Clinical trial NCT03752970
Conditions: Crohn Disease
Sponsor: Boehringer Ingelheim
Start date: 2019-02-05; Completion date: 2022-07-04
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study in adults with Crohn's Disease who also have fistulas near the anus. The study has 2 parts. The first part is to find out more about what causes the fistulas. In this part of the study, tissue samples are taken from patients. The second part of the study tests whether a medicine called spesolimab (BI 655130) helps patients with Crohn's Disease.

Participants get study medication for 24 weeks. The participants are put into 2 groups. It is decided by chance who gets into which group. One group gets an intravenous drip that contains spesolimab every 4 weeks. The other group gets a placebo drip every 4 weeks. The placebo drip looks like the spesolimab drip, but contains no medicine.

The doctors regularly examine fistulas of the participants. The results of the fistula examinations are compared between the groups. The doctors also check the general health of the patients.

Detailed description:

Arms: arm 1: Patients enrolled in the Screening Cohort did not receive study treatment. This was a feasibility phase for fistula preparation and seton placement to determine the tissue samples that were suitable for analysis of the primary endpoint in the Study Cohort. arm 2: Patients with perianal fistulising Crohn's disease received Placebo intravenously every 4 weeks (week 0, 4, 8). At week 12 achievement of combined perianal fistula remission was determined, patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). Patients with combined perianal fistula remission remained on Placebo and were treated with placebo intravenously every 4 weeks (week 12, 16 and 20). arm 3: Patients with perianal fistulising Crohn's disease received Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). At week 12 Placebo patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20).
Interventions: intervention 1: Spesolimab intervention 2: Placebo
Intervention descriptions: intervention 1: Spesolimab 1200 milligram intravenously every 4 weeks (week 0, 4, 8, 12, 16 and 20). At week 12 Placebo patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). intervention 2: Placebo intravenously every 4 weeks (week 0, 4, 8). At week 12 achievement of combined perianal fistula remission was determined, patients without combined perianal fistula remission were switched to spesolimab and were treated with spesolimab 1200 milligram intravenously every 4 weeks (week 12, 16 and 20). Patients with combined perianal fistula remission remained on Placebo and were treated with placebo intravenously every 4 weeks (week 12, 16 and 20).

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Finished product name
Not applicable
Active ingredient name:
BI 655130
Protocol date
12 Sep 2018
Revision date
23 Oct2020
Trial number
1368-0008
Title of trial:
Mechanism of Action and Clinical Effect of BI 655130 in Patients 
with fistulizing Crohn’s Disease
Principal Investigator 
< for single-centre trial 
or > Coordinating 
Investigator< for multi-
centre trial if 
applicable >:
Phone: 
Fax: 
Trial site(s):
Multi-center trial
Clinical phase:
IIa
Objective(s):
∀
To explore the pathomechanisms involved in the generation 
and healing of Crohn’s Disease (CD) associated perianal fistulas
∀
To understand the mode-of-action (MoA) of BI 655130 in 
patients with CD and draining perianal fistulas
Methodology:
Screening Cohort:
is designed as a non-randomized screening cohort in patients with 
perianal fistulizing CD
Study Cohort:
is designed as a randomized, double-blind and placebo-controlled, 
parallel-group phase IIa study of BI 655130


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Number of patients
entered: 
Screening Cohort : Approximately 5 to 8 patients
Study Cohort : Approximately 20 patients 
Number of patients on 
each treatment:
Screening Cohort: not applicable
Study Cohort:
∀
Period 1: Approx. 10 patients per treatment arm (BI 655130 
1200mg i.v. or placebo)
∀
Period 2: Treatment assignment in period 2 will be determined 
by the achievement of combined perianal fistula remission at week 
12.
Diagnosis :
Patients with previously treatment-resistant perianal fistulizing CD 
with clinical indication for seton drainage
Main inclusion criteria:
1. 18-75 years at date of signing informed consent
2. Diagnosis of clinical Crohn´s Disease ≥ 3 months prior to 
screening by clinical and endoscopic evidence and 
corroborated by a histopathology report
3. Has ≥ 1 perianal active* fistula(s) with clinical indication for 
seton drainage (≥ 4 weeks duration before enrolment, as a 
complication of CD). **. 
* Criteria for Active Fistula: As per clinical 
evaluation: Presence of spontaneous drainage or drainage 
after gentle finger compression at the external openings & as 
confirmed by radiological (MRI) exploration . 
** Patients who are screened with a seton drainage in place are
eligible provided the drainage has not been in place for > 3 
months and the patient meets the rest of the eligibility criteria 
4. Additional enterocutaneous or abdominal fistulas are permitted 
(except rectovaginal fistulas)
5. Absent, mild or moderate clinical activity with CDAI < 250. 
CDAI is not applicable for Screening Cohort.
6. Demonstrated in the past inadequate fistula response or loss of 
response or have had unacceptable side effects 
with approved doses of at least one of the following 
compounds: Immunesuppressive agents (e.g. thiopurines, 
methotrexate), TNFɑ antagonists (e.g. infliximab, adalimumab, 
certolizumab pegol; or respective biosimilars), vedolizumab,
ustekinumab, azathioprine and / or antibiotics (cf. section 10.7)
Main exclusion criteria
(Not applicable for 
Screening Cohort)
1. Complications of Crohn’s Disease such as symptomatic strictures, 
functional stenosis distal from fistula(s), short gut syndrome, or 
any other manifestation that might require surgery, could preclude 
the use of the PDAI and CDAI to assess response to therapy, or 


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would possibly confound the evaluation of benefit from treatment 
with BI 655130
2. Rectovaginal fistulas
3. Anticipated to require surgical intervention for CD, including any 
surgical fistula procedures (except seton drainage). See Table 
4.2.2.2:1 for a detailed list of restricted interventions
4. Has an abscess that the investigator feels requires drainage 
beyond fistula drainage with a seton (based on either clinical 
assessment or MRI) 
5. Any kind of bowel resection or diversion within 6 months or any 
other intraabdominal surgery within 3 months prior to screening. 
6. Ileostomy, colostomy or known fixed symptomatic stenosis of the 
intestine at screening.
7. Evidence of colonic mucosal dysplasia or colonic adenomas, 
unless properly removed (properly according to the investigator’s 
assessment)
8. Faecal Microbiota transplant (FMT) within 6 months prior to 
randomization
9. Treatment with: (See table 4.2.2.1:1 for a detailed list of restricted 
treatments)
∀
any non-biologic medication (incl. cyclosporine, JAK 
inhibitors such as tofacitinib, tacrolimus, sirolimus, 
mycophenolate mofetile, S1P modulators, SMAD7 
antisense inhibitors such as mongersen), other than 
those allowed per chapter 4.2.1 within 30 days prior to 
randomisation unless these patients show an 
undetectable plasma concentration
∀
any biologic treatment approved for CD other than 
TNFα inhibitors, within 8 weeks prior to 
randomization unless these patients show an 
undetectable plasma concentration
∀
any investigational or non-approved biologic for CD 
(including but not limited to IL-23 inhibitors) within 
12 weeks prior to randomisation or etrolizumab within 
8 weeks prior to randomization unless these patients 
show an undetectable plasma concentration 
∀
rectal 5-ASA, rectal Tacrolimus, parenteral or rectal 
corticosteroids (incl. budesonide) within 2 weeks prior 
to randomisation
∀
any antibiotics within 1 week prior to randomisation
∀
any prior autologous or allogeneic, haematopoietic 
(HSC) or mesenchymal stem cell (MSC) therapy
∀
any prior exposure to BI 655130
∀
any chronic use of NSAID within 2 weeks prior to 
randomisation


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(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)
∀
any life-attenuated vaccines within 6 weeks prior to 
randomization
Test product(s):
BI 655130 (Screening Cohort: not applicable)
dose:
1200 mg every 4 weeks (q4w): 
∀
Period 1: at week 0, 4, 8
∀
Period 2: at week 12, 16, 20
mode of administration:
Intravenous (i.v.)
Comparator products:
Placebo (Screening cohort: not applicable)
dose:
0 mg (placebo) every 4 weeks (q4w): 
∀
Period 1: at week 0, 4, 8
∀
Period 2: at week 12, 16, 20
mode of administration:
Intravenous (i.v.)
Duration of treatment:
Screening Cohort:               not applicable
Study Cohort: 
             24 weeks
Endpoints
Primary endpoint:
The primary endpoint is the total number of deregulated genes at 
week 4 comparing changes in gene expression from baseline 
between the two treatment groups. Thereby, deregulation of a gene 
is defined based on the baseline adjusted mean difference to 
placebo of gene expression fulfilling the following criteria:
∀
False discovery rate (FDR) adjusted p-value ≤ 0.05
∀
|fold change| ≥ 1.5
∀
genes can be annotated with Ensembl identifiers (version 84 or 
later)
Gene expression is analysed based on biopsies (curettage and inner 
fistula orifice) via RNA sequencing; more details on the gene 
expression analysis can be found in Section 7.3.1
Secondary endpoints:
∀
Proportion of patients with perianal fistula response at week 12 
(defined as closure of at least 50% of external openings, no 
drainage / discharge despite gentle finger compression of 
fistulas that were draining at baseline and without new 
emerging fistulas)


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∀
Proportion of patients with perianal fistula remission at week 
12 (defined as closure of all external openings, no drainage / 
discharge despite gentle finger compression of fistulas that
were draining at baseline and without new emerging fistulas)
∀
Proportion of patients with combined perianal fistula remission
at week 12 (defined as closure of all external openings, no 
drainage / discharge despite gentle finger compression of 
fistulas that were draining at baseline and without new 
emerging fistulas, AND absence collections of >2 cm, 
confirmed by MRI in at least two of three dimensions – blinded 
and centrally read)
Safety criteria:
Physical examination, vital signs, 12-lead ECG, laboratory tests, 
adverse events, serious adverse events and drug-related adverse 
events. The intensity grading of AEs and abnormal laboratory 
values will be performed according to Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0
Statistical methods:
Gene expression analysis via repeated measures linear regression 
model (calculation of total number of deregulated genes at Week 
4).
Descriptive statistics for safety, 
 and efficacy endpoints. 
If feasible, 95% confidence intervals for rate difference in perianal 
fistula response, perianal fistula remission, and further clinical 
efficacy endpoints regarding proportions of patients.
















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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART A: SCREENING COHORT.......................................................................7
FLOW CHART B: STUDY COHORT, PERIOD 1 (SCREENING – WEEK 8)..............8
FLOW CHART C: STUDY COHORT, PERIOD 2 (WEEK 12 – WEEK 
36)............11
TABLE OF CONTENTS ......................................................................................................14
ABBREVIATIONS................................................................................................................18
1.
INTRODUCTION...............................................................................................21
1.1
MEDICAL BACKGROUND.............................................................................21
1.2
DRUG PROFILE................................................................................................22
Mode of action.....................................................................................................22
1.2.1
Data from non-clinical and toxicology studies .................................................22
1.2.2
Data from clinical studies...................................................................................23
1.2.3
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................24
1.4
BENEFIT - RISK ASSESSMENT.....................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................31
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........31
Main objectives....................................................................................................31
2.1.1
Primary endpoint................................................................................................31
2.1.2
Secondary endpoints...........................................................................................31
2.1.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................34
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................34
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................40
3.3
SELECTION OF TRIAL POPULATION .......................................................41
Main diagnosis for trial entry ............................................................................42
3.3.1
Inclusion criteria for Screening Cohort and Study Cohort ............................42
3.3.2
Exclusion criteria ................................................................................................43
3.3.3
Screening Cohort...................................................................................................43
3.3.3.1
Study Cohort .........................................................................................................43
3.3.3.2
3.3.3.2.1
Gastrointestinal Exclusion Criteria.......................................................................43
3.3.3.2.2
Infectious Disease Exclusion Criteria...................................................................44
3.3.3.2.3
General Exclusion Criteria....................................................................................44
Withdrawal of patients from therapy or assessments .....................................45
3.3.4
Discontinuation of trial treatment .........................................................................45
3.3.4.1












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SOC
standard of care
SUSAR
Suspected Unexpected Serious Adverse Reactions
CTL
Clinical Trial Leader
TDMAP
TGF
Trial Data Management and Analysis Plan
Tissue growth factor
t.i.d.
TMDD
ter in die (3 times a day)
target-mediated drug disposition
TMF
TNF
Trial Master File
Tumor necrosis factor
TSAP
UC
Trial Statistical Analysis Plan
Ulcerative colitis
WHO
World Health Organization
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 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%) [R13-2232, R13-2233]. The mean age at CD diagnosis 
is approximately 30 years with a slight predominance of women [R16-1923].
The incidence of CD seems to be increasing with more recent estimates varying from 7.9 to
20.2 cases/100,000, and a prevalence of 161 to 319 cases/100,000 in 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. One third of 
CD patients will develop fistulas at least once during the course of the disease. Perianal 
fistulas are the most common clinical manifestation. At time of CD diagnosis, two third of 
patients present with inflammatory disease and only up to one-third of the patients reveal
stricturing or penetrating complications in the gastrointestinal tract. Thus, the number of 
patients with severe and recurrent problems arising from CD fistulas is considerably high. 
Surgery, though often required, does not always provide a definitive cure [R17-3555].
The mainstay of treatment of moderate to severe CD without fistulae has been with 
glucocorticoid therapy, azathioprine, or 6-mercaptopurine [R13-2269]. More recently, 
biologics consisting of monoclonal antibodies directed at cytokines, thought to mediate the 
pathology, have been used extensively for this indication. 
Routine medical treatment of perianal CD fistulas includes antibiotics, immunosuppressives, 
and anti-TNF antibodies. Most of the evidence on routinely used medical treatment is derived 
from subgroup analyses or secondary outcome measures, while dedicated clinical trials with 
healing of perianal fistula or reduction in the amount of secreting fistula tracts are still 
limited. Amongst anti-TNF antibodies, infliximab is approved in the indication of 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). However, only approximately half of 
infliximab treated patients achieved closure of all fistulas [R00-0812] and relapses were 
common. After 1 year in only approximately a third of patients all fistulas are closed [R04-
0551]. A recently approved approach of injecting allogenic mesenchymal stem cells into the
surgically prepared fistula canal has represented the latest major progress in fistula treatment
achieving remission rates of around 50% after one year [R18-2555]. Surgical therapies aim to 
achieve fistula closure while preserving the anal sphincter function, but show limited efficacy 
based on the limited available evidence. Thus, there remains a significant unmet medical 
need for better treatments of this CD complication [R17-3555].


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1.2
DRUG PROFILE
Mode of action
1.2.1
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R
signalling. Binding of BI 655130 to IL36R is anticipated to prevent the subsequent activation 
of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-
inflammatory and pro-fibrotic pathways with the aim to reduce epithelial cell/ fibroblast/
immune cell-mediated inflammation and to 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).
Data from non-clinical and toxicology studies
1.2.2
Preclinical studies
BI 655130 binds to human IL36R with a binding avidity of less than 1 pM. BI 655130 
inhibits IL36 ligand-stimulated NF-#B activation in HT29 and transformed epithelial cells 
and in primary human dermal fibroblasts or intestinal myofibroblasts with IC90 values in a 
consistent range of 0.7 to 3.7 nM. BI 655130 also inhibits IL8 release in primary human 
intestinal myofibroblasts and Interferon gamma (IFNγ) secretion in human Peripheral Blood 
Mononuclear Cell (PBMC) stimulated with IL36α, IL36β, or IL36γ combined with IL12.
Mutations of two key residues (L234 and L235) to alanine were made to BI 655130 to 
abrogate FcR binding activity and function. Direct assessment of the impact of the mutations 
in the IgG1 FcR binding sites on both antibody-dependent cellular cytotoxicity (ADCC) and 
complement-dependent cytotoxicity (CDC) effector functions revealed that the mutations 
abrogate both ADCC and CDC effector functions and indicate that BI 655130 will be a non-
depleting therapy in vivo.
Toxicology studies
BI 655130 does not bind to IL-36R from common toxicology species. Therefore, meaningful 
toxicity studies of the molecule cannot be performed in any animal species with BI 655130. 
However, hazard identification studies of the mode-of-action (MoA) of IL-36R inhibition 
were performed in mice using a mouse specific anti-IL-36R monoclonal antibody (BI 
674304), which is a mouse IgG2a monoclonal antibody with rat variable regions. In a 13-
week intravenous toxicity study of BI 674304 in mice, no adverse effects of IL-36R 
antagonism were seen at a dose (50 mg/kg, twice weekly) that was 5 fold higher than the dose 
that was protective in an experimental mouse colonic inflammation model. In the 26-week 
toxicity study, male and female mice (20-30/sex/group at 0, 10 and 50 mg/kg/day) were 
administered BI 674304 twice weekly for 26 weeks by intravenous injection via the caudal 
vein. There were no BI 674304-related changes in clinical observations, body weights, food 
consumption, ophthalmology, clinical pathology parameters (hematology, clinical chemistry), 
organ weights, macroscopic or microscopic examinations. The no-observed-adverse-effect 
level (NOAEL) was considered to be 50 mg/kg/day.
The in vitro cytokine release and tissue cross-reactivity assays demonstrate that the risk of 
transient cytokine release in humans is low and that, as expected, BI 655130 stains epithelium 
in a variety of tissues. There were no signs of local irritation after single, 1 mL injections of 


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the subcutaneous formulation in rabbits. These preclinical toxicology data support chronic BI 
655130 dosing in humans.
Data from clinical studies
1.2.3
BI 655130 or placebo (PBO) was administered to 78 healthy volunteers at single ascending 
i.v. doses from 0.001 mg/kg to 10 mg/kg body weight. Safety and tolerability of all tested i.v. 
doses were good. There were no drug-related SAEs. Adverse Events (AEs) categorized as 
related to treatment were observed in 3/19 (15.8 %) subjects in the placebo group and in 7/59 
(11.9 %) subjects treated with BI 655130. The most frequent treatment-emergent AEs were 
nasopharyngitis (BI 655130: 21 %; PBO: 15 %), headache (BI 655130: 9 %; PBO: 15 %), 
influenza like illness (BI 655130: 7 %; PBO: 10 %), and diarrhea (BI 655130: 3 %; PBO: 10
%). There were two AEs of moderate intensity (injection site haematoma, headache), all 
remaining AEs were of mild intensity. There was no apparent relationship between the 
frequency of AEs and the dose. There were no relevant changes compared to placebo for 
laboratory safety, including clinical chemistry, hematology, coagulation parameters, and 
urinalysis. No clinically relevant changes were observed in 12 lead ECGs, vital signs, and 
cardio-monitoring. 
PK analysis showed that exposure (AUC0-tz and Cmax) to BI 655130 increased with 
increasing dose in an approximately dose-proportional manner from 0.3 to 10 mg/kg. The 
effective half-life of BI 655130 is approximately 4 weeks in the linear dose range. Overall, 
PK data so far suggests target-mediated drug disposition (TMDD) kinetics for BI 655130. 
Anti-drug antibodies (ADA) were detected in 8 patients, 3 of those had pre-existing levels. 
Pharmacodynamic effects in this FIH Single Rising Dose trial [c03361085-07] were assessed 
by indirect target engagement (ITE) of IL36R by BI 655130 using an ex-vivo whole blood 
stimulation assay. All doses higher than 0.001 mg/kg were biologically active, corresponding 
to the minimum anticipated biological effect level, MABEL. 
In a multiple rising dose trial, BI 655130 or placebo have been administered to healthy 
volunteers at multiple ascending i.v. doses of 3, 6,10 and 20 mg/kg given qw for 4 weeks (i.e. 
4 administrations) or a single dose of 20 mg/kg (8 subjects each, 3:1 on active or PBO). 
Overall, BI 655130 was well tolerated. All AEs were of mild or moderate intensity; drug-
related AEs of moderate intensity were observed in one subject in the highest dose cohort (20 
mg/kg multiple dosing) BI 655130 treatment group (suspected infusion reaction leading to 
study drug withdrawal). Furthermore, there were no clinically relevant abnormalities on 
treatment with BI 655130 with respect to safety laboratory, vital signs, or ECGs as assessed 
by a central reader. Importantly, based on the preliminary analysis of the ITE studies, more 
than 90 % of peripheral IL36R was engaged for at least 22 weeks after the last application of 
four weekly doses. For further details and most recent results refer to the current 
Investigator`s Brochure [c03320877].
Studies in Patients
Efficacy data are available from a proof of concept study in patients with generalized pustular 
psoriasis (GPP). In 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 


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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 post-
dose, 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%).
Residual Effect Period
The Residual Effect Period (REP) of BI 655130 is 16 weeks after the last administration. This 
is the period after the last dose with measurable drug levels and pharmacodynamic effects 
still likely to be present.
Summary 
BI 655130 is an anti-IL-36R antibody targeting a molecule likely to be involved in intestinal 
fibrosis and fistula generation, and has shown a strong clinical activity to block IL-36R 
signaling in an inflammatory skin disease. IL36R inhibition shows a favorable nonclinical 
safety profile. BI 655130 has been tested in healthy volunteers with single or multiple dosing 
up to four weeks of 20 mg/kg i.v. q.w. Therefore, BI 655130 might be a promising drug to 
treat patients suffering from CD.
BI 655130 drug [c03320877].
1.3
RATIONALE FOR PERFORMING THE TRIAL
This study is planned as a mechanistic pilot study in patients with CD complicated by 
perianal fistulas, who have a clinical indication for surgical treatment with a seton drainage to 
alleviate symptoms and condition the tissue for potential subsequent surgical interventions. 
The objective is to explore the pathomechanisms involved in the generation and healing of 
CD associated perianal fistulas, and to investigate the effect of BI 655130 on these 
mechanisms by using gene expression analyses. Moreover, clinical effect, safety and 
tolerability of BI 655130 treatment in patients with fistulizing CD will also be explored.
The current understanding of the pathomechanisms involved in the evolution of perianal or 
other fistulas arising as complication of CD is limited and based on studies in surgically 
resected tissue specimens or in-vitro studies (Panes, Rimola; Nat Rev Gastroenterol & 
Hepatol 2017, doi:10.1038/nrgastro.2017.104). This study will be the first to investigate 
mechanisms involved in fistula generation and healing sequentially in the same fistula tracts
and/or openings. Since the collection of tissue using curettage and small biopsies has not yet 
been systematically explored, the study will start with a Screening Cohort to establish the 
technical feasibility of the tissue sampling approach. The Study Cohort will initiate as soon as 
feasibility has been confirmed. Irrespective of a potential treatment effect of BI 655130 will 
the mechanistic studies of sequentially assessed fistula tissue increase the understanding of 
the mechanisms underlying fistula generation, which may lead to the identification of new 
treatment targets for this disabling complication of CD.
BI 655130 is currently under development for the treatment of inflammatory skin and bowel 
diseases such as generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), Atopic 




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 The 
outcome of this study will set the stage for large scale studies in patients with fistulizing CD.
The therapeutic benefit or specific adverse events in patients cannot always be anticipated 
during the trial setup. Later on there may be new scientific knowledge about biomarkers and 
other factors contributing to diseases or the action of a drug. In order to be able to address 
future scientific questions, patients will be asked to voluntarily donate biospecimens for 
banking. If the patient agrees, banked samples may be used for future drug development 
projects, e.g. to identify patients that are more likely to benefit from a treatment or experience 
an adverse event, and thereby better match patients with therapies.
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 UC). In 
line with this stage of development, clinical evidence for efficacy of spesolimab in patients is 
limited However, preclinical profiles of BI 655130 and clinical data from healthy volunteer
trials suggest that BI 655130 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. Section 1.2
and the IB [c03320877].
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.
Although no relevant animal species is available for toxicology testing of the highly human 
specific antibody BI 655130, preclinical toxicology studies with a rat anti-mouse surrogate 
antibody have demonstrated the safety of IL-36R inhibition in mice (c03320877), IB Section 
5.1.2). Moreover, a total of 148 healthy volunteers have been exposed in four completed
phase I studies to single or multiple doses of BI 655130 up to very high dose levels of 
20mg/kg given once weekly (qw) for 4 weeks. In all these studies BI 655130 has been safe 
and well tolerated at all tested dose groups (for details cf. IB section 6/safety). In addition, a
first proof-of-concept trial (1368.11) in moderate/severe acute GPP has been completed 
confirming that a single IV dose of 10mg/kg of BI 655130 was safe and tolerable in seven 
patients with moderate or severe acute GPP. As of July 2017, three clinical studies are
ongoing: a 16 week proof-of-concept trial exploring efficacy and safety of BI 655130 in 
patients with moderate/severe Palmoplantar Pustulosis (PPP; 1368.15; n=60); and two 
(1368.4, 1368.10) small pilot studies exploring mechanism and effect of BI 655130 in 
patients with UC (n=10 and 30, respectively). These studies are carefully monitored by the 
sponsor and an independent Data Safety Monitoring Board (DSMB) and have not identified 


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any severe or serious safety signal. Thus, no clearly compound related adverse effect or other 
safety signals have been identified in preclinical or clinical phase I studies.
As with any immune modulating agent, BI 655130 has the theoretical potential to impair 
immune function increasing the risk of infection or cancer. A recent publication has identified 
12 healthy individuals carrying an inherited loss-of-function mutation of the IL-36 receptor 
gene [R17-3632]. The authors found that normal immune function was broadly preserved in 
these individuals, who showed no phenotype of increased risk in infection or cancer. In 
accordance with this observation, no evidence of an increased infection risk has emerged 
from the early trials, though larger studies with a longer follow-up are needed to draw such a 
conclusion. The role of IL-36 in tumour immunity is also not well established at this time and
an increased risk of cancer from an IL-36R antagonist cannot be excluded. These risks will be 
addressed in the study program by careful safety monitoring and risk mitigation measures: (a) 
exclusion of patients with history or increased risk of malignancies or infections; (b) close 
clinical monitoring for AEs, including use of Rheumatology Common Toxicity Criteria 
(RCTC) for severity grading, definition of emerging malignancies as always-serious adverse 
events, definition of opportunistic infections and infusion and anaphylactic reactions as 
adverse events of special interest (AESI); (c) selection of sites experienced in treatment of 
IBD patients with biologics; and (d) surveillance by a fully independent Data Safety 
Monitoring Committee (DMC). 
With regard to potential benefits, BI 655130 (i) has a unique bimodal MoA providing a 
strong scientific rationale to be tested in fistulising CD; (ii) has shown high (>94% inhibition 
of TNF∃or MIP1% secretion) and sustained (>22 weeks after last dose) biological activity in 
healthy volunteers based on an indirect target engagement assay (reference IB, section 6.1 
pharmacology); and (iii) has rapidly cleared pustules and other skin lesions in GPP, a disease 
closely linked to excessive IL36 activity, which indicates that BI 655130 inhibits IL36 in 
human disease and has the potential to treat inflammatory epithelial diseases. Based on the 
PoC achieved in GPP and the strong preclinical rationale, there is a reasonable chance that BI 
655130 may not only alleviate signs and symptoms of active CD but even directly promote 
mucosal and histological healing in luminal and fistulising CD. Mucosal healing is associated 
with improved clinical outcomes (reductions in immunosuppressive treatments, 
hospitalizations, colectomy and colorectal cancer [R16-0572].
Moreover, as the pathogenesis of this condition is not well understood, an improved 
characterisation of the underlying changes in various genetic and epigenetic markers may 
result in the discovery of novel therapeutic targets. The nature of the regulated genes and 
biomarkers will shape the subsequent development of BI 655130 and other compounds in 
IBD to define potential new endpoints, target indications and biomarkers to identify 
responder patient populations.
Therefore, participation in this study may help to generate a future group benefit for patients 
with CD and fistulas, if BI 655130 or other compounds acting on yet to be identified new 
targets prove to be successful in treating this disease.
This trial is a 2-part trial. The Screening Cohort will determine in a small number of patients 
undergoing standard of care surgical procedure, whether identical cytokines and 


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pathomechanisms are active in tissue samples collected from the fistula canal (curettage) and/ 
or from the inner and outer orifice (biopsy), where fistula generation starts with the 
emergence of epithelial-mesenchymal transition (EMT) and tissue invasion. Based on the 
outcome of this cohort, feasibility criteria for Study Cohort may have to be adapted (via 
substantial amendment) to exclude patients where for technical reasons a sufficient biopsy of 
the inner orifice cannot be obtained. Patients in the Screening Cohort will only receive 
standard of care (SOC) for their disease, without subsequent randomization to IMP or PBO. 
The only additional study related procedures are sampling of the curettage tissue and biopsies 
for gene analyses and histology, which should not increase the risks over that of the standard 
procedure. Should these patients not respond to surgical or standard treatment, they can be re-
screened at a later point in time for participation in the Study Cohort, which may come with a 
benefit.
The Study cohort is designed as a randomized, double-blind and placebo-controlled phase IIa
study of BI 655130 in patients with perianal fistulizing CD . Patients may continue pre-
existing conventional or anti-TNF treatment as defined in Section 4.2.2.1. The placebo 
controlled period 1 of 12 weeks will be followed by additional 12 weeks of blinded treatment. 
Treatment in period 2 will depend on the original treatment group and the achievement of a 
strict combined perianal fistula remission outcome at week 12: all patients in the original BI 
655130 group and non-remitters from the original placebo group will be treated with BI 
655130 from week 12 to 24. Remitters to placebo at week 12, will continue placebo till week 
24. The double blinding will be kept by IRT assigning active or placebo based on these 
decision criteria. The total treatment duration is up to 24 weeks; after that time all patients 
having derived an individual benefit will be offered to roll-over into a long-term open label 
extension study (1368-0007). 
∀
The surgical fistula preparation visit (FPV) under anaesthesia and/or sedation is indicated 
as standard of care in the eligible patient population per inclusion criteria. Curettage of 
the fistula canal and insertion of a seton drain represents standard surgical treatment, 
which requires identification of an inner fistula orifice and allows to collect a small 
(1mm) biopsy, while a biopsy at the outer orifice is not compulsory and may be taken 
only in those patients where a clinical indication for unroofing of a perianal abscess or 
fistula exists. The same applies for the second FPV with removal of the seton drain. Thus, 
the FPV procedures are unlikely to increase risks over those inherent to the standard of 
care treatment in these patients.
∀
While a placebo control is needed to explore the efficacy endpoint and safety profile, the
design will assure that all placebo patients not achieving a very strict remission criterion 
will switch over to active drug at week 12, and that patients deriving an individual benefit 
can stay on maintenance treatment for extended periods of time. An active comparator 
would confound safety evaluation and largely reduce the eligible patient population due 
to the expected extensive and diverse pre-treatment history.
∀
The selected dose regimen of BI 655130 is the highest dose evaluated in ongoing 
programs and will at the same time maximize the change of being effective and even at 
steady state will not exceed the exposure tested and found safe in phase I study 1368.2.
∀
Only patients with treatment-resistant perianal fistulizing CD may be enrolled into the 
study demonstrated by primary or secondary failure or unacceptable side effects with 
approved doses of biologics and / or antibiotics. Patients also must have a clinical 


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indication for surgical fistula cleaning and seton drainage. This also indicates the high 
medical need in this patient group.
∀
Reactions to IV administered biologic agents represent the manifestations of systemic 
hypersensitivity reactions including allergic reactions and can occur as anaphylaxis, 
pruritus, hypotension and respiratory distress. Systemic hypersensitivity reactions are 
readily detectable, transient in nature, and manageable with standard medical treatment. 
Specific safety measures will be taken during the trial. Although this has not represented 
an issue in phase I, all patients will be monitored for infusion reactions at the site 
according to Instructions for preparation and Handling of BI 655130.
Other risks of participating in this study include risks related to the trial specific procedures 
including blood sampling, intravenous infusion of study medication, and rectoscopy or 
proctoscopy with biopsy: Blood sampling and intravenous infusions can cause local bruising, 
inflammation, nerve damage and pain. Rectoscopy or proctoscopy with biopsy, although 
generally well tolerated, can be associated with diarrhoea, abdominal pain, perforation, 
bleeding, effects from anaesthetic medications, and infection. 
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also section 5.2.6, adverse events of special interest.
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 in 378 subjects (see Investigators Brochure Version 7) 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.


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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.
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.
Summary of benefit-risk assessment
Due to the current lack of significant mechanism- or compound-related safety signals of BI 
655130 it is considered likely that patients with perianal fistulizing CD will not be exposed to 
undue risks and adverse events in relation to the information that is expected to be gained 
from this trial. Considering the medical need of the development of an effective and well 
tolerated drug specifically and directly treating the structural aspects of CD complicated by 
fistulas, the benefit of this trial is considered to outweigh the potential risks for individual 
patients with perianal fistulizing CD participating in this trial.
The benefit-risk profile is thus considered appropriate for an experimental therapy at this 
early stage of clinical development.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
The Screening Cohort does not directly contribute to the assessment of the trial objectives; its 
purpose is to assess whether eligibility criteria for the Study Cohort have to be amended in 
order to enable an assessment of the trial objectives in the Study Cohort. The patients of the 
Screening Cohort will not be treated with trial medication.
All objectives and endpoints defined in this section are only applicable for the Study Cohort.
Endpoints for the Screening Cohort and their analysis will be defined in the Trial Statistic 
Analysis Plan (TSAP).
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
The primary objectives of this trial are:
∀
To explore the pathomechanisms involved in the generation and healing of CD associated 
perianal fistulas
∀
To understand the MoA of BI 655130 in patients with CD and draining perianal fistulas
Primary endpoint
2.1.2
The primary endpoint is the total number of deregulated genes at week 4 comparing changes 
in gene expression from baseline between the two treatment groups. Thereby, deregulation of 
a gene is defined based on the baseline adjusted mean difference to placebo of gene 
expression fulfilling the following criteria:
∀
FDR adjusted p-value ≤ 0.05
∀
|fold change| ≥ 1.5
∀
genes can be annotated with Ensembl identifiers (version 84 or later)
Gene expression is analysed based on biopsies (curettage and inner fistula orifice) via RNA 
sequencing; more details on the gene expression analysis can be found in Section 7.3.1.
Secondary endpoints
2.1.3
∀
Proportion of patients with perianal fistula response at week 12 (defined as closure of at 
least 50% of external openings, no drainage / discharge despite gentle finger compression
of fistulas that were draining at baseline and without new emerging fistulas)
∀
Proportion of patients with perianal fistula remission at week 12 (defined as closure of all 
external openings, no drainage / discharge despite gentle finger compression of fistulas
that were draining at baseline and without new emerging fistulas)
∀
Proportion of patients with combined perianal fistula remission at week 12 (defined as 
closure of all external openings, no drainage / discharge despite gentle finger compression
of fistulas that were draining at baseline and without new emerging fistulas, AND 
absence collections of >2 cm, confirmed by MRI in at least two of three dimensions –
blinded and centrally read)


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Further details on the planned analyses are given in Section 7.3.


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The following tissue samples will be collected from all perianal fistulas drained by a seton:
∀
Biopsy at the inner fistula orifice
∀
Curettage of the fistula canal
∀
Biopsy at the outer fistula orifice, if clinically indicated
∀
Rectal luminal biopsy (endoscopic): 
2 pairs of biopsies: inflamed region and non-inflamed region
Follow-up period:
The follow-up period will take approx. 3 weeks. The patients can be enrolled in other trials of 
the BI 655130 program and the study cohort of the trial 1368-0008, if they meet the in- and 
exclusion criteria.
Study Cohort
The Study Cohort is designed as a randomized, double-blind and placebo-controlled, parallel-
group phase IIa study of BI 655130, an anti IL-36R antibody, in patients with perianal
fistulizing CD.
Once the gene expression analyses from the obtained fistula canal samples in the 
SCREENING COHORT have confirmed the eligibility criteria, enrolment of the STUDY 
COHORT will be initiated. Otherwise, the sponsor may decide to amend the study (via 
substantial amendment) in order to obtain the relevant tissue from all study participants.
A schematic overview of trial design is shown in figure 3.1:2




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Abbreviations figure 3.1:2
Peri-OP AB: perioperative antibiotic
i.v. admin.: i.v. administration
The Study Cohort will consist of:
∀
screening period, including fistula preparation visits
∀
period 1: 12-week blinded intravenous therapy period
∀
period 2: 12-week blinded intravenous therapy period (treatment assignment depends 
on randomized treatment and achievement of combined perianal fistula remission
after treatment period 1)
∀
Roll over into open label long-term extension study 1368-0007 after EOT (Patients 
completing week 24 of the study and having an individual clinical benefit)
OR
12-week safety follow up period for patients not rolling-over into open label long-
term extension study 1368-0007 (corresponding to 16 weeks after the last dose of BI 
655130)
Screening period, including fistula preparation visit 1c (week -3) and visit 4 (week 4)
The screening period will take up to a maximum of 5 weeks.
During the fistula preparation visit 1c (- 3 weeks), fistula(s) will be drained and a seton will 
be placed and removed at visit 4.
Based on the outcome of the Screening Cohort (gene expression analysis by RNAseq), it will 
be decided whether eligibility criteria have to be amended for Study Cohort.
∀
If only the tissue from the inner orifice but not the fistula canal allows assessing gene 
expression changes the eligibility criteria for Study Cohort will be amended to require 
the availability of an inner orifice biopsy during the baseline FPV.
The following samples will be collected at visit 1c and 4 from all perianal fistulas 
drained by a seton placed at visit 1c:
o
Biopsy at the inner fistula orifice, mandatory
o
Curettage of the fistula canal
o
Biopsy at the outer fistula orifice, if clinically indicated
o
Rectal luminal biopsy (endoscopic): 
2 biopsies: inflamed region and non-inflamed region
∀
If both tissue sources (inner orifice and fistula canal) allow assessing gene expression 
changes, the eligibility in study cohort will not need to limit the study population to 
patients where both tissues are available from the baseline FPV.
The following samples will be collected at visit 1c and 4 from all perianal fistulas 
drained by a seton placed at visit 1c:
o
Biopsy at the inner fistula orifice, optional
o
Curettage of the fistula canal
o
Biopsy at the outer fistula orifice, if clinically indicated
o
Rectal luminal biopsy (endoscopic): 
2 biopsies: inflamed region and non-inflamed region






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administration. These patients, who drop out of the study, will receive standard of care 
treatment per investigator´s discretion.
Patients who complete the EOT visit (visit 9, week 24) in period 2 of this study and who have 
individual clinical benefit may enter the long-term extension study 1368-0007, which offers 
open label active treatment with subcutaneous BI 655130.
Background therapy for underlying CD with conventional immunosuppressants or anti-TNF 
α compounds (provided that is allowed (cf. section 4.2.1).
Individual patient participation is concluded when the patient has completed the last planned 
visit. 
The end of the trial is defined as “last patient out”, i.e. last scheduled visit completed by last 
patient.
An interim analysis of the Study Cohort is planned, please refer to section 7.4
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Section 6.1 and Section 6.2,
respectively.
Table 3.1:1 Study definitions
Rescue Medication
New or increase in dose of any medication 
applied to treat new or persisting symptoms 
related to CD
Disease worsening
Worsening of clinical status or symptoms of 
CD requiring administration of rescue 
medication in the investigator`s opinion – in 
patients without a clinical response
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial is a 2-part exploratory trial. The initial Screening Cohort will determine, whether 
identical pro-inflammatory and pro-fibrotic mediators and pathomechanisms are active in 
tissue samples collected from the fistula canal (via curettage) or from the inner orifice (via 
biopsy), where fistula generation is believed to start with the emergence of epithelial-
mesenchymal transition (EMT) and tissue invasion. Based on the outcome of this cohort, 
feasibility criteria for Study Cohort may have to be adapted (via substantial amendment) to 
exclude patients where for technical reasons a sufficient biopsy of the inner orifice cannot be 
obtained. Patients in the Screening Cohort will only receive standard of care (SOC) for their 
disease, without subsequent randomization to IMP or PBO. 
The Study cohort is designed as a randomized, double-blind and placebo-controlled phase IIa
study. The placebo controlled period 1 of 12 weeks will be followed by additional 12 weeks 
of blinded treatment with active drug or placebo. Treatment in period 2 will depend on the 
original treatment group and the achievement of a strict combined fistula remission outcome 
at week 12: all patients in the original BI 655130 group and non-remitters from the original 


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placebo group will be treated with BI 655130 from week 12 to 24. Remitters to placebo at 
week 12, will continue placebo till week 24. The double blinding will be kept by IRT 
assigning active or placebo based on these decision criteria. The total treatment duration is up 
to 24 weeks; after that time all patients having derived an individual benefit will be offered to 
roll-over into a long-term open label extension study (1368-0007). 
The double blind and placebo controlled induction period 1 of the Study Cohort allows to 
compare gene and biomarker expression in patients with perianal fistulizing CD under 
conditions of placebo treatment or IL36R inhibition. The results will be critical to 
longitudinally characterize the mechanisms of disease involved in the evolution of fistulas, 
and assess the MoA in the active treatment group. The short period of placebo treatment is 
justified due to the previous failure of the selected patients to approved standard of care 
treatments, the subsequent cross-over to double blind treatment with active drug in case there 
is no perianal fistula remission at week 12, and the expected group benefit for patients with 
perianal fistulizing CD resulting from an improved understanding of the pathophysiology of 
this disease and the MoA of a new treatment candidate. The placebo group will also serve as 
appropriate comparator to investigate clinical effect size and safety/tolerability of BI 655130 
in this disease. Placebo patients not achieving a strictly defined combined perianal fistula 
remission (which is unlikely to occur on PBO) will be switched to active drug.
Patients experiencing disease worsening during the treatment period can be discontinued 
from treatment at any time at the investigator`s discretion. Responders to induction treatment, 
in contrast, are expected to benefit from maintenance treatment, e.g. by the achievement of 
luminal and/or fistula remission or mucosal healing, and by prevention of relapses. All 
patients completing the 24 weeks course of the study with an individually perceived clinical 
benefit will be offered to roll-over into an open label long-term study offering continued BI 
655130 treatment for up to additional 7 years.
Since a PoC for BI 655130 is not yet available in CD, the chance of an individual benefit for 
study participants is difficult to estimate, and thus sample size and treatment duration were
limited to a minimum and based on practical feasibility to achieve the study objectives. 
3.3
SELECTION OF TRIAL POPULATION
A total of approximately 5-8 patients will be enrolled in the Screening Cohort at 
approximately 3 sites (approx. 2 patients per site).
Approximately 20 patients will be randomised in the Study Cohort at approx. 20 sites 
(approx. 1 patient per site). A sufficient number of patients will be screened to meet this 
randomisation target. Screening of patients for this trial is competitive. Investigators will be 
notified about screening completion and will then not be allowed to screen additional patients 
for this trial. Screening of patients for Study Cohort may stay open until approximately 15 
patients have valid baseline and post treatment biopsies for primary endpoint analysis. 
Participation of Women of childbearing potential (WOCBP): Please refer to section 4.2.2.4
for acceptable methods of birth control. 


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A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
Main diagnosis for trial entry
3.3.1
Patients with previously treatment-resistant perianal fistulizing CD with clinical indication 
for seton drainage.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
Inclusion criteria for Screening Cohort and Study Cohort
3.3.2
Each patient of Screening Cohort and Study Cohort must meet all of the following inclusion 
criteria to be included into the trial:
1. 18-75 years at date of signing informed consent
2. Male or female patients. Women of childbearing potential (WOCBP)1 must be ready and 
able to use highly effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and correctly. A list of 
contraception methods meeting these criteria are provided in section 4.2.2.4 Restrictions 
regarding women of childbearing potential. Restrictions regarding contraception for 
female patients are not applicable for Screening Cohort.
3. Diagnosis of clinical Crohn´s Disease ≥ 3 months prior to screening by clinical and 
endoscopic evidence and corroborated by a histopathology report
4. Has ≥ 1 perianal active* fistula(s) with clinical indication for seton drainage (≥ 4 weeks 
duration before enrolment, as a complication of CD) **. 
* Criteria for Active Fistula: As per clinical evaluation: Presence of spontaneous 
drainage or drainage after gentle finger compression at the external openings & as 
confirmed by radiological (MRI) exploration . 
** Patients who are screened with a seton drainage in place are eligible provided the 
drainage has not been in place for > 3 months and the patient meets the rest of the 
eligibility criteria 
5. Additional enterocutaneous or abdominal fistulas are permitted (except rectovaginal 
fistulas)
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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6. Absent, mild or moderate clinical activity with CDAI < 250. CDAI is not applicable for 
Screening Cohort.
7. Demonstrated in the past inadequate fistula response or loss of response or have had 
unacceptable side effects with approved doses of at least one of the following 
compounds: Immunesuppressive agents (e.g. thiopurines, methotrexate), 
TNFɑ antagonists (e.g. infliximab, adalimumab, certolizumab pegol; or respective 
biosimilars), vedolizumab, ustekinumab, azathioprine and / or antibiotics (cf. section 
10.7)
8. Patients with family history of colorectal cancer or personal history of increased 
colorectal cancer risk must have had a negative ileocolorectal cancer screening within <1 
year prior to screening per local guidance 
9. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
Exclusion criteria
3.3.3
Screening Cohort
3.3.3.1
No exclusion criteria are applicable for the Screening Cohort.
Study Cohort
3.3.3.2
Patients of Study cohort meeting any of these exclusion criteria must not be enrolled into the 
trial:
3.3.3.2.1
Gastrointestinal Exclusion Criteria
1. Complications of Crohn’s Disease such as symptomatic strictures, functional stenosis 
distal from fistula(s), short gut syndrome, or any other manifestation that might require 
surgery, could preclude the use of the PDAI and CDAI to assess response to therapy, or 
would possibly confound the evaluation of benefit from treatment with BI 655130
2. Rectovaginal fistulas
3. Anticipated to require surgical intervention for CD including any fistula surgical 
procedures (except seton drainage). See Table 4.2.2.2:1 for a detailed list of restricted 
interventions
4. Has an abscess that the investigator feels requires drainage beyond fistula drainage with a 
seton (based on either clinical assessment or MRI)
5. Any kind of bowel resection or diversion within 6 months or any other intraabdominal 
surgery within 3 months prior to screening. 
6. Ileostomy, colostomy or known fixed symptomatic stenosis of the intestine at screening.
7. Positive stool examinations for C. difficile or other intestinal pathogens < 30 days prior to  
screening
8. Evidence of colonic mucosal dysplasia or colonic adenomas, unless properly removed
(properly according to the investigator’s assessment)
9. Faecal Microbiota transplant (FMT) within 6 months prior to randomization
10. Treatment with (See table 4.2.2.1:1 for a detailed list of restricted treatments):


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o
any non-biologic medication (incl. cyclosporine, JAK inhibitors such as 
tofacitinib, tacrolimus, sirolimus, mycophenolate mofetile, S1P modulators, 
SMAD7 antisense inhibitors such as mongersen), other than those allowed per 
chapter 4.2.1 within 30 days prior to randomisation unless these patients show an 
undetectable plasma concentration 
o
any biologic treatment approved for CD other than anti-TNFα inhibitors within 8 
weeks prior to randomization unless these patients show an undetectable plasma 
concentration
o
any investigational or non-approved biologic for CD (including but not limited to 
IL-23 inhibitors) within 12 weeks prior to randomisation or etrolizumab within 8 
weeks prior to randomization unless these patients show an undetectable plasma 
concentration
o
rectal 5-ASA, rectal Tacrolimus, parenteral or rectal corticosteroids (incl. 
budesonide) within 2 weeks prior to randomisation
o
any antibiotics within 1 week prior to randomisation
o
any prior autologous or allogeneic, haematopoietic (HSC) or mesenchymal stem 
cell (MSC) therapy any prior exposure to BI 655130
o
any chronic use of NSAID within 2 weeks prior to randomisation
(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)
o
any life-attenuated vaccines within 6 weeks prior to randomization
3.3.3.2.2
Infectious Disease Exclusion Criteria
11. Increased risk of infectious complications (e.g. due to past organ or stem cell 
transplantation)
12. Live or attenuated vaccination within 6 weeks prior to randomization
13. Patients with a positive QuantiFERON TB test during screening are excluded, unless:
o
Patient had previous diagnosis of active or latent TB and has completed 
appropriate treatment per local practice/guidelines within the last 3 years and at 
least 6 months before first administration of trial medication under this protocol 
(patients may be re-screened once to meet this criterion)
o
Patients with suspected false positive or indeterminate QuantiFERON TB result 
may be re-tested once
o
If Quantiferon not available or providing indeterminate results after
repeat testing : A tuberculin skin test reaction ≥10mm (≥5mm if receiving 
≥15mg/d prednisone or its equivalent)
14. Relevant chronic or acute infections including active tuberculosis, human 
immunodeficiency virus (HIV) infection or viral hepatitis. A patient can be re-screened if 
the patient was treated and is cured from the acute infection.
3.3.3.2.3
General Exclusion Criteria
15. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, or in situ carcinoma of uterine cervix.


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16. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to randomization or planned during study conduct, e.g. hip replacement.
17. Pathological safety lab parameters: haemoglobin < 8 g/dL, total white blood count 
(WBC) < 3000 cells/μl, neutrophils < 1000 cells/μl, thrombocytes < 100.000/μl, 
creatinine ≥ 2 mg/dL, total bilirubin > 2 x ULN with ratio of direct/indirect >1 (patients 
with Gilbert’s syndrome are not excluded), Alkaline Phosphatase >3 x ULN. 
18. Patients who must or wish to continue the intake of restricted medications (see section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
19. Previous enrolment in this trial (exception: patients of screening cohort may be enrolled 
in study cohort)
20. Currently enrolled in another investigational device or drug trial. Specific restrictions for 
patients who have participated recently in another drug trial are listed in section 4.2.2
21. Women who are pregnant, nursing, or who plan to become pregnant  in the trial
22. Evidence of a current or previous disease, medical condition (including chronic alcohol or 
drug abuse) other than crohn´s disease, surgical procedure, medical examination finding 
(including vital signs and electrocardiogram (ECG)), or laboratory value at the screening 
visit outside the reference range that in the opinion of the investigator is clinically 
significant and would make the study participant unreliable to adhere to the protocol or to 
complete the trial, compromise the safety of the patient, or compromise the quality of the 
data
23. History of allergy/hypersensitivity to the systemically administered trial medication agent
or its excipients or to contrast media.
Withdrawal of patients from therapy or assessments
3.3.4
Patients may discontinue trial treatment (not applicable for Screening Cohort) 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.
Every effort should be made to keep the patients in the trial: if possible on treatment (not 
applicable for Screening Cohort), or at least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment (not applicable for Screening Cohort) or withdraw 
consent to trial participation and the reason must be documented in the patient files and CRF.
If the reason for discontinuation is death, this should be reported on the SAE form as well, 
regardless of causal relationship.
Discontinuation of trial treatment
3.3.4.1
Not applicable for Screening Cohort. Applicable for Study Cohort, only.
An individual patient will discontinue trial treatment if:
∀
The patient wants to discontinue trial treatment, without the need to justify the decision.
∀
The investigator clinical judgement advises for it.


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∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
∀
The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment. Please refer to the section 4.2.2 for restricted 
medications.
∀
The patient needs surgical interventions for CD including any fistula surgical procedures
(except seton drainage, see section 4.2.2.2)
∀
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).
∀
For individual stopping rules related to specific adverse events, please see section 4.2.1
In case of a temporary reason, trial treatment should be restarted if medically justified, please 
see section 4.1.4.
Even if the trial treatment is discontinued, the patient remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart B and C and section 6.2.2.
Withdrawal of consent to trial participation
3.3.4.2
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation (not 
applicable for Screening Cohort) and withdrawal of consent to trial participation, as well as
explain the options for continued follow up after trial treatment discontinuation, please see 
section 3.3.4.1 above.
Discontinuation of the trial by the sponsor
3.3.4.3
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
Patients in Screening Cohort will not be treated with trial medication. For this reason, the 
chapter 4.1 is not applicable for Screening Cohort.
Identity of the Investigational Medicinal Products
4.1.1
Table 4.1.1: 1
Description of test product BI 655130 i.v.
Substance:
BI 655130
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
60mg/ml
Posology
Study Cohort: 1200mg every 4 week
∀
Period 1: at week 0, 4, 8
∀
Period 2: at week 12, 16, 20
Route of administration:
Intravenous (i.v.)
Duration of use
24 weeks
Table 4.1.1: 2
Description of test product placebo matching to BI 655130 i.v.
Substance:
Placebo matching to BI 655130
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Not applicable


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Table 4.1.1: 2
Description of test product placebo matching to BI 655130 i.v. cont.
Posology
Study Cohort: 0 mg (placebo) every 4 week
∀
Period 1: at week 0, 4, 8
∀
Period 2: at week 12, 16, 20
Route of administration:
Intravenous (i.v.)
Duration of use
24 weeks
Selection of doses in the trial
4.1.2
The aim of this small exploratory study is to provide the highest likelihood to study the 
mechanism of BI 655130 in CD 
 Based on other effective anti-cytokine drugs in IBD and pre-clinical assays for IL-
36 inhibition, a monotonic rather than a bell-shaped dose-response curve is expected. Thus, 
the highest tolerated dose (1200 mg i.v. q4w) should provide the highest likelihood to achieve 
this objective. This dose is also expected to provide the best chance to induce clinical 
remissions in CD patients. Whether lower doses will be sufficient to achieve maximum 
efficacy will be subject of subsequent studies. This dose regimen is the highest covered by 
current healthy volunteer PK and safety data for individuals. 
Currently approved or investigational biologics (e.g. TNFi, vedolizumab, ustekinumab) have 
established 4-8 weeks duration of induction treatment in CD; a longer induction period of 12 
weeks (patients on placebo in period 1) or 24 weeks (patients on BI 655130 in period 1) was 
selected to allow assessment of the response kinetics for BI 655130, which represents a new 
and clinically non-validated MoA. 
The dosing interval of once every 4 weeks is supported by the long half-life of BI 655130.
Method of assigning patients to treatment groups
4.1.3
Study Cohort, Period 1: Double blind
During visit 2 eligible patients in Study Cohort will be randomised to receive 12 weeks of 
treatment (i.e. three administrations) with BI 655130 1200mg i.v. every 4 weeks or matching 
placebo in a 1:1 ratio according to a randomization plan. The assignment will occur in a 
blinded fashion via Interactive Response Technology (IRT).
Study Cohort, Period 2: Double blind
Treatment in period 2 starting in visit 6 (BI 655130 1200mg i.v. every 4 weeks or placebo)
will be determined by the outcome at week 12 (cf. section 3.1). The assignment will occur in 
a blinded fashion via Interactive Response Technology (IRT).
Details regarding the use of the IRT are described in the site-user manual available in the ISF.


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Drug assignment and administration of doses for each patient
4.1.4
Patients in Study Cohort will be treated with BI 655130 as indicated in the Flow Chart and 
section 3.1.
The medication will be assigned via IRT for period 1 and 2.
Detailed instructions for the preparation of the solution for infusion, the volume to be 
administered and the infusion rate (BI 655130 i.v.) are provided in the ISF.
The administration of the trial medication on all applicable study days will be done under 
supervision of the investigating physician or a designee at the site. If available, a pharmacist 
should prepare the study medication. The so-called four eye principle (two-person rule) 
should be applied for preparation (e.g. choosing the correct vials with the correct medication 
number) and administration of trial medication.
During the COVID-19 pandemic, physical visits to the sites may need to be restricted to 
ensure patient safety. Based on a thorough assessment of the benefits and risks, the 
investigator may discuss with BI to continue the trial treatment and trial medication may be 
shipped to the patient’s home if acceptable according to local law and regulations.
In case of safety concerns, e.g., due to infusion reactions, it is in the discretion of the 
investigator or his/her designee to adapt the infusion scheme, including but not limited to 
slowing down the infusion rate, interrupting the infusion and - provided no further safety 
concern exist - restarting at a slower rate. Further, based on 
 medical judgment he/she will 
provide medications such as steroids, etc., as needed (cf. section 4.2.1 for handling of
infusion reactions). Detailed instructions for handling of infusion reactions are also provided 
in the ISF.
Dose modifications or adjustments are not permitted. In exceptional cases of missed or 
delayed visits, study drug of the following visit should not be administered within 14 days of 
the prior dose. There should be at least 14 days between two consecutive study drug 
administrations.
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
Study Cohort, Period 1 and 2: Double blind
Patients and investigators (including the research staff at the trial site) will remain blinded 
with regard to the randomized treatment assignments until the final database lock for the final 
trial analysis.
The interim analysis, which is the primary analysis of the trial will be performed once all 
randomized patients have completed through 12 weeks of trial treatment. At this time, a 
preliminary database lock will be done and treatment will be unblinded. In order to confirm 
the integrity of the treatment blind while the trial continues through to completion, a logistics 
plan will be developed to describe the mechanisms that are to be put in place to assure that 


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the patients and investigators remain blinded to both individual patient data, as well to the 
primary analysis results. The blind status of trial and project team members at this time will 
also be clarified. The logistics plan will be finalized prior to the treatment unblind for the 
primary analysis.
The randomization code will be kept secret by Clinical Trial Support and will not be
accessible prior to the preliminary database lock for the interim analysis by anyone else
involved in the trial with two exceptions. The bioanalytical laboratory will receive the 
randomization code during the trial conduct in order to avoid testing of placebo patient 
samples for PK and ADA. The bioanalytical laboratory can be regarded as totally 
independent from the trial team. After the last patient completes the Week 12 visit the 
random plan will be released to the bioinformatics group. The bioinformatics group will 
receive the randomisation code in order to start with the pre-processing of gene expression 
data (using limma packages).
Bioinformatics groups and the analytical laboratory will not disclose the randomization code 
until the trial is officially unblinded.
A fully external DMC will perform an un-blinded safety and efficacy assessment at specified 
intervals in order to ensure that patients are protected from potential harm, please refer to 
Section 7.4 for further details.
Unblinding and breaking the code
4.1.5.2
Study Cohort, Period 1 and 2:
Emergency unblinding will be available to the investigator / pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’ s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives and not be shared 
further. 
Treatment unblinding will be performed prior to each DMC meeting as a prerequisite for 
generation of the applicable DMC summaries required.
Packaging, labelling, and re-supply
4.1.6
The investigational products will be provided by BI or a designated CRO. They will be
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.


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Storage conditions
4.1.7
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately. Refer to ISF.
Trial medication must be securely stored, e.g. in a locked refrigerator or at a pharmacy. The 
medication may only be dispensed to trial patients according to the Clinical Trial Protocol
(CTP) by authorized personnel as documented in the trial staff list.
IMP will only be prepared for infusion just prior to the administration. 
Drug accountability
4.1.8
The investigator/pharmacist /investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB / ethics committee ,
∀
Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,
∀
Approval/notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated clinical trial protocol,
∀
Availability of the proof of a medical license for the Principal Investigator,
∀
Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator/pharmacist/ investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor or warehouse / drug distribution centre or alternative disposal of 
unused products. If applicable, the sponsor or warehouse / drug distribution centre will 
maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator / pharmacist / investigational drug storage 
manager must verify that all unused drug supplies have been returned by the clinical trial
patient and that no remaining supplies are in the investigator’s possession


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
Section 4.2.1 is applicable for the Study Cohort and not for the Screening Cohort.
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 
4.2.2.1 for restrictions), which are therefore permitted concomitant medications:
∀Oral 5-ASA compounds, provided that dose has been stable for > 2 weeks prior to  
randomisation, and/or
∀Oral corticosteroids (≤ 20 mg per day of prednisone or equivalent), provided that dose 
has been stable for > 2 weeks prior to randomisation, and/or 
∀Oral budesonide (≤ 9 mg per day ), provided that dose has been stable for > 2 weeks 
prior to randomisation,  and/or 
∀Azathioprine, 6-MP, 6-TG or methotrexate, provided that dose has been stable for > 8 
weeks prior to randomisation
∀Approved anti-TNFα (e.g. infliximab, adalimumab, certolizumab pegol; or respective 
biosimilars) provided that 
i. dose has been stable for at least 6 months prior to screening and
ii.
Rest of eligibility criteria are met ( i.e activity of the fistula based on 
clinical and MRI assessment at screening, see inclusion criterion 4). 
∀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 throughout the trial. The only exceptions are anti-diarrheals, which may 
be adjusted to current symptoms, and steroid reduction, which is allowed after week 12 to a 
minimum dose of 10 mg/d (budesonide: 6 mg/d) according to local standard of care.
Peri-OP antibiotics
Peri-OP antibiotics at the day before until the day after fistula preparation visits (visit 1c and 
4) are allowed if required according to standard of care.
In the event that a patient experiences a disease worsening of CD, as deemed by the 
investigator, during the course of the trial, the decision whether or not to discontinue 
treatment and start rescue treatment should be taken in the discretion of the investigator and 
in discussion with the CTM. Rescue treatment may be any new medication for treatment of 
CD or any increase in dose of a baseline CD medication.
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (cf. Section 3.3) are
permissible. All concomitant medications should be carefully evaluated by the investigator 
and the CTM should be contacted when there are questions regarding concomitant 
medications.


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For further information regarding concomitant therapies and restrictions, see table 4.2.2.1:1.
Details of all concomitant medication will be recorded in the eCRF, along with the main 
reason for prescription. In addition, all prior treatment for CD at Visit 1a will be recorded
including information on reason for discontinuation.
Management of Adverse Events:
Infusion reactions including anaphylactic reaction
∀
In case of infusion reactions including anaphylactic reaction emerging during or after 
infusion of trial medication, the investigator should consider in accordance with severity 
of the reaction and local standard of care to
∀
Immediately interrupt the infusion
∀
Treat with systemic anti-histamines, intravenous steroids, and in case of a severe allergic 
reaction (e.g., anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA as detailed in the Lab Manual (ISF). Consider 
also the evaluation of histamine, serum tryptase, and complement components.
In case of infusion reaction, based on patient`s clinical course and medical judgment, the 
infusion may be re-initiated in case of mild or moderate infusion reactions (according to 
RCTC grading of “allergic reaction / hypersensitivity” in ISF) at lower speed with gradual 
increase to complete the infusion as detailed in the Instructions for Preparation and Handling 
of BI 655130/Placebo in the Investigator Site File.
In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.8 R11-4890) suspected to be caused by the trial medication, the 
investigator should discontinue treatment with trial medication permanently.
When a non-acute hypersensitivity reaction related to immune complexes (i.e., serum 
sickness) is suspected, please draw a sample for the laboratory assessment for circulating 
immune complexes.
Severe infections (according to RCTC grading in Appendix 10.9), serious infections, 
opportunistic or mycobacterium tuberculosis infections
∀
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 trial medication may be restarted when the patient has recovered 
according to investigator’s assessment.
Malignancies
∀
In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix, 
the investigator should discontinue treatment with trial medication. Diagnostics and 
treatment have to be initiated according to local standard of care.


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Restrictions
4.2.2
Section 4.2.2 is applicable for the Study Cohort and not for the Screening Cohort.
Restrictions regarding concomitant treatment
4.2.2.1
Restrictions regarding previous and concomitant treatment are summarized in table 4.2.2.1: 1
Table 4.2.2.1:1
Restrictions regarding previous and concomitant treatment
Medication or class of medications
Restriction 
Any non-biologic medication (incl. 
cyclosporine, JAK inhibitors such as 
tofacitinib, tacrolimus, sirolimus, 
mycophenolate mofetile, S1P 
modulators, SMAD7 antisense 
inhibitors such as mongersen), other 
than those allowed per chapter 4.2.1
Not allowed from 30 days prior to randomisation
, unless undetectable plasma concentration, until 
end of the trial 
For use as rescue medication, refer to Section 
4.2.1.
Any biologic treatment approved for 
CD other than anti-TNF α 
(vedolizumab or ustekinumab)
Not allowed from 8 weeks prior to 
randomisation, unless undetectable plasma 
concentration, until end of the trial
For use as rescue medication, refer to Section 
4.2.1.
Pre-requisites for anti-TNF α treatment, please 
refer to Section 4.2.1.


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Table 4.2.2.1:1
Restrictions regarding previous and concomitant treatment (cont.)
Any investigational or non-approved
biologic for CD (incl. but not limited 
to IL-23 inhibitors, etrolizumab)
Not allowed from 12 weeks prior to 
randomisation, unless these patients show an 
undetectable plasma concentration, until end of 
the trial.
Etrolizumab: Not allowed from 8 weeks prior to 
randomisation, unless undetectable plasma 
concentration, until end of the trial.
For use as rescue medication, refer to Section 
4.2.1.
Any immunomodulator allowed per 
chapter 4.2.1 (azathioprine, 6-
mercaptopurine, 6-TG or 
methotrexate) 
Only allowed during the trial, if dose is stable 
for at least 8 weeks prior to randomisation until 
end of the trial
For use as rescue medication, refer to Section 
4.2.1.
Autologous or allogeneic, 
haematopoietic (HSC) or 
mesenchymal stem cell (MSC)
therapy
Any prior exposure is not allowed
Faecal Microbiota transplant (FMT)
Not allowed from 6 months prior to 
randomization until the end of the trial
BI 655130
Any prior exposure is prohibited
5-ASA
Oral administration:
Only allowed during the trial, if dose is stable 
for at least 2 weeks prior to randomisation until 
end of the trial
Rectal route of administration (5-ASA):
Not allowed from 2 weeks prior to 
randomisation up to end of the trial
For use as rescue medication, refer to Section 
4.2.1.


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Table 4.2.2.1:1
Restrictions regarding previous and concomitant treatment (cont.)
Rectal Tacrolimus
Not allowed from 2 weeks prior to 
randomisation up to end of the trial
Corticosteroids (incl. budesonide)
Oral administration:
Oral budesonide only allowed at a dose of ≤9
mg per day, and with stable dose for at least 
2 weeks prior to randomisation and 
throughout the trial.
Oral steroids only allowed at a dose of ≤ 20 mg
per day of prednisone or equivalent and with 
stable dose for at least 2 weeks prior to 
randomisation and throughout the trial.
Note: Steroids may be reduced after week 12 to 
a min. dose of 10mg/d (budesonide: 6 mg/d) –
see section 4.2.1.
Parenteral administration:
Not allowed from 2 weeks prior to 
randomisation up to end of the trial.
Note: parenteral steroids dosed for less than 24 
hours as treatment of infusion or anaphylactic 
reactions are permitted.
Rectal administration:
Not allowed from 2 weeks prior to 
randomisation up to end of the trial
For use of steroids as rescue medication, refer to 
Section 4.2.1.
NSAID
Chronic use not allowed from 2 weeks prior to 
randomisation up to end of the trial
(Note: occasional use of NSAIDs and 
acetaminophen for headache, arthritis, myalgias, 
menstrual cramps, etc., and daily use of baby or 
low dose (81-162.5mg) aspirin for 
cardiovascular prophylaxis are permitted.)
Life-attenuated vaccines
Not allowed from 6 weeks prior to 
randomisation up to end of the trial


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Table 4.2.2.1:1
Restrictions regarding previous and concomitant treatment (cont.)
Probiotics (e.g. S. boulardii)
Probiotics only allowed if dose is stable for at 
least 4 weeks prior to randomization until end of 
the trial
Antibiotics for IBD 
Not allowed from 1 week prior to randomisation
up to end of the trial.
Peri-OP antibiotics at the day before until the day 
after fistula preparation visits (visit 1c and 4) are 
allowed if required according to standard of care.
Anti-diarrheals
No restrictions
Restricted fistula interventions
4.2.2.2
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. These are summarized in table 4.2.2.2:1. ( no exhaustive 
list).
Table 4.2.2.2:1 Restrictions regarding 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 screening (screening 
visit 1a) until end of the trial 
Restrictions on diet and life style
4.2.2.3
No specific restrictions on diet or life style of the patients are required.
Restrictions regarding women of childbearing potential
4.2.2.4
Female patients of child bearing potential must maintain adequate contraception throughout 
the course of the trial and up to 16 weeks after the last study drug administration.
Women of childbearing potential must use highly effective contraception methods described 
below:
∀
Combined (estrogen and progestogen containing) hormonal birth control associated 
with inhibition of ovulation.
∀
Progestogen-only hormonal birth control associated with inhibition of ovulation.
∀
Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS).
∀
Bilateral Tubal occlusion (blocking of the fallopian tubes).


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∀
Vasectomy of sexual partner (proven effective by absence of sperm on the 
ejaculation).
∀
Complete sexual abstinence (not to have male-female vaginal sex)*.
*Refraining from heterosexual intercourse during the entire trial. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the patient
As monoclonal antibodies can be secreted in milk, women should refrain from breastfeeding 
once they receive the study drug and up to 16 weeks after, i.e. until BI 655130 is eliminated. 
They can start nursing again after this period.
4.3
TREATMENT COMPLIANCE
Study medication will be administered in accordance with the protocol by authorised study 
personnel (e.g. study nurse). 
Any missed dose has to be documented and reported to the CTM.






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Physical examination
5.2.1
A complete physical examination will be performed at the time points specified in the 
flowchart. It includes vital sign assessment and general appearance as well as evaluation of 
all organ systems.
Targeted physical examination will include vital sign assessment and evaluation of organ 
systems associated with AE(s) symptoms or laboratory abnormalities.
Measurement of height and body weight will be performed at the time points specified in the 
flowchart.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
Vital signs
5.2.2
Vital signs evaluations will be performed at visits as shown in the Flow Chart, prior to blood 
sampling.
This includes temperature, pulse rate (electronically or by palpation count for 1 minute), 
systolic/diastolic blood pressure and respiratory rate in a seated position after at least 5 
minutes of rest.
Study Cohort:
At dosing visits vital signs evaluations will be performed pre-dose and additional evaluation 
will be taken at approximately 10 minutes and 1 hour post-dose.
Monitoring for hypersensitivity reactions:
Patients should be closely monitored for signs and symptoms of hypersensitivity reactions for 
approximately 2 hours after the first dose administered at visit 2 and 1 hour following all 
other doses of study drug. Hypersensitivity reactions should be treated according to medical 
standards. Pre-medications for further infusions might be considered and will be agreed on 
between investigator and BI clinical monitor.
The investigator should evaluate the clinical significance of the results. Clinically abnormal 
findings will be reported as baseline condition or AEs.
Safety laboratory parameters
5.2.3
The safety laboratory samples will be taken for the Screening Cohort according to their local 
standard of care. No specific parameters are requested. 
Section 5.2.3 is applicable for the Study Cohort, only.
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1 and 5.2.3:2. For the 
sampling time points please see the Flow Chart. More frequent blood sampling may be done 
whenever the investigator deems necessary. Unscheduled safety laboratory examinations will 
be reported in the CRF along with the results.
All safety laboratory analyses will be performed by a local laboratory.


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It is preferred but the patients do not have to be fasted for the blood sampling for the safety 
laboratory.
It is the responsibility of the investigator to evaluate the laboratory results from the local 
laboratory. 
Clinically relevant abnormal findings as judged by the investigator will be reported as 
baseline conditions or adverse events (please refer to Section 5.2.6).
A clinically relevant value may be either in- or outside the reference range. Clinically 
relevant abnormal laboratory test results must be confirmed and should be repeated until 
normalization or stabilization or until an alternative explanation has been found. Abnormal 
laboratory values will be also graded for intensity by using RCTC Version 2.0 criteria. (R13-
3515).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1) and the DILI Checklist provided in the ISF eDC
system. The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.
Table 5.2.3: 1 Exclusionary testing
Category
Test name
Infection testing
Hepatitis B Surface Antigen (qualitative)1
Hepatitis B core Antibody1
HBV-DNA (quantitative PCR)2
Hepatitis C Antibodies (qualitative)1
HIV-1, and HIV-2 Antibody (qualitative)1
TB screening
QuantiFERON®-TB3, 4
Serum Pregnancy test (only for female patients of 
childbearing potential) 1)
Human Serum Chorionic Gonadotropin
Stool studies to evaluate for enteric pathogens 1)
Salmonella
Shigella
Yersinia
Campylobacter
E. coli
Clostridia difficile toxin
Enteric parasites and their ova (including 
Cryptosporidia)
1 At screening only (visit 1)
2 A HBV-DNA should be conducted if Hepatitis B core Antibody is positive and Hepatitis B 
Surface Antigen is negative (definition of occult HBV infection: B core Antibody is positive, 
Hepatitis B Surface Antigen is negative; HBV DNA detectable).
3 There is the trial site option to perform a PPD skin test
4 If the 1st QuantiFERON®-TB test result is undetermined, a re-test should be performed. If 
the re-test QuantiFERON-TB test result is undetermined, a PPD skin test should be 
performed.


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Table 5.2.3: 2 Laboratory tests
Category
Test name
Haematology
Haematocrit (Hct)
Haemoglobin (Hb)
Glycosylated Hbc (HbA1c) (only at screening)
Red Blood Cell Count/ Erythrocytes
Reticulocyte Count
White Blood Cells / Leukocytes
Platelet Count/ Thrombocytes
Diff. Automatic
Neutrophils (relative and absolute count)
Eosinophils (relative and absolute count)
Basophils (relative and absolute count)
Monocytes (relative and absolute count)
Lymphocytes (relative and absolute count)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils, bands (Stabs)
Neutrophils, polymorphonuclear (PMN)
Eosinophils
Basophils
Monocytes
Lymphocytes
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin time (INR)
Fibrinogen
Enzymes
AST (GOT)
ALT (GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Amylase
Lipase
Electrolytes
Calcium
Sodium
Potassium
Chloride
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


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Table 5.2.3: 2 Laboratory tests (cont.)
Category
Test name
Specific gamma-globulin quantification
IgE1, IgG
Urine Pregnancy test (only for female patients of 
childbearing potential)
Human Chorionic Gonadotropin in urine
Serum Pregnancy test (only for female patients of 
childbearing potential if urine pregnancy test is 
positive)
Human Serum Chorionic Gonadotropin
Hormones (only at screening)
TSH (free T3 and free T4 in case of abnormal TSH 
result) 
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leukocytes
Urine pH
Urine-Sediment (microscopic examination, only if 
urine analysis abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells
Urine Sed. Crys., Unspecified
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
Urine (only at screening)
Albumin (quantitative)
Infections screening
HBV-DNA (quantitative) at EOT Visit2
QuantiFERON-TB test
QuantiFERON®-TB at EOT visit 3, 4
1Only in case of allergic reaction
2 HBV-DNA in case of occult HBV infection (for definition see Table 5.2.3: 1 footnote 2)
3 There is the trial site option to perform a PPD skin test 
4 If the 1st QuantiFERON®-TB test result is undetermined, a re-test should be performed. If 
the QuantiFERON-TB re-test result is undetermined, a PPD skin test should be performed.
Electrocardiogram
5.2.4
12-lead ECGs are performed for the Screening Cohort according to their local standard of 
care. No specific parameters are requested. 
Section 5.2.4 is applicable for the Study Cohort, only.
The 12-lead ECGs will be recorded as scheduled in the flowchart. The investigator or a 
designee will evaluate whether the ECG is normal or abnormal and whether it is clinically 
relevant, if abnormal. ECGs may be repeated for quality reasons and the repeated recording 
used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.


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Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
Other safety parameters
5.2.5
All cases of malignancies that are detected during the trial will be reported as SAEs. Patients 
with a history of malignancy (except for specific cancers) will be excluded from this trial per 
the exclusion criteria (cf section 3.3.3).
Assessment of adverse events
5.2.6
Definitions of AEs 
5.2.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalisation
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
Planned hospitalizations which may be required for administrative reasons to make the 
conduct of visits feasible (e.g. fistula preparation visits 1c and 4) need not to be reported as 
SAEs.
Patients may be hospitalized for administrative reasons during the trial, including 
hospitalization for respite care. These as well as hospitalizations/surgical procedures which 
were planned before the patient signed informed consent need not be reported as SAEs if they 


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have been documented at or before signing of the informed consent and have been performed 
as planned (the condition requiring hospitalization/surgical procedure has not 
changed/worsened after signing the informed consent).
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see section 5.2.6.2.
The following are considered as AESIs:
∀
Infusion reactions including anaphylactic reaction (study cohort, only)
o
Any suspicion of severe infusion reaction and of any potential cases of 
anaphylaxis should be defined and assessed using the criteria discussed in the 
statement paper from Sampson HA (Appendix 10.8 R11-4890).
∀
Severe infections (according to RCTC grading in Appendix 10.9)
∀
Opportunistic and mycobacterium tuberculosis infections 
o
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, 
post-transplant lymphoproliferative disorder (EBV), progressive multifocal 
leukoencephalopathy, 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 


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(visceral only), trypanosoma cruzi infection (Chagas’ disease) (disseminated 
only), campylobacteriosis (invasive only),  shigellosis (invasive only), vibriosis 
(invasive due to vibrio vulnificus), HCV progression (R17-2617)
Hepatic injury (study cohort, only)
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
∀
an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or
∀
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF. 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity grading of AEs will be performed according to Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0 developed by 
 Refer to the ISF for 
intensity/severity classification. Intensity options are:
Grade 1 
mild
Grade 2 
moderate
Grade 3 
severe
Grade 4 
life-threatening
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Investigator´s causality assessment should be provided as requested on the appropriate 
CRF(s) and on the SAE form (if applicable).
Arguments that may suggest that there is a reasonable possibility of a causal relationship to 
drug could be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-existing 
or concomitant diseases, or co-medications).


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∀
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship to 
drug 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.
Adverse event collection and reporting
5.2.6.2
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:
For patients without roll-over from study cohort to subsequent long-term extension study 
1368-0007:
∀
From signing the informed consent onwards until individual patient’s end of trial:
- all AEs (non-serious and serious) and all AESIs.
∀
After the individual patient’s end of the trial: 
- the investigator does not need to actively monitor the patient for new AEs but should 
report any occurrence of cancer and trial treatment related SAEs and trial treatment
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form 
(see chapter “AE reporting to sponsor and timelines”), but not on the CRF.
For patients who roll-over from study cohort to subsequent long-term extension study 1368-
0007:
∀
From signing the informed consent (1368-0008) onwards until the first dose of trial 
medication in 1368-0007:
- all AEs (non-serious and serious) and all AESIs.
   (updates to concomitant therapy should also be included until first dose of trial 
   medication in 1368-0007)














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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Screening Cohort:
All patients from Screening Cohort are to adhere to the visit schedule as specified in the Flow 
Chart A. Visit windows are defined in the Flow Chart. 
Study Cohort:
All patients from Study Cohort are to adhere to the visit schedule as specified in the Flow 
Chart B (visit 1 to 5) and Flow Chart C (visit 6 to 10). 
Visit windows are defined in the Flow Chart. 
Each visit data (with its window) up to EOS is to be counted from Day 1 (Visit 2). If any of 
these visits has to be rescheduled, the date of subsequent visits should be calculated from the 
date of visit 2.
Follow-up visit (EOS, visit 10) refers to the last dose administration of BI 655130 at visit 8 
(Week 20) and is applicable for patients only who will not join the roll-over long-term 
extension study 1368-0007. 
Regarding instructions for drug administration at missed or delayed visits please refer to 
Section 4.1.4.
Screening Cohort and Study Cohort:
Additional visits for the purpose of re-testing of laboratory parameters or AE monitoring may 
be included as deemed necessary by the investigator.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart and the respective 
protocol sections. Refer to Section 5 for explanations of procedures. Additional details on 
procedures at selected visits are provided below.
This trial is devided into two cohorts (cf.section 3.1)
The Screening Cohort is designed as a non-randomized screening cohort in patients with 
perianal fistulizing CD. Based on the outcome of this cohort, feasibility criteria for the Study 
cohort may have to be amended (via substantial amendment) to exclude patients where for 
technical reasons a sufficient biopsy of the inner orifice cannot be obtained.
The patients will not be treated with trial medication.
Study Cohort is designed as a randomized, double-blind and placebo-controlled, parallel-
group phase IIa study of BI 655130, an anti IL-36R antibody, in patients with perianal
fistulizing CD. The double-blind period 1 of 12 weeks (plus 5 weeks screening and fistula 
preparation) will be followed by a double blind period of 12 weeks treatment.




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Safety laboratory
Safety laboratory for patients in the Screening Cohort will be done according to their local 
standard of care. No specific parameters are requested.
If the time window for Visit 1 is other than is specified in the Flow Chart, this should be
agreed at the discretion of the PI, in alignment with the trial monitor on a case by case basis.
Re-screening will be allowed.
For a detailed description of the trial procedures at Visits 1, please refer to the Flow
Chart A.
Fistula preparation and seton placement visit (Visit 2)
6.2.1.2
The Visit 2 should normally take place at day 1.
Rectoscopy / Proctoscopy
A rectoscopy and proctoscopy will be performed according to standard of care at this visit.
Biopsies
During the fistula preparation visit 2, fistula(s) will be drained and a seton will be placed.
The following tissue samples will be collected from all perianal fistulas drained by a seton:
∀
Biopsy at the inner fistula orifice
∀
Curettage of the fistula canal
∀
Biopsy at the outer fistula orifice, if clinically indicated
∀
Rectal luminal biopsy (endoscopic)
2 pairs of biopsies: inflamed region and non-inflamed region
Approximately 5-8 patients with perianal fistulizing CD and a clinical indication for seton 
drainage will be included in the Screening Cohort. The final sample size will be driven by the 
availability of tissue samples not only from curettage but also inner fistula orifice biopsy. 
Enrolment will be stopped once both tissues have been obtained from at least 5 patients.
Refer to Section 15 of the ISF for details.
Physical examination and vital signs
Please refer to section 5.2.1 and 5.2.2.
Safety laboratory
Safety laboratory for patients in the Screening Cohort will be done according to their local 
standard of care. No specific parameters are requested.
For a detailed description of the trial procedures at Visit 2, please refer to the Flow
Chart A.














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The unscheduled visit may include additional collection of blood samples for safety reasons. 
The unscheduled visit may also include additional assessments deemed necessary by the
investigator such as laboratory samples, ECGs, or other procedures which were missed at a
previous visit. 
All unscheduled visits should be described (including the reason for the visit) and 
documented in the medical/source record, and in the eCRF.
Follow up period and trial completion
6.2.2.4
For all patients, termination of trial medication and trial completion must be recorded on the 
corresponding eCRF.
For patients completing the safety FU period, the EOS visit is scheduled at 16 weeks after the
last dose of study drug, ie at week 36 for those discontinuing after completing 24 weeks of
treatment.
All patients of study cohort completing week 24 of the study and having an individual 
clinical benefit may be offered to enter open label long-term extension study 1368-0007, 
which offers open label active treatment with subcutaneous BI 655130. These patients are not 
requested to complete the follow up visit (V 10). They will have their last study visit at visit 
V09, probably co-inciding with the first visit in 1368-0007. For AE and concomitant therapy
reporting the end of study participation is defined as the day of first administration of study 
drug in 1368-0007.
Early treatment discontinuation
Patients of study cohort who terminate study drug early should be encouraged to follow all 
study procedures per the Flow Chart until week 24, but not receive any more study drug at 
the respective visits. Given the patient’s agreement, the patient will undergo the procedures 
for early treatment discontinuation and follow up as outlined in the Flow Chart and Section 
6.2.2.3.
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.
Trial completion
Trial completion is defined as a patient having reached the EOS visit or day of the first 
administration of Spesolimab in 1368-0007. EOS visit will be at week 36 (Visit 10) for 
patients who will not enter subsequent maintenance trial. 
Last visit will be at week 24 (Visit 9) for patients rolling-over into subsequent maintenance 
trial. But individual patient’s end of trial is defined as the day of first administration of 
Spesolimab in 1368-0007.
Regarding instructions for drug administration at missed or delayed visits, please refer to
Section 4.1.4.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
This section is only applicable for the Study Cohort. Planned analyses for the Screening 
Cohort will be defined in the TSAP. These will be separate from the analyses for the Study 
Cohort and will comprise the analysis of disposition, AEs and 
.
7.1
STATISTICAL DESIGN - MODEL
The trial objectives and endpoints are stated in section 2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in a confirmatory sense.
The results including confidence intervals and (adjusted) p-values will be discussed and 
interpreted in the perspective of the exploratory character of the study.
7.3
PLANNED ANALYSES
All individual data will be listed.
The statistical analysis of the Screening Cohort will be based on the following analysis sets:
∀
Enrolled set (ES – Screening Cohort)
This patient set includes all patients of the Screening Cohort who signed informed 
consent. 
It will be used for analyses of patient disposition.
∀
Entered set (ENTS – Screening Cohort)
The entered set includes all patients of the Study Cohort who entered the trial.
The statistical analysis of the Study Cohort will be based on the following analysis sets:
∀
Enrolled set (ES – Study Cohort)
This patient set includes all patients of the Study Cohort who signed informed consent. 
It will be used for analyses of patient disposition.
∀
Randomised set (RS): The randomised set includes all randomised patients, whether 
treated or not.
Since patients in the Screening Cohort will not be randomised, RS only contains 
patients of the Study Cohort.
∀
Safety set (SAF): The safety set includes all patients who were randomised and 
treated with any amount of study drug. The treatment assignment will be determined 
based on the actual treatment the patient received.
Since patients in the Screening Cohort will not be randomised, SAF only contains 
patients of the Study Cohort.
∀
Full analysis set (FAS)
The full analysis set includes all patients of the Study Cohort who provided a baseline 
value and at least one post-baseline value for at least one secondary endpoint or


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further efficacy endpoint. Following the intent-to-treat principle, patients will be 
analysed according to the treatment they were assigned to at randomisation.
∀
RNA sequencing set (RSS): This patient set includes all patients in the safety set who 
provide a valid baseline and at least one valid post-baseline observation for at least 
one gene expression variable of biopsy. This patient set will be used for analyses 
related to RNA sequencing.
By definition of the safety set, RSS only contains patients of the Study Cohort. 
In the TSAP, the FAS definition may be updated, and further analysis data sets may be 
defined.
The following analyses of this trial protocol, in chronological order, are planned:
Week 12 Primary Analysis
The primary analysis of the trial will be performed once all randomised patients have 
completed the first 12 weeks of the trial, and a preliminary database lock will be done. 
Details of the analysis to be performed will be described in the TSAP which is planned to be 
finalized prior to achieving database lock for this primary analysis. Treatment will be 
unblinded at this time.
For further details regarding the maintenance and protection of the blind through the 
continuing trial subsequent to performance of the primary analysis, refer to Section 4.1.5.1.
Final Trial Analysis
The final analysis of the trial will be performed once all randomised patients have completed 
the trial. At this time, the treatment will be officially unblinded.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol deviations (IPDs) will be identified in an initial version of the TSAP and will be 
updated no later than in the Report Planning Meeting and will be provided in the final Trial 
Statistical Analysis Plan (TSAP).
The handling of patients who received a wrong treatment will be described in the TSAP.
Primary endpoint analyses
7.3.1
Primary analysis
The analysis of the gene expression values will be based on the RSS and will be conducted 
for biopsy location inner orifice and curettage. The analyses will be done by ‘actual 
treatment’.
All analyses will be performed using the raw read counts for gene expression. This gene 
expression analysis is conducted for biopsy.




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The secondary efficacy endpoints regarding proportions of patients will be described 
descriptively. 95% confidence intervals for the rate difference will be provided, if feasible. 
Safety analyses
7.3.4
Safety will be assessed based on the assessments listed in Section 5.2. All treated patients
(that is, all patients who received at least one dose of study drug), will be included in the 
safety evaluation. Safety analyses will be descriptive in nature and will be based on BI 
standards. No hypothesis testing is planned.
The analyses will be done by ‘actual treatment’.
Measurements (such as vital signs, or laboratory parameters) or AEs will be assigned to a 
treatment sequence (‘Pbo – Pbo’, ‘Pbo – BI’, ‘BI – BI’), based on the treatments the subject 






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7.6
RANDOMISATION
No randomisation is performed in the Screening Cohort.
In the Study Cohort, patients will be randomised in blocks to double-blind treatment. 
Approximately equal numbers of patients will be randomised to each treatment group using a 
1:1 allocation ratio. 
BI will arrange for the randomisation as well as packaging and labelling of trial medication. 
The randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of approximately 5-8 patients in the Screening Cohort and 
approximately 20 patients in the Study Cohort of this trial. The number of patients is not 
based on a power calculation but on feasibility, coordinating investigator’s experience with 
regard to recruitment and practical considerations.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC)
and the harmonised standards for Medical Devices (ISO 14155, current version).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign (or 
place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
Source documents
8.3.1
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see section 8.3.2). The investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone number, social security number) have properly 
been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
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


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∀
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.
Direct access to source data and documents
8.3.2
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
Storage period of records
8.3.3
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 


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processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
Collection, storage and future use of biological samples and corresponding 
8.5.1
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular 
∀
Sample and data usage has to be in accordance with the separate biobanking informed 
consent 
∀
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials. 
∀
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place 
∀
A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage 
∀
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data 
∀
Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF 
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the ‘individual patient’s end of the trial of the last patient in 
the whole trial (“Last Patient Out”). 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.
The “Individual patient´s end of the trial” is defined as:
&
Patients who do not roll-over to 1368-0007: Follow up visit 10
&
Patients who roll-over to 1368-0007: Day of first administration of Spesolimab in 
1368-0007Early termination of the trial is defined as the premature termination 
of the trial due to any reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The “Last Patient Completes Week 12” date is defined as the date on which the last patient 
in the whole trial attends Visit 6.


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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 Data Monitoring Committee (DMC) will be established. Members of the DMC are 
independent of BI, they are physicians experienced in the treatment of the disease under 
investigation and a statistician. 
The DMC will evaluate safety and efficacy data. The DMC will receive urgent significant 
safety concerns for immediate evaluation. While DMC members may be unblinded, measures 
are in place to ensure the blinding for everyone else involved in the trial. Regular DMC 
meetings will be held at specified intervals. The DMC will recommend continuation, 
modification or termination of the trial as detailed in the DMC charter. DMC 
recommendations as well as the final BI decision will be reported to the appropriate 
Regulatory Authorities (RAs)/Health Authorities (HAs), IRBs/ECs, and to investigators as 
requested by local law. The tasks and responsibilities of the DMC are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF. The investigators will have access to the 
BI clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic 
ISF.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Manager (CTM), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management will be done by BI according to BI SOPs.
Statistical Evaluation will be done by BI or by a Contract Research Organisation (CRO)
according to BI SOPs.


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Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, central reading service for blinded reading of MRI and an IRT 
vendor will be used in this trial. 
Details will be provided in the IRT Manual, MRI Manual and Central Laboratory Manual, 
available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R00-0812
Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, Hogezand RA 
van, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, 
Deventer SJH van
Infliximab for the treatment of fistulas in patients with Crohn's disease.
N Engl J Med 340 (18), 1398 - 1405 (1999)
R04-0551
Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak 
RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, 
Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, 
Deventer SJ van
Infliximab maintenance therapy for fistulizing Crohn's disease.
N Engl J Med 350 (9), 876 - 885 (2004)
R10-6267
Wang DD, Zhang S, Zhao H, Men AY, Parivar K
Fixed dosing versus body size-based dosing of monoclonal antibodies in 
adult clinical trials.
J Clin Pharmacol 49, 1012 - 1024 (2009)
R11-4890
Sampson HA, et al
Second symposium on the definition and management of anaphylaxis: 
summary report - second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium.
2nd Symp of the National Institute of Allergy and Infectious Disease 
(NIAID)/Food Allergy and Anaphylaxis (FAA) Network on the Definition 
and Management of Anaphylaxis, Jul 2005
J Allergy Clin Immunol 117 (2), 391 - 397 (2006)
R13-2231
Baumgart DC, Sandborn WJCrohn's disease.
Lancet 380, 1590 - 1605 (2012)
R13-2232
Latella G, Papi C
Crucial steps in the natural history of infammatory bowel disease.
World J Gastroenterol 18 (29), 3790 - 3799 (2012)
R13-2233
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A
Epidemiology and natural history of inflammatory bowel diseases.
Gastroenterology 140 (6), 1785 - 1794 (2011)
R13-2269
Sandborn WJ
State-of-the-art: immunosuppression and biologic therapy.
Dig Dis 28, 536 - 542 (2010)




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R15-5868
Koenig HH, Ulshoefer A, Gregor M, Tirpitz C von, Reinshagen M, Adler 
G, Leidl R
Validation of the EuroQol questionnaire in patients with inflammatory 
bowel disease.
Eur J Gastroenterol Hepatol 14 (11), 1205 - 1215 (2002)
R15-5871
Stark RG, Reitmeir P, Leidl R, Koenig HH
Validity, reliability, and responsiveness of the 
 in inflammatory 
bowel disease in Germany.
Inflamm Bowel Dis 16 (1), 42 - 51 (2010)
R16-0177
Khanna R, Bouguen G, Feagan BG, D'Haens G, Sandborn WJ, Dubcenco 
E, Baker KA, Levesque BG
A systematic review of measurement of endoscopic disease activity and 
mucosal healing in Crohn's disease: recommendations for clinical trial 
design.
Inflamm Bowel Dis 20 (10), 1850 - 1861 (2014)
R16-0240
Irvine EJ
Development and subsequent refinement of the inflammatory bowel disease 
questionnaire: a quality-of-life instrument for adult patients
R16-0572
Dave M, Loftus EV Mucosal healing in inflammatory bowel disease - a true 
paradigm of success? Gastroenterol Hepatol (New York) 8 (1), 29 - 38 
(2012)
R16-1923
Hovde O, Moum BA Epidemiology and clinical course of Crohn's disease: 
results from observational studies. World J Gastroenterol 18 (15), 1723 -
1731 (2012)
R16-2299
Russell SE, Horan RM, Stefanska AM, Carey A, Leon G, Aguilera M, et al
IL-36alpha expression is elevated in ulcerative colitis and promotes colonic 
inflammation.
Mucosal Immunol, (2016)
R17-2217
Sandborn WJ, Su C, Sands BE, D'Haens GR, Vermeire S, Schreiber S, et al, 
OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain 
Investigators
Tofacitinib as induction and maintenance therapy for ulcerative colitis.
N Engl J Med 376 (18), 1723 - 1736 (2017)
R17-2219
Assche G van, Peyrin-Biroulet L, Sturm A, Gisbert JP, Gaya DR, 
Bokemeyer B, et al
Burden of disease and patient-reported outcomes in patients with moderate 
to severe ulcerative colitis in the last 12 months - multicenter European 
cohort study.
Dig Liver Dis 48, 592 - 600 (2016)


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R17-2221
Feagan BG, Patel H, Colombel JF, Rubin DT, James A, Mody R, et al
Effects of vedolizumab on health-related quality of life in patients with 
ulcerative colitis: results from the randomised GEMINI 1 trial.
Aliment Pharmacol Ther 45, 264 - 275 (2017)
R17-2222
Feagan BG, Reinisch W, Rutgeerts P, Sandborn WJ, Yan S, Eisenberg D, et 
al
The effects of infliximab therapy on health-related quality of life in 
ulcerative colitis patients.
Am J Gastroenterol 102, 794 - 802 (2007)
R17-2223
Colombel JF, Sandborn WJ, Ghosh S, Wolf DC, Panaccione R, Feagan B, 
et al
Four-year maintenance treatment with adalimumab in patients with 
moderately to severely active ulcerative colitis: data from ULTRA 1, 2, and 
3.
Am J Gastroenterol 109, 1771 - 1780 (2014)
R17-2617
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen 
P, et al
Opportunistic infections and biologic therapies in immune-mediated 
inflammatory diseases: consensus recommendations for infection reporting 
during clinical trials and postmarketing surveillance.
Ann Rheum Dis 74, 2107 - 2116 (2015)
R17-3555
Scharl M, Rogler G, Biedermann L
Fistulizing Crohn's disease.
Clin Transl Gastroenterol 8 (7), e106 (2017)
R17-3632
Mahil SK, Catapano M, Meglio P di, Dand N, Ahlfors H, Carr IM, et al
An analysis of IL-36 signature genes and individuals with IL1RL2 
knockout mutations validates IL-36 as a psoriasis therapeutic target.
Sci Transl Med 9, eaan2514 (2017)
R17-4040
Khanna R, Zou G, Stitt L, Feagan BG, Sandborn WJ, Rutgeerts P, et al
Responsiveness of endoscopic indices of disease activity for Crohn's 
disease.
Am J Gastroenterol 112, 1584 - 1592 (2017)
R17-4068
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)


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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)
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Walsham NE, Sherwood RA
Fecal calprotectin in inflammatory bowel disease.
Clin Exp Gastroenterol 9, 21 - 29 (2016)
R17-4246
Chang S, Malter L, Hudesman D
Disease monitoring in inflammatory bowel disease.
World J Gastroenterol 21 (40), 11246 - 11259 (2015)
R18-0017
Panes J, Rimola J
Perianal fistulizing Crohn's disease: pathogenesis, diagnosis and therapy.
Nat Rev Gastroenterol Hepatol 14 (11), 652 - 664 (2017)
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 154 (5), 1334 - 1342 (2018)
R18-2554
Robinson MD, Oshlack A
A scaling normalization method for differential expression analysis of 
RNA-seq data.
Genome Biol 11, R25 (2010)
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Irvine EJ, Feagan B, Rochon J, Archambault A, Fedorak RN, Groll A, 
Kinnear D, Saibil F, McDonald JWD, 
Quality of life: A valid and reliable measure of therapeutic efficacy in the 
treatment of inflammatory bowel disease. 
Gastroenterology 106, 287 - 296 (1994)
R97-3569
Jain A, Buist NRM, Kennaway NG, Powell BR, Auld PAM, Martensson J
Effect of ascorbate of N-acetylcysteine treatment in a patient with 
hereditary glutathione synthetase deficiency. 
J Pediatr 124, 229 - 233 (1994)


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9.2
UNPUBLISHED REFERENCES
c03320877
IL36R antibody in Ulcerative Colitis, Crohn’s Disease, Palmoplantar 
Pustulosis, Pustular Psoriasis and Atopic Dermatitis
c03361085-07 
 Single-blind, partially randomised,
placebo-controlled Phase I study to investigate safety, tolerability,
pharmacokinetics and pharmacodynamics of single rising intravenous doses 
of BI 655130 in healthy male volunteers, 1368.1, 27 Jan 2016.




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III.
Current or prior intolerance
Eligible patients must have had an adverse reaction that meets 1 of the following criteria:
1. Significant acute infusion/administration reaction;
2. Significant delayed infusion/administration reaction (for example, delayed
hypersensitivity or serum-sickness like reaction);
3. Other adverse reaction thought to be related to this drug and leading to its 
discontinuation.


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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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10.9
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (
)
Excerpt out of the publication, cf. R13-3515
1 - Mild
2 - Moderate
3 - Severe
4 - Includes 
Life 
Threatening
Asymptoma
tic, or 
transient 
Short 
duration (< 
1 week)
No change 
in life style 
No 
medication 
or OTC 
Symptomatic 
Duration (1–2 
weeks) 
Alter lifestyle 
occasionally 
Meds relieve. 
(may be 
prescription),
Study drug 
continued
Prolonged 
symptoms, 
reversible, 
major functional 
impairment 
Prescription 
meds/partial 
relief 
May be 
hospitalized<24
h
Temporary 
study drug 
discontinuation, 
or/and dose 
reduced
At risk of death
Substantial 
disability, 
especially if 
permanent.
Multiple meds
Hospitalised 
>24h
Study drug 
discontinued
A.ALLERGIC/IMMUNOLOGIC
A1. Allergic 
reaction/hypersensit
ivity (including 
drug fever)
Transient 
rash; drug 
fever < 38° 
C, transient 
asymptomat
ic 
bronchospa
sm
Generalized 
urticaria 
responsive to 
meds; or drug 
fever > 38° C, 
or reversible 
bronchospasm
Symptomatic 
bronchospasm, 
requiring meds; 
symptomatic 
urticaria 
persisting with 
meds, allergy 
related 
oedema/angioed
ema
Anaphylaxis, 
laryngeal/ 
pharyngeal 
edema, 
requiring 
resuscitation
A2. Autoimmune 
reaction
Serologic or 
other 
evidence of 
autoimmun
Evidence of 
autoimmune 
reaction 
involving a 
Reversible 
autoimmune 
reaction 
involving 
Causes major 
organ 
dysfunction, or 
progressive, not 


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e reaction 
but patient 
asymptomat
ic: all organ 
function 
normal and 
no 
treatment is 
required 
(e.g., 
vitiligo)
non-essential 
organ or 
functions, 
requiring 
treatment other 
than 
immunosuppres
sive drugs (e.g., 
hypothyroidism
)
function of a 
major organ or 
toxicity 
requiring short 
term 
immunosuppres
sive treatment 
(e.g., transient 
colitis or 
anemia)
reversible, or 
requires long 
term 
administration 
of high dose 
immunosuppres
sive therapy
A3. Rhinitis 
(includes 
sneezing, nasal 
stuffiness, post 
nasal discharge)
Transient, 
non-
prescription 
meds 
relieve
Prescription 
med required, 
slow 
Corticosteroids 
or other 
prescription 
med. with 
persistent 
disabling 
symptoms such 
as impaired 
exercise 
tolerance 
NA


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
17. September 2019
EudraCT number
EU number
2017-003090-34
BI Trial number
1368-0008
BI Investigational Product(s)
BI 655130
Title of protocol
Mechanism of Action and Clinical Effect of BI
655130 in Patients with fistulizing Crohn’s Disease
Global Amendment due to urgent safety reason
Global Amendment
Section to be changed
Clinical Trial Protocol Synopsis,
Section 2
Description of change
Secondary endpoints (changes highlighted in bold):
∀
Proportion of patients with perianal fistula 
response at week 12 (defined as closure of at 
least 50% of external openings, no drainage / 
discharge despite gentle finger compression of 
fistulas that were draining at baseline and 
without new emerging fistulas)
∀
Proportion of patients with perianal fistula 
remission at week 12 (defined as closure of all 
external openings, no drainage / discharge
despite gentle finger compression of fistulas
that were draining at baseline and without new 
emerging fistulas)
∀
Proportion of patients with combined perianal 
fistula remission at week 12 (defined as closure 
of all external openings, no drainage / 
discharge despite gentle finger compression of 
fistulas that were draining at baseline and 
without new emerging fistulas, AND absence 
collections of >2 cm, confirmed by MRI in at 
least two of three dimensions – blinded and 
centrally read)
Same for further endpoints “perianal fistula 
response”, “perianal fistula remission”, and 
“combined perianal fistula remission” analysed at 


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different time points.
Rationale for change
Clarification of definitions “Response”, 
“Remission” and “Combined Remission” in order 
to describe that we are evaluating perianal fistulas 
that were draining at the study entry.
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Flow Chart C
Description of change
Visit window of EOT visit 9 extended to 7 days
Rationale for change
Give more flexibility for scheduling the 
investigations (i.E. endoscopy and MRI)
Section to be changed
Flow Chart C, Section 3.1, 5.1.2, 6.2.2, 8.7
Description of change
Endoscopy at EOT visit 9: Distinguish between 
patients who roll-over / do not roll-over to 
maintenance trial 1368-0007:
∀
Patients who NOT roll-over to long-term 
extension study 1368-0007: 
   A rectoscopy OR proctoscopy is 
sufficient and 
 by segment will be 
performed.
∀
Patients who roll-over to long-term 
extension study 1368-0007 which mandates 
a full ileocolonoscopy at baseline: 
Will NOT need to undergo the 
recto/proctoscopy and instead a full 
ileocolonoscopy is mandatory and SES-CD 
will be performed. 
Ileocolonoscopy images will be centrally 
read by an external independent assessor(s); 
management of images will be performed 


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by an external vendor.
Rationale for change
Reduce the efforts for the patients.
Patients who roll-over to 1368-0007 should not do 
a procto/rectoscopy AND a full ileocolonoscopy in 
a short period of time (EOT 1368-0008 and 
baseline 1368-0007). Instead, the baseline 
endoscopy for the maintenance trial 1368-0007
will be done at EOT visit of 1368-0008.
Section to be changed
Flow Chart C, 3.1, 6.2.2.4
Description of change
Clarify that all patients completing week 24 of the 
study and having an individual clinical benefit may
be offered to enter open label long-term extension 
study 1368-0007.
Rationale for change
Clarification
Section to be changed
Section 3.1; Flow Chart B
Description of change
Based on the outcome of the Screening Cohort it 
has been decided to keep the tissue sampling 
approach as described in the current CTP version 
1. The following tissue samples are required during 
fistula preparation visits:
∀
Biopsy at the inner fistula orifice, optional
∀
Curettage of the fistula canal
∀
Biopsy at the outer fistula orifice, if 
clinically indicated
∀
Rectal luminal biopsy (endoscopic): 
2 pairs of biopsies: inflamed region and 
non-inflamed region
Rationale for change
Outcome of the screening cohort added and 
clarification which samples are required during 
fistula preparation visits.
Section to be changed
Section 3.3
Description of change
Screening of patients for Study Cohort may stay 
open until approximately 15 patients have valid 
baseline and post treatment biopsies for primary 
endpoint analysis.
Rationale for change
Minimum of approx. 15 patients may be needed for 
primary endpoint analysis.
Section to be changed
Section 3.3.4.1
Description of change
Add the following bullet point for discontinuation 
from trial treatment:
The investigator clinical judgement advises for it.
Rationale for change
Clarify that based on the judgement of the 
investigator, patients may be discontinued from 
trial treatment.
Section to be changed
Section 4.2.1
Description of change
Updated wording of steroid tapering in order to 


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allow steroid tapering schedule according to 
standard of care.
Rationale for change
Give more flexibility to investigators for steroid 
tapering
Section to be changed
Sections 4.2.1, 4.2.2
Description of change
Peri-OP antibiotics at the day of the fistula 
preparation visits (visit 1c and 4) are allowed if 
required according to standard of care.
Rationale for change
Clarification in respective chapters (already 
described in figure 3.1:1)
Section to be changed
Section 5.2.3
Description of change
Clarification in table 5.2.3:1 (exclusionary testing) 
and 5.2.3:2 (removal of calprotectin from local 
safety laboratory)
Rationale for change
Clarification exclusionary testing: HBV-DNA and 
QuantiFERON®-TB will be repeated at EOT;
Calprotectin will be analysed by central laboratory, 
no additional testing by local laboratory necessary
Section to be changed
Section 5.2.6.2
Description of change
AE reporting: Distinguish between patients who 
roll-over to maintenance trial 1368-0007 and who 
not roll-over.
Patients who roll-over to 1368-0007 AE reporting 
will be done from signing the informed consent 
(1368-0008) onwards until the first dose of trial 
medication in 1368-0007.
Rationale for change
Harmonization of AE reporting with trial 1368-
0007.
Section to be changed
Appendix 10.4
Description of change
Add weighting to 
Rationale for change
Clarification
Section to be changed
Several chapters
Description of change
Minor editorial changes were done across the 
protocol
Rationale for change
Clarification


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11.2
GLOBAL AMENDMENT 2
Date of amendment
02 Apr 2020
EudraCT number
EU number
2017-003090-34
BI Trial number
1368-0008
BI Investigational Product(s)
BI 655130
Title of protocol
Mechanism of Action and Clinical Effect of BI
655130 in Patients with fistulizing Crohn’s Disease
Global Amendment due to urgent safety reason
Global Amendment
Section to be changed
Clinical Trial Synopsis, Section 3.3.2
Description of change
Inclusion criterion 4:
Has ≥ 1 perianal fistula(s) (≥4 weeks duration 
before enrolment, as a complication of CD, 
confirmed by MRI at screening*) actively draining
with clinical indication for seton drainage **. 
*A historical MRI might be sufficient if all these 
conditions are met: 
a) the MRI is performed within ≤ 4 weeks prior to 
screening visit 1a 
b) the patient has not experienced any clinical 
significant changes regarding its perianal CD 
which may induce suspicion of newer 
complications since the historical MRI was done 
(in this case a new MRI at screening is mandatory) 
c) the historical MRI meets quality and technical 
imaging requirements described in the Imaging 
Acquisition Guideline in the ISF 
d) the patient meets the rest of the eligibility 
criteria
**This also applies to patients who currently 
have or had in recent past a seton in place, 
provided these conditions are met:
a) no seton(s) in place for ≥2 weeks prior to the 
first fistula preparation visit 1c
b) fistula(s) are actively draining (as assessed 
per clinical exploration) during screening
Rationale for change
- Clarification added for patients who at the time of 
screening have or had in recent past a seton in 
place.


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- Accept historical MRIs for described conditions 
in order to facilitate screening visits.
Section to be changed
Section 3.3.2
Description of change
Inclusion criterion 7: 
Reference to section 10.7 added
Rationale for change
Clarification
Section to be changed
Section 3.3.2
Description of change
Inclusion criterion 8:
Cancer screening during endoscopy at screening 
removed.
Rationale for change
Ileocolonoscopy during screening no longer 
mandatory. Please refer to the description below.
Section to be changed
Synopsis, Section 3.3.3.2.1, Section 4.2.2
Description of change
Exclusion criterion 9:
Faecal Microbiota transplant (FMT) within 6 
months prior to randomization
Rationale for change
Clarification
Section to be changed
Synopsis, Section 3.3.3.2.1, 4.2.2
Description of change
Exclusion criterion 10:
Allow undetectable plasma concentration for:
- previous non-biologic medication
- previous biologic treatment approved for CD
- previous investigational non-approved biologic 
for CD.
Exclude patients with prior stem cell therapy 
(HSC, MSC).
Rationale for change
- In case of undetectable plasma concentration of 
the described prior therapy, the wash out period 
can be disregarded which should ease the 
recruitment.
- Prior stem cell therapy could have an impact on 
the gene expression and therefore on the primary 
endpoint.
Section to be changed
Section 3.3.3.2.3
Description of change
Exclusion criterion 20 amended:
Currently enrolled in another investigational device 
or drug trial. Specific restrictions for patients 
who have participated recently in another drug 
trial are listed in section 4.2.2
Rationale for change
Refer to section 4.2.2.1 for restriction on prior 
therapies.
Section to be changed
Flow Chart B, Section 6.2.2
Description of change
- Expand visit window of visit 1b:-35 to -21
- Expand visit window of visit 1a: -35 to -22
- (Re)check in-/exclusion criteria during visit 1c 
instead of visit 2






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charts. Therefore, i.v. administration and related 
procedures like vital signs may be done in the 
expanded time window.
Section to be changed
Section 3.1, Section 6.2.2; Section 5.1.2
Description of change
Fistula preparation visit - Decision on biopsies 
during fistula preparation visits and eligibility 
criteria, taking screening cohort results into 
account:
Screening Cohort tissue analyses have shown that 
all tissue sources allow assessing gene expression. 
However, they have also shown differences in gene 
expression depending on the tissue location. (inner 
/ outer fistula orifice and curettage). Thus, it has 
been decided:
1. Not to change the eligibility criteria: No 
need to limit the study population to 
patients where both, tissue from the inner 
orifice and fistula canal, are available
2. To keep the tissue sampling approach as 
stated in the screening cohort from all 
perianal fistulas drained by a seton placed 
at visit 1c
Rationale for change
Describe decision, based on screening cohort 
results, on biopsies to be taken during fistula 
preparation visits and eligibility criteria.
Clarification from which fistulas the biopsies will 
be taken.
Section to be changed
Section 3.1
Description of change
No interim analysis of efficacy and safety data of 
the Study Cohort is planned.
Rationale for change
Clarification that no interim analysis will be done 
in a broaden sense
Section to be changed
Section 3.3
Description of change
Increased number of sites
Rationale for change
Update
Section to be changed
Section 4.1.5
Description of change
Release of random plan to bioanalytical laboratory
(changes highlighted in bold):
After the last patient completes the Week 12 visit 
the random plan will be released to the 
bioinformatics group and the bioanalytical 
laboratory. The bioinformatics group will receive 
the randomisation code in order to start with the 
pre-processing of gene expression data (using 
limma packages). The bioanalytical laboratory 
will receive the randomization code in order to 




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1368-0008
Rationale for change
clarification
Section to be changed
Section 5.3.1
Description of change
PK data may be incorporated into a population 
pharmacokinetic analysis if feasible
Rationale for change
Clarification that PK data from 1368-0008 may 
still be considered via a population 
pharmacokinetic approach
Section to be changed
Section 6.2.2
Description of change
Blood sampling for safety laboratory:
- Ileocolonoscopy removed, see above
- It is preferred but patients do not have to be 
fasted for the blood sampling for the safety 
laboratory (documentation of fasting condition 
requested)
Rationale for change
Clarification
Section to be changed
Section 6.2.2.1
Description of change
Stool sampling prior to visit 1c
Rationale for change
Allow more flexibility on site and check eligibility 
prior to surgical visit 1c
Section to be changed
Section 6.2.2.2
Description of change
Description which biopsies will be taken during 
fistula preparation visit based on results from 
screening cohort
Rationale for change
Clarification
Section to be changed
Section 6.2.2.2
Description of change
Stool sampling for visit 1c and 4 described
Rationale for change
Clarification according to Flow Chart B
Section to be changed
Section 6.2.2.3
Description of change
Procedures for roll-over to trial 1368-0007 
described (patient information)
Rationale for change
Clarification
Section to be changed
Several chapters
Description of change
Minor editorial changes were done across the 
protocol
Rationale for change
Clarification


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11.3
GLOBAL AMENDMENT 3
Date of amendment
23 Oct 2020
EudraCT number
EU number
2017-003090-34
BI Trial number
1368-0008
BI Investigational Product(s)
BI 655130
Title of protocol
Mechanism of Action and Clinical Effect of BI
655130 in Patients with fistulizing Crohn’s 
Disease
Global Amendment due to urgent safety reason
Global Amendment
Section to be changed
Clinical Trial Synopsis, Flow Chart B, Section 
3.3.2, 6.2.2
Description of change
Inclusion criterion 4:
Requirement on removing the seton 2 weeks 
before fistula preparation visit (V1c) for patients 
who present with seton drainage at screening HAS 
BEEN REMOVED-
Thus Criterion 4 is now: Has ≥ 1 perianal active* 
fistula(s) with clinical indication for seton 
drainage (≥ 4 weeks duration before enrolment, as 
a complication of CD). **. 
ADDED: * Criteria for Active Fistula: As per 
clinical evaluation: Presence of spontaneous 
drainage or drainage after gentle finger 
compression at the external openings & as 
confirmed by radiological (MRI) exploration . 
** Patients who are screened with a seton drainage 
are eligible if the patient meets the rest of the 
eligibility criteria.
REMOVED: Historical MRI for baseline 
assessment is no longer allowed (important for 
evaluation of criteria for active fistula)
Rationale for change
Need to remove seton drainage 2 weeks until 1st
surgical visit is not accepted by patients and 
doctors and is endangering trial feasibility. 
Therefore, this requirement has been removed 
provided fistula is actively draining. Criteria for 
active fistula were added to ensure primary 
endpoint of the trial is no compromised.


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Section to be changed
Synopsis, Section 3.3.2
Description of change
Inclusion criterion 7:
Demonstrated in the past inadequate fistula
response or loss of response or have had 
unacceptable side effects with approved doses 
of at least one of the following compounds: …
Rationale for change
Clarification
Section to be changed
Synopsis, Section 3.3.3, 3.3.4.1, 4.2.2.2, 6.2.2.2
Description of change
Clarification that surgical procedures to treat 
fistulas (other than interventions requested for 
visits 1c and 4 according to CTP) are not allowed 
after randomization.
Section 3.3.3 (Exclusion criterion 3):
Anticipated to require surgical intervention for CD 
including any fistula surgical procedures
(except seton drainage). See Table  4.2.2.2:1 for 
a detailed list of restricted interventions
Section 3.3.4.1:
∀
The patient needs surgical interventions for 
CD including any fistula surgical procedures 
(except seton drainage, see section 4.2.2.2)
Section 4.2.2.2:
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. These are 
summarized in table 4.2.2.2:1 ( no exhaustive list).
Table 4.2.2.2:1 was added.
Section 6.2.2.2:
Please refer to section 4.2.2.2 for surgical 
restrictions.
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
Synopsis, Section 1.4, 3.1, 3.3.3 & 4.2.1 & 4.2.2
Description of change
Exclusion criterion 10: Patients may continue 
pre-existing anti-TNF treatment as defined in 
Sections 4.2.1 and 4.2.2.1. Corresponding wording 
updated in sections 1.4 and 3.1.
Rationale for change
Need to discontinue anti-TNF therapy ( SOC for 


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luminal inflammatory activity control in CD 
patients) is not possible on most of target 
population due to the need to ensure controlled 
luminal activity throughout the study. Therefore, 
this requirement has been removed provided anti-
TNFα (e.g. infliximab, adalimumab, certolizumab 
pegol; or respective biosimilars) dose has been 
stable for at least 6 months prior to screening and 
rest of eligibility criteria are met ( i.e activity of 
the fistula based on clinical and MRE assessment 
at screening).
Criteria for active fistula was added to ensure 
primary endpoint of the trial is not compromised
Section to be changed
Section 1.3, 1.4
Description of change
Update of development program of Spesolimab. 
The respective wording was updated in the 
sections mentioned above.
Rationale for change
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.
Section to be changed
Section 1.4
Description of change
Benefit-Risk Assessment in context of COVID-19 
pandemic added
Rationale for change
Clarification
Section to be changed
Section, 3.1, 4.1.5, 7.3, 7.4
Description of change
Introduction of interim analysis once all 
randomised patients have completed the first 12 
weeks of the treatment period (through visit 6). 
Blinding procedures were amended accordingly.
Rationale for change
At visit 6, all patients will have completed the 
randomized treatment part of the trial and the 
primary and secondary endpoint data will be 
available. At that time point, a preliminary 




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Rationale for change
Clarification
Section to be changed
4.2.1
Description of change
Peri-OP antibiotics at the day before until the 
day after fistula preparation visits (visit 1c and 4) 
are allowed if
required according to standard of care.
Rationale for change
Allow more flexibility in order to address local 
standard of care


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




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7.2
CONCOMITANT DISEASES AND MEDICATION .....................................35
7.3
TREATMENT COMPLIANCE........................................................................36
7.4
PRIMARY ENDPOINTS...................................................................................37
7.5
SECONDARY ENDPOINTS.............................................................................37
7.5.1
Key secondary endpoint .....................................................................................37
7.5.2
Secondary endpoints...........................................................................................37
7.7
EXTENT OF EXPOSURE.................................................................................43
7.8
SAFETY ANALYSIS..........................................................................................44
7.8.1
Adverse events.....................................................................................................44
7.8.2
Laboratory data ..................................................................................................47
7.8.3
Vital signs.............................................................................................................48
7.8.4
ECG......................................................................................................................48
7.8.5
Others...................................................................................................................48
7.9
HANDLING OF DMC ANALYSES .................................................................49
8.
REFERENCES....................................................................................................50
10.
HISTORY TABLE..............................................................................................54


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for the Study Cohort.........................................22
Table 6.3: 1
Patient sets analysed.........................................................................................26
Table 6.7:1 
Time windows for assignment of efficacy, safety lab, vital signs to visits for 
statistical analysis.............................................................................................31
Table 7.1: 1
Categories for summary of continuous variables.............................................35
Table 7.8.1: 1 Project standard MedDRA search criteria for User Defined Adverse Event 
Categories (UDAEC) .......................................................................................45
Table 10: 1
History table .....................................................................................................54


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug antibodies
ADS
Analysis Dataset
ALQ
Above the upper Limit of Quantification
BI 
Boehringer Ingelheim
BLQ
Below the lower Limit of Quantification
BM
Biomarker
CARE
Clinical data analysis and reporting environment
CD
Crohn’s Disease
CDAI
Crohn’s Disease Activity Index
CPFM
combined perianal fistula remission 
CRP
C-Reactive Protein
EC
enterocutaneous
eCRF
Electronic case report form
EDC
Electronic Data Capture
ENTS
Entered set
ES
Enrolled set
FAS
Full Analysis Set
FC
fold change
FDR
False Discovery Rate
HMGB1
High-Mobility-Group-Protein B1
hsCRP
high sensitivity C-Reactive Protein
ICH
International Conference On Harmonisation
IL
Interleukin
iPD
Important Protocol Deviations
ISF
Investigator Site File
LLOQ
Lower Limit Of Quantification
MedDRA
Medical Dictionary For Regulatory Activities
MMP-12
Matrix Metalloproteinase-12
MPO
Myeloperoxidase
nAb
Neutralizing Antibodies


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Term
Definition / description
NGAL
Neutrophil Gelatinase-Associated Lipocalin
NRI
no response imputation
OC
observed case
OC-IR
observed cases including rescue
OR
original results
PFM
perianal fistula remission
PFR
perianal fistula response
RAGe
Report appendix generator
RAM
Report Alignment Meeting
RCTC
Rheumatology Common Toxicity Criteria
RS
Randomised Set
RSS
RNA Sequencing Set
SAF
Safety Set
SD
Standard Deviation
SDL
Subject data listing
TOM
Trial Oversight Meeting
UDAEC
User Defined Adverse Event Categories
ULOQ
Upper Limit Of Quantification




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For all patients, data of treatment period 1 will be included in the primary analysis. In 
addition, data up to end of trial will be included for all patients to the time of the preliminary 
database lock. The analysis of treatment period 1 is considered the Primary Analysis. Data of 
treatment period 2 are considered as supportive data.
The week 12 primary analysis will include the following data: disposition, baseline 
characteristics and demographics, concomitant medications including rescue medications, 
exposure data, primary and secondary endpoint data, some further efficacy endpoints (CDAI, 
PDAI, SES-CD, IBDQ, CRP and faecal calprotectin) and adverse events.
Final Trial Analysis
The final trial analysis of all data will be performed once all treated patients have completed 
the trial (up to Visit 10); at that time point, a final database lock will be done and all trial data 
will be reported.
It may happen that data of treatment period 1 that are analysed in the Week 12 analysis are 
subsequently changed due to corrections. Only few minor changes are expected and the 
results of treatment period 1 for the efficacy analysis up to Week 12 are considered the 
primary results.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods planned in 
the CTP (based on Global Amendment 3).
Referring to CTP Section 7.3.2 (Secondary endpoint analyses), 95% CIs for the rate 
difference will be provided. The analysis is incorrectly described in the CTP as rate 
difference. The secondary endpoints are the proportion of patients with a pre-determined 
event at Week 12. Therefore, CIs for the risk difference will be provided. 


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5.
ENDPOINTS
All primary and secondary endpoints are only applicable for the Study Cohort.
Descriptions of endpoints refer to the Study Cohort only, if not stated otherwise. 
5.1
PRIMARY ENDPOINT
CTP Section 2.1.2: The primary endpoint is the total number of deregulated genes at week 4 
comparing changes in gene expression from baseline between the two treatment groups. 
Thereby, deregulation of a gene is defined based on the baseline adjusted mean difference to 
placebo of gene expression fulfilling the following criteria:
∀
FDR adjusted p-value ≤ 0.05
∀
|fold change| ≥ 1.5
∀
genes can be annotated with Ensembl identifiers (version 84 or later)
Gene expression is analysed based on biopsies (curettage and inner fistula orifice) via RNA
sequencing;
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
Secondary efficacy endpoints are as defined in Section 2.1.3 of the CTP: 
∀
proportion of patients with perianal fistula response at week 12
∀
proportion of patients with perianal fistula remission at week 12
∀
proportion of patient with combined perianal fistula remission at week 12
Perianal fistula response is defined as closure of at least 50% of external openings, no 
drainage / discharge despite gentle finger compression of fistulas that were draining at 
baseline and without new emerging fistulas.
Perianal fistula remission is defined as closure of all external openings, no drainage / 
discharge despite gentle finger compression of fistulas that were draining at baseline and 
without new emerging fistulas.
Combined perianal fistula remission is defined as closure of all external openings, no 
drainage / discharge despite gentle finger compression of fistulas that were draining at 
baseline and without new emerging fistulas, AND absence collections of >2 cm, confirmed 
by MRI in at least two of three dimensions – blinded and centrally read).


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In general, the derivations of perianal fistula response, remission, and combined perianal 
fistula remission at a given visit are Boolean functions based on the following, where a 
perianal fistula refers to an external opening:
Let
o
 indicate a given analysis visit;
o
() indicate the count of closed perianal fistulas that were draining at 
baseline at analysis visit ;
o
⍴() indicate the count of open perianal fistulas that were draining at baseline 
at analysis visit ;
o

() be the number of newly emerged perianal fistulas from the baseline to 
analysis visit ;
then perianal fistula response (PFR) for a given patient  is
() =
⎩⎪⎨
⎪⎧0,

()
() + ⍴() < 0.5  
() > 0
1,

()
() + ⍴() ≥0.5 !"# 
() = 0
, and perianal fistula remission (PFM) for a given patient  is
$() = %
0,
 ⍴() > 0  
() > 0
1,

()
() + ⍴() = 1 !"# 
() = 0
, and combined perianal fistula remission (CPFM) for a given patient  is
&$() =
⎩
⎨
⎧0,
 ⍴() > 0  
() > 0  '(()'*"+ > 2'-
1,

()
() + ⍴() = 1 !"# 
() = 0 !"#
'(()'*"+ ≤2'-
Note that these endpoints are derived based on the information reported on the CRF 
remission and response and CRF MRI form at the respective post-baseline visit. Data from 
CRF Fistula Characteristics (Visit 1c) form will not be used as fistula related surgery
performed after Visit 1c reduced the number of open and draining fistulas in a few cases. The 
post-baseline data collected on the CRF remission and response refer to the draining fistulae 
existing after surgery.
Furthermore, the seton will be removed during fistula preparation visit Week 4, hence neither 
response nor remission can be observed at that visit. Therefore, in general fistula 
characteristics data of Week 4 will not be used for any analyses. Week 4 data will only be 
listed.


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Also note that the number of newly emerged perianal fistulas on the remission and response 
form since Visit 1c is the cumulative number up to the visit under consideration.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignments of dose groups, 
and selection of doses, cf. Section 4 of the CTP.
The trial is divided into a Screening Cohort and a Study Cohort. 
Patients of the Screening Cohort will only be treated with the standard of care for their 
disease. The patients will not be treated with trial medication and they will undergo only few 
additional study related procedures.
The Study Cohort is split into two treatment periods. The patients will be randomised to 
receive spesolimab 1200 mg i.v. or matching Placebo for treatment period 1. Depending on 
the outcome at Week 12 (achievement of combined perianal fistula remission after treatment 
period 1), patients will stay on their randomised treatment or switch from Placebo to active 
treatment. Trial medication will be administered intravenously at Week 0, 4, and 8 during 
treatment period 1 and at Week 12, 16, and 20 during treatment period 2. 
In general, results of Study Cohort will be presented separately from results of the Screening 
Cohort, i.e., in different tables. Selected summaries (e.g., demographics) will be prepared for 
the whole trial in addition, i.e., combining data of both cohorts.
Event data of the Study Cohort will be assigned to one of the two treatment periods. Events 
which occurred after first study drug administration (planned at Visit 2) and before the first 
study drug administration after the determination of the combined perianal fistula remission 
outcome (planned at Visit 6) are assigned to treatment period 1. Events occurring after the 
first study drug administration after the determination of the combined perianal fistula 
remission outcome (planned at Visit 6) are assigned to treatment period 2.
Three treatment sequences are assigned in this trial (“Pbo-Pbo”, “Pbo-Speso”, and “Speso-
Speso”). The analysis phases for the Study Cohort are defined in Table 6.1.1.
Generally, visit based data (e.g., laboratory data and vital signs) will be analysed for 
treatment period 1 by treatment (”Pbo” and ”Speso”, i.e., the treatment the patient initially 
received in period 1 independent of the treatment in period 2) and over the whole trial by 
treatment sequence (“Pbo-Pbo”, “Pbo-Speso”, “Speso-Speso” and “Speso”). The treatment 
sequence “Pbo-Pbo” includes only patients who stay on Placebo after Visit 6 (Week 12). 
Similarly, the treatment sequences “Pbo-Speso” and “Speso-Speso” include only patients 
who received Spesolimab during treatment period 2. “Speso” includes all patients initially 
randomized (for efficacy analysis) or initially receiving (for safety analysis) Spesolimab in 
treatment period 1 and includes also patients who were not treated in treatment period 2.
Statistical analysis of event data (e.g., AEs) of the Study Cohort will be done by treatment 
(“Pbo” and “Speso”) for treatment period 1. Over the whole trial the following treatments and 
treatment sequences will be presented: “Pbo (Pbo-Pbo)”, “Pbo (Pbo-Speso)”, “Speso (Pbo-
Speso)”, “Speso (Speso-Speso)”, “Speso”, “Total Pbo” and “Total Speso”. “Pbo (Pbo-Pbo)” 


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includes all events occurring during treatment with Placebo in patients who stay on Placebo 
after Week 12 assessment and “Pbo (Pbo-Speso)” includes all events occurring during 
treatment with Placebo in patients who switched to Speso at Visit 6 (Week 12). “Speso (Pbo-
Speso)” includes all events occurring during treatment with spesolimab in patients initially 
receiving/randomized to Placebo. Similarly, “Speso (Speso-Speso)” includes all events 
occurring during treatment with spesolimab in patients who received spesolimab as first 
treatment and who stay on spesolimab after Week 12 assessment. “Speso” includes all 
patients initially randomized (for efficacy analysis) or initially receiving (for safety analysis) 
Spesolimab in treatment period 1 and includes all patients who were not treated during 
treatment period 2. ”Total Pbo”/“Total Speso” includes all events which occurred during 
treatment with Placebo/spesolimab regardless of the initial treatment.


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Table 6.1: 1
Flow chart of analysis phases for the Study Cohort
Study 
analysis 
phase
Period
Sequ-
ence
Treat-
ment
Label
Start (included)
End (included)
Screening
-
-
Screening
Date of informed 
consent
Date/time of start of 
infusion of first randomized
study drug (Pbo or Speso)
minus 1 minute
On-
treatment
Period 1 Pbo-Pbo
or
Pbo-
Speso
Pbo
Pbo
Date/time of start of 
infusion of first Pbo
(Day 1)
Date/time of start of 
infusion of first Pbo or 
Speso on or after Visit 6
minus 1 minute or in case of 
early termination during 
period 1 date of end of 
infusion of last Pbo prior to 
Visit 6 date + REP 
(112*24 h) at 11:59 p.m. 
(up to date of individual 
patient EoS)
Speso-
Speso
Speso
Speso
Date/time of start of 
infusion of first  
Speso (Day 1)
Date/time of start of 
infusion of first 
administration of Speso on 
or after Visit 6 minus 1 
minute or in case of early 
termination during period 1 
date of end of infusion of 
last Speso prior to Visit 6 
date + REP (112*24 h) at 
11:59 p m. (up to date of 
individual patient EoS)
Period 2 Pbo-Pbo Pbo
Pbo (Pbo-Pbo) Date/time of start of 
infusion of first Pbo 
on or after Visit 6
Date of end of infusion of 
last administration of Pbo + 
REP (112*24 h) at 11:59 
p m. (up to date of 
individual patient EoS)
Pbo-
Speso
or
Speso-
Speso
Speso
Speso (Pbo-
Speso)
or
Speso (Speso-
Speso)
Date/time of start of 
infusion of first 
Speso on or after 
Visit 6
Date of end of infusion of 
last administration of Speso
+ REP (112*24 h) at 11:59 
p m. (up to date of 
individual patient EoS)
Follow-
up1
-
-
F/U
Date of end of 
infusion of last study 
drug (Pbo or Speso) + 
REP (112*24 h) at 
12:00 a m.
Latest of: i) Date of EOS 
visit; ii) last contact date on 
End of Study page at 11:59 
p m.
1 Follow-up phases might not exist, e.g. if the patient’s trial termination date is within 112 days after last administration of 
spesolimab or placebo.
In CTR Section 15 (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE 
tables), the following totals will be provided in addition:
∀
“Total Pbo”, defined as the total over all on-treatment phases involving Placebo (i.e., 
“Pbo” in Period 1 and “Pbo (Pbo-Pbo)” in Period 2)


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∀
“Total Speso”, defined as the total over all on-treatment phases involving Speso (i.e., 
“Speso” in Period 1 and “Speso (Pbo-Speso)” and “Speso (Speso-Speso)” in Period 2)
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only.
In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 
AE tables), the following totals will be provided in addition:
∀
“Total on-trt”, defined as the total over all on-treatment phases, including placebo and 
spesolimab
∀
“Overall” (across treatment), where appropriate.
“Overall” is applicable in disposition, demographics and baseline characteristics, and 
compliance summaries. “Total Speso” should also be presented in safety tables. Where 
applicable, output columns should be arranged in the order as given above.
Events will be assigned the study phases and treatment periods based on the event start date.
AEs occurring during the screening or the follow-up phase will be listed only.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients enrolled in 
this trial.
Consistency check listings (for identification of deviations of protocol-defined time windows) 
and a list of protocol deviations (e.g. deviations in drug administration, in blood sampling 
times, etc.) will be provided to be discussed at the trial oversight meetings, the report 
planning meetings and the report alignment meeting (TOMs/RPMs/RAM). At these 
meetings, it will be decided whether a discrepant data value can be used in analyses or 
whether it must be corrected in the clinical database. Each protocol deviation must be 
assessed to determine whether it is an important protocol deviation (iPD). For definition of 
iPDs, and for the process of identification of these, refer to the BI reference document 
"Identify and Manage Important Protocol Deviations (IPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the TOMs minutes and in the decision log. Categories which are considered to be iPDs in this 
trial are defined in the DV domain (excel Spreadsheet). If the data show other iPDs, the 
definition in the DV domain will be supplemented accordingly by the time of the 
TOMs/BRPMs/RAM.
Not all iPDs will lead to exclusion from analysis sets. iPDs leading to exclusion from analysis 
sets are indicated as such in the DV domain.


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All iPDs and all COVID-19 related PDs will be summarised and listed.
6.3
PATIENT SETS ANALYSED
The following analysis sets will be defined for this trial:
∀
Enrolled set (ES)
This patient set includes all patients of the Screening Cohort and of the Study Cohort 
who signed informed consent.
It will be used for analyses for disclosure of AE data.
∀
Enrolled set – Screening Cohort (ES-Screen)
This patient set includes all patients of the Screening Cohort who signed informed 
consent.
It will be used for analyses of patient disposition for the Screening Cohort.
∀
Entered set (ENTS) – Screening Cohort
The entered set includes all patients of the Screening Cohort who entered the trial (“Will 
the subject enter the study?” is ticked “Yes” on the Eligibility page of the eCRF).
∀
Enrolled set– Study Cohort (ES-Study)
This patient set includes all patients of the Study Cohort who signed informed consent. It 
will be used for analyses of patient disposition for the Study Cohort.
[In case a patient is re-screened, the last attempt will be considered.]
∀
Randomised set (RS) – Study Cohort
The randomised set includes all randomised patients, whether treated or not. 
Since patients in the Screening Cohort will not be randomised, RS only contains patients 
of the Study Cohort.
It is expected that the RS and the FAS (see below) will not differ. Therefore, all analyses 
will be performed on the FAS.
∀
Safety set (SAF) – Study Cohort
The safety set includes all patients who were randomised and treated with any amount of 
study drug. The treatment assignment will be determined based on the actual treatment 
the patient received. 
Since patients in the Screening Cohort will not be randomised, SAF only contains 
patients of the Study Cohort.
∀
Full analysis set (FAS) – Study Cohort
The full analysis set includes all patients of the Study Cohort who provided a baseline 
value and at least one post-baseline value for at least one secondary endpoint or further 
efficacy endpoint.
∀
RNA sequencing set (RSS) – Study Cohort
This patient set includes all patients in the safety set who provide a valid baseline and at 
least one valid post-baseline observation for at least one gene expression variable of 


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biopsy. This patient set will be used for analyses related to RNA sequencing. By 
definition of the safety set, RSS only contains patients of the Study Cohort.
Handling of Treatment Misallocations in Analysis Sets
If a patient is randomized but took incorrect treatment during the study, then the following 
will apply for safety reporting: 
If a patient randomized to Placebo inadvertently is administered a dose of spesolimab during 
the first 12 weeks of the trial then that patient will be reported in the spesolimab treatment 
arm (treatment period 1 and 2) for all safety analyses. If a patient is randomized to 
spesolimab and was only administered placebo during the first 12 weeks of the trial then that 
patient will be reported in the placebo treatment arm (treatment period 1). If a patient is 
randomized to spesolimab and was only administered placebo during the entire trial (that is, 
within both first and last 12 weeks) then that patient will be reported in the placebo treatment 
arm (treatment period 1 and 2).
Primary endpoint analysis: 
If a patient is randomized to placebo/spesolimab but received spesolimab /placebo on Day 1 
then then that patient will be reported in the spesolimab/placebo treatment arm, respectively.
Note that study drug the patient was not randomized to was administered at Week 4 or later 
does not affect the primary endpoint analysis since biopsies are scheduled pre-dose at 
Week 4. 




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Based on the different reasons for patients’ data missing, different approaches will be used to 
assess the impact of missing data on the endpoints of this trial, depending upon the type of 
the endpoint. The following approaches are applied in this trial: 
∀
The original results (OR) approach implies the presentation of data exactly as 
observed (not using time windows as described in Section 6.7 and not setting values 
to missing). OR analysis will be performed on parameters and endpoints for which it 
is not meaningful to apply any imputation rule for the replacement of missing values.
∀
Observed cases (OC) approach will include all collected data, without imputation for 
any missing data but all values measured after any use of rescue medication will be 
excluded from the analysis. Note that patients that took rescue treatment are not kept 
in the denominator for categorical endpoints at subsequent time points.
∀
Observed cases including rescue (OC-IR) approach is an extension of the OC 
approach which includes additionally all values which were measured after rescue 
medication intake.
∀
The no response imputation (NRI) approach is applied for binary endpoints. Missing 
values will be imputed described in the following: 
1. If a patient takes a rescue medication (as defined in Section 5.4.3) for the treatment 
of disease under study or died due to any cause , then all data subsequent to the 
intake of such rescue will be considered to be missing. 
2. For endpoints which are measured at multiple visits, if there are data at visits both 
before and after the visit with a missing outcome, then impute as success only if 
both neighbouring visits also represent a success (independent of whether the 
preceding and following observations were selected for analysis based on time 
windows described in Section 6.7), and there is no intervening rescue treatment use.
For all patients with a missing visit outcome, impute as a failure to achieve a
response.
∀
Imputation technique last observation carried forward (LOCF): The LOCF approach 
will be used as the imputation strategy to replace missing values either at intermediate 
visits or due to early withdrawal from the trial. The last available value, excluding
baseline, will be carried forward to all subsequent visits within the on-treatment 
period at which a measurement is missing. Values measured after the day of first 
rescue medication intake (as defined in Section 5.4.3) will be set to missing and the 
missing values within the on-treatment period will be imputed by LOCF.
The following sections describe which imputation approach is used for the different 
endpoints. 
6.6.1
Withdrawals
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.
6.6.2
Efficacy endpoints
CTP Section 7.5: No imputations for the primary endpoint […] are planned.






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6.6.8
Time since first diagnosis
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows:
∀
If the year of first diagnosis is unknown, time since first diagnosis will be set to missing.
∀
If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th June of that year.
∀
If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For the Screening Cohort, the study day will be defined relative to the day of Visit 2, which is 
defined as Day 1. The start date of Visit 2 will be used in case the Visit 2 procedures are split 
over several days. For the Study Cohort, study day will be defined relative to the day of first 
infusion of trial treatment (Day 1).
The following descriptions refer to the analysis of the Study Cohort.
Measurements reported with date and time and taken prior to start of administration of trial 
treatment will be considered pre-treatment values. Measurements reported with a date only 
(and no time) and taken on the day of first administration of trial treatment will also be 
considered pre-treatment values. These pre-treatment values will be assigned to visits 
according to the nominal visit number as recorded on the eCRF or as provided by the 
laboratory.
Adverse events reported without time on the day of first drug administration in treatment 
period 1 are considered as on-treatment AEs in treatment period 1. AEs reported without time 
on the day of first drug administration in treatment period 2 are considered as on-treatment 
AEs in treatment period 2. In addition, treatment-emergent adverse events which are reported
with a date only (and no time) and which occur on the day preceding the first administration 
of trial treatment in the subsequent extension trial will be considered treatment-emergent AE 
in this parent trial.
Baseline, unless otherwise specified, is defined as the last measurement collected prior to the 
start of administration of the trial treatment. For the analysis of the gene expression values 
(primary endpoint), baseline is the measurement at Visit 1c.
Measurements taken after start of administration of trial treatment will be considered either 
on- or off-treatment values based on the definition in Section 6.1 and will be assigned to 
visits for statistical analysis, if applicable, as defined below (Table 6.7: 1).


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Analysis of AE data, concomitant medication or non-drug therapies, as well as use of rescue 
medication will not be based on visits. Therefore, no assignment to time windows will be 
necessary. Frequency tables for these data will be using on-treatment data only.
All other safety, efficacy and biomarker measurements of the Study Cohort will be assigned 
to visits based on time windows around the planned visit dates, defined relative to the day of 
first administration of trial treatment (which is scheduled for Visit 2). These time windows 
are defined in Table 6.7:1.
Table 6.7:1 
Time windows for assignment of efficacy, safety lab, vital signs to visits for 
statistical analysis
Visit 
name
Planned day
Time window (days)
Visit label
Window
Start (inclusive)
End (inclusive)
V1a
Screening
-35 to -22
n/a
V1b
Screening
-35 to -21
n/a
V1c
Screening
-21
n/a
V2
Baseline
1
n/a
-35 A
1 A
Planned on-treatment visits B
V3
Week 2
15
-13/+4
2
19
V4
Week 4
29
-9/+14
20
43
V5
Week 8
57
-13/+14
44
71
V6
Week 12
85
-13/V6
72
Date of Visit 6
V7
Week 16
113
-13/+14
100
127
V8
Week 20
141
-13/+14
128
155 
V9
Week 24/EoT
169
-13/+14
156
186
End of studyC
V10
Week 36/EoS
253
187D
Day of last value
Days are counted relative to the day of first treatment, which is defined as Day 1.
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made 
after start of infusion of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be 
assigned to Day 1. Such data will be listed only.
B Only ‘on-treatment’ data (i.e. measured within the REP following intake of last dose) are included.
C All data, irrespective of whether ‘on-treatment’ or ‘off-treatment’, are included.
D Data reported on Day 232 or later will be used for by visit analysis. Other data mapped before Day 232 will be 
listed only.   
Repeated and unscheduled efficacy, safety and biomarker measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date of measurement. 
Only one observation per time window will be selected for statistical analysis at a particular 
visit – 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.
Assignment of efficacy observations to visits based on time windows will be based on the 
non-imputed (observed) data after setting values after rescue medication intake to missing (if 
applicable, i.e. for the “LOCF” and “NRI” approaches and the “OC” approach defined in
Section 6.6). Visits which were not assigned a value based on time windows will thereafter 


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be imputed for the NRI approaches defined in Section 6.6. Imputation of efficacy endpoints 
(binary as well as continuous) will be performed based on all available observations, 
irrespective of whether the observation was selected in any time window. 
For derivation of the last value during the on–treatment period, the minimum value during the 
on–treatment period, and the maximum value during the on–treatment period, all values 
during the on-treatment period (including unscheduled and repeated measurements) 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 
(including unscheduled and repeated measurements) will be considered.




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For the Screening Cohort, disposition of the patient population participating in the trial will 
be summarised by the presentation of the frequency of patients enrolled, entered, who 
completed the trial and who were prematurely discontinued from trial, by reason.
For the Study Cohort, disposition of the patient population participating in the trial will be 
summarised by the presentation of the frequency of patients enrolled, enrolled but not 
randomised, randomised, randomised but not treated, treated, who completed trial medication
overall/ in period 1/ in period 2, who were prematurely discontinued from trial medication 
overall/ in period 1/ in period 2, by reason, who completed participation in the trial overall/ in 
period 1/ in period 2, who were prematurely discontinued from trial overall/ in period 1/ in 
period 2, by reason, and who entered the extension trial 1368-0007. The summary will be 
presented by randomised treatment. Further disposition information may be summarised by 
country. 
In addition, number and proportion of patients assigned to spesolimab or placebo, with at 
least one intake of study drug in period 2 will be presented by outcome (achievement of 
combined perianal fistula remission after treatment period 1) and by randomised treatment.
The frequency of patients with iPDs, also summarised by whether or not the iPD led to 
exclusion from the any analysis set, will be presented. An iPD might lead to an exclusion 
from all analyses sets or from one or more analysis sets used for the efficacy analysis (i.e., 
RSS and FAS). The analysis will be based on the ENTS for the Screening Cohort and based 
on the FAS for the Study Cohort. The frequency of patients in each of the different analysis 
sets will also be presented. The analysis will be performed for both cohorts. 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
For the Study Cohort, demographic data and baseline characteristics will be summarised by 
treatment arm based on the FAS and additionally by treatment sequence. Fistula 
characteristics will be summarized for Visit 1a and Visit 1c separately. Number of draining 
fistula and number of non-draining fistula where applicable will be summarized descriptively 
and with categories (0,1,2,3,>3). 
Demographic data will be summarised overall based on the ENTS for the Screening Cohort. 
For the continuous variables described above, the following categories will be defined and 
presented according to the number and percentage of patients in each category:


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Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
< 50 years
50 to < 65 years
65 to < 75 years
≥ 75 years
< 65 years
≥ 65 years
Weight
≤70 kg
>70 to ≤80 kg
>80 to ≤ 90 kg
>90 kg
BMI
< 25 kg/m2
25 to < 30 kg/m2
≥ 30 kg/m2
Time since first diagnosis
≤ 1 year
> 1 to ≤ 5 years
> 5 to ≤ 10 years
> 10 years
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases (i.e. baseline conditions) and concomitant non-drug therapies will be 
coded according to the most recent version of MedDRA. Concomitant medications will be 
coded according to the most recent version of the World Health Organisation – Drug 
Dictionary.
Only descriptive statistics are planned for this section of the CTR. Analyses of concomitant 
diseases and medications will be based on the FAS for the Study Cohort and based on the 
ENTS for the Screening Cohort.
Baseline conditions and diagnosis will be summarised with frequency and percentage of
patients by SOC and preferred name. 
The frequency and percentage of patients with historical medication for Crohn’s Disease will 
be displayed by defined categories (cf. Section 5.4.3) and preferred name. 
A medication/no-drug therapy will be considered concomitant to a treatment, if it
∀
is ongoing at the time of first administration of the respective treatment in the 
treatment period or
∀
starts within the analysis phase of the respective treatment in the treatment period (cf.
Section 6.1 for a definition of treatments and analysis phases).
A medication/non-drug therapy will be considered as prior medication/non-drug therapy, if 
the end date of the medication/therapy is any time prior to the start of first trial treatment. 


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Concomitant medication use (excluding rescue medication, historical medication for Crohn’s 
Disease, and background medication for Crohn’s Disease) will be summarised with 
frequency and percentage of patients by ATC3 class and preferred name. For the Study 
Cohort, summaries will be presented for 
∀
prior medication taken any time prior to Day 1 (the day of start of trial treatment)
∀
concomitant medication taken any time during treatment period 1 (cf. Section 6.1)
∀
concomitant medication taken any time during treatment period 2 ( cf. Section 6.1).
Background medication (eCRF) for Crohn’s Disease will be analysed in the same way and 
presented separately. Concomitant medication and background medication in the Screening 
Cohort will be summarised over the whole study period.
Furthermore, the use of rescue therapy including rescue medication (eCRF) and rescue non-
drug surgical therapy (cf. Section 5.4.3) will be summarised with frequency and percentage
of patients together in one table by category. Summaries will be presented for rescue 
therapies during treatment period 1 and during treatment period 2 (similar as for concomitant 
medication)..
Concomitant use of non-drug therapies will be summarised with frequency and percentage of 
patients by SOC and preferred name. Summaries will be presented for prior non-drug 
therapies, concomitant non-drug therapies during treatment period 1 and during treatment 
period 2 (similar as for concomitant medication) for the Study Cohort. For the Screening 
Cohort, the summaries will be presented over the whole study duration.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the CTR. 
Treatment compliance (as described in Section 5.4.2) will be summarised by visit and overall 
via dose intensity based on the safety set using descriptive statistics (N, mean, SD, minimum, 
median, maximum).
For the patients who discontinued the study treatment prematurely, only the scheduled visits 
before premature discontinuation will be used for the calculation of overall compliance.
The number and percentage of patients with the following overall compliance categories per 
treatment period will be presented: 
∀“< 80% of planned”, and
∀“80% to 100% of planned”
The number of patients who received a dose will also be tabulated per visit.






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7.7
EXTENT OF EXPOSURE
Exposure (as amount administered in mg), duration of infusion (in minutes), and the number 
of active vials used for infusion will be summarised by descriptive statistics (N, mean, SD, 
minimum, median, maximum) per visit and per treatment period based on the SAF. The 
number and percentage of patients according to the duration of infusion will also be classified
by visit and by treatment period according to the following categories:
Duration of infusion (min) categories
∀Duration “< 60 min”,
∀Duration “>=60 min to < 120 min”,
∀Duration “>=120 min to < 180 min”,
∀Duration “>= 180 min”.
The total duration of exposure and total exposure (as amount administered in mg), will be 
summarised by descriptive statistics by treatment period and overall based on the SAF.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the safety set 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 analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs. Exposure-adjusted AE 
summaries will also be presented for the Study Cohort (see further details below).
For further details on summarisation of AE data, please refer to “Analysis and Presentation of 
Adverse Event Data from Clinical Trials” (7) and “Handling of missing and incomplete AE 
dates” (3). 
The analysis of AEs of the Study Cohort will be based on the concept of treatment emergent 
AEs. That means that all AEs will be assigned to screening, on-treatment, or follow-up phase 
as defined in Section 6.1. AEs will be analysed based on actual treatments, as defined in 
Table 6.1: 1. All AEs of the Screening Cohort will be assigned to screening phase.
An overall summary of AEs will be presented. This overall summary will include summary 
statistics for the class of AESIs.
CTP Section 5.2.6.1: The following are considered as AESIs:
∀
Infusion reactions including anaphylactic reaction (study cohort, only)
[…]
∀
Severe infections (according to RCTC grading in Appendix 10.9)
∀
Opportunistic and mycobacterium tuberculosis infections 
[…]
∀
Hepatic injury (study cohort, only)
[…] 
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
The investigator identified AESI will be captured from the eCRF and reported as 
“Investigator reported AESI” table. In addition, user defined adverse event categories
(UDAEC) identified through specific search criteria will be reported separately (cf. 
Table 7.8.1:1)


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Table 7.8.1: 1 Project standard MedDRA search criteria for User Defined Adverse Event 
Categories (UDAEC) 
User Defined AE category
Label
Description
Infections ALL
Combined search strategy based on the individual UDAECs 
for infections described below; the UDAEC “severe 
infections (investigator-defined) will be disregarded for 
this search
- 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, by HLGT
Hypersensitivity ALL
Combined search strategy based on the three individual 
UDAECs for hypersensitivity described below
- Angioedema
Narrow SMQ “Angioedema”
- Hypersensitivity
Narrow SMQ “Hypersensitivity”
- Anaphylactic reaction
Narrow SMQ “Anaphylactic reaction”
Malignancies ALL
- Malignant tumours
Narrow Sub-SMQ “Malignant tumours”
Narrow Sub-SMQ “Haematological malignant tumours”
Narrow Sub-SMQ “Non-Haematological malignant 
tumours”
- Non-melanoma skin cancer 
(NMSC)
Broad Sub-SMQ “Skin malignant tumours” excluding 
HLT Skin melanomas (excl. Ocular)
- Malignancies excluding 
NMSC 
Sub-SMQ “Malignant tumours”  excluding NMSC, where 
NMSC is defined above
Torsades de Pointes
Broad sub-SMQ “Torsade de pointes/QT prolongation”
According to ICH E3 (8), in addition to Deaths and Serious Adverse Events, ‘other
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious
adverse event that led to an action taken with study drug (e.g. discontinuation or dose 
reduced).
The exposure adjusted incidence rate (per 100 patient years) of a selected AE is defined as 
the number of patients experiencing the AE per treatment group during time at risk divided 


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by the total time of patient at risk in that treatment group to contribute an event to the analysis 
multiplied by 100 (per 100 patient years), where
Time at risk (patient years) = (date/time of TEAE onset–study drug start date/time +1)/ 
365.25
If, for a patient, no treatment emergent AE occurred then the end of time at risk will occur at 
the minimum of (date of death; drug stop date+112 days; last contact date per EoS page (if 
patient does not enter a subsequent extension trial); one minute prior to time of first treatment 
in next treatment period or extension trial; analysis cut-off date (for Interim Analysis only)). 
The time at risk in this situation is defined as:
Time at risk (patient years) = (end of time at risk–study drug start date + 1)/365.25
For each TEAE, the exposure-adjusted incidence rate will then be calculated as:
Incidence rate [per 100 patient years (pt-yrs)] = 100 * number of patients with TEAE /
Total TEAE-specific time at risk (patient years).
For patients who do not roll-over into a subsequent extension trial, a listing of all TEAE 
which occur after the individual patient’s end of study will be done.
The exposure-adjusted incidence rate and frequency of patients with AEs will be summarised 
by treatment, primary SOC and preferred term. AEs which were considered by the 
investigator to be drug related will be summarised separately (for the Study Cohort only).
Separate tables will also be provided for patients with SAEs, patients with AEs leading to 
study drug discontinuation, patients with AEs leading to dose reduction, patients with AESIs
(separately for each of the four categories), and patients with UDAECs. The frequency of 
patients with AEs will also be summarised by worst RCTC grading, primary SOC and 
preferred term.
The system organ classes and preferred terms within system organ classes will be sorted by 
descending frequency overall treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of patients with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
For support of lay summaries, the frequency of patients with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature. The analyses will be based on 
BI standards “Display and Analysis of Laboratory Data” (9).
For continuous safety laboratory parameters, normalised values will be derived.
Normalisation means transformation to a standard unit and to a standard reference range. The
process of normalisation, handling of repeat values at the same visit for by-visit displays, as
well as standard analyses for safety laboratory data are described in the BI guidance for the
Display and Analysis of Laboratory Data. All analyses considering multiple times of the 
ULN (as described below) will be based on standardized and not normalized values. For 
continuous safety laboratory parameters, differences to baseline (see Section 6.7) will be 
calculated.
All individual laboratory data will be listed. Values outside the reference range will be 
flagged.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided by visit (including follow up), including the last value on 
treatment, the minimum value on treatment and maximum value on treatment. Graphical 
displays via box plots will be produced for the change from baseline, over time, for each 
continuous laboratory endpoint. Since safety laboratory tests will be performed at the local 
laboratory of each site, this analysis will be based on normalized laboratory values only.
Laboratory values will be compared to their reference ranges; a shift table will be provided 
for the number of patients with a specific RCTC grade at baseline and at the last 
measurement on treatment, as well as the worst grade on treatment. These analyses will be 
based on standardized laboratory values. 
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on normalized converted lab values, i.e. using SI units. These rules will be 
listed in the SDL appendix of the CTR. Frequency tables will summarise the number of 
patients with potentially clinically significant abnormalities during the on-treatment period 
and without the finding at baseline. Patients having an abnormal lab value at baseline will be 
presented separately. A separate listing will present potentially clinically significant abnormal 
lab values; for each functional lab group all patients’ lab values will be listed, if there exists
at least one lab value with clinically significant abnormality within the group.
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥10xULN, and 
≥20xULN will be displayed based on standardized laboratory values. To support analyses of 
liver related adverse drug effects, the frequency of patients with AST and/or ALT ≥3xULN 
with concomitant or subsequent total bilirubin ≥2xULN in a 30 day period after AST/ALT 
elevation will be displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a 
patient can potentially be in both alkaline phosphatase strata in case of multiple AST/ALT 
and bilirubin elevations). The start of the 30 day time span is triggered by each liver enzyme 
elevation above the defined thresholds. Even if a patient changes treatment, i.e., if a patient 




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7.9
HANDLING OF DMC ANALYSES
A fully external DMC, independent of the trial and project teams, will be set-up to review all 
available un-blinded safety data as well as selected efficacy data at regular intervals 
following first-patient-in. Further details are provided in a DMC charter.


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8.
REFERENCES
1.
CPMP/ICH/363/96: “Statistical Principles for Clinical Trials”, ICH Guideline Topic E9, 
Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical Trials, 
current version
2.
001-MCS-40-413_1.0: ”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-TMCP-MAN-0014: “Noncompartmental PK/PD Analyses of 
Clinical Studies”, current version; KMED
5.
KM Asset BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files,
PK/PD Data files and ADA files”, current version; KMED
6.
KM Asset BI-KMED-BDS-HTG-0045: ”Standards for Reporting of Clinical Trials and 
Project Summaries”, current version; KMED
7.
KM Asset BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from 
clinical trials”, current version; KMED
8.
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
9.
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
Initial
11-JAN-19
None
This is the initial TSAP (document 
number c26459747) with necessary 
information for trial conduct
Final 1
10-FEB-22
Analyses are adapted to current BI 
standards, project standards and the 
adapted CTP. 
Secondary endpoint analyses based on 
re-calculated data, not based on 
investigator tick marks. 
Actual treatment defined with respect to 
safety analyses and primary endpoint 
analysis
Details for analyses are added.