Clinical trial NCT03648541
Conditions: Colitis, Ulcerative
Sponsor: Boehringer Ingelheim
Start date: 2018-10-29; Completion date: 2023-05-03
Enrollment: 79 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the long-term safety of BI 655130 (SPESOLIMAB) in patients with moderate to severely active ulcerative colitis, who have completed treatment in previous trials

To evaluate the long-term efficacy of BI 655130 (SPESOLIMAB) in patients with moderate to severely active ulcerative colitis, who have completed treatment in previous trials

Detailed description:

Arms: arm 1: Spesolimab IV infusion arm 2: Spesolimab SC solution for injection
Interventions: intervention 1: Spesolimab
Intervention descriptions: intervention 1: Solution

Protocol documents:
Prot_000.pdf: 




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Diagnosis :
Moderate to severe ulcerative colitis
Main in- and exclusion 
criteria
∀
Male or female patients , aged ≥18 years
∀
Have completed treatment with study drug in the previous trials and 
agree to continue treatment in 1368-0017
∀
Women of childbearing potential (WOCBP)  must be ready to use 
highly effective methods of birth control 
∀
Have not experienced dose limiting adverse events during induction 
treatment with study drug
∀
Have not developed any of the exclusion criteria from the original 
induction study
Test product(s):
BI 655130
dose:
Maintenance: 300mg q4w s.c., 600mg q6w s.c. OR 
Re-induction: 1200mg q4w i.v.
mode of 
administration:
See above ; s.c. as a maintenance treatment and i.v. as re-induction
Comparator products:
Not applicable
dose:
Not applicable
mode of 
administration:
Not applicable
Duration of treatment:
Maintenance treatment : 336 weeks
Re-induction: 12 weeks
Endpoints
Primary endpoint:
Primary endpoint is the exposure adjusted rate of patients reporting a 
treatment emergent adverse event (TEAE) up to week 336 of maintenance 
treatment
Secondary endpoint:
Proportion of patients with clinical remission at week 336 of maintenance 
treatment
Safety criteria:
Physical examination, vital signs, 12-lead ECG, laboratory tests, adverse 
events, serious adverse events and tolerability. The intensity grading of 
AEs and abnormal laboratory values will be performed according to 
Rheumatology Common Toxicity Criteria (RCTC) Version 2.0.
Statistical methods:
Descriptive statistics only.










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Footnotes for all Flow Charts:
1.
Visit V1 of this long-term extension study should be  performed during the last visit (V6/EOT) of the preceding trial 1368-0005 Part 1 or 1368-0004. Assessments 
performed at last visit (V6/EOT) in the previous trial do not have to be repeated at visit 1 in this trial. Patients not eligible to take part in trial 1368-0017 shall 
complete follow-up visit 16 weeks after last dose given in trial 1368-0004 or 1368-0005 Part I.
2.
Visit V1a can be performed via telephone. Main reason for this visit is to check eligibility based on sigmoidoscopy and patient diary results in order to plan the 
next visit. 
3.
Sigmoidoscopies have to be performed  every 48 weeks during maintenance treatment period. Additional sigmoidoscopies are to be done: a) at screening (EOT of 
previous trial); b) at W12 of re-induction period to check response to i.v. re-induction (Flowchart 2); c) In case of disease flare, an unscheduled confirmatory 
sigmoidoscopy has to be performed, followed in12 weeks after i.v. re-induction to check response to disease flare treatment. Two sets of mucosal biopsies will be 
taken; 1 set for gene expression analyses and 1 set for histopathology/IHC analyses at each visit indicated. Sigmoidoscopy images will be centrally read by an 
external independent assessor(s); management of images will be performed by an external vendor. Colonoscopy instead of sigmoidoscopy can be performed if 
required as colon cancer screening per local guidelines. 
4.
Physical examination: C=complete, T=targeted. Refer to Section 5.2.1 and 5.2.2. Measurement of vital signs should precede blood sampling and be assessed pre-
dose at all dosing visits and at screening. In addition, at visits with s.c. study drug administration, vital signs will be assessed at approx. 10 minutes after study drug 
administration. At visits with i.v. study drug administration, vital signs will be assessed at approximately 5 and 60 minutes after study drug administration.
Monitor for signs and symptoms of hypersensitivity reactions for 1h following i.v. study drug administration. 
5.
For women of childbearing potential. A serum pregnancy test will be performed at screening. Urine pregnancy tests will be performed at all other visits indicated 
in the Flow chart. In case of a positive urine pregnancy test, a serum pregnancy test will be done. Urine pregnancy testing should be done prior to administration of 
study drug. Study drug should only be administered in case of a negative test result. More frequent testing should be done if required by the local regulation or per 
investigator judgment.
6.
Includes clinical chemistry, hematology, coagulation and urinalysis assessments. Patient is not required to be fasting prior to blood collection. If fasted mark it on 
laboratory requisition form. At visits with study drug administration blood sampling should be done prior to the study drug administration. For details of laboratory 
tests see Section 5.2.3, Table 5.2.3:1and Table 5.2.3:2. TSH and Glycosylated Hbc (HbA1c) tests have to be done every 48 wks, starting from W36 of maintenance 
treatment period.
7.
Absence of enteric pathogens in stool shall be confirmed as a part of disease flare confirmation using central laboratory.


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10. Inflammatory Bowel Disease Questionnaire (IBDQ) and EQ-5D(-5L) must be completed by the patient on his/her own in a pre-specified order in a quiet area/room 
before any other visit assessments or treatments and, as much as possible, before any interaction with the investigator or other members of the study team. Refer to 
Section 6.2. IBDQ and EQ-5D(-5L) will be collected at every 24 weeks until visit M13 ( Week 144 or equivalent for flare patients), afterwards only at visits with 
sigmoidoscopy, EOT and EOS visit as indicated in the Flowchart.
11. An e-diary will be used by the patient for the reporting of bowel movement frequency and rectal bleeding (blood in stool) for a period of 14 days prior to visits and 
when a patient perceives a worsening of UC symptoms at any time between visits as a precursor to disease flare assessment. This information will be used for the 
calculation of Mayo score. PGA (Physician Global Assessment) should be completed according to flowchart Refer to Section 6.2.1. 
12. First study drug administration will be administered at M1/R1 after response status check is completed
13. For patients who discontinue study medication before scheduled end of treatment, an early EOT visit has to be scheduled.subsequently EOS visit 16 weeks after 
last dose of study medication has to be performed.
14. At visit R4 patient response status to i.v. re-induction has to be checked. Sigmoidoscopy and eDiary data review are part of eligibility check to continue into 
maintenance treatment. Patients who did not respond to i.v. re-induction will be discontinued from study medication and early EOT visit has to be performed. EOS 
visit has to be performed 16 weeks after last dose of study medication (16 weeks after R3 visit). Sigmoidoscopy does not need to be done at EOT visit for these
patients.
15. Visit M1 (flowchart for re-induction non-responders) has to be performed after results of sigmoidoscopy performed at visit R4 are received (usually 5-7 days)
16. For patients with disease flares only, sigmoidoscopy does not need to be repeated if done within 6 weeks prior to EOT visit.
17. Patients who develop a disease flare during maintenance study treatment period confirmed by sigmoidoscopy will receive a single infusion of 1200mg BI 655130
(SPESOLIMAB) i.v. followed 6 weeks later by intensified maintenance treatment with 600mg BI 655130 s.c. q6w until the originally scheduled EOT visit (i.e. at 
week 336 after start of first sc. maintenance treatment) 
18. Cycle of visits F1-x to F4-x (visits every 6 weeks) is repeated until originally scheduled EOT, 336 weeks after initial visit M1, is reached.
19. QuantiFERON-TB test should be done every 48 wks.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART 1A: INDUCTION RESPONDERS V1, V1A, M1-M5B ...........................4
FLOW CHART 1B: INDUCTION RESPONDERS M6-EOS.............................................5
FLOW CHART 2: INDUCTION NON-RESPONDERS.....................................................6
FLOW CHART 3: PATIENTS WITH DISEASE FLARE..................................................7
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1. INTRODUCTION..............................................................................................................18
1.1
MEDICAL BACKGROUND.............................................................................18
1.2
DRUG PROFILE................................................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................34
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........34
2.1.1
Main objectives....................................................................................................35
2.1.2
Primary endpoint(s)............................................................................................36
2.1.3
Secondary endpoint.............................................................................................36
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................38
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................38
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................41
3.3
SELECTION OF TRIAL POPULATION .......................................................42
3.3.1
Main diagnosis for trial entry ............................................................................43
3.3.2
Inclusion criteria .................................................................................................43
3.3.3
Exclusion criteria ................................................................................................43
3.3.4
Withdrawal of patients from therapy or assessments .....................................44
3.3.4.1
Withdrawal from trial treatment ...........................................................................44
3.3.4.2
Withdrawal of consent for trial participation........................................................45
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................45
4.
TREATMENTS...................................................................................................46
4.1
INVESTIGATIONAL TREATMENTS ...........................................................46
4.1.1
Identity of the Investigational Medicinal Product ...........................................46
4.1.2
Selection of doses in the trial..............................................................................46
4.1.3
Method of assigning patients to treatment groups...........................................47


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4.1.4
Drug assignment and administration of doses for each patient......................47
4.1.5
Blinding and procedures for unblinding...........................................................49
4.1.5.1
Blinding.................................................................................................................49
4.1.5.2
Unblinding and breaking the code ........................................................................49
4.1.6
Packaging, labelling, and re-supply...................................................................49
4.1.7
Storage conditions...............................................................................................49
4.1.8
Drug accountability.............................................................................................49
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................50
4.2.1
Other treatments and emergency procedures..................................................50
4.2.2
Restrictions ..........................................................................................................52
4.2.2.1
Restrictions on diet and life style..........................................................................54
4.2.2.2
Restrictions regarding Women of Childbearing Potential....................................54
4.3
TREATMENT COMPLIANCE........................................................................54
5.
ASSESSMENTS..................................................................................................56
5.1
ASSESSMENT OF EFFICACY........................................................................56
5.2
ASSESSMENT OF SAFETY.............................................................................56
5.2.1
Physical examination ..........................................................................................56
5.2.2
Vital signs.............................................................................................................56
5.2.3
Safety laboratory parameters ............................................................................57
5.2.4
Electrocardiogram ..............................................................................................60
5.2.5
Other safety parameters.....................................................................................61
5.2.6
Assessment of adverse events.............................................................................61
5.2.6.1
Definitions of AEs ................................................................................................61
5.2.6.2
Adverse event collection and reporting ................................................................64
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................71
6.
INVESTIGATIONAL PLAN.............................................................................72
6.1
VISIT SCHEDULE.............................................................................................72
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................72
6.2.1
Screening and run-in period(s)..........................................................................72
6.2.2
Treatment period ................................................................................................74
6.2.3
Follow up period and trial completion..............................................................75


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6.2.3.1
Early treatment discontinuation ............................................................................75
6.2.3.2
Trial completion....................................................................................................76
6.2.3.3
Further treatment after the end of the trial ............................................................76
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................77
7.1
STATISTICAL DESIGN - MODEL.................................................................77
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................77
7.3
PLANNED ANALYSES.....................................................................................78
7.3.1
Primary endpoint analyses.................................................................................78
7.3.2
Secondary endpoint analyses .............................................................................78
7.3.4
Safety analyses.....................................................................................................79
7.4
INTERIM ANALYSES ......................................................................................80
7.5
HANDLING OF MISSING DATA ...................................................................81
7.6
RANDOMISATION ...........................................................................................81
7.7
DETERMINATION OF SAMPLE SIZE .........................................................82
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........83
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................83
8.2
DATA QUALITY ASSURANCE ......................................................................84
8.3
RECORDS...........................................................................................................84
8.3.1
Source documents ...............................................................................................84
8.3.2
Direct access to source data and documents.....................................................85
8.3.3
Storage period of records ...................................................................................86
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................86
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........86
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................86
8.6
TRIAL MILESTONES.......................................................................................87
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................87
9.
REFERENCES....................................................................................................89
9.1
PUBLISHED REFERENCES............................................................................89
9.2
UNPUBLISHED REFERENCES......................................................................94
10.
APPENDICES.....................................................................................................95
10.1
MAYO SCORING SYSTEM FOR THE ASSESSMENT OF 
ULCERATIVE COLITIS ACTIVITY .............................................................95
10.2
HISTOLOGIC ACTIVITY SCORE.................................................................96
10.3
EQUIVALENT DOSES OF CORTICOSTEROIDS.......................................98
10.4
PATIENT REPORTED OUTCOMES .............................................................98
10.4.1
Inflammatory Bowel Disease Questionnaire (IBDQ) ......................................98


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10.4.2
EQ-5D-5L.............................................................................................................98
10.5
DIAGNOSIS OF ANAPHYLAXIS ...................................................................99
10.6
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (
) ......................................100
10.7
STEROID TAPERING SCHEME ..................................................................101
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................102
11.1
GLOBAL AMENDMENT 1 ............................................................................102
11.2
GLOBAL AMENDMENT 2 ............................................................................117
11.3
GLOBAL AMENDMENT 3 ............................................................................120
11.4
GLOBAL AMENDMENT 4 ............................................................................121
11.5
GLOBAL AMENDMENT 5 ............................................................................126
11.6
GLOBAL AMENDMENT 6 ............................................................................128
11.7
GLOBAL AMENDMENT 7 ............................................................................130


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ABBREVIATIONS
ADCC
antibody-dependent cellular cytotoxicity
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine transaminase
AST
Aspartate transaminase
BI
Boehringer Ingelheim
b.i.d.
bis in die (twice daily dosing)
BIO
Biologics
BL
Base Line
c
complete
CCDS
Company Core Data Sheet
CD
Crohn’s disease
CDC
complement-dependent cytotoxicity
cf.
confer
CI
Confidence Interval
CML
Clinical Monitor Local
CR
Clinical Remission
CRA
Clinical Research Associate
CRO
Clinical Research Organisation
CRF
Case Report Form, paper or electronic (sometimes referred to as 
“eCRF”)
CRP
C-Reactive Protein
CS
Systemic corticosteroids
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
eDC
electronic Data Capturing
EOS
End of Study
EOT
End of Treatment
ePRO
Electronic Patient Reported Outcome


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EQ-5D(-5L)
Questionnaire developed by EuroQoL Group
ESS
Mayo Endoscopy Score
EU
European Union
EudraCT
European Clinical Trials Database
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full Analysis Set
FC
Flow Chart
FCP
Faecal calprotectin
FcR
Fc receptor - a protein found on the surface of certain cells
FDA
Food and Drug Administration
FIH
First in human
GCP
Good Clinical Practice
GPP
generalized pustular psoriasis
H
hour
HbA1c
Hemoglobin A1c
Hbc
Hemoglobin C
HCRU
Healthcare resource utilisation
HPC
Human Pharmacology Centre
HT29
a human colorectal adenocarcinoma cell line with epithelial 
morphology
i.v.
intravenous
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
IBDQ
Inflammatory Bowel Disease Questionnaire
IC90
inhibitory concentration of 90 (mg/mL)
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFNγ
Interferon gamma
IgE
Immunglobulin E
IgG1
Immunglobulin G1
IHC
immunohistochemistry
IL36R
Interleukin 36R
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITE
indirect target engagement
LoEE
List of Essential Element 
LPDD
Last Patient Drug Discontinuation


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MCID
minimal clinically important difference
MCS
Mayo Clinical Score
MedDRA
Medical Dictionary for Drug Regulatory Activities
mESS
modified Endoscopic Subscore
mMCS
modified Mayo Clinical Score
MoA
Mode of action
MST
Medical Sub Team
NF-kB
nuclear factor 'kappa-light-chain-enhancer' of activated B-cells
NOAEL
no-observed-adverse-effect level
OL
Open-label
OPU
Operative Unit
p.o.
per os (oral)
PBMC
Peripheral Blood Mononuclear Cell
PBO
placebo
pCR
partial Clinical Remission
PD
Pharmacodynamics
PGA
Physician’s global assessment
PMR
Partial Mayo Clinical Score remission
PRO
Patient reported outcome
PoC
proof of concept
PoCC
proof of clinical concept
PPP
palmoplantar pustulosis
Pts.
Patients
q.d.
quaque die (once a day)
q.w.
quatery week (every 4th week)
RBS
rectal bleeding score
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
RHI
Robarts Histology Index
RS
Randomized Set
SAE
Serious Adverse Event
s.c.
subcutaneous
SCR
Screening
SD
Single dose
SF-36
36 question instrument to measure health-related quality of life
SFS
stool frequency score
SMC
Safety Monitoring Committee


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SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
t.i.d.
ter in die (3 times a day)
t
targeted
TB test
blood test that aids in the detection of Mycobacterium tuberculosis, the 
bacteria which causes tuberculosis (TB)
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
TGF-β
tissue growth factor
TMDD
target-mediated drug disposition
TMF
Trial Master File
TNF
Tumor necrosis factor
TNFi
TNFa inhibitor
TSAP
Trial Statistical Analysis Plan
TSH
Thyroid-stimulating hormone
UC
Ulcerative Colitis
ULN
Upper Limit of Normal
v
visit
w
week
WHO
World Health Organization
WOCBP
Woman of childbearing potential
WPAI-UC
Work Productivity and Activity Impairment Questionnaire, Ulcerative 
Colitis -specific version


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1. INTRODUCTION
1.1
MEDICAL BACKGROUND
Ulcerative Colitis (UC) is a chronic inflammatory bowel disease characterized by the key 
symptoms of chronic diarrhea, bloody stools and abdominal pain. It has an estimated 
incidence of 24.3 and 19.2 cases per 100,000 persons per year in Europe and the USA, 
respectively, resulting in a continuously rising prevalence [R15-0886]. UC is characterized 
clinically by abdominal pain, fever, and blood or mucosa-containing diarrhea, and 
pathologically by inflammatory lesions in the gastrointestinal mucosa. Inflammatory lesions 
characteristically occur distal to the terminal ileum, and by confinement of lesions to the 
mucosa and submucosa without transmural inflammation. UC typically follows a relapsing 
and remitting course, and is associated with substantial acute and long-term morbidity and 
increased mortality. The mainstays of drug therapy for UC are: orally administered 
aminosalicylates, glucocorticoids, oral immunosuppressive agents azathioprine and 6-
mercaptopurine, and TNF antagonists. In patients with mild UC, 5-ASAs are safe and 
effective for induction and maintenance treatment. Glucocorticoids, immunosuppressives, 
TNF antagonists, and more recently vedolizumab, are reserved for patients with moderate to 
severe disease, in whom the primary goals of drug therapy are to induce and subsequently to 
maintain remission from signs and symptoms of active disease.
Biologic treatment of moderate/severe UC is associated with approximately one third of 
patients each failing with primary or secondary non-response. In addition, treatment may be 
limited due to safety and tolerability issues. Therefore, despite of therapeutic progress, there 
remains a significant unmet medical need for new treatment options with an improved safety 
and efficacy profile compared to the current therapeutic standard.
1.2
DRUG PROFILE
BI 655130 (SPESOLIMAB) is a humanized antagonistic monoclonal IgG1 antibody that 
blocks human IL36R signaling. Binding of BI 655130 (SPESOLIMAB) to IL36R is 
anticipated to prevent the subsequent activation of IL36R by cognate ligands (IL36 α, β and 
γ) and downstream activation of pro-inflammatory and pro-fibrotic pathways with the aim to 
reduce epithelial cell/ fibroblast/ immune cell-mediated inflammation and interrupt the 
inflammatory response that drives pathogenic cytokine production in inflammatory diseases 
including generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP) and 
inflammatory bowel disease (IBD).
Preclinical studies
BI 655130 (SPESOLIMAB) binds to human IL36R with a binding avidity of less than 1 pM. 
BI 655130 inhibits IL36 ligand-stimulated NF-#B activation in HT29 and transformed 
epithelial cells and in primary human dermal fibroblasts or intestinal myofibroblasts with 
IC90 values in a consistent range of 0.7 to 3.7 nM. BI 655130 (SPESOLIMAB) also inhibits 
IL8 release in primary human intestinal myofibroblasts and IFNγ secretion in human PBMC 
stimulated with IL36α, IL36β, or IL36γ combined with IL12.


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Mutations of two key residues (L234 and L235) to alanine were made to BI 655130 
(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 BI 655130 will be a non-depleting therapy in vivo.
Toxicology studies
BI 655130 (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 BI 655130 (SPESOLIMAB). However, hazard identification studies of the 
mode-of-action (MoA) of IL-36R inhibition were performed in mice using a mouse specific 
anti-IL-36R monoclonal antibody (BI 674304), which is a mouse IgG2a monoclonal antibody 
with rat variable regions. In a 13-week intravenous toxicity study of BI 674304 in mice, no 
adverse effects of IL-36R antagonism were seen at a dose (50 mg/kg, twice weekly) that was 
5 fold higher than the dose that was protective in an experimental mouse colonic 
inflammation model. In the 26-week toxicity study, male and female mice (20-30/sex/group 
at 0, 10 and 50 mg/kg/day) were administered BI 674304 twice weekly for 26 weeks by 
intravenous injection via the caudal vein. There were no BI 674304-related changes in 
clinical observations, body weights, food consumption, ophthalmology, clinical pathology 
parameters (hematology, clinical chemistry), organ weights, macroscopic or microscopic 
examinations. The no-observed-adverse-effect level (NOAEL) was considered to be 50
mg/kg/day.
The in vitro cytokine release and tissue cross-reactivity assays demonstrate that the risk of 
transient cytokine release in humans is low and that, as expected, BI 655130 
(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 BI 655130 (SPESOLIMAB) dosing in 
humans.


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Summary 
BI 655130 (SPESOLIMAB) is an anti IL36R antibody with a high clinical activity to block 
IL36R signaling, as demonstrated in patients with Generalized Pustular Psoriasis, a severe 
inflammatory skin disease driven by uncontrolled IL36 activity. BI 655130 (SPESOLIMAB) 
has been tested in healthy volunteers with multiple dosing up to four weeks of 20 mg/kg i.v. 
q.w. which were all safe and well tolerated. In addition, IL36R inhibition shows a favorable 
nonclinical safety profile. Therefore, BI 655130 (SPESOLIMAB) might be a promising drug 
to treat patients suffering from ulcerative colitis.
For further details and most recent results refer to the current IB [c03320877].
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 655130 is currently under development for the treatment of ulcerative colitis (UC). It`s 
unique dual mode of action targets pro-inflammatory cytokines as well as tissue remodeling 
effects and thus may provide a clear advantage over current drugs and investigational 
compounds, which target inflammation only. The potential BI 655130 (SPESOLIMAB) 
effects on remodeling may directly increase mucosal healing, induce deeper tissue healing 
(histologic remission) and reduce stricturing and fistulizing complications of IBD which will 
provide patients who derived an individual benefit from induction or re-induction treatment
with a long-term treatment option. 
The link between IL36R driven inflammation and epithelial inflammation has led to the 
hypothesis that IL36R signalling may play an important role in inflammatory bowel diseases 
such as UC. This hypothesis was tested using a suite of in vitro and in vivo assays. 


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Immunostaining studies demonstrated that both IL-36R and its ligands are expressed in 
intestinal biopsies from patients with chronic IBD. Human IL36 ligands enhanced epithelial 
intestinal barrier permeability, a hallmark of IBD pathogenesis, based on a study using 
primary human intestinal epithelial cells co-cultured with intestinal myofibroblasts. The link 
between IL36R signalling and IBD was further strengthened by demonstrating that antagonist 
anti-mouse IL36R antibodies ameliorated intestinal inflammation in both acute chemically 
induced and chronic T cell driven murine colitis models. The therapeutic rationale for an 
IL36R antagonist in IBD is further based on the correlation of a set of IL36-induced genes 
upregulated in primary human intestinal myofibroblasts, a disease relevant cell type, with 
gene signatures observed in ulcerative colitis and Crohn’s disease (CD) patients. Finally, 
IL36R signalling in disease relevant cells such as intestinal myofibroblasts and macrophages 
induce not only pro-inflammatory but also tissue remodelling related mediators (e.g., tissue 
growth factor TGF-β, matrix metalloproteinase), which differentiates this mechanism from 
TNF alpha, integrin and IL23 targeting pathways. Altogether these findings indicate that IL36 
is a key regulatory cytokine upstream of various pro-inflammatory and tissue-remodelling 
cytokines including TGF-∃, TNF% and IL23, and support a prominent role of IL36R in 
driving intestinal inflammation and fibrosis.
The most recent and more detailed information is available in the current IB [c03320877]
1.4
BENEFIT - RISK ASSESSMENT
Preclinical profiles of BI 655130 (SPESOLIMAB) and clinical data from healthy volunteers
trials suggest that BI 655130 (SPESOLIMAB) is safe, tolerable and may address an unmet 
medical need in UC patients by a dual anti-inflammatory and anti-fibrotic mechanism of 
action, cf. Section 1.3 and the IB [c03320877].
Results of the PoC trial 1368-0011 in acute GPP demonstrate that BI655130 
(SPESOLIMAB) treatment rapidly clears pustules, the primary lesions in GPP, a disease 
closely linked to loss-of-function mutations in the natural IL36R antagonist. A different 
pustular inflammatory epithelial disease is PPP, which does not show the clear genetic 
association to the IL36 signalling pathway as GPP. Although the small pilot study of
BI655130 (SPESOLIMAB) in 59 patients with this disease (1368.15) failed to achieve the 
primary endpoint, a subgroup analysis has shown a strong dose dependent effect on pustule 
severity, the primary and most burdensome lesion of this disease. These data indicate that 
BI655130 (SPESOLIMAB) indeed inhibits IL36 in human disease and thus has the potential 
to also treat other neutrophil granulocyte related inflammatory epithelial diseases such as 
IBD. The most recent and more detailed information is available in section 6 of the current IB 
[c03320877].


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No relevant animal species is available for toxicology testing of the highly human specific 
antibody BI 655130 (SPESOLIMAB). However, preclinical toxicology studies with a mouse 
surrogate antibody have demonstrated the safety of chronic IL-36R inhibition in mice (IB  
[c03320877] Section 5.2.1).
A total of more than 212 subjects have been exposed to single or multiple i.v. doses of 
BI 655130 (SPESOLIMAB) as of September 2018 (see IB). BI 655130 (SPESOLIMAB) was 
safe and well tolerated in four healthy volunteers trials evaluating the i.v. and s.c. formulation 
(for details cf. Section 1.1 and IB c03320877).
Moreover, two trials exploring efficacy and safety of single (1368-0011) or multiple (1368-
0015) doses of BI655130 (SPESOLIMAB) in patients with Generalized Pustular Psoriasis 
(GPP, n=7) or Palmoplantar Pustulosis (PPP; n=59) demonstrated the favourable safety 
profile of BI655130 (SPESOLIMAB) in these severe inflammatory skin diseases. Finally, 
two (1368 - 0004, 1368-0010) clinical trials exploring efficacy and safety of BI655130 
(SPESOLIMAB) in patients with Ulcerative Colitis (UC; target n=10 and 30) are currently 
ongoing and have not yet indicated a BI655130 (SPESOLIMAB) related safety concern. 
Although no direct benefit for individual patients can be assumed, based on the PoC achieved 
in GPP and the strong preclinical rationale, there is a reasonable chance that BI 655130 
(SPESOLIMAB) may not only alleviate signs and symptoms of active ulcerative colitis but 
even directly promote mucosal and histological healing, which is associated with improved
clinical outcomes (reductions in immunosuppressive treatments, hospitalizations, colectomy 
and colorectal cancer [R16-0572]. Participation in this study may thus help to generate future 
benefit for larger groups of patients with UC, if BI 655130 (SPESOLIMAB) proves to be 
successful in treating this disease. 
The outcome-guided open label treatment with active drug will maximize the patient`s chance 
for individual benefit. Patients not benefitting from up to 24 weeks of BI 655130 
(SPESOLIMAB) induction treatment will discontinue the trial and switch to individualized 
commercial treatment at the investigator`s discretion, which will limit the duration of BI 
655130 (SPESOLIMAB) exposure in patients not individually benefitting from such 
treatment. In contrast, patients achieving a clinical response or remission on induction or re-
induction treatment, and thus benefitting individually from BI 655130 (SPESOLIMAB), will 
have the option to receive long-term treatment to maintain their treatment outcome.
There are no identified or potential risks for BI655130 (SPESOLIMAB), based on the 
toxicology programme or any clinical trials conducted for this product to date (see also 
Section 1.1). No other IL-36 receptor antagonist is currently approved, providing information 
on identified risks in molecules of this class. 
The risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs.


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In order to protect the patient’s safety during conduct of this trial, an independent Data 
Monitoring Committee has been established for the periodic review of clinical trial safety 
data.


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Table 1.4:1
Benefit – Risk Assessment
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, 
rationale for the risk
Mitigation strategy
Investigational Medicinal Product
Drug-induced 
liver injury (DILI)
Rare but severe event, 
thus under constant 
surveillance by sponsors 
and regulators.
Timely detection, evaluation, and follow-
up of laboratory alterations in selected 
liver laboratory parameters to ensure 
patients´ safety. See also Section 5.2.6, 
adverse events of special interest
Systemic 
hypersensitivity 
reaction
After administration of 
any biologic agent or 
protein, there is a 
possibility of occurrence 
of adverse immune 
reactions which can be 
local (e.g redness, 
pruritus, and or swelling 
at the injection site) or 
systemic (e.g. 
anaphylactic reactions).
Patients with a history of allergy/
hypersensitivity to the systemically 
administered trial medication agent or its 
excipients are excluded from the trial.
In case of systemic hypersensitivity 
reactions including anaphylactic reaction 
emerging during or after administration 
of trial medication, the investigator 
should consider in accordance with 
severity of the reaction and local 
standard of care to interrupt and treat the 
condition. Systemic hypersensitivity 
reaction is defined as AESI. It is subject 
to close monitoring and investigators are 
requested assess these conditions using 
the criteria discussed in the statement 
paper from Sampson HA[R11-4890].


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Table 1.4:1
Benefit – Risk Assessment (cont.)
Investigational Medicinal Product
Infections
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of 
infections.
A recent characterization 
of individuals with 
homozygous IL36R KO 
mutations revealed that 
normal immune function 
was broadly preserved 
suggesting that IL36 
signalingpathway
inhibition does not 
compromise host defences 
[R11-4890].
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 AESI for this 
trial.These conditions and serious 
infections are subject to close 
monitoring.
Malignancies
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of a 
decreased immune 
defense against 
malignancies
A recent characterization 
of individuals with 
homozygous IL36R KO 
mutations revealed that 
normal immune function 
was broadly preserved 
suggesting that IL36 
signaling pathway 
inhibition does not 
compromise host 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 BI655130 (SPESOLIMAB).
Diagnostics and treatment have to be 
initiated according to local standard of 
care.
Malignancies represent always serious 
adverse events and are subject to close 
monitoring.


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Table 1.4:1
Benefit – Risk Assessment (cont.)
Trial procedures
Blood Sampling 
As with all blood 
sampling, there is a risk of 
mild pain, local irritation, 
or bruising (a black or 
blue mark) at the puncture 
site. Furthermore, there is 
a small risk of light-
headedness and/or 
fainting. In rare cases, the 
puncture site can also 
become infected or nerves 
may be damaged, 
inducing long-lasting 
abnormal sensations 
(paresthesia), impaired 
sensation of touch and 
persistent pain.
Frequent blood collection 
may cause anemia (low 
red blood cell count), 
which may create a need 
for blood transfusions.
These risks will be addressed by careful 
safety monitoring and risk mitigation 
measures such as
(a) close clinical monitoring for AEs;
(b) selection of experienced sites and 
site staff;
(c) training.
Colonoscopy or 
sigmoidoscopy 
with biopsy
Can be associated with 
diarrhea, abdominal pain, 
perforation, bleeding, 
effects from anaesthetic 
medications, and infection
These risks will be addressed by careful 
monitoring and risk mitigation measures 
such as 
(a)
close clinical monitoring for AEs;
(b)
selection of sites with experienced 
site staff;
(c)
colonoscopy/sigmoidoscopy will 
be done according to the standard 
local care procedure including 
local clinic/hospital consent 
authorizing this procedure
(d)
training


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Table 1.4:1
Benefit – Risk Assessment (cont.)
Trial procedures
SARS CoV-2 
infection
Trial conduct and 
protocol-defined 
procedures do not impose 
more risk to trial 
participants. To address 
potential risks associated 
with operational aspects 
related to the participation 
in clinical trials in the 
context of the COVID-19 
pandemic, different risk 
mitigation measures are 
considered, based on local 
requirements and 
development of the 
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. BI as the sponsor, 
where required, will support the 
investigator in their decision finding. It is 
acknowledged that the investigator may 
decide to implement protocol deviations 
where this protects the safety, wellbeing, 
and/or is in the best interest of the 
patient.


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Table 1.4:1
Benefit – Risk Assessment (cont.)
Trial procedures
Peripheral 
Neuropathy
Three cases reported by 
the investigator as 
Guillain-Barré syndrome 
(GBS) were received in 
ongoing clinical trials 
with spesolimab. A panel 
of independent 
neurologists and experts 
in the study of 
neuropathies assessed the 
3 cases. Only 1 met level 
4 diagnostic certainty for 
the diagnosis of GBS 
(lowest level on Brighton 
scale of 1 to 4). In that 
case, there was a 
coincident infection with 
SARS-CoV-2. The other 2 
cases were assessed as not 
GBS. Observed cases 
showed a heterogenous 
pattern.
As per assessment by the 
panel of external 
neurologists the 
nonspecific symptoms and 
findings in all three cases 
may best be referred to as 
peripheral neuropathy.
Timely detection, evaluation, and follow-
up of suspected peripheral neuropathies
to ensure patients´ safety. 
Use of dedicated questions to elicit 
neurologic history during screening and 
exclusion criteria to avoid selection of 
patients with acute demyelinating 
neuropathy.
Targeted Follow up questions to gather 
detailed information in case of any event 
during trial to ensure proper decision 
making. 
Trial treatment discontinuation criteria as 
well as criteria for trial treatment restart 
are implemented for relevant cases.
Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of Women of Child Bearing Potential 
(WOCBP) in this study is justified. To minimize the risk of unintentional exposure of an 
embryo or fetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods described in Section 4.2.2.2
The preceding trial 1368-0004 has already been completed; last patient last visit occurred on 
24 October 2019.


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The preceding induction trial 1368-0005 was prematurely discontinued on 04 Feb 2020 due 
to failure to meet expected enrollment goals. An unblinded analysis was conducted including 
90 patients who have either completed or discontinued through week 12. At time of trial 
discontinuation, 8 additional patients were ongoing and therefore not included in the interim 
analysis. Last patient last visit occurred on 18 May 2020.
The main results the interim analysis of trial 1368-0005, are summarized in the tables and 
figures below.
Table 1.4:2
Interim Analysis trial 1358-0005 Primary endpoint: Clinical 
Remission at week 12 (RS, NRI)
Placebo
IV
Spesolimab
300 IV SD
Spesolimab
450 IV q4w
Spesolimab
1200 IV q4w
Subjects N (%)
23 (100%)
22 (100%)
21 (100%)
24 (100%)
Subjects with Remission N (%)
0
0
2 (9.5)
2 (8.3)
95% CI
(0, 14.3)
(0, 14.9)
(2.7, 28.9)
(2.3, 25.8)
Risk Difference vs placebo 
(95% CI)
9.5
(−6.4, 28.9)
8.3
(−7.2, 25.8)
Table 1.4:3
Interim Analysis trial 1358-0005 Secondary endpoint: Mucosal 
Healing (Endoscopic Improvement) at week 12 (RS, NRI)
Placebo
IV
Spesolimab
300 IV SD
Spesolimab
450 IV q4w
Spesolimab
1200 IV q4w
Subjects N (%)
23 (100%)
22 (100%)
21(100%)
24 (100%)
Subjects with Endpoint N (%)
0
0
2 (9.5)
2 (8.3)
95% CI
(0, 14.3)
(0, 14.9)
(2.7, 28.9)
(2.3, 25.8)
Risk Difference vs placebo
(95% CI)
9.5
(−6.4, 28.9)
8.3
(−7.2, 25.8)
SD: Single dose; RS: Randomized Set; NRI: No response imputation.
Mucosal healing (endoscopic improvement): defined as modified endoscopic Subscore (mESS) ≤ 1.


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Table 1.4:4
Interim Analysis trial 1358-0005 Secondary endpoint: Clinical 
Response at week 12 (RS, NRI)
Placebo
IV
Spesolimab
300 IV SD
Spesolimab
450 IV q4w
Spesolimab
1200 IV q4w
Subjects N (%)
23 (100%)
22 (100%)
21 (100%)
24 (100%)
Subjects with Endpoint N (%)
5 (21.7)
2 (9.1)
5 (23.8)
6 (25.0)
95% CI
(9.7, 41.9)
(2.5, 27.8)
(10.6, 45.1)
(12.0, 44.9)
Risk Difference vs placebo
(95% CI)
-12.6
(-33.9, 9.6)
2.1
(-22.0, 26.5)
3.3
(-20.7, 26.5)
SD: Single dose; RS: Randomized Set; NRI: No response imputation.
Clinical Response: defined as defined as total MCS reduction ≥3 pts. and ≥30% from BL; AND RBS drop from
baseline by ≥1pt., or absolute RBS ≤1 pt
Figure 1.4:1 Interim Analysis trial 1368-0005 Further endpoint: Median (with Q1 and Q3) of 
absolute values in C-Reactive Protein (CRP) over time for patients with baseline values 
above upper limit of normal (SAF,OC)
SD: Single dose; SAF: Safety Analysis Set, OC: Observed case.


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Figure 1.4:2
Interim Analysis trial 1358-0005 Further endpoint: Median (with Q1 and Q3) 
of absolute values in faecal calprotectine (FCP) over time for patients with baseline values 
above upper limit of normal (SAF, OC)
SAF: Safety Analysis Set, OC: Observed case.
In summary, the results of the interim analysis of trial 1368-0005, show:
∀
No clear efficacy of Spesolimab over placebo on clinical endpoints across studies and 
UC populations.
∀
Effect in the most strict endpoints (clinical remission, mucosal healing) in few 
patients treated with higher doses of Spesolimab (450mg q4w and 1200mg q4w), 
although sample size is too low to show statistical significance.
∀
No dose response effect in primary and secondary clinical endpoints and in secondary 
inflammatory biomarkers.
∀
Spesolimab was safe and well tolerated with no evidence of previously unrecognized 
safety risks.
An analysis of all patients randomized in trial 1368-0005 (total of 98 patients) will be 
conducted after cleaning all data of these patients and subsequent data base lock.
An interim analysis was also conducted on data from patients in trial 1368-0017 who rolled 
over from trial 1368-0005. At time of this interim analysis, 69 patients rolled-over from trial 
1368-0005 to trial 1368-0017; of those, 51 patients who did not achieve clinical response in 


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trial 1368-0005 received re-induction treatment of Spesolimab 1200 mg IV q4w and 18 
patients who achieved clinical response in study 1368-0005 received maintenance treatment 
with Spesolimab 300 mg s.c. q12w. The main clinical results for patients who completed 12 
weeks re-induction treatment or 12 weeks maintenance treatment in trial 1368-0017 are 
summarized in the table below by previous treatment in trial 1368-0005:
Table 1.4:5
Interim Analysis trial 1358-0017 Clinical endpoints for patients who 
completed 12 weeks re-induction treatment (TS-RT, NRI) or 12 
weeks maintenance treatment (TS-MT, NRI) in trial 1368-0017 by 
previous treatment in trial 1368-0005 
Data cut-off: 19 Feb 2020
Placebo
IV
Spesolimab
300 IV SD
Spesolimab
450 IV q4w
Spesolimab
1200 IV q4w
Rolled-over from 1368-0005 to 1368-0017
16
18
20
15
Treated with re-induction (1200mg IV q4w)
10 (100%)
16 (100%)
14 (100%)
10 (100%)
Clinical remission week 12
0
0
0
0
Endoscopic Improvement week 12
0
0
0
0
Clinical response n (%) week 12
1 (10.0)
2 (12.5)
4 (28.6)
2 (20.0)
Treated in maintenance (300mg sc q12w)
5 (100%)
2 (100%)
6 (100%)*
5 (100%)*
Symptomatic remission week 12
0
1 (50.0)
1 (16.7)
2 (40.0)
TS-RT: Treated Set for Re-induction Treatment; TS-MT: Treated Set for Maintenance Treatment; NRI: No 
response imputation
Patients randomized to placebo in trial 1368-0005 who rolled-over to trial 1368-0017 and 
received re-induction treatment in trial 1368-0017, received in total 12 weeks of induction 
treatment with Spesolimab. Patients randomized to Spesolimab in trial 1368-0005 who 
rolled-over to trial 1368-0017 and received re-induction treatment in trial 1368-0017, 
received in total 24 weeks of induction treatment with Spesolimab. None of these patients 
achieved Clinical remission or Endoscopic improvement at week 12 and only few patients 
achieved Clinical response. Few patients who rolled-over from trial 1368-0005 to trial 1368-
0017 and treated with maintenance treatment achieved Symptomatic remission.
Based on the results of the interim analyses of trials 1368-0005 and 1368-0017, the general 
benefit-risk assessment for patients currently treated in trial 1368-0017 cannot be evaluated. 
Therefore for these patients, the benefit-risk should be assessed by the investigator on an 
individual basis to evaluate patient continuation in the trial.
As recruitment of patients has been completed and no patients are ongoing in the preceding 
trials 1368-0004 and 1368-0005, no more patients can be enrolled in trial 1368-0017. 


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Summary of benefit-risk assessment
Due to the lack of mechanism- or compound-related safety signals as well as the antagonistic 
mode of action of BI 655130 (SPESOLIMAB) it is considered unlikely that UC patients be 
exposed to any undue risks in this trial. Considering the medical need of the development of 
an effective and well tolerated drug specifically and directly treating the structural aspects of 
UC, the benefit of this trial is considered to outweigh the potential risks for individual UC 
patients participating in this trial.
Based on the results of the above mentioned interim analysis of the preceding induction trial 
1368-0005 and of trial 1368-0017, a benefit-risk assessment should be done by the 
investigator together on an individual basis to evaluate patient continuation in trial 1368-
0017.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Table 2.1:1
Definitions of Study Outcomes
Outcome
MCS subscore
Total
MCS
Mod.
MCS
Partial
MCS
Additional 
Requirements
RBS
mESS
SFS
PGA
Clinical 
remission
0
≤l
0 or 1, if
drop vs 
BL1 ≥1
-
≤2
CS-free 
remission 
(in pts on CS 
at BL)
0
≤1
0 or 1, if
drop vs 
BL1 ≥1
-
≤2
CS-free ≥12 
wk and PMR 
for ≥12 wk
Clinical 
response
≤1, or
drop vs 
BL1 ≥1
Not 
missing
Not 
missing
Not 
missing
Drop 
vs BL1
≥3 and 
≥30%
Partial MCS 
response
≤1, or
drop vs 
BL1 ≥1
-
Not 
missing
Not 
missing
↓ ≥2 vs 
BL1
Partial MCS 
remission
≤l
-
≤l
≤l
≤2
Endoscopic 
remission
-
0
-
-
Endoscopic 
improvement
-
≤1
-
-
Complete 
remission
-
0
-
-
Robarts 
Histology 
Index (RHI) 
≤6
Disease flare 
(after clinical 
response/remis
sion, i.e. 
applicable on 
maintenance 
treatment 
only)
↑ ≥1 vs
BL2
≥2, 
AND
↑ ≥1 vs 
BL2
↑ ≥2 vs 
BL2
pMCS ↑and 
RBS ↑from 
BL2, conf. in 
2nd indep. 
Visit, with 
mESS &, and
neg. enteric 
pathogens in 
stool
1BL of preceding induction study (1368-0005 Part 1)
2 BL of current maintenance study (1368-0017)


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Table 2.1:1
Definitions of Study Outcomes (cont.)
Outcome
Definition
Maintained remission
CR wk1+48, AND PMR at ≥75% of intervening visits w/o 
flare
Durable remission
CR wk48, and PMR w/o flare in preceding 24 wks
Disease worsening
Worsening of clinical status or UC symptoms, in the investigator’s 
opinion, requiring:
1) [during steroid taper] a suspension of tapering, or, a reversion of 
the steroid daily dose to the preceding daily dose, or,
2) treatment with rescue medication 
Treatment Failure
Disease worsening, 
or a drug-related AE leading to discontinuation of 
study drug
Rescue Medication
New or dose increase of any non-study drug or surgical intervention 
for new or persist. symptoms of UC
Histological remission
(HR)
Robarts Histology Index (RHI ≤6)
All criteria have to be met to qualify for the respective outcome at the same time
•
Abbreviations: CR - clinical remission; pCR - partial clinical remission; CS - systemic 
corticosteroids; RBS – rectal bleeding score; mESS – modified endoscopic subscore; pts.
- patients; RHI - Robarts Histology Index; SFS – stool frequency score; 
PGA – physician’s global assessment; PMR - partial MCS remission; 
MCS – MayoScore; BL – baseline of previous parent induction trial
•
Total MCS is calculated as the sum of RBS, mESS, SFS and PGA
•
Modified MCS is calculated as the sum of RBS, mESS and SFS
•
Partial MCS is calculated as the sum of RBS, SFS and PGA
2.1.1
Main objectives
1. To evaluate the long-term safety of BI 655130 (SPESOLIMAB)in patients with 
moderate to severely active ulcerative colitis, who have completed treatment in 
previous trials 
2. To evaluate the long-term efficacy of BI 655130 (SPESOLIMAB) in patients with 
moderate to severely active ulcerative colitis, who have completed treatment in 
previous trials 


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2.1.2
Primary endpoint(s)
Primary endpoint is the exposure adjusted rate of patients reporting a treatment emergent 
adverse event (TEAE) up to week 336 of maintenance treatment
2.1.3
Secondary endpoint
Proportion of patients with clinical remission at week 336 of maintenance treatment (as 
defined in table 2.1: 1)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This open label (OL), 7 year, single group, long-term extension study investigates the long 
term safety and efficacy of BI 655130 (SPESOLIMAB) in patients with moderate-to-severe 
ulcerative colitis who have completed treatment in previous BI 655130 (SPESOLIMAB) 
induction trials 1368-0005 Part I and 1368-0004. 
Approximately 160 patients who meet the entry criteria are planned to be included in the trial 
from previous induction trials 1368-0005 Part I and 1368-0004. The treatment will be open-
label. Trial will consist of a screening period lasting up to 7 days, followed by a 336 weeks 
maintenance treatment period and a 16 weeks safety follow-up period. Patients rolling-over 
into 1368-0017 trial must complete the 12 weeks treatment period (until EOT visit) in the 
previous induction trial. Patients will be treated according to their previous trial outcome in a 
following way:
∀
Patients who have completed treatment in the previous trials showing a clinical response at 
week 12 will receive BI 655130 (SPESOLIMAB) s.c. maintenance treatment (300mg q4w 
s.c.) through week 336 of this extension study (Flowchart 1).
∀
Patients who have completed treatment in the previous trials, but did not achieve a clinical 
response at week 12, will receive BI 655130 (SPESOLIMAB) i.v. re-induction treatment 
(1200mg q4w i.v. for 12 weeks). Those patients who subsequently reach the clinical 
response (versus baseline of original induction trial) at week 12 of re-induction period, will 
be entered into the 336 weeks s.c. maintenance treatment phase (Flowchart 2); while non-
responders will be discontinued from treatment and complete early EOT visit and safety 
follow-up period.
∀
Patients ongoing on maintenance treatment when CTP version 05 is approved will be asked 
to re-consent to the change in treatment frequency. After consent, patients will switch from 
q12w regimen to q4w regimen. Patients who do not wish to consent to this change will be 
discontinued from the study.
A schematic overview of trial design is shown in Figures 3.1:1 and 3.1:2.


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Figure 3.1:1 Trial design for responders and non-responders
Figure 3.1:2 Trial design in case of a disease flare
d, day; EOS, end-of-stud; EOT, end-of-trial; F, flare; M, maintenance; Q12w, every 12 weeks; R, 
rescue; SC, subcutaneous; SCR, screening; V, visit; W, week
Patients who terminate study drug in 1368-0017 prematurely will be invited to early EOT 
visit instead of next planned visit followed by safety follow up (EOS) 16 weeks after last 
study drug intake.
Several interim analyses of PK, biomarker and clinical data will be performed throughout the 
conduct phase of this 7-year study to support future trial applications, investigator brochures, 
regulatory documents and scientific publications. The final analysis of the entire trial data 


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will be performed once all patients have completed the last scheduled trial visit. The end of 
trial is defined as “last patient out”; i.e. last scheduled visit completed by last patient. 
Steroid tapering:
All patients on oral corticosteroids entering s.c. maintenance treatment who achieve clinical 
response or clinical remission will be requested to taper their prednisone dose or equivalent 
(see Appendix 10.3) of other systemic corticosteroids following a pre-defined scheme (see 
Appendix 10.7).
Patients on oral corticosteroids entering i.v. re-induction treatment due to lack of a clinical 
response in the parent study shall start tapering if response is subsequently confirmed at 
Week 12. 
Patients receiving budesonide MMX at study entry will taper their initial daily dose for 2 
weeks every other day before stopping the drug.
Patients on stable dose of beclomethasone dipropionate will be requested to stop using it after 
they achieve clinical response or clinical remission. 
If a patient undergoing steroid dose reduction in line with the tapering scheme experiences 
disease worsening, further dose reduction may be suspended or the daily corticosteroid dose 
could be reverted to the preceding daily dose, but must not exceed the original daily dose (or 
equivalent) at baseline.
Disease flare treatment:
A disease flare may occur at any time after achievement of a clinical response during 
maintenance s.c. treatment period and is defined as a re-increase in partial MCS score, and a 
re-increase in rectal bleeding score, observed during a regular or unscheduled study visit,
confirmed in an independent subsequent visit and by sigmoidoscopy, in absence of enteric 
pathogens in stool (for complete definition see table 2.1: 1). In case of a suspected disease 
flare, the site will ask the patient to immediately start entering his Mayo score data into the 
eDiary until the next scheduled or unscheduled visit, and then continue entering the data as 
planned (i.e. for 14 days preceding each visit). A patient with a (endoscopically confirmed) 
flare will receive a single i.v. infusion of 1200mg BI 655130 (SPESOLIMAB) as a flare 
treatment followed by intensified maintenance dosing with 600mg sc. BI 655130
(SPESOLIMAB) q6w. No further maintenance dose escalation is foreseen in case of repeated
flares. An additional unscheduled sigmoidoscopy has to be planned at week 12 after the i.v. 
infusion to check the patient`s response status to disease flare treatment. 
Patients who experience a disease flare during steroid tapering should follow the same flare 
treatment instructions specified above, but may suspend further steroid dose reduction or re-
escalate dose once in line with the instructions above.
For details of trial procedures please follow the Flowchart 3 (Patients with Disease Flare).
Patients will be discontinued from treatment if they do not achieve clinical response 
(compared to baseline of original induction trial) or clinical remission within 12 weeks after 
the initiation of disease flare treatment, or if they experience more than 1 confirmed flares
during the trial.


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Allowed concomitantly given immune modulators (AZA, 5MP, MTX; see table 4.2.2:1) can 
be discontinued after ≥52 weeks of s.c. maintenance treatment in patients with durable 
clinical remission per the Investigator`s judgement.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
All patients who complete induction treatment with BI 655130 (SPESOLIMAB) or placebo 
in previous trials 1368-0004 or 1368-0005/Part 1 will roll-over into this trial to receive long-
term treatment with active drug, provided patients derived an individual health benefit from 
either induction or re-induction treatment by achieving a clinical response. Patients not 
responding to induction/re-induction treatment or experiencing more than 1 disease flare in 
the maintenance part of 1368-0017 will be discontinued from the trial treatment per the pre-
defined stopping criteria (cf. section 3.3.4.1) and receive individualized treatment at the 
discretion of the investigator.
Patients rolling over from 1368-0005 Part 1 or 1368-0004 will be monitored for induction
outcome at the EOT visit of these trials and initiate treatment in 1368-0017 upon availability 
of the centrally read endoscopy score (within ≤1 week). The treatment regimen will depend 
on the individual patient outcome in 1368-0005 Part 1 and 1368-0004 (cf. section 3.1 and 
below).
The open label re-induction treatment in non-responders to BI 655130 (SPESOLIMAB)
induction therapy in the original study will offer extended and high dose treatment and help 
to further characterize the response kinetics to BI 655130(SPESOLIMAB). Although 
currently approved or investigational biologics (e.g. tofacitinib, TNFi, vedolizumab) have 
established 4-8 weeks duration of induction treatment in UC [R17-3426, R15-5737, R15-
4915, R17-2217], the new MoA of BI 655130 (SPESOLIMAB) may have a delayed onset of 
action. Re-induction treatment for additional 12 weeks or with escalated dose has been shown 
with other drugs (e.g. JAK inhibitor tofacitinib, IL23 inhibitor risankizumab) to increase 
response and remission rates in IBD [P17-11924]. A similar effect may apply to BI 655130 
(SPESOLIMAB) in UC. For original placebo patients, this trial will provide active induction 
treatment. The re-induction dosing interval of every 4 weeks is supported by the long half-life 
of BI 655130 (SPESOLIMAB) of approximately four weeks and safety data generated in 
Phase I studies. It aims to achieve a high plasma exposure on the plateau of the dose-response 
curve in order to maximize the treatment effect (ref: [c03320877]). Clinical responders to BI 
655130 (SPESOLIMAB) induction are likely to require maintenance treatment in order to 
achieve deeper remission or mucosal healing, and to prevent the occurrence of relapses. The 
initial open label maintenance s.c. dosing interval every 12 weeks was supported by the long 
half-life, sustained target engagement and the high relative bioavailability of the sc. 
formulation found in phase I studies (ref. IB). However, the dosing interval for the 
maintenance dosing interval has been adapted to q4w based on the current observed study 
relapse rate (see Section 11). For dose selection refer to section 4.1.2.


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This long-term study mainly aims to offer active maintenance treatment to patients having 
benefited from such induction or re-induction treatment, and to characterize the safety and 
tolerability of BI 655130 (SPESOLIMAB) long-term treatment. It will also characterize the 
persistence of clinical outcome over a long period of BI 655130 (SPESOLIMAB) treatment. 
Although a placebo control would improve this safety and efficacy assessment, it would 
withhold patients in need from active treatment and is not justifiable for longer than the 12 
weeks in the initial induction study. An active comparator is not suitable for this highly 
treatment-experienced and heterogeneous study population, where any approved treatment 
would have to be tailored towards the patient`s individual treatment history. Moreover, 
patients responding to BI 655130 (SPESOLIMAB) induction treatment are likely to fail 
maintenance treatment if switched to a drug with a different MoA, which they may have 
failed in the past. Therefore, neither an active comparator nor placebo can be justified for the 
time frame and the population studied in this trial.
It is acknowledged that the reporting of data for this open-label, single-arm trial will likely be 
biased due to, among others, selection and reporting bias. This is, however, deemed 
acceptable given that all patients who respond to previous induction/re-induction treatment 
and who continue into this extension trial will be able to receive an active maintenance 
treatment with BI 655130 (SPESOLIMAB) for their ongoing disease.
3.3
SELECTION OF TRIAL POPULATION
Patients in this long-term open label extension trial will be rolled-over from previous 
induction trials 1368-0004 and 1368-0005 Part I. All patients enrolled into the preceding trial 
1368-0005 Part I have failed conventional and/or biologic drugs in the past. Due to the wide 
availability of biologics approved in this indication, it is expected that the vast majority of 
patients enrolled into this first-in-class program will have failed several other biologics in the 
past and thus represent a very advanced population which has the highest unmet medical need 
and will be a typical population for a newly approved biologic. 
Patients enrolled in the preceding phase II exploratory 1368-0004 trial are required to be on 
conventional, non-biologic treatment for UC, with stable treatment doses throughout the trial. 
Patients screened in the 1368-0017 trial have tolerated treatment with study drug in 1368-
0005 Part I and 1368-0004 trials and have completed the 12 weeks treatment period. They 
must be willing to continue long term treatment with BI 655130 (SPESOLIMAB) for up to 7 
years.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.


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3.3.1
Main diagnosis for trial entry
Patients with moderate-to-severely active ulcerative colitis who have completed treatment in
induction trials 1368-0004 or 1368-0005 Part I.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be included into the trial:
1. Male or female patients, aged ≥18 years
2. Signed and dated written informed consent for 1368-0017, in accordance with GCP and
local legislation prior to admission into the trial
3. Women of childbearing potential (WOCBP) must be ready to use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% 
per year when used consistently and correctly. A list of contraception methods meeting 
these criteria is provided in the patient information.
Note: A woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. Tuba ligation is NOT a method of permanent sterilisation. A 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
4. Have completed treatment and the EOT visit in the previous trial and are willing and able 
to continue treatment in 1368-0017.
3.3.3
Exclusion criteria
Patients meeting any of these exclusion criteria must not be enrolled into the trial:
1. Have experienced study treatment-limiting adverse events during induction treatment 
with study drug
2. Have developed any of the exclusion criteria from the original induction study with the 
following exceptions:
∀
Cases of disease limited to the rectum extending <15 cm past the anal verge are 
allowed to be included in study 1368.17.
∀
Cases of latent TB. Patients with newly emerging latent TB during preceding study
are allowed to be included in study 1368.17, provided they receive appropriate 
treatment according to local guidelines.


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3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole 
(“withdrawal of consent”) with very different implications, please see sections 3.3.4.1 and 
3.3.4.2 below.
The decision to withdraw from trial treatment or from the whole trial as well as the reason 
must be documented in the patient files and CRF.
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:
∀
A patient assigned to re-induction treatment does not achieve clinical response at 
week 12 compared to baseline of the original induction trial.
∀
A patient treated for a disease flare does not achieve clinical response (compared to 
baseline of the original induction trial) or clinical remission within 12 weeks after the 
initiation of disease flare treatment.
∀
A patient experience more than 1 confirmed flares during the trial.
∀
The patient wants to withdraw from trial treatment, without the need to justify the 
decision. 
∀
The patient needs to take concomitant drugs that interfere with the investigational 
product. Please refer to section 4.2.1 and 4.2.2 .
∀
The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, or pregnancy).
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to comply with the trial requirements in the future. 
∀
A patient can be discontinued from trial medication at any time if in the opinion of the 
Investigator, continuation with trial medication is not in the patient’s best interest.
∀
For individual stopping rules related to specific adverse events, please see section 
4.2.1 “Other treatments and emergency procedures”.
∀
If peripheral neuropathy is suspected, treatment with spesolimab should be 
temporarily discontinued until a full neurological investigation has been conducted.
After completion of the neurological investigation, treatment can be restarted based 
on medical judgement of the investigator. 


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If a patient has not achieved clinical remission within the first 48 weeks of maintenance 
treatment, investigator should consider trial drug termination based on individual patient 
history and available alternative treatment options.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Charts and section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the CRF. This data will be included in the trial database and reported.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will, however, mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore,
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Product
Table 4.1.1: 1
Description of test product BI 655130 (SPESOLIMAB) i.v. infusion
Substance:
BI 655130 (SPESOLIMAB)
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Chemical form:
Anti-human IL-36 Receptor mAb
Molecular weight:
146 kDa
Unit strength:
BI 655130 (SPESOLIMAB) 300mg/vial (60 
mg/mL), 5 mL fill volume
Route of administration:
Intravenous infusions
Posology:
1200 mg at Week 0, 4 and 8 for re-induction
1200 mg single dose in case of disease flare
Duration of use:
12 weeks
Table 4.1.1: 2
Description of test product BI 655130 (SPESOLIMAB) s.c. solution 
for injection
Substance:
BI 655130 (SPESOLIMAB)
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Chemical form:
Anti-human IL-36 Receptor mAb
Molecular weight:
146 kDa
Unit strength:
BI 655130 (SPESOLIMAB)  150mg/pre-filled 
syringe (150mg/mL)
Route of administration:
Subcutaneous injections
Posology:
300 mg at Week 0 and then every 4 weeks
600 mg every 6 weeks as intensified treatment for 
patients with disease flare
Duration of use:
336 weeks
4.1.2
Selection of doses in the trial
A 12 week re-induction dose regimen of 1200mg i.v. q4w will be administered to patients not 
responding to the original induction treatment with study medication in the parent trial. Based 
on data indicating high and sustained target engagement at doses ≥3mg/kg biweekly and a 
half-life as long as 4-5 weeks in healthy volunteers (cf. sections 6.1 and 6.2 of IB
c03320877), this dose is expected to be at the plateau of the dose/response curve and to 
provide maximal efficacy. This dosing regimen also approximates the highest dose regimen


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that has been tested and was found safe in preceding phase I studies. It therefore is being 
tested in ongoing studies in ulcerative colitis of 1368-0004 and 1368.10.
This dose will provide (i) active induction treatment to patients originally randomized to 
placebo, (ii) dose escalation to patients originally randomized to lower doses of BI 655130 
(SPESOLIMAB) (i.e. 300mg SD or 450mg q4w), and (iii) extended duration of high dose 
induction to patients originally randomized to the same dose level. Under the assumption of a 
monotonic dose response curve, as found for other biologics in IBD treatment, this intensified 
dosing regimen may increase the induction efficacy of BI 655130 (SPESOLIMAB) as 
compared to lower doses or shorter duration of treatment.
The maintenance dose strength of 300mg s.c. was selected based on the assumed need for 
lower BI 655130 (SPESOLIMAB) exposures once a response or remission has been induced, 
as shown for other biologics in the IBD area. It is supported by the favourable bioavailability 
of the s.c. relative to the i.v. formulation (approx. 70%; cf. section 6.2 of [c03320877]). The 
dosing interval of q12w was initially selected based on the phase I findings of a long half-life 
(4-5 weeks) and sustained target engagement (≥90% as compared to baseline for at least 22 
weeks after the last dose administered;[c03320877]). However, regular medical review 
meetings by the sponsor during the study conduct have demonstrated loss-of-response rates in 
initial responders after dose reduction to maintenance dosing, which were higher than those 
found with approved regimens. Under the assumption of a positive dose response relationship 
and given the favourable safety profile of BI 655130 (SPESOLIMAB) even at several fold 
higher IV doses (up to 1200mg q4w for up to 24 weeks), the sponsor has amended the trial to 
increase the regular maintenance dose to 300mg SC every 4 weeks, and the intensified
maintenance dose after flare treatment to 600mg q6w.
4.1.3
Method of assigning patients to treatment groups
During visit M1 eligible patients will be allocated to receive open-label treatment based on 
the clinical outcome achieved in previous trials. 
Patients rolling over from previous induction trials who have achieved a clinical response at 
week 12 in the preceding trial will receive OL BI 655130 (SPESOLIMAB) s.c. maintenance 
treatment (300mg q4w s.c.) until week 336 (for definition of clinical response see Table 
2.1:1).
Patients rolling over from previous induction trials who did not achieve a clinical response in 
the preceding trial will receive 12 weeks of OL BI 655130 (SPESOLIMAB) re-induction 
treatment (1200mg q4w i.v.), and if they respond to this treatment they will continue BI 
655130 (SPESOLIMAB) s.c. maintenance (300mg q4w s.c.) treatment until week 336 (for 
definition of clinical response see Table 2.1:1).
The assignment to treatment will be done via Interactive Response Technology (IRT).
4.1.4
Drug assignment and administration of doses for each patient
In this trial a dose of 300 mg of BI 655130 (SPESOLIMAB) will be administered during 
study visit as subcutaneous injection in the abdomen , in accordance with local standard 


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procedure and as described in “BI 655130 Solution for Injection 150 mg/mL s.c. 
Instructions for Handling and Use”
every 4 weeks for patients starting from visit M1 until EOT visit for patients who responded 
to treatment with study drug in previous trials or gained response after i.v. re-induction
period. The concentration of the application solution will be 150 mg/ml. 
Injection site should not be close to a vein and it should avoid sites where the skin is tender, 
bruised, erythematous, or indurated, and should be alternated to other areas for subsequent
doses.
Detailed instructions for Handling and Use of s.c. injection are provided in the ISF.
Patients have to be closely monitored for local or systemic hypersensitivity reactions for 1 
hour following s.c. study drug administration. Subcutaneous administration of biologic agents 
involves the risk of local (injection site) or systemic hypersensitivity reactions. Therefore,
patients should be closely monitored for signs and symptoms of injection site or systemic 
hypersensitivity reactions following study drug administration. Study personnel should 
observe the injection site for signs of redness, swelling or hardness. They should also ask 
subjects about itching, dizziness or shortness of breath. Patients should be advised that if they 
experience redness, swelling or other changes at the injection site, they should notify site 
personnel. They should further be advised that if they experience itching all over or a feeling 
of being swollen, dizzy or short of breath, they should seek emergency medical attention 
immediately and notify site personnel. 
1200mg BI 655130 (SPESOLIMAB) i.v. q4w administration for 12 weeks will be used for 
patients assigned to i.v. re-induction.
Single 1200 mg BI 655130 (SPESOLIMAB) i.v. administration will be used as disease flare 
treatment. Intravenous infusion including observational time for possible infusion reactions 
will last approximately 2.5 hours. The i.v. treatment will be followed by intensified 
maintenance treatment with 600mg BI 655130 (SPESOLIMAB) q6w.
Detailed instructions for the preparation of the i.v. infusion solution, the volume to be 
administered and the infusion rate are provided in the ISF.
In case of safety concerns, e.g., due to infusion reactions, it is in the discretion of the 
investigator or his/her designee to adapt the infusion scheme (cf. Section 4.2.1 for handling of
infusion reactions). Detailed instructions for handling of infusion reactions are also provided 
in the ISF.
The administration of the trial medication intravenously on all applicable study days will be 
done under supervision of the investigating physician or a designee at the site. If available, a 
pharmacist should prepare the study medication. The four eye principle (two-person rule) 
should be applied for preparation (e.g. choosing the correct vials with the correct medication 
number) and administration of trial medication.
Dose modifications or adjustments are not permitted. In exceptional cases of missed or 
delayed visits, if any of these visits has to be rescheduled, the date of subsequent visit should 
be calculated from Day 1 of maintenance treatment or if the patient is on flare treatment 
from the first s.c. drug administration after the last disease flare. 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
This is an open label, single arm trial; therefore no blinding will be necessary. In this open-
label trial, treatment allocation will not be concealed throughout the trial. 
With regard to the blind of the parent study (1368-0005 part I), patients and investigators will 
remain blinded with regard to the original randomised treatment assignments until after the 
final database lock for the initial induction trial has been performed.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately. Refer to ISF. Trial 
medication must be securely stored, e.g. in a locked refrigerator at the site or at a pharmacy.
The medication may only be dispensed to trial patients according to the Clinical Trial 
Protocol (CTP) by authorized personnel as documented in the trial staff list.
Trial medication will be prepared for infusion just prior to infusion, for further details please 
see preparation instructions in the ISF. 
4.1.8
Drug accountability
The investigator/pharmacist /investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB/ethics committee ,
∀
Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,
∀
Approval/notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated clinical trial protocol,


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∀
Availability of the proof of a medical license for the Principal Investigator (if 
applicable),
∀
Availability of FDA Form 1572 (applicable for US).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other physicians or clinics. 
The investigator/pharmacist/ investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor or warehouse/drug distribution centre or alternative disposal of 
unused products. If applicable, the sponsor or warehouse/drug distribution centre will 
maintain records of the disposal. 
These records will include dates, quantities, batch/serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator/pharmacist/investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator/pharmacist / investigational drug storage 
manager must verify that all unused drug supplies have been returned by the clinical trial
patient and that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
If the patient requires additional medical therapy or dose increase of baseline ulcerative 
colitis medication (other than BI 655130 (SPESOLIMAB) to treat a disease flare or a 
reversion to the preceeding higher daily steroid dose during tapering of steroids) to treat the 
underlying ulcerative colitis due to disease worsening (cf. Table 2.1:1 Definition of Study 
Outcomes), the study drug must be discontinued and patients may receive conventional 
treatment for active disease. In case of disease flare during maintenance treatment period, 
patient must be provided with disease flare treatment (single i.v. dose of 1200 mg BI 655130 
(SPESOLIMAB) infusion) followed by intensified maintenance treatment with 600mg BI 
655130 (SPESOLIMAB) q6w.
In case of undue safety risk for the subject, the subject should discontinue study treatment at 
the discretion of the investigator. If the subject receives a live virus vaccination during the 
study, the subject must discontinue study treatment.
Systemic steroids dosed intravenously or orally for less than 24 hours as treatment of infusion 
or anaphylactic reactions are permitted and do not lead to treatment discontinuation (see 
Table 4.2.2: 1).
If mild-to-moderate infusion or anaphylactic reaction had already occurred in the very same 
patient in the past, pre-treatment with steroids before next IMP administration is permitted  as 
secondary prophylaxis.


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Locally administered steroids as e.g. intraarticular, nasal inhalation or intraocular 
administration are allowed, but their application has to be carefully monitored and reported in 
CRF (see Table 4.2.2: 1).
Management of Adverse Events:
Infusion reactions / Systemic hypersensitivity including anaphylactic reaction
In case of infusion reactions / systemic hypersensitivity including anaphylactic reaction 
emerging during or after infusion / injection(s) of study drug, the investigator should consider 
in accordance with severity of the reaction and local standard of care to:
∀
Immediately interrupt the infusion / Stop further injections 
∀
Treat with systemic anti-histamines, intravenous steroids, and in case of a severe allergic 
reaction (e.g., anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA as detailed in the Lab Manual (available in ISF). 
Additionally consider the evaluation of histamine, serum tryptase, and complement 
components.
In case of infusion reaction / systemic hypersensitivity reaction, based on patient`s clinical 
course and medical judgment, the infusion / injections may be re-initiated in case of mild or 
moderate infusion reactions / systemic hypersensitivity reactions (according to RCTC grading
of “allergic reaction/hypersensitivity” in ISF) at lower speed with gradual increase to complete 
the infusion (in case of an infusion reaction) as detailed in the Instructions for Preparation and 
Handling of BI 655130 (SPESOLIMAB) in the Investigator Site File.
In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.5 R11-4890) suspected to be caused by the trial medication, the 
investigator should discontinue treatment with study drug (see Appendix 10.5 for criteria of 
anaphylaxis).
When a non-acute hypersensitivity reaction related to immune complexes (i.e., serum sickness) 
is suspected, please draw a sample for the laboratory assessment for circulating immune 
complexes (referring to Lab manual).
Severe infections (according to RCTC grading in Appendix 10.6), serious infections, 
opportunistic or mycobacterium tuberculosis infection 
Treatment of the infection should be initiated promptly according to local standard of care. No 
further trial medication should be administered until the active infection is resolved. Treatment 
with trial medication may be restarted when the patient has recovered according to 
investigator’s assessment.
∀
Latent TB must be treated according to local guidelines. Patient can continue the 
treatment. 


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Malignancies
∀
In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix, 
the investigator should discontinue treatment with study drug. Diagnostics and treatment 
have to be initiated according to local standard of care.
4.2.2
Restrictions
Restrictions regarding previous and concomitant treatment are summarized in Table 4.2.2: 1
Table 4.2.2: 1
Restrictions regarding previous and concomitant treatment
Medication or class of medications
Restriction 
Any biologic approved for UC (i.e. 
adalimumab, infliximab, golimumab, 
vedolizumab)
Not allowed until end of the end of IMP treatment
For use as rescue medication, refer to Section 4.2.1.
Any investigational or non-approved
biologic for UC (incl. ustekinumab, 
other IL-23 inhibitors, etrolizumab, 
certolizumab) 
Not allowed until end of the trial
For use as rescue medication, refer to Section 4.2.1.
Any non-biologic immunomodulator, 
(incl. cyclosporine, tofacinib and other 
JAK inhibitors, tacrolimus, sirolimus, 
mycophenolate mofetile)
Not allowed until end of the trial 
For use as rescue medication, refer to Section 4.2.1.
Any immunomodulator allowed per 
inclusion criteria in previous trial 
(Azathioprine, 6-mercaptopurine or 
methotrexate) 
Only allowed during the trial, if dose is stable prior to 
treatment initiation until end of the trial
For use as rescue medication, refer to Section 4.2.1
After ≥52 weeks of maintenance, such treatment can 
be discontinued in patients with durable clinical 
remission per the Investigator`s judgement
natalizumab or rituximab
Any prior exposure is prohibited
5-ASA
Oral administration:
Only allowed during the trial, if dose is stable prior to 
treatment initiation until end of the trial
Rectal route of administration:
Not allowed from screening up to end of the trial 
For use as rescue medication, refer to Section 4.2.1.


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Table 4.2.2: 1
Restrictions regarding previous and concomitant treatment
(continued)
Corticosteroids (incl. budesonide)
Oral administration:
Oral systemic corticosteroids only allowed at a dose 
of ≤ 20mg per day of prednisone or equivalent and 
with stable dose prior to treatment initiation.
Short decrease of dose for treatment of AEs with 
subsequent increase back to initial baseline dose level 
is allowed
Oral budesonide MMX (≤9 mg per day), provided 
that dose has been stable prior to treatment initiation.
Beclomethasone dipropionate allowed with stable 
dose prior to treatment initiation.
Parenteral administration:
Not allowed from prior to screening up to end of the 
trial.
Rectal administration:
Not allowed from screening up to end of the trial
Note: steroids will be tapered upon achievement of a 
clinical response or remission 
Allowed steroid treatments:
Short-term use (<7 days) of systemic (oral or 
parenteral) corticosteroids is allowed for treatment of 
AE not related to the underlying UC.
Parenteral corticosteroids dosed for less than 24 hours 
as treatment of infusion or anaphylactic reactions are 
permitted.
Locally administered steroids as e.g. intra-articular, 
nasal inhalation or intra-ocular administration are 
allowed. 
For use of steroids as rescue medication, refer to 
Section 4.2.1.


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Table 4.2.2: 1
Restrictions regarding previous and concomitant treatment 
(continued)
NSAID
Chronic use not allowed from screening up to end of 
the trial
(Note: Occasional use of NSAIDs and acetaminophen 
for transient symptoms - headache, arthritis, myalgias, 
menstrual cramps, etc., and daily use of baby or low 
dose (81-162.5mg) aspirin for cardiovascular 
prophylaxis are permitted.)
Antidiarrheals
Allowed during the trial as needed
Live-attenuated vaccines
Not allowed from screening up to end of the trial
Antibiotics for IBD
Not allowed from screening up to end of the trial
(antibiotics given for other indications are allowed if 
taken for no longer than 3 weeks)
4.2.2.1
Restrictions on diet and life style
No restrictions.
4.2.2.2
Restrictions regarding Women of Childbearing Potential 
Women of childbearing potential must use the contraception methods described below.
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 for female participants who are 
able to become pregnant include:
1. Combined (estrogen and progestogen containing) hormonal birth control associated with 
inhibition of ovulation.
2. Progestogen-only hormonal birth control associated with inhibition of ovulation.
3. Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS).
4. Tubal occlusion (blocking of the fallopian tubes).
5. Vasectomy of sexual partner (proven effective by absence of sperm on the ejaculation).
6. True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), 
declaration of abstinence for the duration of exposure to the investigational medicinal 
product, and withdrawal are not acceptable methods of contraception
4.3
TREATMENT COMPLIANCE
Study medication will be administered in accordance with the protocol under supervision of 
the investigating physician or a designee at the site.


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Any missed dose has to be documented and reported to the CML.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The changes in UC activity during the trial will be assessed at visits including endoscopies 
using the modified Mayo score (disease activity score, not including the PGA (physician 
global assessment) item, but including the modified ESS (any degree of friability defines a 
score of at least 2), and the Robarts histopathology index (RHI). In addition, the total Mayo 
score (including PGA) will be explored as further endpoint to facilitate indirect comparisons 
against currently approved or investigational drugs.
Please refer to Appendix 10.1 (Mayo Score/modified Mayo score) and to Appendix 10.2
(Robarts histopathology index) for further details.
Endoscopic and histological endpoints will be assessed and scored using independent central 
readers. 
5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:
∀
Adverse events (AEs)
∀
Serious adverse events (SAEs)
∀
Clinical laboratory values (haematology, clinical chemistry, coagulation and urinalysis)
∀
Intensity of adverse events will be assessed by Rheumatology Common Toxicity Criteria 
(RCTC) version 2.0 (refer to Appendix 10.6 and ISF for details)
∀
Physical examination
∀
Vital signs
∀
12-lead ECG
5.2.1
Physical examination
Complete physical examination will include vital sign assessment and general appearance as 
well as evaluation of all organ systems, Targeted physical examination will include vital sign 
assessment and evaluation of organ systems associated with AE(s) symptoms or extra 
intestinal manifestations as well as laboratory abnormalities.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
5.2.2
Vital signs
Vital signs evaluations will be performed at visits as shown in the Flow Chart. This includes 
temperature, pulse rate, systolic/diastolic blood pressure and respiratory rate. Respiratory 
rate, pulse rate, and blood pressure will be measured after patients have been sitting 
comfortably for at least five minutes. Measurement of vital signs should precede blood 


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sampling to avoid the impact of blood sampling on the vital measurements. At dosing visits
vital signs evaluations will be performed pre-dose for both visits with i.v. and s.c. 
administration of study drug. Vital signs will be measured additionally 10 min post-dose after 
s.c. administration and 5 and 60 min. post-dose in case of i.v. study drug administration.
Patients should be closely monitored for signs and symptoms of hypersensitivity reactions for 
1 hour following i.v. study drug administration. Hypersensitivity reactions should be treated 
according to medical standards. Pre-medications for further injections might be considered 
and will be agreed on between investigator and BI clinical monitor.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1. For the sampling time 
points please see the Flowcharts.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients are not required to be fasting for at least 8 hours prior to the blood sample being 
taken.
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 or baseline conditions. (please 
refer to Section 5.2.6).
Laboratory results (i.e. all safety laboratory and clinical laboratory data relevant for current 
clinical practice) of the patients will be available in real time to the respective investigator 
(via laboratory reports) and to the sponsor (via the central laboratory website) and selected 
abnormal laboratory alerts will be flagged to the site and sent to sponsor in real time.
A clinically relevant value may be either within- or outside the reference range. Clinically 
relevant abnormal laboratory test results must be confirmed using an unscheduled visit 
laboratory kit and should be repeated until normalization or stabilization or until an 
alternative explanation has been found. Abnormal laboratory values will be also graded for 
intensity by using RCTC Version 2.0 criteria [R13-3515].
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the ISF EDC 
system. The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.


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Table 5.2.3: 1 Additional testing
Category
Test name
Serum Pregnancy test (only for female patients of 
childbearing potential)1
Human Serum Chorionic Gonadotropin
Stool studies to evaluate for enteric pathogens
(Faecal assessment for enteric pathogens has to be 
done at suspicion of an disease flare to exclude 
enteric infection)
Salmonella
Shigella
Yersinia
Campylobacter
Vibrio
E. coli O157/H7
Clostridia difficile toxin
Enteric parasites and their ova (including 
Cryptosporidia)
1 At screening only (visit 1)


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Table 5.2.3: 2 Laboratory tests
Category
Test name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)
Glycosylated Hbc (HbA1c) (required to be tested
every 48 weeks)
Red Blood Cell Count/ Erythrocytes
Reticulocyte Count
White Blood Cells / Leukocytes
Platelet Count/ Thrombocytes
Diff. Automatic
Neutrophils (relative and absolute count)
Eosinophils (relative and absolute count)
Basophils (relative and absolute count)
Monocytes (relative and absolute count)
Lymphocytes (relative and absolute count)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils, bands (Stabs)
Neutrophils, polymorphonuclear (PMN)
Eosinophils
Basophils
Monocytes
Lymphocytes
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin time (INR)
Fibrinogen
Enzymes
AST (GOT)
ALT (GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Amylase
Lipase
Electrolytes
Calcium
Sodium
Potassium
Chloride
Bicarbonate
Substrates
Glucose
BUN (blood urea nitrogen)
Uric acid
Creatinine
eGFR (estimated by CKD-EPI formula) (only at 
screening)
Bilirubin Total
Bilirubin Direct (if total is elevated)
Bilirubin Indirect (if total is elevated)
Troponin (Reflex, in case of elevated CK) 
Protein, Total
Albumin
C-Reactive Protein (CRP) (high sensitivity)
Cholesterol, total
Triglycerides
LDL-Cholesterol
HDL-Cholesterol


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Table 5.2.3: 2 Laboratory tests (continued)
Category
Test name
Specific gamma-globulin quantification
IgE1, IgG
Urine Pregnancy test (only for female patients of 
childbearing potential)
Human Chorionic Gonadotropin in urine
Serum Pregnancy test (only for female patients of 
childbearing potential if urine pregnancy test is 
positive)
Human Serum Chorionic Gonadotropin
Hormones ( required to be tested every 48 wks)
TSH (free T3 and free T4 in case of abnormal TSH 
result) 
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leukocytes
Urine pH
Urine-Sediment (microscopic examination, only if 
urine analysis abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells
Urine Sed. Crys., Unspecified
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
Urine (only at screening)
Albumin (quantitative)
TB
QuantiFERON®-TB2
Faecal sample 
Calprotectin
Lactoferrin
1Only in case of allergic reaction
2   If the 1st QuantiFERON®-TB test result is undetermined, a re-test should be performed. If the restest 
QuantiFERON-TB test result is undetermined, a PPD skin test should be performed. 
5.2.4
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the flowchart. The investigator or a 
designee will evaluate whether the ECG is normal or abnormal and whether it is clinically 
relevant, if abnormal. ECGs may be repeated for quality reasons and the repeated recording 
used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported as adverse events and will be followed 
up and/or treated as medically appropriate.


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5.2.5
Other safety parameters
Local tolerability at the administration site of the subcutaneous injection will be assessed by 
the investigator at the specified visits as noted in the Flow Chart see section 4.1.1 for further 
details. Any observed local tolerability reactions like “swelling”, “induration”, “heat”, 
“redness”, “pain”, or  any other findings should be reported as an adverse event in the eCRF. 
In case of an infusion reaction monitor the patient per standard of care, grade the intensity of 
the reaction according to RCTC grading (cf. ISF) and proceed as described in section 4.2.2.1.
Also draw plasma sample for IgE and ADA (anti-drug antibodies), as detailed in the CTP 
section 5.2.3 and the lab manual. Assessment according to RCTC implies also reporting as 
AE.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious Adverse Event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
1.
results in death,
2.
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.
3.
requires inpatient hospitalisation or 
4.
requires prolongation of existing hospitalisation,
5.
results in persistent or significant disability or incapacity, or
6.
is a congenital anomaly / birth defect,
or
7.
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.


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Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in section 5.2.6.2, subsections “ AE Collection” and AE reporting to sponsor and 
timelines”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Adverse Events of Special Interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular interest or prospective safety monitoring and safety assessment within this trial.
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:
∀
Systemic hypersensitivity including infusion reaction and anaphylactic reaction
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 10.5, R11-4890).
Severe infections (according to (according to RCTC grading in Appendix 10.6)
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, 
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 


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(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only), shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression [R17-2617]
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
a. ALT or AST >5x ULN
b. ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
c. AST and/or ALT >3 fold ULN combined with an elevation of total bilirubin >2
fold ULN measured in the same blood draw sample
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF. 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
If an alternative cause for the hepatic injury cannot be identified in the follow-up assessments 
specified in the “DILI checklist”, discontinuation of treatment with study drug should be 
considered.
Peripheral Neuropathy
Any event suspected or diagnosed as Peripheral Neuropathy would be considered as an AESI.
For the treatment interruption rules, please see section 3.3.4.1
Intensity (severity) of AEs
The intensity grading of AEs will be performed according to Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0 developed by
 (Appendix 10.6,   R13-
3515). Refer to the ISF for intensity/severity classification. Intensity options are:
Grade 1 
mild
Grade 2 
moderate
Grade 3 
severe
Grade 4 
life-threatening
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 


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Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-existing 
or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
∀
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).
∀
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From the time of first dose of trial drug administration in the extension trial until the individual 
patient’s end of trial: 
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only report any occurrence 
of cancer and trial treatment related SAEs and trial treatment related AESIs of which the investigator may 
become aware of by any means of communication, e.g. phone call. Those AEs should be reported on the BI 
SAE form (see Figure 5.2.6.2:1), but not on the CRF.




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If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable” , or no further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for 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.


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5.6
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements in UC treatment 
trials and will be performed in order to monitor safety aspects or assess treatment response in 
an appropriate way.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Charts. Each visit date 
(with its window) up to EOT is to be counted from Day 1. If any of these visits has to be 
rescheduled, the date of subsequent visit should be calculated from Day 1. EOT refers to the 
last dose administration of BI 655130 (SPESOLIMAB) at week 336. Additional visits for the 
purpose of re-testing of laboratory parameters or AE monitoring may be included as deemed 
necessary by the investigator.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the relevant Flow Chart and the 
respective protocol sections. Refer to Section 5 and Section 10 (Appendices) for explanations 
of procedures. Additional details on procedures at selected visits are provided below. 
Patient Reported outcomes (PROs ) should be completed by the patient on his/her own in the 
pre-specified order in a quiet area/room before any other visit assessments or treatments and, 
as much as possible, before any interaction with the investigator or other members of the 
study team.
The order of completion for PROs is as follows, as applicable for each PRO at relevant visits
according to the Flow Chart:
1. IBDQ
2. EQ-5D-5L
6.2.1
Screening and run-in period(s)
Screening Period
After patients have been informed about the trial, written informed consent in accordance 
with GCP and the local legislation must be obtained prior to performing any study related 
procedures. Once they have consented, the patient is considered to be enrolled in the trial. 
The patient should be recorded on the subject enrolment log. Patient will be assigned a 
patient number and enrolment must be recorded in the eCRF pages.
Screening Visit (Visit 1): 
The Screening visit (Visit 1) should occur 7 days before Visit M1 and be complete no less 
than 3 days prior to Visit M1. 
At this visit, information will be collected for evaluation of trial eligibility as indicated in the
Flow chart 1 or Flow chart 2.


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Visit 1 should be performed in one visit, in combination with EOT visit of the previous 
induction trials 1368-0005 Part 1; 1368-0004. Procedures performed at EOT visit of previous 
trial should not be repeated at V1 of 1368-0017. 
For more details regarding procedures at V1 please refer to Flow chart 1 or Flow chart 2.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding UC) will be reported on the baseline condition eCRF page.
Patients who have a laboratory test value outside the range specified by the inclusion criteria 
may have the test repeated to determine eligibility. The result must be available prior to Visit 
M1 (Day 1). 
Demography
Informed consent date, gender, age, race and ethnic origin will be collected in the eCRF page. 
Also, the patient’s smoking history will be assessed. Information concerning race/ethnicity 
will be collected, as it has been suggested that there may be race/ethnicity variations in the 
incidence, phenotypic manifestations and outcome of UC. Note: In some countries, race may 
not be collected.
Medical and Surgical History
Information on clinically significant previous and concomitant diseases, other than UC, 
should be registered in Baseline conditions as follow up from the previous induction studies.
Blood sampling
Blood samples will be drawn for safety lab, PK, ADA and biomarkers. TSH and 
Glycosylated Hbc (HbA1c) does not need to be assessed at screening visit. These need to be 
assessed first at W36 of maintenance treatment period and then every 48 weeks.
For women of childbearing potential, a serum pregnancy test will be performed. 
Stool sampling
A stool sample will be collected for faecal biomarkers (calprotectin, lactoferrin).
Patient diary
Patients will use an eDiary provided at screening visit for reporting of stool frequency and 
rectal bleeding (blood in stool). Patients have to be asked to enter these data into the eDiary
14 consecutive days prior to each visit which includes assessment of Mayo score, and as well 
when a patient perceives worsening of UC symptoms at any time between visits as a 
precursor to disease flare assessment (see section 3.1). 
The diary will be returned at EOS visit.


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Visit 1.a 
Visit 1a should take place approx. 3-7 days after Visit 1 when sigmoidoscopy assessment will 
be provided by central reader to finalize eligibility assessment. This visit can be done per 
telephone. Patients should be asked for any changes in concomitant therapy or potential AEs 
from V1. 
6.2.2
Treatment period
The treatment period is lasting from Visit M1/R1 until End of Treatment (EOT) Visit.
Study related procedures during treatment period will be performed as specified in the Flow
chart 1,  Flow chart 2 or Flow chart 3, in case patients develop a disease flare.
Patients can be discontinued from trial medication at any time if in the opinion of the 
Investigator, continuation with trial medication is not in the patient’s best interest.
Pregnancy testing
Urine pregnancy testing for all women of child-bearing potential will be conducted on-site at 
visits with study drug administration (4 weeks during i.v. re-induction phase) and must be 
negative to continue treatment. More frequent testing should be done if required by the local 
regulation and / or authority or per investigator judgment.
The pregnancy testing should be done prior to study drug administration. A positive urine 
test must be confirmed with a serum pregnancy test.
Blood sampling
Blood sampling (e.g., for safety lab, BMs) should be done prior to study drug administration 
and prior to sigmoidoscopy, if applicable. It is not requested that patient is fasted prior to 
collection of the safety laboratory testing as indicated in Flowcharts, but patient has to be 
asked and information will be collected on lab requisition form if patient was fasting or not 
8h prior to blood sampling
Sigmoidoscopies
Sigmoidoscopies will be done after blood sampling and prior to study drug administration. 
Sigmoidoscopies will be performed every 48 weeks  during maintenance treatment period 
and at end of re-induction period as indicated in the Flowcharts. Additionally 
sigmoidoscopies have to be done in case of disease flare as indicated in Flowchart 3. During 
sigmoidoscopies, biopsies will be taken for endpoint evaluation at time points as indicated in 
the Flow Chart. Please refer to Section 5 of the ISF for further information on the collection 
and the processing of biopsies.
Colonoscopy instead of sigmoidoscopy can be performed if required as colon cancer 
screening per local guidelines.
PK and ADA sampling
Blood sampling for PK assessments should be done within one hour prior to study drug 
administration.


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Clinical monitoring after study drug administration:
The patient will be monitored for infusion reactions at the site for approximately 1 hour 
following study drug administration. Local tolerability at the administration site of the 
subcutaneous injection will be assessed by the investigator at the specified visits as noted in 
the Flow Chart. 
At all dosing visits vital signs will be assessed pre- and post-dose, please see section 5.2.2 for 
further details.
Unscheduled visits
The patient may be asked for additional unscheduled visits due to safety reason at the 
discretion of the investigator or the sponsor, unless the patient has withdrawn his/her consent. 
The patient may also contact the site due to safety reason for an unscheduled visit. The 
unscheduled visit may include additional collection of blood samples for safety reasons. The 
unscheduled visit may also include additional assessments deemed necessary by the 
investigator such as laboratory samples, ECGs, or other procedures which were missed at a 
previous visit. All unscheduled visits should be described (including the reason for the visit) 
and documented in the medical/source record, and in the eCRF.
Concomitant medication review
Data concerning concomitant medications and procedures will be collected throughout the 
trial, as specified in the Flow Charts. These data will be obtained at scheduled or unscheduled 
trial visits based on information  provided spontaneously by the patient or as a result of 
questioning the patient.
6.2.3
Follow up period and trial completion
For all patients, termination of trial medication and trial completion must be recorded on the 
corresponding eCRF.
For patients completing the safety FU period, the EOS visit is scheduled at 16 weeks after the 
last dose of study drug. For more details please follow Flow Charts.
6.2.3.1
Early treatment discontinuation
Patient who discontinue treatment prior to the planned EOT visit have to be invited for an
early EOT visit as soon as possible. .These patients should be registered as withdrawn from 
treatment in IRT and return to the site for the End of Study (EOS) visit 16 weeks after last 
study drug intake.


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6.2.3.2
Trial completion
Patients who finish the treatment period will return to the site for the End of Study (EOS)
visit 16 weeks after the EOT visit. Completion is defined as a patient having reached the EOS 
visit.  
6.2.3.3
Further treatment after the end of the trial
At the end of the trial, patients will be treated for their UC at the discretion of the 
investigator, according to local UC guidelines (e.g. ECCO guideline R17-0243).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This trial is designed as a single arm, open-label trial in patients with ulcerative colitis who 
have completed the planned treatment period in previous trials 1368-0004 or 1368-0005/Part 
1. The following treatments are planned:
∀
For patients who do not have a clinical response at week 12 of parent trial:
o
Multiple active doses of intravenous BI 655130 (SPESOLIMAB) 1200 mg q4w to 
be administered for 12 weeks (re-induction); responders at week 12 will 
subsequently receive subcutaneous BI 655130 (SPESOLIMAB) 300 mg q4w as 
maintenance treatment for up to 7 years;
∀
For patients who do have a clinical response at week 12 of parent trial:
o
Subcutaneous BI 655130 (SPESOLIMAB) 300 mg q4w as maintenance treatment 
for up to 7 years.
Patients who experience a disease flare (as defined in section 2.1) will be administered 
disease flare rescue medication as a single dose of BI 655130 (SPESOLIMAB) 1200 mg
followed by an intensified maintenance dosing schedule with 600 mg q6w.
For both efficacy and safety data, the following reporting periods will be defined:
o
Maintenance Period
Includes data from the maintenance part of this extension trial.
o
Re-Induction Period
Includes data from the re-induction part of this extension trial, where applicable.
There is no confirmatory statistical testing planned during the analysis of this extension trial; 
only descriptive analyses are intended.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Given the single arm and open-label nature of this trial, all statistical assessments will be 
performed in a descriptive manner only. No hypothesis testing is intended to be performed.


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7.3
PLANNED ANALYSES
There will be 2 main patient populations in this trial for analyses: the treated set for 
maintenance treatment (TS-MT) and the treated set for re-induction treatment (TS-RT).
Treated Set for Maintenance Treatment (TS-MT)
This patient set includes all patients who received at least one dose of maintenance treatment
in the extension trial. It will be the main analysis set for presentation of safety and efficacy
during the maintenance part of the extension trial.
Treated Set for Re-induction Treatment (TS-RT)
This patient set includes all patients who received at least one dose of re-induction treatment
in the extension trial. It will be the main analysis set for presentation of safety and efficacy
during the re-induction part of the extension trial.
Further analysis sets will be defined in the TSAP if necessary.
Important violations of the protocol will include violations of the key inclusion and exclusion
criteria, concomitant use of restricted medications, and any other violations of the protocol 
deemed important by the study team. All decisions concerning important protocol violations 
will be made prior to final database lock for this extension trial.
Standard statistical parameters (number of non-missing values, mean, standard deviation
(SD), median, quartiles, minimum and maximum) or frequency tables (including patient
frequencies and percentages) will be calculated where appropriate.
A Clinical Trial Report will be prepared once the final database lock for this extension trial 
has been performed.
7.3.1
Primary endpoint analyses
Refer to section 7.3.4 for the description of safety analyses including that for the primary 
endpoint. The primary endpoint will be summarized for the maintenance period (described in 
section 7.1).
7.3.2
Secondary endpoint analyses
The evaluation of clinical outcomes based on the Mayo Clinical Score, i.e. clinical remission,
is based upon the endoscopy results obtained from central reading. Only if the centrally read 
endoscopy result is missing at a time-point will the locally read result be used instead.
For the stool frequency and rectal bleeding items reported in the patient diary, an average of 
the last 3 non-missing daily assessments collected within the last 7 days prior to the 
applicable visit will be used for the determination of clinical outcome. If the patient 


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undergoes bowel preparation for endoscopy on any of the days before a visit, the stool 
frequency and rectal bleeding subscores on that day(s) should be considered to be missing. In 
addition, the stool frequency and rectal bleeding subscore will be considered to be missing 
both on the day of and the day after the endoscopy.
Secondary endpoint will be assessed descriptively. Further details will be provided in the 
TSAP.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the residual effect period (REP), a period 
of 16 after the last dose of trial medication, will be assigned to the on-treatment period for 
evaluation. Adverse events occurring in the maintenance and re-induction periods will be 
separately described.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
residual effect period. For patients who switch directly to maintenance treatment at week 12 
of the re-induction period, adverse events occurring on and after the first day of maintenance 
treatment will be included in summaries of the maintenance period only. Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’. For all subjects who received disease flare treatment with BI 655130
(SPESOLIMAB), safety assessments including adverse events, laboratories, vital signs etc. 
which occurred subsequent to such intake will be excluded from presentations according to 
the planned treatment; these data will, however, be included in summaries where all data after 
any use of BI 655130 (SPESOLIMAB) are displayed.


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Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at the database lock.
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 summarised. 
Laboratory data will be analysed descriptively with regard to distribution parameters as well 
as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.4
INTERIM ANALYSES
In order to ensure the patient’s safety during the trial, an external DMC, independent of the 
trial and project teams, will be set-up to review all available un-blinded safety data as well as 
selected efficacy data at regular intervals following first-patient-in. A separate DMC SAP 


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will be produced which describes the analyses required for assessment by the DMC. Further 
details will be provided in a DMC charter.
As the primary aim of this study is to collect long-term safety and efficacy data on the use of 
BI 655130 (SPESOLIMAB) in this population, multiple interim analyses will be done over 
the 7-year conduct phase of this trial to support, for example, regulatory interactions, CTA 
and MAA/BLA submissions, but also to provide important safety and efficacy information to 
the sponsor to guide further development of the compound, and to the investigators via IB 
updates and publications. 
A CTR describing all data collected within this trial will be produced once the last patient in 
the trial has completed the final follow-up visit.
7.5
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will 
still occur and approaches to handle this are proposed below.
For the safety data, including the primary endpoint, no missing data imputations are planned.
For efficacy data, if one or more subscores on the clinical remission (or clinical response), 
calculated using the Mayo Clinic score, are missing at a visit then the overall outcome at that 
visit is also considered to be missing.
With regards to the handling of missing data on those efficacy outcomes derived from the 
MCS, no missing data imputations are planned to be performed.
If a patient experiences disease worsening during the re-induction period, or a disease flare 
during the maintenance period prior to observing the efficacy outcome at a specific visit, then 
all data subsequent to the intake of such rescue medication will be set to missing. Additional 
summaries including all data observed even following rescue medication intake will also be 
done. Further details with regard to what constitutes a rescue intake with potential impact on 
the efficacy data will be described in the TSAP.
For other efficacy endpoints, rules for handling of missing data will be specified in the TSAP 
if necessary.
7.6
RANDOMISATION
Given the single arm nature of this trial, no randomization will be performed.


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7.7
DETERMINATION OF SAMPLE SIZE
Given the descriptive nature of this trial, no sample size calculation has been performed.
Approximately 160 patients who meet the entry criteria are planned for inclusion into this 
trial, rolling over from the preceding trials of 1368-0005 part 1and 1368-0004.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is 
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The investigator 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 obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign (or 


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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 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. For drug accountability, refer to 
section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see section 8.3.2). The investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone number, social security number) have properly 
been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:


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∀
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, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history (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 sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.


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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.
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
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection and future use of 
biological samples and clinical data, in particular
∀
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


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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 Out”). The “Last Patient Drug Discontinuation” (LPDD) date is defined as 
the date on which the last patient at an individual trial site ends trial medication (as scheduled 
per protocol or prematurely). Individual investigators will be notified of SUSARs occurring 
with the trial medication until 30 days after LPDD at their site. Early termination of the 
trial is defined as the premature termination of the trial due to any reason before the end of 
the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
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. 
A project-independent, fully-external data-monitoring committee (DMC), will be established 
to assess the progress of the clinical trial, including an unblinded safety and efficacy 
assessment at specified intervals, and to recommend to the sponsor whether to continue, 
modify, or stop either a single BI 655130 (SPESOLIMAB) dose or the trial due to safety or 
ethical concerns. The tasks and responsibilities of the DMC will be specified in a charter. The 
DMC will maintain written records of all its meetings.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF. The investigators will have access to the 
BI clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic 
ISF. 
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,


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-
ensure appropriate training and information of Local Clinical Monitors (CML), Clinical 
Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, a central images service, e-Diary and an IRT vendor will be 
used in this trial. Details will be provided in the IRT Manual and Central Laboratory Manual, 
available in the ISF.


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9.
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9.1
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colitis patients.
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maintenance trials of ulcerative colitis.
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et al
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inflammatory diseases: consensus recommendations for infection reporting 
during clinical trials and postmarketing surveillance.
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R17-3426
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(Janssen Biotech) (U.S. prescribing information, revised: November
2013).
R17-3632
Mahil SK, Catapano M, Meglio P di, Dand N, Ahlfors H, Carr IM, et al
An analysis of IL-36 signature genes and individuals with IL1RL2 knockout 
mutations validates IL-36 as a psoriasis therapeutic target.
Sci Transl Med 9, eaan2514 (2017)
R96-2382
EuroQol - a new facility for the measurement of health-related quality of life.
Health Policy 16, 199 - 208 (1990)


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R97-3472
Irvine EJ, Feagan B, Rochon J, Archambault A, Fedorak RN, Groll A, Kinnear 
D, Saibil F, McDonald JWD, 
Quality of life: A valid and reliable measure of therapeutic efficacy in the 
treatment of inflammatory bowel disease. 
Gastroenterology 106, 287 - 296 (1994)
R97-3596
Guyatt G, Mitchell A, Irvine EJ, Singer J, Williams N, Goodacre R, Tompkins 
C
A new measure of health status for clinical trials in inflammatory bowel
disease.
Gastroenterology 96, 804 - 810 (1989)
P14-15417
Assche G van, Dignass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, 
Beaugerie L, Gomollon F, Haeuser W, Herrlinger
K, Oldenburg B, Panes J, Portela F, Rogler G, Stein J, Tilg H, Travis S, 
Lindsay JO
Second European evidence-based consensus on the diagnosis and management 
of ulcerative colitis part 3: special situations.
J Crohns Colitis 7 (1), 1 - 33 (2013)
P17-11924
Feagan BG, Sandborn WJ, Panes J, Ferrante M, Louis E, D'Haens G, et al
Efficacy and safety of re-induction treatment with the selective IL-23 inhibitor 
risankizumab in patients with moderate-to-severe Crohn's disease.
24th United Eur Gastroenterology Week (UEGW), Vienna, 15 - 19 Oct 2016
United Eur Gastroenterol J 4 (6), 806 - 807, Abstr LB17 (2016)
9.2
UNPUBLISHED REFERENCES
c03320877
Investigator’s Brochure, BI 655130 for IL36R antibody in Ulcerative Colitis, 
Palmoplantar Pustulosis and Pustular Psoriasis; version 06, dated 04 April
2019
c03361085
 Clinical Trial Protocol: 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. Version 6. 27 Jan 2016.


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


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Table 10.1: 1
Mayo score (adopted from Schroeder et al, 1987)
Components
Subscore
Severity
Score
CLINICAL RESPONSE
(Patient’s Symptoms)
Stool Frequencya (daily)
Normal number of stools for patient
0
1 to 2 stools more than normal
1
3 to 4 stools more than normal
2
≥5 stools more than normal
3
Rectal Bleedingb (daily)
No blood seen
0
Streaks of blood with stool
1
Obvious blood with stool
2
Blood alone passes
3
Physician’s Global 
Assessmentd
Normal
0
Mild disease
1
Moderate disease
2
Severe disease
3
MODIFIED
ENDOSCOPIC 
RESPONSE
(Objective Evidence of 
Inflammation)
Endoscopic Appearancec
Normal
0
Mild disease
1
Moderate disease
2
Severe disease
3
a Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency.
b The daily bleeding score represents the most severe bleeding of the day.
c Modified endoscopic appearance: 0 (normal), Mild (erythema, decreased vascular pattern, granularity), 
Moderate (marked erythema, loss of vascular pattern, any friability, erosions), Severe (spontaneous bleeding, 
ulceration).
d The physician’s assessment acknowledged the three other criteria, the patient’s daily record of abdominal 
discomfort and general sense of well-being, and other observations, such as physical findings and the patient’s 
performance status.
Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid
therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J
Med 1987; 317 (26):1625-1629
10.2
HISTOLOGIC ACTIVITY SCORE
The Robarts histopathology index is a histologic activity score (Mosli et al, Gut2015). The 
total score ranges from 0 (no disease activity) to 33 (severe disease activity).


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Table 10.2: 1
Robarts Histopathology Index (RHI) by components
Component
Intercept
Chronic 
inflammatory 
infiltrate
0=No Increase
1=Mild but unequivocal increase
2=Moderate increase
3=Marked increase
Lamina propria 
neutrophils
0=None
1=Mild but unequivocal increase
2=Moderate increase
3=Marked increase
Neutrophils in epithelium
0=None
1=<5% crypts involved
2=<50% crypts involved
3=>50% crypts involved
Erosion or ulceration
0=No erosion, ulceration, or granulation tissue
1=Recovering epithelium + adjacent inflammation
1=Probably erosion-focally stripped
2=Unequivocal erosion
3=Ulcer or granulation tissue
Mosli MH, Feagan BG, Zou G, et al. Development and validation of a histological index for 
UC. Gut 2015.
Based on this, the RHI will be calculated as follows:
RHI = 1 x chronic inflammatory infiltrate level (4 levels) + 2 x lamina propria neutrophils (4 
levels) + 3 x neutrophils in epithelium (4 levels) + 5 x erosion or ulceration (4 levels after 
combining Geboes 5.1 and 5.2)


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10.3
EQUIVALENT DOSES OF CORTICOSTEROIDS
Drug 
Equivalent dose (mg) 
Conversion factor 
Prednisone 
5 
X 1 
Prednisolone 
5 
X 1 
Triamcinolone 
4 
X 1.25 
6-Methylprednisolone 
4 
X 1.25 
Dexamethasone 
1 
X 5 
Betamethasone 
0,75 
X 6.7 
16-Methylprednisolone 
6 
X 0.8 
Fluocortalon 
5 
X 1 
Cloprednol 
3,75-5 
X 1.0-1.5 
Deflazacort 
6 
X 0.8 
Cortisol (hydrocortisone) 
20 
X 0.25 
Cortisone 
25 
X 0.20
10.4
PATIENT REPORTED OUTCOMES
10.4.1
Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ [R97-3472] is a 32-item self-report questionnaire for patients with IBD to evaluate 
the patient reported outcomes across 4 dimensions: bowel symptoms (loose stools, abdominal 
pain), systemic symptoms (fatigue, altered sleep pattern), social function (work attendance, 
need to cancel social events), and emotional function (anger, depression, irritability). Scores 
range from 32 to 224 with higher scores indicating better outcomes.
10.4.2
EQ-5D-5L
The EQ-5D(-5L) is a standardized instrument developed by the EuroQoL Group for use as a 
generic, preference-based measure of health outcome. The EQ-5D(-5L) questionnaire 
captures two basic types of information, an overall health rating using a visual analog scale 
and a descriptive “profile,” or “health state”. The health state is converted to a single 
weighted index score by applying coefficients from a validated value set. The index score is 
used in both clinical and economic evaluations of health care. These two basic types of 
information cannot be combined and will be reported separately.
The health state index measures five health dimensions. The health states for each respondent 
are converted into a single index number using a specified set of country-specific weights. A 


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higher score indicates a more preferred health status with 1.0 representing perfect health and 
0 representing death. A missing answer on any one question leads to a missing overall score.
For purposes of the analyses for this study, all patients’ EQ-5D(-5L) index scores will be 
calculated using the UK weights. 
The VAS asks respondents to rate their present health status on a 0 - 100 visual analog scale, 
with 0 labelled as “Worst imaginable health state” and 100 labelled as “Best imaginable 
health state.” The VAS score is determined by observing the point at which the subject’s 
hand drawn line intersects the scale.
10.5
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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10.6
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (
)
Table 10.6:1
Severity of AE as described in the Rheumatology common Toxicity 
Criteria (
)
1 - Mild
2 - Moderate
3 - Severe
4 - Includes 
Life 
Threatening
Asymptomatic, or 
transient 
Short duration (< 1 
week)
No change in life 
style 
No medication or 
OTC 
Symptomatic 
Duration (1–2 
weeks) 
Alter lifestyle 
occasionally 
Meds relieve. 
(may be 
prescription),
Study drug 
continued
Prolonged symptoms, 
reversible, major 
functional impairment 
Prescription 
meds/partial relief 
May be 
hospitalized<24h
Temporary study drug 
discontinuation, 
or/and dose reduced
At risk of 
death
Substantial 
disability, 
especially if 
permanent.
Multiple meds
Hospitalised 
>24h
Study drug 
discontinued
A.ALLERGIC/IMMUNOLOGIC
A1. Allergic reaction/
hypersensitivity 
(including drug fever)
Transient rash; 
drug fever < 38° C, 
transient 
asymptomatic 
bronchospasm
Generalized 
urticaria 
responsive to 
meds; or drug 
fever > 38° C, 
or reversible 
bronchospasm
Symptomatic 
bronchospasm, 
requiring meds; 
symptomatic urticaria 
persisting with meds, 
allergy related 
oedema/ angioedema
Anaphylaxis, 
laryngeal/ 
pharyngeal 
edema, 
requiring 
resuscitation
A2. Autoimmune 
reaction
Serologic or other 
evidence of 
autoimmune 
reaction but patient 
asymptomatic: all 
organ function 
normal and no 
treatment is 
required (e.g., 
vitiligo)
Evidence of 
autoimmune 
reaction 
involving a 
non-essential 
organ or 
functions, 
requiring 
treatment other 
than 
immunosuppre
ssive drugs 
(e.g., 
hypothyroidis
m)
Reversible 
autoimmune reaction 
involving function of 
a major organ or 
toxicity requiring 
short term 
immunosuppressive 
treatment (e.g., 
transient colitis or 
anemia)
Causes major 
organ 
dysfunction, or 
progressive, 
not reversible, 
or requires 
long term 
administration 
of high dose 
immunosuppre
ssive therapy


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Table 10.6: 1 
Severity of AE as described in the Rheumatology common Toxicity 
Criteria (
) (Cont.)
1 - Mild
2 - Moderate
3 - Severe
4 - Includes 
Life 
Threatening
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
10.7
STEROID TAPERING SCHEME
Recommended tapering schedule for systemic corticosteroids:
∀
Dose > 15 mg/day prednisone or equivalent: taper daily dose by 5 mg/week until 
receiving 10 mg/day, then continue tapering at 2.5 mg/week until 0 mg/day.
∀
Dose 11 to 15 mg/day prednisone or equivalent: taper daily dose to 10 mg/day for 1 
week, then continue at 2.5 mg/week until 0 mg/day.
∀
Dose ≤10 mg/day prednisone or equivalent: taper daily dose by 2.5 mg/week until 0 
mg/day.
Recommended tapering schedule for oral corticosteroids (other than budesonide):
. 
∀
Dose > 15 mg/day prednisone or equivalent: taper daily dose by 5 mg/week until 
receiving 10 mg/day, then continue tapering at 2.5 mg/week until 0 mg/day.
∀
Dose 11 to 15 mg/day prednisone or equivalent: taper daily dose to 10 mg/day for 1 
week, then continue at 2.5 mg/week until 0 mg/day.
∀
Dose ≤10 mg/day prednisone or equivalent: taper daily dose by 2.5 mg/week until 0 
mg/day.
∀
For oral budesonideAdminister initial daily dose every other day for 2 weeks before 
stopping the drug 
For oral beclomethasone dipropionate
∀
Stop using after achieving clinical response or clinical remission


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
11 Jun 2018
EudraCT number
EU number
2018-000334-35
BI Trial number
1368-0017
BI Investigational Product(s)
BI 655130
Title of protocol
An open label, long term safety trial of BI 
655130 treatment in patients with moderate to 
severely active ulcerative colitis who have 
completed previous BI 655130 trials
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
x
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
x
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
All sections in the Protocol
Description of change
Trial numbers 1368.4; 1368.5 and 1368.17 
changed to 1368-0004; 1368-0005 and 1368-
0017
Rationale for change
Change in sponsor`s systems
Section to be changed
Flowchart 1 
Description of change
Day for V1 changed from -7 to -1 to -7 to -2; 
Vital status collection removed from EOT visit, 
e-diary review added at EOS
Rationale for change
Typo
Section to be changed
Flowchart 2
Description of change
Day for V1 changed from -7 to -1 to -7 to -2; 
EOS: 48 day after EOT correct to 113 days
Rationale for change
Typo
Section to be changed
Flowchart 3
Description of change
Day for flare confirmation changed from 0 to -5 
to -3 and i.v. re-induction day changed to 0
Rationale for change
Typo
Section to be changed
Footnotes to Flowcharts; No. 11
Description of change
An e-diary will be used by the patient for the 
reporting of bowel movement frequency and 


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rectal bleeding (blood in stool) for a period of 14 
days prior to visits.
Added: and when a patient perceives a 
worsening of UC symptoms at any time between 
visits as a precursor to disease flare assessment
Rationale for change
Added for completness
Section to be changed
Footnotes to Flowcharst; No. 13
Description of change
For patients who discontinue treatment 
prematurely, vital status will be collected once a 
year starting from EOT visit until initially 
planned completion date of each individual 
patient.
Removed: ..collected by calls by investigators 
and until EOS
added: until initially planned completion date of 
each individual patient
Rationale for change
Clarification of vital status collection timelines
Section to be changed
Footnotes to Flowcharts; No.15
Description of change
EOS visit has to be performed 16 weeks after last 
dose of study medication (12 weeks changed to16 
weeks after R4 changed to R3 visit). Sigmoidoscopy 
does not need to be done at EOT visit for these 
patients
Rationale for change
Mistakenly entered
Section to be changed
Description of change


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Rationale for change
Section to be changed
Section 3.1
Description of change
Patients who terminate study drug in 1368-0017 
prematurely will be invited to early EOT visit 
instead of next planned visit followed by safety 
follow up 16 weeks after last study drug 
intake.For these patients vital status will be 
collected once a year starting from EOT visit  
until EOS visit.
Added:…until the initially planned completion 
date of each individual patient.
…safety follow-up (EOS)…
Removed: until EOS visit 
Rationale for change
More precise description of vital status 
collection timelines
Section to be changed
Section 3.1. Steroid tapering
Description of change
Added:
Patients receiving budesonide MMX at study 
entry will taper their initial daily dose for 2 
weeks every other day before stopping the drug. 
Patients on stable dose of beclomethasone 
dipropionate will be requested to stop using it 
after they achieve clinical response or clinical 
remission. 
Rationale for change
Information on steroid tapering / stopping rules 
for budesonide MMX and beclomethasone 
dipropionate missing


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Section to be changed
Section 3.3.4.1 Withdrawal from trial treatment
Description of change
Withdrawal criteria: A patient does never 
achieve clinical remission within the first 48 
weeks of maintenance treatment was moved out 
and re-worded:
If a patient has not achieved clinical remission 
within the first 48 weeks of maintenance 
treatment, investigator should consider trial drug 
termination based on individual patient history 
and available alternative treatment options.
Rationale for change
Decision on withdrawal of patient was moved to 
investigator`s decision based on individual 
patient history and available alternative 
treatment options
Section to be changed
Section 4.1.4 Study Drug Assignment and 
Administration of Doses per patient 
Description of change
Wording for s.c. study drug administration 
updated: In this trial a dose of 300 mg of BI 
655130 will be administered during study visit 
as subcutaneous injection in the abdomen every 
12 weeks for patients starting from V2 until 
EOT visit for patients who responded to 
treatment with study drug in previous trials or 
gained response after i.v. re-induction period. 
Added: subcutaneous injection in the abdomen
Removed: in two separate injections 1 mL each 
in abdomen, thighs, gluteal region or upper 
arms. Injections being given in he same area 
should be at least 2 cm apart and should not be 
close to a vein...
Rationale for change
Dosing regimen updated based on results of 
phase I trial 1368-0003
Section to be changed
Section 4.1.4 Study Drug Assignment and 
Administration of Doses per patient
Description of change
Added: Patients have to be closely monitored for 
local or systemic hypersensitivity reactions for 1 
hour following s.c. study drug administration.
…They should further be advised that if they
experience itching all over or a feeling of being 
swollen, dizzy or short of breath, they should 
seek emergency medical attention immediately


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Intravenous infusion including observational 
time for possible infusion reactions will last 
approximately 2.5 hours.
Rationale for change
Detailed instructions on handling of systemic 
hypersensitivity reactions and observational time 
were missing in previous version
Section to be changed
Section 4.1.4 Study Drug Assignment and 
Administration of Doses per patient
Description of change
Dose modifications or adjustments are not 
permitted. In exceptional cases of missed or 
delayed visits, if any of these visits has to be 
rescheduled, the date of subsequent visit should 
be calculated from Day 1. Added: of 
maintenance treatment or if the patient is on 
flare treatment from the first s.c. drug 
administration after the last disease flare
Rationale for change
Additional clarification needed
Section to be changed
4.1.8 Drug Accountability
Description of change
Availability of the proof of a medical license for 
the Principal Investigator 
Added: if applicable
Rationale for change
Additional explanation needed as it is not 
applicable in all countries
Section to be changed
Tab. 4.2.2:1 
Description of change
Any immunomodulator allowed per inclusion 
criteria 
Added: …. in previous trial
Rationale for change
Added for clarification
Section to be changed
Tab.4.2.2:1


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Description of change
Added: Oral systemic corticosteroids only 
allowed at a dose of ≤ 20mg per day of 
prednisone or equivalent and with stable dose 
prior to treatment initiation.
Allowed steroid treatments:
Short-term use (<7 days) of systemic (oral or 
parenteral) corticosteroids is allowed for 
treatment of AE not related to the underlying 
UC.
Parenteral corticosteroids dosed for less than 24 
hours as treatment of infusion or anaphylactic 
reactions are permitted.
Beclomethasone dipropionate allowed with 
stable dose prior to treatment initiation.
Locally administered steroids as e.g. intra-
articular, nasal inhalation or intra-ocular 
administration are allowed. 
steroids will be tapered  upon achievement of a 
clinical response or remission in the subsequent 
maintenance trial.
Removed: …in the subsequent maintenance trial
Rationale for change
Information for use of corticosteroids was 
clarified for clinical practice
Section to be changed
Section 5.2.1 Physical examination
Description of change
Targeted physical examination will include vital 
sign assessment and evaluation of organ systems 
associated with AE(s) symptoms… 
added: or extra intestinal manifestations ….
Rationale for change
Missing information for completeness
Section to be changed
Section 4.2.2 Vital signs, 1st paragraph
Description of change
Added text in bold: . At dosing visits vital signs 
evaluations will be performed pre-dose for both 
visits with i.v. and s.c. administration of study 
drug. Vital signs will be measured 
additionally 10 min post-dose after s.c. 
administration and 5 and 60 min. post-dose in 
case of i.v. study drug administration.
Rationale for change
Omitted in previous version
Section to be changed
5.2.5 Other safety parameters
Description of change
Sentence re-phrased and added text:
Original:


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Local tolerability at the administration site of the 
subcutaneous injection will be assessed by the 
investigator according to “swelling”, 
“induration”, “heat”, “redness”, “pain”, or “other 
findings” at the specified visits as noted in the 
Flow Chart. This assessment should be done 
post-dose.
Changed to:
Local tolerability at the administration site of the 
subcutaneous injection will be assessed by the 
investigator at the specified visits as noted in the 
Flow Chart see section 4.1.1 for further details.  
Any observed local tolerability reactions like 
“swelling”, “induration”, “heat”, “redness”, 
“pain”, or  any other findings should be reported 
as an adverse event in the eCRF.
Rationale for change
More detailed information provided
Section to be changed
5.2.5 Other safety parameters
Description of change
Removed text: All cases of malignancies that are 
detected during the trial will be reported as 
SAEs. Patients with a history of malignancy 
(except for specific cancers) will be excluded 
from this trial per the exclusion criteria (Section 
3.3.3).
Rationale for change
Redundant information
Section to be changed
5.2.6.2 AE Collection and Reporting
Description of change
Sentence re-phrased from:
From then on until the individual patient’s end 
of trial the investigator must report all 
deaths/fatal AEs regardless of relationship, 
related SAEs and related AESIs the investigator 
becomes aware of. 
New wording:
From then on until the initially planned 
completion date of each individual patient the 
investigator must report all deaths/fatal AEs 
regardless of relationship, related SAEs and 
related AESIs the investigator becomes aware 
of. 
Rationale for change
Align with wording for prematurely 
discontinued patients in Footnotes for 
Flowcharts
Section to be changed
Section 5.3.1 Assessment of Pharmacokinetics




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RNA analysis, and three (3) for Histology and 
Immunohistochemistry (IHC) analysis
Rationale for change
Consent for biopsies not needed separately, this 
is part of main ICF. 
Section to be changed
Section 6.2 Details of trial procedures for 
selected visits
Description of change
Following paragraph removed:Measurement of 
vital signs should precede blood sampling and be 
assessed pre-dose at all i.v. dosing visits and at 
approx.5 and 60 minutes after end of infusion At 
visits with s.c. study drug administration, vital 
signs will be assessed at approximately 10 
minutes after study drug administration.
Rationale for change
Redundant information, already in Section 4.2.2.
Section to be changed
Section 6.2.1 Screening visit
Description of change
Visit 1 should preferably be performed in one 
visit combined with EOT visit of previous 
induction trials
Removed: preferably
Rationale for change
Removed to avoid misunderstandings
Section to be changed
Section 6.2.1 Medical and Surgical History
Description of change
Information on clinically significant previous 
and concomitant illnesses, other than UC, or any 
clinically significant signs or symptoms that are 
present before informed consent, or pre-existing 
conditions identified through findings from 
assessments and examinations done during the 
screening visits will be recorded as medical and 
surgical history at screening. For planned 
procedures/hospitalisations during the trial, 
documentation should be completed at the time 
of the screening. Regarding the UC, a detailed 
history of the disease, including date of 
diagnosis, disease extent and severity, 
hospitalizations, and extraintestinal 
manifestations will be collected. Also, previous 
and concomitant treatment for UC will be 
recorded.
Changed to:
Information on clinically significant previous 
and concomitant diseases, other than UC, should 
be registered in Baseline conditions as follow up 
from the previous induction studies. 


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Rationale for change
Not all information is required as it is roll-over 
trial
Section to be changed
Section 6.2.2 Treatment period
Description of change
The treatment period is lasting from 
M1 until End of Treatment (EOT) Visit 
Changed to:
The treatment period is lasting from Visit 
M1/R1…
Rationale for change
typo
Section to be changed
Section 6.2.2 Treatment period
Description of change
Removed paragraphs: 
If upon completion of screening patient 
eligibility was confirmed by achievement of 
clinical response, patients can directly be 
assigned to open label s.c. maintenance 
treatment (see Flow chart 1).
However, if clinical response  has either not yet 
been achieved or has been lost prior to 
screening, patients will receive open label i.v. re-
induction treatment with three infusions of 1200 
mg  BI 655130 (SPESOLIMAB) every 4 weeks. 
At week 12 of re-induction period, patient`s 
response status will be assessed again. If clinical 
response or remission compared to BL in 
induction trial is achieved, patients will switch to 
s.c. maintenance treatment, (see Flow chart 2 ). 
Other patients will be discontinued from 
treatment, complete the trial, and  receive 
standard of care treatment. 
During the s.c. maintenance treatment patients 
will be administered BI 655130 300 mg every 12 
weeks until EOT visit.  Medication will be 
assigned by IRT. All study medication will be 
stored and administered on site by authorized 
study staff only.
Rationale for change
Redundant information 
Section to be changed
Section 6.2.2 Treatment period
Description of change
Study related procedures during treatment period 
will be performed as specified in the Flow chart 
1 and Flow chart 2.


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Patients who develop a disease flare during 
maintenance SC treatment period will receive a 
single i.v. infusion of 1200mg BI 655130 as a 
flare treatment followed by intensified 
maintenance dosing with 300mg sc. BI 655130 
q6w More details regarding disease flare 
confirmation please see in Section 3.1 Disease 
Flare Treatment.
Changed to:
Study related procedures during treatment period 
will be performed as specified in the Flow chart 
1,  Flow chart 2 or Flow chart 3, in case patients 
develop a disease flare
Rationale for change
Redundant information removed
Section to be changed
Section 6.2.2 Treatment period
Description of change
Removed sentence: For details of trial 
procedures please follow the Flowchart 3 
(Patients with Disease Flare).
Rationale for change
Already included in previous sentence
Section to be changed
Section 6.2.2 Treatment period / Clinical 
Monitoring after Study drug Administration
Description of change
Removed: according to “swelling”, “induration”, 
“heat”, “redness”, “pain”, or “other findings”. 
This assessment should be done post-dose.
Added: At all dosing visits vital signs will be 
assessed pre- and post-dose, please see section 
5.2.2 for further details. 
Rationale for change
Redundant information already provided in 
previous sections
Section to be changed
Section 6.2.2 Treatment period / Concomitant 
Medication Review
Description of change
These data will be obtained at scheduled or 
unscheduled trial visits based on information 
provided in the patient diaries.
Removed: provided in patient diaries
Rationale for change
Amended for patient convenience
Section to be changed
Section 6.2.3.1 Early Treatment Discontinuation
Description of change
Paragraph: 
Patient who discontinue treatment prior to the 
planned EOT visit will complete the EOT 
procedures instead of the planned treatment 
period visit. These patients should be registered 


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as withdrawn from treatment in IRT and return 
to the site for the End of Study (EOS) visit 16 
weeks after the early EOT visit. Vital status for 
prematurely discontinued patients will be 
collected by trial staff on a yearly basis per 
telephone until study completion.
Changed to: 
Patient who discontinue treatment prior to the 
planned EOT visit have to be invited for an early 
EOT visit as soon as possible. These patients 
should be registered as withdrawn from 
treatment in IRT and return to the site for the 
End of Study (EOS) visit 16 weeks after last 
study drug intake. Vital status for prematurely 
discontinued patients will be collected by trial 
staff on a yearly basis until the patient`s initially 
planned study completion date.
Rationale for change
Clarification regarding EOT and EOS timing for 
prematurely discontinued patients needed
Section to be changed
Section 7.1 Statistical Design-Model
Description of change
Paragraph:
For efficacy endpoints in both the maintenance 
and re-induction periods, such as for clinical 
remission/response, baseline as the last non-
missing value prior to first treatment in the 
preceding induction (parent) trial will be used. 
For safety endpoints, baseline for the 
maintenance period is considered to be the last 
non-missing value prior to first treatment in the 
maintenance part of the extension trial, while 
baseline for the re-induction period is considered 
to be the last non-missing value prior to first 
treatment in the re-induction part of the 
extension trial. Additional analyses on the safety 
data may also be performed via comparisons 
against the last non-missing value in the original 
induction (parent) trial.
Changed to:
For efficacy endpoints, baseline as the last non-
missing value prior to first treatment in the 
preceding induction (parent) trial will be used. 
For safety endpoints, baseline for the 
maintenance and re-induction periods is 
considered to be the last non-missing value in 
the original induction (parent) trial. Additional 


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analyses on the safety data for the maintenance 
period may also be performed via comparisons 
against the last non-missing value prior to first 
treatment in the maintenance part of the 
extension trial, while baseline for the re-
induction period may also be done versus the 
last non-missing value prior to first treatment in 
the re-induction part of the extension trial. 
Rationale for change
Align the efficacy and safety baseline definitions
Section to be changed
Section 7.3.4 Safety analyses
Description of change
Added: For all subjects who received disease 
flare treatment with BI 655130, safety 
assessments including adverse events, 
laboratories, vital signs etc. which occurred 
subsequent to such intake will be excluded from 
presentations according to the planned treatment; 
these data will, however, be included in 
summaries where all data after any use of BI 
655130 are displayed.
Rationale for change
Align exposure for safety across projects where 
BI 655130 is given as rescue
Section to be changed
Section 7.3.4 Safety analyses
Description of change
Time at risk [subject years] = (date of onset of 
AE – study drug start date in parent trial + 1) / 
365.25 
Removed: in parent trial
Rationale for change
Align exposure for safety across projects where 
BI 655130 is given as rescue
Section to be changed
Section 7.3.4 Safety analyses
Description of change
If, for a subject, no treatment emergent adverse 
event occurred, then the time at risk will be 
censored at the minimum of (drug stop date + 
112 days; last contact date; or, date of database 
snapshot if interim analysis performed).
Changed to: 
….(date of death; drug stop date + 112 days; 
start date of disease flare treatment with BI 
655130;
Rationale for change
Align exposure for safety across projects where 
BI 655130 is given as rescue
Section to be changed
Section 7.5 Handling of Missing data


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Description of change
If a patient experiences disease worsening 
during the re-induction period, or a disease flare 
during the maintenance period prior to observing 
the efficacy outcome at a specific visit, then all 
data subsequent to the intake of such rescue 
Added: ….to the intake of such rescue 
medication
Rationale for change
Mistakenly forgotten word
Section to be changed
Section 7.7 Determination of sample size
Description of change
Approximately 170 patients who meet the entry 
criteria….
Updated: Approximately 160 patients who meet 
the entry criteria…
Rationale for change
typo
Section to be changed
Section 8 Informed Consent, Trial Records, Data 
Protection, Publication Policy and 
Administrative Structure
Description of change
Removed: The trial will be carried out in 
accordance with the Medical Devices Directive 
(93/42/EEC) and the harmonised standards for 
Medical Devices (ISO 14155, current version).
Rationale for change
Not applicable
Section to be changed
Section 8.5.1 Collection, storage and future use 
of biological samples and corresponding data
Description of change
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
Removed:… for the collection , biobanking and
Removed: 
Sample and data usage has to be in accordance 
with the separate biobanking informed consent
Samples and/or data may be transferred to third 
parties and other countries as specified in the 
biobanking ICF
Rationale for change
Not applicable as there will be no biobanking in 
the trial
Section to be changed
10.7
steriod tapering scheme
Description of change
Recommended tapering schedule for oral 
corticosteroids (other than budesonide):


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Changed to:
Recommended tapering schedule for systemic 
corticosteroids:
Rationale for change
Typo
Section to be changed
Section 10.7 Steroid tapering scheme
Description of change
Recommended tapering schedule for oral 
budesonide MMX
Changed to:
Recommended tapering schedule for oral 
corticosteroids with limited systemic 
bioavailability
Added sentence:
Patients on stable dose of beclomethasone 
dipropionate will be requested to stop using it 
after they achieve clinical response or clinical 
remission. 
Rationale for change
Added for clarification


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11.2
GLOBAL AMENDMENT 2
Date of amendment
6 Nov 2018
EudraCT number
EU number
2018-000334-35
BI Trial number
1368-0017
BI Investigational Product(s)
BI 655130
Title of protocol
An open label, long term safety trial of BI 655130 
treatment in patients with moderate to severely 
active ulcerative colitis who have completed 
previous BI 655130 trials
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
x
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
x
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Protocol Synopsis, Main Inclusion and Exclusion 
Criteria
Description of change
Men able to father a child removed
Rationale for change
Reflecting updated IB ver.5.0
Section to be changed
Flowchart 2
Description of change
Coding to visits R1, R2, R3 and R4 added I01, 
I02, I03 and I04 respectively
Rationale for change
To be in line with internal and external databases
Section to be changed
Flowchart 3
Description of change
Sigmoidoscopy note – updated from : first 
sigmoidoscopy 12 weeks from Flare confirmation 
(F0y) to - first sigmoidoscopy 12 weeks from i.v. 
re-induction (R0y), then every 48 weeks from 
R0y
Rationale for change
Mistakenly entered in previous version
Section to be changed
Flowchart 3
Description of change
Diary review requirement added at visit F0y
Rationale for change
Forgotten to be ticked in previous version
Section to be changed
Footnotes to Flowcharts; Footnote 3
Description of change
In case of disease flare, an unscheduled 
confirmatory sigmoidoscopy has to be performed, 
followed in12 weeks after disease flare 


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confirmation replaced by …..after i.v. re-
induction
Rationale for change
Mistakenly entered in previous version
Section to be changed
Section 2.1, tab. 2.1.1
Description of change
Added text: all criteria have to be met to 
qualify for the respective outcome
Rationale for change
Added clarity to definition of outcomes
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 3.3.2, p.34
Description of change
Inclusion criteria#3 removed – men able to father 
a child
Rationale for change
Reflecting changes in IB version 5.0
Section to be changed
Section 4.2.1, p. 42 Management of AE
Description of change
Section cytokine Release Syndrome removed
Rationale for change
Reflecting changes in IB version 5.0
Section to be changed
Section 4.2.1, p. 41 Other Treatments and 
Emergency Procedures
Description of change
Added: If mild-to-moderate infusion or 
anaphylactic reaction had already occurred in the 
very same patient in the past, pre-treatment with 
steroids before next IMP administration is 
permitted  as secondary prophylaxis.
Rationale for change
More clarity for use of steroids as secondary 
prophylaxis
Section to be changed
Section 4.2.2.3 Restrictions regarding women of 
childbearing potential
Description of change
Removed restrictions regarding men and female 
partner(s) of male participants removed 
Rationale for change
Reflecting updated IB ver.5.0
Section to be changed
Section 4.2.2.4 Restrictions regarding male 
participants
Description of change
Restriction regarding sperm donation for male 
participants for the whole duration of the trials 
was removed
Rationale for change
Reflecting updated IB ver.5.0


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Section to be changed
Section 5.2.6.1 Definition of Adverse events
Description of change
Cytokine release syndrome removed from AESI
Rationale for change
Reflecting updated IB ver.5.0


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11.3
GLOBAL AMENDMENT 3
Date of amendment
14 Nov 2018
EudraCT number
EU number
2018-000334-35
BI Trial number
1368-0017
BI Investigational Product(s)
BI 655130
Title of protocol
An open label, long term safety trial of BI 655130 
treatment in patients with moderate to severely 
active ulcerative colitis who have completed
previous BI 655130 trials
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
x
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
x
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Flowchart 3
Description of change
Physical examination added at visit R0y
Rationale for change
Forgotten to be ticked




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Description of change 6
Day update for F0y and R0y
Rationale for change
To reflect the operational aspects
Section to be changed
1.4 BENEFIT-RISK ASSESSMENT
Description of change 7
Benefit-Risk assessment section was re-phrased 
Rationale for change
To reflect latest IB wording and BI project 
standard wording
Section to be changed
Flowcharts, Footnote 1 amended
Description of change 8
Visit V1 of this long-term extension study 
should be  performed during the last visit 
(V6/EOT) of the preceding trial 1368-0005 
Part 1 or 1368-0004. Assessments performed 
at last visit (V6/EOT) in the previous trial do 
not have to be repeated at visit 1 in this trial. 
Changed to: 
1.
Visit V1 of this long-term extension study 
should be  performed during the last visit 
(V6/EOT) of the preceding trial 1368-0005 
Part 1 or 1368-0004. Assessments performed 
at last visit (V6/EOT) in the previous trial do 
not have to be repeated at visit 1 in this trial. 
Patients not eligible to take part in trial 1368-
0017 shall complete follow-up visit 16 weeks 
after last dose given in trial 1368-0004 or 
1368-0005 Part I.
Rationale for change
Clarification of footnote
Section to be changed
Exclusion criteria 3.3.3 amended
Description of change 9
Have developed any of the exclusion criteria 
from the original induction study 
Changed to: 
Have developed any of the exclusion criteria 
from the original induction study with the 
following exceptions:
∀
Cases of disease limited to the rectum 
extending <15 cm past the anal verge are 
allowed to be included in study 1368.17.
∀
Cases of latent TB. Patients with newly 
emerging latent TB during preceding 
study are allowed to be included in study 
1368.17, provided they receive


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appropriate treatment according to local 
guidelines.
Rationale for change
This criterion might be met by clinical patients 
with reduced colonic extension of their initial 
mucosal inflammation who respond to the 
inductions treatment and who could benefit from 
the maintenance treatment in study 1368.17.
In line with the recommendations for patients 
already recruited in study 1368.17 who develop 
latent TB during participation in the study 
1368.17, patients with latent TB could benefit 
from the maintenance treatment in study 1368.17. 
Section to be changed
Section 2.1, table 2.1:1
Definitions of Study Outcomes
+ all sections referring to disease flare definition
Description of change 10
Disease flare definition
Increase in partial MCS score by ≥2 points from 
nadir observed during a regular or unscheduled 
study visit, confirmed  subsequently by 
sigmoidoscopy with the modified Endoscopic 
Subscore (mESS) ≥2 AND a second partial 
Mayo score measurement confirming the 
increase from nadir by ≥2, in absence of enteric 
pathogens in stool - after achievement of a 
clinical response
Changed to:
Increase in partial MCS score by ≥ 2 points from 
baseline (in 2 subsequent visits) and increase in 
rectal bleeding score by ≥ 1 point from baseline 
(in 2 subsequent visits), confirmed by increase of 
modified endoscopic subscore by ≥ 1 point from 
baseline with absolute modified endoscopic 
subscore ≥ 2 points in absence of enteric 
pathogens in stool
Rationale for change
alignment with expert experiences with other UC 
programs
Section to be changed
Flowcharts 1A, 1B, 1C and corresponding 
footnotes, 3; trial design 3:1:1, 3:1:2; sections 
4.1; 7.1
Description of change 11
Change in the dose interval (increased from 
q12w to q4w) for the maintenance treatment and 


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in the dose for intensified maintenance treatment 
after disease flare treatment.
Rationale for change
Amongst the first 24 patients who responded to 
the induction treatment in the previous trials and 
rolled over to trial 1368.17, more than 50% have 
experienced a relapse/flare during the first 6 
months after switch from the induction to the 
maintenance dose. This rate is higher compared to 
the one observed with approved drugs for the 
same condition.
The switch from the higher spesolimab induction 
doses (450 mg q4w i.v. for 12 weeks and 1200 mg 
q4w i.v. for 12 weeks) in the previous trials to the 
current maintenance dose in trial 1368,17 (300 
mg q12w s.c.) represent a reduction in exposure 
by a factor of 6.4 and 17.1 respectively (given a 
70% bioavailability of the s.c. vs the i.v. dose) 
during a 12 week period. The observed drop in 
efficacy may thus be explained by a decrease of 
drug exposure below the threshold required to 
maintain maximum target engagement. The 
individual 300mg SC dose corresponds to 
~210mg IV dose, which for an average 70kg 
person represents the lowest dose of ≥3mg/kg 
achieving maximal target engagement, though 
target engagement in HV was quite sustainable 
for more than 10 weeks (see IB section 6).
However, in UC patients a higher clearance rates 
of biologics and the need for target engagement in 
the gut tissue may require higher dosing than HV.  
Therefore, after one half-life of about 4 weeks (or 
shorter), patients may have developed insufficient 
drug exposure to maintain full target engagement 
in the gut, while q4w dosing may maintain drug 
exposure in the therapeutic range.
Since for study logistics reasons the SC injection 
interval in the intensified maintenance treatment 
cannot be reduced to q4w, a higher dose of 600mg 
will be applied to double the exposure compared 
to the original regimen.
Even assuming a negative spesolimab efficacy on 
ulcerative colitis, the proposed dose change, is 
considered not harmful for the patients, since it is 
lower than the doses previously tested in healthy 


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volunteers (up to 4 doses of spesolimab 20mg/kg 
every 7 days) and the doses administered to 
ulcerative colitis patients (up to 1200 mg i.v. q4w 
for 24 weeks for patients who do not respond to 
the initial induction treatment and receive a re-
induction treatment). 
Therefore, this dose may increase the individual 
benefit without increasing risks to study 
participants.
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change 12
In this trial a dose of 300 mg of BI 655130 
(SPESOLIMAB) will be administered during 
study visit as subcutaneous injection in the 
abdomen 
Changed to:
In this trial a dose of 300 mg of BI 655130 
(SPESOLIMAB) will be administered during 
study visit as subcutaneous injection in the 
abdomen , in accordance with local standard 
procedure and 
as described in “BI 655130 Solution for Injection 
150 mg/mL s.c. Instructions for Handling and Use”
Rationale for change
Inclusion of reference document in the protocol


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11.5
GLOBAL AMENDMENT 5
Date of amendment
24 June 2020
EudraCT number
EU number
2018-000334-35
BI Trial number
1368-0017
BI Investigational Product(s)
BI655130 (SPESOLIMAB)
Title of protocol
An open label, long term safety trial of BI 
655130 (SPESOLIMAB) treatment in patients 
with moderate to severely active ulcerative 
colitis who have completed previous BI 655130 
(SPESOLIMAB) trials
Global Amendment due to urgent safety reasons

Global Amendment
X
Section to be changed
1.4 BENEFIT - RISK ASSESSMENT
Description of change 1
Section 1.4 has been updated based on the results 
of an unblinded interim analysis of the preceding 
induction trial 1368-0005.
Rationale for change
Based on the results of the interim analyses of 
trials 1368-0005 and 1368-0017, the general 
benefit-risk assessment for patients currently 
treated in trial 1368-0017 cannot be evaluated. 
Therefore for these patients, the benefit-risk 
should be assessed by the investigator on an 
individual basis to evaluate patient continuation 
in the trial.
Section to be changed
3.1 OVERALL TRIAL DESIGN AND PLAN
3.3.4.1 Withdrawal from trial treatment
Description of change 2
Recommendations for discontinuation for 
patients experienced flares changed from >2 
confirmed flares within a 12 month time period
to more than 1 confirmed flares during the trial.
Rationale for change
In line with change1, to allow discontinuation of 
patients who experience > 1 flares during the 
trial.
Section to be changed
3.3.4.1 Withdrawal from trial treatment
6.2.2 Treatment period
Description of change 3
Text added in relation to discontinuation of 
patients from trial medication at any time if in 
the opinion of the Investigator, continuation with 
trial medication is not in the patient’s best 
interest.


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Rationale for change
To provide clarification that patients can be 
discontinued from trial medication at any time if 
in the opinion of the Investigator, continuation 
with trial medication is not in the patient’s best 
interest.
Section to be changed
CTP Flowchart 1B
12lead ECG procedure
Description of change 4
12 lead ECG deleted at visits M6a and M7b and 
added at visit M7
Rationale for change
Typos correction
Section to be changed
Table 4.2.2: 1 Restrictions regarding previous 
and concomitant treatment
Description of change 5
Any biologic approved for UC (i.e. adalimumab, 
infliximab, golimumab, vedolizumab) “not 
allowed until end of the trial”
Changed to
“not allowed until end of the IMP treatment”
Rationale for change
To provide clear  instruction about end of 
restriction period
Section to be changed
Flowchart footnote #6, Table 5.2.3: 2 Laboratory 
tests
Description of change 6
TSH and Glycosylated Hbc (HbA1c) tests have to be 
done only once per year
Changed to
TSH and Glycosylated Hbc (HbA1c) tests have to be 
done every 48 wks
Rationale for change
Specification of the timepoint when the specific 
test are required


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11.6
GLOBAL AMENDMENT 6
Date of amendment
05 November 2020
EudraCT number
EU number
2018-000334-35
BI Trial number
1368-0017
BI Investigational Product(s)
BI655130 (SPESOLIMAB)
Title of protocol
An open label, long term safety trial of BI 
655130 (SPESOLIMAB) treatment in patients 
with moderate to severely active ulcerative 
colitis who have completed previous BI 655130 
(SPESOLIMAB) trials
Global Amendment due to urgent safety reasons

Global Amendment
X
Section to be changed
Flow chart 1, footnote 9)
Description of change 1
Stool sampling for faecal biomarkers 
(calprotectin, lactoferrin) to be reduced to 1/24 
weeks for patients in maintenance treatment.
Rationale for change
To simplify the procedures of the trial and 
reduce the long-term burden for patients 
participating in the trial. The proposed schedule 
of stool sampling for faecal biomarkers 
(calprotectin, lactoferrin) is considered adequate 
for patients in maintenance treatment.
Section to be changed
Flowcharts, sections  3.1 and 6.2.3.1
Description of change 2
Requirement of Vital Status collection for 
patients who discontinue study medication 
before EOT is deleted.
Rationale for change
Collection of vital status for patients who have 
discontinued treatment is not considered 
necessary for this long term trial and will reduce 
the burden of visit for these patients.


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Section to be changed
5.2.6.2
Description of change 3
Requirement to collect SAE via fax form 
removed
Rationale for change
Alignment with sponsor internal procedures
Section to be changed
Section 5.2.6.2. AE reporting to sponsor and 
timelines
Description of change 4
Pregnancy testing
Urine pregnancy testing for all women of child-
bearing potential will be conducted on-site every 
12 weeks at visits with study drug administration
Changed to:
Urine pregnancy testing for all women of child-
bearing potential will be conducted on-site at 
visits with study drug administration
Rationale for change
Typo correction in CTP AM 6
Section to be changed
1.4. Benefit – risk assessment
Description of change 5
Table 1.4:1 amended with information related to  
SARS CoV-2 infection 
Rationale for change
Implementation of possible impact of SARS 
CoV-2 infection on clinical study


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11.7
GLOBAL AMENDMENT 7
Date of amendment
23 May 2022
EudraCT number
EU number
2018-000334-35
BI Trial number
1368-0017
BI Investigational Product(s)
BI655130 (SPESOLIMAB)
Title of protocol
An open label, long term safety trial of BI 
655130 (SPESOLIMAB) treatment in patients 
with moderate to severely active ulcerative 
colitis who have completed previous BI 655130 
(SPESOLIMAB) trials
Global Amendment due to urgent safety reasons

Global Amendment
X
Section to be changed
1.4 Benefit risk assessment, table 1.4.1
Description of change 1
Peripheral Neuropathy added
Rationale for change
Project level update
Section to be changed
3.3.4.1 Withdrawal
Description of change 2
Stopping ruled by Peripheral Neuropathy added
Rationale for change
Project level update
Section to be changed
5.2.6.1 AESI
Description of change 3
Peripheral Neuropathy added as AESI
Rationale for change
Project level update
Section to be changed
4.1 Description of test product
Description of change 4
Tables for two old formulations were deleted
Rationale for change
2 old formulations were deleted to align with 
actual IMPD


 
 
 
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Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
 
Trial Statistical Analysis Plan
c23715112-04
BI Trial No.:
1368.17
Title:
Trial Statistical Analysis Plan
An open label, long term safety trial of BI 655130 treatment in 
patients with moderate to severely active ulcerative colitis who 
have completed previous BI 655130 trials
Including Protocol Amendment 6 [include c18806983-06]
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone: 
 Fax: 
Date of statistical 
analysis plan:
13 JAN 2021 SIGNED
Version:
4.0 (Revised TSAP)
Page 1 of 55
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT(S) ................................................................................10
5.2
SECONDARY ENDPOINT(S) ..........................................................................11
Key secondary endpoint(s).................................................................................11
5.2.1
Secondary endpoint(s) ........................................................................................11
5.2.2
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................17
6.1
TREATMENTS...................................................................................................17
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................22
6.3
PATIENT SETS ANALYSED...........................................................................24
6.5
POOLING OF CENTRES .................................................................................26
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................26
Withdrawals ........................................................................................................27
6.6.1
Efficacy endpoints...............................................................................................27
6.6.2
Safety endpoints ..................................................................................................28
6.6.3
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................29
7.
PLANNED ANALYSIS......................................................................................34
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........35
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................36
7.3
TREATMENT COMPLIANCE........................................................................37
7.4
PRIMARY ENDPOINT .....................................................................................37
7.5
SECONDARY ENDPOINTS.............................................................................37
Key secondary endpoint .....................................................................................37
7.5.1


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Secondary endpoints...........................................................................................37
7.5.2
7.8
SAFETY ANALYSIS..........................................................................................40
Adverse events.....................................................................................................41
7.8.1
Laboratory data ..................................................................................................44
7.8.2
Vital signs.............................................................................................................45
7.8.3
ECG......................................................................................................................46
7.8.4
Other ....................................................................................................................46
7.8.5
7.8.5.1
Immunogenicity ....................................................................................................46
7.8.5.2
Extra-intestinal manifestation ...............................................................................46
7.9
HANDLING OF DMC ANALYSES .................................................................46
8.
REFERENCES....................................................................................................47
10.
HISTORY TABLE..............................................................................................55




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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALQ
Above limit of quantification
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
BRAVE
BI RAVE®
RPM 
Report Planning Meeting
BSA
Body surface area
CARE
Clinical data analysis and reporting environment
CR
Clinical remission
CRF
Case report form
CRP
C-reactive protein
CS
Systemic corticosteroids
CTC
Common Terminology Criteria
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOS
End of Study


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Term
Definition / description
EOT
End of treatment
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials
FLF
Faecal lactoferrin
F/U
Follow-up
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IL
Interleukin
IPD
Important protocol deviation
IRT
Interactive response technology
LLOQ
Lower limit of quantification
LOQ
Limit of quantification
MCS
Mayo Clinical Score
MedDRA
Medical Dictionary for Regulatory Activities
mESS
Modified Endoscopic Subscore
MQRM
Medical quality review meeting
NRI
No response imputation
OC
Observed cases
OC-IR
Observed cases including values after rescue medication
OR
Original results
PD
Pharmacodynamic(s)
PGA
Physician Global Assessment
PMR
Partial Clinical Remission
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
RBS
Rectal Bleeding Subscore
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual effect period


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Term
Definition / description
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SDL
Subject data listing
SFS
Stool Frequency Score
SI
Système international d’unités
SMQ
Standardised MedDRA query
SOC
System Organ Class
CTL
Clinical Trial Lead
SAF
Safety Analysis set
SAF-RT
Safety Analysis set for Re-induction Treatment
SAF-MT
Safety Analysis set for Maintenance Treatment
SAF-FT
Safety Analysis set for Flare Treatment
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range
ULOQ
Upper limit of quantification
VAS
Visual analogue scale


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (1), the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the CTP and its amendments, and to include detailed procedures for 
executing the statistical analysis of the primary and secondary variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the clinical trial protocol
(CTP). In particular, the TSAP is based on the planned analysis specification as written in 
CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size.
For other biomarkers not specified as endpoints, a separate document will complement this 
TSAP.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).
Since the primary aim of this study is to collect long-term safety and efficacy data on the use 
of spesolimab (BI 655130) in this population, multiple interim analyses will be done over the 
7-year conduct phase of this trial in order to support, for example, regulatory interactions, 
Clinical Trial Authorizations (CTA), and MAA/BLA submissions, but also to provide 
important safety and efficacy information to the sponsor to guide further development of the 
compound, and to the investigators via IB updates and publications. Any data cut-off to be 
used for the reporting of trial data at interim will be presented in either a separate data 
cleaning plan, or in an appendix to this TSAP. If considered appropriate, an access plan may 
be developed at the time of the interim which describes those personnel who will be allowed 
access to the results of the interim data analysis.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The population label for Treated Set (TS) is updated to be Safety Analysis set (SAF) based on 
current project definition. Thus the TS-RT for re-induction treatment becomes SAF-RT, and 
TS-MT for maintenance treatments becomes SAF-MT.


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5.
ENDPOINTS
For handling of missing data and the occurrence of inter-current events, unless otherwise 
specified, see section 6.6.
Baseline for safety data, unless otherwise specified, is the last value prior to initiation of the 
re-induction treatment (for the re-induction period), or the maintenance treatment (for the 
pre-flare treatment period and post-flare treatment period), or the disease flare treatment (for 
the disease flare treatment period).
For the summary of all efficacy data, only those observations which were collected during the 
on-treatment period (i.e. first dose of spesolimab through to the last dose of spesolimab + 16 
weeks) will be used.
Regarding the analyses of the change from baseline by visit for continuous efficacy endpoints, 
the baseline in current study is used, which refers to the last value prior to initiation of 

the re-induction therapy (i.e. baseline of re-induction period, denoted as R-baseline, 
corresponding to the week 12 assessment on the prior induction trial),

or the maintenance therapy (i.e. baseline of the maintenance trial part, denoted as M-
baseline, corresponding to the week 12 assessment on the prior induction/re-induction 
trial part).
For the specification of baseline definition for derivation of the applicable binary MCS 
endpoints, i.e. clinical response:

the baseline is defined as the last non-missing value reported prior to the first dose of 
study drug on the preceding induction study, i.e., the definition of efficacy baseline from 
the parent trial.
However, for binary MCS endpoints after a disease flare treatment (specifically for disease 
flare treatment period), the baseline is defined as the last value prior to initiation of each 
disease flare treatment (i.e. baseline of disease flare treatment period, refers to data from flare 
confirmation visit with endoscopy or regular maintenance visit with endoscopy before 
administration of each disease flare treatment, denote as Fx-baseline, ‘x’ represents disease 
flare occurrence).
5.1
PRIMARY ENDPOINT(S)
•
Exposure adjusted rate of patients reporting a treatment emergent adverse event (TEAE) 
up to week 336 of maintenance treatment
Please refer to section 7.8.1 for the description of the calculation of exposure-adjusted 
adverse event incidence rates.


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5.2
SECONDARY ENDPOINT(S)
Key secondary endpoint(s)
5.2.1
Not applicable. No key secondary endpoints have been specified in the CTP.
Secondary endpoint(s)
5.2.2
Proportion of patients with clinical remission (CR) at week 336 of maintenance treatment (as 
defined in Table 9.1.1: 1)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
The following treatment options are planned in this study:

For patients who complete treatment in the previous induction study but who do not have 
a clinical response at week 12 (EoT):
o
Multiple active doses of intravenous spesolimab 1200 mg q4w are administered for 
12 weeks (re-induction); responders at week 12 will subsequently receive 
subcutaneous spesolimab 300 mg q4w as maintenance treatment for up to 7 years;

For patients who complete treatment in the previous induction study and who have a 
clinical response at week 12 (EoT):
o
Subcutaneous spesolimab 300 mg q4w as maintenance treatment for up to 7 years.
Note that patients entered into the trial according to CTP version 4.0 or earlier who initially 
received subcutaneous spesolimab 300 mg q12w as maintenance treatment will be switched 
to treatment with spesolimab 300 mg q4w per CTP amendment 5.0.
Patients who experience a disease flare during maintenance treatment (as defined in Table 
9.1.1: 1) will be administered a single intravenous dose of spesolimab 1200 mg followed by 
an intensified subcutaneous maintenance dosing schedule with 600 mg q6w. Note that 
patients entered into the trial according to CTP version 4.0 or earlier may have received an 
intensified subcutaneous maintenance dosing schedule with 300 mg q6w; these patients will 
be switched to 600 mg q6w per CTP amendment 5.0.
The following study phases are defined:


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Re-Induction Period
The analysis phase as described below is applicable to both the efficacy and safety analyses 
of the re-induction period.
Table 6.1: 1
Flow chart of analysis phases for re-induction period
Study analysis 
phase
Description
Start (included)
End (included)
Screening phase
Screening
Earliest of (Date of informed 
consent, first screening 
procedure) 
Date/time of start of infusion of 
first re-induction study drug
minus 1 minute
Re-induction 
treatment phase & 
Residual effects 
period
Re-induction 
on-treatment 
period
Date/time of start of infusion of 
first re-induction study drug 
(Day 1 for re-induction)
Patient does not participate in
maintenance treatment period: 
Date of end of infusion of last 
re-induction study drug + 112 
days at 11:59 pm;
Patient participates in
maintenance treatment period2:
Date/time of injection of first 
maintenance study drug minus 
1 minute
Follow-up1 phase
Off-treatment 
period
Patient does not participate in
maintenance treatment period: 
Date of end of infusion of last 
re-induction study drug + 113
days at 12:00 a.m.
Latest of: i) Date of EOS visit 
(Week 24 visit); ii) last contact 
date on End of Study page at 
11:59 p.m.
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase will 
not extend beyond the start date of the following phase. 
1 The off-treatment period (i.e. Follow-up phase) only exists if the trial completion date is after the date of end of last 
infusion + 112 days, and if patient did not continue into the Maintenance period.
2 This part applies only to patients entering maintenance period after completing re-induction period; it is expected to occur 
within the period defined by REP. Note that for safety data, i.e., AE where date and time are collected, an event which 
occurs on the same day of first dose in the following maintenance period, but prior to the administration are assigned to, 
and reported as a part of the re-induction period.
Assessments done on the same day as the first re-induction treatment dose will be assigned to 
a study analysis phase based on assessment via date and time. If time is not collected for a 
particular assessment, then assignment will be to the screening phase.
The period between last intake of re-induction study drug and first intake of maintenance 
study drug will be considered as a part of the re-induction analysis phase irrespective of the 
duration. For re-induction treated patients who do not subsequently receive maintenance 
treatment, the REP will be applied for the purpose of defining the duration of the on-
treatment period.


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Pre-Flare Treatment Period
The analysis phase as described below is applicable to safety analyses only of the pre-flare 
treatment period.
Table 6.1: 2
Flow chart of analysis phases for pre-flare treatment period
Study analysis 
phase
Description
Start (included)
End (included)
Screening2 phase
Screening
Earliest of (Date of informed 
consent, first screening 
procedure) 
Date/time of injection of first 
maintenance study drug minus 
1 minute
Maintenance 
treatment phase & 
Residual effects 
period 
Maintenance
on-treatment 
period
Date/time of injection of first 
maintenance study drug (Day 1
for maintenance)
Without flare treatment:
Date of injection of last 
maintenance study drug + 112
days at 11:59 p.m.
With flare treatment3:
Date/time of infusion of first 
flare study drug minus 1 
minutes
Follow-up1 phase
Off-treatment 
period
Without flare treatment:
Date of injection of last 
maintenance study drug + 113
days at 12:00 a.m.
Latest of: i) Date of EOS visit 
(Week 352 visit); ii) last 
contact date on End of Study 
page at 11:59 p.m.
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase will 
not extend beyond the start date of the following phase. 
1 The off-treatment period (i.e. Follow-up phase) only exists if the trial completion date is after the date of end of last 
injection + 112 days.
2 The screening phase does not exist for re-induction treated patients who subsequently receive maintenance treatment.
3 Safety data is censored for reporting following intake of disease flare treatment with spesolimab. Measurements collected 
with date only on the day of first flare treatment are assigned to the pre-flare treatment period.
Assessments done on the same day as the first maintenance treatment dose will be assigned to 
a study analysis phase based on assessment via date and time. If time is not collected for a 
particular assessment, then assignment will be to the previous study analysis phase, i.e. to the 
screening phase for patients who directly enter the trial into the maintenance period, or to the 
re-induction phase for patients who directly enter the trial into the re-induction period.
For all subjects who received disease flare treatment with spesolimab during the maintenance 
period, safety assessments (including adverse events, laboratories, vital signs etc.) which 
occurred subsequent to such intake will be excluded from presentations according to the 
actual treatments in a primary approach.
Post-Flare Treatment Period
The analysis phase as described below is applicable to safety analyses only of the post-flare 
treatment period.


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For the post-flare treatment period of the maintenance period, the analysis phases described 
below consider the inclusion of data from the following study parts: disease flare treatment 
with 1200 mg spesolimab single i.v. infusion followed by intensified maintenance dosing 
with 600 mg s.c. spesolimab q6w, up to the (extended) REP from the last dose of spesolimab
(either injection or infusion).
Table 6.1: 3
Flow chart of analysis phases for the post-flare treatment period
Study analysis 
phase
Description
Start (included)
End (included)
Post-flare
treatment phase 
& Residual 
effects period
Post-flare 
treatment period
(REP extended)
Date/time of infusion of first flare
study drug (Day 1)
Date of end of (infusion or 
injection) of last administered 
spesolimab + 112 days at 
23:59
Follow-up1
phase
Off-treatment
period (REP 
extended)
Date of end of (infusion or 
injection) of last administered 
spesolimab + 113 days at 12:00
a.m.
Latest of: i) Date of End-of-
Study visit; ii) last contact 
date on End of Study page at 
23:59
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase will
not extend beyond the start date of the following phase. 
1 The off-treatment period (i.e. Follow-up phase) only exists if the trial completion date is after the date of end of last 
infusion or injection + 112 days.
The post-flare treatment period only applies to those patients who are administered a disease 
flare treatment with spesolimab. Assessments done on the same day as the first disease flare 
treatment dose will be assigned to a study analysis phase based on assessment via date and 
time. If time is not collected for a particular assessment, then assignment will be to the 
previous study analysis phase, i.e. to the pre-flare treatment period.
Overall Maintenance Treatment Period
The overall maintenance treatment period applies to all patients taking at least one dose of
maintenance treatment regardless of flare occurrence. This period will be considered to 
understand long-term efficacy and safety of spesolimab.


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Table 6.1: 4
Flow chart of analysis phases for overall maintenance treatment period
Study analysis 
phase
Description
Start (included)
End (included)
Screening2 phase
Screening
Earliest of (Date of informed 
consent, first screening 
procedure) 
Date/time of injection of first 
maintenance study drug minus 
1 minute
Maintenance 
treatment phase & 
Residual effects 
period 
Maintenance
on-treatment 
period
Date/time of injection of first 
maintenance study drug (Day 1
for maintenance)
Date of end of (infusion or 
injection) of last administered 
spesolimab + 112 days at 23:59
Follow-up1 phase
Off-treatment 
period
Date of end of (infusion or 
injection) of last administered 
spesolimab + 113 days at 12:00 
a.m.
Latest of: i) Date of End-of-
Study visit; ii) last contact date 
on End of Study page at 23:59
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase will
not extend beyond the start date of the following phase. 
1 The off-treatment period (i.e. Follow-up phase) only exists if the trial completion date is after the date of end of last 
injection or infusion + 112 days.
2 The screening phase does not exist for re-induction treated patients who subsequently receive maintenance treatment.
Disease Flare Treatment Period
The analysis phase as described below is applicable to both the efficacy and safety analyses 
of the disease flare treatment period.
The following phases will be used for assessment on the efficacy and AE safety profile only 
in patients who take disease flare treatment with 1200 mg spesolimab single i.v. infusion. 
This analysis phase considers the fixed 12-week duration after administration of a disease 
flare spesolimab infusion up to the time of the planned endoscopy measurement (Rx-Week 
12 defined in Table 6.7: 3).
Table 6.1: 5
Flow chart of analysis phases for disease flare treatment period
Study analysis 
phase
Description
Start (included)
End (included)
Disease flare 
treatment 
phase*
On-treatment
period after flare
infusion with 
spesolimab
Date/time of start of infusion of 
flare treatment (Day 1 for flare 
treatment)
Date of end of infusion of 
flare treatment + 98 days at 
23:59
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase will 
not extend beyond the start date of the following phase. 
*One patient may have multiple disease flare treatment phases if multiple flares happen at different times.
The disease flare treatment period only applies to those patients who are administered a 
disease flare treatment with spesolimab. Assessments done on the same day as the first 
disease flare treatment dose will be assigned to a study analysis phase based on assessment 
via date and time. If time is not collected for a particular assessment, then assignment will be 


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to the previous study analysis phase, i.e. to the pre-flare treatment period for first 
administration of disease flare treatment, or to the post-flare treatment period for subsequent 
administrations.
The selection of data for presentation in this analysis is described in Tables about time 
window in Section 6.7.Treatments will be labelled as follows:
∀
“Re-induction Speso 1200 mg IV q4w” [applicable to the re-induction period]
Selected tables also by prior parent trial treatment
∀
“Pre-Flare SC” [applicable to the pre-flare treatment period, i.e., censoring data after 
intake of first flare treatment, including also the old dosing schedule]
∀
“Post-Flare IV/SC” [applicable to the post flare treatment period, includes also the old 
dosing schedule]
∀
“Overall Maintenance” [applicable to the whole period after maintenance treatment, 
includes also the old dosing schedule]
Selected tables also by prior parent trial treatment
∀
“Disease Flare Speso 1200 mg IV SD” [applicable to the disease flare treatment period]
Selected tables also by prior parent trial treatment
6.2
IMPORTANT PROTOCOL DEVIATIONS
Each protocol deviation must be assessed to determine whether it is an IPD. For definition of 
IPDs, and for the process of identification of these, refer to the BI reference document 
"Identify and Manage Important Protocol Deviations (iPD)" (2).
This is an open label, long term safety trial, all analyses will be performed based on the 
treated population only, i.e., no Full analysis Set or Per Protocol Set will be defined for 
analyses of efficacy. Since no confirmatory efficacy testing is planned, no efficacy related 
iPDs leading to exclusion from analysis set are defined. Efficacy, safety and GCP related 
iPDs are included in Section 4.1 of the Integrated Quality and Risk Management Plan
(IQRMP).
Patients with iPD B.01, i.e., informed consent not available/not done, will be excluded from 
all analyses.


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Table 6.2: 1
Important protocol deviations
Category / Code
Description
Comments
Excluded from
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
Male or female patients,  aged ≥18 years
IC01 
Also check versus derived 
age for patient.
None
A1.02
Women of childbearing potential 
(WOCBP) must use highly effective 
methods of birth control per ICH M3 
(R2) that result in a low failure rate of 
less than 1% per year when used 
consistently and correctly.
IC03
None
A1.03
Have completed treatment and the EOT 
visit in the previous trial and are willing 
and able to continue treatment in 
1368.17.
IC04
None
A2
Exclusion criteria violated 
A2.01
Have experienced study treatment-
limiting adverse events during induction 
treatment with study drug
EC01
None
A2.02
Have developed any of the exclusion 
criteria from the original induction study
EC02, medical review
None
B
Informed consent
B.01
Informed consent not available/not done
Date of informed consent 
missing or no signature on 
patient’s “Declaration of 
Informed Consent”
All analyses
B.02
Informed consent too late
Date of informed consent 
not obtained prior to any 
study related procedure.
Minimum requirement for 
initial informed consent <= 
date of Visit 1/date of any 
study procedure
None
C
Trial medication and randomisation
C3
Administration instruction not 
followed
C3.01
Administration of potential 
contaminated drug
Study drug not prepared 
according to the instruction 
of administration
Medical review
None


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Table 6.2: 1
Important protocol deviations (cont.)
Category / Code
Description
Comments
Excluded from
F
Study specific analysis
F1
Other trial specific violation
F1.01
Incorrect response assessment leads to 
assignment to wrong trial part (i.e. re-
induction or maintenance) or to 
continuation of intensified maintenance 
therapy (following disease flare 
treatment)
Medical review
None
F1.02
Disease flare treatment used without 
sufficient evidence for a disease flare
Medical review
None
G
Other safety related violations
G1
Pregnancy test not done for woman of 
child bearing potential, or pregnant 
during study
Pregnancy test not done at 
any visit where such is 
scheduled and the patient 
did not yet complete 
follow-up.
None
Source: BI reference document ' Identify and Manage Important Protocol Deviations (iPD)' [001-MCS-40-413] (2).
6.3
PATIENT SETS ANALYSED
From CTP Section 7.3:
There will be 2 main patient populations in this trial for analyses: the Safety Analysis set for 
maintenance treatment (SAF-MT) and the Safety Analysis set for re-induction treatment
(SAF-RT).
Safety Analysis set for Maintenance Treatment (SAF-MT)
This patient set includes all patients who received at least one dose of maintenance treatment 
in the extension trial. It will be the main analysis set for presentation of safety and efficacy
during the maintenance part of the extension trial.
Safety Analysis set for Re-induction Treatment (SAF-RT)
This patient set includes all patients who received at least one dose of re-induction treatment 
in the extension trial. It will be the main analysis set for presentation of safety and efficacy
during the re-induction part of the extension trial.
In addition, the following patient sets are defined for analysis.
Enrolled set (ES)
This patient set includes all patients who sign the informed consent. This set will be used for 
disposition analyses.
Safety Analysis set (SAF)


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This patient set includes all patients who received at least one dose of study drug in either the 
re-induction or maintenance periods. This set will be used for presentation of IPDs and 
patient listings.
Safety Analysis set for Flare Treatment (SAF-FT)
This patient set includes all patients who take at least one dose of disease flare treatment of 
1200 mg SD i.v. in the extension trial. This set is the basis for efficacy and safety analysis on 
both the disease flare, and the post-flare treatment periods.
Note that the constitution of treatment sets will differ depending upon the number of patients 
entered into the trial at the time of each interim analysis.
Table 6.3: 1 illustrates the data sets which are to be used for each category class of endpoints, 
as well as treatment periods to be reported for each data sets. For explanation of the different 
methods of handling missing data, cf. Section 6.6.
Table 6.3: 1
Patient sets and treatment periods analysed
Class of endpoints
ES
SAF
SAF-MT
SAF-RT
SAF-FT
Disposition
X
Overall 
maintenance TP
Re-induction TP
Exposure
Pre-flare TP; 
Overall 
maintenance TP
Re-induction TP
Post-flare TP; 
Disease flare TP
IPDs
X
Demographic/baseline 
characteristics
X
X
X
Concomitant medication
X
X
X
Secondary endpoint
Overall 
maintenance TP
Further endpoint
(including biomarker 
endpoint)
Endpoints 
defined for
overall 
maintenance TP
Endpoints defined 
for re-induction TP
Endpoints defined for 
disease flare TP
Adverse event
Pre-flare TP; 
overall 
maintenance TP
Re-induction TP
Post-flare TP; disease 
flare TP
Safety lab, vital sign
Pre-flare TP;
overall 
maintenance TP
Re-induction TP
Post-flare TP; disease 
flare TP
Note: MT=Maintenance Treatment; RT=Re-induction Treatment; FT=Flare Treatment; TP= Treatment Period


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6.5
POOLING OF CENTRES
All patients from all centres will be pooled for statistical analysis. 
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Section 7.5 of the CTP describes the handling of missing data.
The original results (OR) approach implies the presentation of data exactly as observed (not
using time windows and not setting values to missing).
OR analysis will be performed on parameters and endpoints that are either not affected by
patients’ rescue medication use (e.g. plasma concentration level of spesolimab, rescue
medication use itself, or disease flare related endpoints), or, if it is not meaningful to apply 
any imputation rule for the replacement of missing values.


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Withdrawals
6.6.1
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.
Efficacy endpoints
6.6.2
From CTP Section 7.5: With regards to the handling of missing data on those efficacy 
outcomes derived from the MCS, no missing data imputations are planned to be performed.
In order to appropriately handle missing data in this trial, it is first necessary to define which 
are the inter-current events within each trial part, that lead to specific decisions being made 
upon the respective efficacy endpoint outcome, with such decisions being dependent upon the 
occurrence and timing of these events. 
Any occurrence of the following will represent an inter-current event during both the re-
induction and maintenance trial parts: 
∀
Intake of rescue medication (as defined in section 5.4.4).
Data after occurrence of such an event will be censored, and, handled subsequently 
according to the applicable missing data strategy described below.
In addition, any occurrence of the following will represent an inter-current event during the 
maintenance trial part: 
∀
Occurrence of a confirmed disease flare (as defined in Section 5.4.6), or the intake of 
a dose of disease flare medication with 1200 mg BI 655130 SD.
Data after occurrence of such an event will be included in displays of the efficacy endpoints
since treatment with spesolimab i.v. (to treat a disease flare) is not considered to represent a 
failed treatment outcome in this trial.
Efficacy imputation rules
The following rules apply for all treatment periods with defined efficacy endpoints. Missing 
data imputation, when performed, will not be done for missing assessments due to 
implementation of any cut-off date. 
The following imputation strategy will be applied to the reporting of continuous efficacy 
data.
∀
Observed cases (OC) approach: prior to observing the applicable efficacy endpoint, 
data will be reported with no imputation performed on the missing data irrespective of 
whether the data is considered to be randomly missing, or missing due to prior 
occurrence of an applicable intercurrent event.
The following imputation strategy will be important for the display of binary efficacy data:


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∀
No Response Imputation [NRI]: prior to observing the applicable binary efficacy 
endpoint, all missing data will be set to non-response irrespective of whether the data 
is considered to be randomly missing, or missing due to prior occurrence of an 
applicable intercurrent event. Only patients continuing at this visit per time window 
before interim cut-off will be included in the denominator.
The following imputation strategy will be important for the display of, i.e. safety laboratory 
data:
∀
Observed cases including values after any use of rescue medication (OC-IR): this 
approach is an extension of the OC approach which includes all values which were 
measured both before and after any rescue medication intake. The analysis using the 
OC-IR approach is then only based on the patients with observed data.
Safety endpoints
6.6.3
From CTP Section 7.5: For the safety data, including the primary endpoint, no missing data 
imputations are planned.
The only exceptions where imputation might be necessary for safety evaluation are AE dates,
and start and stop dates for concomitant medications. Missing or incomplete AE dates are 
imputed according to BI standards (see KM Asset BI-KMED-BDS-HTG-0035 (3)).


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For patients who are included directly into the maintenance period, measurements reported 
with date and time, and taken prior to start of administration of trial treatment are considered 
to be pre-treatment values. Measurements reported with a date only (and no time) and taken 
on the day of first administration of trial treatment are handled in a similar manner, i.e. 


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assigned as pre-treatment values. These pre-treatment values will be assigned to visits 
according to the nominal visit number as recorded on the eCRF or as provided by the 
laboratory. 
For patients who are included directly into the re-induction period, measurements reported 
with date and time, and taken prior to start of administration of trial treatment are considered 
to be pre-treatment values. Measurements reported with a date only (and no time) and taken 
on the day of first administration of trial treatment are handled in a similar manner, i.e. 
assigned as pre-treatment values.
Baseline for derivation of the binary MCS efficacy endpoints, as well as for the efficacy 
endpoint displays over time are defined in Section 5.
For safety endpoints, baseline for different treatment periods are defined in Section 5.
Measurements taken after start of administration of trial treatment will be considered either 
on- or off-treatment values based on the definition in Section 6.1, and will be assigned to 
visits for statistical analysis, if applicable, as defined below.
Analysis of AE data, concomitant medication or non-drug therapies, as well as use of rescue 
medication will not be based on visits. Therefore, no assignment to time windows will be 
necessary.
For derivation of the last value on treatment, minimum value on treatment, and maximum 
value on treatment, all on-treatment values (whether or not selected in any time window; see 
Table 6.1: 1 and Table 6.1: 4 for definition of the on-treatment period) will be considered; 
these will be derived for analysis of laboratory and vital signs data. For identification of 
potentially clinically significant abnormal laboratory values, all values (whether or not 
selected in any time window) within the on-treatment period will be considered.
Safety lab, vital sign, efficacy and biomarker measurements will be assigned to visits based 
on extended time windows around the planned visit dates, defined relative to the day of first 
re-induction, maintenance, or disease flare treatment depending on analysis phase. These 
extended time windows are defined below as well as their planned analyses.

Re-induction period (Table 6.7: 1): efficacy, safety, and biomarker

Overall maintenance treatment period (Table 6.7: 2): efficacy, safety, and biomarker

Disease flare treatment period (Table 6.7: 3): efficacy, and safety


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Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs and 
biomarker to visits for statistical analysis for re-induction period
Visit 
number
/name
Planned 
day
Time window (Days)
Visit label
Window
(per CTP)
Start 
(per CTP)
End 
(per CTP)
Start 
(extended)
End 
(extended)
V1
Screening/
R-baseline*
-7 to -2
n/a
V1a
Screening
-2 to -1
n/a
I1
RI-Week 0
Day 1
+/-0
1 A
1 A
≤1 A
1 A
Planned On-Treatment Data
I2
RI-Week 4
Day 29
+/-3 
26
32
2
43
I3
RI-Week 8
Day 57
+/-3 
54
60
44
71
I4
RI-Week 12
Day 85
+/-3 
82
88
72
99B
All Data (planned Off-Treatment data)
Unsche
duled
Unscheduled
100
148
EOSC
Week 24/EoS
Day 170
+7
170
177
149
Day of last 
f-up value
Days are counted relative to the day of first i.v. treatment of re-induction period, which is defined as Day 1.
* For derivation of binary MCS based efficacy endpoints, the baseline refers to baseline of parent trial. The R-
baseline for efficacy endpoint displays over time refers to EoT of parent trial (V1 of current study).
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made 
after start of infusion of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be 
assigned to Day 1. Such data will be listed only.
B All data after a patient has taken the first dose in the subsequent maintenance period are not applicable for 
reporting as a part of the re-induction period.
C EOS is only applicable to those patients who do not enrol into the maintenance period.


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Table 6.7: 2
Time windows for assignment of efficacy, safety lab, vital sign and biomarker 
to visits for statistical analysis for overall maintenance treatment period
Visit 
number
/name
Planned 
day
Time window (Days)
Visit label
Window
(per CTP)
Start 
(per CTP)
End 
(per CTP)
Start 
(extended)
End 
(extended)
V1
Screening/
M-baseline*
-7 to -2
n/a
V1a
Screening
-2 to -1
n/a
M1
M-Week 0
Day 1
+/-0 
1 A
1 A
≤1 A
1 A
Planned On-Treatment Data
M2
M-Week 12
Day 85
+/-7 
78
92
2
127
M3
M-Week 24
Day 169
+/-7 
162
176
128 
211
M4
M-Week 36
Day 253
+/-7
246
260
212
295
…
…
…
…
Planned 
date-7
Planned 
date+7
End of 
extended 
window of 
last visit+1 
Midpoint 
of planned 
days 
between 
current 
visit and 
next visit
M29/E
OT
M-Week 
336/EoT
Day 2353
+/-7 
2346 
2360 
End of 
extended 
window of 
last visit+1
Minimum 
of (2395,
LDB+112)
All Data (planned Off-Treatment data)
Unsche
duled
Unscheduled
2396
2444
EOS
EoS
Day 2466
+7
2466
2473
Minimum 
of (2396,
LDB+113)
Day of last 
f-up value
Days are counted relative to the day of first s.c. treatment in maintenance period, which is defined as Day 1 for 
maintenance.
* For derivation of binary MCS efficacy endpoints, the baseline refers to baseline of parent trial. The M-baseline 
for efficacy endpoint displays over time refers to EoT of parent trial (V1 of current study) for initial responders 
and visit I4 (RI-Week 12) for responders after re-induction.
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made 
after start of injection of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be 
assigned to Day 1. Such data will be listed only.
B LD = Day of last treatment received in the overall maintenance treatment period regardless of flare 
occurrence; 


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Table 6.7: 3
Time windows for assignment of efficacy, safety lab, and vital signs to visits 
for statistical analysis for disease flare treatment period
Visit number/name: ‘x’ represents disease flare occurrence.
Days are counted relative to the day of each corresponding flare i.v. treatment, which is defined as Day 1 of 
disease flare treatment period.
* For clinical response/remission assessment after disease flare treatment based on mayo score related 
calculation, the baseline refers to data from flare confirmation visit with endoscopy or regular maintenance visit
with endoscopy before administration of each disease flare treatment.
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made 
after start of infusion of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be 
assigned to Day 1. Such data will be listed only.
Repeated and unscheduled efficacy, safety and biomarker measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date of measurement. 
Only one observation per time window will be selected for statistical analysis at a particular 
visit. Generally, the value which is closest to the protocol planned visit day will be selected.
For composite endpoints based on MCS subscores, the date of PGA assessment will be used 
for time window assignment, and the PGA with the most complete components
(RBS/SFS/mESS) at the same visit will be identified and then the closest will be selected. If 
the date of PGA assessment is missing, the date of endoscopy will be used instead for time 
window assignment and calculation of SFS and RBS, if available. If there are two 
observations which have the same difference in days to the planned day, the later value will 
be selected. If there are two observations on the same day, then [for vital signs per nominal 
time-point] the latest value (according to the date and time) will be selected, [for other 
endpoints] the worst value will be selected.
Assignment of efficacy observations to visits based on time windows will be based on the 
non-imputed (observed) data. 
Visit number/name
Planned 
day
Time window (Days)
Visit label
Window
(per 
CTP)
Start 
(per 
CTP)
End 
(per 
CTP)
Start 
(extended)
End 
(extended)
F0y
Fx-baseline*
-5 to -3
n/a
Fx-Week 0
Fx-Week 0
1
+/-0
1 A
1 A
≤1 A
1 A
Planned On-Treatment Data
Fx-Week 6
Fx-Week 6
Day 43
+/-7 
36
50
2
64
Fx-Week 12
Fx-Week 12
Day 85
+/-7 
78
92
65
99


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7.
PLANNED ANALYSIS
General Remarks
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (001-MCG-159) (7).
The individual values of all patients will be listed, including those collected during the off-
treatment period. Listings will generally be sorted by country, centre number, patient number 
and visit (if visit is applicable in the respective listing). (see Section 7.8.1 below for details).
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Q1 
lower quartile
Median 
median
Q3 
upper quartile
Max 
maximum
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline "Reporting of clinical trials and project summaries" (7).
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective patient set (unless otherwise specified, all patients in the patient set irrespective of
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
Disposition of the patient population for each trial part (re-induction or overall maintenance) 
will be summarised by presentation of the frequency of patients enrolled, treated, enrolled but 
not treated, who completed all doses of trial medication as planned, who completed the PE 
visit (EOT), who completed the trial (EOS), and who were prematurely discontinued, by 
reason. Additional summaries by the parent trial will be produced, and, summaries of the 
maintenance period disposition according to whether or not a patient experienced re-
induction treatment or not will also be done. The frequency of patients with iPDs will also be 
presented; the iPDs will be listed per patient.
To better illustrate the long-term efficacy of the overall maintenance treatment (defined in 
Table 6.1: 4), a summary table regarding patient status over time will be added. The 
cumulative frequency of patients for the following categories will be displayed based on 12-
week interval:
∀
ongoing on study medication, i.e., without early treatment discontinuation by the time 
point


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o
Occurrence of a disease flare, or intake of disease flare medication
o
Intake of rescue medication
o
Any of the above
∀
pre-maturely stopped study medication, i.e., discontinued study medication by the time 
point
o
Occurrence of a disease flare, or intake of a disease flare medication
o
Intake of rescue medication
o
Death
o
Any of the above
For details on the requirements of the first interim data snapshot of this trial, refer to 
additional Section 9.2.1. The second interim analysis requirements are specified in Section 
9.2.2.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Tables will be displayed 
for SAF-MT, SAF-RT and SAF-FT respectively.
For the continuous variables described below, the following categories will be defined and 
presented according to the number and percentage of patients in each category:


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. The analyses of EIM is 
defined in Section 7.8.5.2.
Analyses of concomitant diseases and medication will be based on SAF-MT, SAF-RT, and 
SAF-FT, respectively.
Concomitant diseases (i.e., baseline conditions) will be coded according to the most recent 
version of MedDRA.
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.
Concomitant non-drug therapy will be coded according to the most recent version of
MedDRA.


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7.3
TREATMENT COMPLIANCE
Not applicable since the treatment regimens can be different based on patient status and the
version of signed informed consent.
7.4
PRIMARY ENDPOINT
Refer to section 7.8.1 for the description for adverse events including the primary endpoint..
7.5
SECONDARY ENDPOINTS
Key secondary endpoint
7.5.1
This section is not applicable as no key secondary endpoint has been specified in the protocol.
Secondary endpoints
7.5.2
From CTP Section 7.3.2:


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The evaluation of clinical outcomes based on the MCS, i.e. clinical remission, is based upon 
the endoscopy results obtained from central reading. Only if the centrally read endoscopy 
result is missing at a time-point will the locally read result be used instead.
For the stool frequency and rectal bleeding items reported in the patient diary, an average of 
the last 3 non-missing daily assessments collected within the last 7 days prior to the 
applicable visit will be used for the determination of clinical outcome. If the patient 
undergoes bowel preparation for endoscopy on any of the days before a visit, the stool 
frequency and rectal bleeding subscores on that day(s) should be considered to be missing. In 
addition, the stool frequency and rectal bleeding subscore will be considered to be missing 
both on the day of and the day after the endoscopy.
Secondary endpoint will be assessed descriptively.
The pre-defined secondary endpoint is described with the corresponding further endpoint in 
section 7.6.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed based on each of the SAF-MT and SAF-RT following 
BI standards. No hypothesis testing is planned.
The analyses based on SAF-MT will be done for the pre-flare treatment period (as defined in 
Table 6.1: 2), as well as for the overall maintenance treatment period (as defined in Table 6.1: 
4). The analyses based on SAF-FT will be done for the post flare treatment period (as defined 
in Table 6.1: 3), as well as for the disease flare treatment period (as defined in Table 6.1: 5). 
For additional analysis on the individual flare safety data based on the SAF-FT, all standard 


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safety tables will be provided for each flare occurrence using the analysis phases as defined 
in Table 6.1: 5.
In addition, a subgroup analysis on the overall maintenance treatment period by the number 
of flare treatments (without flare treatment, with only one flare treatment, with two or more 
flare treatments as defined in Section 6.4) will be provided for the following tables based on 
SAF-MT. Additional subgroup analysis (e.g., by pre-flare regimen) will be considered if 
necessary.

Overview on TEAE

TEAE by SOC, preferred term
Adverse events
7.8.1
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs. System organ classes (if 
applicable) will be sorted according to the standard sort order specified by the EMA, 
preferred terms (if applicable) will be sorted by total frequency (within system organ class).
For further details on summarization of AE data, please refer to "Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries" (4) 
[KM Asset BI-KMED-BDS-HTG-0041] and "Handling of missing and incomplete AE dates" 
(3) [KM Asset BI-KMED-BDS-HTG-0035]. 
The analysis of AEs will be based on the concept of treatment emergent AEs. This means that 
all AEs will be assigned to the screening phase, re-induction on-treatment period (i.e. re-
induction treatment phase plus REP), maintenance on-treatment period (i.e. maintenance 
treatment phase plus REP) or off-treatment period (i.e. follow-up) as defined in Section 6.1.
Adverse events occurring in the maintenance and re-induction periods will be separately 
described. Since only the start date of an AE is collected (without start time), any AE 
occurrence on the same day as the first re-induction or first maintenance spesolimab
administration will be assigned to the respective on-treatment period. For patients who switch 
directly to maintenance treatment at week 12 of the re-induction period, adverse events 
occurring on this first day of maintenance treatment will be included in summaries of the 
maintenance period only. Exposure-adjusted adverse event incidence rates (per the primary 
endpoint) will be calculated using the following approach:
1)
The exposure adjusted incidence rate (per 100 subject years) of a selected treatment 
emergent adverse event is defined as the number of subjects experiencing the adverse 
event per treatment group during time at risk divided by the total time of subjects at risk 
in that treatment group to contribute the event to the analysis multiplied by 100 (per 100 
subject years), where: 
2)
Time at risk [subject years] = (date of onset of AE – study drug start date + 1) / 365.25


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For safety analysis on the post-flare treatment periods: Time at risk [subject years] = 
(date of onset of AE – first i.v. disease flare treatment start date + 1) / 365.25
For safety analysis on the disease flare treatment period: Time at risk [subject years] = 
(date of onset of AE – prior i.v. disease flare treatment start date + 1) / 365.25
3)
If, for a subject,  the selected treatment emergent adverse event didn’t occur then the time 
at risk will be censored at min (date of death, date of end of applicable treatment period
per Section 6.1, or date of cut-off if interim analysis performed). For each selected 
treatment emergent AE, the exposure adjusted incidence rate will be calculated as: 
4)
Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with TEAE / 
Total TEAE-specific time at risk [subject years].
An overall summary of AEs will be presented. This overall summary will include summary 
statistics for the class of other significant AEs derived according to an adaptation of the ICH 
E3 (6) and for the class of AESIs.
The following are considered as AESIs (cf. CTP section 5.2.6.1):
∀
Infusion reactions including anaphylactic reaction
∀
Severe infections (according to RCTC grading)
∀
Opportunistic and mycobacterium tuberculosis infections 
∀
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
a.  ALT or AST >5x ULN 
b.  ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
c. AST and/or ALT >3 fold ULN combined with an elevation of total bilirubin >2 fold 
ULN measured in the same blood draw sample
The investigator identified AESI will be captured from the eCRF and reported in the 
“Investigator reported AESI” table. In addition, user defined adverse event concepts 
(UDAEC) identified through specific search criteria will be reported separately (Table 7.8.1: 
1). 


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Adverse Events classified as ‘other significant’ will be reported using an adaptation of the 
ICH E3 (6) and will include those non-serious and non-significant AEs which were reported 
with ‘action taken = drug withdrawn’ or ‘action taken = reduced’.
The exposure-adjusted incidence rate and frequency of patients with AEs will be summarised 
by treatment, primary system organ class and preferred term. AEs which were considered by 
the investigator to be drug related will be summarised separately. Separate tables will also be 
provided for patients with SAEs, patients with AESIs, patients with AE leading to 
discontinuation of the trial, patients with other significant AEs and User-defined Adverse 
Event Concepts (UDAEC) (see Table 7.8.1: 1). AEs will also be summarized by maximum 
intensity based on the RCTC measure (see Section 5.4.1).”


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For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5% (in preferred terms) will be summarised 
by primary system organ class and preferred term. The frequency of patients with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of non-serious AEs with an 
incidence of greater than 5% (in preferred terms) and the frequency of SAEs will be 
summarised.
Laboratory data
7.8.2
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (5). Note that data from the central Laboratory will be used for all displays 
described below, unless otherwise specified.
For continuous safety laboratory parameters, normalized values will be derived.
Normalisation means transformation to a standard unit and to a standard reference range. The
process of normalisation, handling of repeat values at the same visit for by-visit displays, as
well as standard analyses for safety laboratory data are described in the BI guidance for the
Display and Analysis of Laboratory Data (5). All analyses considering multiple times of the
ULN (as described below) will be based on standardized and not normalized values. For
continuous safety laboratory parameters, differences to baseline will be calculated.
Only patients with at least one available post-baseline value will be included in the analysis 
of an individual laboratory parameter. All individual laboratory data will be listed. Values
outside the reference range will be flagged.
Descriptive statistics of laboratory values over time and for the difference from baseline (see
Section 6.7) will be based upon normalized values and provided by visit, including the last 
value on treatment, the minimum value on treatment and maximum value on treatment.
Laboratory values will be compared to their reference ranges; shift tables will be provided for
the number of patients with a specific RCTC grade at baseline versus the grade at the last
measurement on treatment, as well as the worst grade on treatment. These analyses will be 
based on standardized laboratory values.
Potentially clinically significant abnormalities will be identified based on BI standard rules
which are based on normalized converted lab values, i.e. using SI units. These rules will be
listed in the SDL appendix of the CTR. Frequency tables will summarize the number of
patients with potentially clinically significant abnormalities. Patients having an abnormal lab
value at baseline will be presented separately. A separate listing will present potentially
clinically significant abnormal lab values; for each functional lab group all patients’ lab
values will be listed, if there exists at least one lab value with clinically significant
abnormality within the group.
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥ 10xULN, and
≥ 20xULN will be displayed based on standardized laboratory values. To support analyses of
liver related adverse drug effects, the frequency of patients with AST and/or ALT ≥ 3xULN


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combined with a total bilirubin ≥ 2xULN in a 30 day period after AST/ALT elevation will be
displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a patient can 
potentially be in both alkaline phosphatase strata in case of multiple AST/ALT and bilirubin 
elevations).
The start of the 30 day time span is triggered by each liver enzyme elevation above the
defined thresholds. This analysis will be based on standardized laboratory values. A graphical
analysis of the ALT and total bilirubin during the on-treatment period will also be performed;
the so called eDISH plot. In the graph, for each subject, the peak total bilirubin is presented 
as a fold increase over the ULN against the peak ALT as a fold increase over the ULN, on a
log10 scale. The measurements displayed for total bilirubin and ALT may, or may not, occur
on the same date. Two reference lines, 2xULN for total bilirubin and 3xULN for ALT, are
drawn onto the graph in order to divide the plane into four quadrants. Normal cases are in the
lower left quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law quadrant),
while the lower right quadrant is known as the Temple’s corollary range (ALT ≥ 3xULN and
total bilirubin < 2xULN).
An additional display will be produced for the frequency of patients with an elevation of the 
ALT or AST > 3-fold ULN and with the appearance of one or more of the following TEAE: 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%). An occurrence is flagged if, within +/- 7 days of the onset of an AST or 
ALT elevation > 3-fold ULN (including events which start or are ongoing through this 
interval), at least one of the following TEAE terms (excluding PT terms on the secondary 
path) is observed: 
∀
ADAE.AEHLT = "Gastrointestinal and abdominal pains (excl oral and throat)";
∀
ADAE.AEDECOD in ("Vomiting","Fatigue","Nausea","Pyrexia")
∀
ADAE.CQ16NAM = "Skin Rash (BIcMQ narrow)
An occurrence is also flagged if a >5% proportion in the ratio of eosinophils to total white 
blood cells is observed in the same sample as the detected AST/ALT elevation.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and
will be analysed as such.
Vital signs
7.8.3
The analyses of vital signs (blood pressure, pulse rate, body temperature, respiratory rate and 
body weight) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see Section 
6.7) will be provided and will include the last value during on-treatment period, the minimum 
value during on-treatment period, and the maximum value during on-treatment period (see 
Table 6.1:1 for definition of the on-treatment period).


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Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
ECG
7.8.4
Abnormal findings in 12-lead ECG will be reported as baseline conditions (at screening) or as 
AEs (during the trial) if judged clinically relevant by the investigator, and will be analysed as 
such.
No separate listing or analysis of ECG data will be prepared.
Other
7.8.5
7.8.5.1
Immunogenicity
The frequency and percentage of patients with ADAs to spesolimab will be presented by 
visit. ADA will be analyzed descriptively. A potential effect of ADA on PK and safety may 
be evaluated.
7.8.5.2
Extra-intestinal manifestation
During the course of the study's on-treatment period, the frequency and percentage of the 
presence of pre-defined EIM diagnoses will be summarized over time.
7.9
HANDLING OF DMC ANALYSES
An external DMC, independent of the trial and project teams, will be set-up to review all 
available un-blinded safety data as well as selected efficacy data at regular intervals 
following first-patient-in. A separate DMC SAP which describes the analyses required for 
assessment by the DMC will be produced. Further details are provided in a DMC charter.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Statistical Principles for Clinical Trials, current 
version
2
001-MCS-40-413: " Identify and Manage Important Protocol Deviations (iPD)", 
current version; IDEA for CON
3
KM Asset BI-KMED-BDS-HTG-0035 : "Handling of missing and incomplete AE 
dates", current version; KMED
4
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED
5
KM Asset BI-KMED-BDS-HTG-0042: " Display and Analysis of Laboratory Data", 
current version; KMED
6
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
7
001-MCG-159: "Reporting of clinical trials and project summaries", current 
version; IDEA for CON


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1.0
11-Oct-2018
None
This is the initial TSAP with necessary 
information for trial conduct.
2.0
25-Feb-2020
None
This is the final TSAP before first 
interim DBL.
3.0
29-Oct-2020
All
The pre-planned analysis are simplified
and updated, including reducing 
endpoints, deleting compliance 
analysis, reducing subgroups to be 
analysed, more clarifications about 
treatment periods, and missing data 
handling for binary efficacy endpoints.
Section 
7.8.1
Categories of UDAEC are updated.
4.0
13-Jan-2021
Section 
6.3
The name of patient set for analysis is 
updated from Treated set to be Safety 
analysis set.
Section 
6.7
The safety lab and vital sign over time 
for maintenance treatment is 
simplified.
Section 
7.8.1
Categories of UDAEC are updated.