Clinical trial NCT03482635
Conditions: Colitis, Ulcerative
Sponsor: Boehringer Ingelheim
Start date: 2018-03-27; Completion date: 2020-05-18
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial has two sequentially enrolling parts with different objectives. The primary objectives of this trial are

* to prove the concept of clinical activity of BI655130 (SPESOLIMAB) in patients with moderate-to-severely active ulcerative colitis who have failed previous biologic treatments and to identify efficacious and safe dose regimens in Part 1 (Phase II)
* to confirm efficacy and safety of BI655130 (SPESOLIMAB) in patients with moderate-to-severely active ulcerative colitis who have failed previous biologic treatments in Part 2 (Phase III)
* To provide, along with induction study 1368-0018 and the run-in cohort of 1368-0020, the target population to be evaluated in study 1368-0020.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Spesolimab intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for infusion intervention 2: Solution for infusion

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c15932366-04
EudraCT No.:
EU Trial No:
2017-004230-28
BI Trial No.:
1368-0005
BI Investigational 
Product(s):
BI655130 (SPESOLIMAB)
Title:
A Phase II/III Randomized, Double-blind, Placebo-controlled, 
Multicenter Study to Evaluate the Safety and Efficacy of 
BI655130 (SPESOLIMAB) Induction Therapy in patients with 
moderate-to-severely active ulcerative colitis who have failed 
previous biologics therapy
Lay Title:
BI655130 (SPESOLIMAB) induction treatment in patients with 
moderate-to-severe ulcerative colitis
Clinical Phase:
II/III
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigators
Status:
Final Protocol (Revised protocol (based on Global Amendment 
3))
Version and Date:
Version: 4.0
Date: 09 October 2019
Page 1 of 152
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
Company name
Boehringer Ingelheim 
Finished product name
Not applicable
Active ingredient name:
BI655130 (SPESOLIMAB)
Protocol date
02 November 2017
Revision date
09 October 2019
Trial number
1368-0005
Title of trial:
A Phase II/III Randomized, Double-blind, Placebo-controlled, Multicenter Study to 
Evaluate the Safety and Efficacy of BI655130 (SPESOLIMAB) Induction Therapy 
in patients with moderate-to-severely active ulcerative colitis who have failed 
previous biologics therapy
Coordinating 
Investigators:
Trial site(s):
Multi-centre study
Clinical phase:
II/III
Objective(s):
•
to prove the concept of clinical activity of BI655130 (SPESOLIMAB) in 
patients with moderate-to-severely active ulcerative colitis who have failed 
previous biologic treatments and to identify efficacious and safe dose regimens 
in Part 1 (Phase II)
•
to confirm efficacy and safety of BI655130 (SPESOLIMAB) in patients with 
moderate-to-severely active ulcerative colitis who have failed previous 
biologic treatments in Part 2  (Phase III)
•
To provide, along with induction study 1368-0018 and the run-in cohort of 
1368-0020, the target population to be evaluated in the randomised withdrawal 
study 1368-0020.
Methodology:
Randomised, parallel-design, multiple-doses, placebo-controlled, double-blind
(Part 1: three active dose groups and a placebo group; Part 2: two active dose 
groups and a placebo group)
Number of patients
entered: 
160 (part1)
390 (part2)
Number of patients on 
40 Patients per treatment arm (part1)


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each treatment:
130 patients per treatment arm (part2)
Diagnosis :
Patients with moderate-to-severely active ulcerative colitis who have failed 
previous biologic treatments.
Main in- and exclusion 
criteria
Main criteria for inclusion:

Male or female patients, aged 18 to 75 years at date of signing informed 
consent

Diagnosis of ulcerative colitis ≥ 3 months prior to screening by clinical and 
endoscopic evidence corroborated by a histopathology report

Moderate to severe activity (total MCS (Mayo Clinical Score) 6 to 12 with 
a RBS (rectal bleeding score) ≥ 1 AND a SFS (stool frequency score) ≥ 1 
AND mESS (modified Endoscopic Subscore) ≥ 2 within 7-28 days prior to 
first dose)

Well documented failure or intolerance with approved doses of TNF
antagonists and/or vedolizumab in the past
Main criteria for exclusion:

Evidence of abdominal abscess, fulminant colitis or toxic megacolon 

Ileostomy, colostomy, or symptomatic stenosis of the intestine

Treatment with forbidden medication without appropriate wash-out
Clinically significant intestinal or extra-intestinal infection
Test product(s):
BI655130 (SPESOLIMAB)
dose:
Part 1: 300 mg single dose (SD) at week 0; 450 mg or 1200 mg every 4 weeks 
(q4w, at Weeks 0, 4  and 8)
Part 2: 300 mg SD, 450 mg q4w, 750 mg q4w or 1200 mg q4w (at Weeks 0, 4  
and 8);  Two of the above doses will be selected dependent on part 1 results
mode of 
administration:
Intravenous (i.v.)
Comparator products:
Placebo
dose:
0 mg (placebo) at Week 0, 4  and 8
mode of 
administration:
Intravenous (i.v.)
Duration of treatment
12 weeks
Endpoints
Primary endpoint:
Proportion of patients with Clinical Remission at week 12 
(defined as mMCS SFS=0 or 1, if drop ≥1 from BL; and RBS=0; and mESS≤1)
Key Secondary endpoint(s) (Part 2 only):
Proportion of patients with Mucosal Healing at week 12 
(defined as modified endoscopic Subscore (mESS) ≤ 1).
Proportion of patients with Clinical response at week 12 
(defined as total MCS reduction ≥3 pts. and ≥30% from BL; AND RBS drop from 
baseline by ≥1pt., or absolute RBS ≤1 pt.)


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Secondary endpoint (incl. in statistical testing strategy; Part 2 only)
Change in IBDQ score from baseline at week 12
Proportion of patients with combined Mucosal healing and histologic remission at 
week 12 
(defined as mESS ≤ 1 and Robarts Histology Index ≤ 6)
Safety criteria:
Physical examination, vital signs, 12-lead Electrocardiogram (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 trial consists of 2 parts which, for the purpose of statistical analyses, will be 
treated as two independent parts whereby the false positive rate is separately 
controlled within each trial part:
Part 1: 
Demonstrate proof of concept of clinical activity as an induction therapy 
with respect to achieving a non-flat dose response curve on the primary 
endpoint, and subsequently to identify suitable dose regimens for 
BI655130 (SPESOLIMAB) regarding efficacy and safety for further 
pivotal testing in part 2 of this trial. For this purpose, a multiple 
comparison procedure with modelling techniques (MCPMod) approach is 
considered. Randomized set will be used.
Part 2:
Confirm the efficacy and safety of two different doses of BI655130 
(SPESOLIMAB) versus placebo as an induction therapy.
Formal statistical hypothesis testing will be performed at an overall 1-
sided alpha level of 0.025.
Each trial part will be analyzed independently of the remaining trial part, i.e. 

Only patients randomized into part 1 will be included in the analyses of 
part 1, 

Only patients randomized into part 2 will be included in the confirmatory 
analyses of part 2
For trial part 2, the primary analysis of the clinical remission for each dose of 
BI655130 (SPESOLIMAB) versus placebo will be tested using the stratified 
Cochran-Mantel-Haenszel test at a nominal 1-sided 0.025 significance level 
stratified by the randomization stratification factors (prior biologic use and 
concomitant corticosteroid therapy at visit2) and based on the RS. The key 
secondary endpoints will be analysed using the same approach as for the primary 
analysis. Overall, the testing strategy will follow a closed testing principle defining 
two families of endpoints/comparisons. The first family consists of the primary 
endpoint comparisons for each dose of BI655130 (SPESOLIMAB) separately vs 
placebo, whereas the second family is defined by the pre-specified secondary 
endpoint comparisons for each dose of BI655130 (SPESOLIMAB) separately vs 
placebo. For the first family, type I error control is ensured by using the truncated 
Hochberg approach. For the second family, a graphical approach is applied. For 
publication purposes, the 2-sided p-values will also be reported. Note that a 
stratification for Japan versus non-Japan will also be done in order to assure that 
sufficient patients per treatment group are recruited specifically to support 
individual country submission in Japan; this strata will be treated as an operational 
strata and will not be included into the analyses of the primary endpoint in Part 2 of 
the trial.


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FLOW CHART: PART 1/PROOF OF CONCEPT
Trial periods
Screening
Blinded intravenous therapy
Fup
Visit
V1a
(Screening)
V1b
(Pre-
baseline)
V211
V3
V4
V5
V614/EOT
EOS14
Week
-5 to -2
-4 to -1
0
2
4
8
12
24
Day
-35 to -14
- 28 to 
-7
0
14
28
56
84
168
Visit window (days)
N.A.
N.A.
0
±4
±4
±4
±4
+7
Informed consent
X
In-/exclusion criteria
X
X
Demographics
X
eDiary dispensing 
and instructions 10
X
eDiary Upload and 
review
X
X
X
X
X
X
X
Medical history
X
Prior therapies
X
Ulcerative colitis 
history
X
Colonoscopy  +
biopsy1,2
X
Sigmoidoscopy + 
biopsy, mESS 
recording2,3
X
X
PGA
X
X
X
X
X
X
X
Physical exam (incl. 
vital signs)4
XC
XT
XT
XT
XT
XC
XC
XT
Weight
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
X
X
Pregnancy test5
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
Safety laboratory 
tests7
X
X
X
X
X
X
X


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Trial periods
Screening
Blinded intravenous therapy
Fup
Visit
V1a
(Screening)
V1b
(Pre-
baseline)
V211
V3
V4
V5
V614/EOT
EOS14
Week
-5 to -2
-4 to -1
0
2
4
8
12
24
Day
-35 to -14
- 28 to 
-7
0
14
28
56
84
168
Visit window (days)
N.A.
N.A.
0
±4
±4
±4
±4
+7
Infections screening 
(Hep B, Hep C, HIV)
X
QuantiFERON-TB 
test
X
X
Optional blood 
sampling for 
assessment of drug 
levels for previous 
biologics
X
Blood sampling for 
PK
X8
X
X8
X8
X
X
Blood sampling for 
ADAs
X8
X8
X8
X
X
Stool sampling for 
enteric pathogens 6
X
IBDQ9
X
X
X
X
X
X
EQ-5D(-5L)9
X
X
X
X
Contact IRT
X
X
X
X
X
Randomization
X
Study drug 
administration
X11,12
X12
X12
Study completion
X
X
Roll-over into 
1368-001713
X


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Footnotes:
1.
If disease extent has not been documented within past 12 months from screening, a full 
colonoscopy instead of a sigmoidoscopy will be performed during screening period to 
determine the extent of disease.
Colonoscopy and sigmoidoscopy 
images will be centrally read by an external independent assessor(s); management of 
images will be performed by an external vendor.
3.
Sigmoidoscopies will be performed at visit V1b if no colonoscopy is done.
4.
Physical examination: C=complete, T=targeted. Refer to Section 5.2.1. In addition, at 
Visits 2, 4 and 5 vital signs will be assessed at approximately 5 and 60 minutes after the 
end of study drug administration. Monitor for signs and symptoms of hypersensitivity 
reactions for approximately 2 hours after the first dose administered at Visit 2 and 1 hour 
following all other doses of study drug (at Visits 4 and 5).
5.
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. More frequent testing should be done if required by the 
local regulation and / or authority or per investigator judgment.
6. If collection is not possible at Visit 1a, stool sample has to be collected at (or prior to) 
Visit 1b or at an unscheduled visit.
7.
Includes clinical chemistry, haematology, coagulation and urinalysis assessments. Patient 
must be fasting for at least 8 hours prior to blood collection (except screening visit). If 
not fasted, mark on laboratory requisition form. At visits with study drug administration 
this should to be done prior to the study drug infusion.
8. At study visits with study drug administration, pre-dose PK/ADA 
 samples will be obtained approximately within 1 hour
prior to start of i.v. infusion.
9. The IBDQ and EQ-5D(-5L), patient-reported outcome tools, must be completed by the 
patient on his/her own in the pre-specified order in a quiet area/room before any other 
visit assessments or treatments and, as much as possible, before any interaction with the 
investigator or other members of the study team. Refer to Section 6.2
10. 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. Please make sure that time window between visits V1a and visit 
V1b is minimum 7 days.This will ensure that enough eDiary data (SFS and RBS) are 
collected before visit V1b in order to calculate the baseline Mayo score. PGA (Physician 
Global Assessment) should be completed at all visits except visit 1a. Refer to Section 
6.2.1.
11. First study drug administration will be administered at V2.
12. Patients who terminate study drug early should be encouraged to follow all study 
procedures per the Flow Chart until week 12, but not receive any more study drug at the 


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respective visits. These patients do have the option to do EOS visit earlier than week 24, 
16 weeks after last study drug administration. Until then they should follow the Flow 
Chart.
13. All patients completing week 12 of the study will be offered to enter open label trial 
1368-0017. These patients are not requested to complete follow up period and will have 
their End of study visit at visit V6, co-inciding with the BL visit and start of study drug 
administration in 1368-0017.
14. EoS visit will be at week 12 (V6) for patients rolling-over into open label trial 1368-
0017; and at week 24 for patients who will not enter open label trial 1368-0017.


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FLOW CHART: PART 2 / CONFIRMATORY EFFICACY/ SAFETY 
EVALUATION
Trial periods
Screening
Blinded intravenous therapy
Fup
Visit
V1a
(Screening)
V1b
(Pre-
baseline)
V211
V3
V4
V5
V614/
EOT
EOS14
Week
-5 to -2
-4 to -1
0
2
4
8
12
24
Day
-35 to -14
- 28 to -
7
0
14
28
56
84
168
Visit window (days)
N.A.
N.A.
0
±4
±4
±4
±4
+7
Informed consent
X
In-/exclusion criteria
X
X
Demographics
X
eDiary Dispensing and 
instructions10
X
eDiary Upload and 
Review
X
X
X
X
X
X
X
Medical history
X
Prior therapies
X
Ulcerative colitis 
history
X
Colonoscopy  + 
biopsy1,2
X
Sigmoidoscopy + 
biopsy, mESS 
recording2,3
X
X
PGA
X
X
X
X
X
X
X
Physical exam (incl. 
vital signs)4
XC
XT
XT
XT
XT
XC
XC
XT
Weight
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
X
X
Pregnancy test5
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
Safety laboratory tests7
X
X
X
X
X
X
X


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Trial periods
Screening
Blinded intravenous therapy
Fup
Visit
V1a
(Screening)
V1b
(Pre-
baseline)
V211
V3
V4
V5
V614/
EOT
EOS14
Week
-5 to -2
-4 to -1
0
2
4
8
12
24
Day
-35 to -14
- 28 to -
7
0
14
28
56
84
168
Visit window (days)
N.A.
N.A.
0
±4
±4
±4
±4
+7
Infections screening  
(Hep B, Hep C, HIV)
X
QuantiFERON-TB test
X
X
Optional blood 
sampling for assessment 
of drug levels for 
previous biologics
X
Blood sampling for PK
X8
X
X8
X8
X
X
Blood sampling for 
ADAs
X8
X8
X8
X
X
Stool sampling for 
enteric pathogens 6
X
IBDQ
X
X
X
X
X
X
SF-36, FACIT-Fatigue9
X
X
X
X
EQ-5D(-5L) , WPAI-
UC9
X
X
X
X
HCRU15 assessments
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
Randomization
X
Study drug 
administration
X11,12
X12
X12
Study completion
X
X
Roll-over into 1368-
X


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Trial periods
Screening
Blinded intravenous therapy
Fup
Visit
V1a
(Screening)
V1b
(Pre-
baseline)
V211
V3
V4
V5
V614/
EOT
EOS14
Week
-5 to -2
-4 to -1
0
2
4
8
12
24
Day
-35 to -14
- 28 to -
7
0
14
28
56
84
168
Visit window (days)
N.A.
N.A.
0
±4
±4
±4
±4
+7
002013
Footnotes:
1.
If disease extent has not been performed within past 12 months from screening, a full 
colonoscopy will be performed during screening period, instead of the screening and 
baseline sigmoidoscopy, to determine the extent of disease.
2. 
 
At visits with study drug 
administration this should to be done prior to the study drug infusion. Colonoscopy and 
sigmoidoscopy images will be scored using the modified Mayo Endoscopy Score 
(mESS) recorded by the site investigator and centrally read by an external independent 
assessor(s); management of images will be performed by an external vendor.
3.
Sigmoidoscopies will be performed at visit V1b if no colonoscopy is done.
4.
Physical examination: C=complete, T=targeted. Refer to Section 5.2.1. In addition, at 
Visits 2, 4 and 5 vital signs will be assessed at approximately 5 and 60 minutes after the 
end of study drug administration. Monitor for signs and symptoms of hypersensitivity 
reactions for approximately 2 hours after the first dose administered at Visit 2 and 1 hour 
following all other doses of study drug (at Visits 4 and 5).
5.
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. More frequent testing should be done if required by the 
local regulation and / or authority or per investigator judgment.
6. If collection is not possible at Visit 1a, stool sample has to be collected at (or prior to) 
Visit 1b or at an unscheduled visit.
7.
Includes clinical chemistry, haematology, coagulation and urinalysis assessments. Patient 
must be fasting for at least 8 hours prior to blood collection (except screening visit). If 
not fasted mark on laboratory requisition form. At visits with study drug administration 
this should be done prior to the study drug infusion.
8.
At study visits with study drug administration, pre-dose PK/ADA 
 samples will be obtained approximately within 1 hour
prior to start of i.v. infusion.


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9. The IBDQ, FACIT-Fatigue, SF-36, EQ-5D(-5L), and WPAI-UC, patient-reported 
outcome tools, must be completed by the patient on his/her own in the pre-specified 
order in a quiet area/room before any other visit assessments or treatments and, as much 
as possible, before any interaction with the investigator or other members of the study 
team. Refer to Section 6.2.1.
10. 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. Please make sure that time window between visits V1a and visit 
V1b is minimum 7 days.This will ensure that enough eDiary data (SFS and RBS) are 
collected before visit V1b in order to calculate the baseline Mayo score. PGA (Physician 
Global Assessment) should be completed at all visits except visit 1a. Refer to Section 
6.2.1.
11. First study drug administration will be administered at V2.
12. Patients who terminate study drug early should be encouraged to follow all study 
procedures per the Flow Chart until week 12, but not receive any more study drug at the 
respective visits. These patients do have the option to do EOS visit earlier than week 24, 
i.e. 16 weeks after last study drug administration. Until then they should follow the Flow 
Chart.
13. All patients completing week 12 of the study will be offered to enter maintenance trial 
1368-0020. These patients are not requested to complete follow up period and will have 
their End of study visit at visit V6, co-inciding with the BL visit, randomisation and start 
of study drug administration in 1368-0020.
14. EOS visit will be at week 12 (V6) for patients rolling-over into maintenance trial 1368-
0020; and at week 24 for patients who will not enter maintenance trial 1368-0020.
15. Healthcare resource utilisiation (HCRU) data will be captured at every study visit. 


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART: PART 1/PROOF OF CONCEPT .............................................................5
FLOW CHART: PART 2 / CONFIRMATORY EFFICACY/ SAFETY EVALUATION
.................................................................................................................................9
TABLE OF CONTENTS ......................................................................................................13
ABBREVIATIONS................................................................................................................17
1.
INTRODUCTION...............................................................................................20
1.1
DRUG PROFILE................................................................................................20
1.2
MEDICAL BACKGROUND.............................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................22
1.4
BENEFIT - RISK ASSESSMENT.....................................................................23
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................28
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........28
2.1.1
Main objectives....................................................................................................28
2.1.2
Primary endpoint (Part 1 and Part 2)...............................................................28
2.1.3
Key Secondary endpoints (Part 2 / Phase III only)..........................................28
2.1.4
Secondary endpoint (Part 1 and Part 2) ...........................................................28
2.1.5
Secondary endpoints (Part 1 / Phase II only) ...................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................32
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................32
3.1.1
Part 1 / Proof of Concept....................................................................................33
3.1.2
Transition from Part 1 to Part 2........................................................................34
3.1.3
Part 2 / Confirmatory Efficacy/Safety Evaluation...........................................37
3.1.4
Follow-up period:................................................................................................38
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................38
3.3
SELECTION OF TRIAL POPULATION .......................................................39
3.3.1
Main diagnosis for trial entry ............................................................................40
3.3.2
Inclusion criteria .................................................................................................40
3.3.3
Exclusion criteria ................................................................................................41
3.3.3.1
Gastrointestinal Exclusion Criteria.......................................................................41
3.3.3.2
Infectious Disease Exclusion Criteria...................................................................42
3.3.3.3
General Exclusion Criteria....................................................................................42
3.3.4
Withdrawal of patients from therapy or assessments .....................................43
3.3.4.1
Withdrawal from trial treatment ...........................................................................43


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3.3.4.2
Withdrawal of consent for trial participation........................................................44
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................44
4.
TREATMENTS...................................................................................................45
4.1
INVESTIGATIONAL TREATMENTS ...........................................................45
4.1.1
Identity of the Investigational Medicinal Products..........................................45
4.1.2
Selection of doses in the trial..............................................................................46
4.1.3
Method of assigning patients to treatment groups...........................................47
4.1.4
Drug assignment and administration of doses for each patient......................47
4.1.5
Blinding and procedures for unblinding...........................................................48
4.1.5.1
Blinding.................................................................................................................48
4.1.5.2
Unblinding and breaking the code ........................................................................49
4.1.6
Packaging, labelling, and re-supply...................................................................50
4.1.7
Storage conditions...............................................................................................50
4.1.8
Drug accountability.............................................................................................50
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................51
4.2.1
Other treatments and emergency procedures..................................................51
4.2.2
Restrictions ..........................................................................................................53
4.2.2.1
Restrictions regarding previous and concomitant treatment are summarized in 
Table 4.2.2.1: 1 .....................................................................................................53
4.2.2.2
Restrictions regarding women of childbearing potential......................................55
4.3
TREATMENT COMPLIANCE........................................................................55
5.
ASSESSMENTS..................................................................................................56
5.1
ASSESSMENT OF EFFICACY........................................................................56
5.2
ASSESSMENT OF SAFETY.............................................................................56
5.2.1
Physical examination ..........................................................................................56
5.2.2
Vital signs.............................................................................................................57
5.2.3
Safety laboratory parameters ............................................................................57
5.2.4
Electrocardiogram ..............................................................................................60
5.2.5
Other safety parameters.....................................................................................61
5.2.6
Assessment of adverse events.............................................................................61
5.2.6.1
Definitions of AEs ................................................................................................61
5.2.6.2
Adverse event collection and reporting ................................................................64
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................66
5.3.1
Assessment of pharmacokinetics .......................................................................66
5.3.2
Methods of sample collection .............................................................................66
5.3.2.1
Plasma sampling for PK analysis..........................................................................67
5.3.2.2
Plasma sampling for ADA assessment .................................................................67
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................67


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5.5
OTHER ASSESSMENTS...................................................................................70
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................73
6.
INVESTIGATIONAL PLAN.............................................................................74
6.1
VISIT SCHEDULE.............................................................................................74
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................74
6.2.1
Screening and run-in period(s)..........................................................................74
6.2.2
Treatment period(s)............................................................................................76
6.2.3
Follow up period and trial completion..............................................................77
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................79
7.1
STATISTICAL DESIGN – MODEL ................................................................79
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................80
7.3
PLANNED ANALYSES.....................................................................................87
7.3.1
Primary endpoint analyses.................................................................................88
7.3.2
Key Secondary endpoint analyses .....................................................................92
7.3.3
Secondary endpoint analyses .............................................................................92
7.3.5
Safety analyses.....................................................................................................93
7.3.6
Pharmacokinetic and pharmacodynamic analyses..........................................94
7.4
INTERIM ANALYSES ......................................................................................95
7.5
HANDLING OF MISSING DATA ...................................................................96
7.6
RANDOMISATION ...........................................................................................97
7.7
DETERMINATION OF SAMPLE SIZE .........................................................98
7.7.1
Sample size determination for Part 1................................................................98
7.7.2
Sample size determination for Part 2..............................................................100
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ......103
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .........................................................................................................103
8.2
DATA QUALITY ASSURANCE ....................................................................104
8.3
RECORDS.........................................................................................................104
8.3.1
Source documents .............................................................................................104
8.3.2
Direct access to source data and documents...................................................105
8.3.3
Storage period of records .................................................................................106
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......106
8.4.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................106
8.5
TRIAL MILESTONES.....................................................................................107
8.6
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................107
9.
REFERENCES..................................................................................................109


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9.1
PUBLISHED REFERENCES..........................................................................109
9.2
UNPUBLISHED REFERENCES....................................................................115
10.
APPENDICES...................................................................................................116
10.1
MAYO SCORING SYSTEM FOR THE ASSESSMENT OF 
ULCERATIVE COLITIS ACTIVITY ...........................................................116
10.2
HISTOLOGIC ACTIVITY SCORE...............................................................118
10.3
EQUIVALENT DOSES OF CORTICOSTEROIDS.....................................119
10.4
PATIENT REPORTED OUTCOMES ...........................................................119
10.4.1
Inflammatory Bowel Disease Questionnaire (IBDQ) ....................................119
10.4.2
EQ-5D-5L...........................................................................................................119
10.6
DEFINITION OF PRIMARY, SECONDARY NONRESPONSE OR 
INTOLERANCE TO ANTI-INTEGRIN OR ANTI-TNF THERAPY........121
10.7
DIAGNOSIS OF ANAPHYLAXIS .................................................................126
10.8.
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (OMERACT) ......................................127
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................129
11.1
GLOBAL AMENDMENT 1 ............................................................................129
11.2
GLOBAL AMENDMENT 2 ............................................................................135
11.3
GLOBAL AMENDMENT 3 ............................................................................145


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ABBREVIATIONS
ADA
Anti-drug antibodies
ADCC
antibody-dependent cellular cytotoxicity
AE
Adverse Event
AESI
Adverse Event of Special Interest
AUC
Area under the Curve
b.i.d.
bis in die (twice daily dosing)
BL
Base Line
CCDS
Company Core Data Sheet
BIO
Biologics
CD
Crohn’s disease
CDC
complement-dependent cytotoxicity
CI
Confidence Interval
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electrocic (sometimes referred to as “eCRF”)
CTCAE
Common Terminology Criteria for Adverse Events
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CT
Concomitant Therapy
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EDC
EOT
EOS
Electronic Data Capture
End of Treatment
End of Study
ePRO
Electronic Patient Reported Outcome
EQ-5D(-5L)
Questionnaire developed by EuroQoL Group
ESS
Mayo Endoscopy Score
EudraCT
European Clinical Trials Database
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full Analysis Set
FC
Flow Chart
FcR
Fc receptor - a protein found on the surface of certain cells
FIH
First in human
GCP
Good Clinical Practice
GPP
generalized pustular psoriasis
HPC
Human Pharmacology Centre
HCRU
Healthcare resource utilisation
HT29
a human colorectal adenocarcinoma cell line with epithelial morphology
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
IC90
Inhibitory concentration of 90 (mg/mL)


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IEC
Independent Ethics Committee
IFNγ
Interferon gamma
IgG1
Immunglobulin G1
IHC
Immunohistochemistry
IL36R
Interleukin 36R
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITE
indirect target engagement
i.v.
intravenous
LoEE
List of Essential Element 
MCS
Mayo Clinical Score
mMCS
modified Mayo Clinical Score
MedDRA
Medical Dictionary for Drug Regulatory Activities
mESS
modified Endoscopic Subscore 
MST
Medical Sub Team
NF-B
Nuclear factor 'kappa-light-chain-enhancer' of activated B-cells
NOAEL
No-observed-adverse-effect level
OPU
Operative Unit
PBO
Placebo
PBMC
Peripheral Blood Mononuclear Cell
PD
Pharmacodynamics
PK
Pharmacokinetics
pMCS
partial Mayo Clinical Score
p.o.
per os (oral)
PoC
proof of concept
PPP
palmoplantar pustulosis
q.d.
quaque die (once a day)
q.w.
quatery week (every 4th week)
eDC
electronic Data Capturing
RBS
Rectal Bleeding Score
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
RS
Randomized Set
SAE
Serious Adverse Event
s.c.
subcutaneous
SF-36
36 question instrument to measure health-related quality of life
SFS
Stool Frequency Score
SMC
Safety Monitoring Committee
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reactions
TMDD
target-mediated drug disposition
TB test
blood test that aids in the detection of Mycobacterium tuberculosis, the 
bacteria which causes tuberculosis (TB)
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan


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TGF-β
tissue growth factor
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TNF
Tumor necrosis factor
TNFi
TNFinhibitor
TSAP
Trial Statistical Analysis Plan
UC
Ulcerative Colitis
WHO
World Health Organization
WOCBP
Woman of childbearing potential
WPAI-UC
Work Productivity and Activity Impairment Questionnaire, Ulcerative 
Colitis -specific version


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1.
INTRODUCTION
1.1
DRUG PROFILE
BI655130 (SPESOLIMAB) is a humanized antagonistic monoclonal IgG1 antibody that 
blocks human IL36R signaling. Binding of BI655130 (SPESOLIMAB) to IL36R is 
anticipated to prevent the subsequent activation of IL36R by cognate ligands (IL36 α, β and 
γ) and downstream activation of pro-inflammatory and pro-fibrotic pathways with the aim to 
reduce epithelial cell/ fibroblast/ immune cell-mediated inflammation and interrupt the 
inflammatory response that drives pathogenic cytokine production in inflammatory diseases 
including generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP) and 
inflammatory bowel disease (IBD).
Preclinical studies
BI655130 (SPESOLIMAB) binds to human IL36R with a binding avidity of less than 1 pM. 
BI655130 (SPESOLIMAB) inhibits IL36 ligand-stimulated NF-B activation in HT29 and 
transformed epithelial cells and in primary human dermal fibroblasts or intestinal 
myofibroblasts with IC90 values in a consistent range of 0.7 to 3.7 nM. BI655130 
(SPESOLIMAB) also inhibits IL8 release in primary human intestinal myofibroblasts and 
IFNγ secretion in human PBMC stimulated with IL36α, IL36β, or IL36γ combined with 
IL12.
Mutations of two key residues (L234 and L235) to alanine were made to BI655130 
(SPESOLIMAB) to abrogate FcR binding activity and function. Direct assessment of the 
impact of the mutations in the IgG1 FcR binding sites on both antibody-dependent cellular 
cytotoxicity (ADCC) and complement-dependent cytotoxicity CDC effector functions 
revealed that the mutations abrogate both ADCC and CDC effector functions and indicate 
that BI655130 (SPESOLIMAB) will be a non-depleting therapy in vivo.
Toxicology studies
BI655130 (SPESOLIMAB) 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 BI655130 (SPESOLIMAB). 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), which is 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. In the 26-week toxicity study, male and female mice (20-30/sex/group 
at 0, 10 and 50 mg/kg/day) were administered BI 674304 twice weekly for 26 weeks by 
intravenous injection via the caudal vein.  There were no BI 674304-related changes in 
clinical observations, body weights, food consumption, ophthalmology, clinical pathology 
parameters (hematology, clinical chemistry), organ weights, macroscopic or microscopic 
examinations. The no-observed-adverse-effect level (NOAEL) was considered to be 50
mg/kg/day.


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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, BI655130 (SPESOLIMAB)
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 toxicology data support chronic BI655130 (SPESOLIMAB) dosing in
humans.
Clinical PK/PD studies
BI655130 (SPESOLIMAB) 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. 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 BI655130 (SPESOLIMAB). The most 
frequent treatment-emergent AEs were nasopharyngitis (BI655130 (SPESOLIMAB): 21%; 
PBO: 15%), headache (BI655130 (SPESOLIMAB): 9%; PBO: 15%), influenza like illness 
(BI655130 (SPESOLIMAB): 7%; PBO: 10%), and diarrhoea (BI655130 (SPESOLIMAB): 
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. 
PK analysis showed that exposure (AUC0-tz and Cmax) to BI655130 (SPESOLIMAB) increased 
with increasing dose in an approximately dose-proportional manner from 0.3 to 10 mg/kg. 
The effective half-life of BI655130 (SPESOLIMAB) is approximately 4 weeks in the linear 
dose range. Overall, PK data so far suggests target-mediated drug disposition (TMDD) 
kinetics for BI655130 (SPESOLIMAB). Anti-drug antibodies (ADA) were detected in 8 
patients, 3 of those had pre-existing levels. Pharmacodynamic effects in this FIH Single 
Rising Dose trial [c03361085-07] were assessed by indirect target engagement (ITE) of 
IL36R by BI655130 (SPESOLIMAB) using an ex-vivo whole blood stimulation assay. All 
doses higher than 0.001 mg/kg were biologically active, corresponding to the minimum 
anticipated biological effect level, MABEL. 
In a multiple rising dose trial, BI655130 (SPESOLIMAB) or placebo have been administered 
to healthy volunteers at multiple ascending i.v. doses of 3, 6,10 and 20 mg/kg given qw for 4 
weeks (i.e. 4 administrations) or a single dose of 20mg/kg (8 subjects each, 3:1 on active or 
PBO). Overall, BI655130 (SPESOLIMAB) was well tolerated. There were no dose 
dependent AEs, 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 BI655130 (SPESOLIMAB) with respect to safety laboratory, vital signs, or 
ECGs as assessed by a central reader. Importantly, based on the preliminary analysis of the 
ITE studies, more than 90% of peripheral IL36R was engaged for at least 22 weeks after the 
last application of four weekly doses. For further details and most recent results refer to the 
current Investigator`s Brochure [c03320877-07].


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Summary 
BI655130 (SPESOLIMAB) is an anti IL36R antibody with a high clinical activity to block 
IL36R signaling, as demonstrated in patients with Generalized Pustular Psoriasis, a severe 
inflammatory skin disease driven by uncontrolled IL36 activity. IL36R inhibition shows a 
favorable nonclinical safety profile. Importantly, BI655130 (SPESOLIMAB) has been tested 
in healthy volunteers with single or multiple dosing up to four weeks of 20 mg/kg i.v. q.w., 
which were all safe and well tolerated. Therefore, BI655130 (SPESOLIMAB) might be a 
promising drug to treat patients suffering from ulcerative colitis.
For further details and most recent results refer to the current Investigator`s Brochure (IB)
[c03320877-07].
1.2
MEDICAL BACKGROUND
Ulcerative Colitis (UC) is a chronic inflammatory bowel disease characterized by the key 
symptoms of chronic diarrhea, bloody stools and abdominal pain. It 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 immunosuppressive agents azathioprine and 6-
mercaptopurine, and TNF antagonists. In patients with mild UC, 5-ASAs are safe and 
effective for induction and maintenance treatment. Glucocorticoids, immunosuppressives, 
TNF antagonists, and more recently vedolizumab, are reserved for patients with moderate to 
severe disease, in whom the primary goals of drug therapy are to induce and subsequently to 
maintain remission from signs and symptoms of active disease.
Biologic treatment of moderate/severe 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.
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI655130 (SPESOLIMAB) is currently under development for the treatment of ulcerative 
colitis (UC). Its unique dual mode of action targets pro-inflammatory cytokines as well as 
tissue remodeling effects and thus may provide a clear advantage over current drugs and 
investigational compounds, which target inflammation only. The potential BI655130 
(SPESOLIMAB) effects on remodeling may directly increase mucosal healing, induce deeper 


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tissue healing (histologic remission) and reduce stricturing and fistulizing complications of 
IBD.
The link between IL36R driven inflammation and epithelial inflammation has led to the 
hypothesis that IL36R signalling may play an important role in inflammatory bowel diseases 
such as UC. This hypothesis was tested using a suite of in vitro and in vivo assays. 
Immunostaining studies demonstrated that both IL-36R and its ligands are expressed in 
intestinal biopsies from patients with chronic IBD. Human IL36 ligands enhanced epithelial 
intestinal barrier permeability, a hallmark of IBD pathogenesis, based on a study using 
primary human intestinal epithelial cells co-cultured with intestinal myofibroblasts. The link 
between IL36R signalling and IBD was further strengthened by demonstrating that antagonist 
anti-mouse IL36R antibodies ameliorated intestinal inflammation in both acute chemically 
induced and chronic T cell driven murine colitis models. The therapeutic rationale for an 
IL36R antagonist in IBD is further based on the correlation of a set of IL36-induced genes 
upregulated in primary human intestinal myofibroblasts, a disease relevant cell type, with 
gene signatures observed in ulcerative colitis and Crohn’s disease (CD) patients. Finally, 
IL36R 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), which differentiates this mechanism from 
TNF alpha, integrin and IL23 targeting pathways. Altogether these findings indicate that IL36 
is a key regulatory cytokine upstream of various pro-inflammatory and tissue-remodelling 
cytokines including TGF-, TNFand IL23, and support a prominent role of IL36R in 
driving intestinal inflammation and fibrosis.
In addition, data on pharmacokinetics of 12 weeks of BI655130 (SPESOLIMAB) treatment 
in UC patients will be collected and correlated with the pharmacodynamic (PD) treatment 
response. These data will help understand the PK characteristics of BI655130 
(SPESOLIMAB) 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. A robust understanding of the PK/PD response correlation will be 
obtained using a modelling approach and will support dose selection for adult phase III 
testing and the pediatric development program.
The most recent and more detailed information is available in the current IB [c03320877-07].
1.4
BENEFIT - RISK ASSESSMENT
Preclinical profiles of BI655130 (SPESOLIMAB) and clinical data from healthy volunteer 
trials suggest that BI655130 (SPESOLIMAB) is safe, tolerable and may address an unmet 
medical need in UC patients by a dual anti-inflammatory and anti-fibrotic mechanism of 
action, cf. Section 1.2 and the IB [c03320877-07]. Results of the PoC trial 1368-0011 in acute 
GPP demonstrate that BI655130 (SPESOLIMAB) treatment rapidly clears pustules, the 
primary lesions in GPP, a disease closely linked to loss-of-function mutations in the natural 
IL36R antagonist. A different pustular inflammatory epithelial disease is PPP, which does not 
show the clear genetic association to the IL36 signalling pathway as GPP. Although the small 


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pilot study of BI655130 (SPESOLIMAB) in 59 patients with this disease (1368.15) failed to 
achieve the primary endpoint, a subgroup analysis has shown a strong dose dependent effect 
on pustule severity, the primary and most burdensome lesion of this disease. These data 
indicate that BI655130 (SPESOLIMAB) indeed inhibits IL36 in human disease and thus has 
the potential to also treat other neutrophil granulocyte related inflammatory epithelial 
diseases such as IBD. The most recent and more detailed information is available in section 6 
of the current IB [c03320877-07].
No relevant animal species is available for toxicology testing of the highly human specific 
antibody BI655130 (SPESOLIMAB). However, preclinical toxicology studies with a mouse 
surrogate antibody have demonstrated the safety of IL-36R inhibition in mice (IB c03320877-
07, Section 5.1.2).
A total of more than 212 subjects have been exposed to single or multiple i.v. doses of 
BI 655130 as of September 2018 (see IB). BI 655130 was safe and well tolerated in four 
healthy volunteers trials evaluating the i.v. and s.c. formulation (for details cf. Section 1.2 and 
IB c03320877-07).
Moreover, two trials exploring efficacy and safety of single (1368-0011) or multiple (1368-
0015) doses of BI655130 (SPESOLIMAB) in patients with Generalized Pustular Psoriasis 
(GPP, n=7) or Palmoplantar Pustulosis (PPP; n=59) demonstrated the favourable safety 
profile of BI655130 (SPESOLIMAB) in these severe inflammatory skin diseases. Finally, 
two (1368 - 0004, 1368-0010) clinical trials exploring efficacy and safety of BI655130 
(SPESOLIMAB) in patients with Ulcerative Colitis (UC; target n=10 and 30) are currently 
ongoing and have not yet indicated a BI655130 (SPESOLIMAB) related safety concern. 
Although no direct benefit for individual patients can be assumed, based on the PoC achieved 
in GPP and the strong preclinical rationale, there is a reasonable chance that BI655130 
(SPESOLIMAB) may not only alleviate signs and symptoms of active ulcerative colitis but 
even directly promote mucosal and histological healing, which is associated with improved
clinical outcomes (reductions in immunosuppressive treatments, hospitalizations, colectomy 
and colorectal cancer [R16-0572]. Participation in this study may thus help to generate future 
benefit for larger groups of patients with UC, if BI655130 (SPESOLIMAB) proves to be 
successful in treating this disease. 
There are no identified or potential risks for BI655130 (SPESOLIMAB), based on the 
toxicology programme or any clinical trials conducted for this product to date (see also 
Section 1.2). No other IL-36 receptor antagonist is currently approved, providing information 
on identified risks in molecules of this class. 
The risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs.


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In order to protect the patient’s safety during conduct of this trial, an independent Data 
Monitoring Committee has been established for the periodic review of clinical trial safety 
data.
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product
Drug-induced 
liver injury (DILI)
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators.
Timely detection, evaluation, and 
follow-up of laboratory alterations in 
selected liver laboratory parameters to 
ensure patients´ safety. See also 
Section 5.2.6, adverse events of 
special interest
After administration of any 
biologic agent or protein, 
there is a possibility of 
occurrence of adverse 
immune reactions which can 
be local (e.g redness, 
pruritus, and or swelling at 
the injection site) or 
systemic (e.g. anaphylactic 
reactions).
Patients with a history of allergy/
hypersensitivity to the systemically 
administered trial medication agent or 
its excipients are excluded from the 
trial.
In case of systemic hypersensitivity 
reactions including anaphylactic 
reaction emerging during or after 
administration of trial medication, the 
investigator should consider in 
accordance with severity of the 
reaction and local standard of care to 
interrupt and treat the condition. 
Systemic hypersensitivity reaction is 
defined as AESI. It is subject to close 
monitoring and investigators are 
requested assess these conditions 
using the criteria discussed in the 
statement paper from Sampson 
HA[R11-4890].
Infections
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of 
infections.
A recent characterization of 
individuals with 
homozygous IL36R KO 
Screening procedures for infections 
are established for this trial. Patients 
with any relevant chronic or acute 
infections including human 
immunodeficiency virus (HIV), viral 
hepatitis or tuberculosis are excluded 
from the trial. Treatment of infections 
should be initiated promptly 


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mutations revealed that 
normal immune function was 
broadly preserved suggesting 
that IL36 signalingpathway 
inhibition does not 
compromise host defences 
[R11-4890].
according to standards of care.
Severe infections and opportunistic 
infections are considered AESI for 
this trial.These conditions and serious 
infections are subject to close 
monitoring.
Malignancies
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of a 
decreased immune defense 
against malignancies
A recent characterization of 
individuals with 
homozygous IL36R KO 
mutations revealed that 
normal immune function was 
broadly preserved suggesting 
that IL36 signaling pathway 
inhibition does not 
compromise host 
defencesR17-3632
Patients with a recent history of 
malignancy will be excluded from 
participation in this trial.
In case of occurrence of malignant 
neoplasm other than appropriately 
treated basal cell carcinoma or 
squamous cell carcinoma of the skin 
or in situ carcinoma of uterine cervix, 
the investigator should discontinue 
treatment with BI655130 
(SPESOLIMAB).
Diagnostics and treatment have to be 
initiated according to local standard 
of care.
Malignancies represent always 
serious adverse events and are subject 
to close monitoring
Trial procedures
Blood Sampling 
As with all blood sampling, 
there is a risk of mild pain, 
local irritation, or bruising (a 
black or blue mark) at the 
puncture site. Furthermore, 
there is a small risk of light-
headedness and/or fainting. 
In rare cases, the puncture 
site can also become infected 
or nerves may be damaged, 
inducing long-lasting 
abnormal sensations 
(paresthesia), impaired 
sensation of touch and 
persistent pain.
Frequent blood collection 
may cause anemia (low red 
blood cell count), which may 
create a need for blood 
These risks will be addressed by 
careful safety monitoring and risk 
mitigation measures such as
(a) close clinical monitoring for 
AEs;
(b) selection of experienced sites 
and site staff;
(c) training.


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transfusions.
Colonoscopy or 
sigmoidoscopy 
with biopsy
Can be associated with 
diarrhea, abdominal pain, 
perforation, bleeding, effects 
from anaesthetic 
medications, and infection
These risks will be addressed by 
careful monitoring and risk mitigation 
measures such as 
(a)
close clinical monitoring for 
AEs;
(b)
selection of sites with 
experienced site staff;
(c)
colonoscopy/sigmoidoscopy
will be done according to the 
standard local care procedure 
including local clinic/hospital 
consent authorizing this 
procedure
(d)
training
Other risks
Administration of 
Placebo
If the patient is randomized 
to receive a placebo, the 
patient´s condition could get 
worse during the course of 
the trial.
If the patient, including placebo 
treatment patient, requires additional 
medical therapy to treat the 
underlying ulcerative colitis due to 
disease worsening the study drug 
must be discontinued and patients 
may receive conventional treatment 
for active disease.
Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of Women of Child Bearing Potential 
(WOCBP) in this study is justified. To minimize the risk of unintentional exposure of an 
embryo or fetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods described in Section 4.2.2.2
Summary of benefit-risk assessment
Due to the lack of mechanism- or compound-related safety signals and the antagonistic mode 
of action of BI655130 (SPESOLIMAB) it is considered unlikely that UC patients be exposed 
to any undue risks in this trial. Considering the medical need of the development of an 
effective and well tolerated drug specifically and directly treating the structural aspects 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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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
This trial has two sequentially enrolling parts with different objectives. The primary 
objectives of this trial are
•
to prove the concept of clinical activity of BI655130 (SPESOLIMAB) in patients with 
moderate-to-severely active ulcerative colitis who have failed previous biologic 
treatments and to identify efficacious and safe dose regimens in Part 1 (Phase II)
•
to confirm efficacy and safety of BI655130 (SPESOLIMAB) in patients with 
moderate-to-severely active ulcerative colitis who have failed previous biologic 
treatments in Part 2 (Phase III)
•
To provide, along with induction study 1368-0018 and the run-in cohort of 1368-
0020, the target population to be evaluated in the randomised withdrawal study 1368-
0020.
Both parts of the trial share the same endpoints and definitions, though primary, key 
secondary and secondary endpoints will only be included in the statistical testing strategy in 
part 2 (Phase III).
2.1.2
Primary endpoint (Part 1 and Part 2)
•
Proportion of patients with Clinical Remission at week 12 
(defined as mMCS SFS=0 or 1, if drop ≥1 from BL; and RBS=0; and mESS≤1)
2.1.3
Key Secondary endpoints (Part 2 / Phase III only)
•
Proportion of patients with Mucosal Healing at week 12 
(defined as mESS ≤ 1)
•
Proportion of patients with Clinical response at week 12 
(defined as total MCS reduction ≥3 pts. and ≥30% from BL; AND RBS drop from 
baseline by ≥1pt., or absolute RBS ≤1 pt)
Note that for part 2 / Phase III only, the above-defined key secondary endpoints are included into the statistical 
testing strategy in a hierarchical manner subsequest to performance of the test on the primary endpoint. For 
further details, refer to Section 7.2
2.1.4
Secondary endpoint (Part 1 and Part 2)
•
Change in IBDQ score from baseline at week 12


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•
Proportion of patients with combined Mucosal healing and histologic remission 
at week 12
(defined as mESS ≤ 1 and Robarts Histology Index ≤ 6)
Note that for part 2 / Phase III only, the above-defined secondary endpoints are included into the statistical 
testing strategy in a hierarchical manner subsequest to performance of the tests on the key secondary endpoints. 
For further details, refer to Section 7.2
2.1.5
Secondary endpoints (Part 1 / Phase II only)
•
Proportion of patients with Mucosal Healing at week 12 
•
Proportion of patients with Clinical response at week 12 


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Table 2.2.2:1
Definition of Clinical Outcomes
Type of 
Response
MCS subscore
Total  
MCS
Modified 
MCS
RBS
mESS
SFS
PGA
Clinical 
remission
(CR)
0
≤1
0
or
1, and 
drop ≥1 
from 
baseline
≤2
Total Clinical 
remission 
(tCR)
≤1
≤1
≤1
≤1
≤2
Clinical 
response
≤1
or
Reduction 
from BL 
≥1
not 
missing
not 
missing
not 
missing
Reduction 
from BL 
≥3 and 
≥30%
Symptomatic
remission
0
≤1
0
≤1
≤2
•
Abbreviations: RBS – rectal bleeding score; mESS – modified endoscopic subscore;  SFS – stool frequency 
score; PGA – physician’s global assessment;
•
If greyed out, the corresponding criterion (in column) is not relevant to evaluate the corresponding type of 
response(in row) 
•
Total MCS is calculated as the sum of RBS, mESS, SFS and PGA
•
Modified MCS is calculated as the sum of RBS, mESS and SFS
•
Partial MCS is calculated as the sum of RBS, SFS and PGA


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-national, randomised, parallel-group, double-blind, phase II/III trial of 
BI655130 (SPESOLIMAB) in moderate to severe ulcerative colitis. This trial will investigate
and confirm the efficacy and safety of 12 weeks of induction treatment with different dose 
regimens of BI655130 (SPESOLIMAB) in patients with moderate-to-severe ulcerative colitis
who have failed previous biologic treatments in the past. 
The trial comprises two distinct parts with different objectives, but with identical study 
populations, study endpoints and visit schedules.Two of the three BI655130 (SPESOLIMAB)
regimens tested in Part 1 or a dose of 750mg q4w will be selected based on pre-defined 
decision criteria for confirmatory testing in part 2, but will not exceed the highest dose tested 
in part 1. The advantage of the operationally seamless design for the trial sites is the longer 
recruitment window, which will allow to enrol more patients, and to gain experience with the 
protocol measures. The anticipated shortened duration between end of the first trial part and 
start of the next will reduce the risk of measurement errors and protocol violations within Part 
2, the confirmatory part of the trial. The overall expectation is therefore an increase in both 
site efficiency as well as the quality of the study. In addition, the increased experience with 
protocol measures is expected to lead to a reduction in the variability associated with efficacy 
measurements thereby increasing the precision of treatment estimates particularly in the 
confirmatory part, Part 2, of the trial. Finally, the accelerated recruitment compared to two 
separate trials may reduce time to availability of a new drug potentially filling a high unmet 
medical need in this population of patients.
A schematic overview of trial design is shown in Figure 3.1:1.
Figure 3.1:1 Trial Design
(1368-0017) OL LT Extension (SC dosing)
NR
R
1368-0017 
Re-induction 1200 iv.
R
ED
V1    V2 
V3     V4
V5
V6                                               
W0
W2    W4
W8
W12                                             W24
(1368-0020)   Maintenance Phase III 
(randomized)
Part II
n=390
1368-0020 
Re-induction BI 
dose2*  iv. 
R
Placebo (n=130)
BI dose 1* (n=130)
BI dose 2* (n=130)
NR
R
ED
Safety follow-up
Safety follow-up
V1   V2
V3     V4 
V5
V6                                                
W0
W2    W4
W8
W12                                             W24
Part I
n=160
Placebo iv.(n=40)
BI 450 mg q4w  iv.  
(n=40)
BI 1200 mg q4w  iv. 
(n=40)
Enrollment 
interrupted 
IMP adm: IMP administration at week0, 
week4, week8
EOT: End of treatment visit
EOS: End of study visit
ED: early discontinued
R: 
responder
NR: non-responder
*    :  two of the three 
regimens 
tested in Part 1 or a dose of 750mg q4w  
will be selected based on part 1 results 
following pre-defined decision criteria
IMP adm
IMP adm
IMP adm
EOT
IMP adm
IMP adm IMP adm
EOT 
EOS
EOS
BI 300 mg  SD  iv.  
(n=40)


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Table 3.1:1
Study definitions
Rescue Treatment
New or increase in dose of any medication, or a surgical 
procedure, applied to treat new or worsening symptoms related to
ulcerative colitis
Disease worsening
Worsening of clinical status or symptoms of ulcerative colitis 
requiring administration of rescue medication in the investigator`s 
opinion – in patients without a clinical response
Disease flare
Increase in partial MCS score by ≥ 2 points from baseline (in 2 
subsequent visits) and increase in rectal bleeding score by ≥ 1 
point from baseline (in 2 subsequent visits), confirmed by 
increase of modified endoscopic subscore by ≥ 1 point from 
baseline with modified endoscopic subscore abs. increase  by ≥ 2 
points in absence of enteric pathogens in stool
Treatment Failure
Disease worsening, need for rescue medications or surgical 
intervention for treatment of UC; or a study drug-related adverse 
event, leading to discontinuation from treatment with study drug.
For clinical endpoint definitions cf. table 2.2.2:1
The distinct trial parts are defined as follows:
3.1.1
  Part 1 / Proof of Concept 
Part 1 of the trial will consist of a screening period of up to a maximum of 5 weeks and a 
12 week, parallel group, placebo-controlled, double-blind intravenous induction therapy 
period, and a 12 week safety follow-up period for patients not rolling-over into 
maintenance trial 1368-0017.
Approximately 160 eligible patients with moderate to severe ulcerative colitis who have 
failed previous biologic treatments in the past will be randomised in a 1:1:1:1 ratio to one 
of the 4 following treatment groups:
Group 1: Placebo i.v., q4w
(n=40)
Group 2: BI655130 (SPESOLIMAB) 300 mg i.v., single dose (SD)
(n=40)
Group 3: BI655130 (SPESOLIMAB)  450 mg i.v., q4w
(n=40)
Group 4: BI655130 (SPESOLIMAB)  1200 mg i.v., q4w
(n=40)
Enrolment will be competitive. Randomization will be stratified by previous BIO 
treatment failure and concomitant corticosteroid therapy at visit 2/randomization. In 
addition, a stratification for Japan versus non-Japan will be done in order to assure that 
sufficient patients per treatment group are recruited specifically to support individual 
country submission in Japan; this strata will be treated as an operational strata and will 
not be included into the analyses of the primary endpoint. Screening of patients who have 


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failed TNFɑ antagonists-AND-Vedolizumab will be closed once 48 patients have been 
randomized into this stratum (cf. Section 4.1.3).
Part 1 will explore the efficacy (proof of concept of clinical activity) and safety of three
different dose regimens of BI655130 (SPESOLIMAB) compared to placebo as induction 
treatment in ulcerative colitis; the PK/PD relationship in ulcerative colitis will also be 
established and help select the two dose regimens for part 2. A total of 160 patients will 
be randomized (1:1:1:1) to receive 12 weeks of treatment with BI655130 
(SPESOLIMAB) 300 mg i.v. SD, BI655130 (SPESOLIMAB) 450 mg i.v. q4w; 
BI655130 (SPESOLIMAB) 1200 mg i.v. q4w, or matching placebo. At week 12, patients 
will be evaluated for the primary endpoint of clinical remission. 
Patients who terminate study drug early will continue safety follow up in this study until
16 weeks after last study drug administration, while patients who complete the 12-week 
primary endpoint assessment in part 1 of this study will enter the maintenance trial 1368-
0017, which offers open label active treatment with BI655130 (SPESOLIMAB) guided 
by the outcome of Part 1 of the induction trial:
-
patients meeting the clinical response endpoint (cf. Section 5.1) at week 12 will 
receive long-term maintenance treatment with SC maintenance dosing of BI655130 
(SPESOLIMAB) for up to 7 years. 
-
patients not achieving the clinical response (whether on active drug or placebo) at 
week 12 of Part 1 of the trial will undergo a further 12 weeks open label re-induction 
with a high dose i.v. regimen of BI655130 (SPESOLIMAB) in trial 1368-0017, after 
which eligibility will be re-assessed. If the patient subsequently meets the clinical 
response definition, then patients will be entered into the s.c. maintenance part, while
non-responders will be discontinued from the trial 1368-0017.
3.1.2
Transition from Part 1 to Part 2 
1368-005/Part 1 will be the first part to commence. After the last patient has been 
enrolled into part 1, enrollment will be interrupted until the initiation of screening into 
part 2 has been released by the sponsor based on a thorough review of the clinical 
efficacy and safety as well as pharmacokinetic results of part 1 both by the independent 
DMC and a part 1 review committee which includes sponsor representatives, the DMC 
chair and the co-ordinating investigators.
The following doses are available for testing in Part 2 of the trial: 300 mg SD (approx. 
100 mg q4w), 450 mg q4w, 750 mg q4w, and 1200 mg q4w. No other dose is foreseen to 
be selected for Part 2. Criteria have therefore been defined to guide the part 1 review 
committee decision on the initiation of Part 2 and on which of the pre-specified 
BI655130 (SPESOLIMAB) doses will continue into Part 2; the part 1 review committee 
may however select different regimens from the available doses than those pre-defined in 
this section following their review of the data.


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3.1.3
Part 2 / Confirmatory Efficacy/Safety Evaluation
Part 2 of the trial will consist of a screening period of up to a maximum of 5 weeks, a 12 
week, parallel group, placebo-controlled, double-blind intravenous induction therapy 
period, and a 12 week safety follow-up period for patients not rolling-over into 
subsequent maintenance study 1368-0020.
Approximately 390 eligible patients with moderate to severe UC who have failed 
previous biologic treatments in the past will be randomised in a 1:1:1 ratio to one of the 3 
following treatment groups:
Group 1: Placebo i.v. q4w 
(n= 130)
Group 2: BI655130 (SPESOLIMAB) selected low dose i.v. q4w
(n= 130)
Group 3: BI655130 (SPESOLIMAB) selected high dose i.v. q4w
(n= 130)
For the dose selection process for part 2 cf. Section 3.1.2.
Randomization will be stratified by previous BIO treatment failure and concomitant 
corticosteroid therapy at visit 2/randomization. In addition, a stratification for Japan 
versus non-Japan will be done in order to assure that sufficient patients per treatment 
group are recruited specifically to support individual country submission in Japan; this 
strata will be treated as an operational strata and will not be included into the analyses of 
the primary endpoint. Screening of patients who have failed TNFɑ antagonists-AND-
Vedolizumab will be closed once 117 patients have been randomized into this stratum (cf. 
Section 4.1.3).
Part 2 will be one of two independent trials to confirm the efficacy and safety of induction 
treatment with BI655130 (SPESOLIMAB) in a randomized, double-blind, placebo 
controlled design. This part is assumed to have an identical population to that of Part 1 
and will initiate, once review of the completed Part 1 data has been performed and 


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decision on part 2 doses has been taken. This scenario is fully dependent upon the pre-
defined decision criteria for Part 1 having been successfully met (see Section 3.1.2).
Patients who discontinue study drug early will be followed up in this study until 16 weeks 
after last study drug administration, while patients who complete the 12-week primary 
endpoint assessment in part 2 of this study will enter the pivotal maintenance trial 1368-
0020, which offers a randomized maintenance treatment guided by the outcome of Part 2
of the induction trial:
-
patients on BI655130 (SPESOLIMAB) treatment who meet the clinical response 
endpoint (cf. Section 5.1) at week 12 will be entered into the double-blind, placebo 
controlled randomised withdrawal study (1368-0020) and randomized to receive 
subcutaneous treatment with BI655130 (SPESOLIMAB) or placebo until week 52.
-
patients on placebo treatment who meet the clinical response endpoint (cf. Section 
5.1) at week 12 will be entered into the double-blind, placebo controlled randomised
withdrawal study (1368-0020) and mock-randomized to receive subcutaneous 
treatment with placebo until week 52. 
-
patients not achieving a clinical response (whether on active drug or placebo) will 
undergo a further 12 weeks open label i.v. re-induction with BI655130 
(SPESOLIMAB) in study 1368-0020, after which eligibility will be re-assessed. 
Patients who subsequently meet the clinical response definition, will be randomized 
into the randomized withdrawal part of study 1368-0020, while non-responders will 
be discontinued from the trial 1368-0020.
3.1.4
Follow-up period: 
After completion of treatment period, those patients not rolling over into one of the 
maintenance trials (1368-0017 or 1368-0020) will continue safety follow-up for an additional 
12 weeks after the Visit 6.  This observation period covers 16 weeks after the last dose of 
BI655130 (SPESOLIMAB) which represents around 4-5 half lives of BI655130 
(SPESOLIMAB).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This operationally seamless trial design, with separate proof-of-concept (Part 1, phase II) and 
confirmation of efficacy and safety parts (Part 2, phase III), will include pre-defined decision 
criteria for continuing BI655130 (SPESOLIMAB) doses from Part 1 into Part 2 (see Section 
3.1.2), with the intent of ensuring that a positive proof-of-concept will quickly be followed by 
the confirmation of efficacy and safety of this new compound with its unique dual mode-of-
action in patients with ulcerative colitis. Should Part 1 results, however, indicate the need for 
design modifications in Part 2 beyond those pre-specified in the protocol (i.e. pre-specified 
dose selection), then initiation of Part 2 may be postponed until the required modifications 
have been implemented via a global CTP amendment (e.g. other dose regimens or endpoints).


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A parallel group, randomized, double-blind and placebo controlled trial was considered most 
appropriate to demonstrate PoC, while a PK/PD modelling approach will be employed to 
select two doses for subsequent confirmation of the efficacy and safety of BI655130 
(SPESOLIMAB). The placebo control group in Parts 1 and 2 is thus required to compare both 
efficacy and safety of BI655130 (SPESOLIMAB) in patients with moderate-to-severely 
active ulcerative colitis who failed previous biologic treatments. However, all placebo 
patients failing induction treatment will be offered open label active re-induction treatment as 
part of the subsequent maintenance trials.
The selection of target patients with moderate-to-severely active ulcerative colitis who failed 
at least one previous biologic treatment (defined as an inadequate response or loss of 
response to TNF antagonists and/or vedolizumab) is based on the high unmet medical need in 
such patients, where persistent mucosal inflammation is associated with an increased risk of 
disease progression, colon cancer and other complications. 
The treatment duration of 12 weeks with BI655130 (SPESOLIMAB) was selected for both 
parts to exceed the 4-8 weeks duration of induction treatment reflected in the labels of 
biologics currently approved for IBD [R15-4915, R17-1974]. This duration has been 
extended with the aim to maximize treatment efficacy and inform on the optimal induction
duration with this new mode of action. 
The three active induction dose regimens in part 1 of 300mg i.v. SD, 450mg i.v. q4w and 
1200mg i.v. q4w have been selected to represent one partially effective (300mg SD) and two 
effective dose schedules, based on receptor occupancy rates, ITE and PK/PD results from
phase I studies (cf. Section 4.1.2). Part 1 will allow to establish proof-of-concept and 
dose/exposure-response relationship, and thus to select the optimal dose regimens for Part 2 
of this trial. Part 2 will investigate the two most efficacious, tolerable and safe doses from the 
Part 1 regimens, unless an unexpected safety or efficacy finding requires dose modification
beyond the pre-specified transition scenarios in Section 3.1.2 per CTP amendment.
Thus, this trial design is considered adequate to achieve the objectives outlined above.
3.3
SELECTION OF TRIAL POPULATION
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
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.


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3.3.1
Main diagnosis for trial entry
Patients with moderate-to-severely active ulcerative colitis who have failed previous biologic 
treatments.
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
Each patient must meet all of the following inclusion criteria to be included into the trial:
1. 18 - 75 years, at date of signing informed consent, males or females
2. Diagnosis of ulcerative colitis ≥ 3 months prior to screening by clinical and endoscopic 
evidence corroborated by a histopathology report
3. Moderate to severe activity (total MCS 6 to 12 with a RBS ≥ 1 AND an SFS ≥ 1  AND 
mESS ≥ 2 within 7-28 days prior to first dose)
4. Endoscopic activity extending proximal to the rectum (≥ 15 cm from anal verge)
5. Well-documented demonstration of inadequate response or loss of response or have had 
unacceptable side effects with approved doses of TNFɑ antagonists (infliximab, 
adalimumab, golimumab) and/or vedolizumab in the past as per definition in the CTP 
Appendix 10.6 (screening of both TNFɑ antagonists-AND-Vedolizumab failure
patients will be capped once 48 randomized patients in Part 1 and 117 randomized 
patients in Part 2 meet this criterion; patients who have already been screened at the 
time of the cap will continue to be randomized into the study)
6. May be receiving a therapeutic dose of the following: 
-
Oral 5-ASA compounds, provided that dose has been stable for at least the 4
weeks immediately prior to randomisation, and/or
-
Oral corticosteroids (≤ 20 mg per day of prednisone or equivalent), provided that 
dose has been stable for the 2 weeks immediately prior to randomisation, and/or 
-
Oral budesonide (≤ 9 mg per day) or beclomethasone dipropionate (≤ 5 mg per 
day), provided that dose has been stable for the 2 weeks immediately prior to 
randomisation,  and/or 
-
Azathioprine, 6-MP or methotrexate, provided that dose has been stable for the 8 
weeks immediately prior to randomisation.
-
Probiotics (e.g. S. boulardii) provided that dose has been stable for the 4 weeks 
immediately prior to randomisation.
7. Patients with extensive colitis or pancolitis of >10 years duration or family history of 
colorectal cancer or personal history of increased colorectal cancer risk must have had a 
negative colorectal cancer screening within <1 year prior to enrolment (otherwise to be 
done during screening colonoscopy).
8. Women of childbearing potential (WOCBP) must be ready to 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 


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meeting these criteria is provided in Section 4.2.2.2 Restrictions regarding women of 
childbearing potential 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. Tuba 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 for 1368.5, in accordance with GCP and 
local legislation prior to admission into the trial
3.3.3
Exclusion criteria
3.3.3.1
Gastrointestinal Exclusion Criteria
Patients meeting any of these exclusion criteria must not be enrolled into the trial:
1. Evidence of abdominal abscess at screening
2. Evidence of fulminant colitis or toxic megacolon at screening
3. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
4. Treatment with:

any non-biologic medication (e.g. cyclosporine, tacrolimus or mycophenolate mofetil, 
intravenous corticosteroids, tofacitinib), other than those allowed per inclusion 
criteria, which is listed in Section 4.2.2 within 30 days prior to randomisation

any biologic treatment with a TNFantagonist (adalimumab, infliximab, golimumab, 
certolizumab) or vedolizumab within 8 weeks prior to randomisation. (If drug level 
testing for previously used biologic treatment confirms no detectable drug level 
before randomization, patient can be enrolled despite not having completed 8 weeks 
from last treatment.) 

any previous treatment with an approved dose of ustekinumab where locally approved 
and available. 

rectal 5-ASA, parenteral or rectal corticosteroids (incl. budesonide) within 2 weeks 
prior to screening

any investigational non-biologic drug for UC (including but not limited to JAK 
inhibitors, S1P modulators) within 30 days prior to randomisation

any investigational biologic for UC (including IL-12 and IL-23 inhibitors;
etrolizumab) within 8 weeks.  (If drug level testing for previously used biologic 
treatment confirms no detectable drug level before randomization, patient can be 
enrolled despite not having completed 8 weeks from last treatment.)

any prior exposure to BI655130 (SPESOLIMAB), natalizumab or rituximab
5. Positive stool examinations for C. difficile (toxin A/B – test positive) or other intestinal 
pathogens < 30 days prior to screening
6. Have had previous surgery or are anticipated to require surgical intervention for UC


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7. Evidence of colonic moderate/severe mucosal dysplasia or colonic adenomas, unless 
properly removed 
8. Primary sclerosing cholangitis
9. Faecal transplant ≤ 30 days prior to randomisation
3.3.3.2
Infectious Disease Exclusion Criteria
10. Increased risk of infectious complications (e.g. recent pyogenic infection, any congenital 
or acquired immunodeficiency (e.g. HIV), past organ or stem cell transplantation)
11. Live or attenuated vaccination within 6 weeks prior to screening
12. Active or latent TB: Patients with a positive TB test during screening are excluded, 
unless:

Patient had previous diagnosis of active or latent TB and has completed appropriate 
treatment per local practice/guidelines within the last 3 years and at least 6 months 
before first administration of trial medication under this protocol (patients may be re-
screened once to meet this criterion)

A positive QuantiFERON TB (Patients with suspected false positive or indeterminate 
QuantiFERON TB result may be re-tested once) 

If Quantiferon not available or providing indeterminate results after repeat testing, 
tuberculin skin test should be performed: A tuberculin skin test positive reaction 
≥10mm (≥5mm if receiving ≥15mg/d prednisone or its equivalent)
13. Relevant chronic or acute infections including active tuberculosis, human 
immunodeficiency virus (HIV) infection or   viral hepatitis. A patient can be re-screened 
if the patient was treated and is cured from the acute infection.
3.3.3.3
General Exclusion Criteria
14. Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal cell carcinoma or squamous 
cell carcinoma of the skin, or history of cervical cancer in situ (treated >3years); patients 
with remote history of malignancy (≥5 years prior) may be considered and have to be 
discussed with sponsor case-by-case
15. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to randomization or planned during study conduct, e.g. hip replacement.
16. Pathological safety lab parameters: haemoglobin < 9 g/dL, total white blood count 
(WBC) < 3000 cells/µl, neutrophils < 1000 cells/µl, thrombocytes < 100.000/µl, 
creatinine ≥ 2 mg/dL, total bilirubin > 2 x ULN with ratio of direct/indirect >1 (patients 
with Gilbert’s syndrome are not excluded), Alkaline Phosphatase >3 x ULN. –
measured and confirmed by Central laboratory at screening visit. 


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17. Currently enrolled in another investigational device or drug study (for investigational 
studies except any patient who have completed investigational drug treatment including 
residual effect period)
18. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
19. 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 
20. Any psychiatric or social problems possibly interfering with ability to comply with all 
study visits/procedures
21. History of allergy/hypersensitivity to the systemically administered trial medication 
agent or its excipients.
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see Sections 3.3.4.1 and 
3.3.4.2 below.
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 randomization, as well as the
explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and CRF.
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.The patient can no longer be treated with trial medication
for other medical reasons (such as surgery, adverse events, other diseases, or 
pregnancy).

If a hepatic injury alert (as defined in Section 5.2.6.1) is detected without 
identification of an alternative cause in the work-up according to the “DILI checklist”, 
discontinuation of treatment with study drug should be considered.

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 


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or able to stick to the trial requirements in the future. For individual stopping rules 
related to specific adverse events, please see Section 4.2.1 Other treatments and 
emergency procedures.
Patients who terminate study drug early should be encouraged to follow all study procedures 
per the Flow Chart until week 12, but not receive any more study drug at the respective visits.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and Section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the CRF. 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.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see Section 3.3.4.1
above.
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 trial protocol, or the contract impairing the appropriate conduct of 
the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1 Description of test product, BI655130 (SPESOLIMAB)
Substance:
BI 655130 (BI655130 (SPESOLIMAB))
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:
150mg/vial (20mg/mL), 7.5mL fill volume
Route of administration:
Intravenous infusions
Posology:
300 mg single dose at Week 0; or
450 mg, 750 mg or 1200 mg at Week 0, 4  and 8
Duration of use:
12 weeks
Table 4.1.1: 2 Description of test product placebo to BI655130 (SPESOLIMAB)
Substance:
Placebo to BI 655130 (BI655130 (SPESOLIMAB)); 
7.5mL fill volume
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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Table 4.1.1: 3 Description of test product BI655130 (SPESOLIMAB)
Substance:
BI 655130 (BI655130 (SPESOLIMAB))
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:
BI655130 (SPESOLIMAB) 300 mg/vial (60mg/mL), 
5 mL fill volume
Route of administration:
Intravenous infusions
Posology:
300 mg single dose at Week 0; or
450 mg, 750 mg or 1200 mg at Week 0, 4  and 8
Duration of use:
12 weeks
Table 4.1.1: 4 Description of test product placebo to BI655130 (SPESOLIMAB)
Substance:
Placebo to BI 655130 (BI655130 (SPESOLIMAB)), 
5mL fill volume
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
4.1.2
Selection of doses in the trial
The aim of part 1 of the study is to achieve proof-of-clinical-concept and select dose 
regimens for confirmatory testing in part 2. The BI655130 (SPESOLIMAB) dose regimens 
have been selected to represent a potential suboptimal dose (300mg SD) and two effective 
doses, one near (450mg, q4w) and one at (1200mg, q4w) the plateau of the dose response 
curve, based on receptor occupancy rates, ITE and PK/PD results obtained in phase I studies, 
indicating that doses ≥3 mg/kg achieved high target engagement in peripheral blood of 


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healthy volunteers, which has been sustained for at least 22 weeks after last dose, which 
represents the latest follow-up time point (IB c03320877-07). Thus, under consideration of 
the half life of ~4-5 weeks and the extended target engagement in healthy volunteers 
peripheral blood, the 300mg SD regimen, which correspond to ≥3mg/kg body weight for the 
vast majority of UC patients in a typical UC trial (assuming an average weight of 
approximately 75±15kg; R15-1340), this dose could represent a biologically active dose.
However, multiple fold higher doses are likely to be required to achieve larger effects in the 
gut tissue of patients with UC, due to their expected higher clearance rate, target expression 
and the need to penetrate into the tissue. To accommodate for these effects, 4.5-fold (450mg 
q4w) and 12-fold (1200mg q4w) higher doses will also be tested in part 1 of this trial and are 
likely to be near or at the plateau of the dose response curve. In summary it is anticipated that 
the proposed doses of 300 mg SD, 450 mg q4w and 1200 mg q4w over the 12-week period 
will support a robust characterization of the dose-response and exposure-response 
relationship.  
The doses for part 2 will be selected based on the results from part 1 as discussed above (cf. 
Section 3.1) and are expected to provide sufficiently differentiated PK exposures to translate 
into differential efficacy/safety and to allow appropriate exposure/ response analyses after 
completion of part 2. The criteria for dose selection in part 2 are specified in Section 3.1.2.
4.1.3
Method of assigning patients to treatment groups
During visit 2, eligible patients in both study parts will be randomised to receive 12 weeks of 
treatment (i.e. three administrations) with Placebo or either of the two (part 2) or three (part 
1) active dose regimens at equal distribution and stratified according to previous BIO 
experience (TNF-AND-Vedo versus TNF-OR-Vedo), and concomitant corticosteroid therapy 
at visit 2/randomization (yes/no). In addition, a stratification for Japan versus non-Japanwill 
be done in order to assure that sufficient patients per treatment group are recruited 
specifically to support individual country submission in Japan; this strata will be treated as an 
operational strata and will not be included into the analyses of the primary endpoint. In order 
to limit the proportion of last-line-treatment patients, screening of both TNF-AND-Vedo
failure patients will be capped once 48 randomized patients in Part 1 and 117 randomized 
patients in Part 2 meet this criterion; the patients who have been already screened at time of 
implementation of the cap will continue screening procedures in preparation for
randomization into the study.The assignment and capping of enrolment into the TNF-AND-
Vedo stratum will be done via Interactive Response Technology (IRT).
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
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 exist - restarting at a slower rate. Further, based on his medical judgment he/she will 


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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.
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.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
For Part 1 of the study, patients, investigators, as well as sponsor personnel involved in the 
trial conduct or analysis, will remain blinded with regard to the randomised treatment 
assignments until after the database lock for the final week 12 analysis on Part 1 has been 
performed. At this time, all dosing visits will have been completed, although some patients 
who did not roll-over directly into the maintenance trial (1368-0017) will continue the safety 
follow-up. Since the final analysis of part 1 of the trial in terms of both efficacy and safety 
will be complete, and because no further patient dosing visits are planned in this trial part, the 
randomization codes for part 1 will be formally unblinded subsequent to the week 12 
database lock, and the part 1 trial results will be published to support enrolment into part 2 of 
the study.
For Part 2 of the study, patients, investigators, as well as sponsor personnel involved in the 
trial conduct or analysis, will remain blinded with regard to the randomised treatment 
assignments until after the database lock for the final analysis on part 2 of the current trial has 
been performed. Once the database lock has been performed, the sponsor will be officially 
unblinded to the randomization details for this trial part and the part 2 trial results will be 
published to support enrolment into subsequent studies. Patients and investigators will 
continue to remain blinded to the individual treatment allocations in part 2 of the current trial 
through the end of the subsequent maintenance trial, 1368-0020. A logistics plan will be 
developed describing the mechanisms to be put in place to assure that the patients and 
investigators remain blinded to individual patient data, and which is to be finalized prior to 
the treatment unblind for the final analysis on Part 2.


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For each study part, the randomisation codes will be provided to bio-analytics prior to last 
patient out (or prior to last patient out for the week 12 analysis on Part 1) to allow for the 
exclusion from the analyses of PK samples taken from placebo patients. Bio-analytics will 
not disclose the randomisation code or the results of individual measurements for each trial 
part until the applicable trial part has been officially un-blinded to the sponsor. Serum drug 
levels 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 and analysis in accordance with sponsor’s standard procedures.
A fully external DMC will perform an un-blinded safety and efficacy assessment at specified 
intervals in order to ensure that patients are protected from potential harm, please refer to 
Section 7.4 for further details.
4.1.5.2
Unblinding and breaking the code
An emergency code break (envelope) will be available to the investigator / pharmacist / 
investigational drug storage manager (for Japan: only to the investigator). This code break 
may only be opened 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. If the code break for a patient is opened, the sponsor must 
be informed immediately. The reason for opening the code break must be documented on the 
envelope and/or appropriate CRF page along with the date and the initials of the person who 
broke 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 CRF 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 BI’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 not be shared 
further.
Treatment unblinding will be performed prior to each DMC meeting as a prerequisite for 
generation of the applicable DMC summaries required, subsequent to database lock for the 
12-week final analysis on Part 1 of the study, as well as subsequent to the final trial database 
lock at which time analyses on Part 2 of the study will be done. Treatment unblind for study 
Part 1 will be officially released once database lock for the week 12 final analysis on part 1
has been performed. Treatment unblind for study Part 2 will be officially released to the 
sponsor once database lock for the final analysis of part 2 of the current trial has been 
performed; mechanisms to protect the blind of patients and investigators for this trial part will 
be implemented through the end of the subsequent maintenance trial, 1368-0020 and will be 
described in a separate logistic plan (see Section 4.1.5.1).


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4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP). 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 details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) 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 Clinical Trial Protocol
(CTP) by authorized personnel as documented in the trial staff list. IMP will only be prepared 
for infusion just prior to infusion. 
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 clinical trial protocol by the IRB / ethics committee ,

Availability of a signed and dated clinical trial contract between the sponsor and 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,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
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 or warehouse / drug distribution centre or alternative disposal of 
unused products. If applicable, the sponsor or warehouse / drug distribution centre will 
maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to 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 or appointed CRO, the investigator / pharmacist / investigational drug storage 


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manager must verify that all unused drug supplies have been returned by the clinical trial
patient 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 ulcerative 
colitis medication to treat the underlying ulcerative colitis due to disease worsening (cf. Table 
3.1.1 Study Definitions), the study drug must be discontinued and patients may receive 
conventional treatment for active disease. Such patients should stay in the trial but will be 
considered as treatment failures in the intent-to-treat (ITT) analysis.
If infusion or anaphylactic reaction had already occurred in the very same patient in the past,
pre-treatment with steroids before next IMP administration is permitted as secondary 
prophylaxis.
Systemic steroids dosed intravenously or orally for less than 24 hours as treatment of infusion 
or anaphylactic reactions are permitted and do not lead to treatment discontinuation nor to 
assignment as treatment failures in the ITT analysis.
Management of Adverse Events:
Systemic hypersensitivity including infusion reaction and anaphylactic reaction
In case of systemic hypersensitivity including infusion reactions and anaphylactic reaction 
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, intravenous steroids, and in case of a severe allergic 
reaction (e.g., anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA as detailed in the Lab Manual (Section 10 of 
the ISF). Consider also the evaluation of histamine, serum tryptase, and complement 
components.
In case of systemic hypersensitivity including infusion reaction and anaphylactic reaction , 
based on patient`s clinical course and medical judgment, the infusion may be re-initiated in 
case of mild or moderate infusion reactions (according to RCTC grading of “allergic reaction 
/ hypersensitivity” in ISF) at lower speed with gradual increase to complete the infusion as 
detailed 
in 
the 
Instructions 
for 
Preparation 
and 
Handling 
of 
BI655130 
(SPESOLIMAB)/Placebo in the Investigator Site File.


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In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.7 R11-4890) suspected to be caused by the trial medication, the
investigator should discontinue treatment with study drug
When a non-acute hypersensitivity reaction related to immune complexes (i.e., serum 
sickness) is suspected, please draw a sample for the laboratory assessment for circulating 
immune complexes.
Severe infections (according to RCTC grading in Appendix 10.8), serious infections, 
opportunistic or mycobacterium tuberculosis infection 

Treatment of the infection should be initiated promptly according to local standard of 
care. No further trial medication should be administered until the active infection has 
resolved. Treatment with study drug may be restarted when the patient has recovered 
according to investigator’s assessment.
Malignancies

In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix, 
the investigator should discontinue treatment with study drug. Diagnostics and treatment 
have to be initiated according to local standard of care.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding previous and concomitant treatment are summarized in 
Table 4.2.2.1: 1
Table 4.2.2.1: 1
Restrictions regarding previous and concomitant treatment
Medication or class of medications
Restriction 
any biologic approved for UC adalimumab, 
infliximab, golimumab, vedolizumab
Not allowed from 8 weeks prior to randomisation or from 
time when no detectable drug level was confirmed until end 
of the trial
For use as rescue medication, refer to Section 4.2.1
any investigational or non-approved biologic for 
UC (incl. ustekinumab, other IL-23 inhibitors, 
etrolizumab, certolizumab) 
not allowed from 8 weeks prior to randomisation or when 
negative drug level is detected before randomization until end 
of the trial
For use as rescue medication, refer to Section 4.2.1.
Any prior treatment with a dose of Ustekinumab 
approved for UC
only applicable where locally approved and 
available
Any prior exposure is prohibited
Any non-biologic immunmodulator, other than 
those allowed per inclusion criteria #6 (incl. 
cyclosporine, tofacitinib and other JAK 
inhibitors, tacrolimus, sirolimus, mycophenolate 
mofetile)
Not allowed from 30 days prior to randomisation until end of 
the trial 
For use as rescue medication, refer to Section 4.2.1.
Any immunemodulator allowed per inclusion 
criteria #6 (Azathioprine, 6-mercaptopurine or 
methotrexate)
Only allowed during the trial, if dose is stable for at least 8 
weeks prior to randomisation until end of the trial
For use as rescue medication, refer to Section 4.2.1.
Any biologic for treatment for any other 
indication ( e.g. Dupilumab for the treatment of 
atopic dermatitis)
Not allowed from 8 weeks prior to randomisation until end of 
the trial
Fecal microbiota transplantation (FMT)
Not allowed from 30 days prior to randomisation until end of 
the trial
BI655130 (SPESOLIMAB), natalizumab or 
rituximab
Any prior exposure is prohibited
5-ASA
Oral administration:
Only allowed during the trial, if dose is stable for at least 4
weeks prior to randomisation until end of the trial
Rectal route of administration (5-ASA):
Not allowed from 2 weeks prior to screening up to end of the 
trial
For use as rescue medication, refer to Section 4.2.1.


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Table 4.2.2.1: 1
Restrictions regarding previous and concomitant treatment (cont.)
Medication or class of medications
Restriction 
Corticosteroids (incl. budesonide)
Oral administration:
Oral steroids are only allowed if indicated for treatment of UC 
and at a dose of ≤ 20mg per day of prednisone or equivalent 
and with stable dose for at least 2 weeks prior to
randomisation and throughout the trial.
Short (<7 days) decrease of dose for treatment of AEs with 
subsequent increase back to initial baseline dose level is 
allowed
Oral budesonide (≤9 mg per day), provided that dose has been 
stable for the 2 weeks immediately prior to randomisation
Oral beclomethasone dipropionate (≤5 mg per day), provided 
that dose has been stable for the 2 weeks immediately prior to 
randomisation
Parenteral administration:
Not allowed from 2 weeks prior to screening up to end of the 
trial.
Note: parenteral steroids dosed for less than 24hours as 
treatment of infusion or anaphylactic reactions are permitted.
Rectal administration:
Not allowed from 2 weeks prior to screening up to end of the 
trial
Note: steroids will be tapered (or discontinued for 
budesonide) in subsequent maintenance trial.
For use of steroids as rescue medication, refer to Section 
4.2.1.
Allowed steroid treatments:
Short-term use (<7 days) of systemic (oral or parenteral) 
corticosteroids is allowed for treatment of AE not related to 
the underlying UC from 4 weeks prior to randomisation until 
end of the trial.
Locally administered steroids as e.g. intra-articular, nasal 
inhalation or intra-ocular administration are allowed.
NSAID
Chronic use (i.e. daily use for >2 weeks) not allowed from 2 
weeks prior to screening up to end of the trial
(Note: occasional use of NSAIDs and acetaminophen for 
headache, arthritis, myalgias, menstrual cramps, etc., and 
daily use of baby or low dose (81-162.5mg) aspirin for 
cardiovascular prophylaxis are permitted.)
Probiotics 
Only allowed during the trial, if dose is stable for at least 4
weeks prior to randomisation until end of the trial
Live ofattenuated vaccines
Not allowed from 6 weeks prior to screening up
to end of the trial
Antibiotics for IBD 
Not allowed from 4 weeks prior to screening up to end of the 
trial


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4.2.2.2
Restrictions regarding women of childbearing potential 
Women of childbearing potential must use the contraception methods described below. 
This information is provided to the patients in the patient information.
Highly effective methods of birth control for female participants.

Combined (estrogen and progestogen containing) hormonal birth control associated 
with inhibition of ovulation.

Progestogen-only hormonal birth control associated with inhibition of ovulation.

Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS).

Tubal occlusion (blocking of the fallopian tubes).

Vasectomy of sexual partner (proven effective by absence of sperm on the
ejaculation).

True abstinence: When this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation
methods), declaration of abstinence for the duration of exposure to IMP, and 
withdrawal are not acceptable methods of contraception.
4.3
TREATMENT COMPLIANCE
Study medication will be administered in accordance with the protocol, under supervision of 
the investigating physician or a designee at the site. Any missed dose has to be documented 
and reported to the CT Manager.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The changes in UC activity during the trial will be assessed at visits including endoscopies 
using the modified Mayo score (disease activity score, not including the PGA (physician 
global assessment) item, but including the modified ESS (any degree of friability defines a 
score of at least 2), and the Robarts histopathology index (RHI). In addition, the total Mayo 
score (including PGA in addition to modified Mayo Score) will be explored as secondary 
endpoint to facilitate indirect comparisons against currently approved or investigational drugs. 
At all visits, the partial MCS (pMCS; all subscores except mESS) will be recorded to assess 
clinical disease activity.
Mucosal healing will be assessed by endoscopy using a blinded central reader and will be 
defined as a mESS ≤ 1. Local reading will be recorded for exploratory reasons, and to be
used for endpoint assessment if central reading is not available for technical reasons.
Please refer to Appendix 10.1 (Mayo Score/modified Mayo score) and to Appendix 10.2
(Robarts histopathology index) for further details. 
5.2
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
5.2.1
Physical examination
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.


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5.2.2
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 60 minutes post-dose.
Patients should be closely monitored for signs and symptoms of hypersensitivity reactions for 
approximately 2 hours after the first dose administered and 1 hour following all other doses 
of study drug. 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.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1. For the sampling time
points please see the flowchart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. A local laboratory may be used for selected tests in exceptional cases.
Patients should be fasting for at least 8 hours prior to the blood sample being taken (except 
screening visit).
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
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 AEs. 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].
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the ISF EDC
system. The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.


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Table 5.2.3: 1 Exclusionary testing1
Category
Test name
Infections screening (only at screening)
Hepatitis B Surface Antigen (qualitative)
Hepatitis B core Antibody
HBV-DNA (quantitative, PCR)2
Hepatitis C Antibodies (qualitative)
HIV-1, and HIV-2 Antibody (qualitative)
TB screening
QuantiFERON®-TB3, 4
Serum Pregnancy test (only for female patients 
of childbearing potential)
Human Serum Chorionic Gonadotropin 
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)
2 
A HBV-DNA should be conducted if Hepatitis B core Antibody is positive and Hepatitis B Surface Antigen 
is negative (definition of occult HBV infection: B core Antibody is positive, Hepatitis B Surface Antigen is 
negative; HBV DNA detectable).
3
There is the trial site option to perform a PPD skin test
4 
If the 1st QuantiFERON®-TB test result is undetermined, a re-test should be performed. If the restest 
QuantiFERON-TB test result is undetermined, a PPD skin test should be performed. This applies for 
QuantiFERON®-TB test at screening as well as at EOS visit.


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Table 5.2.3: 2 Laboratory tests
Category
Test name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)
Glycosylated Hbc (HbA1c) (only at screening)
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
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


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Table 5.2.3: 2 Laboratory tests (cont.)
Category
Test name
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
Urine (only at screening)
Albumin (quantitative)
Faecal sample 
Calprotectin
Lactoferrin
Infections screening
HBV-DNA (quantitative) EOT Visit2
QuantiFERON-TB test
QuantiFERON®-TB 3, 4, 5
1
Only in case of allergic reaction
2 
HBV-DNA in case of occult HBV infection (for definition see Table 5.2.3: 1 footnote 2)
3
There is the trial site option to perform a PPD skin test instead, if Quantiferon testing is not feasible
4
If the 1st QuantiFERON®-TB test result is undetermined, a re-test should be performed. If the restest 
QuantiFERON-TB test result is undetermined, a PPD skin test should be performed. This applies for 
QuantiFERON®-TB test at screening as well as at EOS visit.
5
The test will only be done at the end of study (EOS) visit in patients not continuing treatment in the 
subsequent maintenance study.
5.2.4
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the flowchart. The investigator or a 
designee will evaluate whether the ECG is normal or abnormal and whether it is clinically 
relevant, if abnormal. ECGs may be repeated for quality reasons and the repeated recording 
used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.


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Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
5.2.5
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 4.2.2.1. 
Also draw plasma sample for IgE and ADA (anti-drug antibodies), as detailed in the CTP 
Section 5.2.3 and the lab manual.
All cases of malignancies that are detected during the trial will be reported as SAEs. Patients 
with a history of malignancy (except for specific cancers) will be excluded from this trial per 
the exclusion criteria (Section 3.3.3).
5.2.6
Assessment of adverse events
5.2.6.1
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, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalisation or 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.


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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. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and AE reporting to sponsor and
timelines”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:

Systemic hypersensitivity including infusion reaction and anaphylactic reaction
o
Any suspicion of severe infusion reaction and of any potential cases of 
anaphylaxis should be defined and assessed using the criteria discussed in the 
statement paper from Sampson HA (Appendix 10.7 R11-4890).

Severe infections (according to RCTC grading in Appendix 10.8)

Opportunistic and mycobacterium tuberculosis infections 
o
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, 
post-transplant lymphoproliferative disorder (EBV), progressive multifocal 
leucoencephalopathy, bartonellosis (disseminated only), blastomycosis, 
toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), 
candidiasis (invasive or pharyngeal), cryptococcosis, other invasive fungi 
(mucormycosis (zygomycosis, rhizopus, mucor, lichtheimia), 
scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 


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mycobacterium, salmonellosis (invasive only), HBV reactivation, herpes simplex 
(invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, penicillium marneffei, sporothrix 
schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), trypanosoma cruzi infection (Chagas’ disease) (disseminated 
only), campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis 
(invasive due to vibrio vulnificus), HCV progression [R17-2617]
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
a.
ALT or AST >5x ULN 
b.
ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
c.
AST and/or ALT >3 fold ULN combined with an elevation of total bilirubin >2  
d.
fold ULN measured in the same blood draw sample
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.
If an alternative cause for the hepatic injury cannot be identified in the follow-up assessments 
specified in the “DILI checklist”, discontinuation of treatment with study drug should be 
considered.
Intensity (severity) 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
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 


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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 trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until the first dose of trial medication in the 
extension trial:
- all AEs (non-serious and serious) and all AESIs.

For patients not rolling over into subsequent open label extension studies:
from signing the informed consent onwards until the individual patient’s end of 
trial( including 16 weeks follow-up visit after last treatment dose) :
- all AEs ( non-serious and serious) and all AESIs.
After the individual patient’s end of the trial: 
the Investigator does not need to actively monitor the patient for AEs but should only 
report any occurrence of cancer  and trial treatment related SAEs and trial treatment 


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related AESIs of which the Investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form, but 
not on the CRF.
Figure 5.2.6.2: 1 Adverse event collection and reporting
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 immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process 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 send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. 
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.All (S)AEs, including those 


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persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable” , or no further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Studies and not the SAE form is to be 
completed. If there is an SAE and/or AESI associated with the pregnancy an SAE form must 
be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
BI655130 (SPESOLIMAB) 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 BI655130 (SPESOLIMAB) 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. 
5.3.2
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


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bioanalytical report, ADA aliquots will be transferred to long term storage for 
possible/optional ADA characterization in the future.
5.3.2.1
Plasma sampling for PK analysis 
For quantification of BI655130 (SPESOLIMAB) plasma concentrations, blood will be taken 
from a forearm vein into a K2EDTA (ethylendiaminetetraacetic acid) anticoagulant
blood-drawing tube at the time points listed in the Flow Chart under plasma PK. Handling
procedures can be found in the lab manual (Section 10 of the ISF).
After completion of the trial, the plasma samples may be used for further methodological
investigations, e.g. for stability testing. However, only data related to the analyte will be
generated by these additional investigations. The study samples will be discarded after
completion of the additional investigations but not later than 5 years upon the final study
report has been signed.
5.3.2.2
Plasma sampling for ADA assessment
For ADA assessment, blood will be taken from a forearm vein into a K2EDTA anticoagulant 
blood-drawing tube at the time points listed in the Flow Chart under plasma ADA. Handling
procedures can be found in the Laboratory manual (Section 10 of the ISF).
After completion of the trial, the plasma samples may be used for further methodological
investigations, e.g. for stability testing. However, only data related to the ADAs will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the final study 
report has been signed.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
The PK and PD data from this study will be used for investigation of the PK/PD relationship 
of BI655130 (SPESOLIMAB).


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5.5
OTHER ASSESSMENTS
Colonoscopy, Sigmoidoscopy
Colonoscopy and sigmoidoscopy will be performed according to standard of care. Local and
central reading will be performed according to information in ISF. Histopathology will be 
performed at a central laboratory.
Biopsy Collection Instructions
With proper consent, two sets of three biopsies (a total of 6 biopsies) will be obtained 
during each endoscopy procedure in the following order: Three (3) 
 
 for Histology and Immunohistochemistry (IHC) analysis
All biopsies taken at a visit should be taken in close proximity to each other (within 3 cm).
In patients where involved area extends to > 20 cm proximal the anal verge the biopsies 
should be taken between 15 and 20 cm.
In patients where involved area extends to < 20 cm proximal the anal verge the biopsies 
should be taken at the most proximal boundary of the involved site (at least 1 cm inside the 
boundary).
The distance of each biopsy sampling from anus must be noted down in the CRF for each 
subject.
All subsequent post-treatment biopsies for a subject should be taken approximately at the 
same distance from the anus, not more than 3 cm distal to the original site of baseline 
biopsies. These biopsies are taken irrespective of the location of the boundary of the involved 
site. 
Biopsies from the bed of the ulcers are not permitted. 
Optional assessment of drug level in blood of biologics used for the treatment of UC before 
screening for this study will be performed prior to randomization. Analysis will be done 
using a central laboratory vendor. This assessment will allow to randomize respective 
patients within a period shorter than 8 weeks when negative drug level of previous biologics 
is detected.
Patient-reported outcomes (PROs)
The following PROs will be used in trial 1368-0005:
IBDQ (Inflammatory Bowel Disease Questionnaire)
The IBDQ is the most frequently used disease-specific PRO instrument for the measurement 
of health-related quality of life in clinical trials with patients with IBD. It contains 32 
questions on bowel and systemic symptoms as well as emotional and social functioning. The 
aim of including the IBDQ is to offer a patient-reported perspective on a range of symptoms


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and impacts that have been shown to be relevant to patients with UC. Its psychometric 
properties in patients with IBD, including UC, are well-documented [R97-3596, R16-0240, 
R97-3472], and it has been used in several UC clinical trials [R17-2222, R15-1340, R17-
2223, R17-2217, R17-2221]. In a recent systematic literature review of disease-specific 
health-related quality of life questionnaires in IBD, it emerged as the measure with the best 
overall psychometric properties [R16-0031].
The response options describe the magnitude or frequency of impairment from 1 (most 
severe) to 7 (no impairment), and the sum score (range: 32-224 points) is reported. A score 
change of 16 is reported to reflect the minimal clinically important difference (MCID) [R16-
0240]. The recall period is 2 weeks.
SF-36 (36-Question Short Form) (part 2 only)
The SF-36 is a widely used instrument to measure health-related quality of life among 
healthy subjects and patients with acute and chronic conditions. It consists of 36 questions 
[R97-1093]. SF-36 scores can be compared across different populations of patients and 
healthy subjects. The purpose of the SF-36 in this study is to assess general health related 
quality of life of patients with UC. The SF-36 has been frequently used in UC and is judged 
to have good psychometric properties [R15-5976, R17-2222, R17-2221].
Response options vary but are mostly a 5- or 3-item Likert scale. Subscales (Physical 
Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-
Emotional, and Mental Health) are reported individually and summarised as Physical 
Component Summary (PCS) and Mental Component Summary (MCS) scores (range: 0-100, 
with a score of 50±10 considered to reflect the US norm [R16-0032]). A 4 point difference is 
recommended as an MCID threshold for between-groups comparisons of the PCS and MCS 
[R16-0033, R15-5876]. Given the nature of UC, the acute version of the SF-36 with a 1-week 
recall period will be used.
FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy – Fatigue) (part 2 
only)
The FACIT-Fatigue is a 13-item questionnaire [R10-6433, R07-4311] that assesses self-
reported fatigue and its impact upon daily activities and function.
The purpose of the FACIT-Fatigue in this study is to assess the impact of fatigue on subjects 
with UC. It has has been reported to have good reliability, validity and responsiveness for 
patients with UC [R15-5869, R15-5866, R15-5867].
Answers are based on a 5-point Likert scale. Responses of “not at all,” “a little,” “somewhat”, 
“quite a bit,” and “very much” are available for each question, and correspond to scores of 0, 
1, 2, 3, and 4, respectively (total score range: 0-52). An MCID of 3-4 points in change score 
has been reported [R16-0029]. The recall period for items is 7 days.


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WPAI-UC (Work Productivity and Activity Impairment Questionnaire, UC-specific 
version) (part 2 only)
The WPAI-UC is the UC-specific version of a frequently used questionnaire with 6 questions 
assessing social functioning, in particular regarding absenteeism, presenteeism and daily 
activity impairment.
Since UC predominantly affects adults of working age, the WPAI-UC is included in order to 
obtain patient-reported information on productivity loss due to UC and thus to estimate its 
societal impact. Validity, reliability and responsiveness in UC are supported by published 
data [R17-2219, R17-2216, R17-2218].
Response options include the number of hours worked and missed (due to UC and due to 
unrelated reasons) and a numeric rating scale (0-10) assessing the impairment of work and 
daily activities due to UC. Work impairment is calculated as the sum of presenteeism and 
absenteeism, with a 7% change in impairment estimated to be clinically meaningful [R15-
5875]. The recall period is 7 days.
EQ-5D-5L (EuroQol 5-level, 5-dimensional health-related quality of life measure)
The EQ-5D self-report questionnaire was developed by the European Quality of Life Group 
(EuroQol Group) and is a standardised instrument for use as a measure of health outcome 
[R96-2382]. It contains 5 questions on different dimensions of health (e.g. mobility, self-care) 
and one visual analogue scale on current health.
The EQ-5D is included primarily to derive utilities for different health states in UC for the 
purpose of cost-effectiveness modelling. In addition, published data also support the validity, 
reliability and responsiveness of its visual analogue scale as a measure of general health-
related quality of life in UC [R15-5871, R15-5868, R17-2219, R17-2221].
Response options include a five-level ordinal scale reporting on the five dimensions of health 
and a visual analogue scale reporting the patient´s self-rated health status as number between 
0 and 100. MCIDs for the five-dimensional part and the visual analogue scale have been 
estimated as 0.074 and 7 points, respectively [R10-0936, R16-0030]. All questions refer to 
the current health status (“today”).
Healthcare resource utilisation (HCRU), part 2 only
For the purpose of a separate health economic analysis (such as cost-utility analysis), health
care resource utilisation (HCRU) data will be collected throughout the study.
Resource use data collected for calculating direct costs will include unscheduled 
hospitalisations, healthcare provider visits, and emergency room/ICU use. 


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5.6
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 data
(with its window) up to EOS is to be counted from Day 0 (Visit 2). If any of these visits has 
to be rescheduled, the date of subsequent visits should be calculated from Day 0 (Visit 2).
There should be at least 14 days between two consecutive study drug administrations.
Follow-up visits (after EOT) refer to the last dose administration of BI655130 
(SPESOLIMAB) at visit V5 (Week 8). Additional visits for the purpose of re-testing of 
laboratory parameters or AE monitoring may be included as deemed necessary by the 
investigator.
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 Section 10 (Appendix) for explanations of
procedures. Additional details on procedures at selected visits are provided below. 
PROs should be completed by the patient on his/her own in the pre-specified order in a quiet 
area/room before any other visit assessments or treatments (including the first administration 
of study medication at V2), and, as much as possible, before any interaction with the 
investigator or other members of the study team.
The order of completion for PROs is as follows, as applicable for each PRO at relevant visits
according to the Flow Chart:
1. IBDQ
2. FACIT-Fatigue (part 2 only)
3. SF-36 (part 2 only)
4. EQ-5D-5L
5. WPAI-UC (part 2 only)
Measurement of vital signs should precede blood sampling and be assessed pre-dose at all 
dosing visits.
6.2.1
Screening and run-in period(s)
After patients have been informed about the trial, written informed consent in accordance 
with GCP and the local legislation must be obtained prior to performing any study related 
procedures.
Once they have consented, the patient is considered to be enrolled in the trial. The patient 
should be recorded on the subject enrolment log. Patient will be assigned a patient number 
and enrolment must be recorded in the eCRF pages.


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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 14 days prior to Visit 2. At this visit, information will be 
collected for evaluation of trial eligibility as indicated in the Flow Chart.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding UC) will be reported on the baseline condition eCRF page.
Patients who have a laboratory test value outside the range specified by the inclusion criteria 
may have the test repeated to determine eligibility. The result must be available prior to Visit 
2 (Day 0).
Demography
Informed consent date, gender, age, race and ethnic origin will be collected in the eCRF page. 
The patient’s smoking and alcohol history will also be assessed. Information concerning 
race/ethnicity will be collected as it has been suggested that there might be race/ethnicity 
variations in the incidence, phenotypic manifestations and outcome of UC. Note: In some 
countries, race may not be collected.
Medical and Surgical History
Information on clinically significant previous and concomitant illnesses, other than UC, or 
any clinically significant signs or symptoms that are present before informed consent, or pre-
existing conditions identified through findings from assessments and examinations done 
during the screening visits will be recorded as medical and surgical history at screening. For 
planned procedures/hospitalisations during the trial, documentation should be completed at 
the time of the screening. Regarding the UC, a detailed history of the disease, including date 
of diagnosis, disease extent and severity, hospitalizations, and extraintestinal manifestations 
will be collected. Also, previous and concomitant treatment for UC will be recorded. 
Blood sampling 
Blood samples will be taken for safety lab, infection screening (HIV, HBV, HCV, TBC). For 
women of childbearing potential, a serum pregnancy test will be performed. 
Optionally blood samples will be taken for drug level analysis of biologics previously used 
for UC.
Stool sampling
A stool sample will be collected to exclude existence of enteric pathogens. If collection is not 
possible at Visit 1a, stool sample has to be collected at (or prior to) Visit 1b or at an 
unscheduled visit. For further details, please refer to the lab manual (Section 10 of the ISF). 
Patient diary
Patients who are eligible at Visit 1a will receive a patient diary to be used for daily reporting 
of stool frequency and rectal bleeding (blood in stool) during the week prior to visits which 
include assessment of Mayo score


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Patients will be instructed on the use of the diary during screening and treatment phase. The 
diary will be returned at EOS visit.
Visit 1b:
The Visit 1b should take place no more than 28 days and no less than 7 days prior to Visit 2.
A full colonoscopy will be performed at this visit to assess disease extent and exclude 
malignancy (per local standard of care, e.g. by serial mucosal biopsies, chromoendoscopy, 
magnification endoscopy or other sensitive measures) if no fully documented procedure is 
available ≤ 12 months prior to screening. If a full colonoscopy is available from the past 12 
months prior to Visit 1, a sigmoidoscopy incl. biopsy will be performed instead. Images will 
be centrally read by an external independent assessor.
Based on the results from sigmoidoscopy (or colonoscopy, if applicable) and clinical 
symptoms of the patient, a baseline Mayo score will be determined. 
Results from the mucosal biopsies will be used as first baseline value for endpoint parameters.
Refer to Section 15 of the ISF for details.
For a detailed description of the trial procedures at Visits 1a and 1b, please refer to the Flow 
Chart.
The time window for Visit 1a and 1b other than is specified in the Flow Chart should be 
agreed at the discretion of the PI, in alignment with the trial monitor on a case by case basis.
Re-screening will be allowed once in part 1 and in part 2 respectively.
6.2.2
Treatment period(s)
The treatment period is from Visit 2 to End of Treatment (EoT) Visit.
Study related procedures will be performed as specified in the Flow Chart. 
Pregnancy testing
Urine pregnancy testing for all women of child-bearing potential will be conducted on-site 
approximately every four weeks and must be negative to continue treatment. The pregnancy 
testing should be done prior to study drug administration. A positive urine test must be 
confirmed with a serum pregnancy test.
Blood sampling
Blood sampling (e.g., for safety lab, BMs) should be done prior to study drug administration 
and prior to sigmoidoscopy, if applicable. Patients should come in a fasted condition. If a 
patient comes in a non-fasted condition, where a fasting condition is required, the visit should 
be performed, the non-fasted condition documented on the laboratory requisition, and the 
patient reminded about the expected conditions. 


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Sigmoidoscopies
Sigmoidoscopies will be done after blood sampling and prior to study drug administration. 
During sigmoidoscopies, biopsies will be taken for endpoint evaluation at time points as 
indicated in the Flow Chart. Please refer to Section 5 of the ISF for further information on the 
collection and the processing of biopsies. 
PK and ADA sampling
At visits with study drug administration, blood sampling for PK assessments should be done 
approximately within one hour prior to study drug administration.
Clinical monitoring after study drug administration:
The patient will be monitored for infusion reactions at the site for approximately 2 hours after   
after the end of first study drug infusion and 1 hour following all other doses of study drug. 
At all visits with study drug administration, vital signs will be assessed pre-dose, and at 
approximately 5 and 60 minutes after end of infusion. 
Unscheduled visits
The patient may be called in for additional unscheduled visits due to safety reason at the 
discretion of the investigator or the sponsor, unless the patient has withdrawn his/her consent. 
The patient may also contact the site due to safety reason for an unscheduled visit. The 
unscheduled visit may include additional collection of blood samples for safety reasons. The 
unscheduled visit may also include additional assessments deemed necessary by the 
investigator such as laboratory samples, ECGs, or other procedures which were missed at a 
previous visit. All unscheduled visits should be described (including the reason for the visit) 
and documented in the medical/source record, and in the eCRF.
Concomitant medication review
Data concerning concomitant medications and procedures will be collected throughout the 
trial, as specified in the Flow Chart. These data will be obtained at scheduled or unscheduled 
trial visits provided spontaneously by the patient or as a result of questioning the patient.
6.2.3
Follow up period and trial completion
For all patients, termination of trial medication and trial completion must be recorded on the 
corresponding eCRF.
For patients completing the safety FU period, the EOS visit is scheduled at 16 weeks after the 
last dose of study drug, ie at week 24 for those discontinuing after completing 12 weeks of 
treatment.
All patients completing the study will be offered to enter open label trial 1368-0017 or 1368-
0020 respectively, where responders will receive SC maintenance treatment, while non-
responders undergo i.v. re-induction. These patients are not requested to complete follow up 
period and will have their EOS visit at visit V6, co-inciding with the BL visit and start of 
study drug administration in 1368-0017 or 1368-0020 respectively.


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Early treatment discontinuation
Patients who terminate study drug early should be encouraged to follow all study procedures 
per the Flow Chart until week 12, but not receive any more study drug at the respective visits. 
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and Section 6.2.3.
Further treatment after the end of the trial
At the end of the trial, patients will be treated for their UC at the discretion of the investigator, 
according to local UC guidelines (e.g. ECCO guideline R17-0243).
Trial completion:
Trial completion is defined as a patient having reached the EOS visit. EOS visit will be at 
week 12 (V6) for patients rolling-over into subsequent maintenance trial; and at week 24 for 
patients who will not enter subsequent maintenance trial.
Regarding instructions for drug administration at missed or delayed visits, please refer to 
Section 4.1.4.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
This trial is designed as a randomised, parallel-group, and double-blind, and placebo-
controlled trial with 3 active doses of BI655130 (SPESOLIMAB) in Part 1 of the trial and 2 
active doses of BI655130 (SPESOLIMAB) in Part 2 of the trial in patients with moderate to 
severe ulcerative colitis who have failed previous biologic treatments in the past. 
The trial consists of 2 parts (cf. Section 3.1) which, for the purpose of statistical analyses, will 
be treated as two independent parts whereby the false positive rate is separately controlled 
within each trial part:
Part 1: To demonstrate proof of concept of clinical activity as an induction therapy on the 
primary endpoint of clinical remission at week 12 with respect to achieving a 
non-flat dose response curve, and subsequently to define suitable dose regimens
for BI655130 (SPESOLIMAB) regarding efficacy and safety for further pivotal 
testing in part 2 of this trial. For this purpose, a multiple comparison procedure 
with modelling techniques (MCPMod) approach is considered.
Part 2: to confirm the efficacy and safety of two different doses of BI655130 
(SPESOLIMAB) versus placebo as an induction therapy.
Formal statistical hypothesis testing will be performed at an overall 1-sided alpha 
level of 0.025.
Each trial part will be analyzed independently of the remaining trial part, i.e. 

Only patients randomized into part 1 will be included in the analyses of part 1, 

Only patients randomized into part 2 will be included in the confirmatory analyses of part 
2
In order to describe the full efficacy, safety and tolerability profile of BI655130 
(SPESOLIMAB) in the population of patients with moderate to severe ulcerative colitis who 
have failed previous biologic treatments in the past, a pooled efficacy and safety analysis by 
dose group will also be generated, if at least one of the BI655130 (SPESOLIMAB) doses is 
identical in both study parts.
Note that statistical testing will be performed based on one-sided hypotheses and p-values. 
For publication purposes also two sided p-values will be derived; details of this will be 
specified in the TSAP.
Decision criteria for determining the achievement of proof of concept and subsequent dose 
selection criteria for the two doses of BI655130 (SPESOLIMAB) that will be studied in Part 
2 of the trial are described in Section 3.1.2.
Randomization for parts 1 and 2 will be stratified based on 


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-
previous BIO treatment failure ( (TNFɑ antagonists-OR-Vedolizumab) versus (TNFɑ
antagonists-AND-Vedolizumab) ) and 
-
concomitant corticosteroid therapy at visit 2/randomization (yes/no)
-
Japan versus non-Japan
To assure that sufficient patients per treatment group are recruited specifically to 
support individual country submission in Japan; this strata will be treated as an 
operational strata and will not be included into the analyses of the primary endpoint.
In addition, due to the low number of patients to be recruited into part 1 of this trial, the 
primary analysis of this part will be performed without consideration of stratification.
The proportion of patients who achieve clinical remission at Week 12 is the primary efficacy 
endpoint for each part of this trial. Clinical remission is defined as achieving an RBS = 0, an
SFS = 0 or = 1 if there is a corresponding decrease ≥1 from baseline, as well as a modified 
ESS ≤1, each of these components being measured as a part of the modified Mayo Clinical 
Score (mMCS). Colonoscopy and sigmoidoscopy images will be centrally read by an external 
independent assessor(s); images will also be read locally. The primary analysis will be 
performed using the centrally-read endoscopy scores; only if centrally-read data are missing 
will the local endoscopy score be used instead.
Considering the binary nature of the primary endpoint, this trial is designed to show an 
increase in the proportion of patients who demonstrate clinical remission for BI655130 
(SPESOLIMAB) relative to Placebo. The primary analysis method for the confirmatory part 
of this trial (Part 2) will be the Cochran-Mantel-Haenszel risk difference estimation stratified 
by the randomization factors of previous BIO treatment failure and concomitant 
corticosteroid therapy at visit 2/randomization.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The null and alternative hypotheses are described below separately for each trial part.
Part 1
The null hypothesis is that there is a flat dose response curve comparing the placebo and the 
BI655130 (SPESOLIMAB) dose groups. The alternative hypothesis is that there is a non-flat 
dose response curve indicating a benefit of BI655130 (SPESOLIMAB) over Placebo. 
The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of Type I error (one sided α of 
20%). The pre-specified models and their parameters used for this test are outlined in Section 
7.3.1 and Section 7.7.
Part 2
Two doses of BI655130 (SPESOLIMAB) are planned to be investigated in this trial part; a 
low dose and a high dose. The exact doses to be included are dependent upon the outcome of 


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trial analysis on part 1 and the subsequent application of decision criteria as described in 
Section 3.1.2.
This part of the trial is designed to confirm that at least one of two selected doses of 
BI655130 (SPESOLIMAB) is superior to placebo in achieving clinical remission at Week 12 
in patients with moderate to severe ulcerative colitis who have failed previous biologic 
treatments in the past. 
The null and alternative hypotheses for each of these two tests on the primary endpoint are 
described as follows:
(1) BI655130 (SPESOLIMAB) low dose vs. Placebo
H0,11: Effect of BI655130 (SPESOLIMAB) low dose on clinical remission at week 12 ≤
Placebo;
  versus
HA,11: Effect of BI655130 (SPESOLIMAB) low dose on clinical remission at week 12 > 
Placebo.
(2) BI655130 (SPESOLIMAB) high dose vs. Placebo
H0,12: Effect of BI655130 (SPESOLIMAB) high dose on clinical remission at week 12 ≤
Placebo;
  versus
HA,12: Effect of BI655130 (SPESOLIMAB) high dose on clinical remission at week 12 > 
Placebo.
Further hypotheses will be tested on the family of secondary endpoints in a hierarchical 
manner. The overall testing strategy used to control the type I error for each of the endpoints 
and for each of the treatments is described below. The null and alternative hypotheses for 
each of the two tests on each of the secondary endpoints are described as follows.
For Mucosal Healing at week 12
(3) BI655130 (SPESOLIMAB) low dose vs. Placebo
H0,21: Effect of BI655130 (SPESOLIMAB) low dose on mucosal healing at week 12 ≤
Placebo;
  versus
HA,21: Effect of BI655130 (SPESOLIMAB) low dose on mucosal healing at week 12 > 
Placebo.
(4) BI655130 (SPESOLIMAB) high dose vs. Placebo
H0,22: Effect of BI655130 (SPESOLIMAB) high dose on mucosal healing at week 12 ≤
Placebo;
  versus
HA,22: Effect of BI655130 (SPESOLIMAB) high dose on mucosal healing at week 12 > 
Placebo.


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For the Clinical Response at week 12
(5) BI655130 (SPESOLIMAB) low dose vs. Placebo
H0,31: Effect of BI655130 (SPESOLIMAB) low dose on clinical response at week 12 ≤
Placebo;
  versus
HA,31: Effect of BI655130 (SPESOLIMAB) low dose on clinical response at week 12 > 
Placebo.
(6) BI655130 (SPESOLIMAB) high dose vs. Placebo
H0,32: Effect of BI655130 (SPESOLIMAB) high dose on clinical response at week 12 ≤
Placebo;
  versus
HA,32: Effect of BI655130 (SPESOLIMAB) high dose on clinical response at week 12 > 
Placebo.
For the change from baseline in IBDQ at week 12
(7) BI655130 (SPESOLIMAB) low dose vs. Placebo
H0,41: Effect of BI655130 (SPESOLIMAB) low dose on change from baseline in IBDQ
at week 12 ≤Placebo;
  versus
HA,41: Effect of BI655130 (SPESOLIMAB) low dose on change from baseline in IBDQ
at week 12 > Placebo.
(8) BI655130 (SPESOLIMAB) high dose vs. Placebo
H0,42: Effect of BI655130 (SPESOLIMAB) high dose on change from baseline in IBDQ
at week 12 ≤Placebo;
  versus
HA,42: Effect of BI655130 (SPESOLIMAB) high dose on change from baseline in 
IBDQ at week 12 > Placebo.
For the combined Mucosal Healing and Histologic Remission at week 12
(9) BI655130 (SPESOLIMAB) low dose vs. Placebo
H0,51: Effect of BI655130 (SPESOLIMAB) low dose on combined Mucosal Healing 
and Histologic Remission at week 12 ≤Placebo;
  versus
HA,51: Effect of BI655130 (SPESOLIMAB) low dose on combined Mucosal Healing 
and Histologic Remission at week 12 > Placebo.


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(10) BI655130 (SPESOLIMAB) high dose vs. Placebo
H0,52: Effect of BI655130 (SPESOLIMAB) high dose on combined Mucosal Healing 
and Histologic Remission at week 12 ≤Placebo;
  versus
HA,52: Effect of BI655130 (SPESOLIMAB) high dose on combined Mucosal Healing 
and Histologic Remission at week 12 > Placebo.
Overall the testing strategy will follow a closed testing principle defining two families of 
endpoints/comparisons. The first family consists of the primary endpoint comparison for both 
doses of BI655130 (SPESOLIMAB) vs placebo, whereas the second family is defined by the
key-secondary (mucosal healing and clinical response) and secondary endpoints (change 
from baseline in IBDQ, and combined Mucosal Healing and Histologic Remission) 
comparisons for both doses of BI655130 (SPESOLIMAB) vs placebo.
Regarding the first family, to control the overall type I error rate at a 1-sided 0.025 alpha 
significance level for both of these two treatment comparisons on the primary endpoint at 
week 12, the (truncated) Hochberg method will be applied. The weight of the truncated 
Hochberg method is chosen as 0.5. Therefore, if both primary endpoint p-values are 
≤0.01875 (one-sided), then both comparisons involving the two BI655130 (SPESOLIMAB)
dose regimens will be declared statistically significant. If the maximum of the p-values for 
the two dose comparisons is >0.01875 (one-sided), then the other p-value will be tested at the 
0.0125 one-sided level and declared to be statistically significant only if that p-value is 
≤0.0125 (one-sided). The remaining alpha, ´, to be used in the second family will be 0.025 
(one-sided) if both primary endpoints show significance. If only one comparison is 
significant then ´ will be 0.025/4=0.00625 according to the truncated Hochberg procedure 
with weight of 0.5. If neither dose is declared to be statistically significant for the primary 
endpoint, then no further testing can be conducted. 
If both doses of BI655130 (SPESOLIMAB) on the primary endpoint are declared to be 
statistically significant, then the following graphical procedure will be used to attribute the 
remaining ´ to the testing of each of the (hierarchically-ordered) key-secondary and 
secondary endpoints as follows:


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Truncated Hochberg with ‘truncation fraction’= ½ 
One-sided alpha level= α
If both doses are
One-sided alpha= α`= α=0.025
Significant on primary
Note: H=High dose of BI655130 (SPESOLIMAB); L=Low dose of BI655130 
(SPESOLIMAB); P=Placebo
First Family
   Clinical Remission
OR
Second Family
α`/2
α`/2
   Mucosal
     Healing
   Clinical Response
   IBDQ Change
   Combined Mucosal
    Healing and
    Histologic Remission
BI low dose
vs.
Placebo
BI high dose
vs.
Placebo
H0,11: P1,L ≤ P1,P
HA,11: P1,L > P1,P
H0,12: P1,H ≤P1,P
HA,12: P1,H > P1,P
H0,21: P2,L ≤ P2,P
HA,21: P2,L > P2,P
H0,22: P2,H ≤P2,P
HA,22: P2,H > P2,P
H0,31: P3,L ≤ P3,P
HA,31: P3,L > P3,P
H0,32: P3,H ≤P3,P
HA,32: P3,H > P3,P
H0,51: P5,L ≤ P5,P
HA,51: P5,L > P5,P
H0,52: P5,H ≤P5,P
HA,52: P5,H > P5,P
H0,41: P4,L ≤ P4,P
HA,41: P4,L > P4,P
H0,42: P4,H ≤ P4,P
HA,42: P4,H > P4,P


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If both doses of BI655130 (SPESOLIMAB) show significance in the first family, then the 
remaining alpha (´=0.025, one-sided) to be used in the secondary family will be equally 
split between the two doses of BI655130 (SPESOLIMAB) leading to an intial of 0.0125 
per comparison. The test of a subsequent secondary endpoint in the hierarchical sequence, for 
a particular dose of BI655130 (SPESOLIMAB), is only performed if the test of the previous 
secondary endpoint on that same dose was successful. If, for one of the doses of BI655130 
(SPESOLIMAB), the test on each of the endpoints (primary, key secondary, and secondary) 
is successful, then the remaining alpha may be passed to the secondary endpoint comparisons 
regarding the other dose leading to an initial level of 0.025 (one-sided).
If only one of the doses of BI655130 (SPESOLIMAB) on the primary endpoint is declared to 
be statistically significant, then the following graphical procedure will be used to attribute the 
remaining ´ to the testing of each of the (hierarchically-ordered) key-secondary and 
secondary endpoints as follows:


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Truncated Hochberg with ‘truncation fraction’= ½ 
One-sided alpha level= α
If only one dose is
One-sided alpha= α`= α/4= 
Significant on primary
0.00625
Note: H=High dose of BI655130 (SPESOLIMAB); L=Low dose of BI655130 
(SPESOLIMAB); P=Placebo; BI= the singe dose of BI655130 (SPESOLIMAB) that was 
successful on the test of the primary endpoint (low or high dose)
First Family
   Clinical Remission
OR
Second Family
α`
Only test the
   Mucosal
successful dose
     Healing
from primary
   Clinical Response
   IBDQ Change
   Combined Mucosal
    Healing and
    Histologic Remission
BI low dose
vs.
Placebo
BI high dose
vs.
Placebo
H0,11: P1,L ≤ P1,P
HA,11: P1,L > P1,P
H0,12: P1,H ≤P1,P
HA,12: P1,H > P1,P
H0,2: P2,BI ≤ P2,P
HA,2: P2,BI > P2,P
H0,3: P3,BI ≤ P3,P
HA,3: P3,BI > P3,P
H0,5: P5,BI ≤ P5,P
HA,5: P5,BI > P5,P
H0,4: P4,BI ≤ P4,P
HA,4: P4,BI > P4,P


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If only one dose of BI655130 (SPESOLIMAB) shows statistical significance in the first
family, then the tests for the secondary family will only be performed with respect to the 
comparisons involving the same dose of BI655130 (SPESOLIMAB) for which the primary 
endpoint was successful, utilizing the remaining alpha (´=0.00625, one-sided) transferred
from the primary family. In this case, there will be no alpha passing to the other dose even if 
all tests on the secondary endpoints are successful. 
(Simulation-based) power calculations with respect to the planned sample size and the chosen
testing strategy for the primary analysis can be found in Sections 7.7.1 and 7.3.1 respectively.
7.3
PLANNED ANALYSES
There will be 4 main patient populations in this trial for analyses: the randomized set (RS), 
the safety analysis set (SAF), the modified RS (m-RS), and the per-protocol set (PPS). Each 
of these populations will be derived separately for each of the 2 trial parts.
Randomized Set (RS)
This patient set includes all randomized patients. Treatment assignment will be as 
randomized. This is the main analysis set for presentation of efficacy on binary endpoints.
Safety Analysis Set (SAF)
This patient set includes all patients who were randomized and received at least one dose of 
study drug. It will be the main analysis set for presentation of safety. Patients will be 
analyzed according to the actual treatment.
Modified Randomized Set (m-RS)
This patient set includes all patients in the RS who had a baseline and at least one post-
baseline measurement for the endpoint under consideration. Treatment assignment will be as 
randomized. This is the main analysis set for presentation of efficacy on continuous data, e.g.
IBDQ. 
Per-Protocol Set (PPS)
This patient set includes all patients in the RS who adhered to the CTP without any IPVs
(potentially affecting the study outcome) which lead to exclusion from the PPS. This set will 
be used for sensitivity analysis on the primary efficacy endpoint.
Further analysis sets, e.g. for the BM assessments, will be defined in the TSAP.
Important violations of the protocol will include violations of the key inclusion and exclusion 
criteria, incorrect medications taken, 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 
respective trial part.
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.


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The following analyses of this trial protocol, in chronological order, are planned:
Part 1 – Week 12 Final Analysis
The analysis will be performed once all randomised patients have completed the first 12 
weeks of Part 1 of the trial, and a database lock will be done. At this time, the final analysis 
of the efficacy and safety data through Week 12 on Part 1 will be performed and the Part 1 
data will be officially unblinded (see also Section 4.1.5.1). Details of the analysis to be
performed will be described in the Part 1 TSAP which is planned to be finalized prior to 
achieving database lock for the Week 12 analysis on Part 1.
The results on Part 1 will be reviewed by the DMC and by a part 1 review committee which 
includes sponsor representatives, the DMC chair and the co-ordinating investigators. The 
decision to amend or to initiate part 2 without modifications (taking into account the decision 
criteria described in Section 3.1.2) will be made by the sponsor based upon the
recommendations of the independent DMC and the part 1 review committee.
Part 2 – Confirmatory Part 2 Analysis
The final analysis will be performed once all randomised patients have completed Part 2 of 
the trial. At this time, the final analysis of the efficacy and safety data on Part 2 will be 
performed. This analysis actually reflects the final analysis of the trial, and the complete 
analysis of trial Part 2 hence there is no need to adjust the alpha level for this particular trial 
part. Details of the analysis to be performed will be described in the Part 2 TSAP which is 
planned to be finalized prior to achieving database lock for Part 2. For details on the nature of 
the unblind at this time, refer to Section 4.1.5.1.
Pooled efficacy and safety analyses of the entire trial, including both Parts 1 and 2, will be 
done, if applicable, as previously described. The follow-up data collected after week 12 for 
patients who continued in the safety follow-up of Part 1 will also be presented.
A Clinical Trial Report will be prepared which will describe the separate analyses performed 
on each of the trial parts, and also the pooled analyses of the entire trial.
7.3.1
Primary endpoint analyses
The evaluation of clinical remission at Week 12 is the primary objective for efficacy in each 
part of this trial and is described using the proportion of patients who achieve clinical 
remission at this time-point based on endoscopy results obtained from central reading. Only if 
the centrally read endoscopy result is missing at a time-point will the locally read result be 
used instead.
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.


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Part 1 – proof of clinical concept
Primary analysis
The primary endpoint is the proportion of patients with clinical remission after 12 weeks of 
treatment. 
The analyses for PoC and dose-finding will be performed using MCPMod techniques [R10-
1424, R15-1961] for binary data whereby several possible dose response models (patterns) 
will be evaluated (while keeping full control of the type I error at 20%, one-sided) to identify 
the best-fitting model. The doses which are included in Part 1 are placebo, and BI655130 
(SPESOLIMAB) 300 mg SD, 450 mg q4w, and 1200 mg q4w; for modelling purposes, 300 
mg SD will be approximated by a dose of 100 mg q4w in order to align doses on a single 
unit.
For the PoC testing and for the sample size calculation the following model assumptions and 
resulting graphs (Figure 7.3.1:1) have been selected to cover both the plausible and a diverse
range of potential dose response patterns:
Linear
Emax:
assumes 90% of the maximum effect is achieved at 300 mg SD dose
Exponential: 
assumes 1% of the maximum effect is achieved at 300 mg SD dose
Logistic: 
assumes 30% of the maximum effect is achieved at 300 mg SD dose and 
85% of the maximum effect is achieved at 450 mg q4w dose 
Sigmoid Emax: assumes 30% of the maximum effect is achieved at 300 mg SD dose and 
75% of the maximum effect is achieved at 450 mg q4w dose
Note that the actual shapes are applied on the parameter scale (logit for binary data) 
according to Pinheiro et al. [R15-4293] and that the q4w dose is used as model parameter.


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Figure 7.3.1: 1: Shape of the considered dose response patterns for the MCPMod analysis
PoC is established if at least one dose response pattern is statistically significant, rejecting the 
null hypothesis of a flat dose response relationship on clinical remission at week 12 jointly 
for each of the candidate dose response models, with a contrast test controlled for the family–
wise type I error rate at a one sided α = 20%. 
If PoC is established, the statistically significant model(s) from the above candidate set are 
refitted to the data to generate new estimates for all model parameters. 
The statistically significant model with the lowest Akaike Information Criterion (AIC) value 
will be determined as the best fitting model and will be used for characterization of the dose-
response curve.
The choice of two target doses to be investigated in Part 2 of the trial – the confirmatory trial 
part – is described in Section 3.1.2. The maximum effective dose, as well as the selection of
the two pre-specified doses for testing in Part 2, will be based on the modelled efficacy
estimates. Only doses within the dose range investigated (0 mg - 1200 mg q4w) will be 
considered.
If considered necessary and for the purpose of further model refinement, MCPMod might be 
repeated on the primary endpoint but with an extended set of shapes including the original 
candidates. Additionally a sensitivity analysis based on model averaging across the 
statistically significant models may be conducted in order to assess the robustness of the 
chosen primary approach. Furthermore, covariates may be taken into account in further


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sensitivity analyses, i.e. inclusion of stratification parameters. Details of these analyses will 
be described in the TSAP.
Further analyses
Unadjusted absolute risk differences of the clinical remission at week 12 between the 
BI655130 (SPESOLIMAB) arms and the placebo group will be provided. In addition 95% 
confidence intervals will be displayed. More details on the above analyses as well as potential 
additional sensitivity analyses will be described in the TSAP.
As a further analysis, a logistic regression model on the proportion of patients achieving 
clinical remission at week 12 with fixed factors for treatment, previous BIO and 
corticosteroid use as strata will also be applied for the RS. In case the model does not 
converge, an exact method may be employed. Otherwise, analyses will be performed 
adjusting for each of the strata (prior biologic use and concomitantcorticosteroid therapy at 
visit 2/randomization) individually.
The likelihood-ratio test will be used to test for differences between treatments. Adjusted 
odds ratios together with 95% confidence intervals will be used to quantify the effect of 
treatment, comparing all treatments to placebo; details will be provided in the TSAP.
Part 2 – formal, confirmatory statistical testing part
The primary analysis of the clinical remission for each dose of BI655130 (SPESOLIMAB)
versus placebo will be tested using the stratified Cochran-Mantel-Haenszel (CMH) test at a 
nominal 1-sided 0.025 significance level stratified by the randomization factors (prior 
biologic use and concomitantcorticosteroid therapy at visit 2/randomization) and based on the 
RS. The difference in the proportion of responders, and the associated confidence intervals 
will be presented for each active group versus the placebo group using the Mantel-Haenszel 
type weighted average of differences using weights as proposed by Greenland & Robins 
[R09-1299]. The approach to control the Type I error for multiple comparisons between the 
two BI655130 (SPESOLIMAB) doses and placebo is described in Section 7.2.
Secondary analysis of the primary endpoint will include:

A logistic regression model on the proportion of patients achieving clinical remission 
at week 12 with fixed factors for treatment, previous BIO, and concomitant 
corticosteroid use at visit 2/randomization as strata will be applied for the RS. In case 
the model does not converge, analyses will be performed adjusting for each of the 
strata (previous BIO and concomitant corticosteroid use at visit 2 /randomization) 
individually. 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.

Sensitivity analysis utilizing the PPS

Sensitivity analyses which utilize alternative methods for the handling of missing data 
as described in Section 7.5.


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Exploratory Pooled Analyses of Parts 1 and 2
In order to describe the full efficacy profile of BI655130 (SPESOLIMAB) in the population 
of patients with moderate to severe ulcerative colitis who have failed previous biologic 
treatments in the past, an integrated analysis of the clinical remission data, by dose group, 
will be generated for the RS, if at least one of the BI655130 (SPESOLIMAB) doses is 
identical in both study parts. Data from Parts 1 and 2 of the trial will be pooled together. The 
objectives of this pooled analysis are:

Increase precision on treatment estimates (and differences to Placebo) in this patient 
population;

Investigate effect of subgroups on the treatment effect, i.e.
o
Race
o
Gender
o
Region
o
Previous BIO use
o
Previous corticosteroid use
o
Other
An exploratory assessment of the pooled data from Parts 1 and 2 will be performed by 
repeating the primary analysis (stratified CMH test) as well as the sensitivity analysis using 
the [Part 2 specified] logistic regression model (including additionally a fixed effect for study 
part); only those treatments which are common to both parts will be included. All p-values 
presented will be considered nominal in nature and no adjustment for multiplicity will be 
made. Subgroups will be assessed descriptively.
7.3.2
Key Secondary endpoint analyses
For Part 1 of the study, there are no key secondary endpoints defined.
For Part 2 of the study, the treatment effects on the key secondary endpoints of mucosal 
healing at week 12, and clinical response at week 12 will be tested in a hierarchical manner as 
a part of the pre-specified testing strategy, subsequent to the test of the primary endpoint, 
which is defined in Section 7.2. The analysis of both endpoints will be performed using the 
same approach as that defined for the primary analysis in part 2 of the study based on the RS.
7.3.3
Secondary endpoint analyses
For both trial parts, the change from baseline of IBDQ scores at Week 12 will be analyzed 
based on the m-RS. It will be analyzed using a restricted maximum likelihood (REML) based 
repeated measures approach. The model will include fixed, categorical effects of treatment, 
visit and treatment by visit interaction, and stratification factors (prior biologic use and
concomitant corticosteroid therapy at visit 2/randomization), as well as the continuous, fixed 
covariates of baseline and baseline by visit interaction. An unstructured covariance structure 
will be used to model the within-patient measurements. The Kenward- Roger approximation 
will be used to estimate denominator degrees of freedom. The primary treatment comparison 
will be the contrast between treatments after 12 weeks of treatments. For Part 1 of the trial, if 
model convergence issues occur due to inclusion of strata in the model, these terms may be 
dropped and separately evaluated. 


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Part 1 – proof of clinical concept
If considered appropriate, a MCPMod approach may also be applied to selected secondary 
endpoints on Part 1 of the trial.
For each secondary binary endpoint, unadjusted absolute risk differences at week 12 between 
the BI655130 (SPESOLIMAB) arms and the placebo group will be provided along with the 
corresponding 95% confidence intervals. A logistic regression model may also be performed 
on the RS using the approach as described above for the further analyses on the primary 
endpoint of Part 1 of the trial.
Part 2 – formal, confirmatory statistical testing part
For Part 2 of the study, the treatment effects on the secondary endpoints of change from 
baseline in IBDQ at week 12 and combined mucosal healing and histologic remission at week 
12 will be tested in a hierarchical manner as a part of the pre-specified testing strategy, 
subsequent to the tests of the key secondary endpoints, which is defined in Section 7.2.
For all secondary endpoints which are binary in nature, the analysis will be performed using 
the same approach as that defined for the primary analysis based on the RS.
7.3.5
Safety analyses
Adverse events will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. Standard BI summary tables and listings will be 
produced. 
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of 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 16 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’. The primary set of safety outputs will be done including data through 
the first 12 weeks of treatment (consistent with the timing of the primary efficacy analysis); 
further outputs will be also produced which include all safety data through the REP.
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 the Medical 
Dictionary for Drug Regulatory Activities (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.
Immunogenicity data will be analysed in a descriptive way.
Pooled Analyses of Parts 1 and 2
In order to describe the full safety and tolerability profile of BI655130 (SPESOLIMAB) in 
the population of patients with moderate to severe ulcerative colitis who have failed previous 
biologic treatments in the past, an integrated analysis of the safety data, by dose group, will 
be generated, if at least one of the BI655130 (SPESOLIMAB) doses is identical in both study 
parts. Data from Parts 1 and 2 of the trial will be pooled together. The objectives of this 
pooled analysis are:

Investigate safety and tolerability of subgroups in this patient population using 
descriptive methods, i.e.
o
Race
o
Gender
o
Region
o
Previous BIO use
o
Previous corticosteroid use
o
Other
7.3.6
Pharmacokinetic and pharmacodynamic analyses
BI655130 (SPESOLIMAB) concentrations will be reported descriptively. No PK parameters 
will be calculated.


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7.4
INTERIM ANALYSES
In order to ensure the patient’s safety during the trial, a fully external DMC (same DMC for 
both parts 1 and 2), 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.
No interim analyses of the primary endpoint(s) are planned for part 1 or for part 2 of the trial.


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The primary analysis of Part 1 of the trial will be performed once all treated patients have 
completed the 12-week treatment period in this trial part; an interim data base snapshot will 
be done.
The primary analysis of Part 2 of the trial will be performed once all treated patients have 
completed this trial part.
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 for all study parts are proposed below.
If one or more subscores on the primary efficacy endpoint, calculated using the Mayo Clinic 
score, are missing at a visit then the overall outcome at that visit is also considered to be 
missing.
With regards to the handling of missing data on the primary efficacy endpoint, Non Response 
Imputation (NRI) will be applied, that is imputing as a failure to achieve a response.
If a patient takes rescue medication for the treatment of ulcerative colitis prior to observing 
the primary endpoint, then all data subsequent to the intake of such rescue will be considered 
to represent a failure to achieve a response (NRI). Further details with regard to what 
constitutes a rescue intake with potential impact on the primary efficacy endpoint will be 
described in the TSAP.
Sensitivity analyses will be performed on the primary (and key secondary) efficacy 
endpoint(s) using a multiple imputation approach for missing data. The method will include 
all post-baseline time-points up to and through week 12. The technical details regarding the 
implementation of the multiple imputation will be specified in the TSAP. Note that only on-
treatment data is used for imputation since even if a patient discontinues following the first 
dose of BI655130 (SPESOLIMAB) on Day 0, the REP of 16 weeks means that no off-
treatment data can be available at the time of the primary (or key secondary) endpoint 
analysis (at week 12):

Utilize all available data regardless of rescue intake, then multiply impute any 
missing data up to and including week 12;

Efficacy data after censoring (i.e. any observation collected after the first intake of 
rescue medication) will be set to missing, then multiply impute all missing data up to 
and including week 12. 
Further sensitivity analyses to assess the robustness of the results on the primary efficacy 
endpoint may be performed and will be described in the TSAP.
For secondary and further endpoints, rules for handling of missing data will be specified in 
the TSAP if necessary. With respect to safety evaluations, it is not planned to impute missing 
values.


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7.6
RANDOMISATION
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 Clinical Trial Report. Access to the 
codes will be controlled and documented.
After screening, eligible patients will be stratified according to previous BIO treatment
failure (TNFɑ antagonists-OR-Vedolizumab versus TNFɑ antagonists-AND-Vedolizumab)
and concomitant corticosteroid therapy (yes/no) at visit2/randomization. There will be four 
strata for analysis purposes:
Stratum 1: TNFɑ antagonists-OR-Vedolizumab failure and concomitant corticosteroid 
therapy at visit 2/randomization;
Stratum 2: TNFɑ antagonists-OR-Vedolizumab failure and NO concomitant corticosteroid 
therapy at visit 2/randomization;
Stratum 3: TNFɑ antagonists-AND-Vedolizumab failure and concomitant corticosteroid 
therapy at visit 2/randomization; 
Stratum 4: TNFɑ antagonists-AND-Vedolizumab failure and NO concomitant corticosteroid 
therapy at visit 2/randomization;
In addition, a stratification for Japan versus non-Japan will be done in order to assure that 
sufficient patients per treatment group are recruited specifically to support individual country 
submission in Japan; this strata will be treated as an operational strata and will not be 
included into the analyses of the primary endpoint.
The randomization system will include a cap for the stratum of patients with double MoA 
failure (strata 3 and 4). Screening of both TNFɑ antagonists-AND-Vedolizumab failure
patients will be capped for part 1 once 48 randomized patients in Part 1 and capped for Part II 
once 117 randomized patients in Part 2 meet this criterion, This capping will apply to new 
patients for screening, while the patients who have been already screened at time of 
implementation of the cap will continue screening procedures in preparation for potential 
randomization into the study.
Within each stratum, patients will be randomized in a 1:1:1:1 randomization ratio (1:1:1 for 
Part 2) to receive either placebo or one of three (two for Part 2) BI655130 (SPESOLIMAB)
dose regimens (low dose, intermediate dose, or high dose). The randomization will be done in 
blocks to achieve balanced allocation. The block size of the randomization will be 
documented in the CTR.
The process of randomization is done via an IRT. Practical aspects of the treatment allocation 
process are detailed in Section 4.1.3.


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7.7
DETERMINATION OF SAMPLE SIZE
The study is intended to show a benefit of BI655130 (SPESOLIMAB) over placebo in terms 
of the difference in proportion of patients achieving clinical remission at Week 12 in both 
Parts 1 and 2.
7.7.1
Sample size determination for Part 1
The aims of Part 1 are two-fold. A first aim is to show a significant non-flat dose-response 
across the different doses of BI655130 (SPESOLIMAB) and placebo assuming a higher rate 
of remission on BI655130 (SPESOLIMAB) versus Placebo of 0.20. Subsequently, at least 
one modelled dose within the (total) dose range considered [0 mg, 1200 mg q4w] should
show a benefit of at least 0.16 (see rationale below) in the proportion of patients achieving 
clinical remission at week 12 compared to placebo for demonstration of PoC (and subsequent
Go decision). In cases where the benefit compared to placebo is less than 0.16 but at least 
0.11 then a more detailed analysis of the part 1 results (e.g. subgroup analyses, PK/PD 
analyses, biomarker analyses) will be done in order to define the optimal path forward. 
Assumptions for the efficacy of the selected doses are provided in the table below.
For placebo, the proportion of patients who achieve clinical remission when a centrally-read 
endoscopy is used is typically very low [R17-2467]; therefore, for Placebo, a fixed rate of 
15% of patients achieving clinical remission at week 12 will be considered for sample size 
planning in this trial.
Based on these assumptions and the planned sample size of 160 (= 40:40:40:40) the success
probability (achieved when the proportion of patients achieving clinical remission at week 12 
on a dose of BI655130 (SPESOLIMAB) exceeds the placebo effect by 0.16) is approximately 
66% for the base case where a maximum difference to placebo of 0.20 is assumed (0.35, 
0.30, 0.25 vs 0.15 for clinical remission rates at week 12 of BI655130 (SPESOLIMAB) high 
to low doses and placebo respectively). In the case that there is no treatment benefit, the false 
positive probability is limited by the α-level for the significance testing of the non-flat dose-
response curve of 20% (one-sided).
The following Table 7.7.1:1 provides success probabilities under different scenarios, whereby 
success is defined as 1) Significant non-flat dose-response achieved AND 2) Treatment 
benefit of at least ‘delta’ compared to placebo for at least one modelled dose within the 
considered dose range.


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Table 7.7.1:1 Probability of achieving the threshold difference in treatments given expected 
treatment response rates and a total sample size of 160 patients (based 
on MCPMod alpha-level of 20% [one-sided]) in Part 1
Scenario
Population Response Rate
Expected 
max. 
Response 
Difference
Delta
Success 
probability*
N per 
treatment 
group
(1:1:1:1)
Low 
dose 
BI
Middle 
dose BI
High 
dose 
BI
Placebo
+
0.25
0.30
0.35
0.15
0.20
0.16
0.672
40
+M+
0.25
0.35
0.35
0.15
0.20
0.16
0.746
40
+L-
0.20
0.30
0.35
0.15
0.20
0.16
0.704
40
Sub-
optimal
0.20
0.25
0.30
0.15
0.15
0.16
0.460
40
Minimal
0.15
0.20
0.25
0.15
0.10
0.16
0.268
40
No Effect
0.15
0.15
0.15
0.15
0.00
0.16
0.020
40
++
0.25
0.40
0.40
0.15
0.25
0.16
0.896
40
+
0.25
0.30
0.35
0.15
0.20
0.11
0.836
40
+M+
0.25
0.35
0.35
0.15
0.20
0.11
0.870
40
+L-
0.20
0.30
0.35
0.15
0.20
0.11
0.855
40
Sub-
optimal
0.20
0.25
0.30
0.15
0.15
0.11
0.675
40
Minimal
0.15
0.20
0.25
0.15
0.10
0.11
0.496
40
No Effect
0.15
0.15
0.15
0.15
0.00
0.11
0.088
40
++
0.25
0.40
0.40
0.15
0.25
0.11
0.952
40
Success probabilities have been calculated using R Version 3.2.2 based on simulations
(10000 simulations per scenario). Thereby the calculations for the PoC step have been 
performed using DoseFinding R-package 0.9-15 [R15-2001]. 
A: Expected + case: Main scenario reflecting assumptions for efficacy of 0.15 (placebo), 0.25 
(low dose), 0.30 (medium dose), and 0.35 (high dose). 
B: Expected +M+ case:  Same scenario as A but assuming a higher response rate for the 
medium dose of 0.35.
C: Expected +L- case:  Same scenario as A but assuming a lower response rate for the low 
dose of 0.20.


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D: Suboptimal: Scenario reflecting a suboptimal maximum response rate. The response rates 
are assumed to be 0.15 (placebo), 0.20 (low dose), 0.25 (medium dose), 0.30 (high dose).
E: Minimal: Scenario with a low treatment benefit of 0.10 maximum compared to placebo. 
Represents a ‘worse-case’ scenario for treatment benefit.
F: No effect: Scenario reflecting no treatment benefit. 
G: Plus Plus: Scenario reflecting large efficacy compared to placebo: 0.15 (placebo), 0.25 
(low dose), 0.40 (medium dose), 0.40 (high dose).
7.7.2
Sample size determination for Part 2
Sample size calculation for part 2 of the trial has been performed with the statistical software 
R, Version 3.3.2.
As noted with the sample size calculation for Part 1, the proportion of patients who achieve 
clinical remission on Placebo when a centrally-read endoscopy is used is typically very low 
[R17-2467]; therefore, for this trial, a fixed rate of 15% of patients achieving clinical 
remission on Placebo at week 12 will be considered for further sample size planning.
Based on an application of the defined testing strategy (see Section 7.2) regarding the 
different endpoints, a simulation based power calculation has been performed for sample size
assessment on both the primary and key secondary endpoints. For this purpose a correlation 
of 0.5 has been assumed between the different endpoints.
Table 7.7.2: 2 presents scenarios for the planning of this trial whereby a difference versus 
Placebo of 0.20 is assumed for the proportion of patients who achieve clinical remission at 
week 12 (the primary endpoint). Calculations were performed using a 1-sided overall alpha 
level of 0.025 with a truncated Hochberg correction (‘truncation fraction’ = 1/2) applied to 
correct for multiplicity as a result of performing 2 treatment comparisons versus Placebo.
In line with the expected treatment benefit on the primary endpoint of clinical remission, it is 
also required that the magnitude of the BI655130 (SPESOLIMAB) response on key 
secondary endpoints, i.e., both the proportion of patients with mucosal healing and the 
proportion of patients with clinical response be at least 0.20 larger than the corresponding 
effect on placebo. Assuming therefore, an overall type 1 error= 0.025 (1-sided), a difference 
of 0.20 for each BI655130 (SPESOLIMAB) dose relative to Placebo in mucosal healing (rate 
assumed for each dose of BI655130 (SPESOLIMAB): 0.35, and placebo: 0.15), and a 
difference of 0.25 in clinical response (rate assumed for each dose of BI655130 
(SPESOLIMAB): 0.60, and placebo: 0.35), and given the total of 390 patients (130 per 
treatment arm), the overall power that both/at least one dose(s) of BI655130 (SPESOLIMAB)
would achieve statistical significance versus placebo for the primary and both key secondary 
endpoints will be approximately 81%/96% respectively (with a graphical approach used to 
attribute the remaining ´ from the test on the primary endpoint in order to correct for 
multiplicity because of multiple endpoints as well as two doses of BI655130 
(SPESOLIMAB)). Note that alpha passing, for the case when both doses of BI655130 


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(SPESOLIMAB) are statistically significant on the primary endpoint and one dose is 
subsequently statistically significant on all endpoints in the secondary family (key secondary 
and secondary), is not considered in the sample size evaluation.
Table 7.7.2: 1 Power to achieve statistical significance for the primary endpoint (clinical 
remission) and both key secondary endpoints (mucosal healing and clinical 
response) on both doses of BI655130 (SPESOLIMAB) under various 
scenarios
Scenario
Population Response Rate
Overall power to 
achieve all 3 endpoints
Power for 
both doses 
of 
BI655130 
(SPESOLI
MAB) to be 
stat. sig.
Power for 
at least one
dose of 
BI655130 
(SPESOLI
MAB) to be 
stat. sig.
Clinical 
remission
(H/L/P)
Mucosal 
Healing
(H/L/P)
Clinical 
Response
(H/L/P)
+
0.35/0.35/0.15
0.35/0.35/0.15
0.60/0.60/0.35
81.4%
95.6%
Sub-optimal
0.30/0.30/0.15
0.30/0.30/0.15
0.60/0.60/0.35
49.1%
77.2%
Minimal
0.25/0.25/0.15
0.25/0.25/0.15
0.60/0.60/0.35
13.5%
36.0%
++
0.40/0.40/0.15
0.40/0.40/0.15
0.60/0.60/0.35
92.3%
98.9%
↓Placebo +
0.30/0.30/0.10
0.30/0.30/0.10
0.60/0.60/0.35
88.2%
97.9%
↓ low dose 
BI
0.35/0.30/0.15
0.35/0.30/0.15
0.60/0.55/0.35
57.8%
89.8%


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Table 7.7.2:2 Power to achieve statistical significance for the primary endpoint (clinical 
remission) on both doses of BI655130 (SPESOLIMAB) under various 
scenarios 
Scenario
Population 
Response Rate
Expected 
Response 
Difference
N per 
treatmen
t group
(1:1:1)
Power for 
both doses of 
BI655130 
(SPESOLIMA
B) to be stat. 
sig.
Power for at 
least one dose of 
BI655130 
(SPESOLIMAB
) to be stat. sig.
High 
dose
BI
Low 
dose
BI
Placebo
+
0.35
0.35
0.15
0.20
130
92.5%
98.6%
Sub-
optimal
0.30
0.30
0.15
0.15
130
69.2%
88.9%
Minimal
0.25
0.25
0.15
0.10
130
31.3%
58.1%
++
0.40
0.40
0.15
0.25
130
99.0%
99.9%
↓
Placebo 
+
0.30
0.30
0.10
0.20
130
96.6%
99.6%
↓ low 
dose BI
0.35
0.30
0.15
0.20/0.15
130
78.7%
96.5%
To be noted that the sample size for Part 2 of the study may be adapted based on results from 
Part 1 in which case a protocol amendment will be required.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
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 the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 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 patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
webpage: 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.
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 investigator or a designee must give a full explanation to trial patients based on the
patient information form. A language understandable to the patient should be chosen, 
technical terms and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or a designee 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 or a designee must sign (or place a seal on) and date the informed consent form. 


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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.
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
CRFs 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
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 patient. 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 patient 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.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see Section 8.3.2). 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 from any copy of the patients’ source documents before sending 
them to the sponsor.
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, year of birth (in accordance with local laws and 
regulations)


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
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)

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 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 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.
An adaptive approach to clinical trial monitoring will be utilised. The sponsor will perform a 
risk assessment of the trial to determine the extent and nature of monitoring required in order 
to ensure the reliability and robustness of the results. Regular review of risk reports will 
provide sponsor oversight during trial conduct and direct monitoring activities to the areas of 
greatest risk which have the most potential impact to patient safety and data quality.
The investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results. 
The CRA and auditor 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 ICH GCP.
An adaptive approach to clinical trial monitoring will be utilised. This is initiated by an 
assessment of the risk associated with the trial combined with identification of critical data 


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and processes. An Integrated Quality and Risk Management Plan documents the strategies 
involved with the implementation of onsite, offsite and central monitoring activities in order 
to direct focus to the areas of greatest risk which have the most potential impact to patient
safety and data quality. Trial oversight is achieved by regular review of a report of risk which 
then influences any monitoring adaptations. 
The investigator /institution will allow on-site trial-related monitoring, audits, IRB/IEC 
review and regulatory inspections. Direct access should be granted to all source documents 
(paper and e-records) including progress notes, copies of laboratory and medical test results
The CRA and auditor 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 ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
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 
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.
8.4.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent


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
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.5
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
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.
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).
8.6
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this 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 on each study Part, and to recommend to the sponsor 
whether to continue, modify, or stop either a single BI655130 (SPESOLIMAB) dose or the 


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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 (see Section 7.4 for further details). 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 (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF. The investigators will have access to the 
BI clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic 
ISF. 
BI has appointed a Clinical Trial Leader (CT Leader), 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 Clinical Trial Manager (CT Manager), 
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 BI 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 the IRT Manual and Central Laboratory Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R07-4311
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E
Measuring fatigue and other anemia-related symptoms with the Functional 
Assessment of Cancer Therapy (FACT) measurement system.
J Pain Symptom Manage 13 (2), 63 - 74 (1997)
R09-1299
Greenland S, Robins JM
Estimation of a common effect parameter from sparse follow-up data.
Biometrics 41, 55 - 68 (1985)
R10-0936
Walters SJ, Brazier JE
Comparison of the minimally important difference for two health state utility 
measures: EQ-5D and SF-6D.
Qual Life Res 14, 1523 - 1532 (2005)
R10-1424
Pinheiro J, Bornkamp B, Bretz F
Design and analysis of dose-finding studies combining multiple comparisons 
and modeling procedures.
J Biopharm Stat 16 (5), 639 - 656 (2006)
R10-6433
Webster K, Cella D, Yost K
The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement 
System: properties, applications, and interpretation.
Health Qual Life Outcomes 1, 79 (2003)
R11-4890
Sampson HA, et al
Second symposium on the definition and management of anaphylaxis: 
summary report - second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium.
2nd Symp of the National Institute of Allergy and Infectious Disease 
(NIAID)/Food Allergy and Anaphylaxis (FAA) Network on the Definition and
Management of Anaphylaxis, Jul 2005
J Allergy Clin Immunol 117 (2), 391 - 397 (2006)
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)
R15-0886
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, 
Benchimol EI, Panaccione R, Ghosh S, Barkema HW, Kaplan GG


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001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
Increasing incidence and prevalence of the inflammatory bowel diseases with 
time, based on systematic review. Gastroenterology 142 (1), 46 – 54 (2012)
R15-1340
Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, 
Assche G van, Axler J, Kim HJ, Danese S, Fox I, Milch C, Sankoh S, Wyant 
T, Xu J, Parikh A, GEMINI 1 Study Group
Vedolizumab as induction and maintenance therapy for ulcerative colitis.
N Engl J Med 369 (8), 699 - 710 (2013)
R15-1961
European Medicines Agency (EMA)
Committee for Medicinal Products for Human Use (CHMP): qualification 
opinion of MCP-Mod as an efficient statistical methodology for model-based 
design and analysis of phase II dose finding studies under model uncertainty 
(23 January 2014, EMA/CHMP/SAWP/757052/2013).
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_pr
ocedural_guideline/2014/02/WC500161027.pdf (access date: 28 April 2015);
London: European Medicines Agency (EMA) (2014)
R15-2001
Bornkamp B, Pinheiro J, Bretz F
Package 'DoseFinding' (February 19, 2015).
http://cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf (access 
date: 28 April 2015); Comprehensive R Archive Network (2015)
R15-4293
Pinheiro J, Bornkamp B, Glimm E, Bretz F
Model-based dose finding under model uncertainty using general parametric 
models.
Stat Med 33 (10), 1646 - 1661 (2014)
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).
http://ec.europa.eu/health/documents/community-
register/2015/20150728132555/anx_ 132555_en.pdf (access date: 31 August 
2015) (2015)


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R15-5737
Entyvio (vedolizumab) for injection, for intravenous use (Takeda 
Pharmaceuticals America) (U.S. prescribing information, revised: 05/2014).
R15-5866
Cohen BL, Zoega H, Shah SA, LeLeiko N, Lidofsky S, Bright R, Flowers N, 
Law M, Moniz H, Merrick M, Sands BE
Fatigue is highly associated with poor health-related quality of life, disability 
and depression in newly-diagnosed patients with inflammatory bowel disease, 
independent of disease activity.
Aliment Pharmacol Ther 39, 811 - 822 (2014)
R15-5867
Yoo S, Jung YS, Park JH, Kim HJ, Cho YK, Sohn CI, Jeon WK, Kim BI, Park 
DI
Fatigue severity and factors associated with high fatigue levels in Korean 
patients with inflammatory bowel disease.
Gut Liver 8 (2), 148 - 153 (2014)
R15-5868
Koenig HH, Ulshoefer A, Gregor M, Tirpitz C von, Reinshagen M, Adler G, 
Leidl R
Validation of the EuroQol questionnaire in patients with inflammatory bowel 
disease.
Eur J Gastroenterol Hepatol 14 (11), 1205 - 1215 (2002)
R15-5869
Tinsley A, Macklin EA, Korzenik JR, Sands BE
Validation of the functional assessment of chronic illness therapy-fatigue 
(FACIT-F) in patients with inflammatory bowel disease.
Aliment Pharmacol Ther 34, 1328 - 1336 (2011)
R15-5871
Stark RG, Reitmeir P, Leidl R, Koenig HH
Validity, reliability, and responsiveness of the EQ-5D in inflammatory bowel 
disease in Germany.
Inflamm Bowel Dis 16 (1), 42 - 51 (2010)
R15-5875
Feagan BG, Reilly MC, Gerlier L, Brabant Y, Brown M, Schreiber S
Clinical trial: the effects of certolizumab pegol therapy on work productivity in 
patients with moderate-to-severe Crohn's disease in the PRECiSE 2 study.
Aliment Pharmacol Ther 31, 1276 - 1285 (2010)
R15-5876
Coteur G, Feagan B, Keininger DL, Kosinski M
Evaluation of the meaningfulness of health-related quality of life 
improvements as assessed by the SF-36 and the EQ-5D VAS in patients with 
active Crohn's disease.
Aliment Pharmacol Ther 29, 1032 - 1041 (2009)


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R15-5976
Bernklev T, Jahnsen J, Lygren I, Henriksen M, Vatn M, Moum B
Health-related quality of life in patients with inflammatory bowel disease 
measured with the short form-36: psychometric assessments and a comparison 
with general population norms.
Inflamm Bowel Dis 11 (10), 909 - 918 (2005)
R16-0029
Cella D, Yount S, Sorensen M, Chartash E, Sengupta N, Grober J
Validation of the Functional Assessment of Chronic Illness Therapy Fatigue 
Scale relative to other instrumentation in patients with rheumatoid arthritis.
J Rheumatol 32 (5), 811 - 819 (2005)
R16-0030
Pickard AS, Neary MP, Cella D
Estimation of minimally important differences in EQ-5D utility and VAS 
scores in cancer.
Health Qual Life Outcomes 5, 70 (2007)
R16-0031
Alrubaiy L, Rikaby I, Dodds P, Hutchings HA, Williams JG
Systematic review of health-related quality of life measures for inflammatory 
bowel disease.
J Crohns Colitis 9 (3), 284 - 292 (2015)
R16-0032
Ware JE
SF-36 health survey update.
Spine 25 (24), 3130 - 3139 (2000)
R16-0033
Frendl DM, Ware JE
Patient-reported functional health and well-being outcomes with drug therapy: 
a systematic review of randomized trials using the SF-36 health survey.
Med Care 52 (5), 439 - 445 (2014)
R16-0240
Irvine EJ
Development and subsequent refinement of the inflammatory bowel disease 
questionnaire: a quality-of-life instrument for adult patients with inflammatory 
bowel disease.
J Pediatr Gastroenterol Nutr 28 (4), S23 - S27 (1999)
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)
R16-4414
Reeve R. Confidence interval of difference of proportions in logistic 
regression in presence ofcovariates. Statistical Methods in Medical Research.
(2016) DOI: 10.1177/0962280216631583


Boehringer Ingelheim
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001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
R16-4416
Schroeder KW, Tremaine WJ, Ilstrup DM
Coated oral 5-aminosalicylic acid therapy for mildly to moderately active 
ulcerative colitis: a randomized study.
N Engl J Med 317 (26), 1625 - 1629 (1987)
R16-5751
Brudno JN, Kochenderfer JN
Toxicities of chimeric antigen receptor T cells: recognition and management.
Blood 127 (26), 3321 - 3330 (2016)
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).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/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)
R17-0243
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)
R17-1974
Stelara (ustekinumab) injection, for subcutaneous or intravenous use (Janssen) 
(U.S. prescribing information, revised: 09/2016).
R17-2216 
Yarlas A, Yen L, Hodgkins P
The relationship among multiple patient-reported outcomes measures for 
patients with ulcerative colitis receiving treatment with MMX formulated 
delayed-release mesalamine.
Qual Life Res 24, 671 - 683 (2015)
R17-2217 
Sandborn WJ, Su C, Sands BE, D'Haens GR, Vermeire S, Schreiber S, Danese 
S, Feagan BG, Reinisch W, Niezychowski W, Friedman G, Lawendy N, Yu D, 
Woodworth D, Mukherjee A, Zhang H, Healey P, Panés J; OCTAVE 
Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. 
Tofacitinib as Induction and MaintenanceTherapy for Ulcerative Colitis. N 
Engl J Med. 2017
R17-2218 
Gibson PR, Vaizey C, Black CM, Nicholls R, Weston AR, Bampton P, et al
Relationship between disease severity and quality of life and assessment of 
health care utilization and cost for ulcerative colitis in Australia: a cross-
sectional, observational study.
J Crohns Colitis 8, 598 - 606 (2014)


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R17-2219 
Assche G van, Peyrin-Biroulet L, Sturm A, Gisbert JP, Gaya DR, Bokemeyer 
B, et al
Burden of disease and patient-reported outcomes in patients with moderate to 
severe ulcerative colitis in the last 12 months - multicenter European cohort 
study.
Dig Liver Dis 48, 592 - 600 (2016).
R17-2221 
Feagan BG, Patel H, Colombel JF, Rubin DT, James A, Mody R, et al
Effects of vedolizumab on health-related quality of life in patients with 
ulcerative colitis: results from the randomised GEMINI 1 trial.
Aliment Pharmacol Ther 45, 264 - 275 (2017)
R17-2222 
Feagan BG, Reinisch W, Rutgeerts P, Sandborn WJ, Yan S, Eisenberg D, et al
The effects of infliximab therapy on health-related quality of life in ulcerative 
colitis patients.
Am J Gastroenterol 102, 794 - 802 (2007)
R17-2223 
Colombel JF, Sandborn WJ, Ghosh S, Wolf DC, Panaccione R, Feagan B, et al
Four-year maintenance treatment with adalimumab in patients with moderately 
to severely active ulcerative colitis: data from ULTRA 1, 2, and 3.
Am J Gastroenterol 109, 1771 - 1780 (2014).
R17-2467
Jairath V, Zou G, Parker CE, Macdonald JK, Mosli MH, Khanna R, et al
Systematic review and meta-analysis: placebo rates in induction and 
maintenance trials of ulcerative colitis.
J Crohns Colitis 10 (5), 607 - 618 (2016)
R17-2617 
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen P, 
et al
Opportunistic infections and biologic therapies in immune-mediated 
inflammatory diseases: consensus recommendations for infection reporting 
during clinical trials and postmarketing surveillance.
Ann Rheum Dis 74, 2107 - 2116 (2015)
R17-3426
Remicade (infliximab) lyophilized concentrate for injection, for intravenous 
use (Janssen Biotech) (U.S. prescribing information, revised: November 
2013).
R17-3632
Mahil SK, Catapano M, Meglio P di, Dand N, Ahlfors H, Carr IM, et al
An analysis of IL-36 signature genes and individuals with IL1RL2 knockout 
mutations validates IL-36 as a psoriasis therapeutic target.
Sci Transl Med 9, eaan2514 (2017)


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R96-2382
EuroQol - a new facility for the measurement of health-related quality of life. 
Health Policy 16, 199 - 208 (1990)
R97-1093
Ware JE, editor
SF-36 Health Survey: Manual and Interpretation Guide. 
Boston: The Health Institute, New England Medical Center (1993)
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)
R97-3596
Guyatt G, Mitchell A, Irvine EJ, Singer J, Williams N, Goodacre R, Tompkins 
C
A new measure of health status for clinical trials in inflammatory bowel 
disease. 
Gastroenterology 96, 804 - 810 (1989)
9.2
UNPUBLISHED REFERENCES
c03320877-06 Investigator’s Brochure, BI655130 for IL36R antibody in Ulcerative Colitis, 
Palmoplantar Pustulosis and Pustular Proriasis; version 06, dated 04 April 
2019
c03361085-07Clinical Trial Protocol, BI Trial No.: 1368.1; 
Single-blind, partially randomized, placebo-controlled Phase I study to 
investigate safety, tolerability, pharmacokinetics and pharmacodynamics of 
single rising intravenous doses of BI 655130 in healthy male volunteers; 
Version 6.0, dated 27 January 2016 


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10.
APPENDICES
10.1
MAYO SCORING SYSTEM FOR THE ASSESSMENT OF ULCERATIVE 
COLITIS ACTIVITY
The Mayo score (Schroeder et al., N Engl J Med, 1987) is a composite disease activity score 
consisting of four items or subscores: stool frequency (relative to normal), rectal bleeding, 
physician’s global assessment, and endoscopic appearance. As proposed by FDA draft 
guidance [R17-0038], the endoscopic subscore is modified so that a value of 1 does not 
include friability. The overall range of the Mayo score is 0-12 (higher scores being worse) 
and each subscore has a range of 0-3 (Table 10.1: 1). At visits without sigmoidoscopy, a 
partial Mayo score without endoscopy subscore will be assessed. The overall range of this
partial Mayo score is 0-9.
In addition, based on FDA’s recommendation [R17-0038], a modified Mayo score will be 
assessed, which excludes physician’s assessment. The overall range of the modified Mayo 
score is 0-9.
The scores for stool frequency and rectal bleeding will be calculated as an average based on 
the last 3 non-missing scores from the 7 days prior to each applicable visit, as collected from 
the patient diary. If the patient undergoes bowel preparation for colonoscopy 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 to be missing both for the day of and the day after the endoscopy.
The endoscopic appearance score will be assessed by both, the investigational site and a 
central reader, who is independent from the investigator.


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Table 10.1: 1
Mayo score (adopted from Schroeder et al, 1987)
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 
Assessmentd
Normal
0
Mild disease
1
Moderate disease
2
Severe disease
3
MODIFIED
ENDOSCOPIC 
RESPONSE
(Objective Evidence of 
Inflammation)
Endoscopic Appearancec
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) Modified endoscopic appearance: 0 (normal), Mild (erythema, decreased vascular pattern, granularity), 
Moderate (marked erythema, loss of vascular pattern, any friability, erosions), Severe (spontaneous bleeding, 
ulceration).
d) 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.
Schroeder KW, Tremaine WJ, Ilstrup DM
Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a 
randomized study.
N Engl J Med 317 (26), 1625 - 1629 (1987) 


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10.2
HISTOLOGIC ACTIVITY SCORE
The Robarts histopathology index is a histologic activity score (Mosli et al, Gut2015). The 
total score ranges from 0 (no disease activity) to 33 (severe disease activity).
Table 10.2: 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
Mosli MH, Feagan BG, Zou G, et al. Development and validation of a histological index for 
UC. Gut 2015.
Based on this, the RHI will be calculated as follows:
RHI = 1 x chronic inflammatory infiltrate level (4 levels) + 2 x lamina propria neutrophils (4 
levels) + 3 x neutrophils in epithelium (4 levels) + 5 x erosion or ulceration (4 levels after 
combining Geboes 5.1 and 5.2)


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10.3
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 
16-Methylprednisolone 
6 
X 0.8 
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
10.4
PATIENT REPORTED OUTCOMES
10.4.1
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.
10.4.2
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 


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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 weights. 
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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10.6
DEFINITION OF PRIMARY, SECONDARY NONRESPONSE OR 
INTOLERANCE TO ANTI-INTEGRIN OR ANTI-TNF THERAPY
The criteria for primary non-response (inadequate initial response), secondary non response 
(response followed by loss of response), or intolerance to vedolizumab, infliximab, 
adalimumabor golimumab are described below.
I.
Primary nonresponse to current or prior therapy with vedolizumab, infliximab, 
adalimumab, or golimumab (inadequate initial response)
Eligible patients must satisfy criteria A, B, and C.
A. Have received induction doses of:

Vedolizumab (2 or 3 doses of ≥300 mg) or

Infliximab (2 or 3 doses of ≥5 mg/kg) or

Adalimumab (at a dose of 160 mg followed by a dose ≥80 mg or at a dose of 80 
mg followed by a dose ≥40 mg or


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
Golimumab (2 or 3 doses of 50 or 100 mg (per locally approved label))
AND
B. Did not initially respond to these induction doses of vedolizumab, infliximab, 
adalimumab, or golimumab as evidenced by the presence of at least 1 of the 
following signs or symptoms related to persistence of Ulcerative Colitis, as 
assessed by a treating physician:

Lack of improvement, or worsening in stool frequency.

Lack of improvement, or worsening in daily abdominal pain.

Occurrence, lack of improvement, or worsening of fever thought to be related to 
Ulcerative Colitis.

Lack of improvement or worsening in rectal bleeding.

Initiation or increase in antidiarrheal medication.
These signs and symptoms of Ulcerative Colitis must have occurred ≤2 weeks after 
receiving the last induction dose of vedolizumab, infliximab, adalimumab, or golimumab, 
and are offered only as a benchmark of the minimally acceptable criteria required to 
designate a patient as having had an inadequate initial response.
AND
C. Have documentation available to the investigator that meets the following 2 
requirements:

Provide the dates and doses of the failed therapy.

Documents that the patient had persistence of disease activity following therapy. 

Examples of acceptable documents include: medical records, letter provided by a 
referring physician, or other “reason for referral” documents (e.g., insurance 
authorization form).
II.
Secondary nonresponse to current or prior therapy with vedolizumab,
infliximab, adalimumab or golimumab (response followed by loss of response)
Eligible patients must satisfy criteria A, B, C, and D.
A. Initially responded to induction therapy
AND
B. Have received at least 2 maintenance doses of:


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
Vedolizumab (at a dose of ≥300 mg) or

Infliximab (at a dose of ≥5 mg/kg) or

Adalimumab (at a dose of ≥40 mg) or

Golimumab (at a dose of ≥ 50 or 100 mg (per locally approved label)
AND
D. Have or had at least 1 of the following signs or symptoms related to recurrence 
of Ulcerative Colitis, as assessed by a treating physician:

Lack of improvement, or worsening in stool frequency.

Lack of improvement, or worsening in daily abdominal pain.

Occurrence, lack of improvement, or worsening of fever thought to be related to 
Ulcerative Colitis.

Lack of improvement or worsening in rectal bleeding.

Initiation or increase in antidiarrheal medication.
These signs and symptoms of Ulcerative Colitis must have occurred ≤2 weeks after 
receiving the last maintenance dose of vedolizumab, infliximab, adalimumabor golimumab
and are offered only as a benchmark of the minimally acceptable criteria required to 
designate a patient as having lost response.
AND
C. Have documentation available to the investigator that meets the following 2 
requirements:

Provide the dates and doses of the failed maintenance therapy.

Documents that the patient had recurrence of disease activity despite the failed 
maintenance therapy. 
Examples of acceptable documents include: medical records, letter provided by a referring 
physician, or other “reason for referral” documents (e.g., insurance authorization form).
III.
Current or prior intolerance to therapy with vedolizumab, infliximab, 
adalimumab, or golimumab
Eligible patients must satisfy criteria A and B.
A. Have had an adverse reaction that meets 1 of the following 3 criteria: 
1.
Significant acute infusion/administration reaction;


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2.
Significant delayed infusion/administration reaction (for example, delayed 
hypersensitivity or serum-sickness like reaction);
3.
Significant injection site reaction.
Definitions of these 3 criteria are provided below. Adverse reactions also must have 
followed ≥1 dose of vedolizumab, infliximab, adalimumab, or golimumab and, in the 
treating physician’s opinion, precluded continued use of the therapy.
1. A significant acute infusion/administration reaction is defined as an adverse 
reaction that was:

Manifested through ≥1 of the following symptoms.
i.
Fever greater than 100°F (37.8°C).
ii.
Chills or rigors.
iii.
Itching.
iv.
Rash.
v.
Flushing.
vi.
Urticaria or angioedema.
vii.
Breathing difficulties (dyspnea, chest pain or tightness, shortness of breath, 
wheezing, stridor).
viii.
Clinical hypotension (pallor, diaphoresis, faintness, syncope), blood pressure 
less than 90 mm Hg systolic and 60 mm Hg diastolic, or a systemic or 
orthostatic drop in systolic blood pressure of greater than 20 mm Hg.
AND

Was considered related to the infusion/administration of vedolizumab, infliximab, 
adalimumab, or golimumab.
2. A significant delayed infusion/administration reaction is defined as an adverse 
reaction that:

Was manifested through 1 or more of the following symptoms:
i.
Myalgias
ii.
Arthralgias
iii.
Fever greater than 100°F (37.8°C).
iv.
Malaise
v.
Rash.


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AND

Occurred > 24 hours and < 15 days after infusion/administration of vedolizumab, 
infliximab, adalimumab, or golimumab.
AND

Was considered related to the infusion/administration of vedolizumab, infliximab, 
adalimumab, or golimumab.
3. A significant injection site reaction is defined as an adverse reaction that:

Was manifested through 1 or more of the following symptoms:
i.
Significant bruising.
ii.
Erythema.
iii.
Hemorrhage.
iv.
Irritation.
v.
Pain.
vi.
Pruritus.
vii.
“Injection site reaction.”
AND

Occurred within 24 hours of an SC injection of adalimumab or golimumab.
AND

Was considered related to the injection.
B. Have documentation available to the investigator that meets the following 2 
requirements:

Provides the date of discontinuation of vedolizumab, infliximab, adalimumab, or
golimumab.

Documents that the patient had intolerance to vedolizumab, infliximab, 
adalimumab, golimumab therapy.
Examples of acceptable documents include: medical records, letter provided by a referring 
physician, or other “reason for referral” documents (e.g., insurance authorization form).


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10.7
DIAGNOSIS OF ANAPHYLAXIS
Clinical Criteria for diagnosing anaphylaxis [R11-4890]
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less 
than (70 mm Hg +[2 x age] from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.


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10.8.
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (OMERACT)
1 - Mild
2 - Moderate
3 - Severe
4 - Includes Life 
Threatening
Asymptomatic, 
or transient 
Short duration 
(< 1 week)
No change in 
life style 
No medication 
or OTC 
Symptomatic 
Duration (1–2 
weeks) 
Alter lifestyle 
occasionally 
Meds relieve. 
(may be 
prescription),
Study drug 
continued
Prolonged 
symptoms, 
reversible, major 
functional 
impairment 
Prescription 
meds/partial relief 
May be 
hospitalized<24h
Temporary study 
drug 
discontinuation, 
or/and dose reduced
At risk of death
Substantial 
disability, 
especially if 
permanent.
Multiple meds
Hospitalised 
>24h
Study drug 
discontinued
A.ALLERGIC/IMMUNOLOGIC
A1. Allergic 
reaction/
hyper-
sensitivity 
(including 
drug fever)
Transient rash; 
drug fever < 
38° C, 
transient 
asymptomatic 
bronchospasm
Generalized 
urticaria 
responsive to 
meds; or drug 
fever > 38° C, 
or reversible 
bronchospasm
Symptomatic 
bronchospasm, 
requiring meds; 
symptomatic 
urticaria persisting 
with meds, allergy 
related 
oedema/angioedema
Anaphylaxis, 
laryngeal/ 
pharyngeal 
edema, requiring 
resuscitation
A2. 
Autoimmune 
reaction
Serologic or 
other evidence 
of autoimmune 
reaction but 
patient 
asymptomatic: 
all organ 
function 
normal and no 
treatment is 
required (e.g., 
Evidence of 
autoimmune 
reaction 
involving a 
non-essential 
organ or 
functions, 
requiring 
treatment 
other than 
immune-
Reversible 
autoimmune 
reaction involving 
function of a major 
organ or toxicity 
requiring short term 
immune-
suppressive 
treatment (e.g., 
transient colitis or 
Causes major 
organ 
dysfunction, or 
progressive, not 
reversible, or 
requires long 
term 
administration of 
high dose 
immune-
suppressive 


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vitiligo)
suppressive 
drugs (e.g., 
hypo-
thyroidism)
anemia)
therapy
A3. Rhinitis 
(includes 
sneezing, 
nasal 
stuffiness, 
post nasal 
discharge)
Transient, non-
prescription 
meds relieve
Prescription 
med required, 
slow 
Corticosteroids or 
other prescription 
med. with persistent 
disabling symptoms 
such as impaired 
exercise tolerance 
NA


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
18 December 2017
EudraCT number
EU number
2017-004230-28
BI Trial number
1368-0005
BI Investigational Product(s)
BI 655130
Title of protocol
A Phase II/III Randomized, Double-blind, Placebo-
controlled, Multicenter Study to Evaluate the 
Safety and Efficacy of BI 655130 Induction 
Therapy in patients with moderate-to-severely 
active ulcerative colitis who have failed previous 
biologics 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
5.2.6.1 Definitions of AEs 
Description of change 1
Hepatic injury
A hepatic injury is defined by the following 
alterations of hepatic laboratory parameters: 
an elevation of AST and/or ALT  >3 fold ULN 
combined with an elevation of total bilirubin >2 
fold ULN measured in the same blood draw 
sample, and/or
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 


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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.
changed to:
Hepatic injury
A hepatic injury is defined by the following 
alterations of hepatic laboratory parameters: 
a.  ALT or AST >5x ULN 
b.  ALT or AST >3x ULN with the appearance of 
fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia 
(> 5%)
c. AST and/or ALT  >3 fold ULN combined with 
an elevation of total bilirubin >2  
fold ULN measured in the same blood draw sample
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.
If an alternative cause for the hepatic injury cannot 
be identified in the follow-up assessments specified 
in the “DILI checklist”, discontinuation of 
treatment with study drug should be considered.
Rationale for change
FDA request for change the definition of hepatic 
injury to be consistent with the FDA Guidance for 
Industry
Section to be changed
3.3.3.3 General Exclusion Criteria
Description of change 2
Pathological safety lab parameters: haemoglobin 
< 8 g/dL,
changed to:


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Pathological safety lab parameters: haemoglobin < 
9 g/dL,
Rationale for change
FDA recommendation for excluding patients with a 
hemoglobin less than 9g/dL (instead of <8g/dL) to 
allow for patients to have fluctuations or a small 
drop in hemoglobin without causing them to 
discontinue the trial.  
Section to be changed
Title page
Description of change 3
Update on CIs addresses
Rationale for change
Administrative change
Section to be changed
Flowchart ½, footnote #5 
Description of change 4
Statement added:  More frequent testing should be
be done if required by the local regulation and / or 
authority or per investigator judgment
Rationale for change
To allow Countries to be compliant with local 
standards
Section to be changed
Flow charts part1 /2, footnote #10
Description of change 5
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. 
In addition, background medication will be 
recorded by patients in diary provided and assessed 
by study staff” changed to:
10. “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.”
Rationale for change
To reflect study operational set up 
Section to be changed
6.2.1.Screening and run-in period(s)
Description of change 6
Patient diary
Patients who are eligible at Visit 1a will receive a 
patient diary to be used for 
1) daily reporting of stool frequency and rectal 
bleeding (blood in stool) during the week prior to 
visits which include assessment of Mayo score, as 
well as 
2) daily intake of concomitant UC medication over 
the whole treatment period. 


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changed to:
Patient diary
Patients who are eligible at Visit 1a will receive a 
patient diary to be used for 
daily reporting of stool frequency and rectal 
bleeding (blood in stool) during the week prior to 
visits which include assessment of Mayo score 
Rationale for change
To reflect study operational set up
Section to be changed
Flow charts part1 /2, footnote #4
Description of change 7
Monitor for signs and symptoms of 
hypersensitivity reactions for approximately 3 
hours after the first dose administered at Visit 2 
Changed to:
Monitor for signs and symptoms of 
hypersensitivity reactions for approximately 2 
hours after the first dose administered at Visit 2
Rationale for change
Typo correction
Section to be changed
Withdrawal from trial treatment
Description of change 8
Added: If a hepatic injury alert (as defined in 
section 5.2.6: 1) is detected without identification 
of an alternative cause in the work-up according to 
the “DILI checklist”, discontinuation of treatment 
with study drug should be considered
Rationale for change
Additional stopping rule added
Section to be changed
4.3 Treatment compliance
Description of change 9
Study medication will be administered in 
accordance with the protocol by authorised study 
personnel (e.g. study nurse). 
Changed to:
Study medication will be administered in 
accordance with the protocol, under supervision of 
the investigating physician or a designee at the site
Rationale for change
To express the requirement that physician should 
be present at administration of study medication
Section to be changed
5.2.6.2 Adverse event collection and reporting


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Description of change 10
Sentence deleted:
Exemptions to SAE reporting
Protocol specified outcome events should be 
collected on the appropriate CRF page only. 
Rationale for change
Protocol doesn´t define exemptions to SAE 
reporting
Section to be changed
5.3.2 Methods of sample collection
Description of change 11
The PK study samples will be discarded after 
completion of the investigations but not later than 3 
years after the final study report has been signed. 
Changed to: 
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.
Rationale for change
Typo correction
Section to be changed
6.2.1 Screening and run-in period(s)
Rationale for change
Administrative change – incorrect sentence 
deletion
Section to be changed
8.1 Trial approval, Patient information, Informed 
consent
Description of change 13
The investigator must give a full explanation to 
trial patients ……
The investigator obtains written consent of the 
patient’s …
The investigator must sign (or place a seal on) and 
date the informed consent form. 
Changed to:
The investigator or a designee must give a full 
explanation to trial patients …
The investigator or a designee obtains written 
consent of the patient’s …
The investigator or a designee must sign (or place a 
seal on) and date the informed consent form. 
Rationale for change
Clarification  on informed consent process
Section to be changed
5.2.6.2 Adverse event collection and reporting
Description of change 14
Following sentence deleted:
Similarly, potential drug exposure during 
pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a 


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written consent of the pregnant partner. 
Rationale for change
No genotoxicity or demonstrated or suspected 
human teratogenicity/fetotoxicity of BI 655130 at 
subtherapeutic systemic exposure levels


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11.2
GLOBAL AMENDMENT 2
Date of amendment
05 October 2018
EudraCT number
EU number
2017-004230-28
BI Trial number
1368-0005
BI Investigational Product(s)
SPESOLIMAB
Title of protocol
A Phase II/III Randomized, Double-blind, Placebo-
controlled, Multicenter Study to Evaluate the 
Safety and Efficacy of SPESOLIMAB Induction 
Therapy in patients with moderate-to-severely 
active ulcerative colitis who have failed previous 
biologics 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
Flow chart 1, 2
Description of change 1
Correction in calculation of trial periods
Rationale for change
Administrative 
Section to be changed
Footnote #4 of Flow Chart, part1and part 2
Description of change 2
In addition, at Visits 2, 4 and 5 vital signs will be 
assessed at approximately 5 and 60 minutes after 
study drug administration. 
Changed to:
In addition, at Visits 2, 4 and 5 vital signs will be 
assessed at approximately 5 and 60 minutes after 
the end of study drug administration.
Rationale for change
To clarify visit procedures
Section to be changed
Footnote #8 of Flow Chart, part1and part 2
Description of change 3
At study visits with study drug administration, pre-
dose PK/ADA/flow cytometry  
 
samples 
changed to:
At study visits with study drug administration, pre-
dose PK/ADA 
 samples
Rationale for change
Correction of statement on planned analysis  
Section to be changed
Footnote #10 of Flow Chart, part1and part 2
Description of change 4
This information will be used for the calculation of 
Mayo score at the visits.
This information will be used for the calculation of 
Mayo score at the visits.


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changed to:
Please make sure that time window between visits 
V1a and visit V1b is minimum 7 days.This will 
ensure that enough eDiary data (SFS and RBS) are 
collected before visit V1b in order to to calculate 
the baseline Mayo score. PGA (Physician Global 
Assessment) should be completed at all visits.  
Rationale for change
To clarify study procedure requirement
Section to be changed
Description of change 5
Rationale for change
Section to be changed
Table 3.1:1  Study definitions
Description of change 6
Rescue Medication 
changed to:
Rescue Treatment
New or increase in dose of any medication applied 
to treat new or persisting symptoms related to 
ulcerative colitis 
changed to:
New or increase in dose of any medication, or a 
surgical procedure, applied to treat new or 
persisting symptoms related to ulcerative colitis
Disease flare:
Increase in partial MCS score by ≥2 points from 
nadir, confirmed at a subsequent visit, AND by 
endoscopy showing an increase by ≥1 point from 
nadir in the modified Endoscopic Subscore (mESS)
changed to:
Disease flare:
Increase in partial MCS score by ≥2 points from 
nadir observed during a regular or unscheduled 
study visit, confirmed  subsequently by 
sigmoidoscopy with the modified Endoscopic 
Subscore (mESS) ≥2 AND a second partial Mayo 
score measurement confirming the increase from 
nadir by ≥2, in absence of enteric pathogens in 
stool
Rationale for change
To provide more detailed specification


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Section to be changed
3.1.2 Transition from Part 1 to Part 2
7.3 Planned Analyses
Description of change 7
The title ‘steering committee’ applied to the 
personnel involved in the review of the completed 
part 1 data has been changed to the ‘part 1 review 
committee’.
Rationale for change
Administrative change – the decision for the doses 
to be continued into Part 2 of the trial involves a 
data review on the completed Part 1 of the trial 
only by identified personnel; there is no 
consideration on data of other trials external to this 
trial in this decision. Hence, there is no 
involvement of a project-wide steering committee. 
More accurately, therefore, a Part 1 review 
committee has instead been defined to reflect that 
data review is solely confined to the completed 
trial part 1 data only.
Section to be changed
3.3.2 Inclusion criteria #3
Description of change 8
Moderate to severe activity (total MCS 6 to 12 
AND mESS ≥ 2 within 7-28 days prior to first 
dose)
changed to:
Moderate to severe activity (total MCS 6 to 12 with 
a RBS ≥ 1 AND an SFS ≥ 1  AND mESS ≥ 2 
within 7-28 days prior to first dose)
Rationale for change
For SFS>=1:
this is to adapt per FDA’s modified definition of 
clinical remission endpoint, in which SFS drop 
from baseline>=1 is required. The adaption in 
SFS>=1 at baseline ensure that all patients enrolled 
in this study have chance to achieve remission after 
treatment of SPESOLIMAB.
For RBS>=1: 
To reflect inclusion criteria in Tofa CTP.
Section to be changed
3.3.2  Inclusion criteria #5
Description of change 9
Demonstrated in the past inadequate response 
or loss of response or have had unacceptable side 
effects with approved doses of TNFɑ antagonists 
(infliximab, adalimumab, golimumab) and / 
or vedolizumab
changed to:
Well-documented demonstration of inadequate 
response or loss of response or have had 
unacceptable side effects with approved doses of 
TNFɑ antagonists (infliximab, adalimumab, 


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golimumab) and/or vedolizumab in the past as per 
definition in the CTP Appendix 10.6 
Rationale for change
To add requirement on documentation 
Section to be changed
3.3.2  Inclusion criteria #6
Description of change 10
Oral budesonide (≤ 9 mg per day ), provided that 
dose has been stable for the 2 weeks immediately 
prior to randomisation
changed to:
Oral budesonide (≤ 9 mg per day) or 
beclomethasone dipropionate (≤ 5 mg per day), 
provided that dose has been stable for the 2 weeks 
immediately prior to randomisation
Rationale for change
To allow previous beclomethasone dipropionate 
treatment 
Section to be changed
3.3.2  Inclusion criteria #8
Description of change 11
Women of childbearing potential (WOCBP) and 
men able to father a child must be ready to 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 Section 4.2.2.2 Restrictions 
regarding women of childbearing potential, in 
Section 4.2.2.3 Restriction  for male participants 
and in the patient information.
changed to:
Women of childbearing potential (WOCBP)  must 
be ready to 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 
Section 4.2.2.2 Restrictions regarding women of 
childbearing potential 
Rationale for change
To align with updated contraception requirements 
in Investigator Broschure,  version 5
Section to be changed
3.3.3.1. Exclusion criteria #9
Description of change 12
Faecal transplant ≤ 6 months before screening
changed to:
Faecal transplant ≤ 30 days prior to 
randomisation
Rationale for change
Update on restricted period
Section to be changed
3.3.3.2  Exclusion criteria #12
Description of change 13
Active or latent TB: Patients with a positive 


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TB test within one month of screening are 
excluded:

A positive QuantiFERON TB (Patients 
with suspected false positive or 
indeterminate QuantiFERON TB result 
may be re-tested once) 

If Quantiferon not available or providing 
indeterminate results after repeat testing : A 
tuberculin skin test reaction ≥10mm (≥5mm 
if receiving ≥15mg/d prednisone or its 
equivalent)
changed to:
Active or latent TB: Patients with a positive 
TB test during screening are excluded, unless:

Patient had previous diagnosis of active or 
latent TB and has completed appropriate 
treatment per local practive/guidelines 
within the last 3 years and at least 6 months 
before first administration of trial 
medication under this protocol (patients 
may be re-screened once to meet this 
criterion)

A positive QuantiFERON TB (Patients 
with suspected false positive or 
indeterminate QuantiFERON TB result 
may be re-tested once) 

If Quantiferon not available or providing 
indeterminate results after repeat testing, 
tuberculin skin test should be performed : A 
tuberculin skin test positive reaction 
≥10mm (≥5mm if receiving ≥15mg/d 
prednisone or its equivalent)
Rationale for change
Alignment with project specific definition on TB 
exclusion
Section to be changed
3.3.3.2  Exclusion criteria #12
Description of change 14
Relevant chronic or acute infections including 
human immunodeficiency virus (HIV) or viral 
hepatitis. A patient can be re-screened if the 
patient was treated and is cured from the 
acute infection.
changed to:
Relevant chronic or acute infections including 
active tuberculosis, human immunodeficiency 
virus (HIV) infection or viral hepatitis. A 
patient can be re-screened if the patient was 
treated and is cured from the acute infection.


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Rationale for change
To specify an active tuberculosis as an exclusion 
criterium
Section to be changed
4.2.1 Other treatments and emergency procedures
Description of change 15
Statement added:
If infusion or anaphylactic reaction had already 
occurred in the very same patient in the past, pre-
treatment with steroids before next IMP 
administration is permited as secondary 
prophylaxis.
Rationale for change
Clarification on prophylaxis 
Section to be changed
4.2.1 Other treatments and emergency procedures
5.2.6.1. Adverse events of special interest
Description of change 16
Following statements deleted:
Cytokine release syndrome (CRS)
This syndrome manifests when a large number of 
immune cells becomes activated and releases 
inflammatory cytokines.
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 
study drug. 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 should be considered. Corticosteroids 
should be reserved for neurologic toxicities and 
CRS not responsive to tocilizumab [R16-5751].

Cytokine release syndrome
o
May manifest when a large number of 
immune cells becomes activated and 
releases inflammatory cytokines. 
Potentially life-threatening 
complications include cardiac 
dysfunction, respiratory distress 
syndrome, neurologic toxicity, renal 
and/or hepatic failure, and disseminated 
intravascular coagulation.
Rationale for change
According to Investigator Brochure, version 5, 
Cytokine release syndrome is not considered as 


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AESI anymore.
Section to be changed
4.2.2 Restriction
Description of change 17
Added:
Fecal micriobiota transplantation (FMT) – not 
allowed from 30 days prior to randomisation until 
end of the trial
Oral administration:
Oral budesonide (≤9 mg per day), provided that 
dose has been stable for the 2 weeks immediately 
prior to randomisation
changed to:
Oral administration:
Oral steroids are only allowed if indicated for 
treatment of UC and at a dose of ≤ 20mg per day of 
prednisone or equivalent and with stable dose for at 
least 2 weeks prior to randomisation and 
throughout the trial.
Oral budesonide (≤9 mg per day), provided that 
dose has been stable for the 2 weeks immediately 
prior to randomisation
Oral beclomethasone dipropionate (≤5 mg per 
day), provided that dose has been stable for the 2 
weeks immediately prior to randomisation
Added:
Allowed steroid treatments:
Short-term use (<7 days) of systemic (oral or 
parenteral) corticosteroids is allowed for treatment 
of AE not related to the underlying UC from 4 
weeks prior to randomisation until end of the trial.
Locally administered steroids as e.g. intra-articular, 
nasal inhalation or intra-ocular administration are 
allowed.
NSAID: Chronic use not allowed from 2 weeks 
prior to screening up to end of the trial
changed to:
NSAID: Chronic use (i.e. daily use for >2 weeks) 
not allowed from 2 weeks prior to screening up to 
end of the trial
Deleted:
Antidiarrheals: Only allowed during the trial, if 
dose is stable for at least 2 weeks prior to 


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randomization and throughout the trial.
Rationale for change
Update on restriction
Section to be changed
4.2.2.2 Restrictions regarding women of 
childbearing potential 
Description of change 18
Highly effective methods of birth control for 
female and female partner(s) of male
participants who are able to become pregnant 
include:
changed to:
Highly effective methods of birth control for 
female participants.
Rationale for change
Consistency with changes in Investigator Brochure, 
version 5
Section to be changed
4.2.2.3 Restrictions for male participants
Description of change 19
Deleted:
4.2.2.3Restrictions for male participants
Men should avoid sperm donation for the entire 
duration of the trial.
Rationale for change
Consistency with changes in Investigator Brochure, 
version 5
Section to be changed
6.2.1 Screening and run- in period (s)
Description of change 20
The Screening visit (Visit 1a) should normally take 
place no more than 35 days before Visit 2 and be 
complete no less than 7 days prior toVisit 2. 
changed to:
The Screening visit (Visit 1a) should normally take 
place no more than 35 days before Visit 2 and be 
complete no less than 14 days prior to Visit 2. 
Visit 1b:
The Visit 1b should take place no more than 8 days 
and no less than 6 day prior to Visit 2.
changed to:
Visit 1b:
The Visit 1b should take place no more than 28
days and no less than 7 day prior to Visit 2.
Rationale for change
Typo correction
Section to be changed
6.2.2 Treatment periods
Description of change 21
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 


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based on information provided in the patient 
diaries, provided spontaneously by the patient or as 
a result of questioning the patient.
changed to:
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 
provided spontaneously by the patient or as a result 
of questioning the patient.
Rationale for change
To reflect the fact that ConMed is not recorded in 
patient diaries.
Section to be changed
7.3 Planned analysis
Description of change 22
The results on Part 1 will be reviewed by the DMC 
and by a steering committee which includes 
sponsor representatives, the DMC chair and the co-
ordinating investigators. The decision to amend or 
to initiate part 2 without modifications (taking into 
account the decision criteria described in Section 
3.1.2) will be made by the sponsor based upon the 
recommendations of the independent DMC and the 
steering committee.
changed to
The results on Part 1 will be reviewed by the DMC 
and by a part 1 review committee which includes 
sponsor representatives, the DMC chair and the co-
ordinating investigators. The decision to amend or 
to initiate part 2 without modifications (taking into 
account the decision criteria described in Section 
3.1.2) will be made by the sponsor based upon the 
recommendations of the independent DMC and the 
part 1 review committee.
Rationale for change
Adapted for steering committee definition
Section to be changed
7.3 Planned analysis
Description of change 23
There will be 4 main patient populations in this 
trial for analyses: the randomized set (RS), the 
treated set (TS), the modified RS (m-RS), and the 
per-protocol set (PPS). Each of these populations 
will be derived separately for each of the 2 trial 
parts.
changed to:
There will be 4 main patient populations in this 
trial for analyses: the randomized set (RS), the 
safety analysis set (SAF), the modified RS (m-RS), 


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and the per-protocol set (PPS). Each of these 
populations will be derived separately for each of 
the 2 trial parts.
Treated Set (TS)
changed to:
Safety Analysis Set (SAF)
Rationale for change
Changes in analysis groups definition
Section to be changed
8.5. Trial milestones
Description of change 24
The start of the trial is defined as the date when 
the first patient in the whole trial signs informed 
insent.
changed to:
The start of the trial is defined as the date when 
the first patient in the whole trial signs informed 
consent.
Rationale for change
Typo correction


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11.3
GLOBAL AMENDMENT 3
Date of amendment
09 October 2019
EudraCT number
EU number
2017-004230-28
BI Trial number
1368-0005
BI Investigational Product(s)
BI655130 (SPESOLIMAB)
Title of protocol
A Phase II/III Randomized, Double-blind, Placebo-
controlled, Multicenter Study to Evaluate the 
Safety and Efficacy of BI655130 (SPESOLIMAB) 
Induction Therapy in patients with moderate-to-
severely active ulcerative colitis who have failed 
previous biologics therapy
Global Amendment due to urgent safety reasons

Global Amendment
X
Section to be changed
All sections
Description of change 1
BI 655130
changed to:
BI 655130 ( SPESOLIMAB)
Rationale for change
Brand name added
Section to be changed
All sections
Description of change 2
Corticosteroid use 
changed to:
Concomitant corticosteroid therapy at V2
Rationale for change
More precise clarification of corticosteroids 
stratification
Section to be changed
Flowchart 1 and 2
Description of change 3
Possibility to measure drug level of previous 
biologics was added 
Rationale for change
Possibility to measure drug level of previous 
biologics was added to give possibility to shorten 
washout period from currently defined 8 weeks per 
Protocol based on results of drug level of previous 
biologics treatment level. 
Section to be changed
Flowchart 1 and 2
Description of change 4
Requirement to contact IRT at EOS visit removed
Rationale for change
Typo in previous version
Section to be changed
Flowchart 1 and 2


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Description of change 5
PGA assessmet added in separate line; Footnote 10 
– PGA collection requirement clarified
Rationale for change
To ensure protocol compliance
Section to be changed
1.4 BENEFIT-RISK ASSESSMENT
Description of change 6
Benefit-Risk assessment section was re-phrased 
Rationale for change
To reflect latest IB wording and BI project 
standard wording
Section to be changed
Description of change 7
Rationale for change
Section to be changed
Tab. 3.1:1 Rescue treatment
Description of change
New or increase in dose of any medication, or a 
surgical procedure, applied to treat new or 
persisting symptoms related to ulcerative colitis
Changed to:
New or increase in dose of any medication, or a 
surgical procedure, applied to treat new or 
worsening symptoms related to ulcerative colitis
Rationale for change
More precise definition
Section to be changed
Tab. 3.1:1 Disease flare
Description of change
Increase in partial MCS score by ≥2 points from 
nadir observed during a regular or unscheduled 
study visit, confirmed  subsequently by 
sigmoidoscopy with the modified Endoscopic 
Subscore (mESS) ≥2 AND a second partial Mayo 
score measurement confirming the increase from 
nadir by ≥2, in absence of enteric pathogens in 
stool - after achievement of a clinical response (as 
defined in table 2.2.2:1)
Changed to:
Increase in partial MCS score by ≥ 2 points from 
baseline (in 2 subsequent visits) and increase in 
rectal bleeding score by ≥ 1 point from baseline (in 


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2 subsequent visits), confirmed by increase of 
modified endoscopic subscore by ≥ 1 point from 
baseline with modified endoscopic subscore abs. 
increase by ≥ 2 points in absence of enteric 
pathogens in stool (as defined in table 2.2.2:1)
Rationale for change
alignment with expert experiences with other UC 
programs
Section to be changed
All Sections
Description of change
Stratification for Japan versus rest of world
Changed to:
Stratification for Japan versus non-Japan
Rationale for change
More precise wording
Section to be changed
3.3.2 Inclusion criteria #5
Description of change
Agonists Changed to: Antagonists
Rationale for change
typo
Section to be changed
3.3.3.1 Exclusion criteria #4
Description of change
any biologic treatment with a TNFantagonist
(adalimumab, infliximab, golimumab) or 
vedolizumab within 8 weeks prior to randomisation
Changed to:
any biologic treatment with a TNFantagonist
(adalimumab, infliximab, golimumab, 
certolizumab) or vedolizumab within 8 weeks prior 
to randomisation. (If drug level testing for 
previously used biologic treatment confirms no 
detectable drug level before randomization, patient 
can be enrolled despite not having completed 8 
weeks from last treatment.) 
Rationale for change
Possibility to measure drug level of previous 
biologics was added to give possibility to shorten 
washout period from currently defined 8 weeks per 
Protocol based on results of drug level of previous 
biologics treatment level.
Adaptation to current status of biologics treatment
Section to be changed
3.3.3.1 Exclusion criteria #4
Description of change
any investigational biologic for UC (including but 
not limited to ustekinumab and other IL-23 
inhibitors) within 12 weeks prior to randomisation
(except etrolizumab: within 8 weeks prior to 


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randomisation)
Changed to:
any investigational biologic for UC (including IL-
12 and IL-23 inhibitors; etrolizumab) within 8 
weeks.  (If drug level testing for previously used 
biologic treatment confirms no detectable drug 
level before randomization, patient can be enrolled 
despite not having completed 8 weeks from last 
treatment.)
Rationale for change
Possibility to measure drug level of previous 
biologics was added to give possibility to shorten 
washout period per Protocol based on results of 
drug level of previous biologics treatment level and 
to align with current standard
Reflecting current status of biologics treatment
Section to be changed
3.3.3.1 Exclusion criteria #5
Description of change
Positive stool examination for C.difficile or other 
intestinal pathogens 
Changed to:
Positive stool examinations for C. difficile (toxin 
A/B – test positive)
Rationale for change
Reflecting requirements for C.difficile positivity 
also included in central lab flagging
Section to be changed
3.3.3.2 Exclusion criteria#14
Description of change
patients with remote history of malignancy (< 10
years prior)
Changed to:
patients with remote history of malignancy (≥5
years prior)
Rationale for change
Project standard
Section to be changed
Section 4.1.1 Identity of the Investigational 
Medicinal Products
Description of change
Added description of test product and placebo for 
CMC12K material
Rationale for change
Required for additional countries to be added later 
in 2020
Section to be changed
Section 4.2.1 Management of AEs
Description of change
Infusion reactions including anaphylactic reactions 
Changed to:
Systemic hypersensitivity including infusion 
reaction and anaphylactic reaction


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Rationale for change
Project standard wording
Section to be changed
Tab. 4.2.2.1 Restrictions regarding previous and 
concomitant treatment
Description of change
Added :
any biologic approved for UC adalimumab, 
infliximab, golimumab, vedolizumab Not allowed 
from 8 weeks prior to randomisation or from time 
when no detectable drug level was confirmed until 
end of the trial
any investigational or non-approved biologic for 
UC (incl. ustekinumab, other IL-23 inhibitors, 
etrolizumab, certolizumab) Not allowed from 8 
weeks prior to randomisation or from time when no 
detectable drug level was confirmed until end of 
the trial
Any prior dose of Ustekinumab approved for UC is 
prohibited
Any biologic for treatment fof  any other indication 
( e.g. Dupilumab for the treatment of atopic 
dermatitis - Not allowed from 8 weeks prior to 
randomisation until end of the trial
Oral corticosteroids: Short (<7 days) decrease of 
dose for treatment of AEs with subsequent increase 
back to initial baseline dose level is allowed
Rationale for change
Reflecting current status of biologics treatment for 
UC and additional restrictions re-evaluated
Section to be changed
Tab. 5.2.3. Laboratory tests footnotes
Description of change
If the 1st QuantiFERON®-TB test result is 
undetermined, a re-test should be performed. If the 
restest QuantiFERON-TB test result is 
undetermined, a PPD skin test should be performed
Added:
This applies for QuantiFERON®-TB test at 
screening as well as at EOS visit.
Rationale for change
More precise wording
Section to be changed
5.2.6.1 Adverse events of special interest ( AESIs)
Description of change
Infusions reactions and anaphylactic reaction 


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Changed to:
Systemic hypersensitivity including infusion 
reaction and anaphylactic reaction
Rationale for change
Project standard
Section to be changed
5.2.6.2 AE Collection section 
Description of change
AE Collection
The investigator shall maintain and keep detailed 
records of all AEs in the patient files.
The following must be collected and documented 
on the appropriate CRF(s) by the investigator:

From signing the informed consent onwards 
until either roll over into subsequent study
1368-0017 or 1368-0020 or until the end of 
residual effect period, REP): (for patients not 
enrolling into the subsequest studies):
- all AEs (non-serious and serious) and all 
AESIs.

For patients not rolling over into subsequent 
studies:
until the individual patient’s end of trial: 
- all related SAEs and all related AESIs.After the 
individual patient’s end of the trial: 
the Investigator does not need to actively monitor 
the patient for AEs but should only report any 
occurrence of cancer  and trial treatment related 
SAEs and trial treatment related relevant SAEs and 
relevant AESIs of which the Investigator may 
become aware of
Changed to:
The investigator shall maintain and keep detailed 
records of all AEs in the patient files.
The following must be collected and documented 
on the appropriate CRF(s) by the investigator:

From signing the informed consent onwards
until the first dose of trial medication in the 
extension trial:
- all AEs (non-serious and serious) and all 
AESIs.

For patients not rolling over into subsequent 
open label extension studies:
from signing the informed consent onwards 
until the individual patient’s end of trial 
(including 16 weeks follow-up visit after last 
treatment dose):


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- all AEs ( non-serious and serious) and all
AESIs.
the Investigator does not need to actively 
monitor the patient for AEs but should only 
report any occurrence of cancer  and trial 
treatment related SAEs and trial treatment 
related AESIs of which the Investigator may 
become aware of by any means of 
communication, e.g. phone call. Those AEs 
should be reported on the BI SAE form, but not 
on the CRF.
Rationale for change
Project standard
Section to be changed
5.2.6.2 AE reporting to sponsor and timelines
Description of change
Fax reporting requirement  removed
Rationale for change
Administrative requirement
Section to be changed
5.4.5 DNA banking
Description of change
Storage of the paxgene Blood DNA tubes changed 
from ambient to frozen 
Rationale for change
Correction to align with lab manual
Section to be changed
5.5. Other Assessments
Description of change
Added: Optional assessment of drug level in blood 
of biologics used for the treatment of UC before 
screening for this study will be performed prior to 
randomization. Analysis will be done using a 
central laboratory vendor. This assessment will 
allow to randomize respective patients within a 
period shorter than 8 weeks when negative drug 
level of previous biologics is detected.
Rationale for change
Additional blood analysis added
Section to be changed
6.1 Visit Schedule
Description of change
If any of these visits has to be rescheduled, the date 
of subsequent visits should be calculated from date 
of previous visit.
Changed to:
If any of these visits has to be rescheduled, the date 
of subsequent visits should be calculated from day 
0 (visit 2). There should be at least 14 days 
between two consecutive study drug 
administrations.


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Rationale for change
Correction of mistake in previous version
Section to be changed
Section 10.1 
Description of change
Added: In addition, the stool frequency and rectal 
bleeding subscore will be considered to be missing 
both for the day of and the day after the endoscopy.
Rationale for change
FDA guidance
Section to be changed
10.6 Definition of primary, secondary nonresponse 
or intolerance to anti-integrin or anti-TNF therapy
Description of change
Golimumab (2 or 3 doses of ≥100 mg)
Changed to: 
Golimumab (2 or 3 doses of 50 or 100 mg (per 
locally approved label )
Where applicable
Rationale for change
typo
Section to be changed
10.6 Definition of primary, secondary nonresponse 
or intolerance to anti-integrin or anti-TNF therapy
Description of change
These signs and symptoms of Ulcerative Colitis 
must have occurred≥2 weeks
Changed to:
These signs and symptoms of Ulcerative Colitis
must have occurred ≤2 weeks
Rationale for change
typo


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15932366
4.0
clinical-trial-protocol-version-04
A Phase II/III Randomized, Double-blind, Placebo-controlled, Multicenter Study to
Evaluate the Safety and Efficacy of BI 655130 (SPESOLIMAB) Induction Therapy
in patients with moderate-to-severely active ulcerative colitis who have failed
previous biologics therapy
Approval-Team Member Drug
Safety
10 Oct 2019 13:46 CEST
Approval-Therapeutic Area
10 Oct 2019 13:49 CEST
Author-Clinical Trial Leader
10 Oct 2019 13:53 CEST
Approval-Team Member Medicine
10 Oct 2019 17:33 CEST
Approval-Biostatistics
11 Oct 2019 07:20 CEST
Verification-Paper Signature
Completion
11 Oct 2019 08:59 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15932366
4.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c22173820-03
BI Trial No.:
1368-0005
Title:
A Phase II/III Randomized, Double-blind, Placebo-controlled, 
Multicenter Study to Evaluate the Safety and Efficacy of BI 
655130 (SPESOLIMAB) Induction Therapy in patients with 
moderate-to-severely active ulcerative colitis who have failed 
previous biologics therapy
Including Protocol Amendment 3 [c15932366-04]
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone: 
Fax: 
Date of statistical 
analysis plan:
02 MAR 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.


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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 .......................................................................................................11
5.1
PRIMARY ENDPOINT .....................................................................................11
5.2
SECONDARY ENDPOINTS.............................................................................11
Key secondary endpoints....................................................................................11
5.2.1
Secondary endpoints...........................................................................................11
5.2.2
Safety endpoints ..................................................................................................13
5.4.1
Rescue treatment.................................................................................................14
5.4.5
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................17
6.1
TREATMENTS...................................................................................................17
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................18
6.3
SUBJECT SETS ANALYSED...........................................................................29
6.5
POOLING OF CENTRES .................................................................................34
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................34
Withdrawals ........................................................................................................35
6.6.1
Efficacy endpoints...............................................................................................35
6.6.2
Safety endpoints ..................................................................................................38
6.6.3
PK data.................................................................................................................39
6.6.4
Time since first diagnosis ...................................................................................39
6.6.6
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................40
7.
PLANNED ANALYSIS......................................................................................42
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........43
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................44
7.3
TREATMENT COMPLIANCE........................................................................45
7.4
PRIMARY ENDPOINT .....................................................................................46
7.5
SECONDARY ENDPOINTS.............................................................................51
Key secondary endpoint .....................................................................................51
7.5.1


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(Other) Secondary endpoints.............................................................................51
7.5.2
Use of rescue medication ....................................................................................59
7.6.4
7.7
EXTENT OF EXPOSURE.................................................................................59
7.8
SAFETY ANALYSIS..........................................................................................59
Adverse events.....................................................................................................59
7.8.1
Laboratory data ..................................................................................................62
7.8.2
Vital signs.............................................................................................................63
7.8.3
ECG......................................................................................................................64
7.8.4
8.
REFERENCES....................................................................................................65
9.
ADDITIONAL SECTIONS ...............................................................................67
Mayo Clinical Score (MCS) and its Subscores.................................................67
9.2.1
Total Mayo score (Total MCS) ..........................................................................70
9.2.2
Modified Mayo score (mMCS)...........................................................................70
9.2.3
Partial Mayo score (Partial MCS).....................................................................70
9.2.4
Overview of Clinical Response and Remission Calculations ..........................70
9.2.6
IBDQ scores.........................................................................................................72
9.2.7
10.
HISTORY TABLE..............................................................................................80


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases...........................................................................17
Table 6.2: 1
Handling of iPDs..............................................................................................19
Table 6.3: 1
Subject sets analysed (first interim database snapshot) ...................................31
Table 6.3: 2
Subject sets analysed (second interim database snapshot)...............................32
Table 6.3: 3
Subject sets analysed (final, updated trial snapshot)........................................33
Table 6.6.2: 1 Missing data approaches for binary efficacy endpoints...................................35
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs and 
biomarker to visits for statistical analysis ........................................................41
Table 7.1: 1
Categories for summary of continuous variables.............................................44
Table 7.4: 1
Contrast coefficients.........................................................................................47
Table 7.4: 2
Summary of all analysis to be performed for primary endpoint ......................50
Table 7.5.2: 1 Summary of analysis for secondary endpoints.................................................53
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events 
Concepts...........................................................................................................61
Table 10: 1
History table .....................................................................................................80


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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
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
ATC3
Anatomical-Therapeutic-Chemical classification level 3
BI
Boehringer Ingelheim
BL
Baseline
BLQ
Below the lower limit of quantification
BMI
Body mass index
BRAVE
BI RAVE®
BSA
Body surface area
CARE
Clinical data analysis and reporting environment
CR
Clinical remission
CRF
Case report form
CRP
C-reactive protein
CTC
Common Terminology Criteria
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOS
End of Study


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Term
Definition / description
EOT
End of treatment
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials
FAS
Full analysis set
F/U
Follow-up
HLGT
High Level Group Term
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IL
Interleukin
Imp-IR
Imputed approach including values after rescue medication
IPD
Important protocol deviation
IQR
Inter Quartile Range
IRT
Interactive response technology
LLOQ
Lower limit of quantification
LOQ
Limit of quantification
mCR
Modified clinical remission
MCS
Mayo Clinical Score
mMCS
Modified Mayo Clinical Score
MedDRA
Medical Dictionary for Regulatory Activities
mESS
Modified Endoscopic Subscore
MI
Multiple Imputation
MQRM
Medical quality review meeting
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
NRI
No response imputation
OC
Observed cases
OC-IR
Observed cases including values after rescue medication


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Term
Definition / description
OR
Original results
pCR
Partial clinical remission
PD
Pharmacodynamic(s)
PGA
Physician Global Assessment
PK
Pharmacokinetic(s)
PPS
Per protocol set
PT
Preferred Term
PV
Protocol Violation
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
RBS
Rectal Bleeding Subscore
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual effect period
RPM
Report planning meeting
RS
Randomized set
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SDL
Subject data listing
SFS
Stool Frequency Score
SI
International System of Units
SMQ
Standardised MedDRA query
SOC
System Organ Class
TEAE
Treatment Emergent Adverse Event
TSAP
Trial statistical analysis plan
UC
Ulcerative Colitis
ULN
Upper limit of normal range
ULOQ
Upper limit of quantification
VAS
Visual analogue scale


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (1), the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the CTP and its amendments, and to include detailed procedures for 
executing the statistical analysis of the primary and secondary variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the clinical trial protocol 
(CTP). In particular, the TSAP is based on the planned analysis specification as written in 
CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomisation.
This trial consists of 2 parts, Part 1 to demonstrate proof of concept of clinical activity as an 
induction therapy in ulcerative colitis (UC), and Part 2 to confirm the efficacy and safety of 
BI 655130 as an induction treatment in UC. For the purpose of statistical analysis, both parts
will be treated as two independent parts whereby the false positive rate is separately 
controlled within each part. Only patients randomized into Part 1 will be included in the 
statistical analyses of Part 1 data. This TSAP contains the analysis specification for the final 
analysis of Part 1.
For further details on the subjects 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. 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 unblind.


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Per CTP, a subsequent interim database snapshot will be done based upon the complete 12-
week data using all patients randomized into the trial. At this time, all displays as described in 
this TSAP will be produced. The results from this analysis will be used for potential authority 
interactions, if applicable.
A final, updated analysis of the trial will be performed once all patients have completed the 
trial. For more details, please refer to Section 6.3.
As a consequence of the early termination of this trial, the conduct of Part 2 in an 
operationally seamless manner subsequent to the completion of Part 1, is no longer 
considered viable.
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 SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
SAS calling R version 3.0.2 or later may be used for calculation of Reeve's confidence 
intervals (2). SAS calling R version 3.0.2 or later with “DoseFinding” package (3) will be 
used for analysis based on Multiple Comparison Modelling (MCPMod).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY


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5.
ENDPOINTS
For all endpoints and unless explicitly specified otherwise, Week 12 refers to Visit 6 
(V6/EOT) using extended time windows as defined in Table 6.7: 1.
For handling of missing data and corresponding sensitivity analysis, see Section 6.6 and 
Section 7.
For a detailed derivation of Mayo Clinical Score (MCS) and corresponding efficacy 
endpoints, please see Section 9.2.
5.1
PRIMARY ENDPOINT
•
Proportion of patients with Clinical Remission at Week 12
(defined as mMCS SFS=0 or 1, if drop ≥1 from baseline; and RBS=0; and mESS≤1)
The mESS used for analysis will be based on the centrally-read endoscopy scores; only if 
centrally-read data are missing will these be replaced by the local endoscopy score.
5.2
SECONDARY ENDPOINTS
Key secondary endpoints
5.2.1
Not applicable. No key secondary endpoints for Part 1 have been specified in the CTP.
Secondary endpoints
5.2.2
•
Proportion of patients with Endoscopic improvement at Week 12
(defined as mESS ≤ 1)
•
Proportion of patients with Clinical response at Week 12
(defined as total MCS reduction ≥3. and ≥30% from baseline; AND RBS drop from baseline 
by ≥1., or absolute RBS ≤1)
•
Change in IBDQ score from baseline at Week 12
Derivation of the IBDQ score is described in Section 9.2.7.
•
Proportion of patients with combined endoscopic improvement and histologic 
remission at Week 12
(defined as mESS ≤ 1 and Robarts Histology Index ≤ 6)


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Derivation of the Robarts Histology Index is described in Section 9.2.5.


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Safety endpoints
5.4.1
Safety will be assessed based on:
•
Adverse events
•
Serious adverse events (SAEs)


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Rescue treatment
5.4.5
According to the definition of rescue treatment in CTP Section 3.1, rescue treatment includes: 
•
Newly administered medications or surgical therapy used to treat the underlying disease
UC due to disease worsening or a disease flare


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
The trial comprises two distinct parts with different objectives. Patients in Part 1 will receive 
treatment with either BI 655130 300 mg i.v. single dose (SD), BI 655130 450 mg i.v. q4w, BI 
655130 1200 mg i.v. q4w, or matching placebo.
For more details of study information on the treatment to be administered, assignment to 
treatment, and selection of dose, refer to Section 4 of the CTP.
The following study phases for Part 1 are defined:
Table 6.1: 1
Flow chart of analysis phases 
Study analysis 
phase
Description
Start (included)
End (included)
Screening phase
Screening
Earliest of (Date of informed 
consent, first screening 
procedure) 
Date/time of start of infusion of 
first study drug minus 1 minute.
Treatment phase & 
Residual effects 
period 
On-treatment 
period
Date/time of start of infusion of 
first study drug (Day 1)
Patient dosed in extension:
Date/time of first dose in 
extension – 1 minute2.
Patient not dosed in extension:
Date of end of infusion of last 
study drug + 112 days at 11:59 
p.m.
Follow-up1 phase
Off-treatment 
period
Date of end of infusion of last 
study drug + 113 days at 12:00 
a.m.
Latest of: i) Date of EOS 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 last contact date is after the date of end of last infusion + 
112 days; does not apply to patients who roll over into the extension trial.
2 Applies only to patients in the parent trial who are dosed in the extension trial. It is expected that roll over will occur within 
2 weeks of the EoT visit in the parent trial, therefore, REP should not be applicable for definition of the on-
treatment period. Note that for adverse event, where date and time are collected, events which occur on the same 
day of first dose in the extension, but prior to this administration are assigned to, and reported as a part of, the 
parent trial.
The first interim database snapshot and analysis of Part 1, will be performed based upon 
those randomized patients in Part 1 who have completed/discontinued through the planned 
first 12 weeks of trial up to the cut-off date (see Section 6.3). The following data will be used
in this analysis:

Selected summaries of the 12-Week data will be summarized up to the minimum of 
the (analysis-specific data cut-off; study day 99), unless otherwise specified. 


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For the second interim database snapshot (the primary analysis per the CTP), to be performed 
once all randomized patients have completed/discontinued through the planned first 12 weeks 
of trial (per CTP specification), the following data will be used:

All 12-Week data will be summarized up to the minimum of the (analysis-specific 
data cut-off; study day 99), unless otherwise specified. 
The final, updated analysis of the trial, will be performed once all patients have completed 
the trial. Generally only listings of the trial data are planned to be done, however, updates on 
the primary and secondary endpoint analysis, as well as select AE displays will be produced 
in order to confirm the consistency of the results to those results obtained at the previous 
interim snapshots. Any clinical relevant changes from the previous interim analyses to the 
final analysis will be addressed in the CTR. 
Treatment groups for analysis are listed as follows:

"Placebo"

"Speso 300 mg IV SD"

"Speso 450 mg IV q4w"

"Speso 1200 mg IV q4w"

“Speso Total” (across all BI treatment arms)

“Overall Total"(across treatments), where appropriate.
“Overall Total” is applicable in disposition, demographics and baseline characteristics, 
compliance summaries and safety tables. “BI Total” should also be presented in safety tables.
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)" (4).
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 (5). The following 
table contains the categories which are considered to be iPDs in this trial. If the data show 


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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 . IPDs will be summarised and listed for the randomized set.
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 date of 
signing informed consent)
LABEL:
Age beyond 18-75 years
IC01
Also check versus derived 
age for patient.
None
A1.02
Diagnosis of ulcerative colitis ≥3 months 
prior to screening by clinical and 
endoscopic evidence and corroborated 
by a histopathology report
LABEL:
Diagnosis too recent or insufficiently 
documented
IC02
Also check derived time 
since diagnosis for patient
None
A1.03
Moderate to severe disease activity, 
defined as: 
Total Mayo Score (MCS) 6 to 12 AND
RBS≥1 AND SFS≥1 AND mESS≥2 
within 7-28 days prior to first dose
LABEL: Mild disease activity
IC03 (per CTP version 3.0)
Also check derived total 
MCS and subscores at 
baseline
For patients enrolled under 
CTP version 1 and 2, the 
violation of IC 03 will be 
detected from medical 
review
PPS
#
A1.04
Endoscopic activity extending proximal 
to the rectum (>=15 cm from anal verge)
LABEL:
Disease not extending to rectum
IC04
None
A1.05
Demonstrated in the past inadequate 
response or loss of response or have had 
unacceptable side effects with approved 
doses of TNFɑ antagonists (infliximab, 
adalimumab, golimumab) and / or 
vedolizumab 
LABEL:
No poor response/tolerance to previous 
biologic therapy
IC05
PPS


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Table 6.2: 1 (cont’d)
Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
A1.06
If patients receive concurrent UC 
treatments, these need to be on stable 
doses.
LABEL:
Concurrent UC treatment not on 
stable dose
IC06 
If patients receive unstable 
dose of probiotics, they will 
not be excluded from PPS.
One day deviation from CTP 
required stable dose time 
window is allowed.
If IC06 is being ticked on 
CRF, but later medical 
review reveals use of 
concurrent UC treatment 
which are not on stable dose, 
then it will be an iPD, and 
lead to exclusion from PPS 
PPS
#
A1.07
Patients with extensive colitis or 
pancolitis of >10 years duration or 
family history of colorectal cancer or 
personal history of increased colorectal 
cancer risk must have had a 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) 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 violated 
GI
Gastrointestinal Exclusion Criteria
GI.01
Evidence of abdominal abscess at 
screening
LABEL:
Abdominal abscess
EC01
None


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Table 6.2: 1 (cont’d)
Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
GI.02
Evidence of fulminant colitis or toxic 
megacolon at screening
LABEL:
Fulminant colitis or toxic megacolon
EC02
None
GI.03
Ileostomy, colostomy, or known fixed 
symptomatic stenosis of the intestine
LABEL:
Ileostomy, colostomy, or stenosis
EC03
None
GI.04
Any concurrent treatment prior to 
screening or randomization as defined 
in EC04 (see CTP Section 3.3.3.1)
LABEL:
Concurrent treatment not as allowed
EC04
One day deviation from CTP 
required time window is 
allowed.
If EC04 is NOT being ticked 
on CRF, but later medical 
review reveals use of restricted 
concurrent UC treatment, then 
it will be an iPD, and lead to 
exclusion from PPS
PPS
#
GI.05
Positive stool examinations for C. 
difficile or other intestinal pathogen 
<30 days prior to screening
LABEL:
Infection with intestinal pathogen
EC05
PPS
GI.06
Have had previous surgery or are 
anticipated to require surgical 
intervention for UC
LABEL:
Required surgical intervention for UC
EC06, based on tick box and 
medical review
PPS
GI.07
Evidence of colonic moderate/severe 
mucosal dysplasia or colonic 
adenomas, unless properly removed
LABEL:
Colonic mucosal dysplasia or 
adenomas
EC07
None
GI.08
Primary sclerosing cholangitis
LABEL:
Primary sclerosing cholangitis
EC08
None


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Table 6.2: 1 (cont’d)
Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
GI.09
Faecal transplant ≤6 months before 
screening
LABEL:
Faecal transplant within 6 months
EC09
None
ID
Infectious Disease Exclusion Criteria
ID.01
Increased risk of infectious complications 
(e.g. recent pyogenic infection, any 
congenital or acquired immunodeficiency 
(e.g. HIV), past organ or stem cell 
transplantation)
LABEL:
Increased risk of infectious complications
EC10
None
ID.02
Live or attenuated vaccination within 6 
weeks prior to screening,
LABEL:
Recent live or attenuated vaccination
EC11
None
ID.03
Active or latent TB: Patients with a 
positive TB test during screening are 
excluded except the situations as listed in 
EC12 in CTP
LABEL:
Active or latent TB
EC12
None
ID.04
Relevant chronic or acute infections 
including human immunodeficiency virus 
(HIV) or viral hepatitis. A patient can be 
re-screened if the patient was treated and is 
cured from the acute infection
LABEL:
Relevant chronic or acute infections
EC13
None
OT
General Exclusion Criteria
OT.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, or history of cervical cancer in 
situ (treated > 3years); patients  with 
remote history of malignancy (<10 years 
prior) may be considered and have to be 
discussed with sponsor case by case
LABEL:
Malignancy within last 5 years
EC14
None


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Table 6.2: 1 (cont’d)
Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
OT.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 major surgery
EC15
None
OT.03
Pathological safety lab parameters: 
haemoglobin <9 g/dL, total white blood 
count (WBC) <3000 cells/µl, neutrophils 
<1000 cells/µl, thrombocytes <100.000/µl, 
creatinine ≥2 mg/dL, albumin <30 g/l, total 
bilirubin >2 x ULN with ratio of 
direct/indirect>1 (patients with Gilbert’s 
syndrome are not excluded), Alkaline 
Phospatase > 3 x ULN. – measured and 
confirmed by Central laboratory at 
screening visit.
LABEL:
Pathological safety lab parameters out of 
required range
EC16
Also check corresponding 
safety lab parameters at 
baseline
None
OT.04
Currently  enrolled in another 
investigational device or drug study
LABEL: 
Enrolment in another study
EC17
None
OT.05
Women who are pregnant, nursing, or who 
plan to become pregnant while in the trial
LABEL:
Pregnant or nursing
EC18
None


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Table 6.2: 1 (cont’d)
Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
OT.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
EC19
None
OT.07
Any psychiatric or social problems  
possibly interfering with ability to 
comply with all study visits/procedures
LABEL:
Psychiatric or social problem
EC20
None
OT.08
History of allergy/hypersensitivity to 
the systemically administered trial 
medication agent or its excipients
LABEL:
Allergy or hypersensitivity to trial 
medication
EC21
PPS
B
Informed consent
B.01
Informed consent not available/not 
done
LABEL:
Informed consent not available 
Based on direct assessment, not 
simply the tick box (which is 
A1.09).
Date of informed consent 
missing or no signature on 
patient’s “Declaration of
Informed Consent”
In this case: Patient’s data will
be removed from database and
not be used at all.
All analyses
#
B.02
Informed consent too late
LABEL:
Informed consent too late
Informed consent date was 
after Visit 1, i.e., after any 
screening procedure 
None


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Table 6.2: 1 (cont’d)
Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
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 arms
BI patient who received BI 
dose not matching treatment 
that was randomized would be 
considered an iPD.
BI 655130 treated  patient who 
fulfils any of the following:
For 300mg SD patients,
•
received >= 1 vial
(150mg) of BI 655130 
verum different from 
planned at any visit
For 450mg q4w patients,
•
received any 2 vials
(300mg) of BI 655130 
verum different from 
planned at any visit or 
overall
For 1200mg q4w patients,
•
received any 3 vials 
(450mg) of BI 655130 
verum different from 
planned at any visit or 
overall
Can only be finally judged 
after 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 (except that 
infusion is interrupted due to safety 
concerns, as described in CTP 
section 4.1.4).
The total planned volume is

100mL if discontinuation 
before visit V2

100 mL at each visit (200mL 
total) if discontinuation 
before V4

100 mL at each visit (300mL 
total) if discontinuation before
V5
The total planned volume overall is 
300 mL.
PPS
C2.02
Wrong treatment schedule
Patient received treatment 2 weeks 
outside scheduled time.
PPS
C3
Randomisation not followed
C3.01
Treated without randomisation
LABEL:
Treated without randomisation
Patient treated according to eCRF, 
but not randomised according to 
IVRS.
RS(i), 
m-RS(i), 
PPS, SAF(i)
C3.02
Randomisation order not followed
LABEL:
Randomisation order not 
followed/stratification error
Stratification error
None
C4
Medication code broken
C4.01
Medication code broken 
inappropriately
LABEL:
Medication code broken
inappropriately 
Medication code was broken prior 
to the DBL for the Week 12 
analysis for no valid reason.
Final decision at the DBL meeting 
based on medical judgment.
PPS
#


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Table 6.2: 1 (cont’d)
Handling of iPDs
Category / 
Code
Description
Comments
Excluded from1
D
Concomitant medication
D1
Prohibited medication use
D1.01
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 – prior to or up to Week 
12
LABEL:
Restricted medication prior to Week
12
If restricted medication is initiated 
during trial
PPS
#
D1.02
Use of restricted medication as per 
CTP Table 4.2.2: 1 when not 
provided as a rescue treatment to 
stabilize a worsening disease 
condition - after Week 12
LABEL:
Restricted medication after Week
12
If restricted medication is initiated 
during trial
None
#
D2
Change in background 
medication
D2.01
Any dose change in background 
concurrent UC treatments when 
not provided as a rescue treatment 
to stabilize a worsening disease 
condition – prior to or up to Week 
12:
Oral 5-ASA compounds
LABEL:
Oral 5-ASA compounds not stable
Medical review, only dose 
increase not used as rescue will 
lead to exclusion from PPS
PPS
#
D2.02
Any dose change in background 
concurrent UC treatments when 
not provided as a rescue treatment 
to stabilize a worsening disease 
condition – prior to or up to Week 
12:
Oral corticosteroids (incl. 
budesonide)
LABEL:
Oral corticosteroids not stable 
Medical review, only dose 
increase not used as rescue 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
For specification on definition of analysis sets, refer to Section 6.3. Analysis of efficacy data according to the PPS will be 
done at the time of the 2nd interim database snapshot only [including all randomized patients through week 12].
Source: BI reference document ' Identify and Manage Important Protocol Deviations (iPD)' [001-MCS-50-413] (4, 6).
1 See Section 6.3 for population definition
Category / 
Code
Description
Comments
Excluded from1
D2.03
Any dose change in background 
concurrent UC treatments when 
not provided as a rescue treatment 
to stabilize a worsening disease 
condition – prior to or up to Week 
12:
Azathioprine, 6-mercaptopurin or 
methotrexate
LABEL:
Azathioprine, 6-mercaptopurin or 
methotrexate not stable
Medical review, only dose 
increase not used as rescue will 
lead to exclusion from PPS
PPS
#
D2.04
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
#
F
Study specific analysis
F1
Other trial specific violation
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
G1.01
Pregnancy test not done for woman 
of child bearing potential, or 
pregnant during study
LABEL:
Pregnancy test not done or pregnant
Pregnancy test not done at any 
visit where such is scheduled 
None


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6.3
SUBJECT SETS ANALYSED
From CTP Section 7.3:
There will be 4 main patient populations in this trial for analyses: the randomized set (RS),
the safety analysis set (SAF), the modified RS (m-RS), and the per-protocol set (PPS).
Randomized Set (RS)
This patient set includes all randomized patients. Treatment assignment will be as
randomized. This is the main analysis set for presentation of efficacy on binary endpoints.
Safety Analysis Set (SAF)
This patient set includes all patients who were randomized and received at least one dose of
study drug. It will be the main analysis set for presentation of safety. Patients will be
analyzed according to the actual treatment.
Modified Randomized Set (m-RS)
This patient set includes all patients in the RS who had a baseline and at least one post-
baseline measurement for the endpoint under consideration. Treatment assignment will be as
randomized. This is the main analysis set for presentation of efficacy on continuous data, e.g.
IBDQ.
Per-Protocol Set (PPS)
This patient set includes all patients in the RS who adhered to the CTP without any iPDs
(potentially affecting the study outcome) which lead to exclusion from the PPS. This set will
be used for sensitivity analysis on the primary efficacy endpoint.
In addition, the following patient sets will be defined for analysis.
Enrolled set (ES)
This patient set includes all patients who signed informed consent. It will be used for analyses 
of patient disposition.
For the first interim database snapshot, modified versions of the ES, RS, SAF, and m-RS will 
be defined: the ESi, RSi, the SAFi, and the m-RSi. 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), and at the time of the 
final, updated trial analysis, the ES, RS, SAF, m-RS, and PPS will be used. Corresponding 


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analyses performed at the time of the first interim database snapshot will use the ESi, RSi, 
SAFi, and m-RSi.
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 
performed prior to each database snapshot of this trial.
Handling of Treatment Misallocations in Analysis Sets
If a subject is randomized but not treated, they will be reported under their randomized 
treatment group for efficacy analysis according to RS, m-RS, and PPS (per the intent-to-
treatment principle).  By definition, however, such patients are excluded from the safety 
analyses as no study medication was taken.
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 RS, m-RS, and PPS, they will be reported under their 
randomized treatment groups. But if the subject has an iPD as defined in Section 6.2, the 
subject will be excluded from PPS for efficacy analysis. 
-
For safety analyses using the SAF, 
•
if a subject is planned with multiple dose administrations of BI 655130 (randomized 
to 450mg q4w, 1200mg q4w), 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 at only some 
dosing occasions. 
•
if a subject is planned with a single dose administration of BI 655130 (randomized to 
300mg SD), they will be reported under BI 655130 300mg SD if the subject receives 
at least one dose of BI 655130 at any visit. A 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, 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, they will be 
reported as BI 655130 300mg SD treatment group.
Table 6.3: 1 (first interim database snapshot), Table 6.3: 2 (second interim database 
snapshot), and Table 6.3: 3 (final trial snapshot) illustrates the data sets which are to be used 


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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.
Table 6.3: 1
Subject sets analysed (first interim database snapshot)
Patient set
Class of endpoint
ESi
RSi
SAFi
m-RSi
Disposition
√
√
Compliance 
√
Exposure
√
iPDs
n.a.
Demographic/baseline 
characteristics
√
Primary efficacy endpoint
(primary analysis only)
√
Secondary efficacy endpoints 
(Binary) (primary analysis only)
√
Secondary efficacy endpoints 
(Continuous) (primary analysis 
only)
√
Safety parameters
√
Use of rescue medication
√
At the time of the first interim database snapshot, only selected analyses on each efficacy 
endpoint will be done. All safety displays will be produced. 


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Table 6.3: 2
Subject sets analysed (second interim database snapshot)
Patient set
Class of endpoint
ES
RS
SAF
m-RS
PPS
Disposition
√
√
Compliance 
√
Exposure
√
iPDs*
√
Demographic/baseline 
characteristics
√
Primary efficacy endpoint
√
√
Secondary efficacy endpoints 
(Binary)
√
Secondary efficacy endpoints 
(Continuous)
√
Safety parameters
√
Use of rescue medication
√
*the patient with iPD of treated but not randomized will only be listed in the footnote of the iPD table. 
At the time of the second interim database snapshot, all analyses per TSAP are scheduled to 
be performed.


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Table 6.3: 3
Subject sets analysed (final, updated trial snapshot)
Patient set
Class of endpoint
ES
RS
SAF
m-RS
Disposition
√
√
Compliance 
n.a.
Exposure
n.a.
iPDs
n.a.
Demographic/baseline 
characteristics
n.a.
Primary efficacy endpoint
(primary analysis only)
√
Secondary efficacy endpoints 
(Binary) (primary analysis only)
√
Secondary efficacy endpoints 
(Continuous) (primary analysis 
only)
√
Safety parameters
(selected displays only)
√
Use of rescue medication
n.a.
At the time of the final, updated database snapshot, only select analyses of the trial data are to 
be performed in order to ensure the consistency in key trial conclusions subsequent to the 
performance of two interim database snapshots.


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6.5
POOLING OF CENTRES
For the main analyses of efficacy to be performed in this trial, all patients from all centres 
will be pooled for statistical analysis. The effect of region on the primary and selected 
secondary efficacy endpoints will also be investigated as described in Section 6.4.
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 (not
using time windows and not setting values to missing).


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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, 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.
Efficacy endpoints
6.6.2
Based on the different reasons for patients’ data missing for different endpoints, various 
approaches will be used to assess the impact of missing data on the efficacy endpoints of this 
trial, depending upon the type of the endpoint. Approaches to be applied are described below.
Missing data imputations will be performed using all available on-treatment data observed up 
to the respective analysis cut-off date. 
Binary efficacy endpoints
With regards to the handling of missing data on binary efficacy endpoints, the following table 
gives an overview of the proposed imputation methods which are described in more detail 
below.
Table 6.6.2: 1 Missing data approaches for binary efficacy endpoints
Binary efficacy 
outcome 
observed or not
Imputation Approach Subsequent to 
Event of Type
Missing due to Other 
reasons
-
Withdrew consent
-
Loss of follow up
-
Data not collected
-
etc.
Rescue intake
Death due to any 
cause
NRI
Observed 
NRI
n.a.
n.a.
Not observed
NRI
NRI
NRI
MI
Observed 
MI
n.a.
n.a.
Not observed
MI
MI
MI
MI-
NRI
Observed 
NRI
n.a.
n.a.
Not observed
NRI
NRI
MI
OC
Observed 
no imputation
n.a.
n.a.
Not observed
no imputation
no imputation
no imputation


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Primary Imputation Approach – No Response Imputation [NRI]
1. If a patient takes a rescue medication (as defined in Section 5.4.5) for the 
treatment of ulcerative colitis or died due to any cause prior to observing the 
primary endpoint for this trial, then all data subsequent to the intake of such rescue 
will be considered to be missing. 
2. For endpoints which are measured at multiple visits (thereby excluding the 
endpoints which are based upon the endoscopic subscore), 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) with no intervening use of rescue 
medication;
For all patients with a missing visit outcome, impute as a failure to achieve a 
response.
Other Imputation Approaches
Observed cases (OC) approach: first, set all data collected after intake of a rescue 
medication to missing; then include all collected data with no imputation performed on 
the missing data. The analysis using OC approach is only based on all patients who 
have non-missing values in the patient set.
Multiple Imputation (MI) approach: use baseline and on-treatment data only, and
impute each Mayo Clinical Score component (SFS, RBS, PGA and mESS) as ordinal 
variables with values 0, 1, 2 and 3. The imputation will be done using OC data as the 
input dataset, and will follow the steps outlined below:
1.
Multiple Imputation of Missing data: use SAS procedure PROC MI with the Fully 
Conditional Specification (FCS) method and corresponding options/statements.
Logistic regression method is used to impute missing values by using the ordering 
of the class level in each variable.
The subscore variables (SFSv, RBSv, PGAv, mESSv) represent the corresponding 
subscore at each visit, where v=2 (baseline), 3 (Visit 3), 4 (Visit 4), 5 (Visit 5) and 6
(Visit 6). All variables are treated as ordinal variable from 0 (best) to 3 (worst). For 
each imputed subscore at specific visit, the subscore at other visits and all other 
subscores at each visit are used as covariates together with the treatment and 
stratification factors (previous BIO experience and prior corticosteroid use).
PROC MI DATA=alldat seed=1000 out=outmcs; 
  CLASS SFS2-SFS6 RBS2-RBS6 PGA2-PGA6 mESS2 mESS6 trt stratum; 
  FCS nbiter=10 logistic(SFS2-SFS6 RBS2-RBS6 PGA2-PGA6 mESS2 mESS6
/details); 
  VAR SFS2-SFS6 RBS2-RBS6 PGA2-PGA6 mESS2 mESS6 trt stratum; 
RUN;


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Note that the seed 1000 will be used throughout. If a second seed is required, 1001 
will be used, and so on as necessary.
2.
Analysis of Completed Datasets: For each completed dataset after multiple 
imputation, it will be used to calculate the clinical mayo score related endpoints, 
e.g., clinical remission, clinical response, endoscopic improvement, etc, and to 
perform the corresponding statistical analysis as specified in Section 7.
3.
Combine Results: PROC MIANALYZE combines the analysis results from step 2 
and generates valid statistical inferences by accounting for the variability introduced 
by the MI process. 
If the above imputation model cannot impute without error on the trial data, then it will 
be abandoned and an alternative model will be used whereby only subscores (SFS, RBS, 
PGA, mESS) at visit 6 (primary analysis time point) will be treated as ordinal variables 
and at all other visits subscores will be treated as continuous variables. If this alternative 
model also cannot impute without error, then it too will be abandoned and a further, even 
simpler, model will be implemented which will impute the primary binary endpoints, 
clinical remission of Yes or No at visit 6, directly (rather than at the subscore level); this 
model will include prior subscores at visits 2, 3, 4 and 5 as continuous variables.
Combined MI and NRI approach (MI-NRI): If a patient takes a rescue medication for 
the treatment of ulcerative colitis or died due to any cause prior to observing the 
primary endpoint for this trial, impute as a failure to achieve response. For all OTHER 
patients with a missing visit outcome, a missing at random assumption will be made, 
and imputation will be done using the MI approach as described above.
Continuous efficacy endpoints
Primary approach (MMRM): for 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. The model will include 
on-treatment data only and OC data as the input dataset.
Multiple Imputation (MI) approach: use on-treatment data only and OC data as the 
input dataset, will impute each continuous endpoint follow the steps outlined below:
1.
Multiple Imputation of Missing data: use SAS procedure PROC MI with the Fully 
Conditional Specification (FCS) method and corresponding options/statements. 
The continuous variables, i.e., IBDQv represent the IBDQ overall score at each 
visit, where v=2 (baseline), 3 (Visit 3), 4 (Visit 4), 5 (Visit 5) and 6 (Visit 6). 
Regression method is used to impute missing values. For each to-be imputed IBDQ 
overall score at a specific visit, the non-missing overall scores are used as covariates 
together with the treatment and stratification factor (previous BIO experience and
prior corticosteroid use).


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PROC MI DATA=alldat seed=1000 out=outmcs; 
  CLASS trt stratum; 
  FCS nbiter=10 reg(/details); 
  VAR IBDQ2-IBDQ6 trt stratum; 
RUN;
Note that the seed 1000 will be used throughout. If a second seed is required, 1001 
will be used, and so on as necessary.
2.
Analysis of Completed Datasets: For each completed dataset after multiple 
imputation, it will be used to perform the corresponding statistical analysis as 
specified in Section 7.
3.
Combine Results: PROC MIANALYZE combines the analysis results from step 2 
and generates valid statistical inferences by accounting for the variability 
introduced by the MI process. 
Observed Case (OC) approach is the same as described above for the binary efficacy 
endpoints
Safety endpoints
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. Observed cases including rescue (OC-IR) approach is an extension of 
the OC approach which includes all values which were measured both before and after any 
rescue medication intake. The analysis using OC-IR approach is only based on the patients 
with observed data.
The only exceptions where imputation might be necessary for safety evaluation are AE dates 
and start and stop dates for concomitant medications. Missing or incomplete AE dates are 
imputed according to BI standards (see 001-MCG-156_RD-01(7)).
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 last contact date, if it is earlier than the last day of the month).

If the day and month of the end date are missing then the end date is set to 31st of 
December of the year (or to the patient's last contact date, if it is earlier than the 31st of 
December of the year).

If the day of the start date is missing the start date is set to first day of the month (except 
for rescue medication, where the day of first trial medication administration will be used 
if first dosing happened in the same month).


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
If the day and month of the start date are missing then the start date is set to 1st January of 
the year (except for rescue medication, where the day/month of first trial medication 
administration will be used if first dosing happened in the same year).

All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance.
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) (8). 
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, time since first diagnosis will be set to 
missing.
•
If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th June of that year.


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•
If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Measurements reported with date and time and taken prior to start of administration of trial 
treatment will be considered pre-treatment values. Measurements reported with a date only 
(and no time) and taken on the day of first administration of trial treatment will also be 
considered pre-treatment values. These pre-treatment values will be assigned to visits 
according to the nominal visit number as recorded on the eCRF or as provided by the 
laboratory.
In addition, treatment-emergent adverse events which are reported with a date only (and no 
time) and which occur on the day preceding the first administration of trial treatment in the 
subsequent extension trial will be considered treatment-emergent AE in this parent trial.
Baseline, unless otherwise specified, is defined as the last measurement collected prior to the 
start of administration of the trial treatment.
Measurements taken after start of administration of trial treatment will be considered 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 below (Table 6.7: 1).
Analysis of AE data, concomitant medication or non-drug therapies, as well as use of rescue 
medication will not be based on visits. Therefore, no assignment to time windows will be 
necessary. Frequency tables for these data will be using on-treatment data only.
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) within the on-treatment period will be considered.
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 below in Table
6.7: 1.


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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 -7
n/a
V1b
Screening
- 28 to -7
n/a
V2
Baseline
Day 1
+/- 0 
1 A
1 A
≤1 A
1 A
On-treatment data only
V3
Week 2
Day 15
+/- 4
11
19
2
22
V4
Week 4
Day 29
+/- 4
25
33
23
43
V5
Week 8
Day 57
+/- 4
53
61
44
71
EOT
Week 12/EoT
Day 85
+/- 4 
81
89
72
Minimum 
of (cut-off, 
99)C
All data (planned off-treatment data)
Unsche
duled
Unscheduled
100
148
EOS B
Week 24/EoS
Day 170
+7
170
177
149
Day of last 
f-up value
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 for patients rolling-over into open label trial 1368-0017, the analysis visit window of EOS should be 
the same as that of Week 12/EOT.
C Cut-off date is not applicable for the final, updated trial analysis.
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, 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. 
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 during the on-treatment period, 
irrespective of whether the observation was selected in any time window. 


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7.
PLANNED ANALYSIS
The following analyses are planned at different stages throughout Part 1 of this trial.
Part 1 – 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 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 ESi, RSi, m-RSi, and SAFi. 
Part 1 – Second Interim Database Snapshot - Week 12 Primary Analysis (All Randomized 
Patients)
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, the complete, 
primary analysis of all efficacy, safety, and PK/ADA data will be done through Week 12, and 
will be performed by the sponsor; biomarker data will be reported, if available.
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, m-RS, SAF, and PPS. 
Part 1 – Updated analysis after final DBL
A final database lock will be done when all randomized patients in Part 1 complete the trial.
A majority of the trial patients are expected to roll-over into the extension trial at Week 12. 
The analyses as described in Section 6.3 of this TSAP will be performed, up to week 12, 
using the subject sets of ES, RS, m-RS, and SAF. Selected safety summaries including all 
data up to the REP, will also be generated.
General Remarks
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials
and project summaries" (001-MCG-159) (9).
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 for details).


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The following standard descriptive statistical parameters will be displayed in summary tables 
for continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Q1
lower quartile
Median 
median
Q3
upper quartile
Max 
maximum
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" (9).
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, 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 only if there are actually missing values.
Due to the long REP, i.e., 16 weeks after last treatment, there will be no off-treatment data 
available at the time of the primary analysis at Week 12. Listings of data presented by-visit, 
which include both on- and off-treatment data, will be produced at the time of the updated
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 PE visit (EOT), who completed the trial (EOS), and who were prematurely 
discontinued, by reason. Disposition will be also be summarized and 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 
analyzed.
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), using the subject sets of ES, RS, m-RS, SAF, 
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, m-RSi, and SAFi.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Analyses of concomitant 
diseases and medication will be based on the RS.
Concomitant diseases (i.e., baseline conditions) 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.


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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, any changes in the pre-existing extra-intestinal diagnoses (improved or 
worsened) as well as the development of newly diagnosed extra-intestinal diagnoses will also 
be summarized.
A medication/non-drug therapy 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 taken 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).
The frequency and percentage of patients with historical medication for UC will be displayed, 
and by number of previous biologic medication used, by number of previous TNFɑ 
antagonists used, and by worst reason for discontinuation in the order of lack of initial 
response, loss of response, intolerance and other. The identification of biologic medication
and TNFa antagonists medication will be based on medical review.
The frequency and percentage of patients taking any background medication for UC will be 
tabulated by type of background therapy, i.e, corticosteroid versus non-corticosteroid. The 
identification of corticosteroid medication will be based on medical review. Further displays 
regarding changes in background medication during the on-treatment period are summarized 
in Section 7.6.4.
Use of rescue medication will be summarised separately (see Section 7.6.4).
Concomitant use of non-drug therapies will be summarised with frequency and percentage. 
Summaries will be presented for

concomitant non-drug therapies taken any time 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) .
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.


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Treatment compliance will be summarised overall and by visit via total volume infused (as a 
% of planned) for the RS using descriptive statistics (N, mean, SD, minimum, median, 
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 100 ml (the volume the patient should have 
received), times 100. If at least 100 mL has been infused, then it is assumed that the full 
planned dose has been administered, i.e. compliance is 100%.
For the patients who discontinued the study treatment prematurely, only the scheduled visits 
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 also be tabulated per visit.
7.4
PRIMARY ENDPOINT
The Multiple Comparison Procedures and Modeling (MCP-Mod) approach (10, 11) is 
implemented in two main steps: (1) trial design stage; (2) trial analysis stage. The procedures 
for the trial design stage, including the selection of candidate models covering a suitable 
range of dose-response shapes and sample size and power calculations, are provided in the 
CTP Section 7.3.1 and 7.7. The procedures for the trial analysis stage are specified below.
The primary endpoint of the clinical remission is binary in nature. The estimate of response 
rate from each dose group is obtained via logistic regression without intercept. In case 0 event 
is observed in one of the dose groups, a penalized regression based on the Firth’s bias 
reduction method (21,22) will be used. The subsequent MCP-Mod analysis are based on the 
response rate on the logit scale. 
The doses which are included in Part 1 are placebo, and BI 655130 300 mg SD, 450 mg q4w, 
and 1200 mg q4w. The primary dose-response analysis of the clinical remission, based on the 
RS, will use MCP-Mod, and each dose regimen will be described via the appropriate q4w 
regimen administered over the 12 week treatment period (i.e. 300 mg SD will be 
approximated by 100 mg q4w; 450 mg q4w and 1200 mg q4w doses will remain unchanged) 
under the assumption that the cumulative concentrations over time (AUC) and thus the 
cumulative total dose is the key driver of the efficacy response in the modelling part of MCP-
Mod. The response rate for each dose group using NRI as the primary missing data handling 
approach (see Section 6.6), as well as the variance-covariance matrix for the primary 
endpoint are estimated by the data.


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The multiple comparison procedure will then be implemented using optimal contrast tests 
which control the family-wise type I error rate at a one-sided α = 0.20. The optimal contrasts 
corresponding to the candidate models are calculated as in the trial design stage and shown in 
Table 7.4: 1. In the trial analysis stage, these optimal contrasts will be updated using the 
expected model means from the candidate set and the estimated variance-covariance matrix 
from the collected data. The updated contrast coefficients will be described in the final CTR.
Table 7.4: 1
Contrast coefficients
Contrast coefficients for dose
Model
Placebo
300 mg BI SD
450 mg BI q4w
1200 mg BI q4w
Linear
-0.395
-0.352
-0.096
0.843
Emax
-0.858
0.178
0.325
0.355
Exponential
-0.304
-0.300
-0.261
0.866
Logistic
-0.525
-0.450
0.336
0.639
Sigmoid Emax
-0.591
-0.370
0.319
0.642
   Note: BI= BI 655130; SD= single dose; q4w= once every 4 weeks.
Proof of concept (PoC) is established if at least one dose-response model is statistically 
significant, thereby rejecting the null hypothesis of a flat dose-response curve and indicating 
a benefit of BI 655130 over placebo. Once PoC has been established, then subsequently, it 
will be tested whether at least one dose of BI 655130 in Part 1 achieves a clinical remission 
rate at Week 12 ≥ 0.16 superior to placebo (i.e. the maximum anticipated effect of BI 655130 
for achieving the primary endpoint, based on the best fitting monotonic dose-response
model).
Once the significance of a dose-response signal is established, the dose-response profile and 
the target dose can be estimated using the best-fitting dose-response model. All significant
dose-response models will be re-fitted to the data without any parameter assumptions to 
generate a set of new estimates of the model parameters from the data. The final dose-
response model will be obtained via the model with the smallest Akaike Information 
Criterion (AIC) (the smaller the AIC value the better the model fit). Estimates for the dose 
groups will be calculated and will be based on the final dose-response model.
R code to perform the evaluations is available in Section 9.4.
Graphical displays of the proportion of patients with clinical remission (including 95% 
confidence interval) based on the final fitted dose-response model will also be presented.
For the purpose of further model refinement, MCP-Mod will be repeated on the primary 
endpoint but with an extended set of shapes including the original candidates (i.e. addition of 


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inverse u-shape). To this end, a quadratic dose-response shape that assumes the maximum 
effect is obtained at the 800mg q4w dose will be included in addition to the others. 
Additionally a sensitivity analysis based on model averaging across the statistically 
significant models may be conducted in order to assess the robustness of the chosen primary 
approach. Model averaging will be based on parametric bootstrap approach by sampling from 
the multivariate normal distribution underlying the logistic regression estimates and then 
fitting each of the models to each of these samples (11, 12).
Furthermore, covariates may be taken into account in further sensitivity analyses, i.e. 
inclusion of stratification parameters. R code is also available in Section 9.4. Please see Table 
7.4: 2 for a complete summary of primary and sensitivity analysis for the primary endpoint
based upon the different methods for handling of missing data, and other strategies for 
assessing the robustness of the treatment effect.


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Table 7.4: 2
Summary of all analysis to be performed for primary endpoint
Summary of analysis
Analysis
Analysis set
Imputation 
Approach
Analysis model
Primary analysis
RS
NRI
MCP-mod
Note: 
For MCP-Mod approach, best fitting model is used and no covariates adjustment is applied, unless otherwise specified.
Standard approach of SFS/RBS calculation (see Section 9.2.1) is applied unless otherwise specified.
For explanation of the different approaches with regard to missing data see Section 6.6. 
NRI = No Response Imputation
MI = Multiple Imputation
MI-NRI = Combined MI and NRI approach
OC = observed cases


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A forest plot which displays the risk differences versus placebo (and corresponding 95% 
confidence intervals) will be produced for the primary analysis and other sensitivity analyses 
on the primary endpoint in a single display. A separate display will be used to illustrate the 
subgroup effects on the primary endpoint.
7.5
SECONDARY ENDPOINTS
All secondary efficacy endpoints in trial Part 1 will be considered exploratory in nature. All 
p-values presented for the secondary endpoints will be considered nominal in nature and no 
adjustment for multiplicity will be made.
Key secondary endpoint
7.5.1
This section is not applicable as no key secondary endpoint has been specified in the protocol 
for Part 1.
(Other) Secondary endpoints
7.5.2
Secondary continuous endpoint
From CTP Section 7.3.3:
For both trial parts, the change from baseline of IBDQ scores at Week 12 will be analysed
based on the m-RS. It will be analyzed using a restricted maximum likelihood (REML) based
repeated measures approach. The model will include fixed, categorical effects of treatment,
visit and treatment by visit interaction, and stratification factors (prior biologic use and
corticosteroid use), as well as the continuous, fixed covariates of baseline and baseline by
visit interaction. An unstructured covariance structure will be used to model the within
patient measurements. The Kenward- Roger approximation will be used to estimate
denominator degrees of freedom. The primary treatment comparison will be the contrast
between treatments after 12 weeks of treatments. For Part 1 of the trial, if model convergence
issues occur due to inclusion of strata in the model, these terms may be dropped and
separately evaluated.
For the IBDQ overall score, adjusted mean changes (and standard error) from baseline to 
Week 12 will be calculated for each treatment on the m-RS using the model described above. 
The adjusted mean (and 95% confidence interval) differences in change from baseline 
between each BI group and the placebo group will be calculated. The calculation of IBDQ 
overall score and handling of missing item data are further described in Section 9.2.7. The 
analysis will be repeated for each domain score of the IBDQ.
SAS code for the above model will be based on the following structure:
PROC MIXED DATA=alldat cl method=reml order=formatted; 
  CLASS ptno trt stratum visit; 
  MODEL ept = stratum visit*trt base*visit / ddfm=kr s CL; 
  REPEATED visit / subject= subject type=un r rcorr; 


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  LSMEANS visit*trt / pdiff=all om cl alpha=0.05 slice=tptno; 
RUN;
For handling of non-convergence, please refer to Section 9.5. Patients will be analyzed 
according to the stratum as indicated on the eCRF.
Graphical displays of the adjusted means and 95% confidence intervals, for both the overall 
IBDQ score as well as per domain over time by treatment, will also be presented. Such 
displays will also be created for the difference of each treatment group to placebo.
The IBDQ overall score and its change from baseline, both overall and per domain, will be 
descriptively summarized for the m-RS by visit as a continuous variable based on the 
observed cases without imputation (OC). 
Sensitivity analysis will be further performed on change from baseline of IBDQ overall score 
using multiple imputation approach. The missing data of IBDQ overall score will firstly be 
imputed via the multiple imputation approach, as described in Section 6.6.2. The REML-
MMRM will then be applied on the completed data after imputation.
Secondary binary endpoints
From CTP Section 7.3.3:
Part 1 – proof of clinical concept
If considered appropriate, a MCPMod approach may also be applied to selected secondary
endpoints on Part 1 of the trial.
For each secondary binary endpoint, unadjusted absolute risk differences at Week 12 
between the BI 655130 arms and the placebo group will be provided along with the 
corresponding 95% confidence intervals. A logistic regression model may also be performed 
on the RS using the approach as described above for the further analyses on the primary 
endpoint of Part 1 of the trial.
The analysis of secondary endpoints, per the approaches described above, will be done on the 
RS. With regards to the handling of missing data, NRI is the primary imputation technique. 
The primary analysis MCPMod approach as described for the primary endpoint will be 
applied to clinical response and to endoscopic improvement only.    
As defined for the primary endpoint, the method to provide a confidence interval for 
unadjusted risk differences is derived from the Wilson method by Newcombe (14).
Graphical displays of the proportion of patients who achieve a response on the applicable 
secondary binary endpoint (including 95% confidence interval), as well the risk difference vs. 
placebo, by treatment will also be presented.


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Table 7.5.2: 1 Summary of analysis for secondary endpoints
Analysis & Endpoints
Analysis set
Imputation 
Approach
Analysis model
Secondary Binary endpoints
-
Clinical response at Week 12
-
Endoscopic improvement at Week 12
Planned Analysis in CTP-1
RS
NRI
Unadjusted absolute risk
Note: 
For MCP-Mod approach, best fitting model is used and no covariates adjustment is applied, unless otherwise specified.


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Standard approach of SFS/RBS calculation (see Section 9.2.1) is applied unless otherwise specified.
For explanation of the different approaches with regard to missing data see Section 6.6. 
NRI = No Response Imputation
MI = Multiple Imputation
OC = observed cases
REML-MMRM = restricted maximum likelihood based mixed effect model with repeated measurement (* the missing data 
will be handled by MMRM model under MAR assumption)
A forest plot which displays the unadjusted risk differences versus placebo (and 
corresponding 95% confidence intervals) will be produced for the different analysis 
approaches in a single display. A separate display will be used to illustrate the subgroup 
effects on the applicable secondary endpoint.


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Use of rescue medication
7.6.4
Frequency of use of rescue treatment (see Section 5.4.5) from randomization up to (and 
before) the Week 12/Visit 6 primary endpoint will be summarized with the number and 
percentage of patients by preferred name for the RS. 
A separate presentation of the number and percentage of patients who had any change in the 
dose of background medication, by reason of dose change, from randomization up to (and 
before) the Week 12/Visit 6 primary endpoint will also be presented.
A Kaplan-Meier analysis of the time to first use of rescue medication (as defined in Section 
5.4.5) will be presented. If no rescue medication was taken, then time will be censored as 
described in Section 5.4.5. 
7.7
EXTENT OF EXPOSURE
The number of subjects who received a dose of trial drug will be tabulated. The duration of
infusion [in minutes] and the amount of treatment received [mg] (actual and weight based)
will be summarised by descriptive statistics (N, mean, SD, minimum, Q1, median, Q3, 
maximum) per visit and overall. The total duration of exposure (days), defined as the date of
start of the first infusion to date of end of the last infusion + 1 day, will also be displayed.
7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the SAF following BI standards. No 
hypothesis testing is planned.
The primary safety analysis will be done based on data through the first 12 weeks of 
treatment at the time of the second interim database snapshot, which is consistent with the 
timing of the primary efficacy analysis per CTP. Further analysis, once the trial is complete 
and has final database lock, will also be done whereby selected summaries which include all 
safety data up to end of the REP will be produced. 
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


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If, for a subject, the selected treatment emergent adverse event (TEAE) didn’t occur then the 
time at risk will be censored at the minimum of either (date of death, [for patients who were 
not dosed in the extension trial] last contact date per EoS page, [for patients who were dosed 
in the extension trial] date of first dose in extension trial – 1 day, randomized drug stop date + 
112 days, minimum of (analysis cut-off date, day 99) [if applicable, i.e. for primary efficacy 
and safety analysis at week 12]). 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" (16) and "Handling of 
missing and incomplete AE dates" (7). 
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. For patients 
who enrol and are dosed in the extension trial, any AE which occurs up to one day prior to 
this first dose of extension trial medication will also be assigned to the on-treatment period in 
this trial.
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 (refer to CTP section 5.2.6.1):

Systemic hypersensitivity including infusion reaction and anaphylactic reaction

Severe infections (according to RCTC grading)

Opportunistic and mycobacterium tuberculosis infections 

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
a.  ALT or AST >5x ULN 


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b.  ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
c. AST and/or ALT >3 fold ULN combined with an elevation of total bilirubin >2  
fold ULN measured in the same blood draw sample
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). 
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events Concepts
Based on the specification provided in ICH E3 (17), 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 drug-related AEs, patients with investigator-
reported 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).
UDAEC
Categories
Infusion/Systemic hypersensitivity 
reactions including anaphylactic 
reactions
Narrow SMQ “Anaphylactic reaction”
Narrow SMQ “Angioedema”
Narrow SMQ “Hypersensitivity”
Severe infections (according to 
RCTC grading)
SOC Infections and infestations of at least severe RCTC grade, by 
HLGT
Opportunistic and mycobacterium 
tuberculosis infections
BIcMQ “Infections”: 
Narrow sub-search 8 “Opportunistic infections including Tuberculosis 
related terms”
Tuberculosis related terms
BIcMQ “Infections”: 
   Narrow sub-search 8.2 “Tuberculosis related terms”
HLT “Tuberculosis infections”
Malignant tumours
(SMQ “Malignancies” – not for display)
(Sub-SMQ “Malignant or unspecified tumours” – not for display)
Narrow Sub-SMQ “Malignant tumours”
Sub-SMQ “Haematological malignant tumours”
Sub-SMQ “Non-Haematological malignant tumours”


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For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5% (in preferred terms) will be summarised 
by treatment, primary system organ class and preferred term. The frequency of patients with 
SAEs will also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of non-serious AEs with an 
incidence of greater than 5 % (in preferred terms) and the frequency of SAEs will be 
summarised.
Laboratory data
7.8.2
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (18). Note that data from the central laboratory will be used for all displays 
described below, unless otherwise specified.
For continuous safety laboratory parameters, normalized values will be derived.
Normalisation means transformation to a standard unit and to a standard reference range. The
process of normalisation, handling of repeat values at the same visit for by-visit displays, as
well as standard analyses for safety laboratory data are described in the BI guidance for the
Display and Analysis of Laboratory Data (18). All analyses considering multiple times of the
ULN (as described below) will be based on standardized and not normalized values. For
continuous safety laboratory parameters, differences to baseline will be calculated.
Only patients with at least one available post-baseline value will be included in the analysis 
of an individual laboratory parameter. All individual laboratory data will be listed. Values
outside the reference range will be flagged.
Descriptive statistics of laboratory values over time and for the difference from baseline (see
Section 6.7) will be based upon normalized values and provided by visit, including the last 
value on treatment, the minimum value on treatment and 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 abnormalities will be identified based on BI standard rules
which are based on normalized converted lab values, i.e. using SI units. These rules will be
listed in the SDL appendix of the CTR. Frequency tables will summarize the number of
patients with potentially clinically significant abnormalities. Patients having an abnormal lab
value at baseline will be presented separately. A separate listing will present potentially
clinically significant abnormal lab values; for each functional lab group all patient’s lab
values will be listed, if there exists at least one lab value with clinically significant
abnormality within the group.


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The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥ 10xULN, and
≥ 20xULN will be displayed based on standardized laboratory values. To support analyses of
liver related adverse drug effects, the frequency of patients with AST and/or ALT ≥ 3xULN
combined with a total bilirubin ≥ 2xULN in a 30 day period after AST/ALT elevation will be
displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a patient can 
potentially be in both alkaline phosphatase strata in case of multiple AST/ALT and bilirubin 
elevations). The start of the 30 day time span is triggered by each liver enzyme elevation 
above the defined thresholds. This analysis will be based on standardized laboratory values. 
A graphical analysis of the ALT and total bilirubin during the on-treatment period will also 
be performed; the so called eDISH plot. In the graph, for each subject, the peak total bilirubin 
is presented as a fold increase over the ULN against the peak ALT as a fold increase over the 
ULN, on a log10 scale. The measurements displayed for total bilirubin and ALT may, or may 
not, occur on the same date. Two reference lines, 2xULN for total bilirubin and 3xULN for 
ALT, are drawn onto the graph in order to divide the plane into four quadrants. Normal cases 
are in the lower left quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law 
quadrant), while the lower right quadrant is known as the Temple’s corollary range (ALT ≥ 
3xULN and total bilirubin < 2xULN).
An additional display will be produced for the frequency of patients with an elevation of the 
ALT or AST > 3-fold ULN and with the appearance of one or more of the following TEAE: 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%). An occurrence is flagged if, within +/- 7 days of the onset of an AST or 
ALT elevation > 3-fold ULN (including events which start or are ongoing through this 
interval), at least one of the following TEAE terms (excluding PT terms on the secondary 
path) is observed: 

ADAE.AEHLT = "Gastrointestinal and abdominal pains (excl oral and throat)";

ADAE.AEDECOD in ("Vomiting","Fatigue","Nausea","Pyrexia")

ADAE.CQ16NAM = "Skin Rash (BIcMQ narrow)
An occurrence is also flagged if a >5% proportion in the ratio of eosinophils to total white
blood cells is observed in the same sample as the detected AST/ALT elevation.
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, 
respiration rate) 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 and will include the last value during on-treatment period, 
the minimum value during on-treatment period, and the maximum value during on-treatment
period (see Table 6.1: 1 for definition of the on-treatment period). Graphical displays via box 


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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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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
Reeve R. Confidence interval of difference in proportions in logistic regression in
presence of covariates. Statistical Methods in Medical Research: 27 issue: 2, 451-
465, 2016. [R16-4414]
3
Bornkamp B, Pinheiro J, Bretz F  Package 'DoseFinding' (February 19, 2015).
http://cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf (access date: 
28 April 2015); Comprehensive R Archive Network (2015). [R15-2001]
4
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”, 
current version; IDEA for CON
5
BI-KMED-COPS-TMP-0001: "Important Protocol Deviation (iPD) log", current 
version; IDEA for CON
6
001-MCS-40-413_RD-00: "List of References to SOP Identify and Mange 
Important Protocol Deviations (iPD)", current version; IDEA for CON
7
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON
8
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; IDEA for CON
9
BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; IDEA for CON.
10
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding studies 
combining multiple comparisons and modelling procedures. J Biopharm Stat 16 
(5), 639-656 (2006). [R10-1424]
11
Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding under model 
uncertainty using general parametric models. Stat Med 33 (10), 1646 – 1661 
(2014). [R15-4293]
12
O’Quigley J, Iasonos A, Bornkamp B, editors. Handbook of methods for designing, 
monitoring, and analysing dose-finding trials. Boca Raton: CRC Press (2017). 
[R18-3141]
13
Brown LD, Cai TT, DasGupta A. Confidence intervals for a binomial proportion 
and asymptotic expansions. Ann Stat 30 (1), 160 – 201 (2002). [R12-3710]


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14
Newcombe RG. Interval estimation for the difference between independent 
proportions: comparison of eleven methods. Stat Med 17, 873 – 890 (1998). [R08-
4386]
15
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; IDEA for CON
16
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON
17
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
18
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; IDEA for CON
19
Japanese Ministry of Health, Labour and Welfare, Format for Preparing the 
Common Technical Document for Submission of New Drug Applications to 
Reduce Total Review Time, 2011 [R18-1356]
20
BI-KMED-COPS-BUP-0007: " Clinical Bridging Study Waiver (BSW) and 
Subgroup Analysis (SGA) Reports for Asian countries”, current version; IDEA for 
CON.
21
Heinze G, Schemper M. A solution to the problem of separation in logistic 
regression. Statistics in Medicine 21: 2409-2419 (2002). 
22
Firth D. Bias reduction of maximum likelihood estimates. Biometrika 80, 27–38
(1993).


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9.
ADDITIONAL SECTIONS
Mayo Clinical Score (MCS) and its Subscores
9.2.1
The Mayo score 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. The overall range of the Mayo score is 0-12 (higher scores being 
worse) and each subscore has a range of 0-3. At visits without sigmoidoscopy but with 
collection of the respective diary elements, 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, a modified Mayo score will be assessed, 
which excludes physician’s assessment. The overall range of the modified Mayo score is 0-9.
For the rectal bleeding and stool frequency subscores, if the patient undergoes bowel 
preparation for endoscopy on any of the days before a visit, the relevant subscores for that 
day(s) should be considered to be missing. In addition, the subscores will be considered to be 
missing for the day of and the day after performance of such endoscopies.
The evaluation of clinical remission at Week 12 is the primary objective for efficacy in Part 1 
of this trial and is described using the proportion of patients who achieve clinical remission at 
this time-point based on endoscopy results obtained from central reading. Only if the 
centrally read endoscopy result is missing at a time-point will the locally read result be used 
instead.
Modified Endoscopic appearance subscore (mESS)
The endoscopic appearance score will be assessed by a central reader, who is independent 
from the investigator. Only a single score will be provided at each applicable visit.
The mESS used for analysis will be based on the centrally-read endoscopy scores; only if 
centrally-read data are missing these will be replaced by the local endoscopy score.
Physician’s Global Assessment subscore (PGA)
The Physician’s Global Assessment subscore will be assessed by the physician. Only a single 
score will be provided at each applicable visit.


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Calculation of SFS/RBS subscores (standard approach)
For the rectal bleeding and stool frequency subscores, if the patient undergoes bowel 
preparation for endoscopy (i.e. either of colonoscopy or sigmoidoscopy) on any of the days 
before a visit, the relevant subscores for that day(s) should be considered to be missing. In 
addition, the subscores will be considered to be missing for the day of and the day after 
performance of such endoscopies.
For the rectal bleeding and stool frequency subscores, if there are duplicate entries for a day, 
the worst (i.e., largest) score will be used to derive the daily subscore.
•
Rectal bleeding subscore (RBS)
The score for 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. Since the 
averaging process might result in non-integer numbers the following classification will be 
used. Assuming the average of the last 3 non-missing entries is & then
'()**+,+')-+./(&) = 0
0 ≤& < 0.5 →789 = 0
0.5 ≤& < 1.5 →789 = 1
1.5 ≤& < 2.5 →789 = 2
2.5 ≤& ≤3 →789 = 3
If fewer than 3 non-missing entries are available in the week prior to the applicable visit then 
the RBS is considered to be missing.
•
Stool frequency subscore (SFS)
The score for stool frequency will be calculated based on the average of the last 3 non-
missing entries (from the patient daily diary) within the week prior to each applicable visit.
Assuming the number of stools of the last 3 non-missing entries are =, = and =?, then these 
numbers are first converted into (daily) stool frequency subscores. Hereby, the stool 
frequency is evaluated in comparison with the reference stool frequency (of the considered 
patient). 
Assuming the normal stool frequency (or reference) is given by @	 then the daily stool 
frequency outcome (adjusted for the normal stool frequency outcome), =
	_ (and 
respectively =
	_, and, =
	_?) is given by
=
	_ = = −@	 ,.C + ∈{), F, '}
Note that @	 represents the patient’s stool frequency when in remission from the disease. If 
the patient cannot recall a time when they have been in remission from disease then @	will 
represent the stool frequency reported from the time before initial onset of disease signs and 
symptoms.


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represent the stool frequency reported from the time before initial onset of disease signs and 
symptoms.
Based on the values for =
	 the following classification will be used to derive the daily 
stool frequency subscores:
'()**+,+')-+./K=
	,
	 L =
⎩
⎨
⎧−∞ < =
	,
	 < 0.5 →9Z9
	 = 0  
0.5 ≤=
	,
	 < 2.5 → 9Z9
	 = 1
2.5 ≤=
	,
	 < 4.5 → 9Z9
	 = 2
4.5 ≤=
	,
	 < ∞→ 9Z9
	 = 3
Total Mayo score (Total MCS)
9.2.2
The total mayo score is calculated by summing up the SFS, the RBS, the mESS and the PGA.
Modified Mayo score (mMCS)
9.2.3
The modified mayo score is calculated by summing up the SFS, the RBS, and the mESS, i.e. 
excluding PGA score. 
Partial Mayo score (Partial MCS)
9.2.4
The partial mayo score is calculated by summing up the SFS, the RBS, and the PGA, i.e. 
excluding the mESS. 
Overview of Clinical Response and Remission Calculations
9.2.6
The following table summarizes the derivation of responses. 


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Table 9.2.6: 1 Definitions of Clinical Response/Remission
Type of 
Response
MCS subscore
Total  
MCS
Modified 
MCS
Partial 
MCS
RBS
mESS
SFS
PGA
Total 
Clinical 
remission 
(tCR)
≤1
≤1
≤1
≤1
≤2
Clinical 
remission
(CR)
0
≤1
0 or 1, if 
drop ≥1 
from 
baseline
≤2
Partial MCS 
remission
(pCR)
≤1
≤1
≤1
≤2
Clinical 
response
≤1
or
Reduction 
from BL ≥1
not 
missing
not 
missing
not 
missing
Reduction 
from BL 
≥3 and 
≥30%
Partial MCS 
response
≤1
or
Reduction 
from BL ≥1
not 
missing
not 
missing
Reduction 
from BL 
≥2 
Endoscopic 
improvement
≤1
Complete 
remission
0 and 
RHI ≤6  
Abbreviations: MCS – Mayo Clinical Score; RBS – rectal bleeding score; mESS – modified endoscopic subscore;  SFS –
stool frequency score; PGA – physician’s global assessment;
If greyed out, the corresponding criterion (in column) is not relevant to evaluate the corresponding type of response.(in row) 


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IBDQ scores
9.2.7
The IBQD questionnaire is designed to measure the effects of inflammatory bowel disease on 
daily function and quality of life.  On this questionnaire there are 32 questions. Each question 
has a graded response scored from 1 through 7. 
To calculate the total IBDQ score, sum scores for all 32 questions. The total IBDQ score 
ranges from 32 to 224. A higher score indicates better quality of life.
In addition, subscores will be calculated for each of the following four domains:
Bowel systems:
Scores for questions (1, 5, 9, 13, 17, 20, 22, 24, 26, and 29) are summed and divided by 10.
Emotional health:
Scores for questions (3, 7, 11, 15, 19, 21, 23, 25, 27, 30, 31, and 32) are summed and divided 
by 12.
Systemic symptoms:
Scores for questions (2, 6, 10, 14, and 18) are summed and divided by 5.
Social Function:
Scores for questions (4, 8, 12, 16, and 28) are summed and divided by 5.
Handling of missing item data for IBDQ:

If for a specific patient at a specific time point no response is given for a 
particular question, provided only one response per domain is missing, then 
the mean score at the specific time point of the corresponding other items of 
the same patient and domain will be imputed

If two or more questions are unanswered for a particular domain  then the 
subscore will be set to missing

The total IBDQ will not be scored, if
-
More than 4 questions missing, or
-
More than 2 questions missing in one domain, or
-
More than 1 questions missing in two domains
Otherwise, the total IBDQ score will be calculated with the missing items
imputed by the mean score of the corresponding other items of the same 
patient and domain


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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
13-Feb-2018
None
This is the initial TSAP with necessary 
information for trial conduct.
2.0
29-Jul-2019
None
This is the final version of core TSAP.
3.0
02-Mar-2020
(all)
This is the revised TSAP due to early 
termination of the study.