Clinical trial NCT05013385
Conditions: Fibrostenotic Crohn´s Disease
Sponsor: Boehringer Ingelheim
Start date: 2021-11-09; Completion date: 2022-05-31
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults, between 18 and 75 years of age, who have narrowings in the small bowel (strictures) due to Crohn's disease. Strictures can lead to bowel obstruction (blockage). People whose symptoms got worse because of strictures can join the study. Participants get standard treatment for Crohn's disease and the strictures. The purpose of the study is to test whether the strictures improve further when treated with a medicine called spesolimab added to standard treatment.

Participants are in the study for about 1 year and 4 months. In the first 3 months, participants get standard treatment only. After 3 months, participants whose condition improved are put into 2 groups randomly, which means by chance. One group gets spesolimab added to their standard treatment. The other group gets placebo added to their standard treatment. Both spesolimab and placebo are given as infusions into a vein. Placebo infusions look like spesolimab infusions but do not contain any medicine. For the first 2 months, participants get the infusions every month. Thereafter, participants get the infusions every 2 months.

During the study, participants have about 11 visits to the study site. The doctors regularly check participants' health and take note of any unwanted effects. At 3 of the visits, doctors take images of the bowel using Magnetic Resonance Imaging and with an endoscope. At these visits, the doctors also take a small sample of bowel tissue (biopsy). The participants note their symptoms of Crohn's disease and how the symptoms affect daily life in an electronic diary. At the end of the study, results from the diaries and bowel imaging are compared between the spesolimab group and the placebo group.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Spesolimab intervention 2: Placebo
Intervention descriptions: intervention 1: Spesolimab intervention 2: Placebo

Protocol documents:
Prot_SAP_000.pdf: 
001-MCS-40-106_RD-03 (19.0) / Saved on: 03 Nov 2020
Clinical Trial Protocol
 
Document Number:
c34096215-03
EudraCT No.
2020-005770-99
BI Trial No.
1368-0059
BI Investigational
Medicinal Product(s)
Spesolimab (BI 655130)
Title
Multi-center, double-blind, randomized, placebo-controlled, phase 
IIa trial to evaluate spesolimab (BI 655130) efficacy in patients 
with fibrostenotic Crohn’s Disease
Lay Title
A study to test whether spesolimab helps people with Crohn’s 
disease who have symptoms of bowel obstruction
Clinical Phase
Phase IIa
Clinical Trial Leader
Phone: +
, Fax: +
Coordinating 
Investigator
Phone: +
, Fax: +
Current Version and 
Date
Version 3.0, 20 Oct 2021
Original Protocol 
Date
08 Feb 2021
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Proprietary confidential information.
2021 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
Original Protocol date
08 Feb 2021
Revision date
20 Oct 2021
BI trial number
1368-0059
Title of trial
Multi-center, double-blind, randomized, placebo-controlled, phase IIa 
trial to evaluate spesolimab (BI 655130) efficacy in patients with 
fibrostenotic Crohn’s Disease
Trial site(s)
Multi-center trial conducted in approximately 30 countries
Clinical phase
IIa
Trial rationale
Proof of Clinical Concept (PoCC)
Trial objective(s)
To demonstrate that spesolimab is effective in maintaining 
Symptomatic Stenosis Response and / or inducing Radiographic 
Stenosis Response in patients with symptomatic Crohn’s Disease 
(CD)-related small bowel stenosis, who have achieved Symptomatic
Stenosis Response after standard medical therapy.
Trial endpoints
Primary endpoints:
Spesolimab superiority vs. placebo on one of the following

Proportion of patients with maintained Symptomatic Stenosis 
Response at Week 48

Proportion of patients with Radiographic Stenosis Response at 
Week 48
Secondary endpoints:

Proportion of patients with maintained Symptomatic Stenosis 
Response at Week 24

Proportion of patients with Radiographic Stenosis Response at 
Week 24
Trial design
This is a randomized, double-blind, placebo-controlled, parallel-
design trial testing one active dose versus placebo.
Total number of patients 
randomized 
100
Number of patients per
treatment group
50
Diagnosis
Fibrostenotic Crohn’s Disease


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Main inclusion criteria

Male and female patients, 18 to 75 years when signing informed 
consent at screening

Established diagnosis of clinical CD prior to screening

Suspicion of symptomatic small bowel stenosis

Presence of abdominal pain after eating or limitation in amount or 
types of food at screening

1 or 2 naïve or anastomotic stenoses in the terminal ileum at 
screening, confirmed by MRE at randomization

Have achieved Symptomatic Stenosis Response before 
randomization (i.e. 7 day average scores <2 for diary questions on 
the abdominal pain after eating AND on the limitation in amount 
or types of food)

Endoscopic activity defined by Colonic Simple Endoscopic Score 
in CD (SES-CD) ≤12 after Lead-in Period, at the time of 
randomization
Main exclusion criteria

No stenosis in reach of ileocolonoscopy

Systemic corticosteroid treatment of current obstructive 
symptoms for >1 week prior to screening

Endoscopic balloon dilation (EBD) or surgical treatment of the 
same small bowel stenosis within the last 6 months prior to 
screening Visit 1

More than 2 small intestinal stenoses

Patients who require immediate EBD or surgical intervention as 
per the investigator´s discretion

Failure of >2 different biological drug classes prior to screening 
(e.g. TNF inhibitors, Integrin Receptor antagonists and 
IL-12 / IL-23 antagonists)

Current complications of CD at screening Visit 1 and 
randomization (Day 1) that would possibly confound the 
evaluation of benefit from treatment with spesolimab

Current stenosis in the colon

Previous strictureplasty on current stricture 

Current ileostomy or colostomy

Any kind of bowel resection or diversion within 6 months of 
screening Visit 1 

Any other intra-abdominal surgery (except for abscess drainage) 
within 3 months prior to screening Visit 1

Colorectal cancer (CRC) present and past (<5 years) history
Test product(s)
Spesolimab (BI 655130)
dose
1200 mg every 4 weeks (Day 1 to Week 8), then 1200 mg every 
8 weeks until Week 40 (last trial drug administration)
mode of 
administration
intravenous (i.v.)
Comparator product(s)
Placebo
dose
Placebo every 4 weeks (Day 1 to Week 8), then Placebo every 


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8 weeks until Week 40 (last administration)
mode of
administration
intravenous (i.v.)
Duration of treatment
48 weeks
Statistical methods
The primary analysis will be performed for the full analysis Set 
(FAS) which is based on the intent-to-treat principle. The primary 
analysis of the unadjusted absolute rate difference versus placebo, 
once all patients have completed through week 48, will be calculated 
simply as the difference in the observed proportion of patients with 
maintained Symptomatic Stenosis Response / Radiographic Stenosis 
Response, based on FAS. A 95% Newcombe confidence interval 
around the difference will also be provided. An interim analysis will 
be conducted when 100% of the patients have completed at least 24 
weeks of treatment.


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FLOW CHART
Trial Periods
Lead-in Period1
Randomized Blinded Treatment Period
FUP2
Screening
Visit
1
21
3
4
5 
6
7
8
9
10
EoT24
11
EoS2
Week 
(-14 to) -12
(-13 to) -10
4
8
16
24
32
40
48
56
Day 
(-98 to) -84
(-91 to) -70 
13
29
±7 
57
±7
113
±7
169
±7
225
±7
281
±7
337
±7
393
+7 
Informed Consent 
X
Demographics
X
Baseline Condition, Medical History 
and CD history4
X
Review of in-/exclusion criteria
X
X
Physical examination5
XC
XT
XC
XT
XT
XT
XC
XT
XT
XC
XC
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
Smoking status
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testing7
Xs
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Safety laboratory8
X
X
X8
X
X
X
X
X
X
X
X
Stool sampling (enteric pathogens) 
X
Therapeutic drug monitoring (pre-
screening biological therapy)9
X
Infections testing10
X
X
S-PRO11
X 
X
X
X
X
X
X
X
X
X
IBDQ, SF-36, and PGI-S scales12
X12
X
X
X
X
X
X
X
X
X
CGI-S and CGI-C scales13
X13
X
X
X
X
X
X
X
X
X
CDAI (Crohn’s Disease Activity 
Index)14
X14
X
X
X
X
X
X
X
X
X
Schedule baseline MRE and 
endoscopy examinations 
X15, 16




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An extension trial is planned to be offered to patients who have an individual benefit from their study drug at End of Treatment (EoT) visit at Week 48. These patients 
are not requested to complete follow up period and the Visit 10 is the last visit for this trial, probably co-inciding with the first visit in the extension trial. For adverse 
event (AE) and Concomitant therapy reporting the end of study participation is defined as the day of first administration of study drug in the extension trial (please see 
Section 6.2.3).
3
Day of Randomization / Day of first administration of randomized trial medication with baseline assessments. Please refer to footnote 15 for the baseline Magnetic 
Resonance Enterography (MRE) and footnote 16 for the baseline endoscopy: These assessments are to be scheduled when 8 weeks of the optimization of the anti-
inflammatory biological treatment are over and at least 2 weeks before the planned randomization at Day 1. Ideally, MRE is to be done first (at least 10 business days 
before Day 1) and endoscopy second (at least 7 business days before Day 1), and both examinations are not on the same day. This is both to ease the burden of the visit 
and to allow for proper central review of the data with eligibility information returned to the site.
4
BC = Baseline Conditions, and Medical History including the Crohn’s Disease history. For details please see Section 6.2.1.
5
Physical examination; C = complete physical examination includes at a minimum general appearance, neck, lungs, cardiovascular system, abdomen, extremities, and 
skin. T = targeted physical examination focuses on evaluation of organ systems associated with AE(s) symptoms or laboratory abnormalities. Measurement of body 
weight will be performed at every visit, height at Visit 1 only. For details please see Section 5.2.1.
6
Vital signs include systolic and diastolic blood pressure and pulse rate, body temperature and respiratory rate. Measurements of vital signs should precede blood 
sampling. In addition, at dosing visits vital signs are to be done pre-dose, approximately 10 minutes and approximately 60 minutes after stop of the infusion. For details 
please see Section 5.2.2.
7
Pregnancy testing is applicable only for women of childbearing potential (WOCBP); For the definition please refer to Section 3.3.3. s = serum pregnancy test 
(performed at screening). u = urine pregnancy tests will be performed at all other visits. Urine pregnancy testing must be done prior to administration of study drug. 
Trial drug must only be administered in case of a negative test result. (S) - in case of a positive urine pregnancy test, a serum pregnancy test will be done.
8
Safety laboratory tests will be done at a central laboratory. The safety laboratory samples relevant for Day 1 are to be taken when the patient comes for the baseline 
MRE examination (10 business days before Day 1) in order to have the laboratory report available at Day 1. For details please see Section 5.2.3.
9
TDM: A blood sample is drawn at screening Visit 1 to determine the plasma drug level and antidrug antibody (ADA) status for the patient´s previous anti-inflammatory 
biological treatment. As soon as the result is available (approximately after 5 to 10 business days), the optimization of the anti-inflammatory biological therapy is to be 
started at Visit 2 according to the algorithm provided in Section 4.2.1.1.
10
For details on infections testing at baseline and EoT Visit (or in case of early trial discontinuation, if applicable) please refer to Tables 5.2.3: 1 and 5.2.3: 2.
11
The Stenosis Patient Reported Outcome (S-PRO) tool is set up as an eDiary (named Stricturing Crohn´s Disease Questionnaire). It is important to start the completion 
of the S-PRO at the screening visit (Visit 1) or as soon as the patient´s situation allows during hospitalization (latest on the day of discharge). The patient will then 
complete the S-PRO daily during the entire duration of the Lead-in Period and on Day 1. After randomization, the patient will complete the S-PRO daily in the week 
preceding a scheduled visit and on the day of the scheduled visit. See Section 5.1.2 and Appendix 10.1.1. In case of worsening of CD symptoms the patient is requested 
to contact the site to make an appointment for an unscheduled visit including MRE and endoscopy examinations. The patient is asked to start the S-PRO completion 
immediately, daily, for (at least) 7 days before the unscheduled visit and on the day of the unscheduled visit. For details of such an unscheduled visit, please see 
Section 6.2.2.




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25
After the EoS visit (= individual patient’s end of the trial) the investigator should report only any cancers of new histology and exacerbations of existing cancer, trial 
drug related SAEs and trial drug related AESIs of which the investigator may become aware and only via the BI SAE form, please see Section 5.2.6.2.1.
In case of an extension trial, this does not apply for patients rolling over into the extension trial.


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FLOW CHART 2: LEAD-IN PERIOD LOGISTICS
Week
W-12
(V1)
W-11
W-10
(V2)
W-9
W-8
W-7
W-6
W-5
W-4
W-3
W-2
W-1
Day 1
(V3)
W1
W2
W3
W4
Corticosteroids 
(mg/d)
40
401
35
30
25
20
15
10
7,5
5
2,5
0
0
Therapeutic 
drug 
monitoring 
(TDM)2
X
Anti-
inflammatory 
biological 
treatment 
optimization3
X
X
X
X
X
X
X
X4
S-PRO4
daily
daily
daily
daily
daily
daily
daily
daily
daily
daily4
daily
daily
Daily in the 
week before
MRE5
X
Endoscopy6
X
Trial drug 
administration7
X
X
IBDQ and
SF-368
X
X
X
PGI-S scales9
X
X
x
X
CGI-S and 
CGI-C
scales10
X
X
x
X
CDAI 
(Crohn’s 
X
(dispen
X
(fill 7 
X
X
(fill 7 
X


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1 Corticosteroid treatment and tapering during the Lead-in Period are described in Section 4.2.1.1. Appendix 10.2 provides the equivalent doses of corticosteroids. The numbers given in this 
table are for prednisolone as an example.
2 Therapeutic Drug Monitoring, i.e. plasma drug level and antidrug antibody (ADA) testing for the patient´s anti-inflammatory biological CD treatment at the time of enrolment (Screening, 
Visit 1). The optimization of the anti-inflammatory biological therapy starts as soon as the laboratory results are available to the investigator. Ideally this is after 1 week (5 business days), 
however, this can also take 2 weeks (10 business days), depending on the laboratory performing this analysis.
3 Based on the patient´s CD treatment at enrolment, the anti-inflammatory biological treatment optimization is to be performed as mandated and described in Section 4.2.2.1. All treatments are 
to be used according to the label. The duration of this optimization must not be shorter than 8 weeks before the baseline Magnetic Resonance Enterography (MRE) and baseline endoscopy are 
assessed.
4 The S-PRO completion (Stricuring Crohn´s Disease Questionnaire) starts ideally at screening Visit 1 or as soon as the patient´s situation allows. It is done daily during the Lead-in Period to 
assess if Symptomatic Stenosis Response is achieved at the time of scheduling the baseline MRE (W-2). Hence, the eigth week (= 7 days) of optimization of the anti-inflammatory 
biological treatment is relevant to assess with the score of 2 questions out of the S-PRO tool if the patient has achieved the Symptomatic Stenosis Response which is prerequisite to 
perform the baseline MRE and endoscopy examinations.
5 The baseline MRE is to be scheduled after 8 weeks of optimization of the anti-inflammatory biological therapy and (at least) 2 weeks before the planned Day 1 with randomization and the first 
dose of trial drug. The central review will provide eligibility information to the site (inclusion criterion number 9).
6 The baseline endoscopy is to be scheduled after a period of 8 weeks of optimization of the anti-inflammatory biological therapy and (at least) 7 business days before the planned Day 1 with 
randomization and the first dose of trial drug. The central review will provide eligibility information to the site (inclusion criterion number 10). Given the different patient preparation needed 
for the MRE and endoscopy examinations, the MRE should be done first and the endoscopy second.
7 Trial drug administration takes place for eligible patients at Day 1 upon randomization (via IRT call).
8 The IBDQ and SF-36 have to be completed at the time of the first S-PRO completion, at V2 and at V3 (tablet at the site)
9 PGI-S scales are completed at W-2 for patients who have NOT achieved a Symptomatic Stenosis Response. PGI-S scales are completed at V3 for patients who have achieved a Symptomatic 
Stenosis Response
10 CGI-S scale starts at Visit 1, the CGI-C scale starts only at Visit 2.
11 The CDAI eDiary is dispensed only for completion 7 days before Visit 2 and before V3.
Disease 
Activity 
Index)11
sed)
days 
prior 
to V2)
days 
prior to 
V3)


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
FLOW CHART 2: LEAD-IN PERIOD LOGISTICS........................................................10
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS AND DEFINITIONS...........................................................................18
1.
INTRODUCTION...............................................................................................22
1.1
MEDICAL BACKGROUND.............................................................................22
1.2
DRUG PROFILE................................................................................................23
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................26
1.4
BENEFIT - RISK ASSESSMENT.....................................................................28
1.4.1
BENEFITS...........................................................................................................28
1.4.2
RISKS...................................................................................................................29
1.4.3
DISCUSSION ......................................................................................................37
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................39
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........39
2.1.1
MAIN OBJECTIVES .........................................................................................39
2.1.2
PRIMARY ENDPOINT(S) ................................................................................39
2.1.3
SECONDARY ENDPOINT(S) ..........................................................................39
2.3
DEFINITION OF STUDY OUTCOMES.........................................................40
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................43
3.1
OVERALL TRIAL DESIGN.............................................................................43
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................45
3.2.1
RATIONALE FOR SELECTED TRIAL POPULATION .............................45
3.2.2
RATIONALE FOR AN ADD-ON THERAPY AND PLACEBO-
CONTROLLED TRIAL ....................................................................................46


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3.2.3
RATIONALE FOR A 48 WEEK DURATION AND FOR PROPOSED 
ENDPOINTS .......................................................................................................46
3.3
SELECTION OF TRIAL POPULATION .......................................................48
3.3.1
MAIN DIAGNOSIS FOR TRIAL ENTRY......................................................48
3.3.2
INCLUSION CRITERIA...................................................................................48
3.3.3
EXCLUSION CRITERIA..................................................................................50
3.3.4
DISCONTINUATION OF PATIENTS FROM TREATMENT OR 
ASSESSMENTS..................................................................................................51
3.3.4.1
DISCONTINUATION OF TRIAL TREATMENT.........................................52
3.3.4.2
WITHDRAWAL OF CONSENT TO TRIAL PARTICIPATION ................53
3.3.4.3
DISCONTINUATION OF THE TRIAL BY THE SPONSOR ......................53
4.
TREATMENTS...................................................................................................54
4.1
INVESTIGATIONAL TREATMENTS ...........................................................54
4.1.1
IDENTITY OF THE INVESTIGATIONAL MEDICINAL PRODUCTS....54
4.1.2
SELECTION OF DOSES IN THE TRIAL AND DOSE MODIFICATIONS54
4.1.3
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS ......55
4.1.4
DRUG ASSIGNMENT AND ADMINISTRATION OF DOSES FOR EACH 
PATIENT.............................................................................................................55
4.1.5
BLINDING AND PROCEDURES FOR UNBLINDING................................56
4.1.5.1
BLINDING ..........................................................................................................56
4.1.5.2
UNBLINDING AND BREAKING THE CODE ..............................................56
4.1.6
PACKAGING, LABELLING, AND RE-SUPPLY..........................................56
4.1.7
STORAGE CONDITIONS ................................................................................57
4.1.8
DRUG ACCOUNTABILITY.............................................................................57
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................57
4.2.1
OTHER TREATMENTS AND EMERGENCY PROCEDURES..................57
4.2.1.1
LEAD-IN ANTI-INFLAMMATORY TREATMENT ....................................58
4.2.1.2
OPTIMIZED ANTI-INFLAMMATORY TREATMENT DURING THE 
BLINDED RANDOMIZED TREATMENT PERIOD....................................59
4.2.1.3
CONCOMITANT MEDICATION ...................................................................59
4.2.1.4
MANAGEMENT OF ADVERSE EVENTS.....................................................60


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4.2.2
RESTRICTIONS ................................................................................................61
4.2.2.1
RESTRICTIONS REGARDING CONCOMITANT TREATMENT ...........61
4.2.2.2
RESTRICTIONS ON DIET AND LIFE STYLE.............................................64
4.2.2.3
CONTRACEPTION REQUIREMENTS .........................................................64
4.3
TREATMENT COMPLIANCE........................................................................64
5.
ASSESSMENTS..................................................................................................65
5.1
ASSESSMENT OF EFFICACY........................................................................65
5.1.1
MAGNETIC RESONANCE ENTEROGRAPHY (MRE)..............................65
5.1.2
STENOSIS PATIENT REPORTED OUTCOME (S-PRO) TOOL...............66
5.1.3
ILEOCOLONOSCOPY WITH SIMPLE ENDOSCOPIC SCORE FOR 
CROHN’S DISEASE (SES-CD)........................................................................66
5.1.4
CROHN’S DISEASE ACTIVITY INDEX (CDAI) .........................................66
5.1.5
IBDQ ....................................................................................................................67
5.1.6
SF-36.....................................................................................................................67
5.1.7
PATIENT’S GLOBAL IMPRESSION OF SEVERITY (PGI-S)...................67
5.1.8
CLINICIAN’S GLOBAL IMPRESSION OF CHANGE (CGI-C) AND 
CLINICIAN’S GLOBAL IMPRESSION OF SEVERITY (CGI-S)..............68
5.2
ASSESSMENT OF SAFETY.............................................................................68
5.2.1
PHYSICAL EXAMINATION ...........................................................................68
5.2.2
VITAL SIGNS.....................................................................................................68
5.2.3
SAFETY LABORATORY PARAMETERS ....................................................69
5.2.4
ELECTROCARDIOGRAM ..............................................................................72
5.2.5
OTHER SAFETY PARAMETERS ..................................................................72
5.2.6
ASSESSMENT OF ADVERSE EVENTS ........................................................73
5.2.6.1
DEFINITIONS OF AES.....................................................................................73
5.2.6.1.1
ADVERSE EVENT.............................................................................................73
5.2.6.1.2
SERIOUS ADVERSE EVENT ..........................................................................73
5.2.6.1.3
AES CONSIDERED “ALWAYS SERIOUS”..................................................74
5.2.6.1.4
ADVERSE EVENTS OF SPECIAL INTEREST ............................................74
5.2.6.1.5
INTENSITY (SEVERITY) OF AES .................................................................75
5.2.6.1.6
CAUSAL RELATIONSHIP OF AES ...............................................................76
5.2.6.2
ADVERSE EVENT COLLECTION AND REPORTING..............................76




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7.2.2
PRIMARY ENDPOINT ANALYSES...............................................................90
7.2.3
SECONDARY ENDPOINT ANALYSES.........................................................90
7.2.5
SAFETY ANALYSES.........................................................................................91
7.2.6
OTHER ANALYSES..........................................................................................92
7.2.7
INTERIM ANALYSIS .......................................................................................92
7.3
HANDLING OF MISSING DATA ...................................................................92
7.4
RANDOMIZATION...........................................................................................92
7.5
DETERMINATION OF SAMPLE SIZE .........................................................93
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........95
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................95
8.2
DATA QUALITY ASSURANCE ......................................................................96
8.3
RECORDS...........................................................................................................96
8.3.1
SOURCE DOCUMENTS...................................................................................96
8.3.2
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS.....................97
8.3.3
STORAGE PERIOD OF RECORDS ...............................................................97
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................98
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........98
8.5.1
COLLECTION, STORAGE AND FUTURE USE OF BIOLOGICAL 
SAMPLES AND CORRESPONDING DATA .................................................98
8.6
TRIAL MILESTONES.......................................................................................98
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................99
9.
REFERENCES..................................................................................................101
9.1
PUBLISHED REFERENCES..........................................................................101
9.2
UNPUBLISHED REFERENCES....................................................................104
10.
APPENDICES...................................................................................................106
10.1
INSTRUCTIONS FOR USE............................................................................106
10.1.1
STENOSIS PATIENT REPORTED OUTCOME (S-PRO) TOOL.............106
10.1.2
SIMPLE ENDOSCOPIC SCORE IN CROHN’S DISEASE (SES-CD)......110
10.1.3
CROHN’S DISEASE ACTIVITY INDEX (CDAI) .......................................111


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10.1.4
IBDQ ..................................................................................................................112
10.1.5
SF-36...................................................................................................................122
10.1.6
PATIENT’S GLOBAL IMPRESSION OF SEVERITY (PGI-S).................127
10.1.7
CLINICIAN’S GLOBAL IMPRESSION OF CHANGE (CGI-C) AND 
CLINICIAN’S GLOBAL IMPRESSION OF SEVERITY (CGI-S)............128
10.2
EQUIVALENT DOSES OF CORTICOSTEROIDS.....................................129
10.3
DIAGNOSIS OF ANAPHYLAXIS .................................................................130
10.4
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (
......................................131
10.5
TRIAL BIOMARKER PLAN..........................................................................132
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................133
11.1
GLOBAL AMENDMENT 1 ............................................................................133
11.2
GLOBAL AMENDMENT 2 ............................................................................147


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ABBREVIATIONS AND DEFINITIONS
ADA
Antidrug Antibody
ADCC
Antibody-dependent Cellular Cytotoxicity
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical (classification system)
AtD
Atopic Dermatitis
AxMP
Auxiliary Medicinal Product
AZA
Azathioprine
BI
Boehringer Ingelheim
CA
Competent Authority
CD
Crohn’s Disease
CDAI
Crohn’s Disease Activity Index
CDC
Complement-dependent Cytotoxicity
CGI-C
Clinician’s Global Impression of Change
CGI-S
Clinician’s Global Impression of Severity
clinROs
Clinician’s Reported Outcomes
Cmax
Maximum Plasma Concentration
CRA
Clinical Research Associate
CRC
Colorectal Cancer
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CTE
Computed Tomography Enterography
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
COVID-19
Corona Virus Disease 2019
DBL
Database Lock
DILI
Drug Induced Liver Injury


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DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
EBD
Endoscopic Balloon Dilation
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoS
End of Study
EoT
End of Treatment
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FUP
Follow-up
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GMP
Good Manufacturing Practice
GPP
Generalized Pustular Psoriasis
HA
Health Authority
HIV
Human Immunodeficiency Virus
HS
Hidradenitis Suppurativa
IGRA
Interferon Gamma Release Assay
IHC
Immunohistochemistry
Ig
Immunglobulin
IL
Interleukin
IL-36R
Interleukin 36 Receptor
INN
International Nonproprietary Names
IND
Investigational New Drug
i.v.
intravenous
IB
Investigator’s Brochure
IBD
Inflammatory Bowel Disease
IBDQ
Inflammatory Bowel Disease Questionnaire
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product


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IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
KO
Knockout
LI
Lead-in
LPLT
Last Patient Last Treatment
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Drug Regulatory Activities
miRNA
Micro Ribonucleic Acid
MoA
Mode of Action
MRD
Multiple Rising Dose
MR(E) 
Magnetic Resonance (Enterography)
MTX
Methotrexate
6-MP
6-Mercaptopurin
Nab
Neutralizing Antibody
NFKB
Nuclear factor kappa-light-chain-enhancer of activated B cells
NSAID
Non-steroidal anti-inflammatory drugs
OPU
Operative Unit
PCS
Physical Component Summary
PGI-S
Patient´s Global Impression of Severity
PD
Pharmacodynamic
PK
Pharmacokinetics
PPD
Purified Protein Derivative
PPP
Palmoplantar Pustulosis
p.o.
per os (oral)
PoCC
Proof of clinical concept
PV
Pharmacovigilance
qw
Weekly
q4w
Every four weeks
q8w
Every eight weeks
RA
Regulatory Authority
RCTC
Rheumatology Common Toxicity Criteria


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REP
Residual Effect Period
REML
Restricted Maximum Likelihood
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAF
Safety Set
SARS-CoV-2
Severe Acute Respiratory Syndrome Corona Virus 2
SB
Small Bowel
SES-CD
Simple Endoscopic Score in Crohn’s Disease
SF-36
36 question instrument to measure health-related quality of life
SOC
Standard of Care
SOP
Standard Operating Procedure
(S-)PRO
Stenosis Patient Reported Outcome
SRD
Single Rising Dose
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TDM
Therapeutic Drug Monitoring
TEAEs
Treatment Emergent Adverse Events
TMF
Trial Master File
TNF
Tumor Necrosis Factor
TSAP
Trial Statistical Analysis Plan
TST
Tuberculin Skin Testing
UC
Ulcerative Colitis
ULN
Upper Level of Normal
(I)US
(Intestinal) Ultrasound
vs.
versus
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Crohn’s disease (CD) is a chronic condition that manifests clinically as recurrent gut 
inflammatory episodes followed by periods of inflammatory remission and is one of the 
recognized subtypes of Inflammatory Bowel Disease (IBD).
Under normal physiologic conditions acute gut inflammation, e.g. viral or bacterial 
gastroenteritis, is followed by a complex tissue repairing or tissue remodelling response. This 
response aims to repair the damage caused by inflammation and to recover normal structure 
and function of the intestinal mucosa and rest of the layers of the gut wall. Tissue 
remodelling response includes among others activation of mesenchymal cells, which produce 
an extracellular matrix, mainly collagen and fibronectin, which leads to wound healing. 
However, in IBD patients, the chronic or recurrent activation of tissue remodelling responses 
leads to excessive accumulation of this extracellular matrix causing destruction of the 
interstitium and increased apposition of collagen or fibronectins, which leads to fibrosis, 
which manifest clinically as intestinal stenosis [R20-2041, R20-2042].
CD patients with small bowel stenosis typically present with acute or subacute episodes of 
symptoms of small bowel obstruction that are currently treated with intensified medical 
therapy, interventional endoscopy or surgery [R20-2037, P20-05765].
Most stenoses on a tissue level have a mixed inflammatory and fibrotic component. Since no 
antifibrotic treatments are currently available [P19-05294], patients are usually first treated 
with anti-inflammatory therapy. Corticosteroids associated to escalation of immune 
modulators or biologic drugs are currently used to induce remission of inflammatory flare in 
the stenotic area and thus, resolve obstruction and avoid surgery [R20-2037, P20-05766]. 
Patients who respond to intensified anti-inflammatory therapy during the acute phase are 
currently offered maintenance of the intensified anti-inflammatory regime to prevent further 
relapses. However, there is no evidence that maintenance of anti-inflammatory therapy 
prevents further relapses and after initial improvement of obstructive symptoms around 50% 
of the patients will still require interventional endoscopy or surgery within 1 year [P20-
05766, R20-3943].
For patients unresponsive to intensified anti-inflammatory therapy, endoscopic intervention 
or surgery are the only currently available options. Endoscopic Balloon Dilation (EBD) is the 
most common endoscopic treatment modality. Short-term symptomatic relief rates after EBD 
have been reported to be as high as 80% in patients with short length stenosis. However, this 
treatment modality is only amenable for stenosis that are within reach of endoscopy, limited 
in number and is associated to major complications such as bleeding or perforation in around 
2-3% of the cases [P20-05765]. Moreover, after initial symptomatic response, relapse is 
almost universal in these patients, 50% of which will finally require surgery [R20-2236, R20-
2235, P20-06254, P20-06255]. Thus, EBD is considered as a temporary bridge to surgery and 
thus, surgical resection or strictureplasty are currently the only left option in patients with 
fibrotic stenosis. However, these are not curative and relapse will appear in the majority of 
patients. Strictureplasty is associated with high morbidity and recurrence rates of 50% within 
a year [R20-2251]. Alternatively, bowel resection is associated with high risk of short bowel 


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syndrome in patients with recurrent, extensive or multiple stenosis [R20-4176] and is 
associated with high rates of recurrence, being almost universal 3 years after surgery [R20-
2234].
IL36 is a group of three cytokines that are overexpressed in the gut of IBD patients [R16-
2300]. They bind to IL36-receptor (IL36R) activating NFKB as well as Mitogen Activated 
Protein Kinases, which leads to the activation of various inflammatory pathways. These 
cytokines have also been shown to strongly activate myofibroblasts, one of the main effector 
cells in intestinal fibrosis [R20-2093].
Recently, it has been shown that cells expressing IL36α, one of the IL36R ligands, are 
significantly increased in the gut mucosa from IBD patients with fibrostenosis compared to 
those without and these were found in close proximity with alpha-SMA+ fibroblasts, one of 
the key effectors of intestinal fibrosis [R19-0857]. The same study showed higher expression 
of IL36α, alpha-SMA+ fibroblasts and type VI collagen in stenotic regions of CD and 
Ulcerative Colitis (UC) patients.
Blockage of IL36R has also been shown to reduce fibrosis in two animal models of chronic 
colitis. Moreover, antagonizing IL36R in these animals was shown to significantly reverse 
already established fibrosis [R19-0857]. In totality, these data strongly suggest IL36 being a 
key player in the generation of intestinal fibrosis, which underlies the clinical complication of 
fibrostenostic bowel obstruction.
1.2
DRUG PROFILE
Mode of action (MoA)
BI 655130 (INN: spesolimab) is a humanized antagonistic monoclonal IgG1 antibody that 
blocks human IL36R signalling. Binding of spesolimab to IL36R is anticipated to prevent the 
subsequent activation of IL36R by cognate ligands (IL36α, β and γ) and downstream 
activation of pro-inflammatory and pro-fibrotic pathways in inflammatory skin and bowel 
diseases such as Generalized Pustular Psoriasis (GPP), Palmoplantar Pustulosis (PPP), Atopic 
Dermatitis (AtD), Hidradenitis Suppurativa (HS), and IBD. Thus, spesolimab may be unique 
in directly suppressing not only pro-inflammatory but also profibrotic mechanisms in these 
diseases.
Key pharmacokinetic characteristics
Pharmacokinetics (PK) analysis showed that exposure (AUC0-tz and Cmax) to spesolimab 
increased with increasing dose in an approximately dose-proportional manner from 0.3 to 10 
mg/kg. The effective half-life of spesolimab is approximately 4 to 5 weeks in the linear dose 
range in healthy volunteers and approximately 3 weeks in GPP patients. For details please see 
the Investigator’s Brochure (IB) [c03320877].
Overall, PK data so far suggests target-mediated drug disposition kinetics for spesolimab.
Pharmacodynamic effects in this first in human Single Rising Dose (SRD) trial [c03361085-
07] were assessed by indirect target engagement of Interleukin 36 Receptor (IL-36R) by 
spesolimab using an ex-vivo whole blood stimulation assay. Preliminary analyses indicate 


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that ≥94% peripheral IL-36R receptor occupancy is achieved with doses ≥0.05mg/kg from 30 
minutes post infusion to 10 weeks.
Drug interactions
Currently there are no data available to suggest interactions of spesolimab.
Residual Effect Period
The Residual Effect Period (REP) of spesolimab is 16 weeks. This is the period after the last 
dose with measurable drug levels and / or pharmacodynamic effects still likely to be present.
The consideration behind the REP derivation is that the half-life of ~4 weeks for spesolimab 
was observed in the healthy volunteer SRD study of 1368.1. However, in the patient trial 
1368.11 where spesolimab was tested in GPP patients, the effective half-life was 23.9 days, 
ie. ~3.4 weeks. Therefore 16 weeks would correspond to approximately 5 half-lives in 
patients, after which time most drug will have been cleared and only less than 3.125% of 
spesolimab will still be available.
Data from non-clinical studies
Spesolimab binds to human IL36R with a binding avidity of less than 1 pM. Spesolimab 
inhibits IL36 ligand-stimulated NF-κB 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. Spesolimab also inhibits IL8 release in primary human 
intestinal myofibroblasts and Interferon gamma (IFNγ) secretion in human Peripheral Blood 
Mononuclear Cell stimulated with IL36α, IL36β, or IL36γ combined with IL12.
Mutations of two key residues (L234 and L235) to alanine were made to 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 spesolimab will be a non-
depleting therapy in vivo.
Toxicology studies
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 
spesolimab. However, hazard identification studies of the 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 
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, 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 spesolimab dosing in humans.
Data from clinical studies
Spesolimab or placebo 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 were good. There were no drug-related Serious Adverse Events (SAE).
Proof of Concept trial 1368.11 was performed in patients with an acute flare of GPP, a 
disease closely linked to loss-of-function mutations in the natural IL36R antagonist. 
Complete data from 1368.11 demonstrate that spesolimab treatment rapidly stops the flare 
and clears pustules, the primary lesions in GPP. Based on rapid clinical responses on pustules 
– the key feature of GPP in trial 1368.11, a placebo controlled Phase II trial (1368.15) has 
been conducted to investigate proof of concept of spesolimab also in patients with PPP, a 
neutrophilic dermatosis with sterile pustules on palms and soles. This trial also showed a 
benefit for patients with PPP, with a clinically relevant response and good safety and 
tolerability. Trial 1368.32 was a Phase IIa, randomized, double-blind, placebo-controlled 
proof-of-concept trial in patients with moderate to severe Atopic Dermatitis (AtD) were 
treated with either 600 mg spesolimab (33 patients) or placebo (18 patients) i.v. every 4 
weeks over a period of 16 weeks (time point of primary analysis) the trial showed a 
meaningful treatment effect from Week 8 onwards. For details please see IB [c03320877].
Trial 1368.5 was a multinational, randomized, parallel-group, double-blind trial of 
spesolimab in patients with moderate-to-severely active UC [c31366073-01]. This trial 
investigated efficacy and safety of 12-week induction treatment with different dose regimens 
of spesolimab in patients who had failed previous biologic treatments in the past. Due to 
recruitment issues, the trial was discontinued in February 2020 after completing 61% of the 
planned recruitment (communication submitted to Investigational New Drug (IND) 127074
on February 14, 2020 (SEQ 0075). An unblinded analysis was conducted including 90 
patients who had either completed or discontinued through Week 12 (data cut-off 31 Jan 
2020). At time of trial discontinuation, 8 additional patients were ongoing and therefore not 
included in the interim analysis.
Although with the sample size achieved, the study was not adequately powered, the results of 
the interim analysis showed no clear efficacy of spesolimab over placebo in primary and 
secondary clinical endpoints, although a few patients in the higher dose groups (450 mg q4w 
and 1200 mg q4w) showed a treatment effect in the strictest endpoints [c31366073-01].
However, changes in the IL-36 inflammatory pathway genes were observed in spesolimab 
clinical responders which were not observed in the placebo clinical responders, suggesting 
target engagement and pathway specific effect of spesolimab linked to clinical outcomes in 
UC patients. !"" # $%&'&%(&)'&%"*+,-.'/'
0'1'/,""2 .'"" 3%"'/,3'$4
In trial 1368.13 in patients with GPP, spesolimab showed an acceptable safety profile. The 
overall rates of adverse events were generally comparable between treatment groups during 


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Week 1. The proportions of patients and incidence rates were balanced between the 2 
treatment groups for most system organ classes (SOCs) except for infections. Time-adjusted 
adverse event incident rates in the spesolimab treatment group were lower at Week 12 than in 
both treatment groups at the end of Week 1. For details please see IB [c03320877].
In trial 1368.4 in patients with moderate to severe active UC (multi-centre, non-randomized, 
uncontrolled (single arm), open-label, exploratory trial which assessed biomarker changes in 
response to IL36 signalling blockade induced by treatment with spesolimab) spesolimab was 
generally well tolerated [c03320877].
In trial 1368.10 spesolimab was tested at a dose of 1200 mg iv q4w for 12 weeks followed by 
24 weeks after the end of the treatment period in patients with mild to moderate UC in 
addition to a stable Tumor Necrosis Factor (TNF) inhibitor background therapy. Spesolimab 
was well tolerated and the safety profile was generally comparable with the safety profile of 
the placebo and no unexpected safety observations were identified [c03320877].
For a more detailed description of the spesolimab (BI 655130) profile, please refer to the IB
[c03320877].
Selected drugs from Anatomical Therapeutic Chemical (ATC) (level 3) L04A 
“Immunosuppressants” are considered Auxiliary Medicinal Products (AxMP) in this trial. 
These are drugs that are authorised to be used in CD and include the TNF-alpha inhibitors 
adalimumab, certolizumab and infliximab, the integrin receptor antagonists natalizumab and 
vedolizumab, and the IL12/23 antagonist ustekinumab. Respective labelling of authorised 
drugs will be provided to sites in the Investigator Site File (ISF).
Summary
Spesolimab is an anti IL-36R antibody with a high clinical activity to block IL-36R signaling, 
as demonstrated in patients with GPP, PPP and AtD inflammatory skin diseases that share 
underlying uncontrolled IL36 activity. In addition, spesolimab has been tested in more than 
180 healthy volunteers and 604 patients for up to 16 weeks. For specific information on risks 
please refer to Section 1.4.2.
Unlike CD, inflammatory damage in UC is limited to the gut mucosa and complications such 
as stenosis and fistulae related to aberrant tissue remodelling responses are uncommon. 
Although, spesolimab did not lead to significant clinical efficacy in UC patients, based on its 
unique antifibrotic mechanism of action it is expected to provide efficacy in reversing or 
delaying progression of fibrostenotic damage in CD subjects, in particular if combined with 
an optimized anti-inflammatory treatment, as investigated in this current study 1368-0059.
1.3
RATIONALE FOR PERFORMING THE TRIAL
CD incidence and prevalence are rising [R15-0886] and around 10% of newly diagnosed 
patients will present with clinically significant gut stenosis, most frequently in the ileum, at 
the time of diagnosis [R16-3819]. Remarkably, around 50% of overall CD patients will 
eventually develop stenosis despite successful anti-inflammatory treatment [R15-6125].
Currently there are several medical treatments available that are efficacious to induce and 
maintain mucosal inflammation remission in CD patients. However, there is no approved 


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therapeutic drug to arrest or reverse the chronically accumulated bowel damage in these 
patients, specifically stenosis [P19-05294].
Clinical trial 1368-0059 is the first prospective, randomized, well-controlled proof of clinical 
concept (PoCC) study to evaluate the effect of an antifibrotic drug on CD-associated small 
bowel fibrostenosis. Lack of previously validated endpoints and outcomes measures tools 
have prevented drug development in this indication until this moment.
Currently, the 
, a leading 
group of experts and institutions in this field, have set out to specifically develop new tools to 
measure clinical and structural (radiological and histological) outcomes in these patients. 
Thus, beyond evaluating spesolimab efficacy in fibrostenotic CD, this PoCC study aims to 
start the development and validation processes of these new tools.
The first is a Patient Reported Outcome tool (S-PRO), named Stricturing Crohn’s Disease 
Questionnaire. This is a questionnaire which has been developed in accordance with current 
Food and Drug Administration (FDA) guidance in collaboration with national and 
international IBD societies to capture symptoms specific to stenotic complication in CD 
patients. Thus, S-PRO, together with other patient reported outcomes (PROs) tools will be 
used in this study to measure symptoms to explore if this instrument might be fit-for-purpose 
to measure symptomatic endpoints in this population.
Besides patient reported clinical symptoms, an ‘objective’ measurement of fibrostenosis 
status and change after treatment in this population is desirable. In CD patients with luminal 
inflammation phenotype, inflammation is currently objectively assessed by endoscopy and 
histological evaluation of samples obtained from the superficial mucosa. However, CD 
stenosis develop mostly in the small bowel, frequently in areas not accessible by endoscopy. 
Moreover, CD-associated fibrostenosis is a transmural process. In CD, fibrosis accumulates 
mainly in the submucosa of the gut wall [P20-10740]. Thus, currently available endoscopic 
techniques would not provide adequate sampling of the tissue of interest [R20-3944].
Hence, cross-sectional imaging is currently the standard to evaluate CD stenosis status in 
individual patients in the clinical setting. Three core imaging features such as prestenotic 
dilation, wall thickening and luminal narrowing have been proposed as the most relevant 
features to describe CD-related stenosis. However, there are no data on the different 
accuracies of applying three, two or one of these items for the diagnosis of CD-related 
stenosis and their relationship with patient clinical or symptomatic status [R20-2233].
Regarding the differentiation of inflammation and fibrosis within a specific stenosis, which 
might guide subsequent therapeutic decisions, available data are also not conclusive. 
Magnetic Resonance Enterography (MRE) is free of ionizing radiation and has been proposed 
as the most accurate and widest available technique to differentiate fibrosis from 
inflammation in CD-related stenosis [P09-14233, R20-3945, R20-3946, R20-3948]. 
Therefore, in this PoCC trial we propose to use MRE to diagnose and assess the stenosis 
status in the targeted population at baseline and after treatment in order to explore the 
radiological variables that might be more closely linked to relevant clinical outcomes in this 
population. These data might provide the basis to develop a standardized radiological 
endpoint to be used in future clinical development.


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In addition, data on PK, antidrug antibodies (ADA) of spesolimab and biomarkers of tissue 
remodelling will be collected. A robust understanding of the PK / Pharmacodynamic (PD)
response correlation might be achieved using a modelling approach and which might support 
dose selection for the subsequent adult and pediatric development program.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see Section 5.4). If the patient agrees, banked 
samples may be used for future biomarker research and drug development projects, e.g. to 
identify patients that are more likely to benefit from a treatment or experience an Adverse 
Event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby 
better match patients with therapies.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Currently no medical treatment is available with evidence based effect on reducing the 
relapse of an acute or subacute symptomatic stenosis episode after initial response to 
intensified medical therapy (i.e. corticosteroids and escalated immunomodulatory or biologic 
regime).
The potential benefits that may be demonstrated in this study include:

Spesolimab may maintain Symptomatic Stenosis Response (as defined in Table 2.3: 1) 
and may prevent further fibrostenosis development or even induce reversal of stablished 
fibrostenosis (measured as Radiographic Stenosis Response, defined in Table 2.3: 1), thus 
reducing relapse and need for invasive interventions (potential for individual patient 
benefit).

The addition of spesolimab on top of current Standard of Care (SOC) therapeutics would 
create an entirely new treatment paradigm for fibrostenosing CD. It would represent the 
first antifibrotic drug for treating a common and severe CD complication that remains a 
high, unmet medical need (potential group benefit).

Beyond the objective of demonstrating PoCC for spesolimab in this disease, the study 
will help to develop the novel S-PRO and stenotic radiographic outcome, which might be 
used as key endpoints in future studies in this indication (see Section 7).
Only patients not requiring endoscopic or surgical intervention at the time of study start will 
be enrolled into the trial. Moreover, during the Lead-in Period all patients will receive high 
dose but short-term pulse of systemic corticosteroids, which usually leads to a symptomatic 
response in about 80% of patients, combined with optimization of anti-inflammatory therapy. 
This represents current SOC for treatment of acute or subacute symptoms of small bowel 
obstruction in non-surgical and no endoscopic candidates with fibrostenotic CD.
Only responders to the Lead-in Period SOC therapy described above will be randomized to 
either spesolimab or placebo on top of their individually optimized anti-inflammatory therapy 
during the Blinded Randomized Treatment Period. Thus, even placebo patients will receive 


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best available SOC during all study periods and no patient is withheld from current best 
practice treatment.
1.4.2
Risks
Preclinical toxicology studies with a mouse surrogate antibody have demonstrated the safety 
of chronic IL36R inhibition in mice (see IB, Section 5.3, c03320877).
A recent publication has assessed the clinical phenotype and immune function in 12 healthy 
individuals harboring an IL36R knock-out polymorphism [R17-3632]. This study showed no 
specific diseases or conditions, in particular of recurrent, severe or opportunistic infections or
malignancies, in the medical records of these subjects. Also, serological and in-vitro studies 
indicated normal levels of non-, tetanus- or varicella-specific immune globulins, and normal 
immune functions as compared to matched controls, indicating that IL36 blockade is likely to 
represent a safe and well tolerated therapeutic concept [R17-3632].
Spesolimab has been shown to be safe and well tolerated in more than 149 healthy volunteers 
exposed in phase I SRD and Multiple Rising Dose (MRD) studies to single or multiple doses 
of spesolimab up to dose levels of 20 mg/kg given once weekly (qw) for 4 weeks; (for details 
see IB, c03320877).
Besides preclinical profiles and clinical data from healthy volunteers, patient trials performed 
to date also suggest that spesolimab is safe and tolerable in patients suffering from different 
skin conditions [c03320877].
In 1368.4, 1368.5 and 1368.10 (patients with UC) trials as well as in 1368.11, 1368.13 
(patients with GPP), 1368.15 (patients with PPP) and 1368.32 (patients with AtD) trials,
overall, spesolimab was well tolerated [c03320877].
No other IL-36 receptor antagonist is currently approved, providing further information on 
identified risks in molecules of this class.
Despite the favourable safety profile so far, as with any immune modulating agent, 
spesolimab has the potential to impair immune function resulting in an increased risk of 
infection. The role of IL36 in tumor immunity is not well established at this time, but an 
increased risk of cancer from an IL36R antagonist, though considered small, cannot be 
excluded. These potential risks of an experimental combination treatment will be addressed 
by careful safety monitoring and risk mitigation measures, which will be implemented in this 
trial of a novel and 1st-in-class MoA: (a) exclusion of patients with history or increased risk 
of malignancies or infections; (b) close clinical monitoring for AEs, including use of 
Rheumatology Common Toxicity Criteria (RCTC) for severity grading, definition of 
emerging malignancies as always-serious adverse events, definition of opportunistic 
infections and infusion reactions and anaphylactic reactions as adverse event of special 
interest (AESI); (c) selection of sites experienced in treatment of IBD patients with biologics; 
and (d) regular surveillance by an independent Data Monitoring Committee (DMC).


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Table 1.4.2: 1 lists possible risks for spesolimab as well as theroretical risks derived from 
general safety considerations of immunomodulatory drugs and from this trial specific 
procedures.
Table 1.4.2:1
Overview of trial related risks
Investigational Medicinal Product spesolimab (BI 655130)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Drug Induced Liver Injury 
(DILI)
Although rare, a potential 
for drug-induced liver 
injury (DILI) is under 
constant surveillance by 
sponsors and regulators. 
Therefore, DILI is 
considered as a standard 
risk in all BI development 
programs.
Timely detection, 
evaluation, and follow-up of 
laboratory alterations in 
selected liver laboratory 
parameters to ensure 
patients´ safety. See also 
Section 5.2.6.1.4, adverse 
event of special interest.
Trial treatment 
discontinuation criteria as 
well as criteria for trial 
treatment restart are 
implemented for relevant 
cases.


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Table 1.4.2: 1
Overview of trial related risks (cont.)
Investigational Medicinal Product spesolimab (BI 655130)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Systemic hypersensitivity 
reaction
After administration of any 
biologic agent or protein, 
there is a possibility of 
occurrence of immediate 
(such as anaphylaxis) or 
delayed (such as drug 
reaction with eosinophilia 
and systemic symptoms)
adverse immune 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 SOC 
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 
to assess these conditions 
using the criteria discussed 
in the statement paper from 
Sampson HA [R11-4890].


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Table 1.4.2: 1
Overview of trial related risks (cont.)
Investigational Medicinal Product spesolimab (BI 655130)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Infections
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of 
infections.
A recent characterisation of 
individuals with 
homozygous IL36R KO 
mutations revealed that 
normal immune function 
was broadly preserved 
suggesting that IL36 
signaling pathway 
inhibition may not 
substantially compromise 
host defences [R17-3632].
In clinical trials with 
spesolimab, a higher 
proportion of patients with 
mild to moderate infections 
was seen in the spesolimab 
treatment group than in the 
placebo treatment group.
Nevertheless, there was no 
indication of an increased 
frequency of patients with 
severe, serious, and 
opportunistic infections in 
association with spesolimab 
treatment.
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 according 
to standards of care.
Severe infections and 
opportunistic infections are 
considered AESIs for this 
trial. These conditions and 
serious infections are 
subject to close monitoring.


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Table 1.4.2: 1
Overview of trial related risks (cont.)
Investigational Medicinal Product spesolimab (BI 655130)
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Malignancies 
Inhibition of the immune 
response with an immune-
modulating biologic may 
potentially impair immune 
defences and thus 
theoretically decrease 
immune defense against 
malignancies.
A recent characterisation 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 defences 
[R17-3632].
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 
spesolimab. Diagnostics and 
treatment have to be 
initiated according to local 
SOC. Malignancies 
represent always serious 
adverse events and are 
subject to close monitoring.
Hematological laboratory 
abnormalities
Hematological laboratory 
abnormalities are not 
considered to present a risk 
due to spesolimab 
administration according to 
current clinical data for 
spesolimab. However, due 
to administration of 
spesolimab in combination 
with anti-inflammatory 
treatments theoretical risks 
with regards to combination 
treatment are taken into 
consideration.
Guidance on assessment and 
mitigation measures with 
regards to hematological 
laboratory abnormalities is 
included into current 
Clinical Trial Protocol 
(Section 4.2.1.4)


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Table 1.4.2: 1
Overview of trial related risks (cont.)
Trial procedures
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
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.
These risks will be 
addressed by careful safety 
monitoring and risk 
mitigation measures such as

close clinical monitoring 
for AEs;

selection of experienced 
sites and site staff;

training.
Infusion of trial medication
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.
These risks will be 
addressed by careful safety 
monitoring and risk 
mitigation measures such as

close clinical monitoring 
for AEs;

selection of experienced 
sites and site staff;

training.


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Table 1.4.2: 1
Overview of trial related risks (cont.)
Trial procedures
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Magnetic Resonance 
Enterography (MRE)
Intravenously applied 
contrast media could cause 
allergic reactions. 
Additionally, contrast 
agents could cause 
problems in patients with 
significant kidney disease. 
MRE assessments could 
lead to peripheral muscle or 
nerve stimulation that may 
feel like a twitching 
sensitation. Heating of the 
body could be caused by the 
radiofrequency energy used 
during MRE scans. The MR 
environment presents in 
general unique safety 
hazards for patients with 
implants, external devices 
and accessory medical 
devices that interfer with the 
magnetic field. The limited 
space of MR scanners may 
cause claustrophobic 
distress in predispositioned 
patients.
The risks will be addressed 
by careful monitoring and 
mitigation measures such as 

close clinical monitoring 
of AEs;

kidney functions will be 
measured before MRE 
assements and patients 
with glomerular filtration 
rate (GFR) <30 mL/min 
are excluded from the 
trial;

patients with contra-
indications for MRE are 
exluded from the trial;

only clinical sites with 
extensive experience in 
MRE assessments and 
trained site staff will be 
selected.


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Table 1.4.2: 1
Overview of trial related risks (cont.)
Trial procedures
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Ileocolonoscopy with 
biopsy
Diarrhea, abdominal pain, 
perforation, bleeding effects 
of anaesthetic medications, 
infection
Selection of sites 
experienced in taking care 
of IBD patients:
These risks will be 
addressed by careful 
monitoring and risk 
mitigation measures such as

close clinical monitoring 
for AEs;

selection of sites with 
experienced site staff;

ileocolonoscopy will be 
done according to the 
standard local care 
procedures including 
local clinic / hospital 
consent authorizing this 
procedure;

training.


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Table 1.4.2: 1
Overview of trial related risks (cont.)
Other risks
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
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.
Trial medication is 
adminsistered on top of 
optimized anti-
inflammatory biological 
therapy. Thus, best active 
SOC treatment is not 
withhold from any patient.
Use of Auxiliary Medicinal 
Products (AxMPs): 
Selected drugs from ATC 
(Level 3) L04A 
“Immunosuppressants” are 
considered AxMPs
Examples of risks which 
might be associated with 
AxMPs use include: 
infections, malignancies and 
hypersensitivity reactions.
No interactions between 
AxMPs and spesolimab are 
expected.
Diagnostics, treatment and 
monitoring have to be
implemented according to 
local SOC.
Use of corticosteroids 
during the Lead-in Period
Examples of associated 
risks: infections, elevation 
of blood pressure, fluid and 
electrolyte disturbances.
Diagnostics, treatment and 
monitoring have to be 
implemented according to 
local SOC.
1.4.3
Discussion
Although no direct benefit for individual patients can be assumed, based on the provision of 
individually optimized CD treatment to all patients, the proof of concept achieved in GPP and 
the strong scientific rationale, there is a reasonable chance that spesolimab may prevent 
further fibrosis development or even reduce established fibrosis in patients with CD-related 
small bowel symptomatic stenosis. This would improve long-term outcomes in these patients, 
for whom currently there are limited effective non-surgical treatments.
Preclinical and clinical data gathered up to this moment strongly suggest that spesolimab is 
safe at the dose regimens proposed for this trial, even if given in combination with other 
immune-modulators or biological therapies.
The benefit-risk profile is thus considered acceptable for an investigational product at this 
stage of clinical development.
Benefit-Risk Assessment in context of COVID-19 pandemic:
Spesolimab is an immune-modulating humanized monoclonal antibody, that blocks the 
human IL-36 receptor and thereby the pro-inflammatory IL-36 pathway. Available non-
clinical and clinical data have not shown an increased frequency of patients with severe, 
serious and opportunistic infections with spesolimab treatment. However, higher proportion 


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of patients with mild to moderate infections was seen in the spesolimab treatment group than 
in the placebo treatment group.
Risk mitigation measures, such as exclusion of patients with increased risk of infections, 
close monitoring of adverse events, as well as guidance on treatment and handling of acute 
infections occurring during the trial are described in the Clinical Trial Protocol (CTP).
As any other acute infection, a suspected or diagnosed Corona Virus Disease 2019
(COVID-19) infection should be treated according to the SOC and interruption of study 
medication should be considered. To date, there is no reliable evidence suggesting a link 
between Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infections and 
the IL-36 pathway targeted by spesolimab. Further investigations are needed to elucidate the 
molecular mechanisms underlying their biological functions in COVID-19. Considering the 
current knowledge of COVID-19 and the implemented risk mitigation measures addressing 
the potential risk of infections, patients with indications in which spesolimab is investigated 
are not per se believed to be at higher risk of COVID-19. Protocol-defined procedures do not 
impose undue risk to study participants.
The benefit-risk assessment of spesolimab remains favourable in the context of the 
COVID-19 pandemic.
To address potential risks associated with operational aspects related to the participation in 
clinical trials in context of COVID-19 pandemic, different risk mitigation measures are 
considered in ongoing and planned spesolimab clinical trials based on local requirements and 
development of pandemic.
The investigators will take the totality of information related to each single patient and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each patient’s (continued) participation in the planned trials. Boehringer Ingelheim (BI) as 
the sponsor, where required, will support the investigator in their decision finding.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
The overall aim of this trial is to proof the concept that spesolimab is effective and safe in the 
long-term treatment of symptomatic small bowel stenosis in patients with established CD.
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
To demonstrate that spesolimab is effective in maintaining Symptomatic Stenosis Response 
and / or inducing Radiographic Stenosis Response (defined in Table 2.3: 1) in patients with 
symptomatic CD-related small bowel stenosis, who have achieved Symptomatic Stenosis 
Response after standard medical therapy.
2.1.2
Primary endpoint(s)
Spesolimab superiority vs. placebo on one of the following:

Proportion of patients with maintained Symptomatic Stenosis Response (defined in 
Table 2.3: 1) at Week 48

Proportion of patients with Radiographic Stenosis Response (defined in Table 2.3: 1) at 
Week 48
2.1.3
Secondary endpoint(s)

Proportion of patients with maintained Symptomatic Stenosis Response (defined in 
Table 2.3: 1) at Week 24

Proportion of patients with Radiographic Stenosis Response (defined in Table 2.3: 1) at 
Week 24


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2.3
DEFINITION OF STUDY OUTCOMES
Definitions of symptomatic and radiographic study outcomes are provided Table 2.3: 1.
Table 2.3: 1
Definitions of Study Outcomes
Symptomatic Stenosis Response
7 days average score for abdominal pain after 
eating* <2
AND
7 days average score for amount or types of food 
limitation* <2
*See questions for symptomatic primary outcome 
and explanation on the scoring in the paragraph 
below this table.
Maintained Symptomatic 
Stenosis Response
Symptomatic Stenosis Response with no confirmed 
Stenosis Relapse after Week 16 post-randomization
Symptomatic Stenosis Relapse
7 days average score for abdominal pain after 
eating* ≥2
AND
7 days average score for amount or types of food 
limitation* ≥2
*See questions for symptomatic primary outcome 
and explanation on the scoring in the paragraph 
below this table.


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Table 2.3: 1
Definitions of Study Outcomes (cont.)
Confirmed Stenosis Relapse
Symptomatic Stenosis Relapse AND radiographic 
confirmation of small bowel obstruction
Radiographic Stenosis Response
a) stricture length improvement (by 25%) + no 
worsening of pre-stenotic small bowel (SB) 
diameter*
OR
b) pre-stenotic SB diameter improvement (by 
50%**) + no worsening of stricture length*
AND
+ no new small bowel stenosis
+ no new pre-stenotic fistula
+ no new stenotic abscess
*no worsening refers to radiographic stenosis no 
progression
**50% improvement in pre-stenotic SB diameter 
refers to dilation over the 20 mm of normal SB 
diameter, i.e. 30 to 25 mm change: 50% 
improvement, 30 to 22.5 mm: 75% improvement
Radiographic Stenosis no 
progression
No worsening from baseline (change <10%) of:
- stricture length
OR
- pre-stenotic SB diameter
AND
+ no new small bowel stenosis
+ no new pre-stenotic fistula 
+ no new stenotic abscess
CDAI response
CDAI decrease of ≥100 points from baseline, OR 
an absolute CDAI ≤150
CDAI remission
CDAI ≤150
Inflammatory flare
Increase in CDAI score by ≥100 points from 
baseline with an absolute CDAI >220
Confirmed inflammatory flare
Increase in CDAI score by ≥100 points from 
baseline with an absolute CDAI >220
+
An absolute colonic SES-CD >12
+
absence of enteric pathogens in stool


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The Symptomatic Stenosis Response and the Symptomatic Stenosis Relapse are calculated 
automatically using 2 questions of the eDiary completed by the patient. 
For both questions, a 7-day average score is calculated based on a scale from 0 to 3 as below. 
First question:
During the last 24 hours, how often did you experience abdominal pain after eating?   [Score] 
□Never   [0]
□Sometimes   [1]
□Often   [2]
□Every time I ate   [3]
□Not Applicable: I could not eat in the last 24 hours because of  my Crohn’s
symptoms   [3]
□Not Applicable: I did not eat in the last 24 hours for other reasons   [considered as 
missing data]
Second question:
During the last 24 hours, how limited were you in the amount or types of food you could eat 
because of your stricturing Crohn's disease?   [Score] 
□Not limited at all   [0]
□A little limited   [1]
□Moderately limited   [2]
□Very limited   [3]
For scoring, average of 7 days information from the eDiary is used. A minimum of 4 days 
eDiary data is required for calculating the score.
In the Lead-in Period these data are collected daily. For eligibility (inclusion criterion number 
8), the last 7 days of the 8 week optimization of anti-inflammatory biological treatment will 
be used to calculate the average score for these two items.
For primary and secondary endpoint assessment at Week 48 and Week 24, respectively, the 
average of 7 days eDiary data are used, collected the week immediately preceding the Week 
48 and Week 24 visits.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
This is a randomized, double-blind, placebo-controlled, parallel-design trial testing one active 
dosage vs. placebo. The trial design is illustrated in Figure 3.1: 1.
Patients with obstructive symptoms due to confirmed CD related stenosis are screened for 
this trial, which includes three periods:
Lead-in Period, Randomized Blinded Treatment Period and Follow-up Period.
Abbreviations: CS = Corticosteroids, MRE = Magnetic Resonance Enterography,
R = Randomization, EoT = End of Treatment Visit, EoS = End of Study Visit, S-PRO = Stenosis Patient Reported Outcome
*last trial drug administration
Figure 3.1: 1: Trial design
Lead-in Period (12 weeks):
Patients with symptoms suggestive of bowel obstruction and with up to two CD-related small 
bowel stenoses (diagnosed by one of the following: Intestinal Ultrasoun (IUS), Computed 
Tomography (CT), Magnetic Resonance (MR), Computed Tomography Enterography (CTE), 
or Magnetic Resonance Enterography (MRE)) will be screened for enrolment into the trial. 
Patients who have indication of endoscopic balloon dilation or surgery are excluded from this 
trial. Only patients with clinical indication of anti-inflammatory treatment as per local SOC, 
are eligible for this trial.
Patients enrolled into the trial may be hospitalized or treated as outpatients and will receive 
standard medical treatment of their CD-stenosis-related obstructive symptoms, which 
includes:


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
2 weeks of corticosteroids which will be slowly tapered according to a standardized 
8 week regimen (for details see Section 4.2.1)
AND

individual optimization of anti-inflammatory biological treatment as described in the 
algorithm included in Section 4.2.1.
Patient symptoms will be captured daily during the Lead-in Period using the S-PRO diary 
starting from the screening visit (Visit 1) or as soon as the patient´s situation allows during 
hospitalisation (latest on the day of discharge).
Patients who during the Lead-in Period, after the 2 weeks of corticosteroids or at any time 
thereafter need further testing or have indication of endoscopic balloon dilation or surgery as 
per investigator judgement, will be considered screening failures and will be discontinued 
from the study.
After 8 weeks of optimized biological anti-inflammatory therapy have been completed, only 
patients who have achieved a Symptomatic Stenosis Response (as defined in Table 2.3: 1) 
and an absent or mild-to-moderate colonic endoscopic activity (colonic SES-CD ≤12) will be 
eligible for randomization into the Blinded Treatment Period.
Patients not achieving Symptomatic Stenosis Response and / or the colonic SES-CD ≤12 
eligibility criteria will be considered screening failures and discontinued from the study and 
undergo other diagnostic tests and treatments as per local guideline / practices.
Randomized Blinded Treatment Period (48 weeks):
Symptomatic stenosis responders to medical Lead-in treatment (as defined in Table 2.3: 1) 
will be randomized to receive either placebo or spesolimab for 48 weeks (with the last trial 
drug administration at Week 40) on top of their optimized biological anti-inflammatory 
therapy.
Randomization will be stratified by number of biologic classes failed prior to screening 
Visit 1 (0-1 versus >1) and stenotic length (≤ versus >5 cm) as measured by baseline MRE.
Patients need to maintain the biological treatment optimized during the Lead-in Period 
throughout the Randomized Blinded Treatment Period. After randomization, only 1 dose 
increase (strength and / or interval) of optimized biological anti-inflammatory therapy is 
allowed until Week 16 after randomization.
Rescue treatment: Any dose escalation after Week 16 post-randomization or de-novo 
initiation of any drug approved for treatment of moderate-to-severe CD during the whole 
length of the study (see Section 4.2.2.1 and Table 4.2.2.1: 1) will be considered a rescue 
treatment. Such patients will be considered as treatment failures in the primary efficacy 
analysis. However, the patient may continue the study as per CTP. This means visits and trial 
drug administration occur as scheduled.
Trial discontinuation: Patients experiencing worsening of stenosis symptoms during the 
Randomized Blinded Treatment Period that are not controlled by anti-inflammatory 


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medication and require endoscopic balloon dilation or surgery will be discontinued from the 
trial. Patients who experience any clinical complication that prevents continuation of the trial 
drug will be discontinued from the trial. Such patients will be considered as treatment failures 
in the primary efficacy analysis.
Follow-up Period:
Patient will undergo a safety follow-up monitoring until Week 56, which is not earlier than 
16 weeks after the last dose of the trial drug at Week 40.
An extension trial might be offered to patients who present an individual clinical benefit from 
their trial drug (whether spesolimab or placebo).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
3.2.1
Rationale for selected Trial Population
We will study the effect of spesolimab in patients with CD-related clinically significant 
intestinal stenosis. The selected population is representative of CD patients with symptomatic 
bowel obstruction referred to large referral centers, like those sites participating in this trial.
Current therapeutic options for the proposed population are unproven, limited or temporary 
efficacy. Escalated anti-inflammatory treatment may alleviate a stenosis with a 
predominantly inflammatory component. Corticosteroids [R20-2043] as well as anti-tumour 
necrosis factor alfa therapy have been shown to induce temporary improvement of 
obstructive symptoms in this population and thus represent the current SOC in many large 
IBD centers worldwide, though still around 50% of patients require endoscopic dilation 
therapy or surgery within 12 months [P20-05766].
To reduce and control part of the inherent heterogeneity of the general fibrostenotic CD 
population which may have different prior treatments and outcomes, history of previous 
stenosis, disease location and phenotype of stenosis as well as type and severity of symptoms 
randomization will be used and will be stratified based on variables known to impact 
outcomes (see Section 7.4). The population will be selected to ensure that only patients with 
the following disease characteristics are randomized:
1. minimum threshold of symptoms.
2. terminal ileum stenosis.
3. no severe colonic luminal disease.
4. fulfil standard radiographic criteria of CD-stenosis as published by the 
 
 [R20-3947].
5. Endoscopy and MRE central read confirmation of 3 and 4, respectively.
6. Response to a standardized duration and individually tailored optimization of biological 
anti-inflammatory treatment representative of SOC (see Section 4.2.1.1 and 
Flow Chart 2) during the Lead-in Period before randomization.


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The targeted population is representative of patients with clinically significant fibrostenotic 
CD who are referred to large referral centers, like those sites participating in this trial, and 
with the highest but preventable risk of requiring invasive (endoscopic or surgical) treatment 
on the mid-term. Current therapeutic options for this population are unproven (maintenance 
of biological anti-inflammatory therapy) or have limited efficacy with universal relapse 
requiring EBD or surgical options, which are also associated to high morbidity and mortality 
rates [R20-2235, R20-2236, P20-06254, P20-06255] (see Appendix 10.4).
These measures are expected to increase the chances to demonstrate clinical efficacy while 
ensuring all patients will receive best available SOC.
3.2.2
Rationale for an Add-On Therapy and Placebo-controlled Trial
Intensified anti-inflammatory treatment may alleviate acute obstructive symptoms of stenosis 
with a predominantly inflammatory component [P19-05294, R20-2037, P20-05765] whereas, 
predominantly fibrotic stenoses are less responsive to available anti-inflammatory treatment 
[R20-2751] and therefore, the latter are currently treated by endoscopic balloon dilation, 
strictureplasty or segmental small bowel resection. However, there is at this time no imaging 
technology available to reliably distinguish between fibrotic- and inflammatory-dominant 
stenoses [R20-2233]. Moreover, there are no therapeutic agents available specifically 
targeting intestinal fibrosis. Thus, current SOC includes optimization of anti-inflammatory 
treatment, which is maintained in responders until patient relapses [R20-2037, P20-05766].
Spesolimab is an antibody that blocks the IL36R in humans. In vivo studies in IL36R 
knockout mice have shown reduced emergence of intestinal fibrosis resulting from chronic 
inflammation, and also reversal of already established intestinal fibrosis in wild type animals 
after treatment with an IL36R antibody [R19-0857]. In humans, IL-36 has been shown to be a 
key driver in the cross-talk between macrophages and fibroblasts, a central pathway that leads 
to collagen VI production in the gut of IBD patients [R19-0857].
We therefore propose to add spesolimab due to its putative predominantly antifibrotic effects 
as an add-on therapy to optimized anti-inflammatory treatment to test its clinical efficacy to 
prevent relapses of symptomatic stenosis in patients with clinically significant stenotic CD 
who present with acute symptoms of bowel obstruction and have responded to intensified 
anti-inflammatory treatment. Combination treatment of 12 weeks with the same spesolimab 
dose regimen on top of anti-TNF inhibitors was found safe and well tolerated in a pilot study 
(N= 22) in mild to moderate UC (see Section 1.4.2). The combination of both, anti-
inflammatory and antifibrotic agents should have a synergistic effect and thus show improved 
efficacy over monotherapy.
The placebo comparator is required to demonstrate efficacy and safety of spesolimab, but the 
combination treatment design does not withhold the best active SOC treatment from any 
patient, and thus is ethically justified.
3.2.3
Rationale for a 48 week duration and for proposed endpoints
In absence of well-controlled prospective trials in this indication, there is sparse information 
on the actual rate of fibrostenotic progression and clinical relapses with SOC treatment in 
these patients. The largest published cohort study in a similar population treated with 


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adalimumab suggests that 50% of patients may relapse within 24 weeks [P20 05766]. 
However, in the mentioned cohort the relapse definition was based on clinical symptoms, 
using a non-validated score and without radiological confirmation.
The kinetics of symptomatic and structural responses of fibrotic stenoses is not understood at 
this time. While the inflammatory component of CD related stenoses may improve quite 
rapidly, as suggested by clinical response to corticosteroids within days, fibrosis regression 
may take months or longer, as suggested by fibrotic diseases in other organs [R11-4827, P16-
11034].
Cross-sectional imaging is the most sensitive and specific way to quantitatively describe and 
monitor intestinal stenosis [R20-2233]. Emerging data from the 
 group 
using MRE indicate that imaging detection of structural changes in stenosis substantially lags 
behind the improvement of symptoms. Moreover, available data in fibrostenotic CD patients 
suggest that substantial numbers of symptomatic relapses accumulate over 6-12 months on 
anti-TNF treatment [P20-05766].
Therefore, a treatment period of 48 weeks is assumed to show the best discrimination 
between active and placebo treatment.
We propose to assess the effect of spesolimab treatment on CD-related stenosis by means of 
two primary endpoints assessing symptomatic and radiographic stenosis response.
The proposed endpoints have been developed in collaboration with the 
 and 
relevant experts in the IBD field.
The Symptomatic Stenosis Response and Relapse outcomes proposed (see Table 2.3: 1) are a 
composite of the reporting frequency of abdominal pain after eating and the grade of 
limitation of food amount and food type. Proposal is based on non-published data generated 
by 
 during the development of a new patient reported outcome 
questionnaire (S-PRO) in patients with CD-related symptomatic small bowel stenosis similar 
to our targeted population (for more details see Section 5.1.2). Abdominal pain is the most 
frequently reported symptom in this population, who also report limitation of types and 
amount of food intake as an adaptive mechanism to avoid symptoms. Those items are seen as 
the most specific and proximal to stenosis.
The Radiographic Stenosis Response and definition (see Table 2.3: 1) proposed are based on 
the CONSTRICT group recommendations and further supported by non-published data 
generated by 
 from a retrospective cohort analysis of 100 fibrostenotic CD 
patients who had MRE imaging at baseline and at 6 months follow-up while on standard 
biological anti-inflammatory therapy. Thus, stricture length and the maximal diameter of the 
proximal small bowel dilation as assessed by MRE show the highest reliability scores and 
sensitivity to change and were thus selected as the key imaging indicators for objective 
efficacy assessment in the present clinical trial. Fistulas developing in pre-stenotic small 
bowel have also been included in the definitions since these develop as the consequence of 
increased stenosis pressure.


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3.3
SELECTION OF TRIAL POPULATION
A total of 100 patients will be randomized in a multicentre setting (at least 100 sites). A 
sufficient number of patients will be screened to meet this randomization target.
Screening of patients for this trial is competitive. Investigators will be notified about 
screening completion and will then not be allowed to screen additional patients for this trial. 
Patients already in screening at this time will be allowed to continue to randomization if 
eligible.
Participation of Woman of childbearing potential (WOCBP): Please refer to Section 4.2.2.3
for acceptable methods of birth control.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
If retrospectively it is found that a patient has been randomized in error (= did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 
contacted immediately. Based on an individual benefit-risk assessment a decision will be 
made whether continued trial participation is possible or not.
3.3.1
Main diagnosis for trial entry
Patients with symptomatic bowel obstruction due to fibrostenotic CD with a maximum of 2 
terminal ileum stenoses (diagnosed by one of the following: IUS, CT, MR, CTE or MRE) and 
who have indication of biological anti-inflammatory therapy will be enrolled into the Lead-in 
Period of the trial. Patients requiring immediate endoscopic or surgical intervention to treat 
bowel obstruction will not be randomized into this trial.
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
At Screening:
1. Established diagnosis of clinical Crohn’s Disease prior to screening by guideline 
supported criteria (e.g. clinical and endoscopic evidence, supported by a histopathology 
report)
2. Suspicion of symptomatic small bowel stenosis
3. Presence at screening visit (or at least 7 days before) of abdominal pain after eating 
(often, every time, not eat because of my Crohn’s symptoms) or limitation in amount or 
types of food (moderately or very limited), assessed by investigator with patient by 
means of the two items used to define the Symptomatic Stenosis Response and Relapse 
(see Section 2.3)
4. 1 or 2 naïve or anastomotic stenoses in the terminal ileum (as per IUS, CT, CTE, 
MR, or MRE imaging), with at least one being in reach of ileocolonoscopy (i.e. a 


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portion of the stenosis is located within 15 cm of the ileocecal valve or ileocecal 
anastomosis) defined by CONSTRICT criteria [R20-3947]:

localized luminal narrowing (luminal diameter reduction by ≥50% relative to normal 
adjacent bowel loop)
AND

bowel wall thickening (≥25% increase relative to adjacent non affected bowel)
AND

either:
o
prestenotic dilation (luminal diameter greater than 3 cm)
OR
o
inability to pass an adult or pediatric colonoscope through the narrowed area 
(not older than 2 weeks) and unequivocal proximal small bowel dilation (but 
may be less than 3 cm)
5. 18 to 75 years of legal age (according to local legislation) at date of signing informed 
consent
6. Male or female patients. Women of childbearing potential (WOCBP)1 must be ready 
and able 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 the patient information 
(and will be described in Section 4.2.2.3 of the CTP)
7. Signed and dated written informed consent, in accordance with Good Clinical Practice 
(GCP) and local legislation prior to admission into the trial
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
At Randomization
8. Have achieved a Symptomatic Stenosis Response (average scores <2 for questions on 
abdominal pain after eating AND on limitation in amount or types of food during the 7 
days after optimized biological anti-inflammatory therapy prior to randomization (see 
Flow Chart 2).
9. MRE confirmation of 1 or 2 naïve or anastomotic stenoses in the terminal ileum, 
with at least one being in reach of ileocolonoscopy (i.e. a portion of the stenosis is 
located within 15 cm of the ileocecal valve or ileocecal anastomosis) defined by 
CONSTRICT criteria [R20-3947]:

localized luminal narrowing (luminal diameter reduction by ≥50% relative to normal 
adjacent bowel loop)
AND

bowel wall thickening (≥25% increase relative to adjacent non affected bowel)
AND

either:
o
prestenotic dilation (luminal diameter greater than 3 cm)
OR


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o
inability to pass an adult or pediatric colonoscope through the narrowed area 
(not older than 2 weeks) and unequivocal proximal small bowel dilation (but 
may be less than 3 cm)
10. Absent, mild or moderate endoscopic activity defined by Colonic Simple Endoscopic 
Score in Crohn’s Disease (SES-CD) ≤12
3.3.3
Exclusion criteria
Gastrointestinal Exclusion Criteria
1. No stenosis is in reach of ileocolonoscopy
2. Systemic corticosteroids treatment of current obstructive symptoms for >1 week prior to 
screening
3. Endoscopic balloon dilation or surgical treatment of the same small bowel stenosis 
within the last 6 months prior to screening Visit 1
4. More than 2 small intestinal stenoses (where 2 stenoses within 3 cm are considered the 
same stenosis, a long segment with multiple areas of narrowing or multiple stenosis, 
that have inflammation between them is counted as 1 stenosis)
5. Patients who require immediate endoscopic balloon dilation or surgical intervention as 
per the investigator´s discretion
6. Failure of >2 different biological drug classes (mechanisms of action) prior to screening 
(e.g. TNF inhibitors, Integrin Receptor antagonists, and IL-12 / IL-23 antagonists)
7. Patients who must or wish to continue the intake of restricted medications (see Section
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
8. Current complications of Crohn’s Disease such as enterocutaneous, internal or 
rectovaginal fistules, short gut syndrome, abscess, or any other manifestation that might 
require surgery or would possibly confound the evaluation of benefit from treatment 
with spesolimab at screening Visit 1 and randomization (Day 1)
9. Current stenosis in the colon (CONSTRICT criteria apply [R20-3947])
10. Previous strictureplasty on current stricture
11. Current ileostomy or colostomy
12. Any kind of bowel resection or diversion within 6 months of screening Visit 1
13. Any other intra-abdominal surgery (except for abscess drainage) within 3 months prior 
to screening Visit 1
14. Positive stool examinations for clostridium difficile or other intestinal pathogens 
<30 days prior to screening
15. Fecal transplant ≤6 months before screening
Infectious Disease Exclusion Criteria
16. Relevant chronic or acute infections including human immunodeficiency virus (HIV) 
and viral hepatitis
17. Active or latent tuberculosis:

Patients with a positive QuantiFERON®-TB test at screening are excluded, unless:


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
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 with suspected false positive or indeterminate QuantiFERON®-TB result may be 
re-tested once

If QuantiFERON®-TB test not available or providing indeterminate results after repeat 
testing: A tuberculin skin test reaction ≥10mm (≥5mm if receiving ≥15mg/d prednisone 
or its equivalent)
General Exclusion Criteria
18. Contraindication to MRE or inability to undergo MRE (e.g. implanted medical devices 
that are contraindicated for MRI and cannot be removed (e.g. cardiac pacemaker, 
neurostimulation systems)), allergy to i.v. gadolinium based contrast agents, acute or 
chronic renal failure that precludes contrast administration (GFR <30 mL/min), severe 
claustrophobia)
19. Pathological safety laboratory parameters: hemoglobin <8 g/dL (<80 g/L), total white 
blood count (WBC) <3000 cells/µl (<3x109/L), neutrophils <1000 cells/µl (<1x109/L), 
thrombocytes <100.000/µl (<100x109/L), creatinine ≥2 mg/dL (≥176.80 µmol/L), total 
bilirubin >2 x ULN with ratio of direct / indirect >1 (patients with Gilbert’s syndrome 
are not excluded), Alkaline Phosphatase >3 x ULN
20. 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, 
squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix. This 
includes colorectal cancer (CRC) present and past (<5 years) history
21. Major surgery (major according to the investigator’s assessment, e.g. hip replacement) 
performed within 12 weeks prior to screening or planned until End of Treatment Visit
22. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other 
condition that, in the investigator’s opinion, makes the patient an unreliable trial
participant)
23. Previous enrolment in this trial
24. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s) at screening Visit 1, or 
receiving other investigational treatment(s)
25. History of allergy / hypersensitivity to the systemically administered trial medication 
agent or its excipients
26. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
3.3.4
Discontinuation of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications (see Sections 3.3.4.1 and 3.3.4.2).
If the patients agree, they should stay in the trial: even if continued trial treatment is not 
possible, they should attend further trial visits to ensure their safety and to collect important 
trial data.


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Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and Case Report Form (CRF). If applicable, 
consider the requirements for AE collection reporting (see Section 5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
Ideally, the patient should attend all remaining visits. Should this not be feasible or should the 
patient not agree, direct patient contacts in accordance with local regulation should occur at 
the scheduled visit time points.
If all of the above is not possible, at least an End of Study (EoS) visit should be done (e.g. by
phone contact or by other means in accordance with local regulations) to collect the most 
relevant information: safety, outcome events or last contact date in case of lost to follow-up.
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment. The patient will be asked to explain the 
reasons but has the right to refuse to answer

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, the safety of the 
patient cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future

The patient needs to take concomitant medication that interferes with the safety of the 
Investigational Medicinal Product (IMP) or other trial treatment

A hepatic injury alert (as defined in Section 5.2.6.1.4) is detected without identification of 
an alternative cause in the work-up according to the “DILI checklist”, the patient should 
not receive subsequent doses of trial treatment. Trial treatment can be restarted if:

Alternative cause is identified AND

Patient has recovered according to investigator assessment AND

After consultation with the sponsor

The patient needs to undergo endoscopic balloon dilation or surgical intervention to treat 
the CD stenosisFor individual stopping rules related to specific adverse events, see 
Section 4.2.1If a patient experiences a moderate or severe opportunistic infection, or if a 
patient experiences any infection that meets serious adverse event (SAE) reporting 
criteria, the patient should be permanently discontinued from study drug

The patient can no longer receive trial treatment for medical reasons such as surgery (see 
Section 5.2.6.1.4), other adverse events, other diseases, or pregnancy
In case of a temporary reason, trial treatment should be restarted with the next scheduled visit 
if medically justified, please see Section 4.1.4.
If new efficacy / safety information becomes available, BI will review the benefit-risk-
assessment and, if needed, pause or discontinue the trial treatment for all patients or take any 
other appropriate action to guarantee the safety of the trial patients.


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Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site

New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.4.1

Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further treatment and follow-up of patients affected will occur as described in 
Section 3.3.4.1.
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
The IMP has been manufactured by BI Pharma GmbH & Co. KG. The spesolimab molecule 
is an anti-human IL-36 receptor monoclonal antibody heterodimer with a molecular weight of 
approximately 146 kDa.
4.1.1
Identity of the Investigational Medicinal Products
The investigational product (test product and matching placebo) is provided in vials of 5 mL.
Table 4.1.1: 1
Test product BI 655130 i.v.
Substance:
BI 655130, spesolimab
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
60 mg/mL
Posology:
1200 mg every 4 weeks (q4w) until Week 8
then 1200 mg every 8 weeks (q8w) until Week 40
(last trial drug administration)
Mode of administration:
Intravenous (i.v.) infusion
Table 4.1.1: 2
Test product Placebo matching BI 655130 i.v.
Substance:
Placebo matching BI 655130, spesolimab
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
Not applicable
Posology:
Placebo every 4 weeks (q4w) until Week 8
then Placebo every 8 weeks (q8w) until Week 40
(last trial drug administration)
Mode of administration:
Intravenous (i.v.) infusion
4.1.2
Selection of doses in the trial and dose modifications
The exposure in CD patients expected for the proposed dose regimen of 1200 mg i.v. q4w is 
lower than the highest exposure tested in healthy subjects in trial 1368.2, which was safe and 
well-tolerated (refer to current IB [c03320877]). Moreover, this regimen has been tested and 
found safe for 12–24 weeks in 85 patients with UC; and is currently being evaluated in an 


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exploratory study in up to 10 patients with perianal fistulizing CD. No dose dependent or 
dose limiting safety signal has been detected so far.
Based on other effective anti-cytokine drugs in IBD and pre-clinical assays for IL-36 
inhibition, a monotonic rather than a bell-shaped dose-response curve is expected.
Therefore the highest tested and tolerated dose regimen should provide the highest likelihood 
to detect a positive effect. Whether lower doses might be sufficient to achieve maximum 
benefit / risk ratio in this particular population will be subject of subsequent studies.
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomized 
to treatment groups according to a randomization plan in a 1:1 ratio at Visit 3 via Interactive 
Response Technology (IRT). The randomization will be stratified according to the number of 
previously failed biologic classes (0-1 vs >1) and stenosis length (≤5 cm vs >5 cm).
Note that the medication number is different from the patient number (the latter is generated 
during screening via the IRT System). Each vial will have an individual medication number 
for dispensation.
4.1.4
Drug assignment and administration of doses for each patient
Detailed instructions for the preparation of the solution for infusion, the volume to be 
administered and the infusion rate (BI 655130 i.v.) are provided in the ISF.
The administration of the trial medication on all applicable study days will be done under 
supervision of the investigator or a designee at the site. For the monitoring of hypersensitivity 
reactions, please refer to Section 5.2.2. If available, a pharmacist should prepare the trial 
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.
During the COVID-19 pandemic, physical visits to the sites may need to be restricted to 
ensure patient safety. Based on a thorough assessment of the benefits and risks, the 
investigator may discuss with BI to continue the trial treatment and trial medication may be 
shipped to the patient’s home if acceptable according to local law and regulations.
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 
 medical judgment he / she
will provide medications such as steroids, etc. as needed (see Section 4.2.1 for handling of 
infusion reactions). Detailed instructions for handling of infusion reactions are also provided 
in the ISF.
Dose modifications or adjustments are not permitted. In exceptional cases of missed or 
delayed visits, study drug of the following visit should not be administered within 14 days of 
the prior dose. There should be at least 14 days between two consecutive study drug 
administrations.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators, and central reviewers will remain blinded with regard to the 
randomized treatment assignments until after the Database Lock (DBL) for the final trial 
analysis.
An interim analysis is planned to be performed when all patients have completed Week 24
and the treatment information will be partially unblinded to selected members of the sponsor 
project team. In order to confirm the integrity of the treatment blind, a logistics plan will be 
set up to ensure that besides patients and investigators, relevant sponsor trial team members 
who are directly involved in the trial conduct remain blinded. The logistics plan will be 
finalized prior to the treatment unblind for the interim analysis.
An independent DMC will perform an unblinded safety and efficacy assessment at specified 
intervals in order to ensure that patients are protected from potential harm, please refer to 
Section 8.7 for further details.
The access to the randomization code will be kept restricted until its release for analysis.
The randomization codes will be provided to bioanalytics before the last patient completed 
the trial to exclude placebo samples from the PK analysis. Bioanalytics will not disclose the 
randomization code or the results of their measurements until the DBL.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator 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.
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 randomization code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance (PV) representatives for processing 
in the PV database system and not be shared further.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated Contract 
Research Organisation (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.


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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 Clinical Research 
Associate (CRA) (as provided in the contact list of the ISF) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor 
when the following requirements are fulfilled:

Approval of the CTP by the Institutional Review Board (IRB) / Ethics Committee (EC),

Availability of a signed and dated clinical trial contract between the sponsor or delegate 
and the investigational site,

Approval / Notification of the Regulatory Authority (RA), e.g. Competent Authority 
(CA),

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated CTP,

Availability of the proof of a medical license for the Principal Investigator (if applicable),

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 or designee 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 medicinal product and trial 
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the CTP and reconcile all investigational 
medicinal products received from the sponsor. At the time of return to the sponsor and / or 
appointed CRO, the investigator or designee must verify that no remaining supplies (unsused 
or partcially used) are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.


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4.2.1.1
Lead-in anti-inflammatory treatment
CORTICOSTEROIDS

Methylprednisolone 40 mg/d i.v. or 40 mg/d of oral prednisolone (or the equivalent dose 
of any systemic steroid formulation. Budesonide is not allowed)

Patients receiving i.v. steroids should be switched to oral prednisolone when clinically 
justified, to complete 2 weeks of steroid treatment followed by a defined tapering regime

Tapering Regime: Decrease by 5 mg/1wk until 10 mg and then decrease by 2.5 mg/1wk 
until 0 mg
OPTIMIZATION OF ANTI-INFLAMMATORY BIOLOGICAL TREATMENT
Anti-inflammatory biological treatment shall be individually optimized dependent on the 
prior (failed) treatment of each patient by introducing approved doses of TNF inhibitors 
(TNFi), vedolizumab, or ustekinumab following the algorithm below, optimization period of 
8 weeks starts with the dose adaptation or treatment change as described and is restricted to
locally approved dosing regimens of proposed agents:
If patient is anti-TNF naïve:
→ start anti-TNF
If patient is on first anti-TNF

if plasma drug levels are below the therapeutic range and ADA negative
→ increase dose or shorten interval as locally approved for treatment of moderate-to-
severe CD. If not applicable switch to second anti-TNF or switch to ustekinumab or 
vedolizumab

if plasma drug levels are in the therapeutic range and ADA positive
→switch to second anti-TNF or switch to ustekinumab

if plasma drug levels are in the therapeutic range and ADA negative
→ switch to ustekinumab
If patient is on second anti-TNF (and has failed ≤1 anti-TNF prior)

if plasma drug levels are below the therapeutic range and ADA negative
→ increase dose or shorten interval as locally approved for treatment of moderate-to-
severe CD. If not applicable switch to ustekinumab or vedolizumab

if plasma drug levels in the therapeutic range or ADA positive 
→ switch to ustekinumab
If patient has failed ≥ 2 anti-TNF and is on vedolizumab
→ switch to ustekinumab
If patient has failed ≥ 2 anti-TNF and is on ustekinumab
→ switch to vedolizumab


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4.2.1.2
Optimized anti-inflammatory treatment during the Blinded Randomized 
Treatment Period
After achievement of Symptomatic Stenosis Response patients need to maintain their 
optimized anti-inflammatory treatment initiated during the Lead-in Period after 
randomization and throughout the Blinded Randomized Treatment Period.
4.2.1.3
Concomitant Medication
All concomitant medications and the reason(s) for use will be documented throughout the 
course of the study. Concomitant therapies for other conditions, e.g. hypertension, diabetes, 
are allowed.
Allowed for CD treatment
Lead-in Period
The following CD therapies are allowed to be initiated or continued with dose optimization 
(as defined per protocol, see Section 4.2.1.1) during the Lead-in Period for anti-inflammatory 
biological treatment optimization. For the categorization of AxMPs, please refer to 
Section 1.2:

TNF inhibitors, as locally approved for treatment of moderate-to-severe CD (infliximab, 
adalimumab, and certolizumab)

Integrin Receptor antagonists as locally approved for treatment of moderate-to-severe CD

Interleukin-12 and -23 antagonists as locally approved for treatment of moderate-to-
severe CD (i.e. ustekinumab)

Azathioprine, 6-mercaptopurin or methotrexate (are allowed in combination with TNF 
inhibitors) but need to be discontinued at least 14 days prior to the randomization with 
first trial drug administration

Systemic Corticosteroids (p.o. or i.v.) (only during the Lead-in Period as defined per 
protocol, see Section 4.2.1.1)
After Randomization
In addition to the above mentioned medications, following CD therapies are allowed to be 
continued without dose modifications:

Oral 5-ASA, stable dose for 4 weeks prior to randomization and throughout the study

Probiotics (e.g. Saccharomyces boulardii), stable dose for 2 weeks prior to randomization 
and throughout the study
After randomization and prior to Week 16, only 1 dose increase (strength and / or interval) of 
optimized biological anti-inflammatory medication is allowed as locally approved for 
treatment of moderate-to-severe CD for that agent. No switch to a different agent is allowed.


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If the patient needs further optimization and no dose increase is possible for that agent as per 
local label, patient can switch to a different agent. This will be considered rescue therapy as 
described below.
Any dose increase after Week 16 post-randomization, or de-novo initiation (switch) of any 
medication approved to treat moderate-to-severe CD throughout all the study period will be 
considered a rescue treatment. Such patients will be considered as treatment failures in the 
primary efficacy analysis. However, the patient may continue the study as per CTP. This 
includes the visit schedule and trial drug administration.
Antidiarrheals for control of chronic diarrhea (e.g. loperamide, diphenoxylate with atropine) 
are allowed at any time during this clinical trial.
4.2.1.4
Management of Adverse Events
Systemic hypersensitivity including infusion reaction and anaphylactic reaction
In case of systemic hypersensitivity including infusion reaction and anaphylactic reaction 
emerging during or after infusion of trial medication, the investigator should consider in 
accordance with severity of the reaction and local SOC to

Immediately interrupt the infusion

Treat with systemic anti-histamines, i.v. steroids, and in case of a severe allergic 
reaction (eg, anaphylactic reaction) epinephrine
Also draw a plasma sample for Immunglobulin (Ig) E and ADA as detailed in the Laboratory 
Manual (filed in the ISF). Also initiate the evaluation of histamine, serum tryptase, and 
complement components.
In case of infusion reaction / systemic hypersensitivity, based on patient’s clinical course and 
medical judgment, the infusion may be re-initiated in case of mild or moderate infusion 
reactions / systemic hypersensitivity (according to RCTC grading in Section 5 of the ISF) at 
lower speed with gradual increase to complete the infusion as detailed in the Instructions for 
Preparation and Handling of spesolimab / Placebo in the ISF. In any case, the total duration 
of infusion should not exceed 90 minutes (1.5 hours) provided that the maximum time 
between the start of preparation and completion of administration of the solution to the 
patient does not exceed 8 hours.
In case of anaphylactic reactions based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.3, [R11-4890]) suspected to be caused by the trial medication, 
the investigator should permanently discontinue treatment with the trial medication.
When a delayed hypersensitivity reaction is suspected, please draw a blood sample for 
laboratory assessment and evaluate for signs of extra-cutaneous organ involvement. The 
decision to discontinue treatment and/or restart treatment after resolution of the reaction 
should be based on reaction type and severity.


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Severe infections (according to RCTC grading in Section 5 of the ISF), mild opportunistic or 
mycobacterium tuberculosis infections
Treatment of the infection should be initiated promptly according to local SOC. No further 
trial medication should be administered until the active infection has resolved. Treatment 
with trial medication 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 trial medication. Diagnostics and treatment 
have to be initiated according to local SOC.
Severe hematological laboratory abnormalities (according to RCTC grading in Section 5 of 
the ISF)
No further trial medication should be administered in case of hematological laboratory 
abnormalities (leucopenia, neutropenia, lymphopenia, low platelets count, hemoglobin
decrease) of Grade 3 or higher. Treatment with trial medication may be restarted when 
hematological laboratory abnormalities decrease below the level of Grade 3, patient has 
recovered based on investigator’s assessment and after consultation with the sponsor.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Restrictions regarding previous and concomitant treatment are summarized in 
Table 4.2.2.1: 1.


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Table 4.2.2.1: 1
Prohibited and restricted medications
Medications or class of medications
Restriction duration
Investigational products
Prohibited from 30 days or 5 half-lives
(whichever is longer) prior to screening 
(Visit 1) and during the study.
Wash-out of 30 days not needed if 
confirmed undetectable plasma 
concentration.
Biologic therapies aside from those used 
for the treatment of Crohn’s disease
Prohibited during the study.
Any non-biologic medication (incl. 
cyclosporine, JAK inhibitors, S1P 
modulators, SMAD7 antisense inhibitors.
Not allowed from 30 days or 5 half-lives
(whichever is longer) prior to screening 
and during the study.
Wash-out of 30 days not needed if 
confirmed undetectable plasma 
concentration.
Azathioprine, 6-mercaptopurin or 
methotrexate (when given in combination 
with biologics)
Not allowed at least 14 days prior to
randomization and during the study
Oral 5-ASA
Oral administration:
Only allowed during the trial, if dose is 
stable for at least 4 weeks prior to 
randomization and during the study.
Probiotics (e.g. Saccharomyces boulardii)
Only allowed during the trial, if dose is 
stable for at least 2 weeks prior to 
randomization and during the study.


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Table 4.2.2.1: 1
Prohibited and restricted medications (cont.)
Medications or class of medications
Restriction duration
Corticosteroids 
Oral administration:
i.v. and oral steroids are allowed per CTP 
during the Lead-in Period, refer to dosing 
and tapering schedule (Section 4.2.1).
Rectal administration:
Not allowed from 2 weeks prior to 
screening up to end of the trial.
Allowed steroid treatments:
Short-term use (<7 days) of systemic (oral 
or parenteral) corticosteroids for treatment 
of AE not related to the underlying CD, 
including treatment of infusion or 
anaphylactic reactions, are permitted 
throughout the study, both during the 
Lead-in Period and after randomization.
Locally administered steroids as e.g. 
intra-articular, nasal inhalation or intra-
ocular administration are allowed.
NSAID
(Non-steroidal anti-inflammatory drugs)
Chronic use: Prohibited
(Note: occasional use of NSAIDs and
acetaminophen for headache, arthritis, 
myalgias, menstrual cramps, etc. and 
daily use of baby or low-dose [81-162.5 
mg] aspirin for cardiovascular 
prophylaxis are permitted).
Live vaccines
Prohibited from 6 weeks prior to 
screening (Visit 1) and during the study.


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4.2.2.2
Restrictions on diet and life style
On days with MRE, trial participants should have nothing by mouth 4 hours prior to this 
procedure.
On days with endoscopy, trial participants need to clean out the colon (colon preparation) by 
drinking a special solution for this procedure on the evening before.
4.2.2.3
Contraception requirements
WOCBP (for the definition please refer to Section 3.3.2) must use a highly effective method 
of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year 
when used consistently and correctly during the trial, and for a period of at least 16 weeks 
after the last study drug administration. Additional double barrier method of contraception is 
not required. A list of contraception methods meeting these criteria is also provided in the 
patient information.
Female Patients:
Acceptable methods of birth control for this trial are:

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal)

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)

Intrauterine device (IUD) or intrauterine hormone-releasing system

Bilateral tubal occlusion

Vasectomised sexual partner with documented absence of sperm
OR
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods, declaration of abstinence for the duration of 
exposure to study drug, and withdrawal are not acceptable.
Male Patients:
Contraception of male trial participants and female partners of male trial participants are not 
required.
4.3
TREATMENT COMPLIANCE
Trial medication will be administered in accordance with the protocol under the supervision 
of the investigator or a designee. The measured plasma concentrations will provide additional 
confirmation of compliance.
Any missed dose has to be documented and reported to the Clinical Trial Manager (CT
Manager).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Efficacy will be assessed both on investigator (or designee) examinations and assessments 
and on Patient Reported Outcomes (PROs).
The MRE examination will be centrally reviewed to evaluate the Radiographic Stenosis 
Response.
The endoscopy (ileocolonoscopy) examination provides information on the inflammation 
status of the terminal ileum and colon. Endoscopy examinations will be centrally reviewed 
and assessed based on the SES-CD. Mucosal biopsies obtained from the terminal ileum and 
colon will serve the histopathology examination and exploration of disease and IL-36 
pathway specific biomarkers.
Clinician’s assessment of CDAI, and the clinician’s reported outcomes (clinROs) CGI-C and 
CGI-S scales assess the status of both the inflammatory and stenotic portion of the 
fibrostenotic CD condition.
PROs include the newly developed S-PRO, as well as IBDQ, SF-36, and the PGI-S scales, 
and the diary portion of the CDAI.
5.1.1
Magnetic Resonance Enterography (MRE)
MRE is performed as indicated in the Flow Chart according to specifications detailed in the 
Central Imaging Vendor Manual (including documents describing image acquisition and 
image review) filed in the ISF. All scans on each patient are performed on scanners that were 
accredited for use by the Central Imaging Vendor. To achieve optimal image quality, patients 
should be nothing by mouth 4 hours prior the procedure. Additionally, MRE is conducted 
after oral ingestion of neutral enteric contrast medium and a spasmolytic agent is given 
immediately before the examination. During the MRE scan, an intravenous contrast medium 
is administered via a single dose. The detailed patient preparation procedure is outlined in the 
Central Imaging Vendor Manual.
Before undergoing MRE examinations, all patients must be checked for the GFR and meet 
the criterion of GFR ≥30 mL/min at screening Visit 2. Additionally, GFR values must be 
obtained before every MRE examination and must not be older than 14 days. Ideally these 
GFR assessments are done locally but can also be performed via central laboratory (reporting 
timelines are to be considered). Before beginning the MRE assessments, the scanning 
procedure should be explained carefully to the patient.
MRE is performed at timepoints given in the Flow Chart, and should be acquired at the 
discretion of the investigators at unscheduled visits in case of a Symptomatic Stenosis 
Relapse. If an unscheduled visit with MRE acquisition occurred within 4 weeks prior to the 
scheduled MRE visit depicted in the Flow Chart, the MRE must not be repeated at the 
planned scheduled visit. In case an MRE, both scheduled and unscheduled, was not 
performed according to the specifications detailed in the Central Imaging Vendor Manual, it 
needs to be repeated within 14 days after the visit.
All MRE scans are digitally transferred for central review within a pre-specified time period 
and the central review is conducted as outlined in the Central Imaging Vendor Manual. The 
evaluation of cross-sectional MRE data focuses on the morphological fibrostenotic 


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characteristics stricture length, pre-stenotic dilation of the bowel lumen and the manifestation 
of pre-stenotic fistulae. MRE images will be stored up to 15 years at the sponsor facilities or 
by an external vendor for future scientific research.
Additionally, non-patient MRE images have to be provided regularly for quality assurance 
purposes according to the Central Imaging Vendor Manual. Further information on MRE is 
provided in a separate manual filed in the ISF.
5.1.2
Stenosis Patient Reported Outcome (S-PRO) Tool
The 
, a leading group of 
experts and institutions in this field, have set out to specifically develop new tools to measure 
clinical and structural (radiological and histological) outcomes in these patients. The Stenosis 
Patient Reported Outcome tool (S-PRO) is developed following FDA guidance in 
collaboration with national and international IBD societies to capture symptoms related 
specifically to stenotic complication in CD patients. The S-PRO questionnaire (Stricturing 
Crohn’s Disease Questionnaire) provides the data for the study outcomes such as 
Symptomatic Stenosis Response and Symptomatic Stenosis Relapse.
The S-PRO is set up as an eDiary and has a recall period of 24 hours. The S-PRO will be 
measured as indicated in the Flow Chart: Daily during the Lead-in Period and daily for 7 days 
preceding the scheduled site visits during the Randomized Blinded Treatment Period.
Additionally, patients will be asked to contact the site at any time they feel a worsening of 
CD symptoms. An unscheduled visit will then be arranged and the patient will be asked to 
immediately start the S-PRO completion, daily, for (at least) 7 days before the unscheduled 
visit. The S-PRO is provided in Appendix 10.1.1.
A 7-day average score will be calculated; scoring method will be described in the Trial 
Statistical Analysis Plan (TSAP).
5.1.3
Ileocolonoscopy with Simple Endoscopic Score for Crohn’s Disease (SES-
CD)
The endoscopic CD activity will be assessed using the SES-CD score. The SES-CD is a 
numerical grading system generating a total score (0-56) composed of 4 variables (presence 
of ulcers, ulcerated surface, affected surface, and presence of narrowings), all of which are 
recorded in 5 segments: terminal ileum, right colon, transverse colon, left colon, and rectum 
[R16-0177].
The SES-CD will be measured at the timepoints noted in the Flow Chart. The SES-CD is 
provided in Appendix 10.1.2. Ileocolonoscopy videos will be done as described in the 
Endoscopy Video Instruction Manual filed in the ISF and digitally transferred for central 
review within a pre-specified time period and the central review is conducted as outlined in 
the Central Imaging Vendor Manual.
5.1.4
Crohn’s Disease Activity Index (CDAI)
The clinical changes in luminal CD activity during the trial will be assessed using the 
Crohn’s Disease Activity Index (CDAI) [R15-5253]. The patient will have to complete the 
CDAI symptom score data in an eDiary daily for 7 days before a visit (scheduled and 
unscheduled).


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The CDAI will be calculated at the timepoints noted in the Flow Chart. The activity score for 
Crohn’s Disease to calculate the CDAI is provided in Appendix 10.1.3.
5.1.5
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)
Each question has graded response choices numbered from 1 to 7. Scores range from 32 to 
224 with higher scores indicating better outcomes.
The IBDQ will be measured at the timepoints noted in the Flow Chart. The IBDQ has a 
2-week recall period and is provided in Appendix 10.1.4.
5.1.6
SF-36
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.
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 3 point difference is 
recommended as an minimal clinically important difference threshold for between-groups 
comparisons of the PCS and MCS [R16-0033].
SF-36 will be measured at the timepoints noted in the Flow Chart. The acute version of the 
SF-36 with a 1-week recall period will be used and is provided in Appendix 10.1.5.
5.1.7
Patient’s Global Impression of Severity (PGI-S)
The PRO PGI-S scale has been developed for mental conditions, but has been used in several 
conditions. 
There are four PGI-S versions measuring: post-prandial abdominal pain, dietary restriction, 
stenosis symptoms overall and stenosis symptoms related impact in daily life. The PGI-S 
scales will be measured at the timepoints noted in the Flow Chart. The PGI-S scales are 
provided in Appendix 10.1.6.


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5.1.8
Clinician’s Global Impression of Change (CGI-C) and Clinician’s Global 
Impression of Severity (CGI-S)
The clinician’s reported outcomes (clinROs) CGI-C and CGI-S have been developed for 
mental conditions, but have been used in several conditions [R19-1932]. Ideally, clinROs 
should be assessed always by the same physician.
The CGI-C is usually rated from trial medication start, in this trial the investigator is asked to 
recall the period since the patient started this study.
Those CGI versions focus on stenosis symptoms overall.
The CGI-C and CGI-S scales will be measured at the timepoints noted in the Flow Chart. The 
CGI-C and CGI-S scales are provided in Appendix 10.1.7.
5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:

Physical examination

Vital signs (blood pressure, pulse rate, body temperature, and respiratory rate)

Safety laboratory values (hematology, clinical chemistry, coagulation, and urinalysis)

12-lead Electrocardiogram (ECG)

Adverse events (AEs)

Adverse events of special interest (AESIs)

Serious adverse events (SAEs)

Intensity of AEs will be assessed by RCTC version 2.0 (refer to ISF for details, and see 
Appendix 10.4)

Immunogenicity (ADA/Nab)
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin.
Targeted physical examination will include evaluation of organ systems associated with 
AE(s) symptoms or laboratory abnormalities.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
Measurement of body weight will be performed at every visit, height at Visit 1 only.
The results must be included in the source documents available at the site.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart prior to blood 
sampling.
This includes body temperature, respiratory rate, systolic and diastolic blood pressure and 
pulse rate (electronically or by palpation count for 1 minute), and in a seated position after 


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approximately 5 minutes of rest. The results must be included in the source documents 
available at the site.
At dosing visits, vital sign evaluations will be performed pre-dose and additional evaluations
will be taken post-dose, i.e. approximately 10 minutes and approximately 60 minutes after 
stop of the infusion.
The investigator should evaluate the clinical significance of the results. Clinically abnormal 
findings will be reported as baseline condition or AEs.
Monitoring for hypersensitivity reactions:
Patients should be closely monitored for signs and symptoms of hypersensitivity reactions for 
approximately 2 hours after the first dose of trial drug administered at Day 1 (Visit 3) and 
1 hour following all other doses of trial drug. Hypersensitivity reactions should be treated 
according to medical standards. Pre-medications for further infusions 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 and 5.2.3: 2. For the 
sampling time points please see the Flow Chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory.
The safety laboratory samples relevant for Day 1 are to be taken when the patient comes for 
the baseline MRE examination (10 business days before Day 1) in order to have the 
laboratory report available at Day 1.
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).
In case the criteria for Potential Severe DILI 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). 
The amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the results of the analysis to the sponsor or delegate.


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Table 5.2.3: 1
Safety laboratory tests
Category
Test name
Hematology
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


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Table 5.2.3: 1
Safety laboratory tests (cont.)
Category
Test name
Substrates
Glucose
BUN (blood urea nitrogen)
Uric acid
Creatinine
eGFR (estimated by CKD-EPI formula) (only at screening 
Visit 2)
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)
Cholesterol, total
Triglycerides
LDL-Cholesterol
HDL-Cholesterol
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), with microscopic 
examination if urine analysis abnormal
Color & Clarity
Specific Gravity
pH
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Nitrite
Blood
Leukocyte Esterase
Urinalysis
Urine Creatinine 
Urine (only at screening)
Albumin (quantitative)
Infections Testing
HBV-DNA (quantitative) at EoT Visit2
QuantiFERON-TB test
QuantiFERON®-TB-Gold Plus at EoT Visit 3, 4
1Only in case of allergic reaction
2 HBV-DNA in case of occult HBV infection (for definition see Table 5.2.3: 2 footnote 2)
3 There is the trial site option to perform a TST (PPD skin test)
4 If the first QuantiFERON®-TB-Gold Plus test result is undetermined, a re-test should be performed. If the
QuantiFERON®-TB-Gold Plus re-test result is undetermined, a PPD skin test should be performed.


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Table 5.2.3: 2
Exclusionary laboratory tests
Category
Test name
Infection Testing
Hepatitis B Surface Antigen (qualitative)1
Hepatitis B core Antibody1
HBV-DNA (quantitative PCR)2
Hepatitis C Antibodies (qualitative)1
HIV-1, and HIV-2 Antibody (qualitative)1
TB Screening
QuantiFERON®-TB-Gold Plus3, 4
Serum Pregnancy test (only for female patients of 
childbearing potential) 1
Human Serum Chorionic Gonadotropin 
Stool studies to evaluate for enteric pathogens 1
Salmonella
Shigella
Yersinia
Campylobacter
E. coli
Clostridia difficile toxin
Enteric parasites and their ova (including Cryptosporidia)
1 At screening only (Visit 1)
2 A HBV-DNA test 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 TST (PPD skin test)
4 If the 1st QuantiFERON®-TB-Gold Plus test result is undetermined, a re-test should be performed. If the re-test 
QuantiFERON-TB-Gold Plus test result is undetermined, a PPD skin test should be performed.
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flow Chart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a 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.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and / or treated 
as medically appropriate.
5.2.5
Other safety parameters
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 (see Section 3.3.3). In case of an infusion reaction / systemic 
hypersensitivity, monitor the patient per SOC, grade the intensity of the reaction according to 
RCTC grading and proceed as described in Section 4.2.1.4.


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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditionsChanges in 
vital signs, ECG, physical examination and laboratory test results, if they are judged 
clinically relevant by the investigator
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the Electronic Case Report Form (eCRF) only.
5.2.6.1.2
Serious adverse event
A 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 prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly / birth defect,

is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse.
Planned hospitalizations which may be required for administrative reasons to make the 
conduct of visits feasible or which are indicated in the situation of acute of obstructive 
symptoms at the time of enrolment need not to be reported as SAEs.
Patients may be hospitalized for administrative reasons during the trial, including 
hospitalization for respite care. These as well as hospitalizations / surgical procedures which


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were planned before the patient signed informed consent need not be reported as SAEs if they 
have been documented at or before signing of the informed consent and have been performed 
as planned (the condition requiring hospitalization / surgical procedure has not changed /
worsened after signing the informed consent).
For Japan only: An event that possibly leads to disability will be handled as ‘deemed serious 
for any other reason’ and, therefore, reported as an SAE.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the Electronic Data Capture (eDC)
system. 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 in Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
Infusion reaction and anaphylactic reaction
Any suspicion of severe infusion reaction and of any potential cases of anaphylaxis should be 
defined and assessed using the criteria discussed in the statement paper from Sampson HA 
(Appendix 10.3, [R11-4890]).
Severe infections (according to RCTC grading in Appendix 10.4 and filed in the ISF)
Opportunistic and mycobacterium tuberculosis infections
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 mycobacterium, 


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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].
Potential Severe DILI
A potential severe DILI that requires follow-up is defined by the following alterations of
hepatic laboratory parameters:

An elevation of AST (Aspartate Aminotransferase) and / or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold 
ULN measured in the same blood sample, or in samples drawn within 30 days of each 
other
OR

ALT and / or AST elevations ≥10-fold ULN.
In addition patients will be discontinued from study treatment if any of the following are 
observed:

ALT or AST >8xULN

ALT or AST >5xULN for more than 2 weeks

ALT or AST >3xULN and (TBL >2xULN or INR >1.5)

ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Any ALT or AST value >3X ULN will be confirmed with a repeat test within 
48 to 72 hours along with obtaining ALP and total bilirubin. If the elevated AST/ALT 
value is confirmed, close monitoring and evaluation for alternative causes of elevation of 
transaminases should be undertaken [P09-12413].
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.
5.2.6.1.5
Intensity (severity) of AEs
The intensity grading of AEs should be performed according to the RCTC Version 2.0 
developed by 
 [R13-3515].
Refer to the ISF for intensity / severity classification.
Grade 1
mild


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Grade 2
moderate
Grade 3
severe
Grade 4 
life-threatening 
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, considering all relevant factors, including pattern of 
reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases and relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the trial 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 etiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the trial 
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

There is an 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
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.


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The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until the individual patient’s end of trial
(= the EoS Visit): 
all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only 
report any occurrence of cancer and trial drug related SAEs and trial drug 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.
In case of an extension trial, this does not apply for patients rolling over into the 
extension trial.
In case of extension trial, for patients, who roll-over:

From signing the informed consent (1368-0059) onwards until the first dose of extension 
trial medication: all AEs (non-serious and serious) and all AESIs. Updates to concomitant 
therapy should also be included until the first dose of extension trial medication.
5.2.6.2.2
AE reporting to the 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 to the sponsor’s unique entry point within 24 
hours of becoming aware of the event, the country specific process will be specified 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 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. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).


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As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and / or AESI, only the Pregnancy Monitoring Form for Clinical 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
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 BI 655130 project. Also, ADAs will be measured and their impact on PK will be 
assessed. Samples that are confirmed positive may be further characterized using a validated 
neutralizing antibody (Nab) assay. 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.
Please refer to the 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
5.3.2.1
Plasma sampling for PK analysis
For quantification of 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 Laboratory Manual in the ISF. After completion of the trial, the plasma samples may 
be used for further methodological investigations, e.g. for stability testing. 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.
5.3.2.2
Plasma / Serum sampling for ADA and Nab 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. For Nab assessment, blood 
will be taken from a forearm vein into a serum blood drawing tube at the time points listed in 
the Flow Chart. Refer to the Laboratory Manual in the ISF for further details.
The plasma / serum samples may be used for further methodological investigations, e.g. for 
stability testing. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years after the final study report has been signed.


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5.4
ASSESSMENT OF BIOMARKER(S)
Biomarkers associated with fibrostenotic CD and IL-36 pathway will be assessed in biopsies, 
peripheral blood and stool samples from patients both pre- and post-treatment with 
spesolimab.
Blood samples (serum), stool samples and biopsies will be collected at time points indicated
in the Flow Chart for the analysis of biomarkers.
All remaining samples will be discarded after completion of the additional investigations but 
not later than 5 years after the final study report has been signed.
The statistical analysis results of the biomarker analyses may be reported in the Clinical Trial 
Report (CTR) or in a separate biomarker report.
The biomarker assay analysis will be performed in a staged approach. The initial analysis will 
focus on selected markers and time points (i.e. baseline, Week 24 and Week 48) and 
depending on these results a decision will be made about further analysis of all samples. This 
is due to the exploratory nature of the mechanism being tested and the timing of effect on 
candidate biomarkers in the study.
5.4.1
Biochemical and cellular biomarkers
Serum samples will be collected to assess changes in protein levels of disease specific
IL-36 pathway specific biomarkers such as but not limited to Pro-C16 and C4M both pre and 
at various time points post treatment with spesolimab.
In addition, stool samples will be collected to assess changes in levels of inflammatory 
markers such as but not limited to calprotectin, haptoglobin, hemoglobin, MMP12, MPO, 
proteinase 3, resistin, serpin A4, PGRPS, properdin, chitinase 3L like 1, lipocalin 2, HMGB1 
and neopterin pre and at various timepoints post-treatment with spesolimab. These 
biomarkers are considered exploratory biomarkers and respective assays will need to be 
qualified to meet the required performance criteria.
Mucosal biopsies for histology and immunohistochemistry (IHC) analyses both pre and post 
treatment with spesolimab will be performed at timepoints outlined in the Flow Chart on 
Day 1 (baseline), Week 24 and Week 48 (End of Treatment (EoT) visit). On Day 1 and Week 
24, these should be collected prior to administration of study drug. Tissue samples will be 
assessed for the expression of markers such as but not limited to IL-36R by IHC.
5.4.2
Pharmacogenomic biomarkers
RNA Sequencing


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Ribonucleic Acid (RNA) sequencing on mucosal biopsies both pre and post treatment with 
spesolimab will be performed at time points outlined in the Flow Chart on Day 1 (baseline), 
Week 24 and Week 48 (EoT visit). On Day 1 and Week 24, these should be collected prior to 
administration of study drug. Transcriptome-wide analysis using RNA sequencing is used to 
identify spesolimab modulated differential gene expression comparing placebo-corrected 
baseline, Week 24 and Week 48 timepoints.
Whole blood samples may be analyzed to assess changes in gene expression both pre and 
post treatment with spesolimab as specified in the Flow Chart. Therefore RNA may be 
isolated from peripheral blood and analyzed by RNA sequencing.
Characterization of stool microbiome and / or stool miRNA
Stool samples may be assessed for microbiome and Micro Ribonucleic Acid (miRNA)
expression pre and and post treatment visits as specified in the Flow Chart.
5.4.3
Methods of sampling collection
Biomarkers sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK / PD data), including addition of samples 
and visits, as long as the total blood volume taken from each patient does not exceed 500 mL.
Such changes would be implemented via CTP amendments.
In addition to biopsies from the strictured area, biopsies from ileum and / or colon / rectum 
will also be collected during ileocolonoscopy for RNA expression and / or IHC at baseline, 
Week 24 and Week 48.
For the assessment of RNA expression from whole blood, a maximum of 8 ml blood will be 
collected and stored at time points indicated in the Flow Chart for subsequent analysis.
For the assessment of soluble protein biomarkers in serum, blood will be collected from a 
forearm vein in a serum separation tube at time points indicated in the Flow Chart.
Detailed instructions for biopsies, biomarkers sampling (serum and stool), handling and
shipment of samples are provided in the ISF or Laboratory Manual.


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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements.
DNA banking
One blood sample will be used for DNA Banking if participation and the separate informed 
consent is agreed upon by the patient as noted below. The DNA Banking sample, derived 
from the original blood sample, will be stored at the sponsor. The stored DNA may 
retrospectively be analysed, e.g. to identify whether there are other genetic factors that could 
contribute to a better therapeutic outcome or a higher risk of developing treatment-related 
adverse drug reactions.
5.5.1
Methods and timing of sample collection
Genomic DNA will be extracted from blood samples according to standard molecular 
genetics methods and analysed by using standard genotyping technologies. Approximately 
8.5 mL blood will be drawn for DNA banking.
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the Laboratory Manual. For sampling timepoints see Flow Chart.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
Magnetic Resonance Enterography (MRE)
Currently, no specific antifibrotic therapies are available for fibrostenotic CD and the drug 
development for this indication is hampered by a lack of standardized definitions and 
endpoint criteria for clinical trials. To overcome this lack of standardization for the 
assessment of fibrostenotic CD, a global, multidisciplinary panel of experts (the CrOhN´S 
disease antifibrotic STRICTure Therapies [CONSTRICT] group) conducted a consensus 
process resulting in the development of a conceptual framework for the conduct of early 
phase clinical trials of antifibrotic agents [R20-3947]. In contrast to classical endoscopic 
examinations and biopsy sampling that are limited to the evaluation of the superficial 
mucosa, routinely applied cross-sectional imaging techniques such as MRE, CTE and 
ultrasound (US) allow the assessment of the entire intestinal wall, which is critical to depict 
the entire fibrostenotic burden. Based on a systematic literature review followed by an expert 
consensus process, the CONSTRICT group identified MRE as the preferred imaging 
modality to diagnose small bowel fibrostenotic CD (sensitivity 55-100%; specificity 91-
200%) [R20-4177]. Although CTE is characterized by similar accuracy as for MRE, the 
absence of radiation exposure favors MRE over CTE for repeated assessments in a 
longitudinal trial setting. Radiologic features suggested by the CONSTRICT group being 
indicative for efficacious response to treatment are improvements in stricture length, pre-
stenotic dilation, localized luminal narrowing and wall thickening. The changes in features 


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were suggested to be evaluated at baseline, as well as 24 and 48 weeks post treatment 
initiation. The CONSTRICT group recommendations were further supported by a 
retrospective cohort analysis of 100 fibrostenotic CD patients conducted by the 
 
. Here, the MRE features stricture 
length and the maximal diameter of the proximal small bowel dilation showed the highest 
reliability scores (unpublished data) and were thus selected as key indicators for objective 
efficacy assessment in the present clinical trial.
Acknowledging the lack of prospectively validated clinical and surrogate efficacy endpoints, 
the resulting clinical trial data will be utilized in collaboration with the 
 to 
further develop the proposed endpoints.
S-PRO
The Stenosis Patient-Reported Outcome (S-PRO) instrument is a new instrument, recently 
developed by the 
. The overall goal of this 
 was to 
develop tools able to evaluate therapy's success or failure in stenotic CD patients. As part of 
this goal, they have developed the S-PRO instrument, which measures signs, symptoms and 
impacts experienced by stenotic CD patients. The instrument has been developed following 
the standard methodology i.e. the FDA 2009 PRO Guidance to Industry, the emerging 
Patient-Focused Drug Development Guidance Series, and current scientific best practices for 
PRO development as presented by the International Society for Pharmacoeconomics and 
Outcomes Research Content Validity Task Force. [R12-5607, R15-5636]. It is the unique 
PRO instrument measuring content relevant to stenotic CD patients; and which has been 
developed for this current context of use (i.e. treatment evaluation). However, its 
psychometric properties have not been evaluated yet. This trial is seen as a good opportunity 
to collect further data on this instrument and evaluate those properties.
CGI-C, CGI-S, PGI-S
The clinROs instruments CGI-C and CGI-S scales as well as the PRO instrument and PGI-S
scales are not standardly included in IBD clinical trials.
Those instruments have been selected and included as anchor measures to assess S-PRO 
validity during this study. In particular, those instruments will be used to evaluate S-PRO 
test-retest validity, concurrent validity, known-Groups validity, ability to detect change and to 
establish meaningful Within-Patient Change. Those instruments are commonly used in that 
purpose. PGI scales are proposed by the FDA as anchor measures to Establish Meaningful 
Within-Patient Change [R12-5607].
The SES-CD, CDAI, IBDQ, SF-36 and safety assessments performed during this trial are 
standard measurements in CD treatment trials and will be performed to assess treatment 
response and monitor safety aspects in an appropriate way.


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6.
INVESTIGATIONAL PLAN
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this CTP may not be feasible at a site. With the consent of the 
patient, sponsor and investigator may agree on alternative, back-up or rescue methodology,
which may include but will not be limited to virtual patient visits and assessments, home 
healthcare nurse visits, and direct-to-patient shipments of trial treatment. The implementation 
of this back-up methodology will depend on patient’s consent, operational feasibility, local 
law and regulations.
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. Each visit date
(with its window) up to EoS Visit is to be counted from Day 1 (Visit 3). If any visit has to be 
rescheduled, subsequent visits should follow the original visit date schedule.
Additional visits for the purpose of re-testing of laboratory parameters or AE monitoring may 
be included as deemed necessary by the investigator.
In case of a suspected worsening of CD symptoms, the patient should contact the site to 
arrange for an unscheduled visit including MRE and endoscopy examinations. Detailed 
descriptions of unscheduled visits and related operational aspects are outlined in 
Section 6.2.2.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Trial procedures to be performed at each visit are listed in the Flow Chart and in the
respective CTP sections.
Patient Reported Outcomes (PROs) such as S-PRO, IBDQ, SF-36 and PGI-S scales 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, and, if possible, before any interaction with 
the investigator or other members of the study team. This applies to every visit with PROs 
(i.e. all visits except the EoS visit).
Measurement of pre-dose vital signs and ECG should precede blood sampling.
The following sequence of predose procedures at each visit (where applicable) is 
recommended:
1. PROs (prespecified order: S-PRO, then follow the prespecified order as provided with 
the tablet at the site)
2. AE and concomitant therapy collection; smoking status
3. Physical examinations (including predose vital signs)
4. ECG
5. Urine pregnancy testing (if applicable)


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6. Stool sampling (can be done any time during a visit or sampled at home, i.e. collecting 
the first stool of the day as close as possible to the planned visit; date and time need to 
be noted on the collection container)
7. Blood and urine sampling, including PK, ADA / Nab, and biomarkers
For assignment of medication numbers of the vials, an IRT call is needed. The trial drug is 
administered followed by the assessment of post-dose vital signs.
For the timing of MRE and endoscopy examinations, please see more detailed information

in Section 6.2.1 for the pre-treatment examinations (baseline, Day 1)

in Section 6.2.2 for the post-treatment examinations at Week 24 and Week 48.
Generally, the MRE examination should be done before the endoscopy examination at all 
scheduled and unscheduled visits if possible.
6.2.1
Lead-in Period
The screening (Visit 1) takes place when the patient presents with acute obstructive 
symptoms of the small bowel.
The trial requirements, including the procedure for the follow-up of prematurely withdrawn 
patients must be fully explained to the patient and written informed consent obtained prior to 
initiating any study related evaluation. The importance of staying in the trial until completion 
of all study requirements will be emphasized. No trial procedures should be done unless the 
patient has consented to taking part in the trial.
Once consented, the patient is considered to be enrolled in the trial and has started the Lead-
in Period. The patient should be recorded on the enrolment log and be registered in IRT as a 
screened patient. Patients will be assigned a patient number generated via the IRT system.
For the comprehensive list of the trial procedures required at the screening Visit 1 please 
refer to Flow Chart. Additionally, please see Flow Chart 2 for more details on the Lead-in 
Period logistics.
It is important to start the completion of the S-PRO starting from the screening visit (Visit 1) 
or as soon as the patient´s situation allows during hospitalization (latest on the day of 
discharge). The PROs IBDQ, SF-36 and PGI-S have to be completed at the time of the first 
S-PRO completion (see above, at Visit 1 or as soon as the patient´s situation allows). S-PRO 
data are collected daily during the Lead-in Period.
At screening (Visit 1), a blood sample is drawn for Therapeutic Drug Monitoring (TDM). 
This means to determine the plasma drug level and status of antidrug antibodies for the 
patient´s anti-inflammatory biological therapy before the enrolment. If the TDM is assessed 
at the central laboratory, the result availability is expected after 10 business days (= 2 weeks). 
Where the TDM assessment can be done at a local laboratory, the result availability is 
possible already after 5 business days (= 1 week). As soon as the TDM results are available,


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the optimization of the anti-inflammatory biological therapy according to the algorithm in 
Section 4.2.1.1 is to be started at Visit 2.
After 8 weeks of optimization of the anti-inflammatory biological therapy, the baseline 
examinations, MRE and endoscopy, are to be scheduled: The ideal order is to perform the 
MRE first and the endoscopy second, and performance of both examinations is not 
recommended on the same day due to different patient preparation.
If endoscopy was done first, 3 days should be between the endoscopy and the MRE 
examination.
For timely provisioning of eligibility information to the site by central review before Day 1 
(V3, randomization), it is important to schedule the baseline MRE at least 10 business days 
(= 2 weeks) before Day 1 (inclusion criterion no. 8) and the baseline endoscopy (including 
biopsies) ideally 7 business days before Day 1 (inclusion criterion no. 10).
For the baseline MRE examination, please note the need of GFR assessment within 14 days 
before the planned MRE examination (either done locally or via central laboratory).
Demography
Informed consent date, gender, age, race and ethnic origin will be collected in the eCRF page. 
Also, the patient’s smoking status will 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 CD. Note: In some countries, race may 
not be collected.
Baseline Conditions
Baseline conditions will be assessed during screening. Chronic diseases, current observable 
conditions, any new clinically relevant findings discovered from the physical examination, 
ECG, safety labs, and any condition requiring therapy (excluding CD) will be reported on the 
Baseline Condition eCRF page.
Infections screening
Infections testing will include tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see 
Section 3.3.3 and Table 5.2.3: 1).
Medical and Surgical History
Information on clinically significant previous and concomitant illnesses, other than CD, 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 on 
the Baseline Condition page in the eCRF.
For planned procedures / hospitalizations during the trial, documentation should be 
completed at the time of the screening. 
Regarding the CD, a detailed history of the disease, including date of diagnosis, disease 
location, behaviour and severity, surgeries, hospitalizations, and extraintestinal 
manifestations will be collected. Also, previous and concomitant treatment for CD will be 
recorded in the CRF.


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Patients who fail screening (i.e. do not meet the eligibility criteria) following Visit 1 
assessments should be registered as a screen failure in IRT.
6.2.2
Treatment period(s)
When the patient is eligible for randomization (i.e. meets all in-, and none of the exclusion 
criteria), randomization via IRT will be performed at Day 1 (= V3). The Randomized Blinded 
Treatment Period is from Day 1 (=V3) to Week 48 (EoT Visit). Procedures described in the 
Flow Chart for each visit should be performed.
6.2.2.1
Scheduled visits during the treatment period
The site should contact the patient before each of the scheduled visits to remind the patient to
start entering his / her S-PRO and CDAI symptom score data into the eDiary daily for the 
7 days preceding the scheduled visit.
Scheduled MRE and endoscopy examinations (Week 24 = V7 and Week 48 = V10), should 
be planned well in advance. These examinations should not be performed on the same day 
due to the different patient preparation.
If possible, the MRE should be done before the endoscopy to avoid intestinal distention 
during endoscopy to interfere with MRE evaluation. If endoscopy was done first, 3 days 
should be between the endoscopy and the MRE examination.
In case an MRE was not performed according to the specifications detailed in the Central 
Imaging Vendor Manual, it needs to be repeated within 14 days after the visit.
Both examinations should preferably be done within a period of -7 days of the scheduled time 
point Week 24 (V7) and Week 48 (V10), respectively.
For the MRE examinations at V7 and V10, please note the need of GFR assessment (either 
done locally or via central laboratory) within 14 days before the planned MRE examination.
6.2.2.2
Unscheduled visits during the treatment period
Reasons that may trigger unscheduled visits:

Safety reason at the discretion of the patient, investigator or the sponsor

Worsening of CD symptoms (suspicion inflammatory flare or stenosis relapse)
All unscheduled visits should be described (including the reason for the visit) and 
documented in the medical / source record, and in the eCRF.
Safety

The unscheduled visit may include additional collection of blood samples and also 
additional assessments such as laboratory samples, ECGs, or other procedures deemed 
necessary by the investigator for safety evaluation.

In case safety related unscheduled visit occurs 7 days or less before next scheduled visit, 
the safety assessments planned for next scheduled visit might be skipped at the 
discretion of the investigator


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Worsening of CD symptoms
Patients experiencing worsening of their CD symptoms should contact the site to schedule a 
visit including MRE and endoscopy examinations. The site will remind the patient to enter S-
PRO and CDAI data into the eDiary until the unscheduled visit date (i.e. eDiary daily data for 
at least 7 days before this visit).
Suspicion of inflammatory flare
CD inflammatory flare, is defined as an increase in CDAI score by ≥100 points from baseline 
with an absolute CDAI >220 (see Table 2.3: 1). This should be confirmed during the 
unscheduled visit, with an absolute colonic SES-CD >12 and absence of enteric pathogens in 
stool.
A patient with a confirmed inflammatory flare (endoscopically confirmed, absolute colonic 
SES-CD >12) will receive optimized biological anti-inflammatory therapy as described in 
Section 4.2.1.2. An additional visit might be planned after the start of the new optimized 
biological anti-inflammatory medication at the discretion of the investigator to check the 
patient`s response status.
Suspicion of Stenosis Relapse
When a Symptomatic Stenosis Relapse is suspected (see definition in Table 2.3: 1), it should 
be confirmed with MRE. However, if the MRE was operationally not feasible and small 
bowel obstruction was confirmed on cross-sectional imaging as per local SOC, MRE does not 
need to be done.
A patient with a Confirmed Stenosis Relapse will be treated as indicated per local SOC. If 
eligible, the patient will be treated with optimized biological anti-inflammatory medication as 
described in Section 4.2.1.2. An additional visit might be scheduled after the start of the new 
optimized biological anti-inflammatory medication at the discretion of the investigator to 
check the patient`s response status. If the patient needs immediate endoscopic or surgical 
treatment, the patient will be discontinued from the trial.
In case the worsening of CD symptoms related unscheduled visit occurs:

7 days or less before next scheduled visit
o
unscheduled visit replaces next scheduled visit
o
thus, ALL VISIT PROCEDURES (including dosing) planned for next scheduled visit 
as indicated in Flow Chart should be performed
o
therefore, next scheduled visit should be skipped

more than 7 days before next scheduled visit
o
unscheduled visit does not replace next scheduled visit
o
VISIT PROCEDURES to be performed: those indicated in the Flow Chart for 
Week 24 (V7) except for:

IRT call

Trial drug administration

blood sampling for protein biomarkers and transcriptomic analysis and stool 
sampling for biomarkers


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o
therefore next scheduled visit should not be skipped and performed as indicated in 
the Flow Chart except for endoscopy and MRE, which do NOT need to be repeated if 
these were performed within 28 days (4 weeks) before Week 24 (V7) and Week 48 
(EoT-V10) visits (which include MRE and endoscopy examinations).
MRE and endoscopy examinations during unscheduled visit, as for scheduled visits, should 
not be performed on the same day due to the different patient preparation. If possible, the 
MRE should be done before the endoscopy to avoid intestinal distention during endoscopy to 
interfere with MRE evaluation.
For the MRE examination at an unscheduled visit, please note the need of GFR assessment 
(either done locally or via central laboratory) within 14 days before the MRE examination.
If possible, the endoscopy examination performed should include the sampling of biopsies.
In case MRE assessments were not performed in alignment with the Central Imaging Vendor 
Manual, the examinations have to be repeated within 14 days.
If such an unscheduled visit with a Symptomatic Stenosis Relapse occurred before Week 16 
(= V6), and the patient continues the visits and trial drug dosing schedule as planned up to 
EoT Visit and is having an individual clinical benefit at Week 48, the extension trial might be 
offered to the patient (see Section 6.2.3).
However, if such an unscheduled visit with a Symptomatic Stenosis Relapse occurred after 
Week 16 (= V6), and the patient continues the visits and trial drug dosing schedule, this 
patient will be considered having no maintained Symptomatic Stenosis Response and will 
not be offered to participate in the extension trial.
6.2.2.3
Roll-over to a possible extension trial
Patients completing the Randomized Blinded Treatment Period at Week 48 (V10) and having 
an individual clinical benefit may be offered to enter an extension trial. Patient information 
for the extension trial (for patients to whom the extension trial will be offered) may be 
performed at Week 40 (V9) since EoT Visit (V10) is coinciding with the first visit for the 
extension trial in most cases.
6.2.3
Follow-up period and trial completion
For all randomized patients, termination of trial medication and trial completion must be 
recorded on the corresponding CRFs.
For patients completing the randomized trial treatment regularly at Week 48 (EoT Visit), the 
safety follow-up visit is scheduled at least 16 weeks after the last dose of study drug at 
Week 40, i.e. at Week 56 (EoS Visit).
In case of extension trial, for patiens who roll-over:
For patients completing the randomized trial treatment regularly at Week 48 (EoT Visit), and 
roll-over to the extension trial, are not requested to complete Visit 11 (EoS Visit) and Visit 10 


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(EoT) will be their last visit. Individual EoS for these patients is defined as the day of first 
administration of spesolimab in the extension trial.
Early treatment discontinuation
Patients who discontinue treatment prematurely prior to the planned visit for the last trial 
drug administration at Week 40 should be registered as withdrawn from treatment in IRT. 
Patients should follow the scheduled visits as much as possible as defined in the Flow Chart.
If the patient is not willing to follow the whole visit schedule, at least the EoT Visit should be 
conducted either immediately or as soon as possible followed by the EoS Visit which is to be 
scheduled at least 16 weeks after the last trial drug administration. All efforts should be made 
to keep the patient in the observation for at least 16 weeks after the last dose of the trial drug.
Trial discontinuation
Patients experiencing worsening of clinical stenosis symptoms during the Randomized 
Blinded Treatment Period, that are not controlled by anti-inflammatory medication and 
require endoscopic balloon dilation or surgery, will be discontinued from the trial. Patients 
who experience any clinical complication that prevents continuation of the trial drug will be 
discontinued from the trial.
Treatment completion
Treatment completion is defined as a patient having completed treatments till planned EoT 
Visit (Week 48).
Trial completion:
Trial completion is defined when a patient has reached the EoS Visit (Week 56, Visit 11). 
In the case of patients rolling over in the extension trial, individual patient´s end of trial is 
defined as the day of the first administration of spesolimab in the extension trial. In this case, 
the last visit will be at Week 48 (Visit 10).
(S)AEs ongoing at individual patient’s end of trial must be further followed up as described 
in Section 5.2.6.2.2.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
This is an exploratory Phase II trial and it is not planned to test any statistical hypotheses in a 
confirmatory sense. The results including confidence intervals and p-values will be discussed 
and interpreted in the perspective of the exploratory character of the trial.
7.2
PLANNED ANALYSES
The efficacy analysis will be performed for the Full Analysis Set (FAS) which is based on the 
intent-to-treat principle, and comprises all patients who are randomized and received at least 
one dose during the trial. Efficacy analyses will be based on the planned treatment (i.e. the 
treatment assigned at randomization). Safety analyses on patients who were randomized and 
received at least one dose during the trial will be based on the actual treatment received; this 
set of patients is called the Safety Set (SAF). All efficacy analyses will be conducted on the 
FAS. All safety analyses will be conducted on the SAF. Further details on endpoint 
development and analyses will be described in the TSAP.
7.2.1
General considerations
This is an exploratory Phase II trial and it is not planned to test any statistical hypotheses in a 
confirmatory sense. The results including confidence intervals and p-values will be discussed 
and interpreted in the perspective of the exploratory character of the trial.
7.2.2
Primary endpoint analyses
The primary objective for efficacy is to evaluate maintained Symptomatic Stenosis Response 
and / or Radiographic Stenosis Response at Week 48. They are summarized as the proportion 
of patients with response at Week 48.
The primary analysis of the unadjusted absolute rate difference versus placebo will be 
calculated simply as the difference in the observed proportion of patients with maintained 
Symptomatic Stenosis Response / Radiographic Stenosis Response based on FAS. A 95% 
Newcombe confidence interval around the difference will also be provided. The influence of 
the stratification factors on the primary endpoints will be characterized as exploratory 
analyses, which will be specified in Trial Statistical Analysis Plan (TSAP).
7.2.3
Secondary endpoint analyses
For the secondary binary endpoints, based on FAS, the unadjusted absolute rate difference 
versus placebo will be calculated and a 95% Newcombe confidence interval around this 
difference will also be provided.


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7.2.5
Safety analyses
In order to ensure the patient’s safety during the trial, a DMC, independent of the trial and 
project teams, will be set-up to review all available unblinded safety data as well as selected 
efficacy data at regular intervals. See Section 8.7 for further details.
The SAF will be used to perform all safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the REP will be considered ‘treatment-emergent’. The 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’. Drug related AEs 
will be tabulated by system organ class and preferred term after coding according to the 
current version of the Medical Dictionary for Drug Regulatory Activities (MedDRA).
In addition, the frequency and severity of adverse events will be tabulated by system organ 
class and preferred term after coding according to the current version of MedDRA.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.


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Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the treatment period of the trial and at the end-of-trial evaluation will be 
assessed with regard to possible changes compared to findings before start of treatment.
7.2.6
Other Analyses
In order to ensure that trial assumptions and expectations will be met, a committee with BI 
internal experts will be set-up to monitor trial progress. See Section 8.7 for further details.
Spesolimab concentrations will be reported descriptively. No PK parameters will be 
calculated. Please see Section 5.3.1 for details regarding assessment of PK.
All biomarker analysis will be exploratory in nature and will be reported descriptively.
7.2.7
Interim Analysis
An interim analysis will be conducted when 100% of the patients have completed at least 24 
weeks of treatment. The results of the analysis will be used for internal planning only and the 
blind of the trial subsequent to this time-point will handled as described in the trial logistic 
plan (see Section 4.1.5.1).
Once all randomized patients have completed 48 weeks of study, the primary analysis of this 
trial at week 48 will be performed. A final DBL will be performed once all randomized 
patients have completed the 16 weeks safety follow-up.
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will 
still occur and approaches to handle this are proposed below.
With respect to safety evaluations, it is not planned to impute missing values.
For primary and secondary binary endpoints, the following will be performed:

If there are data at visits both before and after the visit with a missing outcome, then 
impute as success only if both neighbouring visits also represent a success;

Otherwise, impute as a non-responder
For further endpoints, rules for handling of missing data will be specified in the TSAP.
7.4
RANDOMIZATION
Patients will be randomized in a 1:1 ratio to spesolimab and placebo with stratification 
according to the number of previously failed biologic classes (0-1 vs >1) and stenosis length 
(≤5cm vs >5cm). The randomization schemes will be created using restricted randomization 
procedures. Details regarding the randomization methodology will be reported in the CTR.


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BI will arrange for the randomization and the packaging and labelling of trial medication. 
The randomization 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 randomization method will be documented in the CTR. Access to the codes 
will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
Calculations were performed using simulations performed via the R software, version 3.5.1.
The study is intended to show an increase of spesolimab over placebo in terms of the
difference in proportion of patients achieving Symptomatic Stenosis Response and / or 
Radiographic Stenosis Response (see primary endpoints in Section 2.1.2). There is currently 
no clinical trial data available in the published literature that describes a placebo response 
(add on to the optimized anti-inflammatory treatment) on either maintained Symptomatic
Stenosis Response or Radiographic Stenosis Response at Week 48, in the population of 
patients with obstructive symptoms due to confirmed CD related stenosis.
Based on the treatment failure rates observed from the CREOLE study [P20-05766], there 
were around 50% clinical stenosis relapse within 24 weeks of adalimumab treatment, and 
additional 20% relapse rate within 1 year. Together with the clinical and radiographic experts 
experience, we assume both Symptomatic Stenosis Response rate and radiographic stenosis 
response rates at week 48 of placebo arm are around 0.3.
We target to observe a difference of at least 10% in favour of spesolimab from at least one of 
the two primary endpoints. Simulations were used to derive estimates of the success 
probability that a single trial would demonstrate an observed difference in proportions 
between spesolimab and placebo that was equal or greater than the defined threshold 10% for 
at least one of the two primary endpoints. For identifying such a target threshold, a minimum 
probability of 0.80 was defined. For each trial simulation, the response for each patient on 
each treatment was generated using a binomial distribution utilizing the expected response 
rates as noted in table below, and the trial observed proportions were then directly compared. 
A total of 10,000 trial simulations were performed. The correlation between maintained 
Symptomatic Stenosis Response and radiographic stenosis response is assumed to be 0.5.
Note that the probability of a false positive declaration given the specified target threshold, so 
called negative scenario is also determined.


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Table 7.5: 1
Probability of achieving the threshold differences in treatments given 
expected treatment response rates with a total sample size of 100 
patients
Population Response Rate
Expected 
Response 
Difference
Threshold 
(Observed 
Diff.)
Probability 
Threshold 
Exceeded 1
False 
Positive 
Rate (%) 
2
Clinical
Spe vs Plc
Radiographic
Spe vs Plc
0.35 vs 0.3
0.35 vs 0.3
0.05
0.1
43.3%
22.7%
0.4 vs 0.3
0.4 vs 0.3
0.10
0.1
65.7%
0.45 vs 0.3
0.45 vs 0.3
0.15
0.1
84.0%
1. Assuming the expected response rate difference, the probability that the observed 
spesolimab response rate exceeds that of placebo by at least the threshold amount for at 
least one of two primary endpoints is displayed.
2. The probability that the observed spesolimab response rate exceeds that of placebo by at 
least the threshold amount under the negative scenario that treatments for both primary 
endpoints are equal.
In summary, for a total N of 100 patients, a 1:1 randomization ratio to spesolimab and 
placebo, then under the assumption of a target difference between spesolimab and placebo of 
0.15 for both primary endpoints, then this trial will be able to detect with probability of 84%, 
a superior response rate, versus placebo, which is at least ≥0.1 in magnitude in favour of 
spesolimab for at least one primary endpoint when the population placebo response rate is 
0.30. The corresponding false positive error rate is 22,7%.


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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 Guideline for Good 
Clinical Practise (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014, the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997) and other relevant regulations. Investigators and 
site staff must adhere to these principles. Deviation from the protocol, the principles of ICH 
GCP or applicable regulations will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor or delegate 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 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the CTR.
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 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 delegate 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 delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 


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investigator or 
delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan (or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials), documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
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 the “ALCOA principles” 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 at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Copies of source files (MRE and endoscopy) necessary for central eligibility and / or efficacy 
reads will be provided to an imaging vendor. Before sending or uploading those copies, the 
investigator must ensure that all patient identifiers (e.g. patient’s name, initials, address, 


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telephone number, social security number) have properly been removed or redacted from any 
copy of the patients’ source documents.
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)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits

Medical history (including trial indication and concomitant diseases, if applicable)

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 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 or delegate will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
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.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the World Health 
Organisation (WHO) GCP handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised 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 at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, 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

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
8.6
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 Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site.Early termination of the trial is 


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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
(HA) request.
The IEC / CA 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).
8.7
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.
An Executive Committee consisting of independent experts and sponsor representatives will 
be established to support the Coordinating Investigator who will be the chair of the Executive 
Committee. The composition of the Executive Committee will be documented in the Trial 
Master File (TMF). The tasks and responsibilities will be agreed in contracts between the 
Executive Committee members and the sponsor and also summarised in an Executive 
Committee charter.
A DMC will be established. Members of the DMC are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician.
The DMC will evaluate safety and efficacy data. The DMC will receive urgent significant 
safety concerns for immediate evaluation. While DMC members may be unblinded, measures 
are in place to ensure the blinding for everyone else involved in the trial. Regular DMC 
meetings will be held at specified intervals. The DMC will recommend continuation, 
modification or termination of the trial as detailed in the DMC charter. DMC 
recommendations as well as the final BI decision will be reported to the appropriate 
Regulatory Authorities (RAs) / Health Authorities (HAs), IRBs / ECs, and to investigators as 
requested by local law. The tasks and responsibilities of the DMC are specified in a charter.
Given the exploratory nature of this trial and that there is scarce data from this population, in 
addition to the DMC (see also Section 7.2.5) a committee with BI internal experts on the 
compound and on the specific disease indication, which will be independent of the clinical 
trial team will be set-up to unblindly review trial progress at regular intervals. The review 
will include the individual patient level and aggregated data for all patients including 
screening failures. The observations regarding trial assumptions and expectations (e.g. event 


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rates) may be shared with the project team to enable early decisions on further project 
planning.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI web portal 
Clinergize to access documents provided by the sponsor.
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 CT Managers, CRAs, and investigators of 
participating countries.
In the participating countries the trial will be performed by the respective local or regional 
BI-organisation (Operative Unit, OPU) in accordance with applicable regulations and BI 
SOPs, or by a CRO based on a contract.
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, central reading service for blinded reading of MRE and 
endoscopy, and an IRT vendor will be used in this trial.
Details will be provided in the Laboratory Manual, the Central Imaging Vendor Manual, the 
Endoscopy Video Instruction Manual, and the IRT Manual. These manuals are available in 
the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P09-12413
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. Silver Spring: U.S. Department of Health and Human Services, 
Food and Drug Administration, Center for Drug Evaluation and Research. 
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P09-14233
Punwani S. Rodriguez-Justo M. Bainbridge A. Greenhalgh R. Vita E de. 
Bloom S. et.al. Mural inflammation in Crohn disease: location-matched 
histologic validation of MR imaging features. Radiology. 2009. 252(3): 
712-720.
P16-11034
Hughes G. Toellner H. Morris H. Leonard C. Chaudhuri N. Real world 
experiences: pirfenidone and nintedanib are effective and well tolerated 
treatments for idiopathic pulmonary fibrosis. J Clin Med. 2016. 5(9): 1-12.
P19-05294
Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of 
fibrosis in patients with inflammatory bowel diseases. Gastroenterology. 
2017. 152(2): 340-350.
P20-05765
Rieder F. Latella G. Magro F. Yuksel ES. Higgins PDR. Di Sabatino A. 
et.al. European crohn’s and colitis organisation topical. Review on 
prediction, diagnosis and management of fibrostenosing crohn’s disease. J
Crohn's Colitis. 2016. 10(8): 873-85.
P20-05766
Bouhnik Y. Carbonnel F. Laharie D. Stefanescu C. Hébuterne X. Abitbolet 
V. et.al. Efficacy of adalimumab in patients with Crohn’s disease and 
symptomatic small bowel stricture: a multicentre, prospective, 
observational cohort (CREOLE) study. Gut. 2018. 67: 53-60.
P20-06254
Atreja A. Aggarwal A. Dwivedi S. Rieder F. Lopez R. Lashner BA. et.al. 
Safety and efficacy of endoscopic dilation for primary and anastomotic 
Crohn’s disease strictures. J Crohn’s Colitis. 2014. 8: 392-400.
P20-06255
Van Assche G. Thienpont C. D’Hoore A. Vermeire S. Demedts I. 
Bisschops R. et.al. Long-term outcome of endoscopic dilatation in patients 
with Crohn’s disease is not affected by disease activity or medical therapy. 
Gut. 2010. 59: 320-324.
P20-10740
Torres J. Mehandru S. Colombel JF. Peyrin-Biroulet L. Crohn’s disease. 
Lancet. 2017. 389: 1741-1755.
R11-4827
Noble PW. Albera C. Bradford WZ. Costabel U. Glassberg MK. Kardatzke 
D. et.al. Pirfenidone in patients with idiopathic pulmonary fibrosis 
(CAPACITY): two randomised trials. Lancet. 2011. 377: 1760-9.
R11-4890
Sampson HA. Munoz-Furlong A. Campbell RL. Adkinson NF. Bock SA. 
Branum A. 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. J 
Allergy Clin Immunol. 2006. 117(2): 391-397.
R12-5607
Guidance for industry: patient-reported outcome measures: use in medical 
product development to support labeling claims. Federal Register. 2009.
74(235): 1-43.


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Patrick DL. Burke LB. Gwaltney CJ. Kline Leidy N. Martin ML. Molsen E. 
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design. Inflamm Bowel Dis. 2014. 20(10): 1850-1861.
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Changing pattern over the course of the disease. Gut. 2001. 49: 777–782.
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Mosli MH. Feagan BG. Zou G. Sandborn WJ. D'Haens G. Khanna R. et.al. 
Development and validation of a histological index for UC. Gut. 2015. 66: 
50-58.
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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 
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An analysis of IL-36 signature genes and individuals with IL1RL2 
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Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice with 
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research tool in clinical practice. Psychiatry. 2007. 4(7): 28-37.
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et.al. A pooled analysis of efficacy, safety, and long-term outcome of 
endoscopic balloon dilation therapy for patients with stricturing crohn’s 
disease. Inflamm Bowel Dis. 2017. 23(1): 133-142.
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process. Nature Reviews Gastroenterology and Hepatology. 2009. 6: 228-
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Bowel Disease. Dig Dis. 2013. 31: 186-193.
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bowel obstruction in Crohn’s disease. J Clin Gastroenterol. 1983. 5: 211-
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fibrosis on cross-sectional imaging: a systematic review. Gut. 2019. 68: 
1115-1126.
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predictors. Annals of Gastroenterology. 2017. 30: 1-15.
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Hepatol. 2018. 16: 1260-1267.
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NJ. Long-term follow-up of strictureplasty for Crohn’s disease. British 
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the long term, and escalation of medical therapy improves outcomes in the 
biologic era. Journal of Crohn’s and Colitis. 2016. 10: 1172-8.
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Small Bowel Crohn’s Disease: A Systematic Review. Gastroenterology. 
2020. 158(1): 137-150.
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Tielbeek JA. Ziech ML. Li Z. Lavini C. Bipat S. Willem A. et.al. 
Evaluation of conventional, dynamic contrast enhanced and diffusion 
weighted MRI for quantitative Crohn’s disease assessment with 
histopathology of surgical specimens. Eur Radiol. 2014. 24: 619-29.
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Wagner M. Ko HM. Chatterji M. Besa C. Torres J. Zhang X. et.al. 
Magnetic resonance imaging predicts histopathological composition of ileal 
crohn’s disease. Journal of Crohn’s and Colitis. 2018. 12(6): 718-29.
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Et.al. An expert consensus to standardise definitions, diagnosis and 
treatment targets for anti-fibrotic stricture therapies in Crohn’s disease. 
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et.al. Characterization of inflammation and fibrosis in Crohn’s disease 
lesions by magnetic resonance imaging. Am J Gastroenterol. 2015. 110: 
432-40.
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tomography and magnetic resonance imaging for the diagnosis, assessment 
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Pharmacol Ther. 2011. 34: 125-145.
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Quality of life: A valid and reliable measure of therapeutic efficacy in the 
treatment of inflammatory bowel disease. Gastroenterology.1996. 106: 287-
296.
9.2
UNPUBLISHED REFERENCES
c03320877
Investigator´s Brochure Spesolimab (BI 655130). Current Version.


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c03361085-07
Single-blind, partially randomised, 
placebo-controlled Phase I study to investigate safety, tolerability, 
pharmacokinetics and pharmacodynamics of single rising intravenous doses 
of BI 655130 in healthy male volunteers. 1368.1. 27 Jan 2016.
c31366073-01
Clinical Trial Report 1368-0005: 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. 03 December 2020.


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
10.1.1
Stenosis Patient Reported Outcome (S-PRO) Tool
Stricturing Crohn’s Disease Questionnaire
For each of the following questions, please choose the one response that best describes your 
experience with stricturing Crohn’s disease during the last 24 hours.
1. How severe was your worst abdominal pain during the last 24 hours?
□
No pain at all
□
Mild
□
Moderate
□
Severe
2. During the last 24 hours, how often did you experience abdominal pain after eating?
□
Never
□
Sometimes
□
Often
□
Every time I ate
□
Not Applicable: I could not eat in the last 24 hours because of my Crohn’s symptoms
□
Not Applicable: I did not eat in the last 24 hours for other reasons
3. How severe was your worst abdominal cramping during the last 24 hours?
□
No cramping at all
□
Mild
□
Moderate
□
Severe
4. How severe was your worst abdominal bloating during the last 24 hours?
□
No bloating at all
□
Mild
□
Moderate
□
Severe


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5. How severe was your worst nausea or vomiting during the last 24 hours?
□
No nausea or vomiting at all
□
Mild
□
Moderate
□
Severe
6. How many bowel movements did you have in the last 24 hours?
Enter number of bowel movements: _________
6b. Compared to your usual number of daily bowel movements, does this amount during the 
last 24 hours represent…
□
A lot more than my usual amount
□
Somewhat more than my usual amount
□
A little more than my usual amount
□
The same as my usual amount
□
A little fewer than my usual amount
□
Somewhat fewer than my usual amount
□
A lot fewer than my usual amount
7. How severe was any constipation you had during the last 24 hours? 
□
No constipation at all
□
Mild
□
Moderate
□
Severe
8. How severe was any diarrhea you had within the last 24 hours? 
□
No diarrhea at all
□
Mild
□
Moderate
□
Severe
9. During the last 24 hours, how often did you experience low energy? 
□
Never
□
Sometimes
□
Often
□
Always


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10. During the last 24 hours, how often did you have a lack of appetite?
□
Never
□
Sometimes
□
Often
□
Always
11. During the last 24 hours, how limited were you in the amount or types of food you could 
eat because of your stricturing Crohn's disease?
□
Not limited at all
□
A little limited
□
Moderately limited
□
Very limited
12. During the last 24 hours, how limited were you in completing your usual daily activities 
(for example, running errands, working, preparing food, or doing chores around the home) 
because of your stricturing Crohn's disease?
□
Not limited at all
□
A little limited
□
Moderately limited
□
Very limited
13. During the last 24 hours, how limited were you in physical activities (for example, 
exercising, lifting heavy objects, walking, or biking) because of your stricturing Crohn's 
disease?
□
Not limited at all
□
A little limited
□
Moderately limited
□
Very limited
14. During the last 24 hours, how much were your social activities limited because of your 
stricturing Crohn's disease? 
□
Not limited at all
□
A little limited
□
Moderately limited
□
Very limited


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15. During the last 24 hours, how worried were you that your stricturing Crohn’s disease 
might get worse (such as having an obstruction [e.g., intestinal blockage] or needing 
surgery)?
□
Not at all worried
□
A little worried
□
Moderately worried
□
Very worried
16. During the last 24 hours, how difficult was it to sleep because of your symptoms from 
stricturing Crohn's disease?
□
Not difficult at all
□
A little difficult
□
Moderately difficult
□
Very difficult


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10.1.2
Simple endoscopic score in Crohn’s Disease (SES-CD)
Table 10.1.2: 1
SES-CD Score
Variable
SES CD score
0
1
2
3
Presence of ulcers
None
Aphtous ulcers
Large ulcers
Very large
ulcers
(W0.1-<0.5 cm)
(W0.5-2 cm)
(>W2 cm)
Ulcerated surface
None
<10%
10-30%
>30%
Affected surface
Unaffected 
segment
<50%
50-75%
>75%
Presence of narrowings
None
Single, can be 
passed
Multiple, can 
be passed
Cannot be 
passed
Ileum
Right 
colon
Transverse 
colon
Left 
colon
Rectum
SUM
Presence of ulcers
+
Ulcerated surface
+
Affected surface
+
Presence of narrowings
=
Sum of all 
variables Total


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10.1.3
Crohn’s Disease Activity Index (CDAI)
The Crohn’s Disease Activity Index (CDAI) is comprised of eight variables which are
summed after adjustment with a weighting factor.
Table 10.1.3: 1
Activity score for Crohn’s Disease
Variable
Weighting Factor
Number of liquid or very soft stools in the last 7 days
x 2
Abdominal pain: Average daily rating in the last 7 days
(0=none, 1=mild, 2=moderate, 3=severe)
x 5
General well-being: Average daily rating in the last 7 days
(0=generally well, 1=slightly under par, 2=poor, 3=very poor,
4=terrible)
x 7
Extra-intestinal manifestations*, Current
- Arthritis/arthralgia
- Iritis/uveitis
- Erythema nodosum, pyoderma gangernosum, aphthous stomatitis
- Anal fissure, fistula, or abscess
- Other fistula
- Fever over 37.8°C (100°F) during past 7 days
x 20
Lomitil, Imodium, Opiates for diarrhea in the last 7 days
x 30
Abdominal mass 
(0=no, 2=Questionable, 5=Definite)
x 10
Local Hematocrit (difference standard - current, in % rounded to 
whole)
47% if male
42% if female
x 6
Body weight: Deviation from ideal body weight in %
x 1
*One point each is added for each of the listed complications
















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10.1.5
SF-36
Your Health and Well-Being
This survey asks for your views about your health. This information will 
help keep track of how you feel and how well you are able to do your usual 
activities. Thank you for completing this survey!
For each of the following questions, please mark an 1 in the one box that 
best describes your answer.
1. In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor





1
2
3
4
5
2. Compared to one week ago, how would you rate your health in 
general now?
Much better 
now than one 
week ago
Somewhat 
better 
now than one 
week ago
About the 
same as one 
week ago
Somewhat 
worse 
now than one 
week ago
Much worse 
now than one 
week ago





1
2
3
4
5
3. The following questions are about activities you might do during a 
typical day. Does your health now limit you in these activities? If so, 
how much?
Yes, 
limited 
a lot
Yes, 
limited 
a little
No, not 
limited 
at all

a
Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous sports .................
1 ...........
2 ...........
3


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4. During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities 
as a result of your physical health?
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of
the time

a
Cut down on the amount of 
time you spent on work or 
other activities...............................
1 ......
2...........
3 ...........
4 ...........
5
b
Accomplished less than you 
would like .....................................
1 ......
2...........
3 ...........
4 ...........
5
c
Were limited in the kind of 
work or other activities.................
1 ......
2...........
3 ...........
4 ...........
5
d
Had difficulty performing the 
work or other activities (for 
example, it took extra effort) ........
1 ......
2...........
3 ...........
4 ...........
5
5. During the past week, how much of the time have you had any of the 
following problems with your work or other regular daily activities 
as a result of any emotional problems (such as feeling depressed or 
anxious)?
b
Moderate activities, such as moving a table, pushing 
a vacuum cleaner, bowling, or playing golf........................
1 ...........
2 ...........
3
c
Lifting or carrying groceries...............................................
1 ...........
2 ...........
3
d
Climbing several flights of stairs........................................
1 ...........
2 ...........
3
e
Climbing one flight of stairs...............................................
1 ...........
2 ...........
3
f
Bending, kneeling, or stooping...........................................
1 ...........
2 ...........
3
g
Walking more than a mile...................................................
1 ...........
2 ...........
3
h
Walking several hundred yards ..........................................
1 ...........
2 ...........
3
i
Walking one hundred yards................................................
1 ...........
2 ...........
3
j
Bathing or dressing yourself...............................................
1 ...........
2 ...........
3


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All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of
the time

a
Cut down on the amount of 
time you spent on work or 
other activities...............................
1 ...........
2 ...........
3 ...........
4.........
5
b
Accomplished less than you 
would like .....................................
1 ...........
2 ...........
3 ...........
4.........
5
c
Did work or other activities 
less carefully than usual................
1 ...........
2 ...........
3 ...........
4.........
5
6. During the past week, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely





1
2
3
4
5
7. How much bodily pain have you had during the past week?
None
Very mild
Mild
Moderate
Severe
Very severe






1
2
3
4
5
6
8. During the past week, how much did pain interfere with your normal 
work (including both work outside the home and housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely





1
2
3
4
5
9. These questions are about how you feel and how things have been 
with you during the past week. For each question, please give the one 
answer that comes closest to the way you have been feeling. How 
much of the time during the past week…
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of
the time



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10.During the past week, how much of the time has your physical health 
or emotional problems interfered with your social activities (like 
visiting with friends, relatives, etc.)?
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of
the time





1
2
3
4
5
11.How TRUE or FALSE is each of the following statements for you?
a Did you feel full of life? ..................
1.........
2 .........
3............
4............
5
b Have you been very nervous?..........
1.........
2 .........
3............
4............
5
c Have you felt so down in the 
dumps that nothing could 
cheer you up?...................................
1.........
2 .........
3............
4............
5
d Have you felt calm and 
peaceful?..........................................
1.........
2 .........
3............
4............
5
e Did you have a lot of energy?..........
1.........
2 .........
3............
4............
5
f Have you felt downhearted
and depressed?.................................
1.........
2 .........
3............
4............
5
g Did you feel worn out? ....................
1.........
2 .........
3............
4............
5
h Have you been happy?.....................
1.........
2 .........
3............
4............
5
i Did you feel tired? ...........................
1.........
2 .........
3............
4............
5


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Definitely 
true
Mostly 
true
Don’t 
know
Mostly 
false
Definitely 
false

a
I seem to get sick a little
easier than other people ................
1 ...........
2 ...........
3 ...........
4.........
5
b
I am as healthy as 
anybody I know ............................
1 ...........
2 ...........
3 ...........
4.........
5
c
I expect my health to 
get worse.......................................
1 ...........
2 ...........
3 ...........
4.........
5
d
My health is excellent...................
1 ...........
2 ...........
3 ...........
4.........
5
Thank you for completing these questions!
SF-36v2® Health Survey 1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated. All rights reserved.
SF-36® is a registered trademark of Medical Outcomes Trust.
(SF-36v2® Health Survey Acute, United States (English))


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10.1.6
Patient’s Global Impression of Severity (PGI-S)
Patient´s Global Impression of Severerity (PGI-S) – Post-prandial Abdominal Pain:
Please choose the response below that best describes the frequency of your 
ABDOMINALPAIN AFTER EATING over the past 7 days.
□Never
□Some of the times I ate
□About half of the time I ate
□Most of the times I ate
□Every time I ate
Patient´s Global Impression of Severity (PGI-S) – Dietary Restriction:
Please choose the response below that best describes the level of DIETARYRESTRICTIONS 
you had over the past 7 days.
□None
□Mild
□Moderate
□Severe
□Very severe
Patient´s Global Impression of Severity (PGI-S) – Overall Symptoms
Please choose the response below that best describes the severity of your OVERALL 
SYMPTOMS of OBSTRUCTION (such as abdominal pain or discomfort, restrictions to your 
diet, bowel symptoms, fatigue, and any other symptoms from your stricturing or obstruction)  
over the past 7 days.
□None
□Mild
□Moderate
□Severe
□Very severe
Patient´s Global Impression of Severity (PGI-S) – Symptom Impact/Interference
How much did your symptoms of obstruction INTERFERE WITH YOUR DAILY LIFE 
(such as limiting your activities, causing worry, disrupting your sleep, etc.) over the past 7 
days?
□Not at all
□A little bit
□A moderate amount
□Quite a bit
□Very much


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10.1.7
Clinician’s Global Impression of Change (CGI-C) and Clinician’s Global 
Impression of Severity (CGI-S)
Clinician’s Global Impression of Change in Symptoms (CGI-C):
Since the time the patient started this study, their stricturing Crohn’s disease symptoms have
□Greatly Improved
□Moderately Improved
□Minimally Improved
□Not Changed
□Minimally Worsened
□Moderately Worsened
□Greatly Worsened
Clinician’s Global Impression of Severity – Symptoms (CGI-S):
Please choose the response below that best describes the patient’s severity of stricturing 
Crohn’s disease symptoms at the visit
□None/No Symptoms
□Mild
□Moderate
□Severe
□Very severe


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10.2
EQUIVALENT DOSES OF CORTICOSTEROIDS
Table 10.2: 1
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


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10.3
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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10.4
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (
Excerpt out of the publication, please see [R13-3515]
1 - Mild
2 - Moderate
3 - Severe
4 - Includes 
Life 
Threatening
Asymptoma
tic, 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<24
h
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/hypersensit
ivity (including 
drug fever)
Transient 
rash; drug 
fever <38° 
C, transient 
asymptomat
ic 
bronchospa
sm
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/angioed
ema
Anaphylaxis, 
laryngeal/ 
pharyngeal 
edema, 
requiring 
resuscitation
A2. Autoimmune 
reaction
Serologic or 
other 
evidence of 
autoimmun
e reaction 
Evidence of 
autoimmune 
reaction 
involving a 
non-essential 
Reversible 
autoimmune 
reaction 
involving 
function of a 
Causes major 
organ 
dysfunction, or 
progressive, not 
reversible, or 


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but patient 
asymptomat
ic: all organ 
function 
normal and 
no 
treatment is 
required 
(e.g. 
vitiligo)
organ or 
functions, 
requiring 
treatment other 
than 
immunosuppres
sive drugs (e.g. 
hypothyroidism
)
major organ or 
toxicity 
requiring short 
term 
immunosuppres
sive treatment 
(e.g. transient 
colitis or 
anemia)
requires long 
term 
administration 
of high dose 
immunosuppres
sive 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
10.5
TRIAL BIOMARKER PLAN
Exploratory biomarkers in the biopsies, stool and blood are planned to be assessed at BI or a 
CRO authorized by BI to assess changes in following biomarkers pre- and post-treatment

Transcriptomic profile of biopsies and blood

Protein biomarkers in stool and blood

Immunohistochemistry and histopathology of biopsy

miRNA and / or microbiome in stool samples
For details on timing and sampling and analytical determinations, please refer to Section 5.4
and to the laboratory manual provided in the ISF.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
07 Jun 2021
EudraCT number
EU number
2020-005770-99
BI Trial number
1368-0059
BI Investigational Medicinal 
Product(s)
Spesolimab (BI 655130)
Title of protocol
Multi-center, double-blind, randomized, placebo-
controlled, phase IIa trial to evaluate spesolimab 
(BI 655130) efficacy in patients with fibrostenotic 
Crohn’s Disease.
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Information was specified.
Main inclusion criteria

Male and female patients, 18 to 75 years when 
signing informed consent at screening

Established diagnosis of clinical CD prior to 
screening

Suspicion of symptomatic small bowel stenosis

Abdominal pain after eating or limitation in 
amount or types of food at screening)

1 or 2 naïve or anastomotic stenoses in the 
terminal ileum at screening, confirmed by 
MRE at randomization

Have achieved a Symptomatic Stenosis 
Response (=7 days prior to randomization 
average scores <2 for 1-Abdominal pain after 
eating AND 2- limitation in amount or types of 
food at screening
Main exclusion criteria

No stenosis in reach of ileocolonoscopy

Systemic corticosteroid treatment of current 
obstructive symptoms for >1 week prior to 
screening

Endoscopic balloon dilation (EBD) or surgical 
treatment of the same small bowel stenosis 
within the last 6 months prior to screening Visit 
1


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
More than 2 small intestinal stenoses

Patients who require immediate EBD or 
surgical intervention as per the investigator´s 
discretion

Failure of >2 different biological drug classes 
prior to screening (e.g. TNF inhibitors, Integrin 
Receptor antagonists and 
IL-12 / IL-23 antagonists)

Current complications of CD at screening 
Visit 1 and randomization (Day 1) that would
possibly confound the evaluation of benefit 
from treatment with spesolimab

Current stenosis in the colon

Previous strictureplasty on current stricture 

Current ileostomy or colostomy

Any kind of bowel resection or diversion 
within 6 months of screening Visit 1 

Any other intra-abdominal surgery (except for 
abscess drainage) within 3 months prior to 
screening Visit 1

Colorectal cancer (CRC) present and past (<5 
years) history
Rationale for change
Information was added for clarification, rephrasing 
of wording.
Section to be changed
Clinical Trial Protocol Synopsis – Statistical 
Methods
Description of change
The primary analysis text was specified.
Rationale for change
Information was added for clarification
Section to be changed
Flow Chart
Description of change
Information was added:
-Stool sampling (enteric pathogens) at Screening 
visit 1 
-Therapeutic drug monitoring (pre-screening 
biological therapy)
-CGI scale was renamed
Information was added:
-Schedule baseline MRE and endoscopy 
examinations
Rationale for change
Information was added to Flow Chart for clarity.
Section to be changed
Flow Chart
Description of change
Footnote 1: Lead-in Period information was added
for clarification.


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Rationale for change
Information was added for clarification.
Section to be changed
Flow Chart
Description of change
Footnote 11: S-PRO information was specified.
Rationale for change
Information was added for clarification.
Section to be changed
Flow Chart
Description of change
Information was added:Description of (PROs) was 
specified..
Rationale for change
Information was added for clarification.
Section to be changed
Flow Chart
Description of change
Footnote 13: Information was added. CGI-C = 
Clinician’s Global and Impression of Change; 
CGI-S = Clinician’s
Rationale for change
Information was added for clarification.
Section to be changed
Flow Chart
Description of change
Footnote 15: (GFR) assessment was expanded 
(either done locally or via central laboratory)
Rationale for change
GFR test locally was changed to locally or central 
to allow more flexibility.
Section to be changed
Flow Chart
Description of change
Flow Chart 2 added.
Appendix was added as flowchart 2 for Lead-In 
Period Logistics
Rationale for change
Information was moved and information added for 
clarity.
Section to be changed
Abbreviations and Definitions
Description of change
CGI-I was changed to CGI-C Clinician’s Global 
Impression of Change
PGI-C was deleted.
Rationale for change
Information changed for harmonization.
Section to be changed
1.2. Drug Profile
Description of change
Data from clinical studies
Information added:
(…) !"" # $%&'&%(&)'&%"*+,-.'/'
0'1'/,""2 .'""
3%"'/,3'$4
Information for 1368.4, 1368.10 and 1368.13 trials
and IB was added.
Rationale for change
New information added.


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Section to be changed
1.2. Drug Profile
Description of change
Summary was modified.
Patient numbers was updated.
Rationale for change
Wording rephrased and new information added.
Section to be changed
1.3 Rationale for Performing the Trial
Description of change
Information was added:
(…) The first is a Patient Reported Outcome tool 
(S-PRO), named Stricturing Crohn´s Disease 
Questionnaire. This is a questionnaire which has 
been developed in accordance with current Food 
and Drug Administration (FDA) guidance in 
collaboration with national and international IBD 
societies to capture symptoms specific to stenotic 
complication in CD patients. Thus, S-PRO , 
together with other patient reported outcomes 
(PROs) tools will be used in this study to measure 
symptoms to explore if this instrument might be 
fit-for-purpose to measure symptomatic endpoints 
in this population. 
(…) Therefore, in this PoCC trial we propose to 
use MRE to diagnose and assess the stenosis status 
in the targeted population at baseline and after 
treatment in order to explore the radiological 
variables that might be more closely linked to 
relevant clinical outcomes in this population. 
These data might provide the basis to develop a 
standardized radiological endpoint to be used in 
future clinical development.
Rationale for change
Information was added for clarity.
Section to be changed
1.4.1 Benefits
Description of change
Wording was rephrased.
(…)
Spesolimab may maintain Symptomatic Stenosis 
Response (…).
Beyond the objective of demonstrating PoCC for 
spesolimab in this disease, the study will help to 
develop  novel S-PRO and stenotic radiographic 
outcomes (…).
Rationale for change
Wording rephrased for clarity.
Section to be changed
1.4.2 Risks
Description of change
New information was added:


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In 1368.4, 1368.5 and 1368.10 (patients with UC) 
trials as well as in 1368.11, 1368.13 (patients with 
GPP), 1368.15 (patients with PPP) and 1368.32 
(patients with AtD) trials, overall, spesolimab was 
well tolerated [c03320877].
(…) and (d) regular surveillance by an independent 
Data Monitoring Committee (DMC).
Rationale for change
New information on IB update
Section to be changed
1.4.2 Risks - Table 1.4.2:1 Overview of Trial 
Related Risks
Description of change
Drug Induced Liver Injury (DILI)
Summary of data, rationale for the risk
New information for (DILI) was added.
Rationale for change
Information was added due to FDA 
recommendation after pre-IND package 
submission.
Section to be changed
1.4.2 Risks - Table 1.4.2:1 Overview of Trial 
Related Risks
Description of change
Drug Induced Liver Injury (DILI) 
Mitigation strategy
New information was added: Trial treatment 
discontinuation criteria were added.
Rationale for change
Information was added due to FDA 
recommendation.
Section to be changed
1.4.2 Risks - Table 1.4.2:1 Overview of Trial 
Related Risks
Description of change
Systemic hypersensitivity
reaction
Summary of data, rationale for the risk
New information was added: 
(…) possibility of occurrence of immediate (such 
as anaphylaxis) or delayed (such as drug reaction 
with eosinophilia and systemic symptoms) adverse 
immune reactions.
Rationale for change
Information was added due new IB information.
Section to be changed
1.4.2 Risks - Table 1.4.2:1 Overview of Trial 
Related Risks
Description of change
Infections 
Summary of data, rationale for the risk
New information was added: 


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(…) In clinical trials with spesolimab, a higher 
proportion of patients with mild to moderate 
infections was seen (…).
Nevertheless, there was no indication of an 
increased frequency of patients with severe, 
serious, and opportunistic infections in association 
with spesolimab treatment.(…)
Rationale for change
Information was added due new IB information.
Section to be changed
1.4.2 Risks - Table 1.4.2:1 Overview of Trial 
Related Risks
Description of change
Malignancies
Summary of data, rationale for the risk
Information was rephrased.
Inhibition of the immune response with an 
immune-modulating biologic may potentially 
impair immune defences and thus theoretically 
decrease immune defense against malignancies.
Rationale for change
Information was rephrased due to IB information.
Section to be changed
1.4.2 Risks - Table 1.4.2:1 Overview of Trial 
Related Risks
Description of change
Possible or known risks of clinical relevance for 
this trial- Hematological laboratory abnormalities
Hematological laboratory abnormalities are not 
considered to present a risk due to spesolimab 
administration(…).
Mitigation strategy
Guidance on assessment and mitigation measures 
with regards to hematological laboratory 
abnormalities is included into current Clinical Trial 
Protocol (Section 4.2.1.4)
Rationale for change
Information was added due to FDA 
recommendation.
Section to be changed
1.4.3 Discussion
Description of change
Information was added:
Benefit-Risk Assessment in context of COVID-19 
pandemic
Rationale for change
Information was rephrased due to updated IB 
information.


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Section to be changed
Description of change
Rationale for change
Section to be changed
2.3 Definition of Study Outcomes - Table 2.3: 1 
Definitions of Study Outcomes
Description of change
Symptomatic Stenosis Response and Symptomatic 
Stenosis Relapse
Information was specified:
average score for abdominal pain after 
AND 
average score for amount or types of food 
limitation 
SES-CD>12 was specified.
Rationale for change
Information was specified.
Section to be changed
2.3 Definition of Study Outcome - Table 2.3: 1 
Definitions of Study Outcomes
Description of change
Symptomatic Stenosis Relapse
Information was specified:
7 days average score for abdominal pain after 
eating ≥2 
AND 
7 days average score for amount or types of food 
limitation ≥2
See questions for symptomatic primary outcome 
and explanation on the scoring in the paragraph 
below this table.
Rationale for change
Information was specified.


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Section to be changed
2.3 Definition of Study Outcome - Table 2.3: 1 
Definitions of Study Outcomes
Description of change
The Symptomatic Stenosis Response and the 
Symptomatic Stenosis Relapse are calculated 
automatically using 2 questions of the eDiary 
completed by the patient. 
For both questions, a 7-day average score is 
calculated based on a scale from 0 to 3 
Table and additional information was added.
Rationale for change
Information was added for clarity.
Section to be changed
3.1 Overall Trial Design
Description of change
Trial discontinuation
Information added:
(…) Such patients will be considered as treatment 
failures in the primary efficacy analysis.
Rationale for change
Information was added for clarity.
Section to be changed
3.2.1 Rationale for selected Trial Population
Description of change
Information was specified:
To reduce and control part of the inherent 
heterogeneity of the general fibrostenotic CD 
population (…)
Rationale for change
Information was specified for clarity.
Section to be changed
3.2.2 Rationale for an Add-On Therapy and 
Placebo-controlled Trial
Description of change
Information was corrected:
Combination treatment of 12 weeks with the same 
spesolimab dose regimen on top of anti-TNF 
inhibitors was found safe and well tolerated in a 
pilot study (N= 22 in mild to moderate UC
Rationale for change
Correction
Section to be changed
3.2.3 Rationale for a 48 week duration and for 
proposed endpoints
Description of change
Information added for Abdominal pain information 
was added.
Rationale for change
Information added for clarity.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Wording rephrased: 
No. 1 Established diagnosis of clinical Crohn’s 
Disease (…)
Rationale for change
Wording rephrased to allow more flexibility.


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Section to be changed
3.3.2 Inclusion Criteria
Description of change
Wording rephrased: 
No. 2 Suspicion of small bowel stenosis
Rationale for change
Wording rephrased for clarity.
Section to be changed
3.3.2 Inclusion criteria
Description of change
Wording rephrased: 
No. 3 Presence at screening visit (or at least within 
6 days before screening) ….
Rationale for change
Wording rephrased for clarity.
Section to be changed
3.3.2 Inclusion Criteria 
Description of change
No. 8 Wording was rephrased:
Have achieved a Symptomatic Stenosis Response 
(…).
Rationale for change
To align with S-PRO scoring.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
No 10 Wording was rephrased:
Absent, mild or moderate endoscopic activity 
defined by Colonic Simple Endoscopic Score in 
Crohn’s Disease (SES-CD) ≤12
Rationale for change
Wording was rephrased for clarity.
Section to be changed
3.3.3 Exclusion criteria 
Description of change
Gastrointestinal Exclusion Criteria 
Exclusion criteria 1-5 were reordered and wording 
rephrased.
Rationale for change
Reorder for clarity.
Section to be changed
3.3.3 Exclusion Criteria
Description of change
No 9 Information was added:
Current stenosis in the colon (CONSTRICT 
criteria apply, [R20-3947])
Rationale for change
Reference to constrict criteria added.
Section to be changed
3.3.3 Exclusion Criteria
Description of change
No. 10 was rephrased and splitted:
Previous strictureplasty on current stricture
Rationale for change
Information was changed for clarity
Section to be changed
3.3.3 Exclusion Criteria
Description of change
No 10 splitted and information was added as new 
exclusion criteria No.11.
Current ileostomy or colostomy.


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Rationale for change
Information was changed for clarity
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criteria was splitted:
Any kind of bowel resection or diversion within 6 
months of screening Visit 1
Any other intra-abdominal surgery (except for 
abscess drainage) within 3 months prior to 
screening Visit 1
Rationale for change
Information was changed for clarity
Section to be changed
3.3.3 Exclusion criteria - Infectious Disease 
Exclusion Criteria
Description of change
No 16 Wording was rephrased:
Relevant chronic or acute infections including 
human immunodeficiency virus (HIV) and viral 
hepatitis.
Rationale for change
Information was changed for clarity
Section to be changed
3.3.3 Exclusion criteria - Infectious Disease 
Exclusion Criteria
Description of change
No 17 Exclusion criteria for tuberculosis was 
specified.
Rationale for change
Information was changed for clarity.
Section to be changed
3.3.3 Exclusion criteria - General Exclusion 
Criteria
Description of change
No 21 Information for major surgery was 
rephrased.
Rationale for change
Rephrasing for clarity.
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
Information was added: Discontinue criteria and 
stopping rules.
Rationale for change
Information was added due to FDA 
recommendation.
Section to be changed
4.5.1.1 Blinding
Description of change
Wording was specified
Rationale for change
Wording was specified for clarity.
Section to be changed
4.2.1.1 Lead-in anti-inflammatory Treatment
Description of change
Information was specified for use of 
Corticosteroids.
Rationale for change
Information was specified for clarity.


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Section to be changed
4.2.1.1 Lead-in anti-inflammatory Treatment
Description of change
OPTIMIZATION OF ANTI-INFLAMMATORY 
BIOLOGICAL TREATMENT
Information was added.
Anti-inflammatory biological treatment (…).
Rationale for change
Information was specified for clarity.
Section to be changed
4.2.1.1 Lead-in anti-inflammatory Treatment
Description of change
Text was deleted:
Use of azathioprine [AZA] / 6-mercaptopurin [6-
MP] or methotrexate [MTX]) in combination with 
biologics.
Rationale for change
Information was changed due to FDA 
recommendation. 
Use of azathioprine [AZA] / 6-mercaptopurin [6-
MP] or methotrexate [MTX]) in combination with 
biologics was deleted to avoid overimmuno-
suppression. Information for TNF was specified.
Section to be changed
4.2.1.3 Concomitant Medication - Allowed for CD 
Treatment
Description of change
Lead-In Period, Information added: 
Azathioprine, 6-mercaptopurin or methotrexate 
(are allowed in combination with TNF inhibitors) 
to be discontinued prior to the randomization 
Rationale for change
Information was added due to FDA 
recommendation to avoid overimmuno-
suppression. 
Section to be changed
4.2.1.4 Management of Adverse Events
Description of change
Systemic hypersensitivity including infusion 
reaction and anaphylactic reaction
Information added.
Rationale for change
Information was added for clarification.
Section to be changed
4.2.1.4 Management of Adverse Events
Description of change
Information on time was modified.
Rationale for change
Rephrasing of wording for time based on In-Use 
stability information.
Section to be changed
4.2.1.4 Management of Adverse Events
Description of change
Information was added and wording was 
rephrased.


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Rationale for change
Rephrasing for clarity.
Section to be changed
4.2.1.4 Management of Adverse Events -
Malignancies
Description of change
Information added.
Rationale for change
Information was added due to FDA 
recommendation. 
Section to be changed
4.2.2 Restrictions - Table 4.2.2.1: 1 Prohibited and 
Restricted Medications
Description of change
Information of azathioprine, 6-mercaptopurin or 
methotrexate was changed
Rationale for change
Information was changed due to FDA 
recommendation.
Section to be changed
4.2.2 Restrictions - Table 4.2.2.1: 1 Prohibited and 
Restricted Medications
Description of change
Corticosteroids
Information was added.
Rationale for change
Information was changed for clarity.
Section to be changed
4.2.2.3 Contraception Requirements
Description of change
Typo corrected
Rationale for change
Correction.
Section to be changed
5.1 Assessment of Efficacy
Description of change
Wording was rephrased.
CGI-I and PGI-C deleted.
Clinician’s assessment of CDAI, and the 
clinician’s reported outcomes (clinROs) CGI-C 
and CGI-S scales assess the status of both the 
inflammatory and stenotic portion of the 
fibrostenotic CD condition.
PROs include the newly developed S-PRO, as well 
as IBDQ, SF-36, and the PGI-S scales, and the 
diary portion of the CDAI.
Rationale for change
Information was changed due to FDA 
recommendation.
Section to be changed
5.1.1 Magnetic Resonance Enterography (MRE)
Description of change
Information for central laboratory for GFR test was 
added.
Rationale for change
To allow sites more flexibility.
Section to be changed
5.1.2 Stenosis Patient Reported Outcome (S-PRO) 
Tool


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Description of change
Information was added:
(…) For S-PRO questionnaire (Stricturing Crohn´s 
Disease Questionnaire) And 7-day average score 
Rationale for change
Information was added for clarity.
Section to be changed
5.1.7 Patient’s Global Impression of Severity (PGI-
S)
Description of change
Header was changed and wording was rephrased:
Explanation for PRO PGI-S scale
Rationale for change
Information was changed for clarity.
Section to be changed
5.1.8 Clinician’s Global Impression of Change 
(CGI-C) and Clinician’s Global Impression of 
Severity (CGI-S) scales
Description of change
Header was changed and wording was rephrased.
CGI-C and CGI-S scales process.
Rationale for change
Information was changed after FDA 
recommendation. New anchor questionnaires are 
available.
Section to be changed
5.2.3 Safety laboratory parameters
Description of change
Information for Potential Severe DILI was 
rephrased.
Rationale for change
Information was changed due to FDA 
recommendation.
Section to be changed
5.2.6.1.2 Serious adverse 
Description of change
Format change.
Rationale for change
Format change for clarity.
Section to be changed
5.2.6.1.4 Adverse events of special interest –
Potential DILI
Description of change
Information for potential severe DILI was added.
Rationale for change
Information was changed due to FDA 
recommendation.
Section to be changed
5.2.6.2.1 AE Collection
Description of change
Information was added.
Rationale for change
Information added for clarity.
Section to be changed
5.7 Appropriateness of Measurements
Description of change
Information for clinROs instruments CGI-C and 
CGI-S scales as well as the PRO instruments PGI-


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S scales was added.
Rationale for change
Information was added for clarity.
Section to be changed
6.2 Details of Trial Procedures at Selected Visits
Description of change
PGI-C was deleted.
Rationale for change
Information was harmonized with new PROs.
Section to be changed
6.2.1 Lead-in Period
Description of change
Reference to Flow Chart 2 was added.
Central laboratory for GFR test was added.
Rationale for change
Central laboratory was included to allow 
investigators more flexibility.
Section to be changed
6.2.2.1 Scheduled Visits during the Treatment 
Period
Description of change
Central laboratory was added for GFR assessment
Rationale for change
Central laboratory was included to allow 
investigators more flexibility.
Section to be changed
6.2.2.1 Scheduled Visits during the Treatment 
Period
Information was corrected.
SES-CD>12
Rationale for change
Correction 
Section to be changed
6.2.2.1 Scheduled Visits during the Treatment 
Period
Description of change
Information was added:
In case the worsening of CD symptoms related 
unscheduled visit occurs:
7 days or less before next scheduled visit (…)
more than 7 days before next scheduled visit
Information for GFR assessment (either done 
locally or via central laboratory) was added.
Rationale for change
Information was added for clarity.
Section to be changed
7.2.2 Primary Endpoint Analysis 
Description of change
Correction.
Rationale for change
Correction
Section to be changed
7.2.7 Interim Analysis
Description of change
Information added
Rationale for change
Information added for clarity.


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Section to be changed
7.5 Determination of Sample Size
Description of change
Wording was rephrased.
Rationale for change
Wording was rephrased.
Section to be changed
10. Appendices - Table 10.1.1 Description
Description of change
Information added:
Stricturing Crohn’s Disease Questionnaire
Rationale for change
Final questionnaires available.
Section to be changed
10. Appendices
10.1.6 Patient’s Global Impression of Severity 
(PGI-S) scale 
10.1.7 Clinician’s Global Impression of Change 
(CGI-C) and Clinician’s Global Impression of 
Severity (CGI-S)
Description of change
New questionnaires were added.
Rationale for change
Information was added due to PGI and CGI change 
after FDA recommendation.
11.2
GLOBAL AMENDMENT 2
Date of amendment
20 Oct 2021
EudraCT number
EU number
2020-005770-99
BI Trial number
1368-0059
BI Investigational Medicinal 
Product(s)
Spesolimab (BI 655130)
Title of protocol
Multi-center, double-blind, randomized, placebo-
controlled, phase IIa trial to evaluate spesolimab 
(BI 655130) efficacy in patients with fibrostenotic 
Crohn’s Disease.
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
3.3.4.1
Description of change
Addition of permanent trial treatment 
discontinuation if patient experiences a moderate 
or severe opportunistic infection, or if a patient 
experiences any infection that meets SAE reporting 
criteria.
Rationale for change
Clarification to address FDA request.
Section to be changed
4.2.1.1
Description of change
Clarification that any optimization during the 
Lead-in Period is restricted to approved doses of 


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proposed agents as per local label.
Rationale for change
Clarification to address FDA request.
Section to be changed
4.2.1.3
Description of change
Clarification that any dose escalation allowed 
during the trial is restricted to approved doses of 
proposed agents as per local label.
Rationale for change
Clarification to address FDA request.
Section to be changed
4.2.1.4
Description of change
Deletion of serious infections and clarification that 
a restart of trial medication is possible only for 
mild opportunistic infections.
Rationale for change
To align with changes done to Section 3.3.4.1 upon 
FDA request for clarification.
Section to be changed
4.2.2.1
Description of change
Clarification that investigational drugs are 
restricted either within 30 days or 5 half-lives, 
whichever is longer.
Rationale for change
To align with changes done for non-biologic 
medications upon FDA request for clarification.
Section to be changed
4.2.2.1
Description of change
Clarification that only biologics used for treatment 
of Crohn’s disease will be permitted and that all 
other biologics, for any reason, will be prohibited.
Rationale for change
Clarification to address FDA request.
Section to be changed
4.2.2.1
Description of change
Clarification that non-biologic medications (such 
as cyclosporine, JAK inhibitors, S1P modulators, 
and SMAD7 antisense inhibitors) are restricted 
either within 30 days or 5 half-lives, whichever is 
longer.
Rationale for change
Clarification to address FDA request.
Section to be changed
5.2.6.1.4
Description of change
Specification of patient discontinuation and 
follow-up for potential severe DILI
Rationale for change
Information was changed due to FDA request.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34096215
3.0
clinical-trial-protocol-version-03
Multi-center, double-blind, randomized, placebo-controlled, phase IIa trial to
evaluate spesolimab (BI 655130) efficacy in patients with fibrostenotic Crohn’s
Disease
Author-Clinical Trial Leader
21 Oct 2021 10:43 CEST
Approval-Team Member Medicine
21 Oct 2021 11:26 CEST
Author-Clinical Pharmacokineticist
21 Oct 2021 15:12 CEST
Author-Trial Statistician
22 Oct 2021 09:58 CEST
Approval
 Medicine
22 Oct 2021 19:43 CEST
Verification-Paper Signature
Completion
25 Oct 2021 09:14 CEST


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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34096215
3.0