate, and blood pressure will be measured after patients have been sitting 
comfortably for at least five minutes. Measurement of vital signs should precede blood 
sampling to avoid the impact of blood sampling on the vital measurements. At dosing visits 
(Visits 2, 4 and 5) vital signs evaluations will be performed pre-dose and additional 
evaluations will be taken approximately at 5 minutes post-dose and 120 minutes post-dose.
5.3.3
Safety laboratory parameters
The laboratory tests listed in Table 5.3.3: 1 and 2 will be performed at the central laboratory 
service provider. A local laboratory may be used for selected tests in exceptional cases. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in ISF. For time points of laboratory sampling, see 
Flow Chart.
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 must 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).


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Table 5.3.3: 1
Exclusionary testing1
Category
Test name
Infections screening
Hepatitis B Surface Antigen (qualitative)
Hepatitis C Antibodies (qualitative)
HIV-1, and HIV-2 Antibody (qualitative)
TB screening
Serum Pregnancy test (only for female patients of 
childbearing potential)
Human Serum Chorionic Gonadotropin
Drug level
TNFi trough level
Stool studies to evaluate for enteric pathogens
Salmonella
Shigella
Yersinia
Campylobacter
Vibrio
E. coli O157/H7
Clostridia difficile toxin
Enteric parasites and their ova (including 
Cryptosporidia)
1 At screening only (Visit 1)


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Table 5.3.3: 2
Laboratory tests
Category
Test name
Haematology
Haematocrit (Hct)
Haemoglobin (Hb)
Mean cellular haemoglobin (MCH)
Mean cellular haemoglobin concentration (MCHC)
Mean cellular volume (MCV)
Red Blood Cell Count/ Erythrocytes
Reticulocyte Count
White Blood Cells / Leukocytes
Platelet Count/ Thrombocytes
Diff. Automatic
Neutrophils (relative and absolute count)
Eosinophils (relative and absolute count)
Basophils (relative and absolute count)
Monocytes (relative and absolute count)
Lymphocytes (relative and absolute count)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils, bands (Stabs)
Neutrophils, polymorphonuclear (PMN)
Eosinophils
Basophils
Monocytes
Lymphocytes
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin time (INR)
Fibrinogen
Enzymes
AST (GOT)
ALT (GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Amylase
Lipase
Electrolytes
Calcium
Sodium
Potassium
Chloride
Bicarbonate


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Table 5.3.3: 2
Laboratory tests (continued)
Category
Test name
Substrates
Glucose
BUN (blood urea nitrogen)
Uric acid
Creatinine
eGFR (estimated by CKD-EPI formula) (only at 
screening)
Bilirubin Total
Bilirubin Direct (if total is elevated)
Bilirubin Indirect (if total is elevated)
Troponin (Reflex, in case of elevated CK) 
Protein, Total
Albumin
C-Reactive Protein (CRP) (high sensitivity)
Cholesterol, total
Triglycerides
LDL-Cholesterol
HDL-Cholesterol
Protein electrophoresis (only at screening)
Specific gamma-globulin quantification
IgE1, IgG
Urine Pregnancy test (only for female patients of 
childbearing potential)
Human Chorionic Gonadotropin in urine
Serum Pregnancy test (only for female patients of 
childbearing potential if urine pregnancy test is 
positive)
Human Serum Chorionic Gonadotropin
Hormones (only at screening)
TSH (free T3 and free T4 in case of abnormal TSH 
result) 
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leukocytes
Urine pH
Urine-Sediment (microscopic examination, only if 
urine analysis abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells
Urine Sed. Crys., Unspecified
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
Drug level
TNFi drug level (only at EOT visit)
HBV (hepatitis B virus)-DNA monitoring
HBV-DNA (quantitative PCR) at baseline (Visit 2) 
and EOT Visit
1Only in case of allergic reaction


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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. 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 and the repeat used for analysis. 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 will be stored in the patient’s medical file.
5.3.5
Other safety parameters
In case of an infusion reaction monitor the patient per standard of care, grade the intensity of 
the reaction according to RCTC grading (cf. ISF) and proceed as described in section 4.2. 1.
Also draw plasma sample for IgE and ADA (anti-drug antibodies), as detailed in the lab 
manual.
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.

requires inpatient hospitalisation or 


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
requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
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 reported as a serious 
adverse event regardless of the duration between discontinuation of the trial medication and 
the occurrence of the cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the eDC system. These events should 
always be reported as SAEs as described in section 5.3.6.2.
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. the potential for AEs based on the expected synergistic activity between the 
investigational drug and the TNFi background treatment. AESI need to be reported to the 
sponsor’s Pharmacovigilance Department within the same timeframe that applies to SAE, 
please see section 5.3.6.2. Instructions on how to handle AESI are provided in section 4.2.1.
The following are considered as AESIs:

Infusion reactions including anaphylactic reaction

Cytokine release syndrome
o
May manifest when a large numbers 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.


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
Severe bacterial, fungal, and viral infections

Infection with or reactivation of mycobacterium tuberculosis,

Opportunistic infections 
o
These include pneumocystis pneumonia, toxoplasmosa gondii encephalitis, 
cryptosporidiosis, microsporidiosis, mycobacterium avium;  bacterial respiratory 
disease, bacterial enteric infection, mucocutaneous candidiasis, invasive mycoses, 
CMV, EBV, herpes simpex, varicella zoster;  human herpesvirus 8,  JC virus 
infection (adapted from http://aidsinfo.nih.gov/guidelines).

Lymphoproliferative disorders

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
o
an elevation of AST and/or ALT  >3 fold ULN combined with an elevation of 
total bilirubin >2 fold ULN measured in the same blood draw sample, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity grading of AEs will be performed according to Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0 developed by OMERACT (R13-3515). Refer to the 
ISF for intensity/severity classification. Intensity options are:
Grade 1 
mild
Grade 2 
moderate
Grade 3 
severe
Grade 4 
life-threatening


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Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is 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 study drug treatment continues or remains 
unchanged.


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5.3.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in their 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 study:
- all AEs (non-serious and serious) and all AESIs.

After the individual patient’s end of study: 
- the investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant 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. 
Figure 5.3.6.2: 1 AE reporting
The REP for BI 655130 is defined as 20 weeks after the last trial medication application. All 
AEs which occurred through the treatment phase and throughout the REP will be considered 
as on treatment, please see section 7.3.4. Events which occurred after the REP will be 
considered as post treatment events.
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
End of 
Study


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With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The investigator should determine the causal relationship to 
the trial medication.
The following should also be recorded as an (S)AE in the CRF and 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,
endoscopies if they are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’s end of study 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 into
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 o 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 Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
BI 655130 concentrations will be reported descriptively. No PK parameters will be
calculated.
PK data will be incorporated into a larger pharmacometric analysis with other trials of the BI 
655130 project. Also, ADAs will be measured and their impact on PK will be assessed. The 
relationship between PK and selected efficacy endpoints, biomarkers and AEs may be 
assessed. PK and demographic data together with treatment assignments and dosing 
information may be made available to individuals outside of the trial team for the purpose of 
PK dataset generation in accordance with sponsor’s standard procedures.
Refer to Flow Chart for the time points of PK and ADA sample collection. Date and exact 
time of drug administration and PK and ADA sampling will be recorded on eCRFs. On visits
with study medication dosing, PK and ADA samples should be collected prior to 
administration of study drug. 
5.4.2
Methods of sample collection
Optional use of plasma aliquots: Plasma samples may be used for further methodological 
investigations (ex: for future stability testing). However, only data for measuring the analyte 
and antibody responses to the analyte will be generated by these investigations. The PK study 
samples will be discarded after completion of the investigations but not later than 5 years 
after the final study report has been signed. Following the finalization of the ADA
bioanalytical report, ADA aliquots will be transferred to long term storage for 
possible/optional ADA characterization in the future.
5.4.3
Analytical determinations
5.4.3.1
Analytical determination of BI 655130 plasma concentration
BI 655130 concentrations will be determined by a validated Enzyme Linked Immunosorbent 
Assay (ELISA).
5.4.3.2
Assessment of ADA to BI 655130
The presence of ADA to BI 655130 will be assessed via their detection using a validated 
immunoassay in a tiered approach (screening, confirmatory, and titration analysis as 
appropriate).
5.4.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of pharmacokinetic/pharmacodynamic relationships is planned.


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5.5
ASSESSMENT OF BIOMARKER(S) 
Biomarkers associated with Ulcerative Colitis and the IL-36 pathway will be assessed in 
biopsies, peripheral blood and stools from patients both pre and post treatment with BI 
655130.
Blood samples (serum and plasma), stool samples and biopsies will be collected at time 
points indicated in the Flow Chart for the analysis of biomarkers. After completion of the 
study these samples may be used for not yet specified non-genetic biomarker analyses 
associated with autoimmune diseases as well as method development and evaluation. 
Samples will be stored for a maximum of 3 years (under consideration of local legislation) 
upon signature of the final study report.
Among the biomarkers, CRP and FCP are defined as Further Endpoints (see Section 5.1.3). 
Hence, their statistical analysis results are reported in the final CTR. For all the others, they 
may be reported in a separate biomarker report. 
5.5.1
Biochemical and cellular biomarkers
Serum and plasma will be collected to assess changes in protein levels of disease specific
markers such as but not limited to β defensin 2, neutrophil gelatinase associated lipocalin 
(NGAL), LL-37 and S-100 proteins (A7, A8, A12), CRP, IL-1β, IL-1RA, IL-1a, IL-6, IL-8, 
TNF, LCN2, IL-17A, IL-17F, IL-10, IL-12p70, IL-18, IL-22, IL-23, IFN-γ and VEGF both 
pre and post treatment with BI 655130. In addition, stool samples will be collected to assess
changes in faecal levels of inflammatory markers such as but not limited to calprotectin and
lactoferrin, pre- and at various time points post-treatment with BI 655130. These biomarkers 
are considered exploratory biomarkers and respective assays will need to be qualified to meet 
the required performance criteria.
Mucosal biopsies for histology and immunohistochemistry (IHC) analyses both pre and post 
treatment with BI 655130 will be performed at time points outlined in the Flow Chart and 
should be collected prior to administration of study drug at dosing on day 1 (baseline), Week 
8 and EOT, Week 12. The markers planned to be assessed by IHC may include but not 
limited to MPO, TNF,  IL-1, lipocalin 2/LCN2, ß defensin 2, CD3+ T lymphocytes, 
CD11+ and DC lamp (Dendritic Cells), CD68, and Mac-1 (on Macrophages).
Blood will be taken for flow cytometry analysis at visits indicated in the Flow Chart. Cellular
biomarkers will be assessed using flow cytometry and will include markers of cell 
populations such as but not limited to neutrophils, macrophages, innate lymphoid cells and
other lymphocyte subsets in whole blood.
The biomarker assay analysis of biochemical and cellular biomarkers samples will be 
performed in a staged approach. The initial analysis will focus on selected markers and time 
points (i. e. baseline, Week 12) and depending on these results a decision will be made about 
further analysis of all samples. This is due to the exploratory nature of the mechanism being 
tested and the timing of effect on candidate biomarkers in the study.


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5.5.2
Pharmacogenomic biomarkers
Mucosal biopsies for RNA expression will be collected at baseline, Week 8 and Week 12 to 
assess changes in gene expression levels both pre- and post-treatment with BI 655130. 
For transcriptome-wide gene expression analysis RNA will be isolated from colon biopsies 
and analysed by RNA sequencing.
Whole blood samples for RNA expression will be collected at baseline, Week 8 and Week 12 
to assess changes in gene expression levels both pre and post treatment with BI 655130. 
Therefore RNA will be isolated from peripheral blood and analysed by RNA sequencing.
5.5.3
Methods of sample collection
Biomarkers sampling times and periods may be adapted during the trial based on information
obtained during trial conduct (e.g. preliminary PK/PD data), including addition of samples
and visits. Such changes would be implemented via non-substantial CTP Amendments if 
possible.
Biopsies for RNA expression and IHC will be sampled in the colon during sigmoidoscopy at
baseline and Week 8 and 12.
All biopsies for RNA sequencing analysis will be harvested in RNAlater kept at 4°C for at 
least 24 hours, and then stored at -20 °C. 
For the assessment of RNA expression from whole blood, blood will be collected in 
PAXgene RNA tubes at time points indicated in the Flow Chart.
For the assessment of soluble protein biomarkers in serum, blood will be collected in a serum 
separation tube at time points indicated in the Flow Chart. For the assessment of soluble 
protein biomarkers in plasma, blood will be collected in a Sodium Heparin- anticoagulant 
blood drawing tube at the time points indicated in the Flow Chart. For flow cytometry, whole 
blood will be collected in an ACD drawing tube at the time points indicated in the Flow 
Chart.
Detailed instructions for biopsies, biomarkers sampling (serum, plasma, and stool), handling 
and shipment of samples are provided in the ISF or lab manual.
5.5.4
Analytical determinations
Total RNA from biopsies and whole blood will be isolated using an 
 
The integrity and quantity of RNA will be determined with a 
 
 and a 
Gene expression will be analysed using standard molecular genetic methods and technologies 
such as Next Generation Sequencing and TaqMan Real Time PCR.


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The histopathological evaluation of the colon biopsies will be based on hematoxylin and 
eosin staining using the modified Robarts Histology Index (histologic activity score). Please 
refer to Appendix 10.3 for further details. 
Serum, plasma and stool proteins and cell populations by flow cytometry will be analysed 
using established parameters for each analyte (protein) and the corresponding matrix (serum, 
plasma or stool) and cell subsets (flow cytometry).
Characteristics of the analytical methods for the analysis of colon biopsies, serum and plasma 
biomarkers and stool biomarkers will be given in detail in the clinical trial report or in an 
accompanying technical/biomarker report.
5.5.5
Biobanking
DNA Banking
One blood sample will be used for DNA Banking if participation and the separate informed 
consent is agreed upon by the patient as noted below. The DNA Banking sample, derived 
from the original blood sample, will be stored at the sponsor. The stored DNA may 
retrospectively be analysed, e.g. to identify whether there are other genetic factors that could 
contribute to a better therapeutic outcome or a higher risk of developing treatment-related 
adverse drug reactions.
Note: Participation in the DNA Banking sampling is voluntary and not a prerequisite for 
participation in the trial. The DNA Banking sample will be stored after separate informed 
consent is given in accordance with local ethical and regulatory requirements.
Methods and timing of sample collection
One (1) blood sample for DNA banking will be taken at Visit 2. A maximum of 8.5 mL blood 
will be collected per PAXgene DNA blood sampling tube for those patients who signed a 
separate informed consent concerning the Sample Banking part. The Paxgene Blood DNA 
tubes can be stored and shipped at room temperature within 14 days. If a longer storage and 
shipment period for Paxgene Blood DNA tubes is necessary, the blood samples have to be 
stored at a temperature of -20°C or below. Once frozen, thawing of the samples should be 
avoided. Detailed instructions for pharmacogenomic sampling, handling and shipment of 
samples are provided in the ISF. 
5.6
OTHER ASSESSMENTS
Colonoscopy, Sigmoidoscopy
Colonoscopy and sigmoidoscopy will be performed according to standard of care. Central 
reading will be performed (for more information cf. ISF). Histopathology will be performed 
at a central laboratory. 
Mucosal biopsies


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Biopsies will be sampled from the regions with inflammation in the colon/rectum during all 
colonoscopies/sigmoidoscopies. The procedure for collecting and handling biopsies will be 
provided in the laboratory manual (for more information cf. ISF).
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements in UC treatment 
trials and will be performed in order to monitor safety aspects or assess treatment response in 
an appropriate way.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. Each visit date 
(with its window) 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. 
Additional visits for the purpose of re-testing of laboratory parameters or AE monitoring may 
be included as deemed necessary by the investigator.
Regarding instructions for drug administration at missed or delayed visits please refer to 
Section 4.1.4.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart and the respective 
protocol sections. Refer to Section 5 and 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.
Patient Reported Outcomes (PROs) should be completed by the patient on his/her own in a 
pre-specified order in a quiet area/room before any other visit assessments or treatments, and, 
if possible, before any interaction with the investigator or other members of the study team.
The order of completion for PROs should be as follows, as applicable for each PRO at 
relevant visits according to the Flow Chart:
1) IBDQ
2) EQ-5D(-5L)
6.2.1
Screening and run-in period(s)
No trial procedures should be done unless the patient has consented to taking part in the trial.
Once consented, the patient is considered to be enrolled in the trial and has started screening. 
The patient should be recorded on the screening log and be registered in IRT as a screened 
patient.


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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 8 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, endoscopy and any condition 
requiring therapy (excluding UC) will be reported on the baseline condition eCRF page.
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, date of diagnosis, as well as previous and 
concomitant treatment for UC, will be recorded in the eCRF.
Prior Therapies
Prior therapies related to UC will be collected during screening.
Ulcerative Colitis History
A detailed history of UC, including date of diagnosis, disease severity, hospitalizations, and 
extraintestinal manifestations will be collected during screening.
Blood sampling 
Blood samples will be taken for safety lab and infection screening (HBV, HCV, HIV and 
Quantiferon-TB). For women of childbearing potential, a serum pregnancy test will be 
performed. 


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Stool sampling
A stool sample will be collected to exclude existence of enteric pathogens. Stool sampling 
will be done for faecal calprotectin and lactoferrin, too.
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), as well as 
2) daily intake of concomitant 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 EOS visit. Please refer to ISF for more information.
Visit 1b:
The Visit 1b should take place no more than 28 days and no less than 6 day prior to Visit 2. 
Visit 1b should be at least 1 day after Visit 1a.
A sigmoidoscopy (or full colonoscopy) with serial mucosal biopsies will be performed at this 
visit. A full colonoscopy must only be done, if no colonoscopy has been done in past 3 years 
in order to assess disease extent or to exclude cancer (if applicable per local guideline).
Based on the results from sigmoidoscopy or colonoscopy and clinical symptoms of the
patient, a baseline Mayo score will be determined.
For a detailed description of the trial procedures at Visits 1a and 1b, please refer to the Flow 
Chart.
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).
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. Patients who fail screening following Visit 1a and 1b 
assessments should be registered as a screen failure in IRT.
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. 


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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 administration of study drug. A positive urine test must be 
confirmed with a serum pregnancy test.
Blood sampling
Blood sampling (e.g., for safety lab, biomarkers) should be the last procedure prior to any 
study drug administration and prior to sigmoidoscopy if applicable. 
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 ISF for further information on the collection of 
biopsies.
PK and ADA sampling
At visits with study drug administration, blood sampling for PK and ADA assessments 
should be done pre-dose within 2 hours prior to start of i.v. infusion.
Clinical monitoring after study drug administration:
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.
Patients should be closely monitored for signs and symptoms of hypersensitivity reactions for 
approximately 2 hours after doses administered. Hypersensitivity reactions should be treated 
according to medical standards. Pre-medications for further injections might be considered 
and will be agreed on between investigator and BI clinical monitor.
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, sigmoidoscopy 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.


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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 randomised patients, termination of trial medication and trial completion must be 
recorded on the corresponding eCRF.
A sigmoidoscopy must be performed if a clinical flare of UC occurs during follow up period.
This can be performed within an extra un-scheduled visit.
Early treatment discontinuation:
Patients who discontinue treatment prior to the regular EOT visit, should follow the Flow 
Chart until EOT visit, Week 12. These patients do have the option to do EOS visit earlier, i.e. 
20 weeks (corresponding to residual effect period of study drug) after last study drug 
administration. Until then they should follow the Flow Chart.
Trial completion:
Patients who finish the randomised treatment period will return to the clinic for follow-up 
visits. Completion is defined as a patient having reached the EOS visit.
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 UC guidelines (e.g. ECCO guidelines, R17-0243).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This trial is a study of proof-of-concept in patients with ulcerative colitis. It is designed as a 
randomised, double-blind, and placebo-controlled trial with 2 parallel groups (1 dose of BI 
655130 and placebo). 
The primary objective of this trial is to explore the safety and efficacy of BI 655130 in 
comparison to placebo in patients with ulcerative colitis.
Mucosal healing at Week 12 is the primary efficacy endpoint for this trial. Mucosal healing is 
defined as achieving a Mayo modified endoscopic subscore (mESS) ≤1.
Randomisation will be stratified based on concomitant use (yes, no) of infliximab. However, 
due to the low number of patients to be recruited into this trial, the primary analysis will be 
performed without consideration of stratification. The effects of the stratification variable on 
the primary endpoint will be assessed only in exploratory analyses.
Considering the above design characteristics, as well as the binary nature of the primary
endpoint, this trial is designed to show an increase in the proportion of patients who
demonstrate mucosal healing for BI 655130 relative to placebo via the unadjusted risk 
difference estimate.
7.2
NULL AND ALTERNATIVE HYPOTHESES
There will be no formal hypothesis testing performed in this trial.
As an exploratory Phase II trial in patients with ulcerative colitis, inferences concerning the 
efficacy of BI 655130 will be based on the magnitude of the observed difference(s) in the 
proportion of patients demonstrating mucosal healing at Week 12 compared to placebo, as 
well as on other secondary efficacy endpoints. 
A sample size justification can be found in Section 7.7.
7.3
PLANNED ANALYSES
The efficacy analyses will be performed for the FAS which is based on the intent-to-treat 
principle, and comprises all participants who were randomised, received at least one dose 
during the trial, and had a baseline measurement for the primary endpoint. Efficacy analyses 
will be based on the planned treatment (i.e., the treatment assigned at randomisation). Safety 
analyses on patients who were randomised and received at least one dose during the trial will 
be based on the actual treatment received at the randomisation visit; this set of patients is 
called the Safety Set (SAF). All efficacy analyses will be conducted on the FAS. All safety 
analyses will be conducted on the SAF.


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Important violations of the protocol will include key inclusion and exclusion violations, 
incorrect medications taken, compliance with study medication, concomitant use of restricted 
medications, and any other violations of the protocol deemed important by the study team. 
All decisions concerning important protocol violations will be made prior to un-blinding of 
the database for the primary Week 12 analysis. A per-protocol set (PPS) will be defined as a 
subset of the FAS which excludes all patients with a violation that potentially affects the 
Week 12 efficacy assessment.
Standard statistical parameters (number of non-missing values, mean, standard deviation 
(SD), median, quartiles, minimum and maximum) or frequency tables (including patient 
frequencies and percentages) will be calculated where appropriate.
For continuous secondary or further endpoints, mean changes from baseline will be analysed 
using a restricted maximum likelihood (REML)-based repeated measures approach. Analyses 
will include the fixed, categorical effects of treatment and visit, presence or absence of use of 
infliximab (yes/no), as well as the treatment-by-visit interaction, and continuous, fixed 
covariates of baseline “endpoint” and baseline-by-visit interaction. An unstructured 
covariance structure will be used to model the within-patient measurements. Exploratory 
confidence intervals will be based on least-squares mean differences to placebo using a two-
sided α =0.05.
This is an exploratory trial and formal confirmatory statistical testing will not be performed.
7.3.1
Primary endpoint analyses
The evaluation of endoscopic activity at Week 12 is the primary objective for efficacy in this 
trial and is described using the proportion of patients with mucosal healing at this time-point
based on results obtained from central reading.
The primary analysis of the unadjusted absolute risk difference versus placebo will be 
calculated simply as the difference in the observed proportion of patients with mucosal 
healing at Week12, for the FAS. A 95% Newcombe confidence interval around this 
difference will also be provided.
Exploratory analyses of the primary endpoint will include, in the absence of model 
convergence issues due to occurrence of low cell frequencies, the difference in the proportion 
of patients with mucosal healing at Week 12 between BI 655130 and placebo, for the FAS, 
using a logistic regression approach with a logit link. Fixed classification effects will include 
treatment and presence or absence of use of infliximab (yes/no). The estimates from the 
logistic regression are on the logit scale, and the difference in proportions will be calculated 
as the difference between the predicted probabilities in the treatment groups on the original 
scale, with the confidence interval calculated using the cumulative distribution function 
method of Reeve [R16-4414]; further details will be provided in the TSAP.
Secondary analyses of the primary endpoint will include:


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
Sensitivity analyses utilizing different patients sets (such as the PPS), as well as 
alternative methods for the handling of missing data as described in section 7.5;

Exploration of the relationship between various demographic or baseline characteristics 
data and the primary endpoint will be performed via graphical methods as well as using a 
logit link with
Further details will be provided in the trial statistical analysis plan.
7.3.2
Secondary endpoint analyses
For the secondary binary endpoints related to efficacy, for the FAS, the unadjusted absolute 
risk difference versus placebo will be calculated and a 95% Newcombe confidence interval 
around this difference will also be provided.
For secondary continuous endpoints, mean changes from baseline will be analysed using a 
restricted maximum likelihood (REML)-based repeated measures approach (see section 7.3).
For the stool frequency and rectal bleeding items reported in the patient diary, an average of 
the last 3 non-missing daily assessments collected within the last 7 days prior to the 
applicable visit will be used for the determination of clinical remission. If the patient 
undergoes bowel preparation for endoscopy on any of the days before a visit, the stool 
frequency and rectal bleeding subscores on that day(s) should be considered to be missing. In 
addition, the stool frequency and rectal bleeding subscore will be considered to be missing 
both on the day of and the day after the endoscopy.
7.3.4
Safety analyses
The safety set, described in section 7.3, will be used to perform all 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 adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect 


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period (REP) is defined as 20 weeks after the last dose of trial medication. Adverse events 
that start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’. Drug related AEs will be tabulated by system organ class and preferred 
term 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 adverse events will be 
tabulated by system organ class and preferred term after coding according to the current 
version of 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. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
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.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
BI 655130 concentrations will be reported descriptively. No PK parameters will be calculated. 
7.3.6
Biomarker analysis
The patient set for the evaluation of biomarker assessments (BioMarker Set [BMS]) will
include all treated patients that provide at least one observation for at least one biomarker
matrix. It will be decided in the Report Planning Meeting or the Medical Quality Review
Meeting whether patients having important protocol violations that could have a significant
impact on biomarker analyses are to be excluded from the BMS. Excluded patients will be
listed with their individual parameter values.
The statistical analysis for biomarker assessments is mainly descriptive. Summary statistics
and summary plots are produced for each assessment at each time point, and for changes
from baseline when appropriate.
In particular, for assessments measured on a continuous scale, means, standard deviations, 
quantiles, and percentiles are produced. Confidence intervals for the mean estimates are 
calculated at 95% confidence levels. Changes from baseline at each time point are reported 
similarly.
Summary plots for continuous variables include, but are not necessarily limited to, dot-plot
for each assessment at each time point; side-by-side boxplot and line graph for selected
variables over time.


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For assessments that are categorical or ordinal in nature—for example, results from
histopathological and IHC evaluation (Section 5.5.4), frequency tables are produced. Bar-
plots are presented. Shift-tables are also produced for each variable between baseline and 
each post-baseline value, if feasible.
Correlations between biomarkers and clinical endpoints are also examined descriptively.
Scatter plots are produced at each time point. Due to the small sample size, no hypothesis
testing will be conducted; hence, no confirmative p-values will be reported.
7.3.6.1
Analysis of cellular and biochemical biomarkers
Descriptive statistics and plots as described above are provided. Further details will be
discussed in the TSAP.
7.3.6.2
Pharmacogenomic analyses
Changes in the gene expression profile of mucosal biopsy and whole blood markers from 
baseline to post-baseline will be summarized and described for selected genes. Only 
significantly up- or down-regulated genes are reported. Thresholds for defining significantly 
up- and down-regulations are given in the TSAP. 
Graphical displays such as heatmaps are generated for visual assessments of the changes in 
gene regulations between treatment and placebo group.
Spearman’s correlation coefficients between change from baseline in clinical endpoints (e.g. 
modified PGA) and mucosal biopsy or whole blood RNA expression levels of selected genes 
will be calculated at each time point. Details will be discussed in the TSAP.
7.4
INTERIM ANALYSES
In order to ensure the patient’s safety during the trial, 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 DMC SAP 
which describes the analyses required for assessment by the DMC will be produced and 
finalized prior to first patient randomised into the trial. Further details will be provided in a 
DMC charter.
Once all randomised patients have completed the first 12 weeks of study, a partial database 
lock may be performed in order that a fast track analysis of primary and selected secondary 
and safety endpoints be done; a second data lock would then be done for the remaining 
efficacy and safety data collected up to Week 12. If fast-track analysis is not performed, a 
single database lock will be done for safety and efficacy data collected up to Week 12. At this 
time, the final analysis of these data through Week 12 will be performed. Since the study is 
planned to continue through an additional 24 weeks of further follow-up, and will remain 
blinded, a logistics plan will be developed in order to protect the integrity of the ongoing trial 
data and reporting subsequent to treatment un-blind for both the possible fast track and the 


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complete Week 12 primary analysis. Details of the analysis to be performed for the Week 12 
data will be described in the TSAP which is planned to be finalized prior to achieving 
database lock for the Week 12 analysis. 
An analysis of the entire trial data will be performed once all randomized patients have 
completed the 36 weeks of the study. At this time, the database will be locked, and official 
unblinding of the trial will be performed. Details of the analysis to be performed for the 
completed trial through 36 weeks (End of Study Visit) will be described in the TSAP which 
is planned to be finalized prior to achieving database lock for the Week 12 analysis.
All analyses are planned to be documented in a clinical trial report which is to be prepared at 
the end of the trial.
7.5
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will
still occur and approaches to handle this are proposed below.
With respect to safety evaluations, it is not planned to impute missing values.
For all binary endpoints (i.e. endpoints that are either 1 (patient responded) or 0 (patient did
not respond)), the following will be performed:

If there are data at visits both before and after the visit with a missing outcome, then
impute as success only if both neighbouring visits also represent a success;

Otherwise, impute as a failure to achieve a response (i.e. NRI [No Response Imputation]).
If a patient takes a rescue medication (as defined in section 4.2.1) for the treatment of 
ulcerative colitis prior to observing the primary endpoint for this trial, then all data 
subsequent to the intake of such rescue will be considered to represent a failure to achieve a 
response. Further details on what constitutes a rescue intake with potential impact on efficacy 
outcomes will be described in the TSAP.
As a sensitivity analysis, the primary endpoint will be repeated using the NRI approach but 
including also all values obtained following rescue intake.
Further sensitivity analyses to assess the robustness of the results on the primary endpoint 
may be performed and as such will be described in the TSAP.
For secondary efficacy endpoints which are continuous in nature, the use of a restricted 
maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach 
will ensure that missing data are handled implicitly, via a missing at random assumption, by 
the statistical model.


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7.6
RANDOMISATION
Patients will be randomised in blocks to double-blind treatment. Patients will be randomised
in a 2:1 ratio to BI 655130 and placebo with stratification according to the concomitant use of 
infliximab (yes or no). BI will arrange for the randomisation and the packaging and labelling
of trial medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator so that the resulting treatment will be both 
reproducible and non-predictable. The block size will be documented in the CTR. Access to 
the codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
Calculations were performed using simulations performed via the Statistical Analysis 
Systems (SAS®) software, version 9.4.
The study is intended to show an increase of BI 655130 over placebo in terms of the 
difference in proportion of patients achieving mucosal healing at Week 12 (see primary 
endpoint). There is currently no clinical trial data available in the published literature that 
describes a placebo response on the mucosal healing in the population of patients with 
ulcerative colitis at Week 12 to be recruited into this trial. The success probability for the
primary endpoint on this PoCC trial has, therefore, been derived under the assumption that 
the difference between BI 655130 and placebo is 0.30 and that a total N of 30 patients (fixed 
according to feasibility considerations) will be studied in a 2:1 ratio (that is 20 to receive BI 
655130 versus 10 patients to receive placebo).
Simulations in SAS® were used to derive estimates of the probability that a single trial would 
demonstrate an observed difference in proportions between BI 655130 and placebo that was 
equal or greater than a defined threshold under a positive scenario whereby the expected 
difference in proportions is 0.3 in favour of BI 655130. For identifying such a target 
threshold, a minimum probability of 0.80 was defined. For each trial simulation, the response 
for each patient on each treatment was generated using a binomial distribution utilizing the 
expected response rates as noted in table below, and the trial observed proportions were then 
directly compared. A total of 10,000 trial simulations were performed. Note that the 
probability of a false positive declaration given the specified target threshold, so called 
negative scenario, was also determined.


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Table 7.7: 1
Probability of Achieving the Threshold Difference in Treatments 
given Expected Treatment Response Rates on Mucosal Healing and a 
Total Sample Size of 30 Patients
Population Response 
Rate
Expected 
Response 
Difference
Total N
(2:1)
Threshold
(Observed 
Difference)
Probability 
Threshold 
Exceeded1
False 
Positive 
Rate (%)2
Active BI
Placebo
Response Difference =0.30
0.35
0.05
0.3
30
0.20
78%
1%
0.40
0.10
0.3
30
0.20
75%
5%
0.35
0.05
0.3
30
0.15
89%
5%
0.40
0.10
0.3
30
0.15
84%
14%
0.35
0.05
0.3
30
0.10
94%
17%
0.40
0.10
0.3
30
0.10
90%
27%
1 Assuming the expected response rate difference, the probability that the observed BI 655130 response rate exceeds that of 
placebo by at least the threshold amount is displayed.
2 The probability that the observed BI 655130 response rate exceeds that of placebo by at least the threshold amount under 
the negative scenario that treatments are equal.
In summary, for a total N of 30 patients, a 2:1 randomisation ratio to BI 655130 and placebo, 
then under the assumption of a target difference between BI 655130 and placebo of 0.30 for 
the proportion of responders on the primary endpoint, then this trial will be able to detect 
with probability of 0.84, a superior response rate, versus placebo, which is at least ≥ 0.15 in 
magnitude in favour of BI 655130 when the population placebo response rate is no larger 
than 0.10. The corresponding false positive error rate is 14% (one-sided). Given that only two 
treatments are to be compared, no correction for multiplicity is required.


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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 Boehringer Ingelheim 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 (Investigator Site File).
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional 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 or the 
patient’s legally accepted representative.”
The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign (or 
place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRF) for individual patients will be provided by the sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
For adverse events, an end date may not always be available (e.g. due to hospital discharge 
and later recovery, or change in treating physician), but should be recorded in the source if 
known.
For eCRF all data need to be derived from source documents, which need to be available on-
site (this could be for example physician’s notes in patient files, printouts, patient diaries)
Describe how the data are recorded, e.g. direct entry into the paper CRF / print-outs (e.g. 
laboratory data), data captured and stored electronically, or data transcribed into the CRF.
Describe also the key aspects of the data flow, including the role of external vendors, if 
applicable.
A list of expected source documents is to be provided in this section based on the trial 
specific methodology. Additions should be made as applicable. This may comprise
-
Originals or copies of imaging diagnostics
-
ECG results (original or copies of printouts)
-
EEG results (original or copies of printouts)
-
Lung function test results
-
Endoscopic findings
-
Other results based on outputs of medical machinery equipment, etc.
-
Patient reported outcome forms (including diary) and corresponding investigator 
assessment form.


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If defined in the protocol, additional records may need to be requested from the investigator, 
e.g. information from any referral physicians on patient history relevant for AE reporting or 
data required in connection with outcome event collection in outcome studies.
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.
Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure patient confidentiality.
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 CRF, 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 trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (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)


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
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 
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, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF 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). They may review all CRFs 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 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.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
The rights of the trial patient to privacy and protection of the data / patient notes obtained 
during the trial have to be ensured in accordance with local laws and regulations. Procedures 
for data handling and data protection need to be described in the patient information and 
informed consent form.
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. Patient privacy will 


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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, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with the 
Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good Clinical 
Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from clinical 
trial participants as well as the laboratories' activities for clinical trials sponsored by 
Boehringer Ingelheim are regularly audited. The analytical groups and the banking 
facility are therefore assessed to be qualified for the storage and use of biological samples 
and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
TRIAL MILESTONES
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 the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual investigators will be notified of SUSARs occurring with the trial 
medication until 30 days 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.


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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
9.1
PUBLISHED REFERENCES
P14-15417
Assche G van, Dignass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, 
Beaugerie L, Gomollon F, Haeuser W, Herrlinger K, Oldenburg B, Panes J, 
Portela F, Rogler G, Stein J, Tilg H, Travis S, Lindsay JO; Second European 
evidence-based consensus on the diagnosis and management of ulcerative 
colitis part 3: special situations. J Crohns Colitis 7 (1), 1 - 33 (2013)
R97-3472
Irvine EJ, Feagan B, Rochon J, Archambault A, Fedorak RN, Groll A, Kinnear 
D, Saibil F, McDonald JWD. Quality of life: A valid and reliable measure of 
therapeutic efficacy in the treatment of inflammatory bowel disease. 
Gastroenterology 106, 287 - 296 (1994)
R10-6267
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 49, 1012 - 1024 (2009)
R13-3046
Ordas I, Mould DR, Feagan BG, Sandborn WJ; Anti-TNF monoclonal 
antibodies in inflammatory bowel disease: pharmacokinetics-based dosing 
paradigms; Clin Pharmacol Ther 91 (4), 635 - 646 (2012)
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 34 (6), 1401 
- 1414 (2007)
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 51 (2), 119 - 135 (2012)
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 50 (5), 1773 - 1779 (2006)
R13-4753
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 3 (1), 61 - 66 (2011)


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R13-4754
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 29 (15) (Suppl),, Abstr 2586 (2011)
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: 3 
December 2013) (2013)
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 142 (1), 46 – 54 (2012)
R15-4915
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: 31 August 
2015) (2015)
R16-0172
Peyrin-Biroulet L, et al; Selecting therapeutic targets in inflammatory bowel 
disease (STRIDE): determining therapeutic goals for treat-to-target; Am J 
Gastroenterol 110, 1324 - 1338 (2015)
R16-0572
Dave M, Loftus EV; Mucosal healing in inflammatory bowel disease – a true 
paradigm of success? Gastroenterol Hepatol (New York) 8 (1), 29 – 38 (2012)


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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 22 (Suppl 1),, Abstr O-001 
(2016)
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 3 (6), 563 - 564, Abstr OP054-LB4 (2015)
R16-4413
Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al, 
20000223 Study Group; Combination therapy with etanercept and anakinra in 
the treatment of patients with rheumatoid arthritis who have been treated 
unsuccessfully with methotrexate; Arthritis Rheum 50 (5), 1412 – 1419 (2004)
R16-4414
Reeve R. Confidence interval of difference of proportions in logistic 
regression in presence of covariates. Statistical Methods in Medical Research 0 
(0), 1 – 18 (2016)
R16-4416
Schroeder KW, Tremaine WJ, Ilstrup DM. Coatedoral5-aminosalicylic acid 
therapy for mildly to moderately active ulcerative colitis: a randomized study. 
N Engl J Med 317 (26), 1625 - 1629 (1987)
R16-4481
Kineret (anakinra) (Amgen) (U.S.prescribing information). 
http://www.accessdata.fda.gov/drugsatfda_docs/label 
/2003/anakamg062703LB.pdf (access date: 8 September 2016) (2003)
R16-4637
Han SW, McColl E, Barton JR, James P, Steen IN, Welfare MR;Predictors of 
quality of life in ulcerative colitis: the importance of symptoms and illness 
representations. Inflamm Bowel Dis 11 (1), 24 – 34 (2005)
R16-4652
Mosli MH, Feagan BG, Zou G, Sandborn WJ, D'Haens G, Khanna R, et al. 
Developmentand validation of a histological index for UC. Gut, (2016)


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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 
49 (2), 350 - 355 (2015)
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 30 (4), 197 - 202 (1992)
R16-5751
Brudno JN, Kochenderfer JN; Toxicities of chimeric antigen receptor T cells: 
recognition and management; Blood 127 (26), 3321 - 3330 (2016)
R17-0243
Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, et al
Second European evidence-based consensus on the diagnosis and management 
of ulcerative colitis part 2: current management.
J Crohns Colitis 6, 991 - 1030 (2012)
R17-0038
Guidance for industry: ulcerative colitis: clinical trial endpoints (draft 
guidance) (this guidance document is being distributed for comment purposes 
only) (August 2016, clinical/medical).
weblink:fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guida nces/UCM515143.pdf (access date: 5 January 2016) ; U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER) (2016)
R17-0435
Feagan BG, Sandborn WJ, D'Haens G, Pola S, McDonald JWD, Rutgeerts P, 
et al. The role of centralized reading of endoscopy in a randomized controlled 
trial of mesalamine for ulcerative colitis.
Gastroenterology 145 (1), 149 - 157 (2013)
R17-0441
European Medicines Agency (EMA)
Committee for Medicinal Products for Human Use (CHMP): guideline on the 
development of new medicinal products for the treatment of ulcerative colitis: 
draft (21 July 2016, CHMP/EWP/18463/2006 rev. 1).
weblink:ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/20
16/0 7/WC500211431.pdf (access date: 7 February 2017); London: European 
Medicines Agency (EMA) (2016)
9.2
UNPUBLISHED REFERENCES
c03320877
Investigator’s Brochure BI 655130


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10.
APPENDICES
10.1
DEFINITIONS OF CLINICAL RESPONSE/REMISSION
MCS 
subscore
RBS
mESS
SFS
PGA
Total
Clinical 
remission
≤1
≤1
≤1
≤1
≤2
Modified 
clinical 
remission
0
≤1
0
or
1 and drop ≥1 
from baseline
n.a.
≤2
Partial 
clinical 
remission
≤1
n.a.
≤1
≤1
≤2
Clinical 
response
≤1
Or
Reduction ≥1
-
-
-
Reduction ≥3 
and 30%
or
Reduction ≥2 
and 25% if 
mESS n.a.
Abbreviations: RBS – rectal bleeding score; mESS – modified endoscopic subscore;  SFS – stool frequency score; PGA –
physician’s global assessment;


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10.2
MAYO SCORING SYSTEM FOR THE ASSESSMENT OF 
ULCERATIVE COLITIS ACTIVITY
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 total Mayo score is 0-12 (higher scores being worse) and each subscore has a 
range of 0-3 (Table 10.2: 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 rectal bleeding subscore for that day(s) should be considered 
missing. In addition, the stool frequency and rectal bleeding subscore 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 10.2: 1
Mayo score (adopted from Schroeder et al, 1987 (R16-4416)
Components
Subscore
Severity
Score
CLINICAL RESPONSE
(Patient’s Symptoms)
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
MODIFIED
ENDOSCOPIC 
RESPONSE
(Objective Evidence of 
Inflammation)
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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10.3
HISTOLOGIC ACTIVITY SCORE
The Robarts histopathology index is a histologic activity score (R16-4652). The total score 
ranges from 0 (no disease activity) to 33 (severe disease activity).
Table 10.3: 1
Robarts Histopathology Index (RHI) by components
Component
Intercept
Chronic inflammatory infiltrate
0=No Increase
1=Mild but unequivocal increase
2=Moderate increase
3=Marked increase
Lamina propria neutrophils
0=None
1=Mild but unequivocal increase
2=Moderate increase
3=Marked increase
Neutrophils in epithelium
0=None
1=<5% crypts involved
2=<50% crypts involved
3=>50% crypts involved
Erosion or ulceration
0=No erosion, ulceration, or granulation tissue
1=Recovering epithelium + adjacent inflammation
1=Probably erosion-focally stripped
2=Unequivocal erosion
3=Ulcer or granulation tissue
Based on this, the RHI will be calculated as follows:
RHI = 1 x chronic inflammatory infiltrate level (0-3) + 2 x lamina propria neutrophils (0-3) + 
3 x neutrophils in epithelium (0-3) + 5 x erosion or ulceration (0-3)


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10.4
EQUIVALENT DOSES OF CORTICOSTEROIDS
Drug 
Equivalent dose (mg) 
Conversion factor 
Prednisone 
5 
X 1 
Prednisolone 
5 
X 1 
Triamcinolone 
4 
X 1.25 
6-Methylprednisolone 
4 
X 1.25 
Dexamethasone 
1 
X 5 
Betamethasone 
0,75 
X 6.7 
Fluocortalon 
5 
X 1 
Cloprednol 
3,75-5 
X 1.0-1.5 
Deflazacort 
6 
X 0.8 
Cortisol (hydrocortisone) 
20 
X 0.25 
Cortisone 
25 
X 0.20
Budesonide
1,125
X 4.4 


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10.5
PATIENT REPORTED OUTCOMES
10.5.1
Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ (R97-3472) is a 32-item self-report questionnaire for patients with IBD to evaluate 
the patient reported outcomes across 4 dimensions: bowel symptoms (loose stools, abdominal 
pain), systemic symptoms (fatigue, altered sleep pattern), social function (work attendance, 
need to cancel social events), and emotional function (anger, depression, irritability). Scores 
range from 32 to 224 with higher scores indicating better outcomes.
10.5.2
EQ-5D-5L
The EQ-5D(-5L) is a standardized instrument developed by the EuroQoL Group for use as a 
generic, preference-based measure of health outcome. The EQ-5D(-5L) questionnaire 
captures two basic types of information, an overall health rating using a visual analog scale 
and a descriptive “profile,” or “health state”. The health state is converted to a single 
weighted index score by applying coefficients from a validated value set. The index score is 
used in both clinical and economic evaluations of health care. These two basic types of 
information cannot be combined and will be reported separately.
The health state index measures five health dimensions. The health states for each respondent 
are converted into a single index number using a specified set of country-specific weights. A 
higher score indicates a more preferred health status with 1.0 representing perfect health and 
0 representing death. A missing answer on any one question leads to a missing overall score.
For purposes of the analyses for this study, all patients’ EQ-5D(-5L) index scores will be 
calculated using the UK weights1. The VAS asks respondents to rate their present health 
status on a 0 - 100 visual analog scale, with 0 labelled as “Worst imaginable health state” and 
100 labelled as “Best imaginable health state.” The VAS score is determined by observing 
the point at which the subject’s hand drawn line intersects the scale.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
13 Jun 2017
EudraCT number
2016-004572-21
BI Trial number
1368.10
BI Investigational Product(s)
BI 655130
Title of protocol
Proof-of-concept study of BI 655130 add-on 
treatment in patients with mild-to-moderately 
active ulcerative colitis   during TNF inhibitor 
therapy
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
CLINIAL TRIAL PROTOCOL SYNOPSIS
Description of change
Addition of objective safety and secondary 
endpoint adverse events.
Rationale for change
Clarification that safety assessment is an objective 
of this study because in particular safety is a central 
part of Phase IIa studies.
Section to be changed
CLINIAL TRIAL PROTOCOL SYNOPSIS


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Description of change
Change time point of diagnosis of ulcerative colitis 
to ≥ 5 months prior to screening.
Rationale for change
Clarification of minimum duration of disease in 
order to allow for stable TNFi treatment for ≥ 4 
months prior to randomisation. Induction phase of 
TNFi treatment is not seen as stable TNFi 
treatment.
Section to be changed
FLOW CHART
Description of change
HBV-DNA test was added at baseline (Visit 2) and 
EOT (end of treatment) Visit.
Rationale for change
HBV-DNA monitoring was added to detect any 
cases of HBV (hepatitis B virus) infection 
reactivation in occult HBV infected patients.
Section to be changed
2.2 TRIAL OBJECTIVES
Description of change
Update safety as an objective of this study.
Rationale for change
Clarification that safety assessment is an objective 
of this study because in particular safety is a central 
part of Phase IIa studies.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Change time point of diagnosis of ulcerative colitis 
to ≥ 5 months prior to screening.
Rationale for change
Clarification of minimum duration of disease in 
order to allow for stable TNFi treatment for ≥ 4 
months prior to randomisation. Induction phase of
TNFi treatment is not seen as stable TNFi 
treatment.
Section to be changed
5.1.2 Secondary Endpoint(s)
Description of change
Addition of “treatment emerging adverse events” to 
the list of secondary endpoints.
Rationale for change
Safety measurements are included to the list of 
secondary endpoints to support the study
objectives.
Section to be changed
Table 5.3.3: 2 Laboratory tests


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Description of change
HBV-DNA test was added at baseline (Visit 2) and 
EOT (end of treatment) Visit.
Rationale for change
HBV-DNA monitoring was added to detect any 
cases of HBV (hepatitis B virus) infection 
reactivation in occult HBV infected patients. 
Section to be changed
5.5.5 Biobanking
Description of change
Deletion of last paragraph.
Rationale for change
This is an administrative change to correct 
typographical errors.
Section to be changed
7.3.2 Secondary endpoint analyses
Description of change
Clarification of secondary endpoint analysis related 
to efficacy. 
Rationale for change
Clarification needed, because safety measurements 
are included to the list of secondary endpoints.
Section to be changed
Table 10.2: 1
Description of change
Deletion of “granulariy” from footnote d.
Rationale for change
Correction of assessment of modified endoscopic 
response.
Section to be changed
10.4. EQUIVALENT DOSES OF 
CORTICOSTEROIDS
Description of change
Deletion of “16-Methylprednisolone” from the 
table.
Rationale for change
This is an administrative change to correct 
typographical errors.
Section to be changed
10.4. EQUIVALENT DOSES OF 
CORTICOSTEROIDS
Description of change
Addition of equivalent doses of budenoside.
Rationale for change
Update table with information for budenoside.


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Number of global amendment
2
Date of CTP revision
13 Dec 2017
EudraCT number
2016-004572-21
BI Trial number
1368.10
BI Investigational Product(s)
BI 655130
Title of protocol
Proof-of-concept study of BI 655130 add-on 
treatment in patients with mild-to-moderately 
active ulcerative colitis   during TNF inhibitor 
therapy
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
CLINIAL TRIAL PROTOCOL SYNOPSIS
Description of change
Inclusion criterion 2: deletion of lower body weight 
limit of 60 kg.
Rationale for change
A lower body weight limit is not needed any more. 
Section to be changed
CLINIAL TRIAL PROTOCOL SYNOPSIS
Description of change
Addition of information for inclusion criterion 4: 
unchanged dose includes unchanged dose and 
dosing interval.
Rationale for change
Clarification that unchanged dose consists of 
unchanged dose and unchanged dosing interval.
Section to be changed
FLOW CHART


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Description of change
Addition of sigmoidoscopy as baseline endoscopy. 
Colonoscopy is only required if not done within 
past 3 years.
Rationale for change
A sigmoidoscopy is done at baseline and a 
colonoscopy has only to be done if not done within 
past 3 years.
Section to be changed
FLOW CHART
Description of change
A separate line for HBV-DNA monitoring was 
added.
Rationale for change
This is an administrative change in order to 
emphasize time points for HBV-DNA monitoring.
Section to be changed
1.2 DRUG PROFILE
Description of change
Update information for study 1368.1 and 1368.2. 
Addition of information from population 
pharmacokinetic modelling.
Rationale for change
Update information from phase I studies and 
providing rationale why lower body weight limit is 
not needed anymore.
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
Update information for phase I studies and studies 
with BI 655130 in other indications. Addition of 
information from population pharmacokinetic 
modelling.
Rationale for change
Update safety information of BI 655130 and 
providing rationale why lower body weight limit is 
not needed anymore.
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
Update information of risks by endoscopies.
Rationale for change
A sigmoidoscopy is done at baseline and a 
colonoscopy has only to be done if not done within 
past 3 years.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criterion 2: deletion of lower body weight 


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limit of 60 kg.
Rationale for change
A lower body weight limit is not needed anymore.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Addition of information for inclusion criterion 4: 
unchanged dose includes unchanged dose and 
dosing interval.
Rationale for change
Clarification that unchanged dose consists of 
unchanged dose and unchanged dosing interval.
Section to be changed
4.1.2 Selection of doses in the trial
Description of change
Deletion of lower body weight limit of 60 kg.
Rationale for change
A lower body weight limit is not needed anymore.
Section to be changed
6.2.1 Screening and run-in period(s)
Description of change
Update information for endoscopies.
Rationale for change
A sigmoidoscopy is done at baseline and a 
colonoscopy has only to be done if not done within 
past 3 years.
Section to be changed
9.1 PUBLISHED REFERENCES
Description of change
Update references.
Rationale for change
Reference was added. 
Section to be changed
Update references.
Description of change
9.2 UNPUBLISHED REFERENCES
Rationale for change
Administrative change to correct title of 
investigator’s brochure.


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Number of global amendment
3
Date of CTP revision
04 Mar 2019
EudraCT number
2016-004572-21
BI Trial number
1368.10
BI Investigational Product(s)
BI 655130
Title of protocol
Proof-of-concept study of BI 655130 add-on 
treatment in patients with mild-to-moderately 
active ulcerative colitis   during TNF inhibitor 
therapy
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
CLINIAL TRIAL PROTOCOL SYNOPSIS
Description of change
Inclusion criterion 1: Change upper limit of age 
from 60 years to 75 years.
Rationale for change
Upper age limit is changed to 75 years in order to 
facilitate recruitment into the study.
Section to be changed
CLINIAL TRIAL PROTOCOL SYNOPSIS
Description of change
Inclusion criterion 2: Change upper limit of body 
weight from 100 kg to 120 kg.
Rationale for change
To allow for inclusion of patients up to 120 kg 
weight in order to facilitate recruitment into the
study. 


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Section to be changed
CLINIAL TRIAL PROTOCOL SYNOPSIS
Description of change
Inclusion criterion 4: Add information for 
possibility of TNFi treatment with adalimumab and 
golimumab with doses unchanged for ≥2 months.
Patients may or may not have received up to 2 
different prior TNFi treatments.
Rationale for change
TNFi treatment with golimumab is possible, too. 
TNFi treatment with adalimumab and golimumab 
needs to be on stable dose ≥2 months prior to 
randomisation only, because of their more frequent 
dosing interval in comparison to infliximab. 
Patients do not need to be on their first TNFi 
treatment, but may have received up to 2 different 
prior TNFi treatments. These changes are made in 
order to facilitate recruitment into the study.
Section to be changed
CLINIAL TRIAL PROTOCOL SYNOPSIS
Description of change
Endpoints: Change of primary endpoint to 
“mucosal healing (MCS mESS ≤1) at Week 12” 
instead “at Week 8”. Change of secondary endpoint
to “clinical remission based on Mayo score (total 
MCS ≤2 points, and all subscores ≤1 point) at 
Week 12” instead “at Week 8”. Change of 
secondary endpoint to “histological remission 
(Robarts (RHI) score ≤6) at Week 12” instead “at 
Week 8”. Delete endpoint “mucosal healing (MCS 
mESS ≤1) at Week 8”.
Rationale for change
Primary endpoint and secondary endpoints are 
changed to Week 12 instead Week 8, because 
initial data indicate a potential for slower onset of 
action for this MoA. Week 12 is now a project 
standard time-point for primary efficacy 
measurement.
Section to be changed
CLINIAL TRIAL PROTOCOL SYNOPSIS
Description of change
Statistical methods: Update information for 
primary objective to be evaluated at Week 12 
instead at Week 8.
Rationale for change
Primary endpoint is changed to Week 12 instead 
Week 8, because initial data indicate a potential for 
slower onset of action for this MoA. Week 12 is 


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now a project standard time-point for primary 
efficacy measurement.
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
Potential benefits: Delete information for “2nd
line” TNFi.
Rationale for change
TNFi treatment may be 2nd or 3rd TNFi treatment
as rescue treatment, because inclusion criterion 4 is 
changed.
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
Potential risks: Add information that body weight 
up to 120 kg is not expected to affect PK and 
efficacy of study drug.
Rationale for change
Upper weight limit is changed to 120 kg.
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
Potential risks: Correction of “exudative”.
Rationale for change
This is an administrative change to correct a 
typographical error.
Section to be changed
3.1 OVERALL TRIAL DESIGN AND PLAN
Description of change
Update information for primary endpoint 
assessment at Week 12 instead at Week 8. Delete 
sentence about secondary endpoint assessment 
after 12 weeks.
Rationale for change
Primary endpoint is changed to Week 12 instead 
Week 8, because initial data indicate a potential for 
slower onset of action for this MoA. Week 12 is 
now a project standard time-point for primary 
efficacy measurement.
Section to be changed
3.1 OVERALL TRIAL DESIGN AND PLAN
Description of change
Figure 3.1: 1: Update figure for primary endpoint 
and TNF inhibitor.
Rationale for change
Primary endpoint is changed to Week 12 instead 
Week 8. TNFi treatment with adalimumab and 
golimumab needs to be on stable dose ≥2 months 


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prior to randomisation.
Section to be changed
3.1.1 Administrative structure of the trial
Description of change
Update information for DMC, i.e. now fully 
external DMC.
Rationale for change
DMC is changed from a partially external to a fully 
external DMC.
Section to be changed
3.2 DISCUSSION OF TRIAL DESIGN, 
INCLUDING THE CHOICE OF CONTROL 
GROUP(S)
Description of change
Update information and rationale for prior and 
current TNFi treatment.
Rationale for change
TNFi treatment with golimumab is possible, too. 
Patients do not need to be on their first TNFi 
treatment, but may have received up to 2 different 
prior TNFi treatments.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criterion 1: Change upper limit of age 
from 60 years to 75 years.
Rationale for change
Upper age limit is changed to 75 years in order to 
facilitate recruitment into the study.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criterion 2: Change upper limit of body 
weight from 100 kg to 120 kg.
Rationale for change
To allow for inclusion of patients up to 120 kg 
weight in order to facilitate recruitment into the
study.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criterion 4: Add information for 
possibility of TNFi treatment with adalimumab and 
golimumab with doses unchanged for ≥2 months. 
Patients may or may not have received up to 2
different prior TNFi treatments.
Rationale for change
TNFi treatment with golimumab is possible, too. 


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TNFi treatment with adalimumab and golimumab 
needs to be on stable dose ≥2 months prior to 
randomisation only, because of their more frequent 
dosing interval in comparison to infliximab. 
Patients do not need to be on their first TNFi 
treatment, but may have received up to 2 different 
prior TNFi treatments. These changes are made in 
order to facilitate recruitment into the study.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criterion 3: Prior use of more than two 
different TNF inhibitors is not allowed.
Rationale for change
Patients do not need to be on their first TNFi 
treatment, but may have received up to 2 different 
prior TNFi treatments. This change is made in 
order to facilitate recruitment into the study.
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
Update information for primary endpoint 
assessment at Week 12 instead at Week 8.
Rationale for change
Primary endpoint is changed to Week 12 instead 
Week 8, because initial data indicate a potential for 
slower onset of action for this MoA. Week 12 is 
now a project standard time-point for primary 
efficacy measurement.
Section to be changed
5.1.1 Primary Endpoint(s)
Description of change
Change of primary endpoint to “mucosal healing 
(MCS mESS ≤1) at Week 12” instead “at Week 8”
Rationale for change
Primary endpoint is changed to Week 12 instead 
Week 8, because initial data indicate a potential for 
slower onset of action for this MoA. Week 12 is 
now a project standard time-point for primary 
efficacy measurement.
Section to be changed
5.1.2 Secondary Endpoint(s)
Description of change
Delete several endpoints at Week 8 and move to 
further endpoints.
Rationale for change
Endpoints at Week 8 are changed from secondary 


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endpoints to further endpoints, because initial data 
indicate a potential for slower onset of action for 
this MoA.
Section to be changed
5.5.1 Biochemical and cellular biomarkers
Description of change
Correction of “Week 8” and “Week 12”, i.e. 
spelling with capital letter.
Rationale for change
These are administrative changes to correct 
typographical errors.
Section to be changed
5.5.1 Biochemical and cellular biomarkers
Description of change
Add information that biomarker assay analysis will 
be performed in a staged approach.
Rationale for change
Biomarker assay analysis is updated.
Section to be changed
7.1 STATISTICAL DESIGN - MODEL
Description of change
Update information for primary endpoint at Week 
12 instead at Week 8.
Rationale for change
Primary endpoint is changed to Week 12 instead 
Week 8, because initial data indicate a potential for 
slower onset of action for this MoA. Week 12 is 
now a project standard time-point for primary 
efficacy measurement.
Section to be changed
7.2 NULL AND ALTERNATIVE HYPOTHESIS
Description of change
Update information for primary endpoint at Week 
12 instead at Week 8.
Rationale for change
Primary endpoint is changed to Week 12 instead 
Week 8, because initial data indicate a potential for 
slower onset of action for this MoA. Week 12 is 
now a project standard time-point for primary 
efficacy measurement.
Section to be changed
7.3 PLANNED ANALYSES
Description of change
Update information for primary endpoint at Week 
12 instead at Week 8.
Rationale for change
Primary endpoint is changed to Week 12 instead 
Week 8, because initial data indicate a potential for 


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slower onset of action for this MoA. Week 12 is 
now a project standard time-point for primary 
efficacy measurement.
Section to be changed
7.3.1 Primary endpoint analyses
Description of change
Update information for primary endpoint analysis 
according to method of Reeve.
Rationale for change
Primary endpoint analysis is updated.
Section to be changed
7.4 INTERIM ANALYSES
Description of change
Update information for DMC, i.e. now fully 
external DMC.
Rationale for change
DMC is changed from a partially external to a fully 
external DMC.
Section to be changed
7.7 DETERMINATION OF SAMPLE SIZE
Description of change
Update information for primary endpoint at Week 
12 instead at Week 8.
Rationale for change
Primary endpoint is changed to Week 12 instead 
Week 8, because initial data indicate a potential for 
slower onset of action for this MoA. Week 12 is 
now a project standard time-point for primary 
efficacy measurement.
Section to be changed
9.1 PUBLISHED REFERENCES
Description of change
Update references.
Rationale for change
One reference is added, one reference is deleted. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11253289
4.0
clinical-trial-protocol-version-04
Proof-of-concept study of BI 655130 add-on treatment in patients with
mild-to-moderately active ulcerative colitis during TNF inhibitor therapy.
Author-Clinical Trial Leader
05 Mar 2019 15:16 CET
Approval-Therapeutic Area 
05 Mar 2019 20:53 CET
Approval-Team Member Medicine
05 Mar 2019 20:58 CET
Approval-Biostatistics
06 Mar 2019 04:16 CET
Approval-Clinical Pharmacokinetics
06 Mar 2019 14:11 CET
Verification-Paper Signature
Completion
13 Mar 2019 07:54 CET


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11253289
4.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
C28709494-03
BI Trial No.:
1368-0010
Title:
Proof-of-concept study of BI 655130 add-on treatment in patients 
with mild-to-moderately active ulcerative colitis during TNF 
inhibitor therapy
Including Protocol Amendment 3 [c11253289-04]
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone: 
Fax: 
Date of statistical 
analysis plan:
04 March 2020 REVISED
Version:
3.0
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2020 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.


Boehringer Ingelheim
Trial No: 1368-0010 – 3.0 (Final)
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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....................10
5.
ENDPOINTS .......................................................................................................12
5.1
PRIMARY ENDPOINT .....................................................................................12
5.2
SECONDARY ENDPOINTS.............................................................................12
Key secondary endpoints....................................................................................12
5.2.1
Secondary endpoints...........................................................................................12
5.2.2
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................18
6.1
TREATMENTS...................................................................................................18
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................19
6.3
SUBJECT SETS ANALYSED...........................................................................28
6.5
POOLING OF CENTRES .................................................................................32
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................32
Withdrawals ........................................................................................................32
6.6.1
Efficacy data........................................................................................................33
6.6.2
Safety data ...........................................................................................................34
6.6.3
PK data.................................................................................................................34
6.6.4
Biomarker data ...................................................................................................34
6.6.5
Time since first diagnosis ...................................................................................35
6.6.6
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................35
7.
PLANNED ANALYSIS......................................................................................38
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........39
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................41
7.3
TREATMENT COMPLIANCE........................................................................42


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7.4
PRIMARY ENDPOINT .....................................................................................42
Primary analysis of the primary endpoint........................................................42
7.4.1
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
7.4.2
primary endpoint ................................................................................................43
7.5
SECONDARY ENDPOINTS.............................................................................45
Key secondary endpoints....................................................................................45
7.5.1
7.5.1.1
Primary analysis of the key secondary endpoint(s) ..............................................45
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key 
secondary endpoint(s) ...........................................................................................45
(Other) Secondary endpoints.............................................................................45
7.5.2
7.7
EXTENT OF EXPOSURE.................................................................................49
7.8
SAFETY ANALYSIS..........................................................................................50
Adverse events.....................................................................................................50
7.8.1
Laboratory data ..................................................................................................53
7.8.2
Vital signs.............................................................................................................54
7.8.3
ECG......................................................................................................................54
7.8.4
Others...................................................................................................................55
7.8.5
8.
REFERENCES....................................................................................................56
10.
HISTORY TABLE..............................................................................................67


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Trial No: 1368-0010 – 3.0 (Final)
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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases...........................................................................18
Table 6.2: 1
Handling of iPDs..............................................................................................20
Table 6.3: 1
Subject sets analysed........................................................................................30
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs and
biomarker to visits for statistical analysis ........................................................36
Table 7.1: 1
Categories for summary of continuous variables.............................................40
Table 7.4.2: 1 Summary of all analyses to be performed for the primary endpoint................44
Table 7.5.2: 1 Summary of all analyses to be performed for the secondary endpoints...........46
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events 
Concepts...........................................................................................................52
Table 10: 1
History table .....................................................................................................67


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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
ALQ
Above limit of quantification
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BM-SAP
Biomarker Statistical Analysis Plan
BMI
Body mass index
BRAVE
BI RAVE®
BRPM 
Blinded Report Planning Meeting
CARE
Clinical data analysis and reporting environment
CHI3L1
Faecal chitinase 3-like-1
CR
Clinical remission
CRF
Case report form
CRP
C-reactive protein
CTC
Common Terminology Criteria
CTP
Clinical trial protocol
CTR
Clinical trial report
DBLM
DMC
Database lock meeting
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOS
End of Study
EOT
End of treatment


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Term
Definition / description
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials
FAS
Full analysis set
FLF
Faecal lactoferrin
F-NGAL
Faecal neutrophil gelatinase-associated lipocalin
HMGB1
High-mobility group box 1 protein
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IL
Interleukin
iPD
Important protocol deviation
IRT
KM
Interactive response technology
Kaplan-Meier
LD
Day of Last dose/infusion received
LLOQ
Lower limit of quantification
LOQ
Limit of quantification
MCS
Mayo Clinical Score
MedDRA
Medical Dictionary for Regulatory Activities
mESS
Modified Endoscopic Subscore
MPO
myeloperoxidase
MQRM
Medical quality review meeting
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
NRI
Non response imputation
NRI-IR
Non Response Imputation including rescue medication
OC
Observed cases
OC-IR
Observed cases including values after rescue medication
OR
Original results
pCR
Partial MCS remission
PD
Pharmacodynamic(s)
PG
Pharmacogenomic(s)


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Term
Definition / description
PGA
Physician Global Assessment
PK
Pharmacokinetic(s)
PPS
Per protocol set
PT
Preferred Term
PD
Protocol Deviation
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
RBS
Rectal Bleeding Subscore
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual effect period
RS
Randomized set
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SD
Standard deviation
SDL
Subject data listing
SFS
Stool Frequency Score
SMQ
Standardised MedDRA query
SOC
System Organ Class
tCR
Total clinical remission
TCM
Trial Clinical Monitor
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range
ULOQ
Upper limit of quantification
VAS
Visual analogue scale


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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 protocol, 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 Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomisation.
The screening of patients in the study was prematurely discontinued on February 4th, 2020. 
At that time, 22 patients had been randomized into the study and 15 patients had completed 
the trial. Five patients had completed through Week 12, but were still ongoing in the trial, and 
another two patients had not yet completed Week 12 and were still ongoing in the trial. There 
were no patients in the screening period. A decision was made that an early interim analysis 
of the Week 12 data would be done in order to discuss the results with both internal and 
external experts allowing for an early decision on the future of the project to be made.
The data cut-off for the interim snapshot of the database is February 4th, 2020. Of the five 
patients who have already completed Week 12 but are still ongoing, all five of them 
completed Week 12 prior to this cut-off date, leaving a total of 20 patients available for the 
interim analysis. The strategy for data cleaning in preparation for the interim snapshot of the 
database will be specified in a separate data cleaning plan.
The following data reporting strategy for safety and efficacy (along with any PK, ADA, and 
biomarker data which is available) is planned:
-
A selection of data up to the Week 12 visit is to be summarized (including, at a 
minimum, the primary and secondary endpoints, as well as adverse event data). 
As a consequence of trial termination and of the need for a rapid decision on the 
future of the project, this analysis will be performed using the data of the 20
patients who have completed/discontinued through Week 12 prior to the cut-off 
date. 
For further details on the subject sets thus defined, refer to Section 6.3. For further details on 
the data to be included into the Week 12 analysis, refer to Table 6.7: 1. Further specification 
on the safety summaries to be performed at the time of the interim database snapshot are 
specified in Section 7.8.1. A logistics and access plan, which will describe any measures used 
to protect the blind and integrity of the ongoing trial will be finalized prior to database 
snapshot and treatment unblinding.
In accordance with the CTP, a second interim database snapshot will be performed once all 
randomized patients complete/discontinue through Week 12. At this time, all displays as 


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Trial No: 1368-0010 – 3.0 (Final)
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described in this TSAP will be produced. The results from this analysis will be used for 
potential authority interactions, if applicable. 
A final analysis of the trial will be performed once all patients have completed the trial. For 
more details, please refer to Section 6.3.
Study data will be stored in a trial database within the BRAVE system. 
The statistical analyses will be performed within the validated working environment CARE, 
including
), 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). 


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses stated in the CTP (latest version) will be performed as planned with the 
following adaptations.
For within-project consistency, the following efficacy endpoints were modified, added or re-
named.
The further endpoint “Clinical response” and “Time to flare” were modified as follows: 

Clinical response (total MCS decrease from baseline ≥3 points, and by ≥30%; AND 
RBS decrease from baseline by ≥1 point, or abs. ≤1) at Week 8 and at Week 12

Time to flare was modified as time to suspected flare (increase in partial MCS by ≥2
from nadir)
The following endpoints were added to the list of further endpoints:

Partial MCS response (Partial MCS (i.e. excluding mESS) decrease from baseline ≥2
points; AND RBS decrease from baseline by ≥1 point, or absolute value ≤1) over time

Complete remission (Robarts Histology Index ≤ 6 and mESS=0) at Weeks 8 and 12

Endoscopic remission (mESS=0) at Week 8 and at Week 12

Percent change in faecal lactoferrin (FLF) at all measured time points as compared to 
baseline

Change from baseline in SFS by visit (calculated as the average of the last 3 SFS 
measurements used in the derivation of the partial Mayo score)

Change from baseline in RBS by visit (calculated as the average of the last 3 RBS 
measurements used in the derivation of the partial Mayo score)
The following endpoints have been renamed as below (see also Table 9.2.5: 1):
Primary endpoint:

“Mucosal healing” at Week 12 has been renamed “Endoscopic improvement” at 
Week 12
Secondary endpoints:

“Clinical remission” at Week 12 has been renamed “Total clinical remission (tCR)” at 
Week 12

“Modified clinical remission” at Week 12 has been renamed “Clinical remission 
(CR)” at Week 12
Further endpoints:

“Clinical remission” at Week 8 has been renamed “Total clinical remission (tCR)” at 
Week 8

“Modified clinical remission” at Week 8 has been renamed “Clinical remission (CR)” 
at Week 8


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
“Partial clinical remission” at Week 8 and at Week 12 has been renamed “Partial 
MCS remission (pCR)” at Week 8 and at Week 12
Subsets of the subject sets (see Section 6.3) are now defined which include only those 
patients who completed/discontinued through Week 12 prior to the cut-off date February 4th, 
2020. These subsets will be used for the reporting of the outputs at the time of the first 
interim database snapshot.
The Reeve method for calculating confidence intervals was removed from the analysis plan 
in Section 7 due to low enrollment.
The subgroup analysis was expanded to include the concomitant use of steroids (yes/no) and 
prior TNFi failure (yes/no) (see Section 6.4).


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5.
ENDPOINTS
For all endpoints and unless explicitly specified otherwise, Week 8 refers to visit V5 using 
extended time windows as defined in Table 6.7: 1.
For all endpoints and unless explicitly specified otherwise, Week 12 refers to EOT visit using 
extended time windows as defined in Table 6.7: 1.
For handling of missing data and corresponding sensitivity analyses, see Section 6.6.
5.1
PRIMARY ENDPOINT
Endoscopic improvement (MCS mESS ≤1) at Week 12 is the primary endpoint.
Derivation of the mESS is described in Section 9.2: 1.
5.2
SECONDARY ENDPOINTS
Key secondary endpoints
5.2.1
Not applicable – there are no key secondary endpoints for this trial.
Secondary endpoints
5.2.2
The secondary endpoints are listed below.

Treatment emerging adverse events

Total Clinical remission (tCR) based on Mayo score (total MCS ≤2 points, and all 
subscores ≤1 point) at Week 12

Histological remission (Robarts (RHI) score ≤6) at Week 12

Clinical remission (CR) based on Mayo score (total modified MCS ≤2 and: RBS =0, 
SFS =0 or 1 and drop ≥1 from baseline, AND mESS ≤1) at Week 12
Derivation of tCR, CR, and Histological remission is described in Section 9.2.


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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, see Section 4 of the CTP.
All patients will receive either intravenous doses of 1200mg of BI 655130 solution for 
infusion (at Weeks 0, 4 and 8), or placebo.
The following study phases are defined:
Table 6.1: 1
Flow chart of analysis phases
Study analysis 
phase
Description
Start (included)
End (included)
Screening phase
Screening
Earliest of: i) Date of informed
consent; ii) 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 EOS visit 
(Week 36 visit); ii) last contact 
date on End of Study 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 off-treatment period (i.e. Follow-up phase) only exists if the trial completion date is after the date of end of last 
infusion + 140 days.
The first interim database snapshot analysis will be performed based on the randomized
patients who have completed/discontinued through the planned first 12 weeks of the trial up 
to the cut-off date, February 4th, 2020. For a description of the subject sets to be analysed, 
see Section 6.3. The following data will be used in this analysis:

Selected summaries of the 12-week data will be performed up to the minimum of the 
(analysis-specific data cut-off; study day 99), unless otherwise specified.
The second interim database snapshot, to be performed once all randomized patients have 
completed/discontinued through the planned first 12 weeks of the trial (per CTP 
specification), will use the following data:

All 12 weeks of data will be summarized up to the minimum of the (analysis-specific 
data cut-off; study day 99), unless otherwise specified.
The final analysis of the trial will be performed once all patients have completed the planned 
36 weeks of trial; results will be summarized including all on-treatment data from the trial.


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The selection of data for presentation by visit in these analyses is described in Table 6.7: 1.
Treatment groups for the analysis will be labelled as follows:

"Placebo"

"Speso 1200mg IV q4w"

"Overall Total" (across all arms), where appropriate.
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 (3). The following 
table contains the categories which are considered to be iPDs in this trial. If the data show 
other iPDs, for example, based on monitor visits to the sites, then 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 randomized set.


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Table 6.2: 1
Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
18-75 years, males or females (at Visit 1 
and 2)
LABEL:
Age beyond 18-75.
IC01
Also check versus derived 
age for patient.
None
A1.02
Body weight ≤120 kg (at Visit 1 and 2)
LABEL:
Weight beyond 120kg.
IC02
Also check versus reported 
body weight for patient
None
A1.03
Diagnosis of ulcerative colitis ≥5 months 
prior to screening by clinical and 
endoscopic evidence and corroborated 
by a histopathology report.
LABEL:
Diagnosis too recent / insufficiently 
documented.
IC03
Also check derived time 
since diagnosis for patient
None
A1.04
Receiving their TNFi treatment with 
infliximab (INF) with doses unchanged 
for ≥4 months prior to randomisation 
and detectable drug trough levels in 
blood; or adalimumab or golimumab 
with doses unchanged for ≥2 months 
prior to randomisation and detectable 
drug trough levels in blood
LABEL:
TNFi treatment changed / not detectable.
IC04
PPS
A1.05
Mild or moderate disease activity, 
defined as: 
Total Mayo Score (MCS) (≤10), with
-
modified endoscopic subscore 
(mESS) ≥2, AND
-
disease extending 5 cm or more 
from anal verge
LABEL:
Disease activity not mild or moderate.
IC05
Also check derived total 
MCS and mESS at baseline, 
and distance from anal verge 
at baseline
PPS
A1.06
If patients receive concurrent UC 
treatments, these need to be on stable 
doses.
LABEL:
UC treatment not on stable dose.
IC06 
Also manually review 
concomitant medications as 
use of concurrent UC 
treatment.
If patients receive unstable 
dose of probiotics, they will 
not be excluded from PPS 
PPS


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Table 6.2: 1 (cont’d) Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
A1.07
Patients with extensive colitis of >10 
years duration or family history of 
colorectal cancer or personal history of 
increased colorectal cancer risk must 
have had an negative colorectal cancer 
screening within <1 year prior to 
screening (otherwise to be done during 
screening colonoscopy).
LABEL:
Increased risk for colorectal cancer
IC07
None
A1.08
Women of childbearing potential 
(WOCBP) and men able to father a child 
must use highly effective methods of 
birth control per ICH M3 (R2) that result 
in a low failure rate of less than 1% per 
year when used consistently and 
correctly.
LABEL:
Contraception methods not used.
IC08
None
A2
Exclusion Criteria
A2.01
Extensive colonic resection, subtotal or 
total colectomy
LABEL:
Extensive resection, or colectomy.
EC01
None
A2.02
Ileostomy, colostomy, or known fixed 
symptomatic stenosis of the intestine
LABEL:
Ileostomy, colostomy, or stenosis.
EC02
None
A2.03
Prior use of more than two different 
TNF inhibitor or vedolizumab
LABEL:
Use of more than two different TNF 
inhibitors or vedolizumab.
EC03
Also check the historical 
medication 
PPS
A2.04
Any treatment limiting safety or 
tolerability issue of the concurrent TNF 
inhibitor
LABEL:
Treatment limiting issue of TNFi. 
EC04
PPS
A2.05
Concurrent treatment with rectal 5-ASA 
compounds, parenteral or rectal 
corticosteroids (incl. budesonide) within  
2 weeks, any investigational drug within 
12 weeks or 5 half-lives, whatever is 
longer, or any prior dose of natalizumab 
or rituximab prior to screening
LABEL:
Co-treatment not as allowed.
EC05
PPS


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Table 6.2: 1 (cont’d) Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
A2.06
Patients who must or wish to continue 
the intake of restricted medications (see 
CTP Section 4.2.2.1) or any drug 
considered likely to interfere with the 
safe conduct of the trial
LABEL:
Use of restricted medication.
EC06
PPS
A2.07
Evidence of infection with C. difficile or 
other intestinal pathogen <28 days prior 
to screening
LABEL:
Infection with intestinal pathogen.
EC07
PPS
A2.08
Currently require or are anticipated to 
require surgical intervention for UC
LABEL:
Requires surgical intervention for UC.
EC08
PPS
A2.09
Colonic moderate or severe mucosal 
dysplasia 
LABEL:
Colonic mucosal dysplasia.
EC09
None
A2.10
Colonic adenomas (unless properly 
removed)
LABEL:
Colonic adenomas.
EC10
None
A2.11
Primary sclerosing cholangitis
LABEL:
Primary sclerosing cholangitis.
EC11
None
A2.12
Faecal transplant ≤6 months before 
screening
LABEL:
Faecal transplant within 6 months. 
EC12
None
A3
Infectious Disease Exclusion Criteria
A3.01
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)
LABEL:
Increased risk of infectious 
complications. 
EC13
None
A3.02
Active or latent TB (Patients with 
positive QuantiFERON TB test are 
excluded. Patients with suspected false 
positive or undeterminable 
QuantiFERON TB result may be re-
tested)
LABEL:
Active or latent TB.
EC14
None


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Table 6.2: 1 (cont’d) Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
A3.03
Any severe infection <30 days prior to 
screening, including chronic or acute 
hepatitis B or C infection
LABEL:
Severe infection within 30 days.
EC15
None
A4
General Exclusion Criteria
A4.01
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
LABEL:
Malignancy within last 5 years.
EC16
None
A4.02
Major surgery (major according to the 
investigator’s assessment) performed 
within 12 weeks prior to randomisation 
or planned during the study, e.g. hip 
replacement.
LABEL:
Recent or planned major surgery.
EC17
None
A4.03
Pathological safety lab parameters: 
haemoglobin <8.5 g/dL, total white 
blood count (WBC) <3500 cells/µl, 
neutrophils <1000 cells/µl, thrombocytes 
<75.000/µl, albumin <30 g/l, creatinine 
≥2 mg/dL, aspartate aminotransferase 
(AST) or alanine aminotransferase 
(ALT) >2 x ULN, total bilirubin >1.5 x 
ULN (patients with Gilbert’s syndrome 
are not excluded).
LABEL:
Pathological safety lab parameters 
abnormal.
EC18
Also check corresponding 
safety lab parameters at 
baseline
None
A4.04
Currently  enrolled in another 
investigational device or drug study, or 
less than 12 weeks (or 5 half-lives, 
whichever is greater) since ending 
another investigational device or drug 
study(s), or receiving other 
investigational treatment(s)
LABEL:
Recent enrollment in other study.
EC19
None
A4.05
Women who are pregnant, nursing, or 
who plan to become pregnant while in 
the trial
LABEL:
Pregnant or nursing.
EC20
None


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Table 6.2: 1 (cont’d) Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
A4.06
Evidence of a current or previous 
disease, medical condition (including 
chronic alcohol or drug abuse) other 
than ulcerative colitis, 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
LABEL:
Unreliable protocol adherence or 
compromised safety.
EC21
None
B
Informed consent
B.01
Informed consent 
not available
LABEL:
IC not available.
Based on direct assessment, not simply the tick 
box 
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 
analyses
#
B.02
Informed consent 
too late
LABEL:
IC too late.
Informed consent date was after Visit 1
None
C
Trial medication 
and 
randomisation
C1
Incorrect trial 
medication
C1.01
Incorrect 
medication received 
by patients in 
placebo arm
Placebo patient who received >= 1 vial (150mg) 
of BI 655130 verum overall /at any dosing visit
Can only be finally judged after DBL since 
unblinding information is required
PPS
C1.02
Incorrect 
medication received 
by patients in BI 
arm
BI patient who received BI dose not matching 
treatment that was randomized would be 
considered an iPD.
Patients randomized to BI 655130 1200mg 
q4w, but received any >=3 vials (450mg) of BI 
655130 verum different from planned at any 
visit or overall
Can only be finally judged after interim DBL 
since unblinding information is required
PPS


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Table 6.2: 1 (cont’d) Handling of iPDs
Category / 
Code
Description
Comments
Excluded 
from1
C2
Non-compliance
C2.01
Non-compliance with study drug 
intake- - administered dose too low
Administered overall infusion volume 
is less than 80% of the total planned 
volume.
The total planned volume is

60mL if discontinuation up to 
and including visit V2

120mL if discontinuation up to 
and including V4

180mL if discontinuation up to 
and including V5
The total planned volume overall is 
180 mL.
PPS
C2.02
Non-compliance with study drug 
intake- - administered dose too high
Administered overall infusion volume
is greater than 120% of the total 
planned volume
The total planned volume is

60mL if discontinuation up to 
and including visit V2

120mL if discontinuation up to 
and including V4

180mL if discontinuation up to 
and including V5
The total planned volume
overall is 180 mL.
None
C3
Randomization not followed
C3.01
Treated without randomisation
LABEL:
Treated without randomisation.
Patient treated according to eCRF, 
but not randomised according to 
IVRS.
RS(i), 
SAF(i), 
FAS(i), 
PPS
C4
Medication code broken
C4.01
Medication code broken 
inappropriately
LABEL:
Medication code broken 
inappropriately
Medication code was broken prior to 
Week 12 for no valid reason.
Final decision at the DBL meeting 
for the Week 12 analysis based on 
medical judgment.
PPS
#
D
Concomitant medication
D1
Previous medication
D1.01
Washout of previous medication too 
short
LABEL:
Washout too short.
PPS
#
D2
Prohibited medication use
D2.01
Use of restricted medication as per CTP 
Table 4.2.2.1: 1 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
PPS
#


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Table 6.2: 1 (cont’d) Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
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
None
#
D3
Change in Background medication
Note: Background 
medication is split into:
concurrent UC treatments
Background TNFi medi-
cation (e.g. infliximab)
D3.01
Concurrent UC treatments need to be on 
stable doses prior or up to Week 12:
Oral 5-ASA compounds
LABEL:
Oral 5-ASA compounds not stable 
Medical review, per 
investigator’s judgement, 
any dose increase used as 
rescue treatment due to 
disease worsening or not 
improved, this will not be 
considered as iPD. Only 
dose increase not as rescue 
use will lead to exclusion 
from PPS
PPS
#
D3.02
Concurrent UC treatments need to be on 
stable doses prior or up to Week 12:
Oral corticosteroids
LABEL:
Oral corticosteroids not stable 
Medical review, per 
investigator’s judgement, 
any dose increase used as 
rescue treatment due to 
disease worsening or not 
improved, this will not be 
considered as iPD. Only 
dose increase not as rescue 
use will lead to exclusion 
from PPS
PPS
#
D3.03
Concurrent UC treatments need to be on 
stable doses prior or up to Week 12:
Azathioprine, 6-mercaptopurin or 
methotrexate
LABEL:
Azathioprine 6-mercaptopurin or 
methotrexate not stable 
Medical review, per 
investigator’s judgement, 
any dose increase used as 
rescue treatment due to 
disease worsening or not 
improved, this will not be 
considered as iPD. Only 
dose increase not as rescue 
use will lead to exclusion 
from PPS
PPS
#


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Table 6.2: 1 (cont’d) Handling of iPDs
# PV will be detected manually
1For specification on definition of analysis sets, refer to Section 6.3. Analysis of efficacy data according to the PPS will not 
be done at the time of the 1st interim database snapshot.
Source: BI reference document: “Identify and Manage Important Protocol Deviations (iPD)” [ 001-MCS-40-413] (2).
Category / 
Code
Description
Comments
Excluded from1
D3.04
Concurrent UC treatments need to be on 
stable doses prior or up to Week 12:
Probiotics (e.g. S. boulardii) 
LABEL:
Probiotics not stable 
Medical review
None
#
D3.05
Any dose change in background TNF 
inhibitor medication when not provided as a 
rescue treatment to stabilize a worsening 
disease condition – prior to or up to Week 12 
LABEL:
Dose change in background TNFi prior 
Week 12
Dose change in background 
TNF inhibitor therapy is 
not allowed per CTP 
section 4.2.2 from 
Screening through End of 
Treatment. 
PPS
#
D3.06
Any dose change in background TNF 
inhibitor medication when not provided as a 
rescue treatment to stabilize a worsening 
disease condition – after Week 12
LABEL:
Dose change in background TNFi after 
Week 12
Dose change in background 
TNF inhibitor therapy is 
not allowed per CTP
section from Screening 
through End of Treatment. 
None
#
E
Missing data
<not specified>
F
Study specific analysis
<not specified>
F1
Other trial specific violation
<not specified>
F1.01
Incomplete diagnosis of ulcerative colitis 
LABEL:
Incomplete diagnosis of UC
Medical review
PPS
#
F1.02
Primary endpoint assessment more than 2 
weeks before planned day
LABEL:
Primary endpoint assessment > 2 weeks
before planned.
PPS
F2
Certain violations of procedures used to 
measure primary or secondary efficacy 
data
<not specified>
G
Other safety related violations
G1
Pregnancy test not done for woman of child 
bearing potential or pregnant during study
LABEL:
Pregnancy test not done
Pregnancy test not done at 
any visit where such is 
scheduled 
None


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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 the informed consent form. It will be 
used for analyses of patient disposition.

Randomized set (RS): 
This patient set includes all patients who were randomized into the trial. 
It will be used for analyses of patient disposition and patients with iPDs.

Safety analysis set (SAF): 
This patient set includes all randomized patients who received at least one dose of 
study drug. It will be the main analysis set for presentation of safety. Treatment 
assignment will be analyzed according to the actual treatment.
For the primary analysis to be performed once all patients have completed through the Week
12 visit, and the final trial analysis, the following additional patient sets will be defined.

Full analysis set (FAS): 
This patient set includes all patients in the SAF who had a baseline measurement 
available for the primary endpoint. Treatment assignment will be as randomized. This 
is the main analysis set for presentation of efficacy.

Per protocol set (PPS): 
This patient set includes all patients in the FAS who adhered to the CTP without any 
iPDs which are flagged for exclusion from the PPS in the table above.
This set will be used for sensitivity analysis on the primary efficacy endpoint.
For the first interim database snapshot, modified versions of the ES, RS, SAF, and FAS will 
be defined: the ESi, RSi, SAFi, and the FASi. Each of the modified patient sets will include 
those patients from the original set who completed/discontinued through the Week 12 visit on 
or prior to the cut-off date (see Section 3). Each of these modified patient sets will be handled 
according to the same procedures used to derive the full patient sets.
For the analyses to be performed at the time of the second interim database snapshot (when 
all randomized patients have completed/discontinued through Week 12), the ES, RS, SAF, 
FAS, and PPS will be used. Corresponding analyses performed at the time of the first interim 
database snapshot will use the ESi, RSi, SAFi, and FASi.
For the final analysis, the ES, RS, SAF, FAS, and PPS will be used.
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 DBLM. A separate DBLM will be held 
prior to each database snapshot of this trial.


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Handling of Treatment Misallocations in Analysis Sets
If a subject is randomized but not treated, by definition such patients are excluded from FAS 
and PPS for efficacy analysis and excluded from SAF for safety analyses as no study 
medication was taken. However, they will be included in RS and reported under their 
randomized treatment group for sensitivity efficacy analysis. Please refer to Section 7.4 for 
more details.
If a subject is treated but not randomized, they will be excluded from both efficacy analysis 
and safety analysis by definition. However, subjects under such circumstances will be 
summarized in the final clinical trial report.
If a subject is randomized but took incorrect treatment during the study, then:
-
For efficacy analyses according to FAS, PPS, and RS, they will be reported under their 
randomized treatment groups. But if the subject has an iPD as defined in Section 6.2, 
then they will be excluded from PPS for efficacy analysis. 
-
For safety analyses using the SAF, 
•
if a subject is randomized with BI 655130 1200mg q4w treatment, then they will be 
reported under their randomized treatment group for safety analysis because the 
overall safety profile will be driven by the amount of drug received in totality over 
the entire treatment duration. It is not likely that the safety profile will deviate from 
the planned treatment regimen if the subject receives only one or two vials of the 
incorrect medication during only some dosing occasions. The subject will be 
assigned to the placebo treatment group only if they don’t receive any BI 655130
during the entire treatment period.
•
if a subject is planned with placebo treatment group, then they will be reported under 
placebo if no treatment with BI 655130 is received at any visit. If the subject
receives > = 1 vial (> = 150mg) of BI 655130 during the entire treatment duration, 
then they will be reported as BI 655130 1200mg treatment group.
Table 6.3: 1 (first interim database snapshot), and Table 6.3: 2 (second interim database 
snapshot and final trial snapshot) illustrate the data sets which will 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 see Section 6.6.


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Table 6.3: 1
Subject sets analysed (first interim database snapshot)
Patient set
Class of endpoint
RSi
ESi
SAFi
FASi
Disposition
OR
OR
Compliance 
OR
Exposure
OR
iPDs
OR
Demographic/baseline 
characteristics
OR
Primary endpoint
NRI*, OC*
NRI, 
OC
Secondary efficacy endpoints
NRI*, OC*
NRI,
OC
Further efficacy endpoints
All: OC
Binary: NRI
Continuous: MMRM
PK concentr.& ADA&DNA
OC (if available)
Biomarker endpoints
OC (CRP, FLF, 
FCP. Others: if 
available)
Safety parameters
OR,
OC-IR
Use of rescue medication
OR
For explanation of the different approaches with regard to missing data see Section 6.6.
OR = original results.
NRI = No Response Imputation excluding values after rescue medication taken
OC = observed cases excluding values after rescue medication taken
OC-IR = observed cases including also values after rescue medication taken
LOCF = Last observation carried forward
*only when RS are different from FAS
At the time of the first interim database snapshot, only the primary analysis on each efficacy 
endpoint will be done. All safety displays will be produced. No inferential subgroup analyses
will be performed. 


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Table 6.3: 2
Subject sets analysed (second interim database snapshot and final trial 
snapshot)
Patient set
Class of endpoint
RS
ES
SAF
FAS
PPS
Disposition
OR
OR
Compliance 
OR
Exposure
OR
iPDs*
OR
Demographic/baseline 
characteristics
OR
Primary endpoint
NRI**, OC**
NRI, 
OC
NRI,
OC
Secondary efficacy endpoints
NRI**, OC**
NRI,
OC
Further efficacy endpoints
All: OC
Binary: NRI
Continuous: MMRM
PK concentr.& ADA&DNA
OC
Biomarker endpoints
OC
Safety parameters
OR,
OC-IR
Use of rescue medication
OR
For explanation of the different approaches with regard to missing data see Section 6.6. 
OR = original results.
NRI = No Response Imputation excluding values after rescue medication taken
OC = observed cases excluding values after rescue medication taken
OC-IR = observed cases including also values after rescue medication taken
LOCF = Last observation carried forward
* any patient with the iPD of treated but not randomized (C3.02) will only be listed in the footnote of the iPD table.
**only when RS are different from FAS
At the time of the second interim and final trial database snapshots, all analyses per TSAP are 
scheduled to be performed.


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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.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Section 7.5 of the CTP describes the handling of missing data.
The original results (OR) approach implies the presentation of data exactly as observed, i.e., 
not using time windows and not setting values to missing. 
OR analysis will be performed on parameters and endpoints that are either not affected by 
patients’ rescue medication use (e.g., plasma concentration level of BI 655130, or rescue 
medication use itself), or, if it is not meaningful to apply any imputation rule for the 
replacement of missing values.
Withdrawals
6.6.1
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.


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Efficacy data
6.6.2
Based on the different reasons for a subject to have missing data, various approaches will be 
used to assess the impact of missing data on the different efficacy endpoints of this trial. The 
approaches to be applied are described below.
Missing data imputations at the primary analysis at Week 12, that is, once all patients have 
achieved the Week 12 visit, will be performed using all available on-treatment data observed 
up to the respective analysis cut-off date. 
Binary efficacy endpoints
For all binary endpoints (i.e. endpoints that are either 1 (patient responded) or 0 (patient did
not respond)), the following will be performed as the primary imputation approach (analysis 
type: Non Response Imputation [NRI]):
1. If there are data at visits both before and after the visit with a missing outcome, 
then impute as success only if both neighbouring visits also represent a success
(independent of whether the preceding and following observations were selected 
for analysis based on time windows described in Section 6.7);
2. Otherwise, impute as a failure to achieve a response 
If a patient takes a rescue medication as defined in Section 5.4.5 for the treatment of 
ulcerative colitis prior to observing the primary endpoint for this trial, then all data 
subsequent to rescue treatment will be considered to represent a failure to achieve a response. 
Further approaches to the handling of missing data will be performed as follows:
Observed cases (analysis type: OC) approach will be used as a sensitivity analysis and 
will include all collected data, 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).
Observed cases including rescue (analysis type: OC-IR) approach will be used as a 
further sensitivity analysis and is an extension of the OC approach which includes all 
values which were measured after rescue medication intake.
Missing data after premature discontinuation will not be imputed when following the OC and 
OC-IR approach.
Continuous further efficacy endpoints
For further efficacy endpoints which are continuous in nature, the use of a restricted 
maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach, if 
applicable, will ensure that missing data are handled implicitly, via a missing at random 
assumption, by the statistical model.


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The continuous further efficacy endpoints will also be summarized by visits descriptively via 
the OC approach (described above for the binary efficacy endpoints).
Safety data
6.6.3
From CTP Section 7.5: With respect to safety evaluations, it is not planned to impute 
missing values.
For safety data that are displayed by time point (or visit) of measurement, the OC-IR 
approach will be used.
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 BI-KMED-BDS-HTG-0035: "Handling of missing 
and incomplete AE dates" (4)).
Partial start and stop dates for concomitant medications and background, rescue, as well as
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 that year (or to the patient's trial completion date, if it is earlier than the 
31st of December of that year).
•
If the day of the start date is missing the start date is set to the 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 the 1st of
January of that year (except for rescue medication, where the first dosing day/month will 
be used if the 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.
PK data
6.6.4
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5). 
Biomarker data
6.6.5
Missing biomarker data (NOS - no sample, NOR - no valid result, NOA - not analysed) will 
not be imputed. 


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For disease specific (protein) markers (from serum or stool samples) the following handling 
of data below or above the limit of quantification will be applied:
•
BLQ data will be replaced by 0.5 · LLOQ. Hereby LLOQ will be the maximum used 
lower reference limit for classification of BLQs. All values lower than LLOQ will be 
imputed (regardless of whether they are classified as BLQ or not).
•
ALQ data will be replaced by ULOQ, if ULOQs are available and are greater than 
observed study values (i.e. the highest solution was applied for the measurement). 
Otherwise, ALQ data will be excluded from the analysis.
The OC approach (see Section 6.6.2) will be used to present the data.
The handling of other biomarkers, e.g. RNA expression, will be specified in a separate
document.
Time since first diagnosis
6.6.6
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows:

If the year of first diagnosis is unknown, then time since first diagnosis will be set to 
missing.

If day and month of the first diagnosis are unknown, then time since first diagnosis will 
be calculated as if diagnosed on the 30th of June of that year.

If only the day of the first diagnosis is unknown, then 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 the date and time and that were 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 that were 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 the start of administration of the trial treatment will be considered 
either on- or off-treatment values based on the definition in Section 6.1, and will be assigned 
to visits for statistical analysis, if applicable, as defined in Table 6.7: 1.
Neither analysis of AE data, concomitant medication, non-drug therapies, nor use of rescue 
medication will be based on visits. Therefore, no assignment to time windows will be 
necessary.


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Frequency tables for AE data will be using on-treatment data only up to the time of the 
planned trial analysis (Week 12, or Week 36). Frequency tables for concomitant medication, 
non-drug therapies, and rescue medication will be based on all available data up to the time 
of the planned trial analysis (Week 12, or Week 36).
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.
A graphical analysis of the ALT and total bilirubin will be performed (so called eDISH plot) 
based on the available data obtained during the on-treatment period.
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 V2). These extended time windows are defined in
Table 6.7: 1.
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs and
biomarker 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 -8
n/a
V1b
Screening
- 28 to -6
n/a
V2
Baseline
Day 1
+/- 0
1 A
1 A
≤1 A
1 A
On-treatment data only
V3
Week 2
Day 15
+/- 2
13
17
2
22
V4
Week 4
Day 29
+/- 3
26
32
23
43
V5
Week 8
Day 57
+/- 3 
54
60
44
71
EOT
Week 12/EoT
Day 85
+/- 4 
81
89
72
99*
FU1
Week 16/FU1
Day 113
+/- 4 
109
117
100
134
FU2
Week 22/FU2
Day 155
+/- 4 
151
159
135
Min(175, 
LD+140)
All data (on- and off-treatment)
FU3 B
Week 28/FU3
Day 197
+/- 4 
193
201
176
225
EOS B
Week 36/EOS
Day 253
+/- 4
249
257
226
Day of last 
follow up
valueB
For primary analysis for efficacy (Week 12) – Data after minimum (cut-off C , Day 99) will not be used for 
analyses
For final analysis – Data after (LDD + 140) will not be used for any planned on-treatment analyses
Days are counted relative to the day of first 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 Day 1. Such data will be listed only.
B Note that measurements assigned to the Week 28/FU3 or Week 36/EOS visits but after LD+140 are intended 
to represent off-treatment (i.e., follow-up) measurements, as they are made after the end of the on-treatment 


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period.
C The cut-off date is not applicable for the final trial analysis.
D LD = Day of Last dose/infusion received
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, the later value 
will be selected. If there are two observations on the same day, then for vital signs the latest 
value (according to the date and time) will be selected, and for other endpoints the worst 
value will be selected.
Assignment of efficacy 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 "NRI" and the "OC" approaches defined in Section 6.6).
For visits without an assigned value based on time windows, a value will thereafter be 
imputed as defined in Section 6.6. Imputation of efficacy endpoints, when applicable, will be 
performed based on all available observations obtained, irrespective of whether the 
observation was selected in any time window.


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7.
PLANNED ANALYSIS
All efficacy analyses will be purely exploratory in nature. The following analyses are planned 
at different stages throughout the trial.

First Interim Database Snapshot – Week 12 Analysis 
The analysis will be performed using all randomized patients who completed/discontinued 
through the Week 12 visit on or prior to the cut-off date (see Section 3). A database snapshot 
will then be done. At this time, an interim analysis of the efficacy and safety data through 
Week 12 will be performed by the sponsor.
The individual patient cut-off date for inclusion of data into the analysis is the minimum of 
the analysis-specific cut-off date, or study day 99, as described in Table 6.7: 1.
The analyses for this snapshot will be performed using the subject sets of ESi, RSi, SAFi, and 
FASi (see Section 6.3).

Second Interim Database Snapshot – Week 12 Analysis (Primary Analysis for CTR)
The analysis will be performed using all randomized patients who completed/discontinued 
through the Week 12 visit. A database snapshot will then be done. At this time, a complete 
analysis of all efficacy, safety, and PK/Biomarker data will be done through Week 12, and 
will be performed by the sponsor.
The individual patient cut-off date for inclusion of data into the analysis is the minimum of 
the analysis-specific data cut-off, or study day 99, as described in Table 6.7: 1.
The analyses as described in Section 6.3 of this TSAP will be performed using the subject 
sets of ES, RS, SAF, FAS, and PPS.

Final analysis (Week 36)
The analyses of the entire efficacy, safety, and biomarker data collected through the full 36 
weeks of follow-up will be performed once all entered patients have completed the trial (up 
to EOS Visit); at that time point, a final database lock will be done and all on treatment data 
through Week 36 will be reported.
General Remarks
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (001-MCG-159) (10).
The individual values of all patients will be listed, including those collected during the off-
treatment period. 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 following standard descriptive statistical parameters will be displayed in summary tables 
for continuous variables:


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N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Q1
lower quartile
Median 
median
Q3
upper quartile
Max 
maximum
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline "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 group; unless otherwise specified, this includes all patients in the 
respective patient set whether they have non-missing values or not. Percentages will be 
rounded to one decimal place. The category missing will be displayed if and only if there are 
missing values. 
For the final trial analysis up to Week 36, displays of certain safety endpoints, such as AE,
will be produced only for the on-treatment period. Displays of endpoints presented by-visit, 
additional outputs, which include both on- and off-treatment data, will be produced at the 
time of update analysis after final DBL (see also Section 6.7). 
Disposition of the patient population participating in the trial will be summarised by 
presentation of the frequency of patients screened, entered, screened but not entered, treated, 
entered but not treated, who completed all doses of trial medication as planned, who 
completed the EOT visit, who completed the EOS visit, and who were prematurely 
discontinued, by reason. Disposition will be listed by country.
The frequency of patients with iPDs will be presented for the RS by treatment. The iPDs will 
be listed per patient indicating whether or not the iPD led to exclusion from patient sets 
analysed.
The frequency of patients in each of the different analysis sets will also be presented by 
treatment.
All Section 7 analyses described below are presented for the second interim database 
snapshot (based on all randomized patients) and the final analysis using the subject sets of 
ES, RS, SAF, FAS, and PPS. A sub-selection of these analyses will be performed at the time 
of the first interim database snapshot using the subject sets of ESi, RSi, FASi, and SAFi.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
Descriptive statistics will be presented by treatment for demographic parameters and baseline 
characteristics based on the FAS.


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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
< 65 years
≥ 65 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
Total MCS at baseline
< 4
4 to <6
6 to <8
8 to <=10


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7.2
CONCOMITANT DISEASES AND MEDICATION
Analyses of concomitant diseases and medication will be based on the FAS.
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.
Concomitant non-drug therapy will be coded according to the most recent version of 
MedDRA.
Concomitant diseases which are present at start of the study, as well as characteristics of the 
trial disease, will be descriptively summarized by treatment. 
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 by treatment. During the 
course of the study's on-treatment period, any changes in the pre-existing extra-intestinal 
diagnoses (improved or worsened) by visit (including as an overall on-treatment assessment), 
as well as the development of newly diagnosed extra-intestinal diagnoses will also be 
summarized.
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 study analysis 
phases).
Concomitant medication use (excluding rescue medication, historical medication for UC and 
background medication) will be summarised by treatment with frequency and percentage of 
patients by preferred name. Summaries will be presented for 

concomitant medication started any time prior to the Week 12 visit (for any patient with a 
missing Week 12 visit, available data will be summarized up to the end of the Week 12 
time window, see Table 6.7: 1).

concomitant medication started any time on or after the Week 12 visit, and prior to EoS.
The frequency and percentage of patients with historical medication for UC will be displayed, 
and by reason for discontinuation. In addition, the reason for discontinuation will also be 
presented by type of medication.
The frequency and percentage of patients taking any background medication for UC will be 
tabulated by type of background therapy. Further displays regarding changes in background 
medication during the on-treatment period will be summarized in Section 7.6.4.
Use of rescue medication will be summarised separately (see Section 7.6.4).


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Concomitant use of non-drug therapies will be summarised with frequency and percentage. 
Summaries will be presented for:

concomitant non-drug therapy started any time prior to the Week 12 visit (for any patient 
with a missing Week 12 visit, available data will be summarized up to the end of the 
Week 12 time window, see Table 6.7: 1).

concomitant non-drug therapy started any time on or after the Week 12 visit, and prior to 
EoS.
7.3
TREATMENT COMPLIANCE
Treatment compliance will be summarised overall and by visit via total volume infused (as a 
% of planned) for the FAS using descriptive statistics (N, mean, SD, minimum, median, and 
maximum). The volume infused (as a % of planned) is defined as the volume infused at a 
visit (in ml as recorded in the eCRF), divided by 60 ml (the volume the patient should have 
received), times 100.
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 number and percentage of patients with the following overall compliance categories will 
be presented: 

"<50% of planned", 

"50 to <80% of planned"

"80 to 100% of planned".
The number of patients who received a dose will be tabulated per visit.
7.4
PRIMARY ENDPOINT
The binary primary efficacy endpoint will be described using patient frequencies and 
percentages for the FAS (or its derivatives - see Section 6.3). The underlying mESS will be 
based on central reading - replacing missing values with results based on investigator 
assessment.
Primary analysis of the primary endpoint
7.4.1
The primary analysis of the primary endpoint will be based on Section 7.3.1 of the CTP. 
From CTP Section 7.3.1: The primary analysis of the unadjusted absolute risk difference 
versus placebo will be calculated simply as the difference in the observed proportion of 
patients with mucosal healing at Week 12, for the FAS. A 95% Newcombe confidence interval 
around this difference will also be provided.
The method to provide confidence intervals for single proportions will be based on the 
Wilson method (14). The method to provide confidence intervals for the unadjusted risk 


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differences is derived from the Newcombe method (15), and is constructed from the Wilson 
score confidence interval for each of the single proportions.
As described in Section 7.2 of the CTP, there will be no formal hypothesis testing performed 
in this trial.
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
7.4.2
endpoint
The further analysis of the primary endpoint will be based on Section 7.3.1 of the CTP as 
below. 
From CTP Section 7.3.1: Exploratory analyses of the primary endpoint will include, in the 
absence of model convergence issues due to occurrence of low cell frequencies, the difference 
in the proportion of patients with mucosal healing at Week 12 between BI 655130 and 
placebo, for the FAS, using a logistic regression approach with a logit link. Fixed 
classification effects will include treatment and presence or absence of use of infliximab 
(yes/no). The estimates from the logistic regression are on the logit scale, and the difference 
in proportions will be calculated as the difference between the predicted probabilities in the 
treatment groups on the original scale, with the confidence interval calculated using the 
cumulative distribution function method of Reeve.
Prior to the first interim database lock, it was decided that the Reeve confidence intervals will 
not be used due to low enrolment. 
The subgroup analysis will create three logistic regression models for the primary endpoint 
for the covariates listed in Table 6.4: 1. The SAS code for the logistic regression model is as 
follows:
proc logistic data=indata;
  class trt (ref="&_j.") / param=GLM;
  model resp = trtseq &covar. / link=LOGIT CovB;
  lsmeans trt / cl ILINK;
run;
Other analyses of the primary endpoint will include:

Sensitivity analyses utilizing different patients sets (such as the PPS), as well as 
alternative methods for the handling of missing data as described in CTP Section 7.5;

Exploration of the relationship between various demographic or baseline characteristics 
data and the primary endpoint will be performed via graphical methods as well as using 
a logit link with 
A separate logistic regression model for the primary endpoint with each of the following 
baseline covariates and including treatment as well as treatment-by-covariate interaction as 
fixed effects will be fit:


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Categorical: 
o Sex 
o Smoking status (previous/current or never)
Continuous:
o Age
o BMI
o Time to disease diagnosis
Parameter estimates from the logistic model will be presented. The estimated response rate 
for each treatment arm across the range of observed covariate values will be displayed 
graphically.
Note that exploratory and other analyses of the primary endpoint are planned to be performed 
at the time of the Week 12 primary analysis only, unless otherwise specified.
Table 7.4.2: 1 below summarizes the primary and further analyses as described above, 
together with the sensitivity analyses and subgroup analysis.
Table 7.4.2: 1 Summary of all analyses to be performed for the primary endpoint
Summary of analysis
Analysis
Analysis set
Imputation 
Approach
Analysis model
Primary analysis
FAS
NRI
Unadjusted absolute risk difference
Sensitivity (a) -1
RS*
NRI
Unadjusted absolute risk difference
Sensitivity (a) -2
FAS
OC
Unadjusted absolute risk difference
Sensitivity (a) -3
RS*
OC
Unadjusted absolute risk difference
Sensitivity (a) -4
PPS
NRI
Unadjusted absolute risk difference
Sensitivity (a) -5
PPS
OC
Unadjusted absolute risk difference
Further analysis
FAS
NRI
Adjusted risk difference via logistic 
regression
Subgroup analysis
FAS
NRI
Adjusted risk difference via logistic 
regression including different 
covariates
Note: 
For explanation of the different approaches with regard to missing data see Section 6.6. 
NRI = No Response Imputation excluding data after rescue treatment
OC = Observed Cases excluding data after rescue treatment
*Only when RS is different from FAS


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7.5
SECONDARY ENDPOINTS
Key secondary endpoints
7.5.1
This section is not applicable as no key secondary endpoints have been specified.
7.5.1.1
Primary analysis of the key secondary endpoint(s)
This section is not applicable as no key secondary endpoints have been specified.
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key secondary 
endpoint(s)
This section is not applicable as no key secondary endpoints have been specified.
(Other) Secondary endpoints
7.5.2
Analysis of secondary endpoints is described in Section 7.3.2 of the CTP.
From CTP Section 7.3.2: 
For the secondary binary endpoints, for the FAS, the unadjusted absolute risk difference 
versus placebo will be calculated and a 95% Newcombe confidence interval around this 
difference will also be provided.
A logistic regression analysis on the binary secondary efficacy endpoints, per the approach 
described for the primary endpoint, will also be done on the FAS. As defined for the primary 
endpoint, the method to provide confidence intervals for single proportions will be based on 
Wilson (14), and for unadjusted risk differences is derived from the Wilson method by 
Newcombe (15). 
Table 7.5.2: 1 below summarizes all of the analyses to be performed for the secondary
endpoints.


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Table 7.5.2: 1 Summary of all analyses to be performed for the secondary endpoints
Summary of analysis
Analysis
Analysis set
Imputation 
Approach
Analysis model
Planned analysis 
in CTP
FAS
NRI
Unadjusted absolute risk difference
Sensitivity-1
FAS
OC
Unadjusted absolute risk difference
Sensitivity-2
FAS
NRI
Adjusted risk difference via logistic 
regression
Sensitivity-3*
FAS
NRI
Unadjusted absolute risk difference
(worst case approach on SFS/RBS 
calculation)
Note: 
Standard approach of SFS/RBS calculation is applied unless otherwise specified.
*only applicable to the secondary endpoints of clinical remission and total clinical remission and the further endpoint of 
clinical response. 
For explanation of the different approaches with regard to missing data see Section 6.6. 
NRI = No Response Imputation excluding data after rescue treatment
OC = Observed Cases excluding data after rescue treatment


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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 [minutes] and the amount of treatment received [mg] (actual and weight based) will 
be summarised by descriptive statistics (N, mean, SD, minimum, median, maximum) per visit
and overall. The total duration of exposure [days), defined as the time from start of the first 
infusion to time of end of the last infusion plus one day, will also be displayed.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the SAF following BI standards. No 
hypothesis testing is planned.
For the first interim database snapshot analysis, selected safety data, such as AE listings and 
displays, beyond the Week 12 visit up to the earliest of the REP/cut-off date will be done for 
the SAFi (see Section 6.3). 
For the second interim database snapshot analysis (the primary analysis for the CTR), a 
similar approach will be taken as above for the first snapshot. The final analysis will include 
all safety data up to the end of the trial.
Adverse events
7.8.1
AEs will be coded with the most recent version of MedDRA. Patients will be analysed 
according to the actual treatment received.
The exposure adjusted incidence rate (per 100 subject years) of a selected treatment emergent
adverse event is defined as the number of subjects experiencing the adverse event per
treatment group during time at risk divided by the total time of subjects at risk in that
treatment group to contribute the event to the analysis multiplied by 100 (per 100 subject
years), where:
Time at risk [subject years] = (date of onset of TEAE – study drug start date + 1) 
/365.25
If, for a subject, the selected treatment emergent adverse event didn’t occur then the time at
risk, for the analysis phases according to randomized treatment, will be censored at the 
minimum of either date of death, last contact date per EoS page, or randomized drug stop 
date + 140 days. For each selected treatment emergent AE, the exposure adjusted incidence 
rate will be calculated as:
Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with AE 
/Total AE-specific time at risk [subject years].
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
exposure adjusted incidence rates (per 100 subject years) as well as 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) across all treatment arms, or, if a 
total column across all arms is not foreseen in the table, by total frequency (within system 
organ class) within the BI arm.
For details on summarization of AE data, please refer to "Handling and summarization of 
adverse event data for clinical trial reports and integrated summaries" (7) [001-MCG-156] 
and BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates" (4). 


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The analysis of AEs will be based on the concept of treatment emergent AEs. Since only the 
start date of an AE is collected (without start time), any AE occurrence on the same day as
the first BI 655130 administration will be assigned to the on-treatment period.
An overall summary of AEs will be presented by treatment. This overall summary will 
include summary statistics for the class of other significant AEs according to sponsor 
definition based on ICH E3 and for the class of AESIs.
The following are considered as AESIs (see CTP section 5.3.6.1):

Infusion reactions including anaphylactic reaction

Cytokine release syndrome

Severe bacterial, fungal, and viral infections

Infection with or reactivation of mycobacterium tuberculosis,

Opportunistic infections 

Lymphoproliferative disorders

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
o
an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
The investigator identified AESI will be captured from the eCRF and reported in the
“Investigator reported AESI” table. In addition, User-defined Adverse Event Concepts 
(UDAEC) identified through specific search criteria will be reported separately (see Table 
7.8.1: 1). For these displays, separate tables will be created for each AESI category wherein 
frequencies by treatment group will be given.


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Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events Concepts
User Defined Adverse 
Event Concepts
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”
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 exposure-adjusted incidence rate and 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, patients with AESIs, patients with AE leading to 
discontinuation of the trial, patients with other significant AEs and User-defined Adverse 
Event Concepts (UDAEC) (see Table 7.8.1: 1). AEs will also be summarized by maximum 
intensity based on the RCTC measure (see Section 5.4.1).
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.


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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.
Laboratory data
7.8.2
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 all 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 (using on treatment data) and for the 
difference from baseline (see Section 6.7) will be based upon standardized values and 
provided by visit, including summaries of the last value on treatment, the minimum value on 
treatment, and the maximum value on treatment. Graphical displays via box plots will be 
produced for the change from baseline over time for each continuous laboratory endpoint.
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
measurement on treatment, as well as the worst grade on treatment. These analyses will be 
based on standardized laboratory values.
Potentially clinically significant on-treatment abnormalities will be identified based on BI 
standard rules, which are based on normalized converted lab values, i.e., using the 
International System of 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 for patients without a possibly clinically significant abnormality at baseline. A 
separate listing will present potentially clinically significant abnormal lab values. If there 
exists at least one lab value with a clinically significant abnormality within a functional lab 
group, then for each functional lab group all patient’s lab values will be listed.
The frequency of patients with AST or ALT elevations ≥ 3x ULN, ≥ 5x ULN, ≥ 10x ULN, 
and ≥ 20x ULN 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 ≥ 2x ULN in a 30-day period after AST/ALT 
elevation will be displayed, stratified by alkaline phosphatase < 2x ULN and ≥ 2x ULN (a 


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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 on-treatment 
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 or total bilirubin and ALT may, or may 
not, occur on the same date. Two reference lines, 2x ULN for total bilirubin and 3x ULN 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 ≥ 
3x ULN and total bilirubin < 2x ULN).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and
will be analysed as such.
Vital signs
7.8.3
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. At each on-treatment time-point, three assessments will be 
presented: the pre-dose measurement, the +5 minutes post-dose measurement, and the +2 
hours post-dose measurement; change from baseline refers to the original baseline value. The 
summary will include additionally, the last value, the minimum value, and the maximum 
value during the on-treatment period presented for each of the three visit measurement times 
separately (see Table 6.1: 1 for the definition of the on-treatment period). Graphical displays 
via box plots will be produced for the change from baseline over time for each continuous 
vital sign endpoint.
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.
ECG
7.8.4
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.


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Others
7.8.5
The frequency and percentage of patients with ADA to BI 655130 will be presented by visit.
ADA will be analysed descriptively. A potential effect of ADA on PK and safety may be 
evaluated.


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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
BI-KMED-COPS-TMP-0001: “Important Protocol Deviation (iPD) log”, current 
version; IDEA for CON
4
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON
5
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON
6
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; IDEA for CON
7
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON
8
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; IDEA for CON
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
BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; IDEA for CON
11
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON
12
Devlin N, Shah K, Feng Y, Mulhern B, van Hout B. Valuing Health-Related Quality 
of Life: An EQ-5D-5L Value Set for England. OHE Research Paper 16/01. 
London: Office of Health Economics; 2016 [R17-3268]
13
SAS/STAT(R) 9.2 User's Guide, Second Edition. 
http://support.sas.com/documentation/cdl/en/statug/63033/HTML/default/viewer.ht
m#statug_lifetest_a0000000260.htm (retrieved 16-May-2018)
14
Brown LD, Cai TT, DasGupta A. Confidence intervals for a binomial proportion 
and asymptotic expansions. Ann Statistics 30, 160-201, 2002 [R12-3710]


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15
Newcombe R.G. Interval estimation for the difference between independent 
proportions: Comparison of eleven methods. Stat Methods Med Res 17, 873-890  
1998 [R08-4386]
16
Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, et al.: Development and 
validation of the Nancy histological index for UC . Gut 2017; 66:43–49. [R18-
1193]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial 1.0
19-May-2017
 
None
First approved version before first 
patient in.
1.1 (Stable 
TSAP)
01-Aug-2017
 
(multiple)
Stable TSAP after team comments at 
TSAP walkthrough, basis for initial 
programming. Various additions, 
including: Code for Reeve's method 
added; text for IBDQ and EQ-5D was 
amended. Analyses of biomarkers was
removed to be shifted to a separate 
BM-SAP.
2.0
26-Aug-2019
(all)
This is the final version of core TSAP
3.0
04-Mar-2020
(all)
This is the revised TSAP due to early 
termination of the study.