Clinical trial NCT04362254
Conditions: Crohn Disease
Sponsor: Boehringer Ingelheim
Start date: 2020-05-15; Completion date: 2022-09-23
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main objectives of this study are to evaluate the long-term safety of spesolimab in patients with perianal fistulising Crohn's disease who have completed treatment in parent trials and to evaluate the long-term efficacy of spesolimab in patients with perianal fistulising Crohn's disease, who have completed treatment in parent trials

Detailed description:

Arms: arm 1: During the maintenance treatment period 300 milligram (mg) Spesolimab was given by subcutaneous injection at Week 0 and then every 4 weeks for a total duration of 89 weeks.

Patient with a confirmed fistula relapse received a single intravenous infusion of 1200 mg Spesolimab followed by an intensified subcutaneous spesolimab maintenance dosing of 600 mg Spesolimab every 4 weeks.
Interventions: intervention 1: Spesolimab
Intervention descriptions: intervention 1: Spesolimab

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
28 November 2019
Revision date
21 January 2021
BI trial number
1368-0007
Title of trial
An open label, long term safety trial of spesolimab treatment in 
patients with fistulising Crohn’s disease who have completed 
previous spesolimab trials
Coordinating 
Investigator
Trial site(s)
Multi-centre trial
Clinical phase
II
Trial rationale
Provide to patients with fistulising Crohn’s disease extended acces to 
a potentially beneficial treatment and evaluate long term tolerability,
safety, and efficacy.
Trial objective(s)
1. To evaluate the long-term safety of spesolimab in patients with
fistulising Crohn’s disease who have completed treatment in previous 
trials.
2. To evaluate the long-term efficacy of spesolimab in patients with
fistulising Crohn’s disease who have completed treatment in previous 
trials.
Trial endpoints
Primary Endpoint
∀
Exposure adjusted rate of patients with treatment emergent 
adverse event (AEs) up to week 336
Secondary Endpoints
∀
Proportion of patients with perianal fistula remission at weeks 
48, 96, 144, 192, 240, 288, and 336 
∀
Proportion of patients with perianal fistula response at weeks 
48, 96, 144, 192, 240, 288, and 336
Trial design
Open label (OL), 7 year, single group, long-term extension study
Total number of treated 
patients
Up to 20
Number of patients on 
each treatment
All patients will receive spesolimab.
Diagnosis
Patients with fistulising Crohn’s disease
Main in- and exclusion 
criteria
Inclusion Criteria
∀
Patient older than 18 years


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∀
Has completed all treatments as assigned and the EOT visit in 
the previous induction trial in fistulising CD and is willing and 
able to continue treatment in 1368-0007
∀
Has obtained an individual health benefit, per investigator 
judgement (such as fistula response or remission or other 
clinical improvement), from treatment in the parent trial.
∀
Signed and dated written informed consent for 1368-0007 in 
accordance with GCP and local legislation prior to admission
into the trial
∀
Women of childbearing potential (WOCBP) must be ready to 
use highly effective methods of birth control per ICH M3 (R2) 
Exclusion criteria
∀
Have experienced study treatment-limiting adverse events 
during induction treatment with study drug
∀
Have developed any condition which meets the exclusion 
criteria from the original induction study
∀
Any condition which in the opinion of the investigator affects 
the safety or ability to participate in this trial
Test product(s)
Spesolimab, BI 655130
dose
300 mg s.c./4 weeks
1200 mg i.v. followed by 600 mg s.c./4 weeks in case of fistula 
relapse
mode of 
administration
Subcutaneous (s.c.)
Intravenous (IV) in case of fistula relapse
Comparator product(s)
Not applicable
dose
Not applicable
mode of
administration
Not applicable
Duration of treatment
Approximately 7 years
Statistical methods
Descriptive statistics only. 






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FLOWCHART 1B: M14-M84
See flow chart 1A for procedures to be done depending on visit type. The same visit schedule 
repeats yearly until the end of seven years as follows.
These treatment visits will follow the same ±7 day visit window.
M14-M25
Visit
M14
M15
M16
M17
M18
M19
M20
M21
M22
M23
M24
M25
Week
52
56
60
64
68
72
76
80
84
88
92
96
Day
365
393
421
449
477
505
533
561
589
617
645
673
Visit 
type
C
C
D
C
C
E
C
C
D
C
C
F#
M26-M37
Visit
M26
M27
M28
M29
M30
M31
M32
M33
M34
M35
M36
M37
Week
100
104
108
112
116
120
124
128
132
136
140
144
Day
701
729
757
785
813
841
869
897
925
953
981
1009
Visit
type
C
C
D
C
C
E
C
C
D
C
C
F*
M38-M49
Visit
M38
M39
M40
M41
M42
M43
M44
M45
M46
M47
M48
M49
Week
148
152
156
160
164
168
172
176
180
184
188
192
Day
1037
1065
1093
1121
1149
1177
1205
1233
1261
1289
1317
1345
Visit 
type
C
C
D
C
C
E
C
C
D
C
C
F*
M50-M61
Visit
M50
M51
M52
M53
M54
M55
M56
M57
M58
M59
M60
M61
Week
196
200
204
208
212
216
220
224
228
232
236
240
Day
1373
1401
1429
1457
1485
1513
1541
1569
1597
1625
1653
1681
Visit 
type
C
C
D
C
C
E
C
C
D
C
C
F*
M62-M73
Visit
M62
M63
M64
M65
M66
M67
M68
M69
M70
M71
M72
M73
Week
244
248
252
256
260
264
268
272
276
280
284
288
Day
1709
1737
1765
1793
1821
1849
1877
1905
1933
1961
1989
2017
Visit 
type
C
C
D
C
C
E
C
C
D
C
C
F*
M74-M84
Visit
M74
M75
M76
M77
M78
M79
M80
M81
M82
M83
M84
Week
292
296
300
304
308
312
316
320
324
328
332
Day
2045
2073
2101
2129
2157
2185
2213
2241
2269
2297
2325
Visit 
type
C
C
D
C
C
E
C
C
D
C
C
*Visit type F after visit M25: no blood and stool sampling for biomarkers 












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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART 1.....................................................................................................................4
FLOWCHART 1A: V1, M1-M13...........................................................................................4
FLOWCHART 1B: M14-M84................................................................................................6
FLOWCHART 1C: END OF TREATMENT AND END OF STUDY VISITS ................7
FLOW CHART 2A: PATIENTS WITH INFLAMMATORY FLARE WITH NO 
FISTULA RELAPSE............................................................................................8
FLOW CHART 2B: FISTULA RELAPSE (WITH OR WITHOUT A LUMINAL 
FLARE)..................................................................................................................9
FLOW CHART 2C: PATIENTS WITH FLARE/FISTULA RELAPSE –EOT/EOS 
VISIT....................................................................................................................10
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................16
1.
INTRODUCTION...............................................................................................19
1.1
MEDICAL BACKGROUND.............................................................................19
1.2
DRUG PROFILE................................................................................................20
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................22
1.4
BENEFIT - RISK ASSESSMENT.....................................................................23
1.4.1
Discussion.............................................................................................................27
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................29
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........29
2.1.1
Main objectives....................................................................................................29
2.1.2
Primary endpoint(s)............................................................................................30
2.1.3
Secondary endpoint(s) ........................................................................................30
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................32
3.1
OVERALL TRIAL DESIGN.............................................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................34
3.3
SELECTION OF TRIAL POPULATION .......................................................35
3.3.1
Main diagnosis for trial entry ............................................................................35
3.3.2
Inclusion criteria .................................................................................................35
3.3.3
Exclusion criteria ................................................................................................36
3.3.4
Withdrawal of patients from treatment or assessments..................................36
3.3.4.1
Discontinuation of trial treatment .........................................................................36
3.3.4.2
Withdrawal of consent to trial participation .........................................................37








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ABBREVIATIONS
ADCC
Antibody-dependent Cellular Cytotoxicity 
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AP
Abdominal Pain
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
CA
Competent Authority
CD
Crohn’s disease
CDC
Complement-dependent Cytotoxicity 
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
EC
Enterocutaneous
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EOS
End of Study
EOT
End of Treatment


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EudraCT
European Clinical Trials Database
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GPP
Generalized Pustular Psoriasis
HA
Health Authority
HIV
Human Immunodeficiency Virus 
i.v.
intravenous
IB
Investigator’s Brochure
IBD
Inflammatory Bowel Disease
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LPLT
Last Patient Last Treatment
MCID
Minimal Clinically Important Difference 
MedDRA
Medical Dictionary for Drug Regulatory Activities
MoA
Mode-of-action 
MRI 
Magnetic Resonance Image
NAB
Neutralizing Antibodies
OL
Open Label
OPU
Operative Unit
PBO
Placebo
PoCC
Proof of Clinical Concept
 


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RCT
Randomized Controlled Trial
RCTC
Rheumatology Common Toxicity Criteria 
REP
Residual Effect Period
s.c.
subcutaneous
SAE
Serious Adverse Event
SF
Stool Frequency
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TEAE
Treatment Emergent Adverse Event 
TSAP
Trial Statistical Analysis Plan
UC
Ulcerative Colitis
ULN
Upper Level of Normal
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Crohn’s Disease (CD) is a chronic relapsing, remitting inflammatory disease of the
gastrointestinal tract clinically characterized by abdominal pain, fever, and bloody or mucus-
containing
diarrhoea 
(R13-2231).
The 
disease 
affects 
the 
gastrointestinal 
tract 
discontinuously from mouth to anus, but most commonly the ileum and colon (40%), 
followed by the small bowel only (30%), and the colon only (25%) (R13-2233). The mean 
age at CD diagnosis is approximately 30 years with a slight predominance of women (R16-
1923).
Repeated episodes of acute gut inflammation and epithelial damage in these patients lead to 
abnormal tissue remodeling responses, with aberrant epithelial to mesenchymal transition 
(EMT) repairing process. Altered EMT is one of the key drivers of fistula formation in 
patients with IBD.  [R20-2041, R20-2042]. 
The incidence of CD seems to be increasing with more recent estimates varying from 7.9 to
20.2 cases/100,000 per year, and a prevalence of 161 to 319 cases/100,000 in populations of 
North America and Europe (R13-2231). Mucosal lesions may be complicated not only by 
stricture formation, but also by perforation and fistula formation, which may require 
hospitalization for medical or surgical management.
Fistulas represent one of the most important complications in patients with CD and have a 
deep impact on patients’s wellbeing. At time of CD diagnosis, two third of patients present 
with inflammatory disease and up to one-third of the patients already reveal stricturing or 
penetrating complications of their inflammatory bowel disease. One third of CD patients will 
develop fistulas at least once during the course of the disease. Perianal fistulas are the most 
common and their presence has been shown to be a risk factor for pourer outcomes in these 
patients (R19-2044, R19-2046). Surgery, though often required to treat perianal fistulas, often 
does not provide a definitive cure (R17-3555).
There is a paucity of randomized controlled trials (RCTs) for the treatment of fistulizing CD. 
Established treatment, however, includes treatment of associated luminal disease, particularly 
rectal disease, which it has been shown to influence fistula outcomes. Current standard 
medical treatments used for treatment of related draining perianal fistulas include antibiotics,
which are useful to treat infection but do not appear to have long-term effects on the fistula 
itself, immunosuppressives, and anti-TNF agents. Most of the evidence on routinely used 
medical treatment is derived from subgroup analyses or secondary outcome measures, while 
there is limited evidence from clinical trials with perianal fistula healing as a main outcome. 
Amongst anti-TNF agents, infliximab has been approved for treatment of perianal fistulising 
active Crohn`s disease, in adult patients who have not responded despite a full and adequate 
course of therapy with conventional treatment (including antibiotics, drainage and 
immunosuppressive therapy). This comes from one positive RCT with infliximab on the 
patient group. However, only approximately half of infliximab treated patients achieved 


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closure of all fistulas (R00-0812) and after 1 year only a third of fistulas remain closed (R04-
0551). Two recent meta-analyses did not show any effect of anti-TNF therapy for fistulising 
CD (R15-4344, R19-2045). Recently a large RCT has shown the efficacy of the injection of 
allogenic mesenchymal stem cells (Alofisel®) to induce remission of complex fistulas. The 
remission rate delta was only 16% compared to placebo; however, patients who received 
active treatment had significantly lower relapse rates at one year of follow up (R18-2555).
Alofisel® is approved in the EU to induce remission of complex fistulas.   The loss of clinical 
response to these agents is a substantial clinical problem. Other biologics are used off-label 
for treating fistulas such as adalimumab, certolizumab, ustekinumab and vedolizumab. The 
majority of patients with CD with perianal fistulas will require some surgical procedure 
(abcess drainage, seton placement, fistulotomy, fistulectomy or, in some instances, bowel 
resection) on top of the medical treatment. Surgical interventions aim to achieve fistula 
closure while preserving the anal sphincter function. However, they have shown limited 
efficacy and sphincter function cannot always be preserved.  
Currently, it is believed that combined medical and surgical therapy might be more effective 
than one treatment modality alone (R17-3555).
1.2
DRUG PROFILE
Mode of action
Spesolimab is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL-
36R signaling. Binding of spesolimab to IL-36R is anticipated to prevent the subsequent 
activation of IL-36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-
inflammatory and pro-fibrotic pathways with the aim to reduce epithelial cell/ fibroblast/ 
immune cell-mediated inflammation and interrupt the inflammatory response that drives 
pathogenic cytokine production in inflammatory diseases including generalized pustular 
psoriasis (GPP), palmoplantar pustulosis (PPP) and inflammatory bowel disease (IBD).
Preclinical studies
Spesolimab binds to human IL-36R with a binding avidity of less than 1 pM and 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. 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. Thus, spesolimab inhibition of both inflammatory and fibrotic 
pathways might hold promise to treat inflammatory bowel disease, especially Crohn’s 
disease. This condition manifests with increased gut wall inflammation and fibrosis, which 
lead to altered tissue remodelling, tissue penetration and, hence, to strictures and fistulas 
manifestations. (P19-05294, R19-2047).
Mutations of two key residues (L234 and L235) to alanine were made to spesolimab to 
abrogate FcR binding activity and function. Direct assessment of the impact of the mutations 
in the IgG1 FcR binding sites on both antibody-dependent cellular cytotoxicity (ADCC) and 
complement-dependent cytotoxicity CDC effector functions revealed that the mutations 


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abrogate both ADCC and CDC effector functions and indicate that spesolimab will be a non-
depleting therapy in vivo.
Toxicology studies
Spesolimab does not bind to IL-36R from common toxicology species. Therefore, 
meaningful toxicity studies of the molecule cannot be performed in any animal species with
spesolimab. However, hazard identification studies of the 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, spesolimab stains 
epithelium in a variety of tissues. There were no signs of local irritation after single, 1 mL 
injections of the subcutaneous formulation in rabbits. 
These preclinical toxicology data support chronic spesolimab dosing in humans.
Data from clinical studies
Spesolimab or placebo (PBO) was administered to 78 healthy volunteers at single ascending 
i.v. doses from 0.001 mg/kg to 10 mg/kg body weight. Safety and tolerability of all tested i.v. 
doses was good. There were no drug-related SAEs. 
PK analysis showed that exposure (AUC0-tz and Cmax) to spesolimab increased with increasing 
dose in an approximately dose-proportional manner from 0.3 to 10 mg/kg. The effective half-
life of spesolimab is approximately 4 weeks in the linear dose range. Overall, PK data so far 
suggests target-mediated drug disposition (TMDD) kinetics for spesolimab.
Pharmacodynamic effects in this FIH Single Rising Dose trial (c03361085) were assessed by 
indirect target engagement (ITE) of IL-36R by spesolimab using an ex-vivo whole blood 
stimulation assay. Preliminary analyses indicate that ≥94% peripheral IL-36R receptor 
occupancy is achieved with doses ≥0.05mg/kg from 30 minutes post infusion to 10 weeks.
In a multiple rising dose trial, spesolimab or placebo have been administered to healthy 
volunteers at multiple ascending i.v. doses of 3, 6, 10, and 20 mg/kg given qw for 4 weeks 
(thus, for an individual of 75Kg, a maximum dose of 1500mg iv was given every week for 4 
weeks) or a single dose of 20 mg/kg (8 patients each, 3:1 on active or PBO). Overall,
spesolimab was well tolerated. There were no dose dependent AEs, AEs considered to be 


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dose limiting and no SAEs. In all cases the AEs were of mild or moderate intensity.
Furthermore, there were no clinically relevant abnormalities on treatment with spesolimab
with respect to safety laboratory, vital signs, or ECGs as assessed by a central reader. For 
further details and most recent results refer to the current Investigator`s Brochure (IB) 
(c03320877-08).
Studies in Patients
Efficacy data are available from a proof of concept study in patients with generalized pustular
psoriasis (GPP). In this trial (1368.11) seven patients received a single intravenous dose of 10
mg/kg BI 655130, and were monitored for 20 weeks. At week 1 after dosing, Generalized
Pustular Psoriasis Physician Global Assessment (GPPGA) score of clear or almost clear (0 or 
1) was achieved in five patients, and by Week 4 in all seven patients. Within 48 hours 
postdose, pustules were completely cleared in three patients, by week 1 in five patients and 
by week 2 in six of seven patients. A major improvement in (GPPASI) was observed in all 
patients with a mean (SD) percent change from baseline of 73.2% (16.2) at week 2; by week 
4, this was further reduced to 82.0% and was maintained to week 20 (83.6%).
In the PoCC trial in PPP 1368.15 were a total of 59 patients were randomized, two patients 
experienced severe AEs in each of the three trial arms (300 mg, 900 mg BI 655130 and 
Placebo). One SAE was reported in the 300 mg spesolimab arm and one in the placebo arm. 
Four AEs (10.5%) in patients treated with BI 655130 and three AEs (14.3%) in patients 
treated with placebo led to discontinuation of trial medication. Three patients in the 900 mg 
spesolimab arm and two in the placebo arm experienced a significant AE (according to 
project definition). No AESI were reported. No clinically relevant abnormalities on treatment 
with spesolimab with respect to safety laboratory and vital signs were observed. Overall, BI 
655130 was well tolerated and no safety signal was identified in trial 1368.15. See table 
6.3.1.2:4 from IB (c03320877-08)
Summary 
Spesolimab is an anti IL-36R antibody with a high clinical activity to block IL-36R signaling, 
as demonstrated in patients with Generalized Pustular Psoriasis (GPP) and Palmoplantar 
Pustulosis (PPP), both severe inflammatory skin diseases driven by uncontrolled IL36 
activity. IL-36R inhibition shows a favourable nonclinical safety profile. In addition, 
spesolimab has been tested in more than 180 healthy volunteers and 45 PPP or GPP patients 
for up to 16 weeks. All tested dose groups up to 20 mg/kg i.v. q.w. were safe and well 
tolerated and did not demonstrate any particular safety signal clearly related to spesolimab. 
Therefore, spesolimab might be a promising drug to treat patients suffering from IBD.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Spesolimab unique dual mode of action targets pro-inflammatory cytokines as well as tissue 
remodeling defects seen in CD patients that lead to fistulas and stricture formation. Thus,
spesolimab may provide a clear advantage over current drugs and investigational compounds, 
which target inflammation only.The potential spesolimab effects on IBD related defective 
tissue remodeling may directly increase mucosal healing, induce deeper tissue healing 


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(histologic remission) and reduce the worst complications of CD, stricturing and fistulising, 
which are known to be risk factors for worst outcomes in these patients. 
This study will provide patients who derived an individual health benefit from treatment in 
the preceding trial with a long-term treatment option and potentially improve quality of life. 
In parallel, this study will help to characterize the long-term safety and efficacy profile of
spesolimab in CD.
1.4
BENEFIT - RISK ASSESSMENT
BI 655130 represents an investigational drug which has largely completed phase I and is
currently undergoing phase II evaluation in various indications (GPP, PPP, AtD and IBD). In
line with this stage of development, clinical evidence for efficacy of spesolimab in patients is
limited. However, preclinical profiles of spesolimab and clinical data from healthy 
volunteers’ trials suggest that the compound is safe, tolerable and may address an unmet 
medical need in CD patients by a dual anti-inflammatory and anti-fibrotic mechanism of 
action, cf. the IB (c03320877-08). 
There are no identified or potential risks for spesolimab, based on the toxicology programme 
or any clinical trials conducted for this product to date (see also Section 1.2). 
Preclinical toxicology studies with a mouse surrogate antibody have demonstrated the safety 
of chronic IL-36Rinhibition in mice (IB Section 5.1.2 c03320877-08,). A recent publication 
has assessed the clinical phenotype and immune function in 12 healthy individuals harboring 
an IL-36R knock-out polymorphism (R17-3632). This study demonstrated the absence of any 
specific diseases or conditions, in particular of recurrent, severe or opportunistic infections or 
malignancies, in the medical records of these patients. Also, serological and in-vitro studies 
indicated normal levels of non-, tetanus- or varicella-specific immune globulins, and normal 
immune functions as compared to matched controls, indicating that IL36 blockade is likely to 
represent a safe and well tolerated therapeutic concept.
More than 180 healthy volunteers have been exposed in phase I SRD and MRD studies to 
single or multiple doses of spesolimab up to dose levels of 20mg/kg given once weekly (qw) 
for 4 weeks. spesolimab was safe and well tolerated in healthy volunteers trials at all dose 
groups up to the highest tested dose of 20 mg/kg body weight given once a week for up to 4 
weeks (for details IB c03320877-08). 
Results from the PoCC trial 1368-0011 in acute GPP, a disease closely linked to loss-of-
function mutations in the natural IL-36R antagonist, demonstrate that spesolimab treatment 


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rapidly clears pustules, the primary lesions in GPP.  In this trial, no clinically relevant 
abnormalities on treatment with spesolimab with respect to safety laboratory and vital signs 
was observed. None of the reported AEs was severe, serious or led to discontinuation. No 
AEs were reported as significant.
A different pustular inflammatory epithelial disease is PPP, which does not show the clear 
genetic association to the IL36 signalling pathway as GPP. A small pilot study of spesolimab 
in 59 patients with this disease (1368.15) has failed the primary endpoint (REF latest version 
of IB or Data on File). However. a subgroup analysis has shown a strong dose dependent 
effect on pustule severity, the primary and most burdensome lesion of this disease. In this PPP 
trial 1368.15, spesolimab was well tolerated and no safety signal was identified in trial 1368.15 ( 
see more detailed information in IB) These data indicate that 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 (c03320877-08).
A PoCC-Phase IIa trial in 51 patients with AtD (1368.32) has also failed the primary 
endpoint. However, results suggest a meaningful treatment effect after 8 weeks of treatment 
with Spesolimab compared to placebo (c03320877-08). Spesolimab was well tolerated, and 
no safety signal was identified in trial 1368.32.     
BI has decided to discontinue the development of spesolimab in UC. The decision is based on
available results of the phase II clinical trials (1368-0004, 1368-0005, 1368-0010, and 1368-
0017) conducted in patients with UC which show a lower than expected efficacy on clinical
endpoints. The decision is not related to or triggered by any safety findings. Data from
ongoing and completed clinical trials in UC and other conditions show a good safety and
tolerability profile of spesolimab with no evidence of any new safety risks. The anticipated 
benefit and the safety data obtained thus far support the continuation of the
spesolimab clinical development programme in all other indications under study.
No other IL-36 receptor antagonist is currently approved or in advanced phases of clinical 
development. Thus, there is no information available on identified risks for other molecules 
of this class. 
Based on the strong rationale (section 1.3), there is a reasonable chance that spesolimab may 
promote healing in fistulising CD. Moreover only patients deriving an individual health 
benefit from spesolimab in the parent study (e.g. by achieving a fistula response or remission 
or other clinical improvement), will be offered to roll-over into this study and directly receive 
open label active spesolimab maintenance treatment (300mg s.c. q4w) for up to 7 years. 
Patients experiencing a fistula relapse in this long-term study will be offered to receive high 
dose treatment (1200mg IV single dose) followed by an intensified spesolimab maintenance 
treatment (600mg s.c. q4W). Patients who present a luminal inflammatory flare without 
fistula relapse might receive antiinflammatory therapy as per SOC to treat luminal flare based 
on clinician judgement while continuing the same spesolimab maintenance dose (300 or 600 
mg s.c. q4w).


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Patients who present a fistula relapse with negative spesolimab drug level (with or without 
ADA) or who experience fistula relapse more than twice within a 12 month time period will 
be discontinued and switched to available SOC at the investigator`s discretion. This will 
allow patients to receive an initial high dose spesolimab re-treatment, whilst limiting the 
duration of spesolimab exposure in patients no longer benefitting from treatment.
Therefore, based on the eligibility criteria and the safety profile as currently known (see 
section 1.2), all patients participating in this trial are expected to receive clinical benefit with 
acceptable risks. Participation in this study may thus help to maintain individual benefit ant to 
generate future benefit for larger groups of patients with CD if spesolimab proves to be 
successful in treating this disease. 
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
Table 1.4:1 Further IMP or trial related risks and mitigation measures
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
Reactions to i.v. administered 
biologic agents represent the 
manifestations of systemic 
hypersensitivity reactions and 
include anaphylaxis, pruritus, 
hypotension and respiratory 
distress. 
Definition of Systemic 
hypersensitivity including 
infusion reaction and anaphylactic 
reaction as adverse events of 
special interest (AESI)
Selection of sites experienced in 
treatment of IBD patients with 
biologics
Implementation of a fully 
independent data-monitoring 
committee (DMC)
Close monitoring of patient after 
infusion at the site according 
Instructions for preparation and 
Handling of spesolimab.
The short-term use of parenteral 
systemic steroids is allowed in this 
study.
Systemic hypersensitivity 
reactions are readily detectable, 
transient in nature, and usually 
manageable with standard medical 
treatment.


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Table 1.4:1 (cont) Further IMP or trial related risks and mitigation measures
Hypothetical risks of clinical 
relevance for this trial
Summary of data, rationale for 
the risk
Mitigation strategy
Infections
Inhibition of the immune response 
with an immune-modulating 
biologic may increase the risk of 
infections.
A recent characterization of 
individuals with homozygous IL-
36R KO mutations revealed that 
normal immune function was 
broadly preserved suggesting that 
IL36 signaling pathway inhibition 
does not compromise host 
defences (R17-3632).
Screening procedures for 
infections will be established for 
this trial. Patients with any 
relevant chronic or acute 
infections including human 
immunodeficiency virus (HIV), 
viral hepatitis or tuberculosis are 
excluded from the trial. Treatment 
of infections should be initiated 
promptly according to standards 
of care.
Severe infections and 
opportunistic infections are 
considered AESIs for this trial. 
These conditions and serious 
infections are subject to close 
monitoring.
Malignancies
Inhibition of the immune response 
with a immune-modulating 
biologic may increase the risk of a 
decreased immune defense against 
malignancies.
A recent characterization of 
individuals with homozygous IL-
36R KO mutations revealed that 
normal immune function was 
broadly preserved suggesting that 
IL36 signaling pathway inhibition 
does not compromise host 
defences (R17-3632).
In case of occurrence of malignant 
neoplasm other than appropriately 
treated basal cell carcinoma or 
squamous cell carcinoma of the 
skin or in situ carcinoma of 
uterine cervix, the investigator 
should discontinue treatment with 
spesolimab.
Diagnostics and treatment have to 
be initiated according to local 
standard of care.
Malignancies represent always 
serious adverse events and are
subject to close monitoring
Trial procedures
Local hematoma, bruising, skin 
erythema.  
Risk associated with 
infusion/subcutaneous injection
Use of experienced sites
Diarrhea, abdominal pain, 
perforation, bleeding effects of 
anaesthetic medications, infection
Risks associated with 
Colonoscopy and biopsy
Selection of sites experienced in 
taking care of IBD patients


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1.4.1
Discussion
Patients entering this trial will already have received a benefit from treatment with
spesolimab in a preceeding trial. This, in adition to the medical need for effective and well 
tolerated drug specifically and directly treating the structural aspects of CD makes it 
conceivable to anticipate that the benefits of receiving further treatment will outweigh the 
risks in these patients. Moreover, since there are no mechanism- or compound-related safety 
alarm signals from all above mentioned data from spesolimab, it is highly likely that eligible 
patients for the study, CD patients with perianal fistulising disease, will not be exposed to 
undue risks and adverse events. 
The benefit-risk profile is thus considered appropriate for an experimental therapy at this 
stage of clinical development.
Benefit-Risk Assessment in context of COVID-19 pandemic.
BI 655130 is an immune-modulating humanized monoclonal antibody that blocks the human
IL-36 receptor and thereby the pro-inflammatory IL-36 pathway. Available non-clinical and
clinical data have not shown an increased risk of infections with BI 655130. However, similar 
to other immune modulating biological treatments, BI 655130 may hypothetically increase 
the risk of infections. Risk mitigation measures, such as exclusion of patients with increased 
risk of infections, close monitoring of adverse events, as well as guidance on treatment and 
handling of acute infections occurring during the trial are described in the clinical trial 
protocol. As any other acute infection, a suspected or diagnosed COVID-19 infection should 
be treated according to the standard of care and interruption of study medication should be 
considered.
Currently, information about the immune response in patients with COVID-19 is sparse and
inconclusive. There are some reports suggesting high-levels of pro-inflammatory cytokines in
the severe cases, with much of the morbidity associated with coronavirus infection,
potentially related to immune activation and inflammation. To date, there is no reliable
evidence suggesting a link between SARS-CoV-2 infections and the IL-36 pathway targeted
by BI 655130. Considering the current knowledge of COVID-19 and the implemented risk
mitigation measures addressing the potential risk of infections, patients studied in trials with
BI 655130 are not believed to be at higher risk of COVID-19 due to their background or
concomitant diseases. Protocol-defined procedures do not impose undue risk to study
participants. The benefit-risk assessment of BI 655130 remains favourable in the context of 
the COVID-
19 pandemic.
To address potential risks associated with operational aspects related to the participation in 
clinical trials in context of COVID-19 pandemic, different risk mitigation measures are 
considered in ongoing and planned BI 655130 clinical trials based on local requirements and 
development of pandemic.


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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.


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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
perianal fistula 
remission
closure of all external openings, no drainage / discharge despite gentle finger 
compression, that were open and draining at baseline (BL)  of parent trial and closure of 
all external openings that were newly emerged during the parent trial or this trial
perianal fistula 
response
closure and no drainage /discharge despite gentle finger compression of at least 50% in 
number of external openings regardless of the onset time, compared with the number of 
open and drainage fistulas at baseline of parent trial 
2.1.1
Main objectives
1. To evaluate the long-term safety of spesolimab in patients with perianal fistulising 
Crohn’s disease who have completed treatment in parent trials 
2. To evaluate the long-term efficacy of spesolimab in patients with perianal fistulising 
Crohn’s disease, who have completed treatment in parent trials 


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2.1.2
Primary endpoint(s)
Exposure adjusted rate of patients reporting a treatment emergent adverse event (TEAE) up 
to week 336 of maintenance treatment
2.1.3
Secondary endpoint(s)
∀
Proportion of patients with perianal fistula remission at weeks 48, 96, 144, 192, 240, 288,
and 336
∀
Proportion of patients with perianal fistula response at weeks 48, 96, 144, 192, 240, 288,
and 336
Further details on the planned analyses are given in Section 7.3.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This open label (OL), single group, long-term extension study of approximately 7 year
duration, investigates the long term safety and efficacy of spesolimab in patients with 
perianal fistulas due to Crohn’s disease who have completed treatment in a parent
spesolimab trial. It is expected that a maximum of 20 patients will roll-over from study 
1368-0008. Patients from other trials of spesolimab who meet the eligibility criteria may 
also be included in this trial in future and this will increase the number of participants. 
Patients rolling over will be monitored for induction outcome at the EOT visit of the original 
trial and perform V1 of 1368-0007 at the same time, and initiate treatment upon availability 
of the MRI and endoscopy results.
Maintenance Treatment
Patients rolling-over into 1368-0007 trial must complete the treatment period in the preceding
trial with an individual benefit (as per investigator`s judgement).
The maintenance treatment in this study will be open-label and will evaluate one dose 
regimen (300mg s.c. q4w) of spesolimab. The trial will consist of a screening period lasting 
for a maximum of 14 days, followed by a 336 week maintenance treatment period and a 16 
week safety follow-up period.
Proctoscopy or rectoscopy, as per routine clinical practice will be performed for all patients at 
EOT visit of the parent study and once every 48 weeks in this study to evaluate mucosal 
healing and to provide mucosal biopsy specimens for molecular pharmacodynamic 
assessments. Patients participating in the study will consent to undergo an ileocolonoscopy in 
case of a suspected flare. Full iIleocolonoscopy/ colonoscopy or sigmoidoscopy instead of 
proctoscopy or rectoscopy could be performed if clinically indicated as per investigator 
judgement.
A schematic overview of trial design is shown in Figures 3.1:1 and 3.1:2.
Figure 3.1:1 Trial design


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Fistula relapse or luminal inflammatory flare treatment:
During this 7-year study, patients may experience worsening of their Crohn`s disease either 
by experiencing a fistula relapse or a luminal inflammatory flare.
Fistula relapse is suspected if ≥1 external fistula orifice re-emerges, which was open at 
baseline or newly emerged during the preceding trial but was closed at completion of the 
parent study or at any time during the current trial; or which emerged newly. Fistula relapse 
is confirmed in a second independent visit (Flowchart 2B). 
A patient with a confirmed fistula relapse will receive a single i.v. infusion of 1200mg 
spesolimab. At week 4 after the single i.v. infusion dose, patients will continue with an 
intensified subcutaneous spesolimab maintenance dosing of 600mg q4W, as seen in Figure 
3.1:2. An additional visit has to be planned at week 12 after the single i.v. infusion to check 
the patient`s response status. For patients with fistula relapse, this week 12 assessment will 
include clinical assessment, 
 and MRI, which will guide investigator judgment of 
patient response status. 
Luminal inflammatory flare, is defined as an increase in PRO-2 score [sum of 7-day weighted 
stool frequency (SF)  and  abdominal pain (AP) , components of the 
, using the original 
 multiplying factors of 2 for SF and 5 for AP] by >50 points from baseline of the 
current trial, plus an increase in 
 score by ≥100 points from baseline of the current trial 
with an absolute 
>220 in a second independent confirmation visit, with an absolute 
, in absence of enteric pathogens in stool. In case of a suspected inflammatory 
flare, the site will ask the patient to immediately start entering his 
 symptom score data 
into the eDiary until the next scheduled or unscheduled visit at which a flare confirmation 
assessment will be performed, and then to continue entering the data as planned (i.e. for 10 
days before each visit). 
A patient with a luminal inflammatory flare (endoscopically confirmed) without fistula 
relapse might be treated as per SOC based on clinician judgement while continuing the same 
spesolimab maintenance dose according flow chart 2A After 12 weeks of flare confirmation 
(visit F3) a new rectoscopy/proctoscopy and 
 assessment will be performed to assess
luminal flare response to SOC as per investigator judgement. For details of trial procedures, 
please follow the Flow chart 2A. 


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Figure 3.1:2 Trial design in case of fistula relapse
Figure 3.1:3 Trial design in case of luminal inflammatory flare
Patients who are no longer deriving a clinical benefit will be required to discontinue 
treatment. See Section 3.3.4.1 for details
Several interim analyses of PK, biomarker, and clinical data will be performed throughout the 
conduct phase of this study to support future trial applications, investigator brochures, 
regulatory documents, and scientific publications. The final analysis of the entire trial data 
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.
An independent Data Monitoring Committee is established to evaluate safety data of all 
ongoing spesolimab studies periodically, and to provide feedback on whether or not to 
continue the study with or without modifications.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Patients who complete treatment with spesolimab or placebo in parent trial and had
individual health benefit from induction treatment will be offered to roll-over into this trial to 
receive long-term treatment with active drug.
This long-term study mainly aims to offer active maintenance treatment to patients who have 
benefited from induction treatment in a trial of spesolimab, and to characterize the safety and 
tolerability of spesolimab long-term treatment. It will also characterize the persistence of 
clinical outcome over a long period of spesolimab treatment and the efficacy of high dose 
rescue treatment for fistula relapses. Although a placebo control would improve this safety 


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and efficacy assessment, it would withhold patients in need from active treatment and is not 
justifiable for longer than the treatment period in the parent 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 spesolimab induction 
treatment are likely to maintain their response on continued treatment with spesolimab, but 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 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 derived an individual health benefit from previous 
induction treatment and who continued into this extension trial will be able to receive an 
active maintenance treatment with spesolimab for their ongoing disease.
3.3
SELECTION OF TRIAL POPULATION
Patients in this long-term open label extension trial will be rolled-over after participating in a 
parent induction trial with spesolimab.
Patients must have tolerated treatment in the parent trial and have completed the treatment 
period. They must be willing to continue long term treatment with 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 Investigator Site File (ISF) irrespective of whether they have been treated 
with the investigational drug or not.
3.3.1
Main diagnosis for trial entry
Patients with fistulising Crohn’s disease who have completed treatment in the parent trial.
Please refer to Section 8.3.1 (Source documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be included into the trial:
1. Patient older than 18 years
2. Has completed all treatments (placebo or active treatment) and the EOT visit in the 
parent induction trial in fistulising CD and is willing and able to continue treatment in 
1368-0007.


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3. Has obtained an individual health benefit, per investigator judgement (such as fistula 
response or remission or other clinical improvement), from treatment in the parent
trial.
4. Signed and dated written informed consent for 1368-0007 in accordance with GCP 
and local legislation prior to admission into the trial.
5. 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. Tubal ligation is NOT a method of permanent sterilisation. A 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
3.3.3
Exclusion criteria
Patients meeting any of these exclusion criteria must not be enrolled into the trial:
1.
Have experienced treatment-limiting adverse events during induction treatment 
with study drug.
2.
Have developed any condition which meets the exclusion criteria from the original 
induction study.
3.
Any condition which in the opinion of the investigator affects the safety or ability 
to participate in this trial.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and
3.3.4.2 below.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Sections 5.2.6.2.1 and 
5.2.6.2.2).
3.3.4.1 Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:


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∀
The patient wants to discontinue trial treatment, without the need to justify the decision.
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of the investigator and/or sponsor representative, is not willing or able 
to adhere to the trial requirements in the future.
∀
A patient treated for a luminal inflammatory flare or fistula relapse meets one of the 
criteria for discontinuation as described below.
∀
The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment. Please refer to Section 4.2.1 and 4.2.2.
∀
The patient needs surgical interventions for CD including any fistula surgical procedures 
(except seton drainage, see Table 4.2.1.2:1)
∀
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).
∀
The patient is required to stop treatment due to a specific adverse events as described in 
Section 4.2.1
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flow Chart and Section 6.2.3.
Treatment discontinuation
Patients with a fistula relapse will be discontinued from treatment if one of the following 
occurs:
-
If patient has no clinical benefit after reinduction as per investigator judgement
-
Fistula relapse with negative drug levels at the confirmation visit (with or without 
positive ADA).
-
Ocurrence of >2 confirmed fistula relapses within a 12 month period.
Patients can discontinue trial treatment at any time they feel they are losing the benefit from 
continuing treatment with the study drug.
Patients who terminate the study drug in 1368-0007 prematurely should complete an early 
EOT visit instead of the next planned visit followed by a safety follow up (EOS) visit 16 
weeks after the last study drug intake. 
3.3.4.2 Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.


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If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation. 
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. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further follow up of patients affected will occur as described in Section 3.3.4.1.
The investigator/trial site will be reimbursed for reasonable expenses incurred in case of trial
termination (except in case of the third reason).


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4.
TREATMENTS
4.1 
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1:1 Spesolimab solution for s.c. injection 
Substance:
Spesolimab, BI 655130
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH¬ Co. KG
Unit strength:
Spesolimab 150mg/pre-filled syringes (150mg/mL)
Moleculal weight
146 kDa
Unit strength
Spesolimab 150mg / syringe or vial (to be switched 
to 300mg when 2mL syringe or vials are available) 
Posology:
300 mg at Week 0 and then every 4 weeks (2 
injections every visit with 1mL syringes/ 1 injection 
when switching to 2ml device)
600 mg every 4 weeks as intensified treatment for 
patients with fistula relapse (4 injections every visit 
with 1mL syringes/ 1 injection when switching to 
2ml device)
Mode of administration:
Subcutaneous injections
Table 4.1.1: 2
Spesolimab i.v. infusion
Substance:
Spesolimab, BI 655130
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Spesolimab 300mg/vial (60mg/mL) 
Posology:
1200 mg single dose in case of fistula relapse
Method and route of administration:
Intravenous infusion


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4.1.2
Selection of doses in the trial and dose modifications
This trial, 1368-0007, aims to offer a maintenance treatment for patients with perianal CD 
who have failed available therapies and whom are considered to have benefited from 
previous induction therapy in the parent trial. 
The spesolimab subcutaneous dose regimen chosen for 1368-0007 has thus been selected 
with the objective of achieving maintenance of induction therapy effect with the safest profile 
based on available data from Phase I and Phase II studies in HV and patients with PPP and 
UC, respectively.  
Bioavailability of the s.c. relative to the i.v. formulation of spesolimab is approx. 50%-70 % 
(cf. section 6.2 of IB c03320877-08). A subcutaneous dose of 300mg would therefore 
correspond to ~210 mg as an i.v. dose and thus represents the lowest dose of 3 mg/kg which 
was found to be fully active in the indirect target engagement assays in studies 1368-0001 
and 1368-0002.
The dosing interval of every 4 weeks (q4w) was selected based on the half-life of 
approximately 4-5 weeks in healthy volunteers and PPP patients, as determined in the PoCC 
trial 1368-0015 and phase I studies 1368-0001 and 1368-0002, respectively. Thus, after one 
half life (~4 weeks) patients` exposure would drop below the threshold required to maintain 
maximal target engagement. 
In patients experiencing a fistula relapse, a single 1200mg i.v. high treatment dose will be 
administered, followed by a maintenance dose of 600mg q4w, as defined in Section 3.1 to 
double the exposure compared to the original failing maintenance regimen. 
The loading i.v. dose of 1200mg is expected to be at the plateau of the dose/response curve 
and to provide maximal efficacy based on data indicating high and sustained target 
engagement at doses ≥3mg/kg and a half-life as long as 4-5 weeks in healthy volunteers and 
PPP patients respectively (cf. sections 6.1 and 6.2 of the IB c03320877-08). This dosing 
regimen will achieve exposures below the highest dose regimen that was found safe in phase 
I studies. It therefore is also being tested in ongoing studies in IBD trials. These doses may be 
adapted later (via protocol amendment) based on emerging data from other trials with 
spesolimab.
4.1.3
Method of assigning patients to treatment groups
Not applicable, as all patients in this trial will receive the same treatment.
4.1.4
Drug assignment and administration of doses for each patient
During visit M1, eligibility criteria will be assessed and eligible patients will be allocated to 
receive open-label active treatment. The assignment of treatment will be done via Interactive 
Response Technology (IRT). The appropriate medication number will be assigned and 
documented in the CRF.


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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 must 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. Study 
personnel should observe the injection site for signs of redness, swelling or hardness. They 
should also ask patients 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. 
A single dose of 1200 mg spesolimab i.v. will be used as fistula relapse treatment. 
Intravenous infusion including observational time for possible infusion reactions will last 
approximately 2.5 hours.
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.
During the COVID-19 pandemic, physical visits to the sites may need to be restricted to 
ensure patient safety. Based on a thorough assessment of the benefits and risks, the 
investigator may discuss with BI to continue the trial treatment and trial medication may be 
shipped to the patient’s home if acceptable according to local law and regulations.
In case of safety concerns, e.g. due to infusion reactions, it is in the discretion of the 
investigator or his/her designee to adapt the infusion scheme (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 fistula relapse
treatment  from the first s.c. drug administration after the last fistula relapse. 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
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. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal 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 Clinical Research 
Associate (CRA), as provided in the list of contacts, must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB / ethics committee
∀
Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site
∀
Approval/notification of the regulatory authority, e.g. competent authority
∀
Availability of the curriculum vitae of the Principal Investigator
∀
Availability of a signed and dated clinical trial protocol
∀
Availability of the proof of a medical license for the Principal Investigator
∀
Availability of FDA Form 1572 (if applicable)
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 


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sponsor <and/or> appointed CRO, the investigator or designee must verify that all unused or 
partially used 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
4.2.1.1 Allowed concomitant therapies
CD-Related Treatments
Patients in this trial may be on conventional immunosuppressants or anti-TNFα biologic
treatment for CD. These may consist of one or more of the following drugs (cf. Section 
4.2.1.2
for restrictions), which are therefore permitted concomitant medications:
∀
Oral 5-ASA compounds, provided that dose has been stable prior to randomisation in 
parent trial and during current trial, and/or
∀
Oral corticosteroids (≤ 20 mg per day of prednisone or equivalent), provided that dose
has been stable prior to randomisation in parent trial and during current trial, and/or
∀
Oral budesonide (≤ 9 mg per day), provided that dose has been stable in parent trial 
and during current trial, and/or
∀
Azathioprine, 6-MP, 6-TG or methotrexate, provided that dose has been stable in 
parent trial and during current trial,
∀
Approved anti-TNFα (e.g. infliximab, adalimumab, certolizumab pegol; or respective
biosimilars) provided that dose has been stable in parent trial and during current trial
∀
Probiotics (e.g. S. boulardii) provided that dose has been stable for > 4 weeks prior to
randomisation
∀
Regular use of anti-diarrheals
Dose has to be stable before rolling over and throughout the trial. The only exceptions are 
anti-diarrheals, which may be adjusted to current symptoms, and steroid reduction.
Patients who present a luminal flare (but no fistula relapse) might receive standard of care 
treatment for moderate-to-severe CD, while continuing with their spesolimab maintenance 
dose. Thus, on top of the concomitant therapies listed above, patients with luminal flare ( but 
no fistula relapse) are also allowed to receive concomitant approved doses for treatment of 
moderate to severe CD including ( but not limited to) the following therapies: 
∀
anti-TNFα (this might be associated to Azathioprine / 6-MP/ MTX)
∀
Integrin receptor antagonists
∀
IL12/ 23 antagonists 
Steroids


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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 4.2.1.2:1).
If mild-to-moderate infusion or anaphylactic reaction had already occurred in the same 
patient in the parent trial or occurs in this trial, the patient may be pre-treated with steroids as 
secondary prophylaxis before future IMP administrations.
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
Peri-OP antibiotics
Peri-OP antibiotics are allowed if required according to standard of care.
Other treatments
Stable doses of concomitant therapies for chronic conditions, for which neither the condition
nor the treatment are judged to exclude the patient from participation are permissible. All 
concomitant medications should be carefully evaluated by the investigator and the sponsor 
representative should be contacted when there are questions regarding concomitant
medications.
Management of Adverse Events:
“Systemic hypersensitivity including infusion reaction and anaphylactic reaction” 
In case of infusion reactions / systemic hypersensitivity including anaphylactic reaction 
emerging during or after infusion / injection(s) of trial medication, 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, i.v. steroids, and in case of a severe allergic 
reaction (eg, anaphylactic reaction) epinephrine
-
Draw a plasma sample for IgE and ADA as detailed in the Lab Manual (ISF)
-
Consider the evaluation of histamine, serum tryptase, and complement components
In case of infusion reaction /systemic hypersensitivity, based on patient’s clinical course and 
medical judgment, the infusion may be re-initiated / the injection(s) may be continued in case 
of mild or moderate infusion reactions / systemic hypersensitivity (according to RCTC 
grading in ISF) at lower speed with gradual increase to complete the infusion / injections as 
detailed in the Instructions for Preparation and Handling of spesolimab in the Investigator 
Site File. In any case, the total duration of infusion should not exceed 90 minutes (1.5 hours) 
provided that the maximum time between the start of preparation and completion of 
administration of the solution to the patient does not exceed 150 minutes (2.5 hours). 


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In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (R11-4890) suspected to be caused by the trial medication, the investigator 
should permanently discontinue treatment with the spesolimab.
When a non-acute hypersensitivity reaction related to immune complexes (i.e., serum 
sickness) is suspected, a sample for the laboratory assessment for circulating immune 
complexes (referring to Lab manual) will be taken.
Severe infections (according to RCTC grading in the ISF), serious infections, opportunistic or 
mycobacterium tuberculosis infection 
Treatment of the infection should be initiated promptly according to local standard of care. 
No further trial medication should be administered until the active infection has resolved. 
Treatment with spesolimab 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. 
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.
4.2.1.2 Restricted medications
Restrictions regarding previous and concomitant treatment are summarized in the following 


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Table 4.2.1.2:1 Restrictions regarding concomitant treatment
Medication or class of medications
Restriction 
Any biologic or non-biologic drug
approved for CD other than the anti 
TNFα listed in section 4.2.1.1
Not allowed until end of the trial *
  Approved doses for treatment of moderate-to-severe CD are allowed for
rescue medication ONLY in patients who present with luminal
inflammatory flare BUT NO FISTULA RELAPSE.
Any investigational or non-approved 
biologic or non-biologic for CD 
Not allowed until end of the trial
Autologous or allogeneic 
haematopoietic (HSC) or 
mesenchymal stem cell (MSC) 
therapy
Not allowed until end of the trial 
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 4.2.1.1
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 
in this study.
Oral budesonide (≤9 mg per day), provided that dose has been stable prior 
to treatment initiation in this study.
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 CD. 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.
NSAID
Chronic use not allowed from screening to end of the trial
(Note: occasional use of NSAIDs and acetaminophen for headache, 
arthritis, myalgias, menstrual cramps, etc., and daily use of baby or low 
dose (81-162.5mg) aspirin for cardiovascular prophylaxis are permitted.)
Probiotics 
Only allowed during the trial provided that dose has been stable prior to 
treatment initiation and up to end of the trial
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)


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4.2.1.3 Restricted fistula interventions
Surgical interventions for CD are not allowed during the trial. 
Any surgical intervention or procedure for perianal and enterocutaneous fistulas (except seton 
drainage) are also not allowed (patient shall be discontinued) since they would interfere with 
the clinical endpoints of the trial. Some examples are summarized in table 4.2.1.3:1 (not an 
exhaustive list).
Table 4.2.1.3:1 Examples of restricted procedures for perianal and enterocutaneous fistulas
Procedure for perianal and 
enterocutaneous fistulas
Restriction 
-
Cutting of fistulas
-
Shortening of fistulas
-
Splitting of fistulas
-
Fibrin glue
Not allowed from start of until end of the trial 
4.2.2
Other restrictions
4.2.2.1
Restrictions on diet and life style
No restrictions on diet or lifestyle of the patients are required.
4.2.2.2
Contraception requirements
Women of childbearing potential 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 during the trial, and for a period of at least 16 weeks after the last study drug 
administration. A double barrier method of contraception is not required. A list of 
contraception methods meeting these criteria is provided in the patient information.
Female Patients
Acceptable methods of birth control for this trial are: 
∀
Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal) 
∀
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable) 
∀
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
∀
Bilateral tubal occlusion 
∀
Vasectomised sexual partner with documented absence of sperm 
Or
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 


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symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
Male Patients: 
Contraception of male trial participants and female partners of male trial participants are not 
required.
4.3
TREATMENT COMPLIANCE
Study medication will be administered in accordance with the protocol under supervision of 
the investigating physician or a designee at the site.
Any missed dose has to be documented and reported to the CTM.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
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 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.
The results must be included in the source documents available at the site. 


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5.2.2
Vital signs
Vital signs evaluations will be performed at visits as shown in the Flow Chart. This includes 
body temperature, pulse rate, systolic/diastolic blood pressure and respiratory rate. 
Respiratory rate, pulse rate, and blood pressure will be measured after patients have been 
sitting comfortably for at least five minutes. Measurement of vital signs should precede blood 
sampling to avoid the impact of blood sampling on the vital sign measurements. At dosing 
visits, vital sign evaluations will be performed pre-dose for both visits with i.v. and s.c. 
administration of study drug. At s.c. dosing visits, vital signs will be assessed at 
approximately 10 minutes after study drug administration. Also, at visit M1 and visit M2 (s.c. 
dosing visits) additional vital signs assessments will be performed approximately 60 minutes 
post-dose (i.e. 60 min. after last injection). At visits with i.v. dose administration, vital sign 
evaluations will be performed pre-dose and additional evaluations will be taken at 5 and 60 
minutes post-dose
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 do not have to be fasted for the blood sampling for the safety laboratory. 
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 (see Section 5.2.6).
The central laboratory will transfer the results of the analysis to the sponsor.
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 (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 Laboratory tests
Category
Test name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)
Glycosylated Hbc (HbA1c) (required to be tested at screening and 
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


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Table 5.2.3: 1 (cont) Laboratory tests
Category
Test name
Substrates
Glucose
BUN (blood urea nitrogen)
Uric acid
Creatinine
eGFR (estimated by CKD-EPI formula) (only at 
screening)
Bilirubin Total
Bilirubin Direct (if total is elevated)
Bilirubin Indirect (if total is elevated)
Troponin (Reflex, in case of elevated CK) 
Protein, Total
Albumin
C-Reactive Protein (CRP) 
Cholesterol, total
Triglycerides
LDL-Cholesterol
HDL-Cholesterol
Specific gamma-globulin quantification
IgE1, IgG
Infections testing
Hepatitis C Antibodies (qualitative)4
HIV-1, and HIV-2 Antibody (qualitative)4
Hepatitis B Surface Antigen (qualitative)5
Hepatitis B core Antibody5
AntibodyHBV-DNA (quantitative PCR)2,5
TB screening
QuantiFERON®-TB3,6
Urine Pregnancy test (only female patients of 
childbearing potential)
Human Chorionic Gonadotropin in urine
Serum Pregnancy test (only female patients of 
childbearing potential if urine pregnancy test is 
positive) 
Human Serum Chorionic Gonadotropin 
Hormones (required to be tested at screening and 
every  48 weeks)
TSH (free T3 and free T4 in case of abnormal TSH 
result) 
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leukocytes
Urine pH
Urine-Sediment (microscopic examination, only if 
urine analysis abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells
Urine Sed. Crys., Unspecified
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
Urine (only at screening)
Albumin (quantitative)
Faecal sample 
Calprotectin


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1Only in case of allergic reaction
2 A HBV-DNA should be conducted if Hepatitis B core Antibody is positive and Hepatitis B surface Antigen is negative. 
3If the 1st QuantiFERON®-TB test result is undetermined, a re-test should be performed. If the re-test QuantiFERON-TB 
test result is undetermined, a PPD skin test should be performed.
4HCV and HIV at screening only. 
5HBV at screening and EOT. 
6In patients with a previously (i.e. in ongoing extension trial) negative QuantiFERON®-TB test, the test should be repeated 
every 48 weeks, as long as the results are negative.
Table 5.2.3: 2 Additional testing
Category
Test name
Stool studies to evaluate for enteric pathogens 
(Faecal assessment for enteric pathogens has to be 
done V 1 and at suspicion of an disease flare to 
exclude enteric infection)
Salmonella
Shigella
Yersinia
Campylobacter
E. coli 
Clostridia difficile toxin
Enteric parasites and their ova (including 
Cryptosporidia)
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the flowchart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported as adverse events and will be followed 
up and/or treated as medically appropriate.
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.
Local tolerability at the administration site of spesolimab will be assessed by the investigator 
during the study drug administration visit and at the time of AE assessment by questioning 
retrospectively since the last visit. 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.  


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5.2.6
Assessment of adverse events
5.2.6.1 Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀Worsening of the underlying disease or of other pre-existing conditions 
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only. However, if these abnormalities are 
AEs of the parent trial and still ongoing after first dose in extension trial, they should not be 
recorded as baseline conditions. In such situations section 5.2.6.2 should be followed.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death;
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe;
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity;
-
is a congenital anomaly / birth defect;
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 


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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 in Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6 subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs (see Section 
5.2.6.2.2).
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
∀
an 
elevation 
of 
AST 
(Aspartate 
Aminotransferase) 
and/or 
ALT
(Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, and/or
∀
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal 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.
Systemic hypersensitivity including infusion reaction and anaphylactic reaction
Any suspicion of severe infusion reaction systemic / hypersensitivity reaction and of any 
potential cases of anaphylaxis should be defined and assessed using the criteria in Appendix 
10.8 (R11-4890). All confirmed and suspected cases of systemic hypersensitivity, including 
infusion reaction and anaphylactic reaction, will be reported as AESIs. 
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.  


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In case of an infusion reaction monitor the patient per standard of care, grade the intensity of 
the reaction according to RCTC grading (see ISF) and proceed as described in Section 4.2.1 
Also draw plasma sample for IgE and ADA (anti-drug antibodies), as detailed in the CTP 
section 5.2.3 and the lab manual. 
Severe infections (according to RCTC grading in ISF)
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, 
strongyloides 
(hyperinfection 
syndrome 
and 
disseminated 
forms 
only), 
paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only),  shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression (R17-2617)
5.2.6.1.5
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, and
available in ISF) (R13-3515). Intensity options are:
Grade 1 
mild
Grade 2 
moderate
Grade 3 
severe
Grade 4 
life-threatening
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug.


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∀
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 reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the 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
5.2.6.2.1
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 (special notes on SAE form reporting where needed):
∀
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.
∀
All AEs that started in the parent trial (onset date in parent trial) and are still ongoing 
after 1st IMP administration in the extension trial:
-
Re-record the AE in the extension trial eCRF with the same information as it was 
recorded in the parent trial. 
-
Should the AE end during the course of the extension trial,
 update both - the extension trial eCRF and the parent trial eCRF. If the parent 
trial is already locked, update only the extension trial eCRF. In this case the 


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update for the parent trial will be handled outside of the eCRF of the parent 
trial.
-
However, concerning reporting on the SAE form (if applicable), the follow-up 
report will still be sent on the parent trial SAE form, no new SAE form is to be 
completed for the extension trial.
-
If the intensity of an ongoing AE changes after 1st IMP administration in the 
extension trial:
 update both - the extension trial eCRF and the parent trial eCRF- with the end 
date for the initial/previous intensity. If the parent trial is already locked, 
update only the extension trial eCRF. In this case the update for the parent trial 
will be handled outside of the eCRF of the parent trial. 
 The AE with the new intensity will be handled as new event; this means it is 
only recorded in the extension trial eCRF.
 Example: If the intensity increased then the new AE name/term 
should contain “Worsening of…” or “Exacerbation of…”
Considerations for reporting on the SAE form, when intensity change qualifies 
as worsening/exacerbation of an event that had already been reported on the 
SAE form:
- corresponding follow up report to be sent on the parent trial SAE form with 
date of worsening as event end date. 
- extension trial SAE form to be sent as initial report for the extension trial for 
new event “Worsening/Exacerbation of….” with date of worsening as onset 
date.
Considerations for reporting on the SAE form, when intensity change qualifies 
as worsening/exacerbation of an event and requires for the first time reporting 
on the SAE form (meeting for the first time seriousness/AESI criteria):
- only extension trial SAE form to be sent - as initial report for the extension 
trial for new event “worsening/exacerbation of….” with date of worsening as 
onset date.
∀
All AEs with an end date before the 1st IMP administration in the extension trial, even if 
Informed Consent of the extension trial was already signed:
-
Record only in the eCRF of the parent trial. 
-
In case of an AE reportable on the SAE form, send the update only on the SAE 
form of the parent trial. 
-
Do not re-record in the extension trial eCRF, do not complete a new SAE form for 
the extension trial.
∀
After the EoS visit in the extension trial:
The investigator does not need to actively monitor the patient for new AEs but should 


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only report any occurrence of cancer (cancer of new histology, exacerbations of existing 
cancer, if applicable) 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 Section 5.2.6.2.2) for the 
extension trial, but not on the CRF (neither on CRF for extension nor for partent trial).
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All 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.
For further details specific to the AE reporting of this extension trial see Section 5.2.6.2.1.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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5.6
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements in CD 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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For more details regarding procedures at V1 please refer to Flow Chart 1 or Flow Chart 2.
Baseline Conditions
These are ongoing conditions with onset date prior trial inclusion. However, if these 
conditions are AEs of the parent trial and still ongoing after first dose in extension trial, they 
should not be recorded as baseline conditions. In such situations section 5.2.6.2 should be 
followed.
Patients who have a laboratory test value outside the range specified by the elegibility 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 CD. Note: In some countries, race may 
not be collected.
Medical and Surgical History
Information on clinically significant previous and concomitant diseases, other than CD, 
should be registered in baseline conditions as follow up from the parent induction studies.
Blood sampling
Blood samples will be drawn for safety lab, infection screening, 
. Safety 
labs will be done at local lab only at this visit.There will be specific Central lab kits for 
parameters not checked at EOT of parent trial, as infection screening, HbA1C, THS, urine 
protein.
From this visit, all labs will be done through the Central Lab Details will be 
provided in the laboratory manual and the ISF.


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Pregnancy testing
For women of childbearing potential, a urine pregnancy test will be performed. 
Infection screening
Infection testing will include tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see 
Table 5.2.3:1).
Quantiferon TB testing 
Patients with suspected false positive or indeterminate QuantiFERON TB result may have the 
test repeated once. If after repeat testing the QuantiFERON TB result is “indeterminate” a 
PPD skin test may be performed locally. A tuberculin skin test reaction >10mm (> 5mm if 
receiving >15mg/d prednisone or its equivalent) is considered positive. 
Patients who now test positive for QuantiFERON TB test may continue and receive treatment 
in this study if further work up (according to local practice/guidelines) establishes 
conclusively that the patient has no evidence of active tuberculosis. 
If presence of latent tuberculosis is established, patients can receive anti-tuberculosis 
treatment (according to local practice/guidelines) and continue receiving study medication. 
6.2.2
Treatment period(s)
The treatment period is lasting from Visit M1 until End of Treatment (EOT) Visit.
Study related procedures during treatment period will be performed as specified in the Flow 
chart 1 and Flowcharts 2, in case patients develop an inflammatory flare or fistula relapse. 
Pregnancy testing
Urine pregnancy testing for all women of child-bearing potential will be conducted on-site 
every 4 weeks at visits with study drug administration and must be negative to continue 


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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, 
) should be done, if applicable, prior to study drug 
administration and prior to rectoscopy/proctoscopy. It is not required 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 8 hours prior to blood sampling.
Endoscopy (Proctoscopy/rectoscopy/sigmoidoscopy/ colonoscopy or full ileocolonoscopy). It 
will be performed once per year during treatment period. Additionally, ileocolonoscopies 
have to be done in case of disease flare as indicated in Flowchart 2. 
Ileocolonoscopy can be performed instead of proctoscopy or rectoscopy if required per local 
guidelines (i.e. colon cancer screening or others)  or routine clinical practice. 
Stool sampling
A stool sample will be collected for faecal biomarkers.
Clinical monitoring after 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 and 


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also 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.
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 CD at the discretion of the investigator, 
according to local CD guidelines.


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE
This trial is designed as a single arm, open-label trial in patients with fistulising Crohn’s 
disease who have completed the planned treatment period in the parent induction trial. 
There is no confirmatory statistical testing planned during the analysis of this extension trial,
only descriptive analyses are intended.
7.1
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.
7.2
PLANNED ANALYSES
7.2.1
General considerations
There will be only one patient population in this trial for analyses – the Treated Set (TS). The 
TS includes all patients who received at least one dose of study drug. It will be the main 
analysis set for presentation of both safety and efficacy. 
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.
7.2.2
Primary endpoint analyses
Refer to Section 2.1.2 for the description of the primary endpoint. The primary analyses will 
be descriptive in nature. All treated patients will be included in the primary analyses. No
hypothesis testing is planned.
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 of this trial and end of the residual effect period 


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(REP), a period of 16 weeks after the last dose of trial medication, will be assigned to the on-
treatment period for evaluation.
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’. For all patients who, due to a fistula relapse received the 
intensified treatment with 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 spesolimab are displayed.
Exposure-adjusted adverse event incidence rates will be calculated using the following 
approach:
The incidence rate (per 100 patient years) of a selected adverse event (also known as the 
incidence density rate or person-time incidence rate) is defined as the number of patients
experiencing the adverse event during the time at risk divided by the total time of patients at 
risk to contribute an event to the analysis multiplied by 100, where:
Time at risk (in subject years) = ((date of onset of AE – study drug start date) + 1) / 
365.25
The study drug start date refers to the start date of this trial. If, for a patient, no treatment 
emergent adverse event occurred, then the time at risk will be censored at the minimum of: 
date of death; drug stop date + 112 days; start date of CD inflammatory flare or fistula relapse 
treatment with spesolimab; last contact date; or, date of database snapshot if an interim 
analysis was performed.
For each AE, the incidence rate will therefore be calculated as:
Incidence rate = 100 * number of patients with TEAE / Total TEAE-specific time at 
risk.
Exact 95% confidence intervals around the observed AE incidence rate will also be provided.
7.2.3
Secondary endpoint analyses
Refer to Section 2.1.3 and Table 2.1:1 for a description of the secondary endpoints. All 
secondary endpoints will be assessed descriptively. Details will be provided in the TSAP.


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7.2.5
Safety analyses
Refer to Section 7.2.2 for a description of the analyses of the primary endpoint, which for the 
present trial is a safety endpoint.
For the additional safety analyses described below, all treated patients will be included. In 
general, these additional 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 in this trial and the
end of the REP. Refer to Section 7.2.2 for the complete description of a treatment-emergent 
adverse event.
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 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.
7.2.7
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 safety data as well as selected 
efficacy data at regular intervals following first-patient-in. A DMC SAP which describes the 
analyses required for assessment by the DMC will be produced and finalized prior to the first 
patient included into the trial. Further details will be provided in a DMC charter.


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As the primary aim of this study is to collect long-term safety and efficacy data on the use of
spesolimab in this population, multiple interim analyses will be done over the duration 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.
Since patients will be enrolled into this study over a time period of several years and in line 
with the exploratory nature and open label design of the study, such analyses will be
performed on demand and are not feasible to be pre-defined.
A CTR describing all data collected within this trial will be produced after the last patient in 
the trial has completed the final follow-up visit.
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will 
still occur and approaches to handle this are proposed below.
For the safety data, including the primary endpoint, no missing data imputations are planned.
For the efficacy outcomes derived from 
, no missing data 
imputations are planned to be performed.
If a patient experiences an inflammatory flare or fistula relapse 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 of all data 
observed, including data gathered following rescue medication intake, will also be provided. 
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.
7.4
RANDOMISATION
Given the single arm nature of this trial, no randomisation will be performed.
7.5
DETERMINATION OF SAMPLE SIZE
Given the descriptive nature of this trial, no sample size calculation has been performed.
Up to 20 patients who meet the entry criteria are planned for inclusion into this trial, rolling 
over from the parent trial. The parent trial’s study cohort has a size of 20.


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8.
INFORMED 
CONSENT, 
TRIAL
RECORDS, 
DATA 
PROTECTION, 
PUBLICATION 
POLICY, 
AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014 the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997) and other relevant regulations. Investigators and 
site staff must adhere to these principles. Deviation from the protocol, the principles of ICH 
GCP or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 


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investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
section 4.1.8
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Copies of source documents will be provided to the Sponsor. Before sending or uploading 
those copies, the investigator must ensure that all patient identifiers (e.g. patient’s name, 


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initials, address, phone number, social security number) have properly been removed or 
redacted from any copy of the patients’ source documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
∀
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The 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.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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


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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 spes olimab 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 ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), 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 


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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, and an IRT vendor will be used in this 
trial. Details will be provided in the IRT Manual and Central Laboratory Manual, available in 
the ISF.


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9.
REFERENCES
9.1
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Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and 
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Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, et.al.
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Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in 
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E, Baker KA, Levesque BG.A systematic review of measurement of 
endoscopic disease activity and mucosal healing in Crohn's disease: 
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et al. Four-year maintenance treatment with adalimumab in patients with 
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Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen 
P, et al Opportunistic infections and biologic therapies in immune-mediated 
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2107 - 2116 (2015)
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An analysis of IL-36 signature genes and individuals with IL1RL2 
knockout mutations validates IL-36 as a psoriasis therapeutic target.
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Khanna R, Zou G, Stitt L, Feagan BG, Sandborn WJ, Rutgeerts P, et al. 
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Irvine EJ, McMaster IBD Study Group.Usual therapy improves perianal 
Crohn's disease as measured by a new disease activity index. J Clin 
Gastroenterol 20 (1), 27 - 32 (1995)
R17-4073 
Samaan MA, Puylaert CAJ, Levesque BG, Zou GY, Stitt L, Taylor SA, et 
al.The development of a magnetic resonance imaging index for fistulising 
Crohn's disease. Aliment Pharmacol Ther 46, 516 - 528 (2017)
R17-4076
Losco A, Vigano C, Conte D, Cesana BM, Basilisco G.Assessing the 
activity of perianal Crohn's disease: comparison of clinical indices and 
computer-assisted anal ultrasound.Inflamm Bowel Dis 15 (5), 742 - 749 
(2009)
R18-2555
Panes J, Garcia-Olmo D, Assche G van, Colombel JF, Reinisch W, 
Baumgart DC, et al, ADMIRE CD Study Group Collaborators.Long-term 
efficacy and safety of stem cell therapy (Cx601) for complex perianal 
fistulas in patients with Crohn's disease.Gastroenterology. 2018. 154 (5): 
1334 - 1342 
P19-05294
Rieder F, Fiocchi C, Rogler G. Mechanisms, management, and treatment of 
fibrosis in patients with inflammatory bowel diseases. Gastroenterology 
2017. 152: 340-350 e6
R19-2044
Loly C, Belaiche J, Louis E. Predictors of severe Crohn's disease. Scand J 
Gastroenterol. 2008. 43: 948-954


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R19-2045 
De Groof EJ, Sahami S, Lucas C, et al. Treatment of perianal fistula in 
Crohn’s disease: a systematic review and meta-analysis comparing seton 
drainage and anti-tumour necrosis factor treatment. Colorectal Dis. 2016.
18: 667-675
R19-2046 
Beaugerie L, Sokol H. Clinical, serological and genetic predictors of 
inflammatory bowel disease course. World J Gastroenterol. 2012. 18: 3806-
3813
R19-2047 
Gordon IO, Agrawal N, Willis E, et al. Fibrosis in ulcerative colitis is 
directly linked to severity and chronicity ofmucosal inflammation. Aliment 
Pharmacol Ther. 2018. 47: 922-939
R20-2041
Rieder F, Fiocchi C. Intestinal fibrosis in IBD - a dynamic, multifactorial 
process. Nat Rev Gastroenterol Hepatol. 2009. 6: 228-235.
R20-2042
Rieder F, Fiocchi C. Mechanisms of tissue remodeling in inflammatory 
bowel disease. Dig Dis. 2013. 31: 186-193.
R96-2382 
EuroQol - a new facility for the measurement of health-related quality of 
life. Health Policy.1990. 16: 199-208
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. 1994. 106: 287 - 296
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. 1989. 96: 804 - 810
9.2
UNPUBLISHED REFERENCES
c03320877-08
Investigator’s Brochure, BI 655130 current version
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


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10.6
EQUIVALENT DOSES OF CORTICOSTEROIDS
Drug 
Equivalent dose (mg) 
Conversion factor 
Prednisone 
5 
X 1 
Prednisolone 
5 
X 1 
Triamcinolone 
4 
X 1.25 
6-Methylprednisolone 
4 
X 1.25 
Dexamethasone 
1 
X 5 
Betamethasone 
0,75 
X 6.7 
16-Methylprednisolone 
6 
X 0.8 
Fluocortalon 
5 
X 1 
Cloprednol 
3,75-5 
X 1.0-1.5 
Deflazacort 
6 
X 0.8 
Cortisol (hydrocortisone) 
20 
X 0.25 
Cortisone 
25 
X 0.20


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In order to obtain the equivalent dose of prednisone, please multiply the dose taken by the 
patient by the value in the column ‘Conversion Factor’. See Table 4.2.1.2:1. 


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10.8
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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be performed and when ileocolonoscopy is 
mandatory or optional. 
Rationale for change
See description above. 
Section to be changed
Footnotes 5.19
Description of change
Include MRI at EOT visit, quantiferon tested every 
48 weeks
Rationale for change
Clarifications and corrections.
Section to be changed
Section 2.1 and section 2.1.3
Description of change
Endoscopic and 
 
removed from 
secondary to further endpoints
Rationale for change
Patient population is expected to have low 
endoscopic and 
 
 as per eligibility 
criteria (perianal disease and 
 < 250). 
Therefore, the chance for this small sample size 
study to reliable evaluate spesolimab effect on 
endoscopic inflammation beyond the rectum is 
very low. Hence, this clinical outcome will be 
explored but has been removed from main 
endpoints 
Section to be changed
Section 2.1 and 3.1
Description of change
Definition of CD inflammatory flare.
Rationale for change
Changed
 of flare to an absolute 
value instead of a change from baseline as there 
will not be ileocolonoscopy performed at 
screening. 
Section to be changed
Section 3, Section 6.2.1, Section 6.2.2
Description of change
Ileocolonoscopy is not mandatory.  Instead recto-or 
proctoscopy requested for screening and yearly 
afterwards 
 
 for segment rectum. Ileocolonoscopy 
only mandatory as a confirmation of flare. .  
Rationale for change
Ileocolonoscopy is not needed for eligibility 
purposes and neither for assessment of perianal 
activity. This patient population (perianal CD) is 
expected to have low inflammation scores as per 
eligibility criteria. Thus, the chance for this small 
sample size study to reliable evaluate spesolimab 
effect on endoscopic inflammation beyond the 
rectum is very low. Hence, this clinical outcome 
will be explored but there is no justification for a 
full ileocolonoscopy to be mandatory.
Section to be changed
Section 3.3.4.1
Description of change
Change of criteria for treatment discontinuation in 
case of flare/fistula.
Rationale for change
Leave the decision to terminate treatment to the 
investigator judgement, allowing the investigator to 


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decide if there is clinical benefit for the patient 
instead of restricting the chance to continue to
those who meet restricted definition of clinical 
response  as per as a more global approach to 
patient clinical improvement, since these patients 
might not have other available options. 
Section to be changed
4.1.1
Identity of the Investigational Medicinal 
Products
Description of change
Inclusion of number of injection/vial  per dosis
Rationale for change
Clarification of posology
Section to be changed
Table 4.2.1.2:1 Restrictions regarding concomitant 
treatment
Description of change
Restriction for autologous or allogeneic 
haematopoietic (HSC) or mesenchymal stem cell 
(MSC) therapy
Rationale for change
Inclusion on restriction of a therapy
Section to be changed
Section 5.1
Description of change
Endoscopic CD activity amended: assessment by 
recto-or proctoscopy using 
 for the 
segment rectum
Rationale for change
See above. Ileocolonoscopy 
Section to be changed
Section 5.1.3
Description of change
Vibrio removed from infection testing
CRP: high density analysis not required
Type of E. coli removed (O157/H7)
Rationale for change
This test  not needed for safety profile of 
Spesolimab
Section to be changed
5.2.6.2.1 and footnotes 17 and 19
Description of change
Procedure for reporting AEs and SAEs considering 
both parent and extension trial. 
Rationale for change
Clarification of procedure for reporting AEs. 
Section to be changed
Section 5.4.3 and 5.5
Description of change
Change on location of biopsies, only from rectum.
Rationale for change
Adapt to change in ileocolonoscopy/rectoscopy
/proctoscopy and biopsies only taken from rectum


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11.2
GLOBAL AMENDMENT 2
Date of amendment
21 January 2021
EudraCT number
EU number
2019-001673-93
BI Trial number
1368-0007
BI Investigational Medicinal 
Product(s)
Spesolimab (BI 655130)
Title of protocol
An open label, long term safety trial of spesolimab
treatment in patients with fistulising Crohn’s 
disease who have completed previous spesolimab
trials
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Flow chart 1A, 1C
Description of change 1
Inclusion of blood sampling for biomarkers, and 
removal of stool sampling for lactoferrin. 
Clarification on infection testing and urine 
albumin. Change time window for visit M1-V1.
Rationale for change
New biomarkers needed in aligment with parent 
trial and other clarifications to avoid discrepancies 
between local and central lab.
Section to be changed
Flow chart 2A and 2B, footnote 14 and 22, sections
1.4, 3.1, 4.2.1, Figure 3.1:3.
Description of change 2
Differentiate luminal inflammatory flare from 
fistula relapse treatment. New flow chart for 
patients with only inflammatory flare.
For safety labs: change visit where labs are 
required to FLn, F1, F3, F5.
Rationale for change
Patients who maintain fistula response but present 
luminal inflammatory flare could be treated with 
SOC concomitantly with spesolimab.
For safety labs, correction needed.
Section to be changed
Footnotes 3, 6,8 ,21
Description of change 3
3.Include additional vital signs assessments  at visit 
M1 and M2.
6. Clarification on TSH and HbA1C
8. inclusion of blood biomarkers testing
21. clarification on infection testing at EOT visit.
Rationale for change
Align with protocol changes and avoid 
misunderstanding.
Section to be changed
Section 1.1, 1.2, 1.3
Description of change 4
Update on news on the disease, treatment and study 
data included. Update on spesolimab  UC 


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development status.
Rationale for change
Update investigators on latest status of spesolimab 
development in IBD and other indications.
Section to be changed
Section 1.4
Description of change 5
Rewording of section to include new spesolimab 
data and Covid-19 procedures.
Rationale for change
Update to reflect current drug profile. Inclusion of 
benefit-risk assessment in context of Covid-19 
pandemia.
Section to be changed
Section 2.2.1 and Table 5.2.3:1
Description of change 6
Remove faecal lactoferrin 
Rationale for change
Not relevant for this indication.
Section to be changed
Section 3.3.4.1 and table 4.2.2:2
Description of change 7
Clarification that surgical procedures to treat 
fistulas are not allowed after randomization and 
patient should be discontinued.
Rationale for change
Clarification to investigators that previously 
restricted surgical procedures include procedures to 
treat perianal and /or enterocutaeous fistulas since 
these would confound efficacy endpoints.
Section to be changed
Section 4.1.4 
Description of change 8
During the COVID-19 pandemic, physical visits to 
the sites may need to be restricted to ensure patient 
safety. Based on a thorough assessment of the 
benefits and risks, the investigator may discuss 
with BI to continue the trial treatment and trial 
medication may be shipped to the patient’s home if 
acceptable according to local law and regulations.
Rationale for change
Challenges due to covid-19 are acknowledged and 
the flexibility should be given to administer the 
trial medication at home taken the requirements 
described above into account.
Section to be changed
Section 4.2.1 and table 4.2.1.2:1 
Description of change 9
Reorganisation of information on concomitant 
treatments. Inclusion of stable doses of anti-TNF as 
allowed concomitant treatment during the study. 
Clarifications on steroids and antibiotics treatment 
and allowed surgeries.
Inclusion of approved medications to treat 
moderate-to-severe luminal inflammatory flares as 
concomitant therapy in patients with fistula 
response but who present luminal flare.
Rationale for change
Clarify use of concomitant treatments. To align 
with new eligibility criteria in parent trial 1368.8, 
which allows stable doses of  anti-TNF therapy 




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12.
REFERENCES FOR CTP AUTHORS
NA


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
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Document Number: 
Technical Version Number:
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Meaning of Signature  
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SAP_001.pdf: 








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2.
LIST OF ABBREVIATIONS
Term
Definition / description
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
BIcMQ
BI customized MedDRA queries
BLQ
Below the lower limit of quantification
BMI
Body mass index
CARE
Clinical data analysis and reporting environment
CR
Clinical remission
CRF
Case report form
CTC
Common Terminology Criteria
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
EOS
End of Study
EOT
End of treatment
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials
F/U
Follow-up
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IL
Interleukin


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Term
Definition / description
IPD
Important protocol deviation 
LLOQ
Lower limit of quantification
LOCF
Last observation carried forward
LOQ
Limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analysed
NOR
No valid result
NOS
No sample available
OC
Observed cases
OC-IR
Observed cases including values after rescue medication
OR
Original results
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual effect period
SAE
Serious adverse event
SAF
Safety Analysis Set
SD
Standard deviation
SDL
Subject data listing
SMQ
Standardised MedDRA query
SOC
System Organ Class
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range
ULOQ
Upper limit of quantification






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5.2.2
Secondary endpoints
•
Proportion of patients with perianal fistula remission at week 48, 96, 44, 192, 240, 288, 
and 336
•
Proportion of patients with perianal fistula response at week 48, 96, 44, 192, 240, 288, 
and 336
Please refer to Table 2.1:1 of the CTP for a complete description of the secondary endpoints.
As described in Section 4, due to limitations in the CRF collection of data, it is not feasible to 
calculate either of these two secondary endpoints. Nonetheless, the derivation algorithms for 
these two endpoints, as originally proposed, are maintained and described below.
The derivations of perianal fistula remission and response are Boolean functions based on the 
following, where a fistula refers to an external opening: 
Let
∀
 indicate a given analysis visit;
∀
() indicate the count of open fistulas (± drainage/discharge upon gentle finger 
compression) at ;
∀
	() be the number of newly emerged fistulas (± drainage/discharge upon gentle 
finger compression) from the baseline of the parent trial to ;
∀
BL be the number of open and draining fistulas at the baseline of the parent trial.
Then, perianal fistula remission (PFM) for a given patient 
 is
(
) =
⎩
⎨
⎧0,
 ()
 + 	 > 0
1,
 ()
 + 	 = 0
, and perianal fistula response (PFR) for a given patient 
 is
(
) = 
0,
 ()
 > 0.5
1,
 ()
 ≤0.5


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, refer to CTP Section 4. 
Patients who experience a fistula relapse during the maintenance treatment (as defined in CTP 
Table 2.1: 1) will be administered a single intravenous dose of spesolimab 1200 mg followed 
by an intensified subcutaneous maintenance dosing schedule with 600 mg q4w. 
The following study periods are defined:
Table 6.1: 1
Flow chart of analysis periods which apply to all patients.
Analysis period
On-/off-
treatmen
t
Start (included)
End (included)
Screening period
(Approx.. 1-2wks)
Off-
treatment
Earliest of (Date of 
informed consent, 
first screening 
procedure)
Date/time of injection of first s.c. 
maintenance study drug minus 1 
minute.
Overall maintenance
period1
(Approx... 336 wks)
On-
treatment
Date/time of first s.c.
maintenance study 
drug.
Date of last administered spesolimab 
(irrespective of formulation) + 112 
days at 11:59pm.
Follow-up period2
Off-
treatment
Date of last study 
drug administration 
(irrespective of 
formulation) + 113
days at 12:00 AM.
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 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.
2 The follow-up period only exists if the trial completion date is after the date of end of last injection/infusion plus REP.
The on-treatment period is defined as the overall maintenance period (including REP).
For all analysis periods, assessments done on the same day as the first maintenance treatment 
dose will be assigned to the appropriate analysis phase based on the assessment of date/time. 
If time is not collected for an assessment, then assignment will be to the previous analysis 
phase, e.g., to the screening phase.
Treatment Labels
Treatments will be labelled as follows:
∀
“Overall Speso”






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o
If the day of the end date is missing, then the end date is set to last day of the month 
(or to the patient’s last contact date, if it is earlier than the last day of the month).
o
If the day and month of the end date are missing then the end date is set to 31st of 
December of the year (or to the patient’s last contact date, if it is earlier than the 
31st of December of the year).
o
If the day of the start date is missing, the start date is set to the first day of the month.
o
If the day and month of the start date are missing then the start date is set to the 1st of 
January of the year.
All other cases need to be assessed by the trial team on an individual basis, using the above 
points as guidance.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Measurements reported with date and time and taken prior to the start of administration of 
trial treatment are pre-treatment values. Measurements reported with a date only (and no time) 
and taken on the day of first administration of trial treatment are 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. 
Refer to Section 5.2 for baseline definitions for each applicable efficacy endpoint in this trial. 
For safety endpoints, the baseline is defined as the last value prior to initiation of the 
maintenance treatment (Visit M1).
Analysis of AE data, concomitant medication or non-drug therapies will not be based on 
visits. Therefore, no assignment to time windows will be necessary.


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Only one observation per time window will be selected for statistical analysis at a particular
visit – the value which is closest to the protocol planned visit day will be selected. If there are
two observations which have the same difference in days to the planned day, but which are
not measured on the same day, the later value will be selected. If there are two observations
on the same day, the later value will be selected.   
For derivation of the last value on treatment, minimum value on treatment, and maximum 
value on treatment, all on-treatment values (whether selected in any time window or not; see 
Table 6.1: 1 for definition of the on-treatment period) will be considered. These will be 
derived for analysis of laboratory and vital signs data. For identification of potentially 
clinically significant abnormal laboratory values, all values (whether selected in any time 
window or not) within the on-treatment period will be considered.    


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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.
Considering the early termination of this long-term extension trial and the use of an
abbreviated CTR (aCTR) for trial results reporting, part of the planned trial analyses will not 
be performed. For details, please refer to section 4. 


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report by using the SAF only.
The presentation of EIM is defined in Section 7.8.5.1.
Concomitant diseases (i.e., baseline conditions) will be coded according to the most recent 
version of MedDRA. Baseline here refers to the baseline of this current long-term safety trial.
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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A medication/non-drug therapy will be considered concomitant to treatment, if it is ongoing at 
the start of this trial’s treatment or starts within the on-treatment period (see Section 6.1 for a 
definition of study analysis periods).
7.3
TREATMENT COMPLIANCE
As described in section 4, reporting of treatment compliance is not required for an aCTR.
7.4
PRIMARY ENDPOINT(S)
The primary endpoint for this open label, long-term safety trial is a safety endpoint.
7.4.1
Primary analysis of the primary endpoint(s)
Refer to TSAP, Section 7.8.1.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
None specified.
7.5.2
(Other) Secondary endpoints
Refer to TSAP, Section 5.2.2. for a description of the secondary endpoints. 
As described in Section 4, due to limitations in the CRF collection of data, it is not feasible to 
calculate either of the two secondary endpoints. A listing at the individual patient level 
showing the status of fistulas for each treated patient will instead be prepared.


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7.7
EXTENT OF EXPOSURE
A table of total treatment exposure [mg] across the overall maintenance period will be 
summarized for the SAF for spesolimab s.c. and spesolimab i.v., respectively. For the time at 
risk, and for the total duration of exposure(weeks), data will also be tabulated as a frequency 
table with categorized treatment duration, (i.e., >0 to 48 weeks, >48 to 96 weeks, >96 to 144 
weeks) for the SAF for ‘Overall Speso’ only.
7.8
SAFETY ANALYSIS
All safety analyses will be performed following BI standards. No hypothesis testing is 
planned.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA. 
The analysis 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 "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (4) [KM Asset BI-KMED-BDS-HTG-0041] and 
"Handling of missing and incomplete AE dates" (3) [KM Asset BI-KMED-BDS-HTG-0035]. 


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The analysis of AEs will be based on the concept of treatment emergent AEs. This means that 
all AEs will be assigned to either the screening period, the applicable on-treatment period, or 
the off-treatment period (i.e. follow-up) as defined in Section 6.1. Since only the start date of 
an AE is collected (without start time), any AE which occurs on the same day as the first 
maintenance treatment will be assigned to the respective on-treatment period.
Refer to CTP Section 7.2.2 for a description of the calculation of exposure-adjusted adverse 
event incidence rates (per the primary endpoint).
The AE summaries described below will be produced for the following treatment periods:
∀
The overall maintenance period [based on the SAF]
An overall summary of AEs will be presented. This overall summary will include the class of 
AESIs. Refer to CTP Section 5.2.6.1.4 for a description of what is considered as an AESI.
The investigator identified AESI will be captured from the eCRF and reported in the 
“Investigator reported AESI” table. In addition, user defined adverse event categories
(UDAEC) identified through specific search criteria will be reported separately; the UDAEC 
applicable to this trial are stored centrally and will be referenced for this presentation. 
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’.
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events Categories
(UDAEC)
User-defined AE category
Label 
Description
Infections ALL
Combined search strategy based on the individual UDAECs 
for infections described below
- Opportunistic infections
Narrow SMQ “Opportunistic infections”
- Tuberculosis infections
BIcMQ “Infections”:
Narrow sub-search 8.2 “Tuberculosis related terms” 
- Serious infections
all serious events in SOC “Infections and infestations”
- Severe infections
all events in SOC “Infections and infestations” of at least 
severe RCTC grade
Hypersensitivity ALL
Combined search strategy based on the individual UDAECs 
for hypersensitivity described below
- Anaphylactic reaction
Narrow SMQ “Anaphylactic reaction”
- Angioedema
Narrow SMQ “Angioedema”
- Hypersensitivity
Narrow SMQ “Hypersensitivity”


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User-defined AE category
Label 
Description
- DRESS, algorithmic
Based on broad SMQ “Drug reaction with eosinophilia and 
systemic symptoms” (SMQ code 20000225), defined using 
algorithm as follows: 
A or (B and C and D) or (B and C and E) or (B and D and E)
where the categories A, B, C, D and E are defined 
categorisations of the PTs of the SMQ. For PTs of category 
A only narrow scope is used, for all other categories broad 
scope is used. 
For identification of potential DRESS through the 
combination of adverse event occurrences within each of 
the categories B, C, D and E, adverse event start and end 
dates will be used. For the latter, potential DRESS is then 
identified if, within a 7-day period after occurrence of a 
relevant contributing event (assessed on each day 
between start and end date [inclusive] of the initiating
event), there is at least one adverse event reported (based 
on start date only) from each of the other applicable 
categories within a specific combination of categories as 
described above (in parentheses).
If the end date is missing, the event is considered to be 
ongoing, and end date will be the last day of the applicable 
treatment period.
- DRESS, narrow
Narrow SMQ “Drug reaction with eosinophilia and 
systemic symptoms”, any event within category A only
Malignancies ALL
- Malignant tumours
Narrow Sub-SMQ “Malignant tumours”
(Display also
-
Narrow Sub-SMQ “Haematological malignant 
tumours”
-
Narrow Sub-SMQ “Non-Haematological malignant 
tumours”)
- Malignancies excluding non-melanoma skin 
cancer (NMSC )
Sub-SMQ “Malignant tumours” excluding NMSC, where 
NMSC is defined as broad Sub-SMQ “Skin malignant 
tumours” excluding HLT Skin melanomas (excl. Ocular)
Peripheral Neuropathy ALL
- Guillain-Barré Syndrome
Narrow SMQ “Guillain-Barré syndrome” (SMQ code 
20000131) 
- Peripheral Neuropathy
Narrow SMQ “Peripheral Neuropathy” (SMQ code 
20000034)


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User-defined AE category
Label 
Description
- Demyelination
Narrow SMQ “Demyelination” (SMQ code 20000154)
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 Categories (UDAEC) (see Table 7.8.1: 1). AEs will also be 
summarized by maximum or worst intensity based on the RCTC measure (see Section 5.4.1).
Listings for AEs by Primary System Organ Class and Preferred Term and SARS-Cov-2 
infections at each individual level will be provided.


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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
001-MCS-36-472: " Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON
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
8
KM Asset BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of 
Laboratory Data”, current version; KMED


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
DD-MMM-YY
None
This is the final TSAP 
Final
02-Feb-22
None
This is the final TSAP prior to first 
interim analysis
2.0
28-OCT-22
All 
sections
After the sponsor’s decision of early 
termination of this long-term safety
trial due to non-promising efficacy 
results from the parent trial, and before 
final database lock, revisions and 
necessary updates are made through 
this TSAP.