Clinical trial NCT04762277
Conditions: Hidradenitis Suppurativa
Sponsor: Boehringer Ingelheim
Start date: 2021-04-06; Completion date: 2022-04-21
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with a chronic inflammatory skin disease called hidradenitis suppurativa. The purpose of this study is to find out whether a medicine called spesolimab helps people with moderate to severe hidradenitis suppurativa.

Participants are put into 2 groups by chance. One group takes spesolimab. The other group takes placebo. Every participant has twice the chance of being in the spesolimab group than in the placebo group. Participants get spesolimab or placebo as an infusion into a vein every week for the first 3 weeks. Afterwards, they get spesolimab or placebo as injections under the skin every 2 weeks. Placebo infusions and injections look like spesolimab infusions and injections but do not contain any medicine.

Participants are treated in the study for about 3 months. During this time, they visit the study site about 9 times. After completing this part of the study, participants are offered to join another clinical study in which all participants get spesolimab. Participants who cannot join the other study, stay in this study for about 4 more months. During this time, participants do not take spesolimab nor placebo but they visit the study site 2 times to have their health checked.

At study visits, doctors thoroughly check the skin of participants to count lumps (nodules) and boils (abscesses). The results between the spesolimab group and the placebo group are compared after 3 months of treatment. The doctors also regularly check the general health of the participants.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Spesolimab - solution for infusion intervention 2: Placebo matching spesolimab - solution for infusion intervention 3: Spesolimab- solution for injection intervention 4: Placebo matching to spesolimab- solution for injection
Intervention descriptions: intervention 1: Solution for infusion intervention 2: Solution for infusion intervention 3: Solution for injection intervention 4: Solution for injection

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
TITLE PAGE
Document Number:
c32824792-02
EudraCT No.
EU Trial No.
2020-003672-40
BI Trial No.
1368-0052
BI Investigational
Medicinal Product(s)
Spesolimab (BI 655130)
Title
Randomized, double-blind, placebo-controlled, study of 
spesolimab in patients with moderate to severe hidradenitis 
suppurativa
Lay Title
A study to test whether spesolimab helps people with a skin 
disease called hidradenitis suppurativa
Clinical Phase
IIa
Clinical Trial Leader
Phone: 
Coordinating 
Investigator
Version and Date
Version:
Final version 2.0
Date:
05 JUL 2021
Page 1 of 117
Proprietary confidential information.
2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
28 Oct 2020
Revision date
05 Jul 2021
BI trial number
1368-0052
Title of trial
Randomized, double-blind, placebo-controlled, study of 
spesolimab in patients with moderate to severe hidradenitis 
suppurativa
Coordinating Investigator
Trial site(s)
Multi-centre trial conducted in approximately 16 countries
Clinical phase
IIa
Trial rationale
Hidradenitis suppurativa (HS) is an inflammatory disease 
characterised by recurrent, painful abscesses and fistulous tracts. 
HS and generalized pustular psoriasis (GPP) have similarity in 
neutrophil infiltration and pustules, with pustules in HS being 
subcutaneous. IL-36 alpha, beta and gamma mRNA expression 
are upregulated in lesional skin in HS patients. Based on the role 
of IL-36 driving TH17 and TH1 responses in GPP (published 
and our internal data) and from animal models of atopic 
dermatitis (AtD), the hypothesis is that IL-36 is also a key driver 
of Th17 responses in skin of HS patients.  Study 1368-0052 is 
proof-of-clinical-concept study in HS designed to assess the 
efficacy and safety of Spesolimab in this patient population.
Trial objective(s)
The primary objective is to estimate the effect of spesolimab
compared to placebo for the mean percent change from baseline 
in total abscess and inflammatory nodule count at Week 12. 
Trial endpoints
The primary endpoint is the percent change from baseline in total 
abscess and inflammatory nodule count at Week 12. 
Secondary endpoints are defined as described below: 
-Percent change from baseline in draining fistula count at Week 
12
-Achievement of Hidradenitis Suppurativa Clinical Response 
(HiSCR) at Week 12.


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-Absolute change from baseline in International Hidradenitis 
Suppurativa Severity Score System (IHS4) value at Week 12
-Absolute change from baseline in HASI score at Week 12
-Achievement of PGA score of 0 or 1 at Week 12
- Achievement of at least 30% reduction from baseline in 
Numerical rating scale (NRS30) in Patient’s Global Assessment 
of HS Pain at Week 12
-Occurrence of complete elimination of draining fistulas at Week 
12
-Occurrence of at least one flare (defined as at least 25 % increase 
in AN count with a minimum increase of 2 relative to baseline)
up to Week 12.
-Absolute change from baseline in DLQI Score at Week 12.
-Absolute change from baseline in HiS-QoL Total Score at Week 
12.
The following safety endpoint is also defined:
  -The occurrence of Treatment Emergent Adverse Events 
(TEAEs)
Trial design
International, multi-center, placebo-controlled, double blind, 
randomized trial assessing the efficacy and safety of spesolimab 
versus placebo in patients with moderate to severe HS over 12
weeks 
Total number of patients
randomized
45
Number of patients on each 
treatment
30 active arm
15 placebo arm
Diagnosis
Hidradenitis suppurativa
Main in- and exclusion 
criteria
Inclusion Criteria:
•
Male or female adult patients, 18 years of age or older
•
Have moderate to severe HS for at least 1 year prior to 
the baseline visit, as determined by the investigator
•
Have HS lesions in at least 2 distinct anatomic area
•
Has a total abscess and inflammatory nodule (AN) count 
of greater than or equal to 5. 
•
Biologic naïve or TNFi-failure for HS
•
Total draining fistula count of less than or equal to 20
Exclusion criteria:
•
Presence of active skin lesions other than HS that interferes 
with the assessment of HS.
Test product 1
Spesolimab 
dose
1200mg weekly at Weeks 0, 1 and 2 for a total loading dose of 
3600mg  
mode of administration
intravenous (i.v.)
Test product 2
Spesolimab 
dose
1200 mg every 2 weeks at Weeks 4, 6, 8 and 10   
mode of administration
subcutaneous (s.c.)
Comparator product(s)
Placebo


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dose
Matching
mode of administration
intravenous (i.v.) at weeks 0, 1 and 2
subcutaneous (s.c.) every 2 weeks at Weeks 4, 6, 8 and 10   
Duration of treatment
12 weeks
Statistical methods
The primary objective of the trial is to demonstrate proof of 
clinical concept activity of spesolimab on the percent change 
from baseline in total abscess and inflammatory nodule count 
using a mixed effect model for repeated measurements 
(MMRM). No formal statistical testing is planned. For the proof 
of concept, the treatment effects of spesolimab compared to 
placebo will be estimated. Hereby, the adjusted difference in 
percentage change from baseline in total abscess and 
inflammatory nodule count between spesolimab and placebo 
will be evaluated.  
For primary analysis of the primary endpoint, all measurements 
will be included but those data collected after the use of rescue 
therapy for the purpose of disease worsening will be censored. 
The stratification factor, TNFi-naive population versus TNFi-
failure population will be included into the model.


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FLOWCHART
Trial Periods
Screening
Treatment Period
EoT
Safety Follow-Up
Visit
1
2
Baseline
3
4
5
6
7
8
EoT2
FUP 1  
EoS
Day
-28 to -1
11
8
15
29
43
57
71
85
56 days 
after last 
drug 
admin.
112 days 
after last 
drug 
admin.
Weeks 
-4
0
1
2
4
6
8 
10
12
8 weeks 
after last 
drug 
admin.
16 weeks 
after last 
drug 
admin.
Time window for 
visits (days)
n.a.
none
±1
±1
±3
±3 
±3 
±3 
±3 
±7 
+7 
Informed consent 
X
Review of in-
/exclusion criteria
X
X
Demographics
X
Medical history
X
Physical 
examination3
Xc
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Vital signs4
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
Pregnancy test5
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory 
tests6
X
X
X
X
X
X
X
X
X
X
Infection Testing7
X
X
Hs-CRP
X
X
X
12-lead ECG
X
X
X
X
X
X
Randomization
X
Administer trial 
drugs8
X
X
X
X
X
X
X
PK Sampling9
X
X
X
X
X
X
X
X
X
X
ADA/Nab 
Sampling9
X
X
X
X
X
X
X
Blood sample 
(Serum soluble 
protein biomarkers)
X
X
X
X
Whole blood RNA 
sequencing
X
X
X
X
DNA banking 
(optional)10
X
Skin Biopsy: 
Lesional
X
X
X
Skin Biopsy: Non-
lesional
X
Ultrasound lesion 
evaluation11
X
X
X


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Trial Periods
Screening
Treatment Period
EoT
Safety Follow-Up
Visit
1
2
Baseline
3
4
5
6
7
8
EoT2
FUP 1  
EoS
Day
-28 to -1
11
8
15
29
43
57
71
85
56 days 
after last 
drug 
admin.
112 days 
after last 
drug 
admin.
Weeks 
-4
0
1
2
4
6
8 
10
12
8 weeks 
after last 
drug 
admin.
16 weeks 
after last 
drug 
admin.
Time window for 
visits (days)
n.a.
none
±1
±1
±3
±3 
±3 
±3 
±3 
±7 
+7 
Abscess count
Inflammatory 
nodule count. 
Non-inflammatory 
nodule count
Draining Fistula 
count.
X
X
X
X
X
X
X
X
X
Photography
X
X
X
Hidradenitis 
Suppurativa Clinical 
Response (HiSCR)
X
X
X
X
X
X
X
International 
Hidradenitis 
Suppurativa 
Severity Score 
System (IHS4)
X
X
X
X
X
X
X
X
X
Hidradenitis 
Suppurativa Area 
Severity Index 
(HASI)
X
X
X
X
X
X
X
X
Hidradentis 
Suppurativa
Physician's Global 
Assessment (HS-
PGA)
X
X
X
X
X
X
X
X
X
Dermatology Life 
Quality Index 
(DLQI)
X
X
X
X
X
Hidradenitis 
Suppurativa Quality 
of Life (HiS-QoL)
X
X
X
X
X
FACIT-Fatigue 
scale
X
X
X
X
X
Patient Global 
Assessment of 
Change (PGI-C)
X
X
X
X
Patient Global 
Assessment of 
Severity (PGI-S)
X
X
X
X
X
Columbia-Suicide 
Severity rating 
Scale (C-SSRS)12
X
X
X
X
X
X
X
X
X
X
X


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Trial Periods
Screening
Treatment Period
EoT
Safety Follow-Up
Visit
1
2
Baseline
3
4
5
6
7
8
EoT2
FUP 1  
EoS
Day
-28 to -1
11
8
15
29
43
57
71
85
56 days 
after last 
drug 
admin.
112 days 
after last 
drug 
admin.
Weeks 
-4
0
1
2
4
6
8 
10
12
8 weeks 
after last 
drug 
admin.
16 weeks 
after last 
drug 
admin.
Time window for 
visits (days)
n.a.
none
±1
±1
±3
±3 
±3 
±3 
±3 
±7 
+7 
Dispense Patient’s 
Diary13
X
X
X
X
X
X
X
X
Review returned
Patient’s Diary14
X
X
X
X
X
X
X
X
All adverse events15
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
therapy
X
X
X
X
X
X
X
X
X
X
X
Roll over into OLE 
trial16
X
Completion of 
patient participation 
X
1 Day of Randomization / Day of first intake of randomized medication. If needed, some visit 2 assessments 
may be conducted 2 days before or after the actual visit date after consultation with the Sponsor.
2 Patients who discontinue trial treatment prematurely should undergo the End of Treatment (EoT) visit as soon 
as possible. All patients not entering the OLE trial are expected to complete the EoT visit, a FUP1 visit 8 weeks 
after their last trial drug intake and a final EoS visit 16 weeks after their last trial drug intake. For patients 
entering the OLE trial at week 12, the EoT visit will be their EoS visit in trial 1368-0052. (see also footnotes #8
and #16)
3 Xc is a complete physical examination. Xt is a targeted physical examination. See section 5.2.1.
4 Measurements of vital signs should precede blood sampling to avoid the impact of blood sampling on the vital 
measurements at all dosing visits. Additional assessments of vital signs should be performed at 10 minutes post-
dose for s.c administrations and 5 minutes and 1 hour post dose for i.v. administrations.
5 Women of childbearing potential only. A serum pregnancy test will be performed at screening. Urine 
pregnancy tests will be performed at all other visits indicated in the Flowchart. In case of a positive urine 
pregnancy test, a serum pregnancy test will be done. Urine pregnancy testing should be done prior to 
administration of study drug. Study drug should only be administered in case of a negative test result. More 
frequent testing should be done if required by the local regulation or per investigator judgment.
6 It is preferred but patients do not have to be fasted for the blood sampling for the safety laboratory. At visits 
with study drug administration this should be done prior to the study drug administration. See Table 5.2.3:2 for 
detailed information of the tests. If needed, safety lab samples for Visit 2 can be drawn within 48 hours before 
the actual visit date.
7 Infection Testing: At screening and at EoT visit. See section safety laboratory parameters for complete list of 
testing required (see Table 5.2.3:1).
8 Patients who terminate study drug early should do the EoT visit as soon as possible. These patients will then 
do FUP1 and EoS visits, 8 and 16 weeks after last study drug administration respectively. 
9 At study visits with study drug administration, pre-dose PK/ADA/Nab samples will be obtained approximately 
within 1 hour prior to start of i.v. infusion or s.c. injection.
10 Desoxyribonucleid Acid (DNA) banking sample is optional. This sampling is only possible if the patient 
agreed by signing a separate informed consent. For details please see Section 5.5.
11 At selected sites, where ultrasound is available, it is required to do ultrasound lesion evaluation and to guide 
biopsies. At sites without ultrasound capabilities, biopsies will be done without ultrasound guidance.


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12 At Screening, the C-SSRS baseline/screening scale will be completed.  At all subsequent visits the “Since 
last visit” scale will be completed.
13 At visits 4, 5, 6, 7 and 8 two weekly diaries and a buffer of one additional week to capture surplus time 
window of visit will be dispensed to patients. Patient Diary to capture daily NRS score, analgesic use and other 
interventions to manage pain.
14 Patient’s Diaries returned by patients must be reviewed while the patient is in the consultation, so that any 
information can be clarified in an interview with the patient, if needed.
15 Local tolerability at the administration site of spesolimab will be assessed by the investigator during the study 
drug administration visit and at the time of AE assessment by questioning retrospectively since the last visit.  
Any observed local tolerability reaction, e.g. “swelling”, “induration”, “heat”, “redness” should be reported as 
adverse event. 
16 All patients completing week 12 of the study may be offered to enter the open label extension study 1368-
0067. These patients are not requested to complete follow up period and will have their End of study visit at 
EoT visit, co-inciding with the first visit in 1368-0067.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOWCHART.........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................17
1.2.1
Mode of action.....................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................19
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
1.4.1
Benefits.................................................................................................................20
1.4.2
Risks .....................................................................................................................21
1.4.2.1
COVID-19:............................................................................................................26
1.4.3
Discussion.............................................................................................................27
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................28
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........28
2.1.1
Main objectives....................................................................................................28
2.1.2
Primary endpoint(s)............................................................................................28
2.1.3
Secondary endpoint(s) ........................................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................30
3.1
OVERALL TRIAL DESIGN.............................................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................31
3.3
SELECTION OF TRIAL POPULATION .......................................................32
3.3.1
Main diagnosis for trial entry ............................................................................32
3.3.2
Inclusion criteria .................................................................................................32
3.3.3
Exclusion criteria ................................................................................................33
3.3.4
Withdrawal of patients from treatment or assessments..................................34
3.3.4.1
Discontinuation of trial treatment .........................................................................35
3.3.4.2
Withdrawal of consent to trial participation .........................................................36
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................36
4.
TREATMENTS...................................................................................................37
4.1
INVESTIGATIONAL TREATMENTS ...........................................................37
4.1.1
Identity of the Investigational Medicinal Products..........................................37
4.1.2
Selection of doses in the trial and dose modifications......................................38
4.1.3
Method of assigning patients to treatment groups...........................................39


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4.1.4
Drug assignment and administration of doses for each patient......................39
4.1.5
Blinding and procedures for unblinding...........................................................40
4.1.5.1
Blinding.................................................................................................................40
4.1.5.2
Unblinding and breaking the code ........................................................................41
4.1.6
Packaging, labelling, and re-supply...................................................................41
4.1.7
Storage conditions...............................................................................................41
4.1.8
Drug accountability.............................................................................................42
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................42
4.2.1
Other treatments and emergency procedures..................................................43
4.2.1.1
Systemic hypersensitivity including infusion reaction and anaphylactic reaction43
4.2.1.2
Severe infections (according to RCTC grading), serious infections, opportunistic 
or mycobacterium tuberculosis infections ............................................................44
4.2.1.3
Malignancies.........................................................................................................44
4.2.1.4
Suicidality .............................................................................................................44
4.2.2
Restrictions ..........................................................................................................44
4.2.2.1
Restrictions regarding concomitant treatment ......................................................44
4.2.2.2
Rescue treatment...................................................................................................45
4.2.2.3
Antibiotic use during the trial ...............................................................................45
4.2.2.4
Analgesics use during the trial..............................................................................46
4.2.2.5
Lesion intervention ...............................................................................................46
4.2.2.6
Restrictions on diet and life style..........................................................................46
4.2.2.7
Contraception requirements..................................................................................46
4.3
TREATMENT COMPLIANCE........................................................................47
5.
ASSESSMENTS..................................................................................................48
5.1
ASSESSMENT OF EFFICACY........................................................................48
5.1.1
Patient diary ........................................................................................................50
5.2
ASSESSMENT OF SAFETY.............................................................................50
5.2.1
Physical examination ..........................................................................................50
5.2.2
Vital signs.............................................................................................................51
5.2.3
Safety laboratory parameters ............................................................................51
5.2.4
Electrocardiogram ..............................................................................................55
5.2.5
Other safety parameters.....................................................................................55
5.2.5.1
Suicidality .............................................................................................................55
5.2.6
Assessment of adverse events.............................................................................56
5.2.6.1
Definitions of AEs ................................................................................................56
5.2.6.1.1
Adverse event........................................................................................................56
5.2.6.1.2
Serious adverse event............................................................................................56
5.2.6.1.3
AEs considered “Always Serious”........................................................................57
5.2.6.1.4
Adverse events of special interest.........................................................................57
5.2.6.1.5
Intensity (severity) of AEs....................................................................................58
5.2.6.1.6
Causal relationship of AEs....................................................................................58
5.2.6.2
Adverse event collection and reporting ................................................................59
5.2.6.2.1
AE Collection........................................................................................................59
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................60
5.2.6.2.3
Pregnancy..............................................................................................................60


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................60
5.3.1
Assessment of pharmacokinetics .......................................................................60
5.3.2
Methods of sample collection .............................................................................61
5.3.2.1
Plasma sampling for pharmacokinetic analysis ....................................................61
5.3.2.2
Sampling for ADA/Nab assessment .....................................................................61
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................62
5.4.1
Biochemical and cellular biomarkers................................................................62
5.4.2
Pharmacogenomics biomarkers.........................................................................62
5.4.3
Methods of sample collection .............................................................................62
5.5
BIOBANKING ....................................................................................................63
5.6
OTHER ASSESSMENTS...................................................................................63
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................63
6.
INVESTIGATIONAL PLAN.............................................................................64
6.1
VISIT SCHEDULE.............................................................................................64
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................64
6.2.1
Screening..............................................................................................................65
6.2.2
Treatment period(s)............................................................................................66
6.2.3
Follow-up period and trial completion..............................................................67
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE......................................................................................................................68
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................68
7.2
PLANNED ANALYSES.....................................................................................68
7.2.1
General considerations .......................................................................................68
7.2.2
Primary endpoint analyses.................................................................................69
7.2.3
Secondary endpoint analyses .............................................................................70
7.2.5
Safety analyses.....................................................................................................71
7.2.6
Other Analyses ....................................................................................................71
7.2.7
Interim Analyses .................................................................................................72
7.3
HANDLING OF MISSING DATA ...................................................................72
7.4
RANDOMIZATION...........................................................................................72
7.5
DETERMINATION OF SAMPLE SIZE .........................................................73
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........76
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................76
8.2
DATA QUALITY ASSURANCE ......................................................................77
8.3
RECORDS...........................................................................................................77
8.3.1
Source documents ...............................................................................................77
8.3.2
Direct access to source data and documents.....................................................78
8.3.3
Storage period of records ...................................................................................78
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................79


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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........79
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................79
8.6
TRIAL MILESTONES.......................................................................................79
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................80
9.
REFERENCES....................................................................................................82
9.1
PUBLISHED REFERENCES............................................................................82
9.2
UNPUBLISHED REFERENCES......................................................................84
10.
APPENDICES.....................................................................................................85
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ANTIDRUG 
ANTIBODY (ADA) AND NEUTRALIZING ANTIBODY (NAB) BLOOD 
SAMPLING.........................................................................................................85
10.2
HIDRADENITIS SUPPURATIVA CLINICAL RESPONSE (HISCR)........86
10.3
INTERNATIONAL HIDRADENITIS SUPPURATIVA SEVERITY SCORE 
SYSTEM (IHS4)..................................................................................................87
10.4
HIDRADENITIS SUPPURATIVA PHYSICIAN GLOBAL ASSESSMENT
(HS-PGA).............................................................................................................88
10.5
HIDRADENITIS SUPPURATIVA AREA AND SEVERITY INDEX 
(HASI) ..................................................................................................................89
10.6
PAIN NUMERICAL RATING SCALE (NRS)................................................91
10.7
DERMATOLOGY LIFE QUALITY INDEX (DLQI) ....................................92
10.8
HIDRADENITIS SUPPURATIVA QUALITY OF LIFE (HIS-QOL)..........94
10.9
FACIT-FATIGUE...............................................................................................97
10.10
PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C) ........................98
10.11
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S)......................99
10.12
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)..............100
10.12.1
Columbia-Suicide Severity rating Scale (C-SSRS) baseline version............100
10.12.2
Columbia-Suicide Severity rating Scale (C-SSRS) since last visit version ..106
10.13
DIAGNOSIS OF ANAPHYLAXIS .................................................................111
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................112


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ABBREVIATIONS
ADA
Anti-drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AMP
Auxiliary Medicinal Products
AN count
Abscess and Inflammatory Nodule count
APC
Antigen Presenting Cell
AST
Aspartate Aminotransferase
AtD
Atopic Dermatitis
AUC
Area under the Curve
b.i.d.
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
CA
Competent Authority
CI
Confidence Interval
Cmax
Maximum Concentration
Cmin
Minimum Plasma Concentration
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CRS
Cytokine release syndrome (CRS)
CTCAE
Common Terminology Criteria for Adverse Events
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DC
Dendritic Cells
DILI
Drug Induced Liver Injury
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee


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EC
Ethics Committee
ECG
Electrocardiogram
(e)COA
(electronic) Clinical Outcome Assessment
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoS
End of Study
EoT
End of Treatment
EudraCT
European Clinical Trials Database
FACIT
Functional Assessment of Chronic Illness Therapy 
FC
Flowchart
FUP
Follow-up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GPP
Generalized Pustular Psoriasis
HA
Health Authority
HADS
Hospital Anxiety and Depression Scale
HASI
Hidradenitis Suppurativa Area and Severity Index
HiSCR
Hidradenitis Suppurativa Clinical Response  
HiS-QoL
Hidradenitis Suppurativa Quality of Life
HIV
Human Immunodeficiency Virus
HS
Hidradenitis Suppurativa
hs-CRP
High-Sensitivity C-Reactive Protein 
i.v.
intravenous
IB
Investigator’s Brochure
IBD
Inflammatory Bowel Disease
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IGRA
Interferon Gamma Release Assay
IHS4
International Hidradenitis Suppurativa Severity Score System 
IL-36
Interleukin 36
IL-36R
Interleukin 36 Receptor
INN
International Non-Proprietary Name
IRB
Institutional Review Board


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IRT
Interactive Response Technology
ISF
Investigator Site File
ITT
Intention To Treat
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
i.v.
Intravenous
kg
Kilogram
KO
Knockout
LPLT
Last Patient Last Treatment
LPLV
Last Patient Last Visit
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligram
MMRM
Mixed effect Model for Repeated Measurements
MoA
Mechanism of Action
MRD
Multiple Rising Dose
Nab
Neutralizing Antibody
NRI
Non Response Imputation
NRS
Numerical Rating Scale
NRS30
Reduction of 30% in Numerical Rating Scale
OLE
Open Label Extension
OPU
Operative Unit
PD
Pharmacodynamics
PGA
Physician Global Assessment
PK
Pharmacokinetics
PPD
Purified Protein Derivative
PPP
Palmoplantar Pustulosis
q.d.
quaque die (once a day)
qw
Every week
q2wk
Once every 2 weeks
RA
Regulatory Authority
RCTC
Rheumatology Common Toxicity Criteria
REML
Restricted Maximum Likelihood
REP
Residual Effect Period


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SAE
Serious Adverse Event
s.c.
subcutaneous
SC
Steering Committee
s.e.
Standard error
SoC
Standard of Care
SOC
System Organ Class
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TEAE
Treatment-Emergent Adverse Events
TH
T helper
t1/2
Half Life Time
tmax
Timepoint of Maximum Plasma Concentration
TNF
Tumor Necrosis Factor
TNFi
TNF inhibitor
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TST
Tuberculin-Skin testing
ULN
Upper Level of Normal
vs.
versus
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Hidradenitis suppurativa (HS) is an inflammatory skin disease characterised by recurrent, 
painful abscesses and fistulous tracts. Patients with HS objectively have one of the lowest 
quality of life measures of any dermatologic disease. Lesions characteristically occur in the 
axillary, groin, infra-mammary, and/or anogenital regions of the body. HS lesions may 
progress to form sinus tracts and expansive abscesses. Sequelae include significant pain, 
scarring, and psychological distress. The average age of onset is during the early 20s [R20-
3184]. The global prevalence of HS is reported between 0.0003% and 4.1%. Underdiagnosis 
or improper diagnosis is common. Overall, HS prevalence varies significantly based on 
population studied; however, the disease appears to be more common than was previously 
considered [R20-3176].
Treatment often begins with topical or oral antibiotics, such as topical clindamycin and oral 
tetracycline, followed by the use of other antibiotics if there is no improvement.
When topical medications and oral antibiotics fail, or the disease has progressed, biologics are 
recommended [R20-3177]. Adalimumab is the only approved biologic, with the response rate 
of 42%-59% versus placebo response of 26% – 28%, with a schedule of weekly subcutaneous 
dosing. 
When the medical management is ineffective, surgery is the only option.
Some of the most burdensome HS symptoms from patient perspective are pain, drainage and 
explosive openings, itch, skin tightness (scarring), odour, fatigue and flu-like symptoms. 
Patients reported to be unsatisfied with the level of control offered by currently available 
treatment options and unmet needs from the patient perspective include the need for new 
medical treatments with favourable efficacy and tolerability profiles. In qualitative evidence, 
the most important treatment goals from the patient perspective were pain, drainage (including 
explosive openings) and fatigue.
1.2
DRUG PROFILE
1.2.1
Mode of action
Spesolimab is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R 
signaling. Binding of spesolimab to IL36R is anticipated to prevent the subsequent activation 
of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-inflammatory 
and pro-fibrotic pathways with the aim to reduce epithelial cell/ fibroblast/ immune cell-
mediated inflammation and interrupt the inflammatory response that drives pathogenic 
cytokine production in inflammatory diseases including generalized pustular psoriasis (GPP), 
palmoplantar pustulosis (PPP) and inflammatory bowel disease (IBD).
Spesolimab binds to human IL36R with a binding avidity of less than 1 pM.
Spesolimab inhibits IL36 ligand-stimulated NF-kB activation in HT29 and transformed
epithelial cells and in primary human dermal fibroblasts or intestinal myofibroblasts with
IC90 values in a consistent range of 0.7 to 3.7 nM. Spesolimab also inhibits IL8 release in 


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primary human intestinal myofibroblasts and IFNγ secretion in human PBMC stimulated with 
IL36α, IL36β, or IL36γ combined with IL12.
Mutations of two key residues (L234 and L235) to alanine were made to spesolimab to 
abrogate FcR binding activity and function. Direct assessment of the impact of the mutations 
in the IgG1 FcR binding sites on both antibody-dependent cellular cytotoxicity (ADCC) and 
complement-dependent cytotoxicity CDC effector functions revealed that the mutations 
abrogate both ADCC and CDC effector functions and indicate that spesolimab will be a non-
depleting therapy in vivo.
Spesolimab does not bind to IL-36R from common toxicology species.
Therefore, meaningful toxicity studies of the molecule cannot be performed in any animal
species with spesolimab. However, hazard identification studies of the mode-of-action (MoA) 
of IL-36R inhibition were performed in mice using a mouse specific anti-IL-36R monoclonal 
antibody (BI 674304), which is a mouse IgG2a monoclonal antibody with rat variable regions. 
In a 13-week intravenous toxicity study of BI 674304 in mice, no adverse effects of IL-36R 
antagonism were seen at a dose (50 mg/kg, twice weekly) that was 5 fold higher than the dose 
that was protective in an experimental mouse colonic inflammation model. In the 26-week 
toxicity study, male and female mice (20-30/sex/group at 0, 10 and 50 mg/kg/day) were 
administered BI 674304 twice weekly for 26 weeks by intravenous injection via the caudal 
vein. There were no BI 674304-related changes in clinical observations, body weights, food 
consumption, ophthalmology, clinical pathology parameters (hematology, clinical 
chemistry), organ weights, macroscopic or microscopic examinations. The no-observed-
adverse-effect level (NOAEL) was considered to be 50 mg/kg/day.
The in vitro cytokine release and tissue cross-reactivity assays demonstrate that the risk of 
transient cytokine release in humans is low and that, as expected, spesolimab stains 
epithelium in a variety of tissues. There were no signs of local irritation after single, 1 mL 
injections of the subcutaneous formulation in rabbits. 
These preclinical toxicology data support chronic spesolimab dosing in humans.
Spesolimab or placebo (PBO) was administered to 78 healthy volunteers at single ascending 
i.v. doses from 0.001 mg/kg to 10 mg/kg body weight. Safety and tolerability of all tested i.v. 
doses was good. There were no drug-related SAEs. AEs categorized as related to treatment 
were observed in 3/19 (15.8%) subjects in the placebo group and in 7/59 (11.9%) subjects 
treated with spesolimab. The most frequent treatment-emergent AEs were nasopharyngitis 
(spesolimab: 21%; PBO: 15%), headache (spesolimab: 9%; PBO: 15%), influenza like illness 
(spesolimab: 7%; PBO: 10%), and diarrhea (spesolimab: 3%; PBO: 10%). There were two 
AEs of moderate intensity (injection site haematoma, headache), all remaining AEs were of 
mild intensity. There was no apparent relationship between the frequency of AEs and the 
dose.
There were no relevant changes compared to placebo for laboratory safety, including clinical 
chemistry, haematology, coagulation parameters, and urinalysis. No clinically relevant 
changes were observed in 12-lead ECGs, vital signs, and cardio-monitoring.
PK analysis showed that exposure (AUC0-tz and Cmax) to spesolimab increased with 
increasing dose in an approximately dose-proportional manner from 0.3 to 10 mg/kg.
The effective half-life of spesolimab is approximately 4 weeks in the linear dose range. 
Overall, PK data so far suggests target-mediated drug disposition (TMDD) kinetics for 


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spesolimab. Anti-drug antibodies (ADA) were detected in 8 patients, 3 of those had pre-
existing levels. Pharmacodynamic effects in this FIH Single Rising Dose trial [c03361085] 
were assessed by indirect target engagement (ITE) of IL36R by spesolimab using an ex-vivo 
whole blood stimulation assay. Preliminary analyses indicate that ≥94% peripheral IL36R 
receptor occupancy is achieved with doses ≥0.05mg/kg from 30 minutes post infusion to 10 
weeks.
In a multiple rising dose trial, spesolimab or placebo have been administered to healthy 
volunteers at multiple ascending i.v. doses of 3, 6,10 and 20 mg/kg given qw for 4 weeks (i.e. 
4 administrations) or a single dose of 20mg/kg (8 subjects each, 3:1 on active or PBO). 
Overall, spesolimab was well tolerated. There were no dose dependent AEs, AEs considered 
to be dose limiting and no SAEs. In all cases the AEs were of mild or moderate intensity. 
Furthermore, there were no clinically relevant abnormalities on treatment with spesolimab
with respect to safety laboratory, vital signs, or ECGs as assessed by a central reader. For 
further details and most recent results refer to the current Investigator’s Brochure (IB) 
[c03320877-09].
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 spesolimab, and were monitored for 20 weeks. At week 1 after dosing, Generalized 
Pustular Psoriasis Physician Global Assessment (GPPGA) score of clear or almost clear (0 or 
1) was achieved in five patients, and by Week 4 in all seven patients. Within 48 hours 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 spesolimab is 16 weeks. This is the period after the last 
dose with measurable drug levels and pharmacodynamic effects still likely to be present.
Summary
Spesolimab is an anti IL36R antibody with a high clinical activity to block IL36R signaling, 
as demonstrated in patients with Generalized Pustular Psoriasis, a severe inflammatory skin
disease driven by uncontrolled IL36 activity. Spesolimab has been tested in healthy 
volunteers with multiple dosing up to four weeks of 20 mg/kg i.v. q.w. which were all safe 
and well tolerated. In addition, IL36R inhibition shows a favourable nonclinical safety profile. 
Therefore, spesolimab might be a promising drug to treat patients suffering from hidradenitis 
suppurativa.
For further details and most recent results refer to the current IB [c03320877-09].
1.3
RATIONALE FOR PERFORMING THE TRIAL
Adalimumab (TNFi) is the only approved biologic for HS, with the response rate of 42%-
59% versus placebo response of 26% – 28%, with a schedule of weekly subcutaneous dosing. 


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Long-term safety concerns are pertinent in the treatment of HS, where the dosing regimen of 
biologics is typically more intensive compared to other inflammatory diseases, such as 
psoriasis. Considering the above, a more efficacious and safer molecule with better dosing 
regimens is a substantial need in HS patients.         
Spesolimab is an IL-36R antagonist currently in development for the treatment of GPP. HS 
and generalized pustular psoriasis (GPP) have similarity in neutrophil infiltration and 
pustules, with pustules in HS being subcutaneous. IL-36 alpha, beta and gamma mRNA 
expression are upregulated in lesional skin in HS patients with a decrease in IL-36RN 
expression [R20-3047].  Internal ISH staining of HS lesions also confirms the increased 
expression of ligands. IL-36 is thought to be a central upstream mediator of an inflammatory 
loop which further activates the keratinocytes, amplifying the secretion of chemokines that 
lead to infiltration of immune cells to the skin. Infiltrated DCs and monocytes can be activated 
by IL-36 (internal data and published) to potentiate the APC function of DCs and also lead to 
secretion of chemokines and cytokines that can recruit more immune cells including 
neutrophils. IL-36 is a potent activator of neutrophil infiltration and in the context of HS,
neutrophils are shown to undergo netosis leading to secretion of AMPs and type I Interferons 
[R20-3155]. Based on the role of IL-36 driving TH17 and TH1 responses in GPP (published 
and our internal data) and from animal models of atopic dermatitis (AtD), the hypothesis is 
that IL-36 is also a key driver of TH17 responses in skin of HS patients.
Study 1368-0052 is proof-of-clinical-concept study in HS designed to assess the efficacy and 
safety of spesolimab in this patient population. The results from this trial will enable the 
design of the further development.
1.4
BENEFIT - RISK ASSESSMENT.
1.4.1
Benefits
Preclinical profiles of spesolimab and clinical data from healthy volunteer and patient trials 
suggest that spesolimab is safe, tolerable and may address an unmet medical need in patients 
with hidradenitis suppurativa by an anti-inflammatory mechanism of action. Efficacy in HS 
has not been established. The data from the completed proof of concept trial 1368.11, in 
patients with an acute flare of GPP, demonstrate that spesolimab treatment rapidly stops the 
flare and clears pustules, the primary lesions in GPP, a disease closely linked to loss-of 
function mutations in the natural IL-36R antagonist. (See: spesolimab IB, document number
c03320877-09)
No relevant animal species is available for toxicology testing of the highly human specific 
antibody spesolimab. However, preclinical toxicology studies with a mouse surrogate 
antibody have demonstrated the safety of chronic IL-36R inhibition in mice (Spesolimab IB, 
document number c03320877-09, section 5.1.2). A recent publication has assessed the 
clinical phenotype and immune function in 12 healthy individuals harboring an IL-36R 
knock-out polymorphism. This study demonstrated the absence of any specific diseases or 
conditions, in particular of recurrent, severe or opportunistic infections or malignancies, in 
the medical records of these subjects. Also, serological and in-vitro studies indicated normal 
levels of non-, tetanus- or varicella-specific immune globulins, and normal immune functions 
as compared to matched controls, indicating that IL-36 blockade is likely to represent a safe 
and well tolerated therapeutic concept.


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More than 140 healthy volunteers have been exposed in phase I SRD and MRD studies to 
single or multiple doses of spesolimab up to dose levels of 20mg/kg given once weekly for 4 
weeks. Spesolimab was safe and well tolerated in three healthy volunteers' trials at all dose 
groups up to the highest tested dose of 20 mg/kg body weight given once a week for up to 4 
weeks (for details see spesolimab IB, document number c03320877-09). Moreover, several 
clinical studies are ongoing as of May 2020, exploring efficacy and safety of spesolimab in 
different indications as: Atopic Dermatitis, Ulcerative colitis, Crohn’s Disease, Generalized 
Pustular Psoriasis, and Palmoplantar Pustulosis. Spesolimab has been tested in single dose 
(10 mg/kg i.v.) in GPP and in multiple doses up to 900 mg i.v. in PPP which were all safe 
and well tolerated.
In general, these studies indicate some evidence of efficacy in inflammatory skin disease.
Based on the PoC achieved in GPP and the strong preclinical rationale, there is a reasonable 
chance that spesolimab may alleviate signs and symptoms of HS. Participation in this study 
may help to generate future benefit for larger groups of patients with HS, if spesolimab proves 
to be successful in treating this disease. 
Patients completing the 12 weeks of treatment in this trial, will be offered to roll-over to 
receive open label active spesolimab maintenance treatment for up to 2 years in an open label 
extension (OLE) study. Patients experiencing worsening of HS will have the possibility to 
receive rescue treatment. Patients who fail to rescue treatment or cannot receive further trial 
medication (ie unbearable AEs) will be discontinued and switched to available SoC at the 
investigator`s discretion. This will limit the duration of spesolimab exposure in patients no 
longer benefitting from treatment. 
1.4.2
Risks
Table 1.4.2:1 lists possible risks for spesolimab as well as theoretical risks derived from 
general safety considerations of immunomodulatory drugs and from this trial specific 
procedures.
No other IL-36 receptor antagonist is currently approved, providing information on identified 
risks in molecules of this class. 
In order to protect the patient’s safety during conduct of this trial, an independent Data
Monitoring Committee (DMC) has been established for the periodic review of clinical trial 
safety data.


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Table 1.4.2:1 Overview over trial related risks 
Hypothetical risks of 
clinical relevance for this 
trial 
Summary of data, 
rationale for the risk
Mitigation strategy
Spesolimab
Drug-induced liver injury 
(DILI)
Although rare, a potential 
for drug-induced liver 
injury (DILI) is under 
constant surveillance by 
sponsors and 
regulators.Therefore, DILI 
is considered as a standard 
risk in all BI development 
programs.
Timely detection, 
evaluation, and follow-up 
of laboratory alterations in 
selected liver laboratory 
parameters to ensure 
patients’ safety. See also 
section 5.2.6, adverse 
events of special interest.
Trial treatment 
discontinuation criteria as 
well as criteria for trial 
treatment restart are 
implemented for relevant 
cases.
Systemic Hypersensitivity 
reaction
After administration of any 
biologic agent or protein, 
there is a possibility of 
occurrence of immediate 
(such as anaphylaxis) or 
delayed (such as drug 
reaction with eosinophilia 
and systemic symptoms)
adverse immune reactions 
Patients with a history of 
allergy/hypersensitivity to 
the systemically 
administered trial   
medication agent or its 
excipients are excluded 
from the trial.
In case of systemic 
hypersensitivity reactions 
including anaphylactic 
reaction emerging during 
or after administration of 
trial medication, the 
investigator should 
consider in accordance 
with the severity of the
reaction and local standard 
of care to interrupt and 
treat the condition. 
Systemic hypersensitivity 
reaction is defined as an 
adverse event of special 
interest (AESI). It is 
subject to close monitoring 


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and investigators are 
requested to assess these 
conditions using the 
criteria discussed in the 
statement paper from 
Sampson HA [R11-4890].
Infections
Inhibition of the immune 
response with an 
immunomodulating 
biologic may increase the 
risk of infections.
A recent characterization 
of individuals with 
homozygous IL-36R KO 
mutations revealed that 
normal immune function 
was broadly preserved 
suggesting that IL-36 
signaling pathway 
inhibition may not 
substantially compromise 
host defenses [R17-3632].
In clinical trials with 
spesolimab, a higher 
proportion of patients with 
mild to moderate infections 
was seen in the spesolimab 
treatment group than in the 
placebo treatment group.
Nevertheless, there was no 
indication of an increased 
frequency of patients with 
severe, serious, and 
opportunistic infections in 
association with 
spesolimab treatment.
Screening procedures for 
infections will be 
established for this trial. 
Patients with any relevant 
chronic or acute infections 
including human 
immunodeficiency virus 
(HIV), viral hepatitis or 
tuberculosis are excluded 
from the trial. Treatment of 
infections should be 
initiated promptly 
according to standards of 
care.
Severe infections and 
opportunistic infections are 
considered AESIs for this 
trial. These conditions and 
serious infections are 
subject to close 
monitoring.
Malignancies
Inhibition of the immune 
response with an 
immunomodulating 
biologic may potentially 
impair immune defences 
and thus theoretically 
Patients with a recent 
history of malignancy will 
be excluded from 
participation in this trial.
In case of occurrence of 
malignant neoplasm other 
than appropriately treated 


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decrease immune defense 
against malignancies.
A recent characterization 
of individuals with 
homozygous IL-36R KO 
mutations revealed that 
normal immune function 
was broadly preserved 
suggesting that IL-36 
signalling pathway 
inhibition does not 
compromise host defenses.
[R17-3632].
basal cell carcinoma or 
squamous cell carcinoma 
of the skin or in situ 
carcinoma of uterine 
cervix, the investigator 
should discontinue 
treatment with spesolimab.
Diagnostics and treatment 
have to be initiated 
according to local standard 
of care.
Malignancies represent 
always serious adverse 
events and are subject to 
close monitoring
Trial procedures
Blood sampling
As with all blood sampling, 
there is a risk of mild pain, 
local irritation, or bruising 
(a black or blue mark) at 
the puncture site. 
Furthermore, there is a 
small risk of 
lightheadedness and/or 
fainting. In rare cases, the 
puncture site can also 
become infected or nerves 
may be damaged, inducing 
long-lasting abnormal 
sensations (paresthesia), 
impaired sensation of touch 
and persistent pain.
These risks will be 
addressed by careful safety 
monitoring and risk 
mitigation measures such 
as
(a) close clinical 
monitoring for AEs;
(b) selection of 
experienced sites and 
site staff;
(c) Safety 
recommendations 
provided in laboratory 
manual.
Skin biopsy
Can cause local bruising, 
inflammation, nerve 
damage and pain.
These risks will be 
addressed by careful safety 
monitoring and risk 
mitigation measures such 
as
(a) close clinical 
monitoring for AEs;
(b) selection of 
experienced sites and 
site staff;
(c) staff training
Other risks


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Administration of Placebo
If the patient is randomized 
to receive a placebo, the 
patient´s condition could 
get worse during the trial.
Minimize the number of 
patients on the placebo 
group using adequate 
statistical model. 
The use of rescue 
medication is foreseen in 
this trial for patients 
experiencing a worsening 
of their HS condition.
Suicidal ideation and 
behavior
Increased risk of suicidal 
ideation and behavior is 
present in the population of 
patients with hidradenitis 
suppurativa
‘Baseline/ 
screening’ 
version of C-SSRS will be 
administered with the aim 
to exclude patients with 
active moderate to severe 
symptomatology 
present 
within a specified time prior 
to 
the 
screening 
or 
screening visit. ‘Since last 
visit’ version of C-SSRS 
will be administered with 
the aim to monitor patient’s 
safety during the trial and to 
initiate
actions for the 
patient’s safety if such 
actions 
are 
deemed 
necessary.
All C-SSRS reports of 
suicidal ideation type 4 or 
5 and all reports of suicidal 
behavior represent SAEs 
and are subject to close 
monitoring.
These risks will be addressed by careful safety monitoring and risk mitigation measures, 
which will be implemented in this trial of a novel and 1st-in-class MoA: (a) exclusion of 
patients with history or increased risk of malignancies or infections or allergy; (b) close 
clinical monitoring for AEs, including definition of malignancies as always-serious adverse 
events, definition of opportunistic infections and mycobacterium tuberculosis infections, 
severe infections and systemic hypersensitivity including infusion reaction and anaphylactic 
reactions as adverse events of special interest (AESI); (c) selection of sites experienced in 
treatment of HS patients with biologics; and (d) implementation of a fully independent data-
monitoring committee (DMC).
Reactions to injections/infusions: Specific safety measures will be taken during the trial. 
Following the injection/infusion the patients will be monitored for reactions at the site 
according to Instructions for Preparation and Handling of Spesolimab/Placebo in the 


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Investigator Site File. Subcutaneous injection has been well tolerated in a small phase I study 
(1368-0003; see spesolimab IB, document number c03320877-09) and will be carefully 
monitored for local tolerability in this study. Intravenous infusion has been well tolerated in 
various clinical trials and will continue to be monitored for tolerability in trial 1368-0052.
Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of Women of Child Bearing Potential 
(WOCBP) in this study is justified. To minimize the risk of unintentional exposure of an 
embryo or fetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods.
1.4.2.1
COVID-19
To date, there is no reliable evidence suggesting a link between SARS-CoV-2 infections and 
the IL-36 pathway. Further investigations are needed to elucidate the molecular mechanisms 
underlying their biological functions in COVID-19. According to the CDC there is limited 
information regarding risk factors for severe COVID-19 disease. Based on currently available 
information and clinical expertise, older adults and people of any age who have serious poorly
controlled underlying medical conditions might be at higher risk for severe illness from 
COVID-19. Patients with evidence of a current or previous disease/medical condition that is 
clinically significant in the opinion of the investigator are excluded from participation in all 
trials with spesolimab. On the basis of the currently available evidence and considering the 
population included in the clinical trials, the spectrum of patient characteristics in the 
spesolimab program across all investigated indications does not suggest an undue risk of more 
severe COVID-19 infections.
Similar to other immune modulating biological treatments, spesolimab may potentially 
increase the risk of infections. Therefore, risk mitigation measures, such as exclusion of 
patients with increased risk of infections, close monitoring of adverse events, as well as 
guidance on handling of acute infections occurring during the trial have been included in 
spesolimab clinical trial protocols. As for 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. Considering the current knowledge of COVID-19 
and the implemented risk mitigation measures addressing the potential risk of infections, 
patients with indications in which spesolimab is investigated are not per se believed to be at 
higher risk of COVID-19. Protocol-defined procedures do not impose undue risk to study 
participants.
To address potential risks associated with operational aspects related to the participation in
clinical trials in context of COVID-19 pandemic, different risk mitigation measures are
considered in ongoing and planned spesolimab clinical trials based on local requirements and
development of pandemic.
The benefit-risk assessment of spesolimab remains favourable in the context of the COVID-
19 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


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required, will support the investigator in their decision making. It is acknowledged that the
investigator may decide to implement protocol deviations where this protects the safety,
wellbeing, and/or is in the best interest of the patient. Regarding COVID-19 vaccination in 
patients receiving immune-modulating drugs like spesolimab, the impact on the protective 
effect of COVID-19 vaccines is not known but could be lower.
1.4.3
Discussion
Due to the lack of mechanism- or compound-related safety signals of spesolimab, it is 
expected that patients with moderate to severe HS will not be exposed to unacceptable, undue 
risks and adverse events. 
Considering the medical need for development of an effective and well tolerated drug for the 
therapy of HS, the benefit of this trial is considered to outweigh the potential risks.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
This is a proof of clinical concept trial to investigate the efficacy and safety of spesolimab
compared to placebo in patients with moderate to severe hidradenitis suppurativa (HS).
The primary objective is to estimate the effect of spesolimab compared to placebo for the 
mean percent change from baseline in total abscess and inflammatory nodule count at Week 
12. Secondary objectives are the evaluation of efficacy of spesolimab on secondary endpoints 
versus placebo.
The comparisons of interest for each efficacy objective are those of all treated patients but 
excluding the effects of rescue therapy.
2.1.2
Primary endpoint(s)
The primary endpoint is the percent change from baseline in total abscess and inflammatory 
nodule count at Week 12. 
2.1.3
Secondary endpoint(s)
Secondary endpoints are defined as described below: 

Percent change from baseline in draining fistula count at Week 12

Achievement of Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12. 
HiSCR is defined as at least a 50% reduction in the total AN count with no increase in 
abscess count and no increase in draining fistula count relative to baseline.

Absolute change from baseline in International Hidradenitis Suppurativa Severity 
Score System (IHS4) value at Week 12

Absolute change from baseline in HASI score at Week 12

Achievement of PGA score of 0 or 1 at Week 12

Achievement of at least 30% reduction from baseline in Numerical Rating Scale 
(NRS30) in Patient’s Global Assessment of HS Pain at Week 12

Occurrence of complete elimination of draining fistulas at Week 12

Occurrence of at least one flare (defined as at least 25 % increase in AN count with a 
minimum increase of 2 relative to baseline) up to Week 12.

Absolute change from baseline in DLQI Score at Week 12.

Absolute change from baseline in HiS-QoL Total Score at Week 12.
The following safety endpoint is also defined:

The occurrence of Treatment Emergent Adverse Events (TEAEs)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is an international, phase IIa multi-center, double-blind, placebo controlled trial 
assessing the efficacy and safety of spesolimab in patients with moderate to severe HS. 
Approximately 45 patients will be randomized. A sufficient number of patients will be 
screened to meet this randomization target. 
After signing the informed consent, patients will enter the screening period for up to 28 days
and if all eligibility criteria are met, patients will be randomized in a 2:1 ratio to either active 
group or placebo group. The randomization will be stratified for TNFi-naive population 
versus TNFi-failure population. Approximately 33 patients from TNFi-naive population and 
12 patients from TNFi-failure population are planned to be randomized respectively. Primary 
failure of TNF treatment is defined as lack of efficacy after at least 3 months of treatment 
with an agent blocking TNF-alpha and secondary failure is defined as loss of clinical efficacy 
in a patient after initial response to an agent blocking TNF-alpha.
Once randomized, patients will start a treatment period of 12 weeks. The first three weeks 
patients will be given an initial loading dose of 3600 mg i.v. spesolimab (1200 mg i.v. every 
week at Wk 0, Wk 1 and Wk 2), or matching placebo. At the time of use the i.v. solutions for 
dosing will be prepared as detailed in the instruction in the ISF. From week 4 and until week 
10 patients will receive a maintenance subcutaneous dose of 1200 mg spesolimab every 2 
weeks, or matching placebo. Patients completing week 12 of the study, will roll-over to an 
open-label extension (OLE) study if they agree and meet the eligibility criteria of the OLE 
trial. These patients are not required to complete the follow up period and their EoT visit will 
be considered also their end of study visit, co-inciding with the first visit in the OLE trial 
1368-0067.
Patients who permanently discontinue trial drug earlier than week 12, or do not qualify to 
enter the OLE trial for any other reason, will be invited to do the EoT visit instead of the next 
planned visit and will then enter a 16 weeks safety follow-up period. The first visit in the 
safety follow-up period will be scheduled 8 weeks after their last study drug administration 
and the second visit will be scheduled 16 weeks after their last study drug administration. 
This is the end of study visit and patients will finish their participation in the study after 
completing this visit.


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Figure 3.1:1 Trial Design
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A parallel group, randomized, double-blind and placebo controlled trial was considered most 
appropriate to demonstrate PoC. The placebo control group is required to compare both 
efficacy and safety of spesolimab in patients with moderate-to-severe hidradenitis 
suppurativa who are biologic naïve or have failed previous TNFi treatments. However, a 2:1 
randomization schema will help reducing the number of patients assigned to the placebo arm. 
Additionally, if eligible, patients will be invited to roll-over to an OLE trial with active drug. 
The treatment duration of 12 weeks with spesolimab was selected to evaluate sustained 
efficacy over flares in these patients. 
The loading dose of three i.v. administrations followed by the maintenance subcutaneous 
biweekly dosing was selected to optimize the exposure of spesolimab to evaluate its efficacy 
in HS. The intravenous loading dose is selected to maximize the treatment response, the 
duration of response and to reach steady state earlier. A loading dose may also allow for an 
earlier onset of response. This is followed by maintenance dose given subcutaneously so as 
to sustain the response.
Thus, this trial design is considered adequate to achieve the objectives outlined above.


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3.3
SELECTION OF TRIAL POPULATION
A total of approximately 45 patients will be randomized in this trial. A sufficient number of
patients will be screened to meet this randomized goal. Patients will be recruited across 
multiple sites in multiple countries. The minimum planned number of patients per site is 1 –
2.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A pre-trial screening log collecting reasons for screen failures will be maintained in the 
Investigator Site File (ISF) where possible. Also, a log of all patients enrolled into the trial
(i.e. who have signed informed consent) will be maintained in the ISF irrespective of whether 
they have been treated with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
Patients can be re-screened (see also section 6.2.1) on a case by case basis after consultation 
with Sponsor. These patients will need to sign a new informed consent. The re-screener will 
get a new unique patient number, subject numbers from screen-failed patients cannot be re-
used. If a patient is re-screened and there are valid screening determinations from his/her 
previous participation in the trial, like for example safety labs, performed within 28 days prior 
to baseline (visit 2), these do not need to be repeated. 
3.3.1
Main diagnosis for trial entry
Adult patients with moderate to severe Hidradenitis Suppurativa will be included in the trial 
if they fulfill all the inclusion criteria and do not present with any of the exclusion criteria.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Male or female adult patients, 18 years of age or older.
2. Signed and dated written informed consent in accordance with ICH Good Clinical 
Practice (GCP) and local legislation prior to the start of any screening procedures.
3. Moderate to severe HS, based on IHS4 criteria, for at least 1 year prior to the baseline 
visit, as determined by the investigator through participant interview and/or review of 
the medical history. (If IHS4 scoring is not available, equivalent scoring based on 
scoring systems as HS-PGA or Hurley are acceptable based on documented 
investigator assessment)
4. HS lesions in at least 2 distinct anatomic area (right/left axillary, inguinal, 
inframammary, perineal)
5. Biologic naive or TNFi-failure for HS.


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6. Inadequate response to an adequate course of appropriate oral antibiotics for treatment 
of HS in the last 1 year, as per investigator discretion. This is not applicable for TNFi-
failure patients
7. Total abscess and inflammatory nodule (AN) count of greater than or equal to 5. 
8. Total draining fistula count of less than or equal to 20.
9. Women of childbearing potential (WOCBP1) 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, for the duration of the trial 
and 16 weeks after last administration. A list of contraception methods meeting these 
criteria is provided in the patient information. (see also Section 4.2.2.7))
3.3.3
Exclusion criteria
1. Presence of active skin lesions other than HS that interfere with the assessment of HS.
2. Use of restricted medications as below. Please see section 4.2.2 for further information.

Topical corticosteroids over HS lesions within 1 week of Visit 2.

Systemic antibiotics within 4 weeks of visit 2.

Systemic non-biologic immunomodulatory and/or immunosuppressive agents use 
within 4 weeks (or 5 half lives, whichever is longer) of visit 2.

Biologic agents use within 12 weeks or 5 half-lives, whichever is longer, prior to 
visit 2. 

Opioid analgesics within 2 weeks of visit 2.

Live virus vaccine within 6 weeks of visit 2.
3. Prior exposure to any immunosuppressive biologic other than TNFi for HS. 
4. Prior exposure to IL-36R inhibitors including spesolimab.
5. Treatment with any investigational device or investigational drug of chemical or 
biologic nature within a minimum of 30 days or 5 half-lives of the drug, whichever is 
longer, prior to visit 2.
6. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
Women who stop nursing before the study drug administration do not need to be 
excluded from participating.
7. History of allergy/hypersensitivity to the systemically administered trial medication 
agent or its excipients.
8. Patient with a transplanted organ (with exception of a corneal transplant > 12 weeks 
prior to screening) or who have ever received stem cell therapy (e.g., Remestemcel-L).
9. Any documented active or suspected malignancy or history of malignancy within 5 
years prior to the screening visit, except appropriately treated basal cell carcinoma of 
the skin, squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix.
10.   Active or latent TB:

Patients with active tuberculosis should be excluded.

Patients will be screened with Interferon Gamma Release Assay (IGRA) such as 
QuantiFERON or T-spot. Patients with positive IGRA are excluded unless they 
                                                
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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have completed treatment for active or latent tuberculosis per investigator 
discretion, at the time of screening.

Patients with indeterminate QuantiFERON or invalid/borderline T-spot may be 
retested with IGRA (once) and if inconclusive should have a PPD skin test.

PPD skin test, also called Tuberculin- Skin testing (TST), can be performed if IGRA 
is not available or inconclusive. A tuberculin skin test reaction ≥10mm (≥5mm if 
receiving ≥15mg/d prednisone or other immunosuppressant) is considered positive. 
Patients with a positive TST are excluded unless they have completed treatment as 
above. 
11. Active systemic infection within 2 weeks of visit 2. Patients can be re-screened after 
treatment of the acute infection, as per investigator discretion.
12. Relevant chronic infections as determined by the investigator, including human 
immunodeficiency virus (HIV) or viral hepatitis. In case of a positive hepatitis C 
antibody test, a positive reflex testing for Hepatitis C RNA PCR is considered positive.
13. Major surgery (major according to the investigator) performed within 12 weeks prior 
to first study drug administration or planned during the study (e.g. hip replacement, 
aneurysm removal, stomach ligation)
14. Severe, progressive, or uncontrolled hepatic disease, defined as >3-fold Upper Limit of 
Normal (ULN) elevation in AST or ALT or alkaline phosphatase, or >2-fold ULN 
elevation in total bilirubin. Patients with Gilbert´s syndrome can be included unless 
total bilirubin elevation is >5-fold ULN at screening visit and unless proportions of 
bilirubin fractions are inconsistent with diagnosis of Gilbert´s syndrome.
15. Evidence of a current or previous disease, medical condition (including chronic alcohol 
or drug abuse or any condition) other than HS, surgical procedure, psychiatric or social 
problems, medical examination finding (including vital signs and ECG), or laboratory 
value at the screening outside the reference range that in the opinion of the investigator 
is clinically significant and would compromise the safety of the patient or compromise 
the quality of the data, make the study participant unreliable to adhere to the protocol, 
comply with all study visits/procedures or to complete the trial.
16. Planned use of laser or other hair removal procedures over HS-affected areas during the 
trial period.
17. Any suicidal ideation of type 4 or 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thoughts with method and intent but without specific plan, or active suicidal 
thoughts with method, intent and plan).
18. Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behavior). 
19. Previous enrolment in this trial. (exception: patients re-screened)
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible, on treatment, or at 
least to collect important trial data.


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Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see sections 5.2.6.1 and 5.2.6.2).
If the reason for discontinuation is death, this should be reported on the SAE form as well, 
regardless of causal relationship.
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:
The patient wants to discontinue trial treatment, without the need to justify the decision.
The patient has repeatedly shown to be non-compliant with important trial procedures and, 
in the opinion of 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 such as 
o
immunosuppressive agents (including biologics),
o
systemic corticosteroids for HS,
o
opioid analgesics
o
systemic antibiotics for HS before week 4
o
Systemic antibiotics for HS without meeting criteria for disease worsening (as 
defined in Section 4.2.2.2)
o
metformin (unless on a stable dose for 12 weeks before visit 2 for a non-HS 
indication)
o
spironolactone (unless on a stable dose for 12 weeks before visit 2 for a non-HS 
indication)
o
live vaccines. 
o
The patient can no longer receive trial treatment for medical reasons (such as
major surgery, adverse events, other diseases, malignancies as per Section 
4.2.1.3, or pregnancy). If a hepatic injury alert (as defined in Section 5.2.6.1.4) is 
confirmed without identification of an alternative cause in the work-up according 
to the “DILI checklist” the patient should not receive subsequent doses of trial 
treatment

The patient develops suicidal ideation or any suicidal behavior (See Section 4.2.1.4)

For individual stopping rules related to specific adverse events, please see section 4.2.1
other treatments and emergency procedures.
In case of a temporary reason, trial treatment should be restarted if medically justified, please 
see section 4.1.4.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the CRF. This data will be included in the trial database and reported.


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If new efficacy/safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, should undergo the procedures for early treatment discontinuation and follow-up
as outlined in the Flowchart and section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site.

New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see section 3.3.4.1.
Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
Further follow up of patients affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1 Test product spesolimab solution for infusion
Substance:
Spesolimab
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Chemical form:
Anti-human IL-36 Receptor mAb
Molecular weight:
146 kDa
Unit strength:
Spesolimab 450mg/vial (60mg/mL x 7,5mL)
Route of administration:
Intravenous infusions
Posology:
Active arm:
1200mg weekly at Weeks 0, 1 and 2 for a total 
loading dose of 3600mg  
Table 4.1.1: 2 Test product BI matching placebo solution for infusion
Substance:
Placebo matching to spesolimab
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Placebo to match spesolimab 450mg/vial 
(60mg/mL x 7,5mL)
Route of administration:
Intravenous infusions
Posology:
Placebo arm:
Placebo weekly at Weeks 0, 1 and 2 matching a 
total loading dose of 3600mg spesolimab


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Table 4.1.1: 3 Test product spesolimab solution for injection
Substance:
Spesolimab
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Chemical form:
Anti-human IL-36 Receptor mAb
Molecular weight:
146 kDa
Unit strength:
Spesolimab 300mg/pre-filled syringe (150mg/mL 
x 2mL)
Route of administration:
Subcutaneous injections
Posology:
Active arm:
1200 mg every 2 weeks at Weeks 4, 6, 8 and 10   
Table 4.1.1: 4 Test product BI matching placebo solution for injection
Substance:
Placebo matching to spesolimab
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Placebo to match spesolimab 300mg / Pre-filled 
syringe. (150mg/mL x 2mL)
Route of administration:
Subcutaneous injections
Posology:
Placebo arm:
Placebo every two weeks at Weeks 4, 6, 8 and 
10.
4.1.2
Selection of doses in the trial and dose modifications
The aim of this trial (1368-0052) is to provide proof of clinical concept that spesolimab is 
active in treating moderate to severe hidradenitis suppurativa when compared with placebo. 
It will also help understanding if this benefit is clinically relevant and sufficient to grant 
further clinical development of spesolimab in this indication.
Patients in the active arm will receive a loading dose of 3600mg spesolimab in 3 weekly 
intravenous administrations of 1200mg spesolimab each (week 0 to week 2. This is 3 
infusions in total for the loading dose). Patients in the placebo arm will receive matching 
placebo intravenous administrations at the same planned timepoints.
From week 4 to week 10 (both included) patients will receive subcutaneous injections of 
1200mg spesolimab or matching placebo every two weeks (4 injections per visit for a 
maximum of 4 visits)
This dose/regimen was selected to optimize the exposure of spesolimab to evaluate its 
efficacy in hidradenitis suppurativa. The intravenous loading dose is selected to maximize the 


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treatment response, the duration of response, and to reach a steady state sooner. A loading 
dose may also allow for an earlier onset of response prior to 12 weeks. The intravenous 
loading dose is followed by a subcutaneous maintenance dose given every 2 weeks. This dose 
is the maximum subcutaneous dose that can be conveniently given based on the injection 
volume and number of injections.
4.1.3
Method of assigning patients to treatment groups
An Interactive Response Technology (IRT) will be used to screen eligible patients, perform 
drug assignment, manage initial/re-supply ordering of drug supplies and handle emergency
un-blinding. The investigator will receive all necessary instructions to access the IRT from
the Sponsor. Detailed IRT functions and procedures will be documented in the user 
requirement specifications mutually agreed to by the sponsor and the IRT vendor.
After the assessment of all in- and exclusion criteria, each eligible patient will be randomized 
to receive 12 weeks of treatment with spesolimab or placebo according to a randomization
plan in a 2:1 ratio at visit 2 in a blinded fashion via Interactive Response Technology (IRT). 
Randomization will be stratified by TNFi-naive population versus TNFi-failure population. 
At randomization as well as subsequent medication administration visits, IRT will assign 
medication numbers. Note that the medication number is different from the patient number 
(the latter is generated during screening via the IRT System). Each syringe and vial will have 
an individual medication number for dispensation.
4.1.4
Drug assignment and administration of doses for each patient
Patients will be treated with spesolimab or matching placebo as indicated in the Flowchart
and section 3.1.
The medication will be assigned via IRT.
Patients will receive i.v. spesolimab at week 0, 1 and 2.
Detailed instructions for the preparation of the solution for infusion, the volume to be
administered and the infusion rate are provided in the ISF.
Patients will receive spesolimab s.c. injections at week 4, 6, 8 and 10.
Injection site should not be close to a vein and it should avoid sites where the skin is tender, 
bruised, erythematous, or indurated, and should be alternated to other areas for subsequent 
doses.
Detailed instructions for use and handling of spesolimab syringes are provided in the ISF.
Patients have to be closely monitored for local or systemic hypersensitivity reactions for 1 
hour following s.c. or i.v. study drug administration. Patients should be closely monitored for 
signs and symptoms of injection site or systemic hypersensitivity reactions following study 
drug administration. Study personnel should observe the injection site for signs of redness, 
swelling or hardness. They should also ask subjects about itching, dizziness or shortness of 
breath. Patients should be advised that if they experience redness, swelling or other changes 


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at the injection site, they should notify site personnel. They should further be advised that if 
they experience itching all over or a feeling of being swollen, dizzy or short of breath, they 
should seek emergency medical attention immediately and notify site personnel.
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.
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, if any of these visits has to be rescheduled, the date of subsequent visit should 
be calculated from baseline (visit 2). After visit 3, in case of delayed visits, IMP can be 
administered with a minimum interval of 7 days from the next dose, only after discussion and 
approval from the sponsor. 
Trial treatment may be restarted after a temporary reason for treatment discontinuation on a 
case by case basis and after consultation with the sponsor. Reasons for temporary treatment 
discontinuation may include but are not limited to pandemic lockdown, temporary 
hospitalization, severe infections, hepatic injury if an alternative cause is identified and patient 
has recovered as per investigator.
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 
still decide to continue the trial treatment and trial medication may be administered at patient’s 
home if acceptable according to local law and regulations.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients and investigators involved in the trial conduct will remain blinded with regard to the 
randomized treatment assignments until after database lock for the final trial analysis. The 
randomization code will be kept secret by Clinical Trial Support up to the final database lock.
If the trial team agrees to perform the primary analysis and the final analysis separately (see
section 7.2), then a database lock for the primary analysis will be done and treatment will be 
unblinded to trial and project team members.


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If the trial team agrees to perform the primary analysis and final analysis as one single analysis 
(at the time of trial completion), then patients, investigators, and sponsor personnel involved 
in the trial conduct will be unblinded to the randomized treatment assignments after the 
database lock has been performed.
The randomization codes will be provided to bioanalytics prior to last patient completed to 
allow for the exclusion from the analyses of pharmacokinetic (PK) samples taken from 
placebo patients. Bioanalytics will not disclose the randomization code or the results of their 
measurements 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 8.7 for further details.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomization code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A temperature 
log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate CRA (as provided in the list of contacts) must be contacted immediately. Refer to 
ISF. Trial medication must be securely stored, e.g. in a locked refrigerator at the site or at a 
pharmacy.
The medication may only be dispensed to trial patients according to the Clinical Trial Protocol 
(CTP) by authorized personnel as documented in the trial staff list.


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Trial medication will be prepared for infusion just prior to infusion, for further details please 
see preparation instructions in the ISF.
4.1.8
Drug accountability
The investigator, pharmacist, or designee will receive the investigational drugs delivered by 
the sponsor when the following requirements are fulfilled:
Approval of the clinical trial protocol by the IRB / ethics committee 
Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,
Approval/notification of the regulatory authority, e.g. competent authority,
Availability of the curriculum vitae of the Principal Investigator,
Availability of a signed and dated clinical trial protocol,
Availability of the proof of a medical license for the Principal Investigator (if applicable),
Availability of FDA Form 1572 (if applicable.).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics outside this clinical trial. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor <and/or> appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
This section provides information on restrictions regarding concomitant treatment prior to 
randomization and during the trial, including a definition on rescue therapy for the treatment 
of worsening of HS.


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4.2.1
Other treatments and emergency procedures
Systemic steroids dosed intravenously or orally for less than 24 hours as treatment of 
infusion or anaphylactic reactions are permitted and do not lead to treatment discontinuation 
nor to assignment as treatment failures in the ITT analysis.
4.2.1.1
Systemic hypersensitivity including infusion reaction and anaphylactic reaction
In case of systemic hypersensitivity including infusion reaction and anaphylactic reaction 
emerging during or after infusion / injection(s) of trial medication, the investigator should 
consider in accordance with severity of the reaction and local standard of care to
- Immediately interrupt the infusion (if i.v) or stop further injections (if s.c.).
- Treat with systemic anti-histamines, intravenous steroids, and in case of a severe allergic
reaction (e.g., anaphylactic reaction) epinephrine
- in case of s.c. administration give epinephrine in case of signs of hypersensitivity and add 
further treatments, e.g. oxygen, iv fluids, antihistamines and systemic corticosteroids as 
needed. 
Also draw a plasma sample for IgE and ADA as detailed in the Lab Manual in the ISF (Central 
laboratory). 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) at lower speed with gradual increase to complete the infusion as detailed in the 
Instructions for Preparation and Handling of Spesolimab/Placebo in the Investigator Site File.
In any case, the total duration of infusion should not exceed 180 minutes (3 hours). If the 
infusion exceeds 180 minutes, it should be stopped and the infusion should be skipped. Patient 
should be called for the next scheduled visit as planned.
In case of systemic hypersensitivity, based on patient’s clinical course and medical judgment, 
the injection(s) may be continued in case of mild or moderate systyemic hypersensitivity
(according to RCTC grading) to complete the injections as detailed in the Instructions for 
Preparation and Handling of Spesolimab/Placebo in the Investigator Site File.
In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.13 [R11-4890]) suspected to be caused by the trial medication, the 
investigator should discontinue treatment permanently with spesolimab.
When a delayed hypersensitivity reaction is suspected, please draw a blood sample for 
laboratory assessment and evaluate for signs of extra-cutaneous organ involvement. The 
decision to discontinue treatment and/or restart treatment after resolution of the reaction should 
be based on reaction type and severity.


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4.2.1.2
Severe infections (according to RCTC grading), 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 spesolimab may be restarted when the patient has recovered according to 
investigator’s assessment.
4.2.1.3
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 permanently discontinue treatment with spesolimab. Diagnostics and 
treatment have to be initiated according to local standard of care.
4.2.1.4
Suicidality
In case the patient develops suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal 
thoughts with method and intent but without specific plan, or active suicidal thoughts with 
method, intent and plan) or any suicidal behavior (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behavior), the patient should immediately be referred 
to a mental health professional for further work-up and permanently discontinue trial 
treatment.
Overall, the choice of Standard of Care treatment will be left at the discretion of the 
investigator. The sponsor will not provide/supply SoC treatment (s) to the sites.
Any of the above treatments in this section must be documented in the source data, including 
an estimate on dispensed medication, and documented in CRF (concomitant medications) and 
the corresponding AE if applicable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The following medications/ medication classes are restricted during trial treatment and prior 
to visit 2 for durations as specified below. Please see section 3.3.4 for withdrawal information 
regarding the use of restricted medications.


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Table 4.2.2.1:1 Restricted Medications.
Medication
Washout period prior to V2 (baseline)
Systemic antibiotics1
4 weeks 
Systemic corticosteroids2
1 week
Biologics causing immunosuppression
12 weeks or 5 half-lives whichever is 
longer
Other systemic immunomodulatory and 
immunosupresssive agents
4 weeks or 5 half-lives whichever is 
longer
Live vaccines
6 weeks 
Opioid analgesics
2 weeks 
Spironolactone3
1 week
Metformin3
1 week
Topical cannabis oil4
1 week
Topical corticosteroids for HS5
1 week 
1 For more information on the use of systemic antibiotics please see section 4.2.2.3.
2Systemic corticosteroids as short courses can be used for indications other than HS. 
3 Restricted if used for HS. If used for non-HS indication, dose should be stable for at least 12 weeks
prior to V2.
4 Restricted if used over HS-affected areas. Other alternative therapies for HS are restricted, unless 
permitted after discussion with PI and trial team.
5 Topical corticosteroids are allowed for indications other than HS if the areas are not affected by HS
concurrently.
4.2.2.2
Rescue treatment
HS Disease worsening is defined as a 150% increase in AN count from baseline. Rescue 
medication is generally defined as the treatment for disease worsening and includes systemic 
antibiotics and/or immunosuppressive biologics such as TNF-inhibitors. In this trial, 
immunosuppressive biologics are not allowed. For more information on the use of antibiotics
during the trial see section 4.2.2.3. The sponsor will not provide/supply these treatment(s) to 
the sites.
4.2.2.3
Antibiotic use during the trial
Non HS use:
Systemic antibiotics can be used for indications other than HS and for a duration of less than 
or equal to 4 weeks during the entire course of the trial (from randomization up to the last 
treatment administration).


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HS disease worsening (as defined above in section 4.2.2.2):
At or after week 4, if the patient requires systemic antibiotics for disease worsening as per the 
investigator, monotherapy with either doxycycline 100mg orally twice daily or alternative as 
per investigator discretion, may be used for a maximum period of 2 weeks, and not more than 
a total of 4 weeks during the entire course of the trial.
Concomitant use of systemic antibiotic therapy for treatment of HS other than for disease 
worsening, or before week 4, is not allowed and will lead patient to permanent treatment 
discontinuation (see Section 3.3.4.1). 
4.2.2.4
Analgesics use during the trial
Opiate analgesics are restricted for HS and non-HS indications. 
If a subject is on a non-opioid analgesic for HS and non-HS indication (e.g. osteoarthritis), 
the subject may continue the analgesic, provided the dose is stable for 14 days prior to 
Baseline and is anticipated to remain stable throughout the study.
If a subject's pain (HS-related or non-HS-related) worsens after Baseline, they may initiate or 
increase the non-opioid analgesic therapy.
Use of analgesics will be documented in the Patients Diary and the CRF.
4.2.2.5
Lesion intervention
In the event that an acutely painful lesion occurs that requires immediate intervention, 
physicians will have the option to perform protocol-allowed interventions.
Only two types of interventions are allowed: Intra-lesional steroid and Incision and Drainage 
(I&D). If I&D is performed, only over the counter antiseptic wash can be used. Concomitant 
medications associated with the lesion intervention must be captured in the medical records.
A total of two protocol-allowed interventions are permissible. An intervention can maximally 
occur on two different lesions at the same time or on the same lesion at two different study 
visits. If the subject requires more than two interventions, then they may be discontinued from 
the study.
4.2.2.6
Restrictions on diet and life style
No specific restrictions on diet or life style of the patients are required.
4.2.2.7
Contraception requirements
WOCBP (for the definition please refer to section 3.3.2) must use highly effective methods 
of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year 
when used consistently and correctly during the trial, and for a period of at least 16 weeks 
after the last study drug administration. A double barrier method of contraception is not 


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required. A list of contraception methods meeting these criteria is also provided in the patient 
information.
Female Patients
Acceptable methods of birth control for this trial are: 
-
Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal) 
-
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable) 
-
Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
-
Bilateral tubal occlusion 
-
Vasectomised sexual partner with documented absence of sperm 
Or
Patients must abstain from male-female sex. This is defined as being in line with the preferred 
and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, symptothermal, 
post-ovulation methods; declaration of abstinence for the duration of exposure to study drug; 
and withdrawal are not acceptable.
Male Patients: 
Contraception of male trial participants and female partners of male trial participants are not 
required.
4.3
TREATMENT COMPLIANCE
Administration of the study medication will be done in the study center under the supervision 
of the investigator or a designee. The measured plasma concentrations will provide additional 
confirmation of compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The primary, secondary and further endpoints of the study are specified in sections 2.1.2
and 2.1.3, and 2.2.2, respectively.
1. The HiSCR (Hidradenitis Suppurativa Clinical Response) is one of the most well-
known and widely used outcome assessment in clinical trials. HiSCR is defined as at 
least a 50% reduction from baseline in the total abscess and inflammatory nodule count, 
with no increase in the abscess or draining fistula count. [R20-2976]
HiSCR will be evaluated at the timepoints mentioned in the Flowchart and the detail is 
provided in Appendix 10.2
2. IHS4 – IHS4 is a valid, clinical scoring system for dynamic assessment of HS severity. 
Determining IHS4 requires counting nodules, abscesses and draining fistulae/sinus 
tracts making it straightforward to apply in clinical trials [R20-3045]. IHS4 will be 
evaluated at the timepoints mentioned in the Flowchart and the detail is provided in 
Appendix 10.3
3. HS-PGA – This documents the physician’s assessment of the patient’s HS at a given 
timepoint. It scores patient disease severity as either clear or minimal or mild or 
moderate to severe or very severe, based on abscesses, draining fistulae, inflammatory 
nodule and non-inflammatory nodule [R20-3046]. HS-PGA will be evaluated at the 
timepoints mentioned in the Flowchart and the detail is provided in Appendix 10.4
4. HASI - HASI is modelled after the Psoriasis Activity and Severity Index (PASI). Four 
classic signs of HS-related inflammation (erythema, induration, open ulcer and draining 
tunnels) are included. Each variable in HASI is scored on a Likert scale (0–3) for each 
predetermined body region. For BSA assessment, the number of palms (one palm 
indicated 1% of the patient’s BSA) involved for each body region (head, right axilla, 
left axilla, anterior chest, back, anterior bathing trunk, posterior bathing trunk, other) is 
assessed. This is converted to a percentage of that region. An area score was assigned 
to each region using the PASI approach (0 = none, 1 = 1–9%, 2 = 10–29%, 3 = 30–
49%, 4 = 50–69%, 5 = 70–89%, 6 = 90– 100%). To calculate the regional HASI score, 
the sum of the four clinical variable scores is multiplied by the area score of each 
involved region. This value is then multiplied by the proportion of the BSA of that 
region, to give a regional HASI score. Regional HASI scores are added together to give 
the cumulative total HASI score (range 0–72). HASI will be evaluated at the timepoints 
mentioned in the Flowchart and the detail is provided in Appendix 10.5
5. Pain NRS
The HS Pain NRS is an endpoint for the assessment of HS-related pain severity for 
clinical trials with patients with HS. As it is a unidimensional measure of pain intensity 
and can be administered daily with minimal subject burden. Recall period is 24h and 
response is given by an 11-point scale ranging from 0 to 10. Appendix 10.6
6. DLQI
The Dermatology Life Quality Index (DLQI) is a patient-administered, ten-question, 
quality of life questionnaire that covers six domains including symptoms and feelings, 
daily activities, leisure, work and school, personal relationships and treatment [R05-
2548]. The DLQI has a one-week recall period. Response categories include “not 


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relevant” (score of 0), “not at all” (score of 0), “a little” (score of 1), “a lot” (score of 
2) and “very much” (score of 3). Question 7 is a “yes”/ “no” question where “yes” is 
scored as 3.
The DLQI will be analyzed under six headings as follows [R05-2548]:
Domain
Question Number
Score
Symptoms and feelings
Questions 1 and 2
Score maximum 6
Daily activities
Questions 3 and 4
Score maximum 6
Leisure
Questions 5 and 6
Score maximum 6
Work and school
Question 7
Score maximum 3
Personal Relationships
Questions 8 and 9
Score maximum 6
Treatment
Question 10
Score maximum 3
DLQI total score is calculated by summing the scores of each question resulting in a 
range of 0 to 30 where 0-1 = no effect on patient’s life, 2-5 = small effect, 6-10 = 
moderate effect, 11-20 = very large effect, and 21-30 = extremely large effect on 
patient’s life. The higher the score, the more the quality of life is impaired. If one 
question is left unanswered this is scored 0 and the total score is summed and expressed 
as usual out of a maximum of 30; for analysis by subscore only, the corresponding 
subscore is considered to be missing. If 2 or more questions are left unanswered 
(missing), DLQI total score is treated as missing. A 4-point change from baseline is 
considered a clinically important difference. Appendix 10.7
7. HiS-QoL (hidradenitis suppurativa quality of life)
HiS-QoL is a patient-administered, 17-item instrument to measure HS-specific quality 
of life in clinical trials with a 7-day recall period [R20-3156]. The 17-item HiS-QoL 
included four symptom items, eight activity-adaptation items and five psychosocial 
items. The item scores are summed to create a total ranging from 0 to 68, with higher 
scores indicating more severe impact on HRQOL. The subscale scores range from 0 to
16 for symptoms, 0 to 20 for psychosocial and 0 to 32 for activities-adaptations.
Appendix 10.8
8. FACIT-Fatigue
The FACIT-Fatigue is a 13-item questionnaire ([R10-6433], [R07-4311], [R16-0029]) 
that assesses self-reported fatigue and its impact upon daily activities and function. 
Answers are based on a 5-point Likert scale. Responses of “not at all,” “a little,” 
“somewhat”, “quite a bit,” and “very much” are available for each question, and 
correspond to scores of 0, 1, 2, 3, and 4, respectively (total score range: 0-52). A 
minimal clinically important difference (MCID) of 3-4 points in change score has been 
reported [R16-0029]. The recall period for items is 7 days. Appendix 10.9


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9. PGI-C
The PGI-C is a 1-item tool assessing the change of HS start of taking the study 
medication by 5-point Likert-type scale. The tool is required for anchoring of other 
instruments and endpoints. Appendix 10.10
10. PGI-S
The PGI-S is a 1-item tool assessing the severity of HS over the last week by 4-point 
Likert-type Scale. The tool is required for anchoring of other instruments and endpoints.
Appendix 10.11
5.1.1
Patient diary 
The Patient Global Assessment of HS Pain will be completed on a daily diary by subjects 
from Screening through Week 12. 
If pain diaries are not completed for at least the seven consecutive days just prior to the 
Baseline visit, the subject may not be randomized.
The Patient Global Assessment of HS Pain will be used to assess the worst HS pain. Ratings 
will range from 0 (no HS pain) to 10 (HS pain as bad as you can imagine).
For the daily assessments being completed from Screening to Week 12, subjects should be 
instructed to complete the assessment before they go to bed, and respond to the items based 
on a recall period of the "last 24 hours".
Further instructions on diary and diary completion can be found in the ISF.
5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:

Physical examination

Vital signs

Clinical laboratory values (haematology, clinical chemistry, coagulation and
urinalysis)

12-lead ECG

Adverse events

Serious adverse events (SAEs)

Intensity of adverse events will be assessed by Rheumatology Common Toxicity
Criteria (RCTC) version 2.0 (refer to ISF for details)
5.2.1
Physical examination
Physical examinations will be performed at the time points specified in the Flowchart. 
A complete physical examination will be done at screening. It includes at a minimum general 
appearance, neck, lungs, cardiovascular system, abdomen, extremities, and skin.
For subsequent visits, targeted physical examinations will be done. These will include the
evaluation of organ systems associated with AE(s) symptoms or laboratory abnormalities.


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Measurement of height and body weight and waist circumference will be performed at the 
time points specified in the Flowchart. BMI will be automatically calculated. 
The results must be included in the source documents available at the site.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flowchart, prior to blood 
sampling.
This includes temperature, respiratory rate, systolic and diastolic blood pressure and pulse 
rate (electronically or by palpation count for 1 minute). Respiratory rate, pulse rate, and blood 
pressure will be measured after patients have been sitting comfortably for at least five 
minutes. The results must be included in the source documents available at the site.
Measurement of vital signs should precede blood sampling to avoid the impact of blood 
sampling on the vital measurements.
Vital signs will be measured additionally 10 min post-dose after s.c. administration and 5 
and 60 min. post-dose in case of i.v. study drug administration.
Hypersensitivity reactions should be treated according to medical standards. Pre-medications 
for further injections might be considered and will be agreed on between investigator and the 
Sponsor. 
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1 and 5.2.3:2. For the
sampling time points please see the Flowchart. 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.
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.


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Table 5.2.3:1 
Infection testing at screening and EoT visit
Category
Test name
Infection Testing
Hepatitis B Surface Antigen (qualitative)5
Hepatitis B core Antibody5
HBV-DNA (quantitative) at screening and EoT 
Visit1
Hepatitis C Antibodies (qualitative) 5
HIV-1, and HIV-2 Antibody (qualitative) 5
QuantiFERON®-TB-Gold Plus2, 3, 4
T-spot TB test
Serum Pregnancy test (only for female patients of
childbearing potential) 
Human Serum Chorionic Gonadotropin
1 A HBV-DNA should be conducted if Hepatitis B core Antibody is positive and Hepatitis B Surface Antigen 
is negative. These evaluations should be conducted at screening and at the EoT visit
2 There is the trial site option to perform a PPD skin test.
3 Patients with indeterminate QuantiFERON or invalid/borderline T-spot may be retested with IGRA (once) 
and if inconclusive should have a PPD skin test. .
4 In subjects with a negative QuantiFERON®-TB-Gold Plus or PPD skin test, the test should be repeated at 
the EoT visit. Results of the PPD test should be collected in the CRF.
5 If determined as negative at screening, there’s no need to retest at EoT. 
Table 5.2.3:2
Safety laboratory tests
Category
Test name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)
Glycosylated Hbc (HbA1c) (Only at baseline)
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)


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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
Creatinine6
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 and HS-CRP (high 
sensitivity – CRP))5
Cholesterol, total
Triglycerides
LDL-Cholesterol
HDL-Cholesterol
Specific gamma-globulin 
quantification
IgE1
Urine Pregnancy test (only for female 
patients of childbearing potential)
Human Chorionic Gonadotropin in urine


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Serum Pregnancy test (only for female 
patients of childbearing potential at 
screening. At later visits only if urine 
pregnancy test is positive)
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 visit 2
Interferon Gamma Release Assay 
QuantiFERON®-TB or T-spot 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 Patients with indeterminate QuantiFERON or invalid/borderline T-spot may be retested with IGRA (once) 
and if inconclusive should have a PPD skin test. .
4 In subjects with a negative QuantiFERON®-TB-Gold Plus or PPD skin test, the test should be repeated at 
the EoT visit. 
5 At screening and at EoT or EOS (as applicable) visits, a blood sample will be obtained to measure hs-CRP. 
This analysis will be done in the local laboratory.
6 Creatinine can be measured by any of the three serum creatinine assays listed in the table below:
Short name
Name of serum creatinine assay
Substrate
Other information
CREE
Creatinine, enzymatic
creatinine
Enzymatic
CREJIDMS
Creatinine, Jaffe, IDMS
creatinine
Jaffe reaction, IDMS standardized
CREJ
Creatinine, Jaffe, Not IDMS
creatinine
Jaffe reaction, Not IDMS 
standardized


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5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flowchart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance, if abnormal. ECGs may be 
repeated for quality reasons and the repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated 
as medically appropriate.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated 
as medically appropriate.
5.2.5
Other safety parameters
All cases of malignancies that are detected during the trial will be reported as SAEs. Patients 
with a history of malignancy (except for specific cancers) will be excluded from this trial per 
the exclusion criteria (Section 3.3.3).
5.2.5.1
Suicidality
Suicidal thoughts and behavior will be assessed by the Columbia-Suicide Severity Rating 
Scale (C-SSRS, [R08-1147]).
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report. In this trial paper forms will be used for the assessment of the C-SSRS® and results 
will be transcribed into the e-CRF.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the Screening Visit/Visit 1 (using the ‘baseline/ screening’ version) with the 
aim to exclude patients with active moderate to severe symptomatology within a specified 
time prior to the screening or screening visit. The lifetime and the past year history of suicidal 
ideation and behavior will also be recorded.
After the screening visit, the assessment ‘since last visit’ version will be performed at each 
visit. The investigator is to review positive and negative reports for plausibility and clinical 
relevance. Doubtful reports may be repeated or reports may be validated by a consulting 


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psychiatrist or other mental health professional expert. If there is a confirmed positive report 
of suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the patient, and/or is to consult a mental health professional. If the 
positive report is confirmed, appropriate actions for the patient’s safety have to be initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behavior, without suicidal intent’, standard AE / SAE reporting rules are 
to be applied.
For each negative report (suicidal ideation type 1, 2 or 3) after the start of the trial, the 
investigator is to decide based on clinical judgment whether it represents an Adverse Event 
(AE) as defined in the protocol, and if it is considered an AE then it must be reported 
accordingly.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1   Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions 
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the following 
criteria:
1. results in death,
2. is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe,
3. requires inpatient hospitalisation or prolongation of existing hospitalisation
4. results in persistent or significant disability or incapacity,
5. is a congenital anomaly / birth defect,


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6. is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation 
or development of dependency or abuse. 
5.2.6.1.3  AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be considered 
to be “serious” even though they may not have met the criteria of an SAE as defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4  Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:
Systemic hypersensitivity including infusion reaction and anaphylactic reaction
Any suspicion of severe infusion reaction systemic / hypersensitivity reaction and of any 
potential cases of anaphylaxis should be defined and assessed using the criteria discussed in 
the statement paper from Sampson HA (Appendix 10.13 [R11-4890]).
Severe infections (according to RCTC grading)
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, 
strongyloides 
(hyperinfection 
syndrome 
and 
disseminated 
forms 
only), 


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paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only),  shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression [R17-2617].
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine Aminotransferase)
≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold ULN measured in the 
same blood draw sample, or in samples drawn within 30 days of each other
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.
5.2.6.1.5  Intensity (severity) of AEs
The intensity grading of AEs will be performed according to Rheumatology Common
Toxicity Criteria (RCTC) Version 2.0 developed by 
 [R13-3515]. Refer to the 
ISF for intensity/severity classification. 
Intensity options are:
Grade 1 
mild
Grade 2
moderate
Grade 3 
severe
Grade 4 
life-threatening
5.2.6.1.6Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of 
a causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
The event is consistent with the known pharmacology of the drug.


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The event is known to be caused by or attributed to the drug class.
A plausible time to onset of the event relative to the time of drug exposure.
Evidence that the event is reproducible when the drug is re-introduced.
No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).
The event is typically drug-related and infrequent in the general population not exposed to 
drugs (e.g. Stevens-Johnson syndrome).
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller effect 
size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
No plausible time to onset of the event relative to the time of drug exposure is evident (e.g. 
pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of drug 
administration; an allergic reaction weeks after discontinuation of the drug concerned).
Continuation of the event despite the withdrawal of the medication, taking into account the 
pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1 AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
For patients not rolling over to OLE trial, the following must be collected and documented 
on the appropriate CRF(s) by the investigator:
-
From signing the informed consent onwards until the individual patient’s end of 
study: 
all AEs (serious and non-serious) and all AESIs.
-
After the individual patient’s end of study:
the investigator does not need to actively monitor the patient for new AEs but should 
only report any occurrence of cancer and trial treatment related SAEs and trial 
treatment related AESIs of which the investigator may become aware of by any 
means of communication, e.g. phone call. Those AEs should be reported on the BI 
SAE form (see section 5.2.6.2.2), but not on the CRF.
For patients rolling over to OLE trial the following must be collected and documented on 
the appropriate CRF(s) by the investigator:


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-
From signing the informed consent of the parent trial onwards until the first dose of 
trial medication in the extension trial: 
all AEs (serious and non-serious) and all AESIs.
5.2.6.2.2 AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3 Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
Protocol specified exempted events should be collected on the appropriate CRF page only.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Spesolimab concentrations will be reported descriptively. No PK parameters will be 
calculated. PK data will be incorporated into a larger pharmacometric analysis with other 
trials of the spesolimab project. Also, ADAs will be measured and their impact on PK will 
be assessed. The relationship between PK and selected efficacy endpoints, biomarkers and 


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AEs may be assessed. PK and demographic data together with treatment assignments and 
dosing information may be made available to individuals outside of the trial team for the 
purpose of PK dataset generation in accordance with sponsor’s standard procedures.
Refer to the Flowchart for the time points of PK and ADA/Nab sample collection. Date and 
exact time of drug administration and PK and ADA/Nab sampling will be recorded on CRFs. 
On visits with study medication dosing, PK and ADA/Nab samples should be collected prior 
to administration of study drug. 
5.3.2
Methods of sample collection
5.3.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of spesolimab plasma concentrations, approximately 3.0 mL of blood will 
be taken from a forearm vein into a K2EDTA (ethylendiaminetetraacetic acid) anticoagulant 
blood-drawing tube at the time points listed in the Flowchart under PK sampling. Handling 
procedures can be found in the laboratory manual in the ISF.
Samples will be stored in a freezer set at the analytical laboratory until the finalization of the 
clinical trial report (CTR). The plasma samples may be used for further methodological 
investigations, (e.g. stability testing) however, only data related to the analyte will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.
5.3.2.2
Sampling for ADA/Nab assessment
For ADA assessment, approximately 3.0 mL of blood will be taken from a forearm vein into
a K2EDTA anticoagulant blood-drawing tube at the time points listed in the Flowchart under 
plasma ADA/Nab. For Nab assessment, approximately 3.0 mL of blood will be taken from 
a forearm vein into a serum blood drawing tube at the time points listed in the Flowchart
under ADA/Nab Sampling. Handling procedures can be found in the laboratory manual in 
the ISF.
Samples will be stored in a freezer set at the analytical laboratory until they are analyzed. 
The plasma/serum samples may be used for further methodological investigations, e.g.for 
further investigations to characterise ADA response or to address
Health Authority questions regarding the results/methodology, however only data related to 
the anti-drug antibodies will be generated by these additional investigations. The study 
samples will be discarded after completion of the additional investigations but not later than 
5 years after the final study report has been signed.


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5.4
ASSESSMENT OF BIOMARKER(S)
This section refers to exploratory biomarkers. Established biomarkers of efficacy and safety 
are described and discussed in sections 5.1 and 5.2.
Blood samples (serum and whole blood for RNA sequencing), skin biopsies for 
immunohistochemistry (IHC) and RNA sequencing will be collected at time points indicated 
in the Flowchart for the analysis of biomarkers. After completion of the study these samples 
may be used for not yet specified non-genetic biomarker analyses associated with 
autoimmune diseases as well as method development and evaluation.
5.4.1
Biochemical and cellular biomarkers
The role of spesolimab on the IL36R pathway will be demonstrated by assessing biomarkers 
in skin biopsies and blood including, but not limited to IL36α and IL36γ at different time 
points post treatment compared to baseline. To demonstrate treatment effect of spesolimab in 
the peripheral compartment, pre- and at various time points post treatment, physiological 
response biomarkers including, but not limited to CRP, lipocalin 2, and S100 proteins will be
evaluated. In addition, to understand the tissue-specific impact of spesolimab over time, skin 
biopsies (lesional and non-lesional) will be collected at baseline and at selected time points 
post treatment. The skin biopsies will be used for assessment of skin protein biomarkers using 
techniques such as immunohistochemistry (IHC).
5.4.2
Pharmacogenomics biomarkers
Skin biopsies and blood samples (PBMCs) will be taken at time points indicated in the 
Flowchart and used for RNA extraction and subsequent gene expression analysis to identify 
genes involved in the drug’s mechanism of action or the pathology of the disease.
5.4.3
Methods of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints refer to the Flowchart.
For the skin biopsies, one (1) punch biopsy from lesional skin (for histopathologic, 
immunohistopatholic and RNASeq) will be performed at baseline prior to receiving treatment 
(V2), on Visit 5 and on Visit EoT. A paired non-lesional skin biopsy will also be collected at 
baseline. At sites with ultrasound capability, ultrasound will be used to identify dermal 
tunnels and deep abscesses in the sites of inflammation so as to take accurate biopsies RNA 
and IHC samples can be taken from one biopsy sample bisected in two pieces. One (1) piece 


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for RNA extraction. One (1) piece for IHC. At sites without ultrasound capability, biopsies 
will be obtained without ultrasound guidance.
Please refer to the ISF for further instructions regarding selection, collection, handling, 
storing and shipment.
For the assessment of RNA expression whole blood will be collected from a forearm vein and  
stored according to standard procedure provided in ISF.
5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial.
Biobanking will only occur after a separate biobanking informed consent has been given in
accordance with local ethical and regulatory requirements.
Unspecified DNA Banking:
An additional blood sample for DNA banking will be collected in PAXgene Blood DNA tube
at Visit 2 (see FlowChart). The DNA Banking sample, derived from the original blood
sample, will be stored at Boehringer Ingelheim. The stored DNA may be retrospectively
analysed.
5.6
OTHER ASSESSMENTS
Photographs
Subjects will be asked to have photographs taken of their disease response during the study. 
Subjects who consent will have photographs taken at the designated study visits listed in the 
Flowchart. The cameras for the photographs will be standardized and supplied to the site by 
a central photography service. Sites will submit the digital images to the centralized 
photography service. Training and detailed instructions will be provided by the central 
photography vendor.
5.7
APPROPRIATENESS OF MEASUREMENTS
All methods used are standard methods.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flowchart. Each visit date
(With its window) up to EoT is to be counted from Visit 2 at Day 1 (first trial drug 
administration day). If any of these visits has to be rescheduled, the date of subsequent visit 
should be calculated from Day 1. 
EoT refers to the End of Treatment visit at week 12 (or earlier if a patient terminates study 
drug before week 12). 
For patients not rolling over to OLE trial, FUP1 refers to Follow-up visit 1 which will be 
scheduled 8 weeks after last study drug administration. EoS refers to the End of Study visit 
which will be scheduled 16 weeks after last study drug administration (after REP period).
For patients rolling over to OLE trial, EoT and EoS dates will be the same. These patients 
will not undergo the safety follow-up period (i.e will not do FUP1 and EoS visits) because 
they will be followed in the OLE trial. For these patients EoT visit of this trial and first visit 
of the OLE trial should occur the same day.
Additional visits for the purpose of re-testing of laboratory parameters or AE monitoring may 
be included as deemed necessary by the investigator.
In exceptional cases, if standard visits at the trial sites are impossible because of COVID-19 
related safety risks, the investigator must assess the risk-benefit for each individual patient 
and may decide to perform a visit remotely if this is in the best interests of the patient and if 
agreed with the sponsor.
All COVID-19 related deviations from the original schedule of visits and procedures will be 
documented and the implications considered for the analysis of the trial data.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the relevant Flowchart and the 
respective protocol sections. Refer to section 5 and section 10 (Appendices) for explanations 
of procedures. Additional details on procedures at selected visits are provided below.
Patient Reported outcomes (PROs) should be completed by the patient on his/her own in a 
quiet area/room before any other visit assessments or treatments and, as much as possible, 
before any interaction with the investigator or other members of the study team.
Measurements of vital signs should precede blood sampling to avoid the impact of blood 
sampling on the vital measurements and be assessed pre-dose at all dosing visits.
The Baseline/screening scale of the C-SSRS will be administered for eligibility confirmation 
and the follow-up scale at all visits for assesment of suicidality.
Assessments/procedures to be done before study drug administration when applicable:


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At visits with study drug administration safety labs and urine pregnancy test should be done 
prior to the study drug administration. Pre-dose PK/ADA samples will be obtained 
approximately within 1 hour prior to start of i.v. infusion or s.c. injections administration.
The following sequence of procedures (where applicable) is recommended and can be done 
within each visit window (See Flowchart):
1. PROs 
2. C-SSRS
3. AE and concomitant therapy collection; smoking/tobacco/nicotine status
4. Physical examinations (including predose vital signs)
5. ECG
6. Abcess and inflammatory nodule count
7. Draining fistula count
8. HiSCR, IHS4, HS-PGA and HASI assessment
9. Photographs of skin lesions
10. Ultrasound lesion evaluation (if applicable. See section 5.4.3)
11. Skin biopsies
12. Blood and urine sampling, blood for hs-CRP, urine pregnancy testing (if 
applicable), PK, ADA/Nab, and biomarkers.
13. Assign (IRT call) /Administer study drug
14. Local tolerability
15. Post-dose vital signs
Due to COVID-19 pandemic restrictions, the trial conduct may need to be adjusted and
remote visits performed as instructed by the Sponsor, based on each patient benefit-risk 
assessment.
6.2.1
Screening 
Screening Period
Study requirements, including the procedure for the follow-up of prematurely withdrawn 
patients must be fully explained to the patient and written informed consent obtained prior to
initiating any study-related evaluation. The importance of staying in the trial until completion
of all study requirements will be emphasized. No trial procedures should be done unless the
patient has consented to taking part in the trial.
Once consented, the patient is considered to be enrolled in the trial and has started screening.
The patient should be recorded on the enrolment log and be registered in IRT as a screened 
patient. Patients will be assigned a patient number generated via the IRT system.
Screening (Visit 1) should normally take place no more than 28 days before Visit 2. Visit 1 
procedures may be completed over multiple physical visits, if needed. The time window for 
Visit 1 may be extended at the discretion of the CT Manager in conjunction with the CT 
Leader on a case by case basis.
For the comprehensive list of the trial procedures required at the Screening Visit (Visit 1) 
please refer to Flowchart. Patients who have a laboratory test value that makes their 
participation uncertain may have the test repeated to determine eligibility; however, the result 


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must be available prior to Visit 2 (Day 1). Baseline conditions and medical history will be 
assessed during screening.
Demographics:
Informed consent date, gender, ethnicity and race (if allowed by local law) will be collected 
and reported in the eCRF.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy will be reported on the Baseline Condition eCRF page. The smoking status and 
history based on the calculation of pack-years will be collected as well.
Infections screening
Infections testing will include tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see
section 3.3.3 and Table 5.2.3:1).
Medical History:
Medical history of HS, including the previous treatment, will be collected and reported in the 
eCRF.
Information on clinically significant previous and concomitant illnesses, other than HS, or 
any clinically significant signs or symptoms that are present before informed consent, or pre-
existing conditions identified through findings from assessments and examinations done 
during the screening visits will be recorded as medical and surgical history at screening on 
the Baseline Condition page in the eCRF.
Patients who fail screening (i.e. does not meet the eligibility criteria) following Visit 1 
assessments should be registered as a screen failure in IRT.
Re-Screening
Re-screening of a previously screen failed patient will be permitted once in a case by case 
basis in agreement with the Sponsor. Details of IRT procedures can be found in the IRT 
manual located in the Investigator Site File (ISF).
For the comprehensive list of the trial procedures required at the Screening Visit (Visit 1) 
please refer to the Flowchart.
Re-screened patients will need to sign a new informed consent before any re-screening 
procedures and will be given a new unique subject number. If a patient is re-screened and
there are valid screening determinations from his/her previous participation in the trial, like 
for example safety labs, performed within 28 days prior to baseline (visit 2), these do not need 
to be repeated.
6.2.2
Treatment period(s)
When eligibility of the patient to participate in the trial is confirmed, randomization via IRT 
will be performed at Visit 2. The treatment period is from Day 1 to Week 12 (End of
Treatment, EoT). Procedures described in the Flowchart for each visit should be performed.


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Loading Period
During the first 3 weeks of the treatment period, the loading dose(s) are administered at 3
visits (Visit 2 to Visit 4) with weekly 90min iv infusions of 1200mg spesolimab. 450mg vials 
of 7.5mL each will be used to prepare the infusions. Please see the Flowchart and section 3.1
for further details.
Maintenance Period
From visit 5 to visit 8, maintenance doses are administered subcutaneously by pre-filled 
injections of 2mL containing 300mg spesolimab each. 4 injections will be used at each visit 
for a total dose of 1200mg every two weeks. 
At visits during the treatment period, venepuncture (i.e. safety laboratories, PK, ADA,
biomarkers) and skin biopsies should be the last procedures performed prior to study drug
administration. Only after all blood specimens are collected, and urine pregnancy testing (if 
applicable) is done, will each eligible patient receive a dose of the assigned trial medication.
6.2.3
Follow-up period and trial completion
For all randomized patients termination of trial medication (EoT) and trial completion (EoS) 
must be recorded on the corresponding CRFs.
For patients completing the randomized trial treatment regularly at Week 12 (EoT) and not 
rolling-over to the OLE trial, safety follow-up visits will be performed at Week 20 (FUP1 
Visit) and at Week 28 (EoS, EoS Visit).
Patients who roll-over to the OLE trial will complete their participation in the trial at week 
12 (EoT visit) 
Early treatment discontinuation
Patients who discontinue treatment prematurely prior to the planned EoT visit (Week 12) 
should be registered as withdrawn from treatment in IRT.
Patients should follow the scheduled visits as much as possible as defined in the Flowchart, 
this is: the EoT should be conducted either immediately or as soon as possible, followed by 
the FUP1 visit 8 weeks after the last trial drug administration date and the EoS visit 16 weeks 
after the last trial drug administration date. All efforts should be made to keep the patient in 
observation for at least 16 weeks after the last dose of the study drug.
Treatment completion
Treatment completion is defined as a patient having completed treatments till planned EoT 
visit (Week 12).
Trial completion:
Trial completion is defined as a patient having reached the EoS Visit per protocol (or rolled-
over to OLE trial and therefore have completed an EoT/EoS visit).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The primary objective of the trial is to demonstrate proof of clinical concept activity of 
spesolimab on the percent change from baseline in total abscess and inflammatory nodule 
count using a mixed effect model for repeated measurements (MMRM). No formal statistical 
testing is planned. For the proof of concept, the treatement effects of spesolimab compared 
to placebo will be estimated. Hereby, the adjusted difference in percentage change from 
baseline in total abscess and inflammatory nodule count between spesolimab and placebo will 
be evaluated. 
For primary analysis of the primary endpoint, all measurements will be included but those 
data collected after the use of rescue therapy for the purpose of disease worsening will be 
censored. The stratification factor, TNFi-naive population versus TNFi-failure population 
will be included into the model.
7.1
NULL AND ALTERNATIVE HYPOTHESES
No hypothesis testing will be performed in the confirmatory sense. All the analyses will be 
performed in an exploratory fashion to better understand the efficacy and safety profile of 
spesolimab.
7.2
PLANNED ANALYSES
The primary analysis of the trial will be performed once all randomized patients have either
(1) completed the 12 weeks treatment period of the trial, or (2) have reached the 12 weeks 
after starting of treatment if early discontinued from the trial treatment. Final trial analysis is 
planned to be performed at the end of the study once all randomized patients have completed 
the study (including any follow-up period), if applicable. The primary analysis and final 
analysis may be performed as a single analysis (at the time of trial completion), if, prior to 
the time of the primary analysis, the trial team agrees that the expected time interval between 
the planned analyses is insufficient to justify the performance of separate analyses.
Details of treatment unblinding for the primary analysis and final analysis are described in 
section 4.1.5.1. Details of the analysis to be performed will be described in the TSAP.
7.2.1
General considerations
The following populations are planned in this trial for main efficacy and safety analyses:
Treated Set (TS)
This patient set includes all patients who were randomized and received at least one dose of
study drug. It will be the main analysis set for presentation of efficacy and safety. Patients 
will be analyzed according to the actual treatment.


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Per-Protocol Set (PPS)
This patient set includes all patients in the safety analysis set who adhered to the CTP without 
any Important Protocol Deviations (IPDs) potentially affecting the study outcome which lead 
to exclusion from the PPS. This set will be used for sensitivity analysis on the primary 
endpoint.
Important deviations of the protocol will include deviations of the key inclusion and exclusion
criteria, incorrect medications taken, concomitant use of restricted medications and any other 
deviations of the protocol deemed important by the study team. All decisions concerning 
important protocol deviations will be made prior to un-blinding of the database for the final 
trial analysis.
Further analysis sets, e.g. for the biomarker assessments, will be defined in the Trial Statistical
Analysis Plan (TSAP).
Standard statistical parameters (number of non-missing values, mean, standard deviation
(SD), median, quartiles, minimum and maximum) or frequency tables (including patient
frequencies and percentages) will be calculated where appropriate.
7.2.2
Primary endpoint analyses
The difference in percent change from baseline in total abscess and inflammatory nodule at 
Week 12 between spesolimab and placebo is the primary endpoint of this trial. All on-
treatment data are planned to be included into analysis but any data after use of any rescue 
therapy will be censored in line with the primary objective to estimate the treatment effect in 
treated patients assuming they do not receive rescue therapy (priamry estimand). To account 
for the repeated nature of the data, the primary analysis is a restricted maximum likelihood
(REML) based approach using a mixed model with repeated measurements (MMRM) 
comparing the adjusted relevant difference between the two arms. 
The analysis will include the fixed categorical effects of treatment at each visit, stratum and 
the fixed continuous effect of baseline at each visit. Visit will be treated as the repeated 
measure with an unstructured covariance structure to model the within-patient measurements.
The statistical model will be as follows:
 = 
 +  + Φ + 
With
 response variable for patient  in stratum m at visit  receiving treatment 

baseline measurement of patient , i=1,2,…


coefficient of baseline effect at visit 

effect of treatment  at visit , j=3,…,9 and k=1, 2

effect of stratum , m=1,2

random error associated with visit  of patient . 
Errors are independent between patients with ~(0, ∑) and ∑is an unstructured 
covariance matrix.


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The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Due to the exploratory character of this trial no significance test 
will be done. However, least-squares means (adjusted means) of each arm as well as adjusted 
treatment differences will be provided together with two-sided 95 %-confidence intervals for 
each time point.
The patients will be analysed according to the stratum to which they belong (regardless of 
any mis-assignment to treatment based on identification of the wrong stratum), as such an 
error occurs before randomization and is therefore consistent with regulatory guidance.
Procedures to follow if the analysis fails to converge will be described in the TSAP.
Secondary analysis of the primary endpoint will include:
-
A sensitivity analysis utilizing the PPS to evaluate the impact on treatment outcomes 
of patients who may have relevant deviations from the conduct described in the CTP;
-
The effect of stratum (TNFi-naive population versus TNFi-failure population) on the 
primary endpoint will be descriptively displayed via subgroup assessments.
7.2.3
Secondary endpoint analyses
The continuous secondary endpoints at Week 12 will be analysed using a MMRM approach 
based upon the estimand concept and model specification as described for the primary 
endpoint.
The binary secondary endpoints will be evaluated descriptively by treatment arm via 
frequency tables (with 95% confidence interval) based on TS. If needed, a logistic regression 
model on binary endpoint at Week 12 will be applied as well. The model will include 
treatment and stratification factor (TNFi-naive population versus TNFi-failure population) as
two categorical variables. As in the case of the primary estimand, any binary data collected 
after use of any rescue therapy will be censored and then imputed using the NRI method as 
described in section 7.3.
Further details will be provided in the TSAP.


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7.2.5
Safety analyses
Adverse events will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. Standard Boehringer Ingelheim’s summary tables 
and listings will be produced.
All randomized and treated patients will be included in the safety analysis. In general, safety 
analyses will be descriptive in nature and will be based on BI standards. No hypothesis testing 
is planned. Statistical analysis and reporting of adverse events will concentrate on treatment-
emergent adverse events (TEAE). To this end, all adverse events occurring between start of 
treatment and end of the residual effect period will be considered ‘treatment-emergent’; the 
residual effect period (REP) is defined as 16 weeks after the last dose of trial medication. 
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class (SOC) and preferred term after coding according to the current version of the 
MedDRA at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The later will be 
done via comparison of laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.Vital signs, physical examinations, or other safety-relevant data 
observed at screening, baseline, during the course of the trial and at the end-of-trial evaluation 
will be assessed with regard to possible changes compared to findings before start of 
treatment.
Immunogenicity data will be analysed in a descriptive way.
7.2.6
Other Analyses
Biomarker analyses
The statistical analysis for biomarker assessments (cf. Section 5.4) is mainly descriptive. 
Summary statistics and summary plots are produced for each assessment at each time point, 
and for changes from baseline when appropriate.
Correlations between biomarkers and clinical endpoints may also be examined 
descriptively.
For a visual assessment of this analysis scatter plots may be produced.
Changes in the gene expression profile from baseline to post-baseline will be summarized
and described for selected genes. Significantly up- or down-regulated genes are reported. 


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Thresholds for defining significantly up- and down-regulations will be given in the statistical 
analysis plan.
Further details will be discussed in the statistical analysis plan.
7.2.7
Interim Analyses
No interim analysis is planned in this trial.
In order to ensure the patient’s safety during the trial, a fully external DMC, independent of
the trial and project teams, will review all available unblinded safety data as well as selected
efficacy data at regular intervals following first-patient-in. A DMC SAP which describes the
analyses required for assessment by the DMC will be produced. Further details will be
provided in a DMC charter.
7.3
HANDLING OF MISSING DATA
For primary efficacy endpoint and other endpoints which are continuous in nature, the use of 
a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) 
approach, if feasible, will ensure that missing data are handled implicitly, via a missing at 
random assumption, by the statistical model.
For efficacy endpoints which are binary nature, a Non Response Imputation (NRI) approach
will be applied to the missing visits up to Week 12; that is, imputing as a failure to achieve a 
response in the visits with missing endpoint score, however:
-
If there are available data at the visits both before and after the visit with a missing 
outcome, then impute as a success only if both the preceding and the following 
measurement indicate success and no rescue medication has been given during this 
period.
-
Otherwise, impute as a failure to achieve a response (i.e. no response imputation)
NRI is a conservative imputation scheme because it assumes that use of rescue therapy or 
missing data due to any other reason is related to treatment failure. In addition, for secondary 
binary endpoint, HiSCR at Week 12, multiple imputation based method will be applied as 
sensitivity analysis.
Further sensitivity analyses to assess the robustness of the results on efficacy endpoint will 
be described in the TSAP if necessary.
With respect to safety evaluations, it is not planned to impute missing values.
7.4
RANDOMIZATION
BI will arrange for the randomization and the packaging and labelling of trial medication. The 
randomization list will be generated using a validated system, which involves a 
pseudorandom number generator so that the resulting treatment will be both reproducible and 


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nonpredictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
Stratification of the randomization will be performed for TNFi-naive population versus TNFi-
failure population. Approximately 33 patients from TNFi-naive population and 12 patients 
from TNFi-failure population are planned to be randomized. Once either subpopulation has 
recruited the planned number of patients, the screening of that subpopulation may be 
considered to be closed.
Within each stratum, patients will be randomized in a 2:1 randomization ratio to receive
Sepsolimab vs placebo. The randomization will be done in blocks to achieve balanced 
allocation.
The process of randomization is done via an IRT. 
7.5
DETERMINATION OF SAMPLE SIZE
This is a proof of clinical concept trial to explore a benefit of spesolimab over placebo in 
terms of the primary endpoint, percent change from baseline in total abscess and 
inflammatory nodule count at Week 12 based on the MMRM method.
With reference to the pivotal trials of Adalimumab [R20-3157] which is the only approved 
biologic for HS, it is expected that patients on placebo arm could achieve approximately a 
20% reduction after 12 weeks of treatment. In contrast, it is expected patients on spesolimab
arm could achieve a 60% to 65% reduction which is around 40% to 45% superior to placebo.
The standardized deviation is assumed to be 45% for each arm.
The pivotal trials of Adalimumab [R20-3157] shows that the primary endpoint, percent 
change from baseline in total abscess and inflammatory nodule count at Week 12, is skewed 
in both active treatment arm and the placebo arm. Under such situation of skewness, for 
primary endpoint, MMRM method is still valid as the asymptotic normality of the distribution 
of the point estimate still holds. However, the commonly used “exact” methods for calculating 
sample size become inappropriate in this case, as they are based on a normality assumption 
of the data. Therefore, a simulation method is used to calculate the sample size as below:
Step 1: Data for the primary endpoint for both arms are generated from Gamma 
distributions respectively to allow for skewed distributions. The distributions for the 
percent change are parameterized using the published summary statistics from 
Adalimumab trial data [R20-3157]. The 10,000 datasets are generated 
Step 2: For each repetition of the 10,000 iterations, the mean difference between the two 
arms is calculated. The proportion of iterations with a difference of at least 30% in favor 
of Spesolimab is calculated for each parameterization setting.
It is assumed that there is no missing data for the primary endpoint so the final primary 
endpoint analysis using MMRM is expected to be on complete data. Therefore, in the sample 
size calculation, the mean difference between two arms derived from the simulation above, 


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which only considers the single time point of interest (at week 12) should approximate the 
week 12 estimate derived from the MMRM method using all time points over time. All 
calculations are performed on R version 3.3.2 and the results are summarized in Table 7.5:1. 


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Table 7.5: 1 Probabilities to observe at least 30% difference on % change from baseline in 
total abscess and inflammatory nodule count at Week 12 for spesolimab (30 pts) vs.placebo
(15 pts)
Assumed % change from 
baseline for spesolimab (SD) vs. 
Placebo (SD)
Probabilities to detect at least 30% difference 
for spesolimab vs. placebo
-20% (45%) vs -50% (45%)
0 %
-20% (45%) vs -20% (45%)
2.3%
-50% (45%) vs -20% (45%)
49.9%
-55% (45%) vs -20% (45%)
62.9%
-60% (45%) vs -20% (45%)
75.4%
-62% (45%) vs -20% (45%)
80.1%
-65% (45%) vs -20% (45%)
85.2%
-50% (45%) vs -30% (45%)
23.8%
-55% (45%) vs -30% (45%)
35%
-60% (45%) vs -30% (45%)
49.3%
-65% (45%) vs -30% (45%)
62.4%
Therefore, with an expected 62% reduction from baseline in total abscess and inflammatory 
nodule count at Week 12 on spesolimab and 20% reduction on placebo, the probabilities to 
detect at least 30% difference of spesolimab relative to placebo is 80.1%. 


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


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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 risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well 
as identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
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.


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For the CRF, data must be derived from source documents, for example:
Patient identification: gender, year of birth (in accordance with local laws and regulations)
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
Dates of patient’s visits, including dispensing of trial medication
Medical history (including trial indication and concomitant diseases, if applicable)
Medication history
Adverse events and outcome events (onset date (mandatory), and end date (if available))
Serious adverse events (onset date (mandatory), and end date (if available))
Concomitant therapy (start date, changes)
Originals or copies of laboratory results and other imaging (e.g. photographs) or testing 
results, with proper documented medical evaluation (in validated electronic format, if 
available)
Patient reported outcome forms (including diary) and corresponding investigator
assessment form.
ECG results (original or copies of printouts)
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
Prior to allocation of a patient to a treatment into a clinical trial, there must be documented 
evidence in the source data (e.g. medical records) that the trial participant meets all 
inclusion criteria and does not meet any exclusion criteria. The absence of records (either 
medical records, verbal documented feedback of the patient or testing conducted specific 
for a protocol) to support inclusion/exclusion criteria does not make the patient eligible for 
the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular
Sample and data usage has to be in accordance with the separate biobanking informed 
consent
The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples collected 
in clinical trials
An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place
A fit for the purpose documentation (biomarker proposal, analysis plan and report) ensures 
compliant usage
A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site. Early 
termination of the trial is defined as the premature termination of the trial due to any reason 
before the end of the trial as specified in this protocol.


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Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A 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 unblinded safety and efficacy data in order to recommend whether 
the trial should continue, be modified or stopped due to safety or ethical concerns. 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 ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to 
1. manage the trial in accordance with applicable regulations and internal SOPs,
2. direct the clinical trial team in the preparation, conduct, and reporting of the trial,
3. ensure appropriate training and information of Clinical Trial Managers (CT Managers), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.


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


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R20-3047
Hessam S, Sand M, Gambichler T, Skrygan M, Rueddel I, Bechara 
FG. Interleukin-36 in hidradenitis suppurativa: evidence for a 
distinctive proinflammatory role and a key factor in the 
development of an inflammatory loop. British Journal of 
Dermatology 178, pp761–767 (2018)
R20-3184
Zouboulis et al, Hidradenitis Suppurativa / Acne Inversa: criteria for 
diagnosis, severity assessment, classification and disease evaluation, 
231(2):184-90 (2015)
R20-3176
Saunte DM et al.: Diagnostic delay in hidradenitis suppurativa is a 
global problem. Br J Dermatol. 173(6):1546–9 (2015)
R20-3177
Zouboulis CC, et al. EDF Guideline for Hidradenitis Suppurativa / 
Acne Inversa (HS) – S1 Guideline. European Dermatology Forum. 
JEADV 2015, 29, 619–644 (2015)
R20-3155
Byrd et al. Neutrophil extracellular traps, B cells, and type I 
interferons contribute to immune dysregulation in hidradenitis 
suppurativa, Sci Transl Med ; 11; eaav5908 (2019)
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)
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)
R20-2976
Kimball et al. HiSCR (Hidradenitis Suppurativa Clinical Response): 
a novel clinical endpoint to evaluate therapeutic outcomes in 
patients with hidradenitis suppurativa from the placebo-controlled 
portion of a phase 2 adalimumab study. J Eur Acad Dermatol 
Venereol, 30, 989–994 (2016)
R20-3045
Zouboulis CC, Tzellos T, Kyrgidis A, Jemec GBE, Bechara FG, 
Giamarellos-Bourboulis EJ, et al, European Hidradenitis 
Suppurativa Foundation Investigator Group. Development and 
validation of the International Hidradenitis Suppurativa Severity 


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Score System (IHS4), a novel dynamic scoring system to assess HS 
severity. Br J Dermatol 2017 ; 177; 1401-1409 (2017)
R20-3046
Kimball, A. B. et al. Adalimumab for the treatment of moderate to 
severe hidradenitis suppurativa: a parallel randomized trial. Ann. 
Intern. Med. 157, 846–855 (2012).
R20-3156
Kirby et al. The Hidradenitis Suppurativa Quality of Life (HiS-
QoL) score: development and validation of a measure for 
clinicaltrials. British Journal of Dermatology (2020) 183, pp340–
348
R10-6433
Webster K, Cella D, Yost K. The Functional Assessment of Chronic 
Illness Therapy (FACIT) Measurement System: properties, 
applications, and interpretation. Health Qual Life Outcomes 2003 ; 
1; 79
R07-4311
Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. 
Measuring fatigue and other anemia-related symptoms with the 
Functional Assessment of Cancer Therapy (FACT) measurement 
system. J Pain Symptom Manage 1997 ; 13(2) ; 63-74.
R16-0029
Cella D, Yount S, Sorensen M, Chartash E, Sengupta N, Grober J. 
Validation of the Functional Assessment of Chronic Illness Therapy 
Fatigue Scale relative to other instrumentation in patients with 
rheumatoid arthritis. J Rheumatol 2005 ; 32(5) ; 811-819.
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, 
Tsuji W, Stevens R, Fries J, Witter J, Johnson K, Lassere M, 
Brooks P. Standardizing assessment and reporting of adverse effects 
in rheumatology clinical trials II: the Rheumatology Common 
Toxicity Criteria v.2.0. J Rheumatol 2007 ; 34(6) ; 1401-1414.
R08-1147
Posner K. State of the science: measurement of suicidal adverse 
events and the Columbia Suicide Severity Rating Scale. 47th 
NCDEU Ann Mtg, Boca Raton, 11 - 14 Jun 2007. 2007 ; 15
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 2015 ; 74; 2107-2116.
R05-2548
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a 
simple practical measure for routine clinical use. Joint Ann Mtg of 
the British Association of Dermatologists and the Canadian 
Dermatology Association, Oxford, 6 - 10 Jul 1993. Clin Exp 
Dermatol 1994 ; 19; 210-216.
R20-3157
Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, 
Zouboulis CC, Armstrong AW, Kerdel F, Gold MH, Forman SB, 
Korman NJ. Two phase 3 trials of adalimumab for hidradenitis 


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suppurativa. New England Journal of Medicine. 2016 Aug 
4;375(5):422-34.
9.2
UNPUBLISHED REFERENCES
c03320877-09
Investigator’s Brochure, spesolimab for IL36R antibody in 
Ulcerative Colitis, Palmoplantar Pustulosis and Pustular Psoriasis; 
version 09, dated 21 May 2021. 
c03361085
 Clinical Trial Protocol: 
Single-blind, partially randomized, placebo-controlled Phase I study 
to investigate safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising intravenous doses of spesolimab
in healthy male volunteers. 1368.1. Version 6. 27 Jan 2016.


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10.
APPENDICES
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK), ANTIDRUG 
ANTIBODY (ADA) AND NEUTRALIZING ANTIBODY (NAB) BLOOD 
SAMPLING
Table 10.1: 1 Time schedule for PK/ADA/Nab blood sampling during treatment
Treatment 
Course
Visit
Day
Time Point [hh:min]
CRF 
Time
/PTM
Event
Sample 
No.
2
1
Just before drug 
administration
-1:00
PK/ADA/
Nab Blood
1
3
8 (+1)
Just before drug 
administration
-1:00
PK Blood
2
4
15 (+1)
Just before drug 
administration
-1:00
PK/ADA/
Nab Blood
3
5
29 (+3)
Just before drug 
administration
-1:00
PK/ADA/
Nab Blood
4
6
43 (+3)
Just before drug 
administration
-1:00
PK Blood
5
7
57 (+3)
Just before drug 
administration
-1:00
PK/ADA/
Nab Blood
6
8
71 (+3)
Just before drug 
administration
-1:00
PK Blood
7
EOT
See Flowchart
PK/ADA/
Nab Blood
8
FUP 1
See Flowchart
PK/ADA/
Nab Blood
9
EoS
See Flowchart
PK/ADA/
Nab Blood
10


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10.2
HIDRADENITIS SUPPURATIVA CLINICAL RESPONSE (HISCR)
Defined as at least a 50% reduction from baseline in the total abscess and inflammatory 
nodule count, with no increase in the abscess or draining fistula count.
Fig. Source: HUMIRA Hidradenitis Suppurativa Clinical Response (HiSCR) Data (humiradermpro.com)


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10.3
INTERNATIONAL HIDRADENITIS SUPPURATIVA SEVERITY 
SCORE SYSTEM (IHS4)
International Hidradenitis Suppurativa Severity Score System (IHS4). A nodule 
(inflammatory nodule) is a raised, threedimensional, round, infiltrated lesion with a 
diameter of >10 mm. An abscess is a tender but fluctuating mass with a diameter of >10 
mm, surrounded by an erythematous area; the middle of an abscess contains pus. A 
draining tunnel is a raised, tender but fluctuating longitudinal mass of variable length and 
depth, ending at the skin surface, and sometimes oozing a fluid. Fistulae and sinuses are 
examples of tunnels.
Source:
the European Hidradenitis Suppurativa Foundation Investigator Group, Zouboulis C.C., Tzellos 
T., Kyrgidis A., Jemec G.B.E., Bechara F.G., et al. Development and validation of the International Hidradenitis 
Suppurativa Severity Score System (IHS 4), a novel dynamic scoring system to assess HS severity . Br J 
Dermatol. 2017 Nov; 177 (5): 1401-1409.


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10.4
HIDRADENITIS SUPPURATIVA PHYSICIAN GLOBAL 
ASSESSMENT (HS-PGA)


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10.5
HIDRADENITIS SUPPURATIVA AREA AND SEVERITY INDEX 
(HASI)
HASI is modelled after the Psoriasis Activity and Severity Index (PASI).
Four classic signs of HS-related inflammation (erythema, thickness, drainage, tenderness) 
are included. 
Each variable in HASI is scored on a Likert scale (0–3) for each predetermined body 
region. 
For BSA assessment, the number of palms (one palm indicated 1% of the patient’s BSA) 
involved for each body region (head, right axilla, left axilla, anterior chest, back, anterior 
bathing trunk, posterior bathing trunk, other) is assessed. 
This is converted to a percentage of that region.


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10.6
PAIN NUMERICAL RATING SCALE (NRS)
Please rate the severity of your Hidradenitis suppurativa (HS) pain in the past 24 hours at its 
worst?
Please mark the number on the 0 to 10 scale below
0
1
2
3
4
5
6
7
8
9
10
No 
pain
Worst 
possible 
pain


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10.7
DERMATOLOGY LIFE QUALITY INDEX (DLQI)
DERMATOLOGY LIFE QUALITY INDEX
DLQI
Hospital No:
Date:
Name:
Score:
Address:
Diagnosis:
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK.  Please tick one box for each question.
1.
Over the last week, how itchy, sore, 
Very much

painful or stinging has your skin 
A lot

been? 
A little

Not at all

2.
Over the last week, how embarrassed
Very much

or self conscious have you been because 
A lot

of your skin?
A little

Not at all

3.
Over the last week, how much has your 
Very much

skin interfered with you going
A lot

shopping or looking after your home or 
A little

garden?       
Not at all

Not relevant

4.
Over the last week, how much has your 
Very much

skin influenced the clothes
A lot

you wear?
A little

Not at all

Not relevant 

5.
Over the last week, how much has your 
Very much

skin affected any social or 
A lot

leisure activities?
A little

Not at all

Not relevant

6.
Over the last week, how much has your 
Very much

skin made it difficult for 
A lot

you to do any sport?
A little

Not at all

Not relevant 

7.
Over the last week, has your skin prevented
Yes

you from working or studying?
No

Not relevant 

If "No", over the last week how much has 
A lot

your skin been a problem at 
A little

work or studying?
Not at all



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8.
Over the last week, how much has your 
Very much

skin created problems with your 
A lot

partner or any of your close friends
A little

or relatives? 
Not at all

Not relevant

9.
Over the last week, how much has your 
Very much

skin caused any sexual
A lot

difficulties?
A little

Not at all

Not relevant 

10.
Over the last week, how much of a 
Very much

problem has the treatment for your
A lot

skin been, for example by making
A little

your home messy, or by taking up time? 
Not at all

Not relevant 

Please check you have answered EVERY question. Thank you.
AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors.


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10.8
HIDRADENITIS SUPPURATIVA QUALITY OF LIFE (HIS-QOL)
This questionnaire is designed to measure how Hidradenitis Suppurativa (HS) impacts 
you.
PLEASE READ THESE DIRECTIONS:
It is important to:
1. Think about your HS over the past 7 days
2. Think about your HS only, not another condition.
3. For each line select the single best option
COPYRIGHT © 2019 Property of the authors and Pennsylvania State University 
All rights reserved


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Please select the single best option for each item
In the past 7 days, how 
much has your HS caused 
problems with:
UNABLE 
TO DO
due to 
my HS
Extremely Very much ModeratelySlightly
Not at all
1. Walking (not for exercise)
[ ]
2. Exercising (for example: 
swimming, jogging, biking, yoga, 
aerobics)
[ ]
3. Sleeping
4. Washing yourself
5. Getting dressed
6. Your concentration
In the past 7 days, how have your 
current or potential new HS 
lesions influenced:
Extremely
Very much
Moderately Slightly
Not at all
7. What you wear to avoid discomfort
In the past 7 days, how bothered 
have you been by:
Extremely
Very much
Moderately Slightly
Not at all
8. Pain
9. Itch
10. Drainage
11. Odor


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Please select the single best option for each item
In the past 7 days, how much 
has HS caused you to feel:
Extremely
Very much
Moderately Slightly
Not at all
12. Down or depressed
13. Embarrassed
14. Anxious or nervous
In the past 7 days, how much 
has HS:
Extremely Very 
much
Moderately Slightly Not at 
all
15. Made sexual activity difficult
I am not 
sexually 
active
[ ]
UNABLE
TO DO 
due to 
my HS
[ ]
16. Affected your desire for sexual 
activities
In the past 7 days, how much 
has HS:
Extremely Very 
much
Moderately Slightly Not at 
all
17. Influenced your ability to 
work or study
I do not 
work or 
study
[ ]
UNABL
E TO
DO 
due to 
my HS
[ ]


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10.9
FACIT-FATIGUE
FACIT Fatigue Scale (Version 4)
Below is a list of statements that other people with your illness have said are 
important. Please circl or mark one number per line to indicate your response 
as it applies to the past 7 days.
Not at 
all
A little 
bit
Some-
what
Quite 
a bit
Very 
much
HI7
I feel fatigued
0
1
2
3
4
HI12
I feel weak all over
0
1
2
3
4
An1
I feel listless (“washed out”)
0
1
2
3
4
An2
I feel tired
0
1
2
3
4
An3
I have trouble starting things because 
I am tired
0
1
2
3
4
An4
I have trouble finishing things because 
I am tired
0
1
2
3
4
An5
I have energy
0
1
2
3
4
An7
I am able to do my usual activities
0
1
2
3
4
An8
I need to sleep during the day
0
1
2
3
4
An12
I am too tired to eat
0
1
2
3
4
An14
I need help doing my usual activities
0
1
2
3
4
An15
I am frustrated by being too tired to 
do the things I want to do
0
1
2
3
4
An16
I have to limit my social activity 
because I am tired
0
1
2
3
4


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10.10
PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C)
Please choose the response below that best describes the overall change in your Hidradenitis 
Suppurativa (HS) since you started taking the study medication.
(Choose one box only)
[1] ___
Much better
[2] ___
A little better
[3] ___
No change
[4] ___
A little worse
[5] ___
Much worse


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10.11
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S)
Please choose the response below that best describes the overall severity of your 
Hidradenitis Suppurativa (HS) over the past week:
[0] ___
None
[1] ___
Mild 
[2] ___
Moderate
[3] ___
Severe


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10.12
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)
10.12.1
Columbia-Suicide Severity rating Scale (C-SSRS) baseline version
COLUMBiA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)
Baseline/Screening Version
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; 
Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.
Disclaimer:
This scale is intended to be used by individuals who have received training in its administration. 
The questions contained in the Columbia-Suicide Severity Rating Scale are suggested probes. 
Ultimately, the determination of the presence of suicidal ideation or behavior depends on the 
judgment of the individual administering the scale.
Definitions of behavioral suicidal events in this scale are based on those used in The 
Columbia Suicide History Form, developed by John Mann, MD and Maria Oquendo, MD, 
Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State Psychiatric 
Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & 
Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In 
M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements 
contact posnerk@nyspi.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.


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SUICIDAL IDEATION
Ask questions 1 and 2. If both are negative, proceed to “Suicidal 
Behavior” section. If the answer to question 2 is “yes”, ask questions 3, 
4 and 5. If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below.
Lifetime: 
Time 
He/She Felt 
Most 
Suicidal
Past __ 
Months
1.  Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and 
not wake up.
Have you wished you were dead or wished you could go to 
sleep and not wake up?
If yes, describe:
Yes No
Yes No
2.  Non-Specific Active Suicidal Thoughts
General non-specific thoughts of wanting to end one’s 
life/commit suicide (e.g., “I’ve thought about killing myself”) 
without thoughts of ways to kill oneself/associated methods, 
intent, or plan during the assessment period.
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes No
Yes No
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to 
Act
Subject endorses thoughts of suicide and has thought of at least 
one method during the assessment period. This is different than a 
specific plan with time, place or method details worked out (e.g., 
thought of method to kill self but not a specific plan). Includes 
person who would say, “I thought about taking an overdose but I 
never made a specific plan as to when, where or how I would 
actually do it… and I would never go through with it.”
Have you been thinking about how you might do this?
If yes, describe:
Yes No
Yes No
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports 
having some intent to act on such thoughts, as opposed to “I 
have the thoughts but I definitely will not do anything about 
them.”
Have you had these thoughts and had some intention of acting 
on them?
If yes, describe:
Yes No
Yes No


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5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some 
intent to carry it out.
Have you started to work out or worked out the details of how 
to kill yourself? Do you intend to carry out this plan?
If yes, describe:
Yes No
Yes No
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of 
ideation (i.e.,1-5 from above, with 1 being the least severe and 5 being the most 
severe). Ask about time he/she was feeling the most suicidal.
Most Severe
Most Severe
Lifetime -Most Severe Ideation:   
___________
Type # (1-5)
Description of Ideation
Past X Months -
Most Severe Ideation:   
___________
Type # (1-5)
Description of Ideation
Frequency
How many times have you had these thoughts?
____
____
(1) Less than 
once a week
(2) Once a 
week
(3) 2-5 times 
in week
(4) Daily or 
almost daily
(5) Many 
times each 
day
Duration
When you have the thoughts how long do they last?
(1) Fleeting - few seconds or 
minutes
(2) Less than 1 hour/some of the 
time
(3) 1-4 hours/a lot of time
(4) 4-8 hours/most of 
day
(5) More than 8 
hours/persistent or 
continuous
____
____
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want 
to?
(1) Easily able to control 
thoughts
(2) Can control thoughts with 
little difficulty
(3) Can control thoughts with 
some difficulty
(4) Can control thoughts 
with a lot of difficulty
(5) Unable to control 
thoughts
(0) Does not attempt to 
control thoughts
____
____
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) -
that stopped you from wanting to die or acting on thoughts of committing 
suicide?
(1) Deterrents definitely 
stopped you from attempting 
suicide
(2) Deterrents probably stopped 
you
(3) Uncertain that deterrents 
stopped you
(4) Deterrents most 
likely did not stop you
(5) Deterrents definitely 
did not stop you
(0) Does not apply
____
____


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Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing 
yourself? Was it to end the pain or stop the way you were feeling (in other words 
you couldn’t go on living with this pain or how you were feeling) or was it to get 
attention, revenge or a reaction from others? Or both?
(1) Completely to get attention, 
revenge or a reaction from 
others
(2) Mostly to get attention, 
revenge or a reaction from 
others
(3) Equally to get attention, 
revenge or a reaction from 
others and to end/stop the 
pain
(4) Mostly to end or stop 
the pain (you couldn’t 
go on living with the 
pain or how you were 
feeling)
(5) Completely to end or 
stop the pain (you 
couldn’t go on living 
with the pain or how 
you were feeling)
(0) Does not 
apply
____
____


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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask 
about all types)
Lifetime
Past __ Years
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. 
Behavior was in part thought of as method to kill oneself. Intent does not have to be 100%. 
If there is any intent/desire to die associated with the act, then it can be considered an 
actual suicide attempt. There does not have to be any injury or harm, just the 
potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken 
so no injury results, this is considered an attempt.
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically 
from the behavior or circumstances. For example, a highly lethal act that is clearly not an 
accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from 
window of a high floor/story). Also, if someone denies intent to die, but they thought that 
what they did could be lethal, intent may be inferred.
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______as a way to end your life?
Did you want to die (even a little) when you_____?
Were you trying to end your life when you_____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing 
yourself (like to relieve stress, feel better, get sympathy, or get something 
else to happen)? (Self-Injurious Behavior without suicidal 
intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes No
Yes No
Total # of 
Attempts
______
Total # of 
Attempts
______
Yes No
Yes No
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) 
from starting the potentially self-injurious act (if not for that, 
actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any 
pills, this becomes an attempt rather than an interrupted attempt. Shooting: Person has gun 
pointed toward self, gun is taken away by someone else, or is somehow prevented from 
pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. 
Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: 
Person has noose around neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life 
but someone or something stopped you before you actually did anything?
If yes, describe:
Yes No
Yes No
Total # of 
interrupted
______
Total # of 
interrupted
______
Aborted Attempt:
When person begins to take steps toward making a suicide attempt, but stops themselves 
before they actually have engaged in any self-destructive behavior. Examples are similar to 
interrupted attempts, except that the individual stops him/herself, instead of being stopped 
by something else.
Has there been a time when you started to do something to try to end your 
life but you stopped yourself before you actually did anything?
If yes, describe:
Yes No
Yes No
Total # of 
aborted
______
Total # of 
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include 
anything beyond a verbalization or thought, such as assembling a specific method (e.g., 
buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things 
away, writing a suicide note).
Have you taken any steps towards making a suicide attempt or preparing 
to kill yourself (such as collecting pills, getting a gun, giving valuables 
away or writing a suicide note)?
If yes, describe:
Yes No
Yes No


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Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes No
Yes No
Answer for Actual Attempts Only
Most 
Recent 
Attempt 
Date:
Most Lethal 
Attempt 
Date:
Initial/First 
Attempt 
Date:
Actual Lethality/Medical Damage:
0.  No physical damage or very minor
physical damage (e.g., surface 
scratches).
1.  Minor physical damage (e.g., lethargic 
speech; first-degree burns; mild 
bleeding; sprains).
2.  Moderate physical damage; medical 
attention needed (e.g., conscious but 
sleepy, somewhat responsive; second-
degree burns; bleeding of major vessel).
3.  Moderately severe physical damage; 
medical hospitalization and likely 
intensive care required (e.g., comatose 
with reflexes intact; third-degree burns 
less than 20% of body; extensive blood 
loss but can recover; major fractures).
4.  Severe physical damage; medical
hospitalization with intensive care 
required (e.g., comatose without 
reflexes; third-degree burns over 20% of 
body; extensive blood loss with unstable 
vital signs; major damage to a vital area).
5.  Death
Enter 
Code
______
Enter Code
______
Enter Code
______
Potential Lethality: Only Answer if 
Actual Lethality=0
Likely lethality of actual attempt if no 
medical damage (the following examples, 
while having no actual medical damage, 
had potential for very serious lethality: put 
gun in mouth and pulled the trigger but 
gun fails to fire so no medical damage; 
laying on train tracks with oncoming train 
but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but 
not likely to cause death
2 = Behavior likely to result in death 
despite available medical care
Enter 
Code
______
Enter Code
______
Enter Code
______


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10.12.2
Columbia-Suicide Severity rating Scale (C-SSRS) since last visit 
version
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS)
Since Last Visit
Version 1/14/09
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; 
Brown, G.; Fisher, P.; Zelazny, J.; Burke, A.; Oquendo, 
M.; Mann, J.
Disclaimer:
This scale is intended to be used by individuals who have received training in 
its administration. The questions contained in the Columbia-Suicide Severity 
Rating Scale are suggested probes. Ultimately, the determination of the 
presence of suicidal ideation or behavior depends on the judgment of the 
individual administering the scale.
Definitions of behavioral suicidal events in this scale are based on those 
used in The Columbia Suicide History Form, developed by John Mann, 
MD and Maria Oquendo, MD, Conte Center for the Neuroscience of 
Mental Disorders (CCNMD), New York State Psychiatric Institute, 1051 
Riverside Drive, New York, NY, 10032. (Oquendo M. A., Halberstam B. & 
Mann J. J., Risk factors for suicidal behavior: utility and limitations of 
research instruments. In M.B. First [Ed.] Standardized Evaluation in 
Clinical Practice, pp. 103 -130, 2003.)
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, New York, 10032; 
inquiries and training requirements contact posnerk@nyspi.columbia.edu
© 2008 The Research Foundation for Mental Hygiene, Inc.


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SUICIDAL IDEATION
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If 
the answer to question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 
and/or 2 is “yes”, complete “Intensity of Ideation” section below.
Since Last Visit
1.  Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake 
up.
Have you wished you were dead or wished you could go to sleep and not wake up?
If yes, describe:
Yes
No
2.  Non-Specific Active Suicidal Thoughts
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing 
myself”) without thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment 
period.
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes
No
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. 
This is different than a specific plan with time, place or method details worked out (e.g., thought of method 
to kill self but not a specific plan). Includes person who would say, “I thought about taking an overdose but I 
never made a specific plan as to when, where or how I would actually do it…..and I would never go through 
with it”.
Have you been thinking about how you might do this?
If yes, describe:
Yes
No
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as 
opposed to “I have the thoughts but I definitely will not do anything about them”.
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
Yes
No
5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to 
carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out 
this plan?
If yes, describe:
Yes
No
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 
from above, with 1 being the least severe and 5 being the most severe).
Most Severe
Most Severe 
Ideation:
________
Type # (1-5)
Description of Ideation
Frequency
How many times have you had these thoughts?
____
(1) Less than 
once a 
week
(2) Once a week
(3) 2-5 times in week
(4) Daily or almost 
daily
(5) Many times 
each day
Duration
When you have the thoughts how long do they last?
(1) Fleeting - few seconds or minutes
(2) Less than 1 hour/some of the time
(3) 1-4 hours/a lot of time
(4) 4-8 hours/most of day
(5) More than 8 hours/persistent or 
continuous
____
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts
(2) Can control thoughts with little difficulty
(4) Can control thoughts with a lot of 
difficulty
____


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(3) Can control thoughts with some difficulty
(5) Unable to control thoughts
(0) Does not attempt to control thoughts
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped 
you from wanting to die or acting on thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting 
suicide
(2) Deterrents probably stopped you
(3) Uncertain that deterrents stopped you
(4) Deterrents most likely did not stop 
you
(5) Deterrents definitely did not stop 
you
(0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself? 
Was it to end the pain or stop the way you were feeling (in other words you couldn’t go 
on living with this pain or how you were feeling) or was it to get attention, revenge or a 
reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from 
others
(2) Mostly to get attention, revenge or a reaction from 
others
(3) Equally to get attention, revenge or a reaction from 
others and to end/stop the pain
(4) Mostly to end or stop the pain (you 
couldn’t go on living with the pain 
or how you were feeling)
(5) Completely to end or stop the pain 
(you couldn’t go on living with the 
pain or how you were feeling)
(0) Does not apply
____


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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Since Last 
Visit
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part 
thought of as method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die 
associated with the act, then it can be considered an actual suicide attempt. There does not have to be any 
injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is 
broken so no injury results, this is considered an attempt.
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be 
inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, 
but they thought that what they did could be lethal, intent may be inferred.
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______as a way to end your life?
Did you want to die (even a little) when you_____?
Were you trying to end your life when you_____?
Or Did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to 
relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious 
Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes
No
Total # of 
Attempts
______
Yes
No
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not 
for that, actual attempt would have occurred).
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this becomes an 
attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by 
someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, even if the gun fails to 
fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person 
has noose around neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything?
If yes, describe:
Yes
No
Total # of 
interrupted
______
Aborted Attempt:
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually 
have engaged in any self-destructive behavior. Examples are similar to interrupted attempts, except that the 
individual stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you 
stopped yourself before you actually did anything?
If yes, describe:
Yes
No
Total # of aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a 
verbalization or thought, such as assembling a specific method (e.g., buying pills, purchasing a gun) or preparing 
for one’s death by suicide (e.g., giving things away, writing a suicide note).
Have you taken any steps towards making a suicide attempt or preparing to kill yourself 
(such as collecting pills, getting a gun, giving valuables away or writing a suicide note)?
If yes, describe:
Yes
No
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes
No
Suicide:
Yes
No
Answer for Actual Attempts Only
Most Lethal 
Attempt 
Date:
Actual Lethality/Medical Damage:
0.  No physical damage or very minor physical damage (e.g., surface scratches).
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
Enter Code


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2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; 
second-degree burns; bleeding of major vessel).
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose 
with reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major 
fractures).
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; 
third-degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital 
area).
5.  Death
______
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical 
damage, had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no 
medical damage; laying on train tracks with oncoming train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care
Enter Code
______


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10.13
DIAGNOSIS OF ANAPHYLAXIS
Clinical Criteria for diagnosing anaphylaxis [R11-4890]
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 han (70 mm Hg +[2 x age] from 1 to 10 years, and less than 90 
mm Hg from 11 to 17 years.
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


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Date of amendment
05 July 2021
EudraCT number
EU number
2020-003672-40
BI Trial number
1368-0052
BI Investigational Medicinal 
Product(s)
Spesolimab (BI 655130)
Title of protocol
Randomized, double-blind, placebo-controlled, 
study of spesolimab in patients with moderate to 
severe hidradenitis suppurativa
Global Amendment due to urgent safety reasons
No
Global Amendment
Section to be changed
Protocol Title
Description of change
From
Randomized, double-blind, placebo-controlled, 
study of spesolimab in patients with moderate or
severe hidradenitis suppurativa
To 
Randomized, double-blind, placebo-controlled, 
study of spesolimab in patients with moderate to
severe hidradenitis suppurativa
Rationale for change
HS severity grading is not a binary value 
Section to be changed
Flowchart
Description of change
The line of “Patient’s Global Assessment of HS 
Pain” has been deleted.
Rationale for change
It’s part of the Patient’s Diary.
Section to be changed
Flowchart
Description of change
Footnote #1 has been updated with the addition of 
the text in bold: 
1 Day of Randomization / Day of first intake of 
randomized medication. If needed, some visit 2 
assessments may be conducted 2 days before 
or after the actual visit date after consultation
with the Sponsor.
Footnote #6 has been updated with the addition of 
the text in bold:
It is preferred but patients do not have to be fasted 
for the blood sampling for the safety laboratory. 
At visits with study drug administration this 
should be done prior to the study drug 
administration. See Table 5.2.3:2 for detailed 
information of the tests. If needed, safety lab 


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samples for Visit 2 can be drawn within 48 
hours before the actual visit date.
Rationale for change
Introduce flexibility for investigators and patients
Section to be changed
2.1.3 Secondary endpoint(s) and Protocol 
synopsis
Description of change
The 
following
secondary 
endpoints 
were 
rephrased as:

Achievement of Hidradenitis Suppurativa 
Clinical Response (HiSCR) at Week 12.

Achievement of PGA score of 0 or 1 at 
Week 12.

Achievement of at least 30% reduction 
from baseline in Numerical Rating Scale 
(NRS30) in Patient’s Global Assessment of 
HS Pain at Week 12.

Occurrence of complete elimination of 
draining fistulas at Week 12

Occurrence of at least one flare (defined as 
at least 25 % increase in AN count with a 
minimum increase of 2 relative to baseline) 
up to Week 12.
And a secondary safety endpoint was added:

The occurrence of Treatment Emergent 
Adverse Events (TEAEs)
Rationale for change
Clarification as per Country Authority request.
Section to be changed
Description of change
Rationale for change
Section to be changed
3.3.2 Inclusion Criteria and Protocol synopsis
Description of change
Criterion #3: the following sentence has been 
added to the criterion “(If IHS4 scoring is not 
available, equivalent scoring based on scoring 
systems as HS-PGA or Hurley are acceptable 
based on documented investigator assessment)”
Rationale for change
Clarification needed because maybe IHS4 was 
not in use at the time the patient was diagnosed. 


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Section to be changed
Exclusion criteria. 
Description of change
Exclusion criterion 2: added:
Systemic non-biologic immunomodulatory and/or 
immunosuppressive agents use within 4 weeks (or 
5 half lives, whichever is longer) of visit 2.
Rationale for change
Consistency with other protocol sections.
Section to be changed
3.3.3 Exclusion criteria. 
Description of change
Exclusion criterion 4 has been deleted

Patients who must or choose 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. 
Rationale for change
To avoid duplicates.
Section to be changed
3.3.3 Exclusion criteria. 
Description of change
Exclusion criteria 2 bullet points 1 and 2 had been 
re-worded adding the text in bold:

Topical 
corticosteroids 
over 
HS 
lesions within 1 week of Visit 2.
Rationale for change
To be more precise and clearer.
Section to be changed
3.3.3 Exclusion criteria.
Description of change
#3 reworded as:
“Prior exposure to any immunosuppressive 
biologic other than TNFi for HS”
#4 added: 
“Prior exposure to IL-36R inhibitors including 
spesolimab.”
Rationale for change
Clarification
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criterion 14 has been updated as 
follows:

Severe, 
progressive, 
or 
uncontrolled 
hepatic disease, defined as >3-fold Upper 
Limit of Normal (ULN) elevation in AST 
or ALT or alkaline phosphatase, or >2-fold 
ULN elevation in total bilirubin. Patients 
with Gilbert´s syndrome can be included 
unless total bilirubin elevation is >5-fold 
ULN at screening visit and unless 
proportions of bilirubin fractions are 
inconsistent with diagnosis of Gilbert´s 
syndrome. 
Rationale for change
Changed as per Country Authority request.
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
The following scenarios were added to this 
section:

Systemic antibiotics for HS before week 
4.


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
Systemic antibiotics for HS without 
meeting criteria for disease worsening (as 
defined in section 4.2.2.2)

Influenza live vaccines are not longer 
permitted. Updated also in section 4.2.2.1. 

If a hepatic injury alert (as defined in 
Section 5.2.6.1.4) is confirmed without 
identification of an alternative cause in the 
work-up according to the “DILI checklist” 
the patient should not receive subsequent 
doses of trial treatment. 

The patient develops suicidal ideation or 
any suicidal behaviour (details on grading 
are given in Section 4.2.1.4 only to avoid 
duplicated information)
Rationale for change
Consistency with other protocol sections
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
Trial treatment may be restarted after a temporary 
reason for treatment discontinuation on a case by 
case basis and after consultation with the sponsor. 
Reasons 
for 
temporary 
treatment 
discontinuation may include but are not limited 
to 
pandemic 
lockdown, 
temporary 
hospitalization, severe infections, hepatic injury 
if an alternative cause is identified and patient 
has recovered as per investigator.
Rationale for change
Reasons for temporary interruption (in bold 
above) have been added at Country Authority 
recommendation.
Section to be changed
4.2.1.4 Suicidality
Description of change
The following clarification in bold was added:
In case the patient develops suicidal ideation 
of type 4 or 5 in the C-SSRS (i.e. active 
suicidal thoughts with method and intent but 
without specific plan, or active suicidal 
thoughts with method, intent and plan) or 
any suicidal behavior (i.e. actual attempt, 
interrupted attempt, aborted attempt, or 
preparatory acts or behavior), the patient 
should immediately be referred to a mental 
health professional for further work-up and 
permanently discontinue trial treatment.
Rationale for change
Clarification
Section to be changed
4.2.2.2 Rescue treatment
Description of change
1 The following sentence was deleted:
If a patient receives rescue treatment, the decision 
to maintain the patient on trial treatment will be 


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decided with discussion between the investigator 
and sponsor.
2 The following was added: “In this trial, 
immunosuppressive biologics are not allowed”
Rationale for change
1 As per country Regulatory Authority request
2 Clarification
Section to be changed
4.2.2.3 Antibiotic use during the trial
Description of change
For HS disease worsening, the following was 
added: 
At or after week 4, if the patient requires systemic 
antibiotics for disease worsening as per the 
investigator, monotherapy with either 
doxycycline 100mg orally twice daily or 
alternative as per investigator discretion, may 
be used for a maximum period of 2 weeks, and 
not more than a total of 4 weeks during the 
entire course of the trial.
Concomitant use of systemic antibiotic therapy for 
treatment of HS other than for
disease 
worsening, or before week 4, is not allowed and 
will lead patient to permanent treatment 
discontinuation (see Section 3.3.4.1). 
Rationale for change
As per country Regulatory Authority request
Section to be changed
Table 5.2.3:2 Safety Laboratory Tests
Description of change
Electrolytes: Bicarbonate was deleted from the 
list
Specific gamma-globulin quantification: IgG has 
been deleted from the list.
Substrates: The related footnote was changed 
from “At baseline and at EoT or EOS (as 
applicable) visits, a blood sample will be obtained 
to measure hs-CRP. This analysis will be done in 
the local laboratory” to “At screening and at EoT 
or EOS (as applicable) visits, a blood sample will 
be obtained to measure hs-CRP. This analysis 
will be done in the local laboratory”
Rationale for change
Bicarbonate and IgG: not longer mandated as per 
BI Standard. 
HS-CRP: Correction. Consistency with 
Flowchart. 
Section to be changed
5.2.6.1.4 Adverse events of special interest
Description of change
The text in bold has been added:
Hepatic injury
A hepatic injury is defined by the following 
alterations of hepatic laboratory parameters: 


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an 
elevation 
of 
AST 
(Aspartate 
Aminotransferase) 
and/or 
ALT 
(Alanine 
Aminotransferase) ≥3 fold ULN combined 
with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, 
or in samples drawn within 30 days of each 
other
Rationale for change
Update.
Section to be changed
6.2 Details of trial procedures at selected visits.
Description of change
It has been clarified that study visit procedures 
can be done within the corresponding visit 
window.
The suggested sequence of procedures has been 
revisited. 
Rationale for change
Patient centricity
Section to be changed
7.5 Determination of Sample Size
Description of change
More detailed rationale and justification for the 
calculated sample size is provided.
Rationale for change
As per country Regulatory Authority request
Section to be changed
All applicable sections
Description of change
New IB v9 dated on 20 May 2021 is used for 
reference instead of version 6
Rationale for change
New version of IB v9 dated on 20 May 2021 is 
now available 
Section to be changed
All applicable sections
Description of change
BI655130 replaced by Spesolimab
Rationale for change
Consistency


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32824792
2.0
clinical-trial-protocol-version-02
Randomized, double-blind, placebo-controlled, study of spesolimab in patients with
moderate or severe hidradenitis suppurativa
Approval-Clinical Trial Leader
05 Jul 2021 11:35 CEST
Approval-Biostatistics
06 Jul 2021 03:22 CEST
Approval-Medical Monitor
06 Jul 2021 13:23 CEST
Approval-
 Medicine
07 Jul 2021 18:47 CEST
Approval-Team Member Medicine
12 Jul 2021 09:15 CEST
Verification-Paper Signature
Completion
12 Jul 2021 10:29 CEST


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(Continued) Signatures (obtained electronically) 
 
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2.0

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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c35110764-01
BI Trial No.:
1368-0052
Title:
Randomized, double-blind, placebo-controlled, study of 
Spesolimab in patients with moderate to severe hidradenitis 
suppurativa (HS).
Including Protocol Amendment 1 [include c32824792-02]
Investigational
Product(s):
Spesolimab (BI 655130)
Responsible trial 
statistician(s):
Tel.: 
Fax:
Date of statistical 
analysis plan:
28 DEC 2021
Version:
1.0 Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
5.
ENDPOINTS(S) ..................................................................................................10
5.1
PRIMARY ENDPOINT(S) ................................................................................10
5.2
SECONDARY ENDPOINT(S) ..........................................................................10
5.2.1
Key secondary endpoint(s).................................................................................10
5.2.2
Secondary endpoint(s) ........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................15
6.1
TREATMENT(S)................................................................................................15
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................16
6.3
SUBJECT SETS ANALYSED...........................................................................24
6.5
POOLING OF CENTRES .................................................................................26
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................26
6.6.1
Withdrawals ........................................................................................................26
6.6.2
Efficacy data........................................................................................................26
6.6.3
Safety data ...........................................................................................................28
6.6.4
PK data.................................................................................................................29
6.6.5
Biomarker data ...................................................................................................29
6.6.6
Time since first diagnosis ...................................................................................29
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................29
7.
PLANNED ANALYSIS......................................................................................32
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........33
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................34
7.3
TREATMENT COMPLIANCE........................................................................35
7.4
PRIMARY ENDPOINT(S) ................................................................................35
7.4.1
Primary analysis of the primary endpoint(s) ...................................................35
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoint(s)............................................................................................36
7.5
SECONDARY ENDPOINT(S) ..........................................................................37


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7.5.1
Key secondary endpoint(s).................................................................................37
7.5.2
(Other) Secondary endpoint(s) ..........................................................................37
7.7
EXTENT OF EXPOSURE.................................................................................40
7.8
SAFETY ANALYSIS..........................................................................................40
7.8.1
Adverse Events ....................................................................................................41
7.8.2
Laboratory data ..................................................................................................43
7.8.3
Vital signs.............................................................................................................45
7.8.4
ECG......................................................................................................................45
7.8.5
Local tolerability .................................................................................................45
7.8.6
Others...................................................................................................................45
7.9
ANALYSIS OF COVID19 IMPACT ................................................................45
7.10
HANDLING OF DMC ANALYSES .................................................................46
7.11
OTHERS..............................................................................................................46
7.11.1
Biomarkers ..........................................................................................................46
7.11.2
Immunogenicity...................................................................................................46
7.11.3
Pharmacokinetics................................................................................................47
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............48
9. 
REFERENCES....................................................................................................49
11.
HISTORY TABLE..............................................................................................65


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases of the study according to randomized 
treatment ...........................................................................................................15
Table 6.2: 1
Important protocol deviations...........................................................................16
Table 6.3: 1
Overview of use of patient analysis sets by class of endpoint and handling of 
estimand and missing data................................................................................25
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs and
biomarker to visits for statistical analysis.........................................................30
Table 7.1: 1
Categories for summary of continuous variables .............................................34
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events 
Concepts ...........................................................................................................42
Table 11: 1
History table .....................................................................................................65


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug antibodies
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALQ
Above the upper limit of quantification
ALT
Alanine aminotransferase
AN
Abscess and inflammatory nodule
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
BSA
Body surface area
CARE
Clinical data analysis and reporting environment
CGI
Clinical Global Impression
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CRP
C-reactive protein
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DNA
Deoxyribonucleic acid
EC
Estimand concept
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials
FACIT
Functional Assessment of Chronic Illness Therapy


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Term
Definition / description
FUP 
Follow-up
gCV
Geometric coefficient of variation
GCP 
Good Clinical Practice
gMean
Geometric mean
GPP
Generalized pustular psoriasis
HASI
HS Area and Severity Index
HS
Hidradenitis suppurativa
HS-PGA
HS Physician Global Assessment
HiSCR
Hidradenitis suppurativa clinical response
HS-CRP
High-Sensitivity C-Reactive Protein
IHS4
International Hidradenitis Suppurativa Severity Score System
IL-36 
Interleukin 36
IL-36R 
Interleukin 36 Receptor
NRS
numerical rating scale
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
HiS-QoL
Hidradenitis suppurativa quality of life
iPD
Important protocol deviation
ICEs
Intercurrent events
MAP
Meta-Analytic Predictive
i.v. 
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
DLQI
Dermatology Life Quality Index
NRI
No response imputation
OC 
Observed cases
OR
Original results
OLE 
Open Label Extension
PD
Pharmacodynamic(s), protocol deviation
PE
Primary endpoint
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PPS
Per protocol set
PT
Preferred term


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Term
Definition / description
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
REP
Residual effect period
RNA
Ribonucleic acid
RPM
Report planning meeting
RS
Randomized set
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SI
SOC
Système international d’unités
System organ class
TS
Treated set
TSAP
Trial statistical analysis plan
UDAEC
User-defined Adverse Event Category
ULN
Upper limit of normal range
VAS
Visual analogue scale
MCMC
Markov Chain Monte Carlo


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analyses described in the CTP and its amendments, 
and to include detailed procedures for executing the statistical analysis of the primary and 
secondary variables and other data. 
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, and randomization.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by
, and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).
Study data will be stored in a trial database within the BRAVE system.
Analyses of the biomarker and gene expression data are described in a separate biomarker 
SAP, unless otherwise specified in this document.
This is a multicenter, randomized, double-blind, placebo-controlled Phase IIa study with 
Spesolimab/placebo in patients with moderate to severe HS. In total, approximately 45 
patients will be randomized to receive Spesolimab/ placebo (2:1). Study medication (1200 mg 
Spesolimab or matching Placebo) is administered intravenously at Baseline, Week 1 and 2
and then subcutaneously every two weeks at Weeks 4, 6, 8, and 10. Patients completing Week 
12 of the study, will roll-over to an extension study if they agree and meet the eligibility 
criteria of the extension trial. (see Flow Chart of CTP). 
The primary and secondary efficacy endpoints of the trial will be evaluated at Week 12. This 
TSAP fully specifies the analyses of the trial.


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint of the study is: 

Percent change from baseline in total abscess and inflammatory nodule (AN) count at 
Week 12. 
See Section 10.1.1 for further details on the derivation of the abscess and inflammatory 
nodule count.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)
Secondary Endpoints at Week 12 are defined as described below: 

Percent change from baseline in draining fistula count at Week 12
(Only patients with at least one draining fistula at baseline will be used for analysis).

Achievement of Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12. 
HiSCR is defined as at least a 50% reduction in the total AN count with no increase in 
abscess count and no increase in draining fistula count relative to baseline.

Absolute change from baseline in International Hidradenitis Suppurativa Severity Score 
System (IHS4) value at Week 12

Absolute change from baseline in HASI score at Week 12

Achievement of PGA score of 0 or 1 at Week 12

Achievement of at least 30% reduction from baseline in Numerical rating scale (NRS30) 
in Patient’s Global Assessment of HS Pain at Week 12

Occurrence of complete elimination of draining fistulas at Week 12
(Only patients with at least one draining fistula at baseline will be used for analysis).

Occurrence of at least one flare (defined as at least 25 % increase in AN count with a 
minimum increase of 2 relative to baseline) up to Week 12

Absolute change from baseline in DLQI Score at Week 12

Absolute change from baseline in HiS-QoL Total Score at Week 12
See Section 10.1 for further details regarding endpoint definition and derivation.
The following safety endpoint is also defined: 

The occurrence of Treatment Emergent Adverse Events (TEAEs)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on the treatment to be administered, assignment to treatment, and 
selection of dose, cf. Section 4 of the CTP.
The study phases are defined relative to randomized dose at Day 1 as below:
Table 6.1: 1
Flow chart of analysis phases of the study according to randomized treatment
Study analysis 
phase
Description
Start (included)
End (included)
Screening phase
Screening
Earliest of (Date of 
informed consent, 
first screening 
procedure)
Date/time of start of the first 
study dose minus 1 minute.
Loading 
treatment phase
On-treatment 
period
Date/time of start of 
the first study 
loading dose (Day 1)
Earlier of: i) Date/time of start 
of the first maintenance dose
minus 1 minute; or, ii) Date of 
end of last loading dose + 112 
days at 11:59 p.m. if patient 
early discontinued study 
treatment before the first 
maintenance dose
Maintenance 
treatment phase 
(primary 
analysis at week 
12)
Date/time of start of 
the first study 
maintenance dose (if 
applicable)
Earlier of : i) Date/time of start 
of the first dose in the 
extension trial 1368.67; or, ii) 
Date of end of last maintenance 
dose + 112 days at 11:59 p.m, 
iii) cut-off date for primary 
analysis.
Follow-up
phase1 (if 
applicable)
Off-
treatment 
period (if 
applicable)
Date of end of last 
study dose + 113
days at 0:00 a.m.
Latest of: i) Date of EOS visit; 
ii) last contact date on trial 
termination page at 11:59 p.m. 
iii) Date/time of start of first 
dose in the extension trial 
1368.67;
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase will 
not extend beyond the start date of the following phase. 
1 The off-treatment period (i.e. Follow-up phase) only exists if the date of EoS visit or the last contact date is after the date of 
end of last administration + 112 days.
Treatment groups for the analysis phases according to the randomized/actual treatment on 
Day 1 (see Table 6.1: 1) will be labelled as follows:


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
"Placebo" (i.e. randomized to receive /actual received Placebo)

"Speso" (i.e. randomized to receive /actual received Spesolimab)

"Overall Total"(across treatments), where appropriate.
“Overall Total” is applicable in disposition, demographics and baseline characteristics, 
compliance summaries, AE, clinically significant abnormal lab values and others if needed. 
Where applicable, output columns should be arranged in the order as given above.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
database (i.e., enrolled patients). Consistency check listings (for identification of deviations of 
time windows) and a list of protocol deviations will be provided to be discussed at the 
RPM/DBLM. At this meeting, it will be decided whether a discrepant data value can be used 
in analyses or whether it must be queried in the clinical database. Each protocol deviation 
must be assessed to determine whether it is an important Protocol Deviation (iPD). These 
categories are described below in order to ensure that those iPD which lead to exclusion from 
the PPS are suitably documented before unblinding and locking of data.
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)". (8)
If any patients fulfil the iPD categories, then they are to be summarized and will be captured 
in the RPM/DBLM minutes via an accompanying Excel spreadsheet (3). The following table 
contains the categories which are considered to be iPDs in this trial. If the data show other 
iPDs, for example, based on monitor visits to the site(s), then this table will be supplemented 
accordingly by the time of the RPM/DBLM. Not all iPDs will lead to exclusion from analysis 
sets. iPDs leading to exclusion from analysis sets are indicated as such in Table 6.2: 1.
IPDs will be summarized and listed for the randomized set.
Table 6.2: 1
Important protocol deviations
Category/
Code
Description
Comments
Excluded 
from1
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
Male or female adult patients, 18 
years of age or older
LABEL: Age not met
IC01
Also require programmatic check 
PPS


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A1.02
Moderate to severe HS, based on 
IHS4 criteria, for at least 1 year 
prior to the baseline visit
LABEL: medical history of HS 
not met based on IHS4
IC03
PPS
A1.03
HS lesions in at least 2 distinct 
anatomic areas
LABEL: HS lesions in less than 2 
anatomic areas
IC04
PPS
A1.04
Biologic naïve or TNFi-failure 
for HS
LABEL: Not Biologic naïve or 
TNFi-failure for HS
IC05
PPS
A1.05
Inadequate response to an 
adequate course of appropriate 
oral antibiotics for treatment of 
HS in the last 1 year, for TNFi 
biologic naïve patients
LABEL: Inadequate response to 
oral antibiotics for HS for TNFi 
naïve patients
IC06
PPS
A1.06
Total abscess and inflammatory 
nodule (AN) count of greater
than or equal to 5
LABEL: AN count<5
IC07 
PPS
A1.07
Total draining fistula count of 
less than or equal to 20
LABEL:
Draining fistula count>20
IC08
PPS
A1.08
Women of childbearing potential 
must be ready and able to use 
highly effective methods of birth 
control, for the duration of the 
trial and 16 weeks after last 
administration.
LABEL: Women not use birth 
control
IC09
None
A2
Exclusion criteria violated
General Exclusion Criteria


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A2.01
Presence of active skin lesions 
other than HS that interferes with 
the assessment of HS
LABEL: Presence of active skin 
lesions other than HS
EC01
PPS
A2.02
Use of restricted/prohibited 
medication per protocol
LABEL: use of 
restricted/prohibited medication
EC02
See the further list in section 
4.2.2 in CTP
PPS
A2.03
Prior exposure to any 
immunosuppressive biologic 
other than TNFi for HS
LABEL: Prior exposure to any 
immunosuppressive biologic 
other than TNFi for HS
EC03
PPS
A2.04
Prior exposure to IL-36R 
inhibitors including Spesolimab
LABEL: Prior exposure to IL-
36R inhibitors
EC04
PPS
A2.05
Treatment with any 
investigational device or 
investigational drug of chemical 
or biologic nature within of 30 
days or 5 half-lives of the drug, 
whichever is longer, prior to visit 
2
LABEL: Treatment with any 
investigational device or 
investigational drug of chemical 
or biologic nature
EC05
PPS
A2.06
Women who are pregnant, 
nursing, or who plan to become 
pregnant while in the trial.
LABEL: 
Pregnant or nursing
EC06
None


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A2.07
History of 
allergy/hypersensitivity to the 
systemically administered trial 
medication agent or its excipients
LABEL: History of 
allergy/hypersensitivity
EC07
PPS
A2.08
Patient with a transplanted organ 
(with exception of a corneal 
transplant >12 weeks prior to 
screening) or who have ever 
received stem cell therapy 
LABEL: patient with 
transplanted organ or stem cell 
therapy
EC08
None
A2.09
Any documented active or 
suspected malignancy or history 
of malignancy within 5 years 
prior to the screening visit, 
except appropriately treated basal 
cell carcinoma of the skin, 
squamous cell carcinoma of the 
skin or in situ carcinoma of 
uterine cervix
LABEL: Active or suspected
malignancy
EC09
None
A2.10
Active or latent TB:
LABEL: Active or latent TB
EC10
None
A2.11
Active systemic infection within 
2 weeks of visit 2. Patients can be 
re-screened after treatment of the 
acute infection
LABEL: Active systemic 
infection
EC11
PPS
A2.12
Relevant chronic infections as 
determined by the investigator, 
including human 
immunodeficiency virus (HIV) or 
viral hepatitis.
EC12
None


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A2.13
Major surgery performed within 
12 weeks prior to first study drug 
administration or planned during 
the study
LABEL: Major surgery 
performed or planned during the 
study
EC13
None 
A2.14
Severe, progressive, or 
uncontrolled hepatic disease, 
defined as >3-fold Upper Limit 
of Normal (ULN) elevation in 
AST or ALT or alkaline 
phosphatase, and >2-fold ULN 
elevation in the total bilirubin 
LABEL: Severe, progressive, or 
uncontrolled hepatic disease
EC14
Also check versus screen Lab 
values
None
A2.15
Evidence of a current or previous 
disease, medical condition other 
than HS, surgical procedure, 
psychiatric or social problems, 
medical examination finding, or 
laboratory value at the screening 
outside the reference range that 
would compromise the safety of 
the patient or compromise the 
quality of the data, make the 
study participant unreliable to 
adhere to the protocol, comply 
with all study visits/procedures or 
to complete the trial.
LABEL: Relevant conditions 
with concern on adherence or 
compliance
EC15
None
A2.16
Planned use of laser or other hair 
removal procedures over HS-
affected areas during the trial 
period
LABEL: Planned use of laser or 
other hair removal procedures 
EC16
PPS
A2.17
Any suicidal ideation of type 4 or 
5 on the C-SSRS in the past 12 
months
LABEL: Any suicidal ideation of 
type 4 or 5 on the C-SSRS 
EC17
None


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A2.18
Any suicide behaviour in the past 
2 years
LABEL: Any suicide behaviour 
in the past 2 years
EC18
PPS
A2.19
Previous enrolment in this trial 
except for patients re-screened.
LABEL: Previous enrolment in 
this trial except for patients re-
screened
EC19
PPS
B
Informed consent
B1
Informed consent not available
LABEL: No IC form
IC02
Date of informed consent 
missing or no signature on 
patient’s “Declaration of 
Informed Consent”
In this case: Patient’s data will 
not be used at all.
All
B2
Informed consent too late
LABEL:
IC too late.
IC02
Informed consent date was after 
Visit 1
None
C
Trial medication and 
randomisation
C1
Incorrect trial medication
C1.01
Study drug medication not taken 
at all
LABEL:
Study drug medication not taken 
at all.
PPS, SAF
C1.02#
Patient skipped an intermediate 
dose without proper reason
LABEL:
Patient skipped an intermediate 
dose without proper reason.
Patient missing a dose at an 
intermediate visit without proper 
reason when dose at a later 
scheduled visit has been taken.
Decision based on medical 
judgment.
PPS


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C1.03#
Patient skipped an intermediate 
dose due to COVID 19
LABEL: Patient skipped an 
intermediate dose due to COVID 
19
Patient missing a dose at an 
intermediate visit when dose at a 
later scheduled visit has been
taken due to covid-19
Decision based on medical 
judgment.
PPS
C2
Incorrect Dosing
C2.01
Incorrect medication received 
prior to Week 12
LABEL:
Incorrect dose received prior to 
Week 12
Randomized patient who 
received or miss one or more 
incorrect syringes of treatment
not as planned at any scheduled 
visit prior to Week 12
Can only be finally judged after 
DBL since unblinding 
information is required
PPS
C3
Randomization not 
followed
C3.01
Treated without randomisation
LABEL:
Treated without randomisation.
Patient treated according to 
eCRF, but not randomised 
according to IVRS.
RS, SAF,  
PPS
C3.02
Randomization order of 
stratification not followed
LABEL:
Stratification error
Stratification error regarding 
TNFi naïve and TNFi-failure
Programming check and manual 
review after DBL
PPS
C4
Medication code broken
C4.01
Medication code broken before 
week 12 inappropriately
LABEL:
Code broken early without valid 
reason.
Medication code was broken 
prior to DBL for no valid reason.
Final decision at the DBL 
meeting based on medical 
judgment.
PPS
D
Concomitant medication
D1
Previous medication
D1.01#
Washout of previous medication 
too short
LABEL:
Washout too short.
Washout period too short – See 
Table 4.2.2.1:1 in CTP
PPS
D2
Prohibited medication use


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D2.01#
Use of restricted medication 
(other than systemic antibiotics) 
for HS (with potential influence 
of efficacy data) prior to or up to 
week 12
Label: Use of restricted 
medication other than systemic 
antibiotics for HS
See the list of restricted 
medication in section 4.2.2 of 
CTP, manual assessment at 
MQRM/RPM/DBLM
PPS
D2.02#
Use of antibiotic before week 4 
for HS 
LABEL: Use of antibiotic before 
week 4 for HS
See section 3.3.4.1 of CTP for 
details, manual assessment at 
MQRM/RPM/DBLM
PPS
D2.03#
Inappropriate use of Systemic 
antibiotics for HS disease 
worsening at/after week4.
LABEL: Inappropriate use of 
Systemic antibiotics for HS 
disease worsening at/after week4
Including usage 1) without 
meeting criteria for HS disease 
worsening, or 2) longer duration 
than allowed 
See section 4.2.2 of CTP for 
details, manual assessment at 
MQRM/RPM/DBLM
PPS
E
Missing data
<not specified>
F
Study specific analysis
<not specified>
G
Other safety related 
violations
G1.01
Pregnancy test not done for 
woman of child bearing potential 
before IMP administration
LABEL:
Pregnancy test not done.
Pregnancy test not done at any 
visit when it is scheduled and the 
patient did not yet complete 
follow-up.
None
# PV will be detected manually
Source: BI reference document 'Identify and Manage Important Protocol Deviations (iPD)' [001-MCS-50-413] (8,12).
1 See Section 6.3 for population definitions 


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6.3
SUBJECT SETS ANALYSED
The following analysis sets will be defined for this trial:
Enrolled Set (ES)
This patient set includes all patients who signed informed consent. It will be used for 
analyses of patient disposition.
Randomized Set (RS):
This patient set includes all randomized patients. Treatment assignment will be as 
randomized. 
Safety Analysis Set (SAF):
This patient set includes all patients who were randomized and received at least one 
dose of study drug. This is the main analysis set for efficacy and safety. Patients will 
be analyzed according to the actual treatment received.
Per-Protocol Set (PPS):
This patient set includes all patients in the randomized set who adhered to the CTP 
without any iPDs which are flagged for exclusion from the PPS in the table above.
The PPS will be used for sensitivity analysis on the primary endpoint.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at latest at the RPM/DBLM.
Handling of Treatment Misallocations in Analysis Sets
If a patient is randomized but not treated, they will not be reported under their randomized 
treatment group for efficacy and safety analysis according to PPS, and SAF. 
If a subject is treated but not randomized, they will be excluded from the efficacy analysis and 
safety analysis by definition. However, subjects under such circumstances will be described in 
the final clinical trial report.
If a subject is randomized but takes incorrect treatment during the study, then:

For efficacy and safety analyses using the SAF which are based on actual treatment: 
•
If a subject is planned to receive administration of Spesolimab (randomized to 
Speso), then they will be reported under the Spesolimab group if the subject receives 
at least 1 vial of randomized Spesolimab.
•
If a subject is planned to receive placebo treatment, then they will be reported under 
the placebo arm if they are treated and receive no vial of randomized Spesolimab. If 
the subject receives >= 1 vial of randomized Spesolimab, then the patient will be 
handled differently for efficacy analysis and safety analysis. It will keep as placebo
for efficacy reporting. For safety, then the patient will be reported as treated with 
Spesolimab treatment group.


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Table 6.3: 1
Overview of use of patient analysis sets by class of endpoint and handling of 
estimand and missing data 
Class of Endpoints
ES
RS
SAF
PKS
PPS
Disposition
OR
OR
Compliance and exposure
OR
iPD
OR
Demographic/baseline 
characteristics
OR
OR
Concomitant medication
OR
Primary endpoint
EC-H-MMRM
EC-H-MMRM1
EC-H-MMRM4
EC-S-MMRM1
OC2,
OC-IR2
EC-H-MMRM1
Secondary binary efficacy 
endpoints
EC-H-NRI, 
EC-H-NRI1
EC-H-NRI4
OC2
EC-H-MI3
Secondary continuous 
efficacy endpoints
EC-H-MMRM
EC-H-MMRM1
EC-H-MMRM4
EC-S-MMRM3
OC2
Further efficacy endpoints 
Binary:
EC-H-NRI
Continuous:
EC-H-MMRM1
All:
OC2,
Concentration & ADA
OR
OR
Safety data
OR
OC-IR
1 sensitivity/further analysis 
2 descriptive display only
3 selected endpoints.
4 subgroup analysis
For explanation of the different approaches with regard to missing data see Section 6.6.
EC-H: Hybrid strategy by implementing estimand concept. Any data post rescue medication use will be censored.
EC-S: Supplementary strategy by implementing estimand concept. Any data collected after use of any rescue therapy or 
restricted medication are censored.
OC = observed cases excluding values after any use of rescue medication.
OC-IR = observed cases including also values after any use of rescue medication.
OR = original results. 


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6.5
POOLING OF CENTRES
No analysis is planned to explore the effect of individual centres; all centres will be pooled for 
analysis.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Section 7.3 of the CTP describes the handling of missing data.
The original results (OR) approach implies the presentation of data exactly as observed (not 
using time windows and not setting values to missing).
OR analysis will be performed on parameters and endpoints that are either not affected by 
patients’ rescue therapy use (e.g., plasma concentration level of spesolimab, rescue therapy 
itself), or it is not meaningful to apply any imputation rule for the replacement of missing 
values.
6.6.1
Withdrawals
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.
6.6.2
Efficacy data
Based on the different reasons for patients’ data missing for different endpoints, various 
approaches will be used to assess the impact of missing data on the efficacy endpoints of this 
trial, depending upon the type of the endpoint (cf. Table 6.3: 1). Approaches to be applied are 
described below.


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Missing data imputations will be performed using all available on-treatment data observed up 
to the respective analysis cut-off date, if applicable. 
Some efficacy endpoints are defined with a particular binary outcome, i.e. Achievement of 
PGA score of 0 or 1. Then imputation is planned to take place only at the binary level, i.e., the 
PGA score itself as a ordinal variable will not be imputed, but the binary endpoints derived 
based on these scores will be imputed, unless otherwise specified.
Continuous efficacy endpoints
For efficacy endpoints which are continuous in nature, the use of a restricted maximum 
likelihood (REML)-based mixed effect model with repeated measures (MMRM) approach, if 
applicable, will ensure that missing data are handled implicitly, via a missing at random 
assumption, by the statistical model. 
In addition, the efficacy endpoints during randomized treatment period may be displayed 
descriptively using following methods:

Observed cases (OC) approach will include all collected data, without imputation for any 
missing data. Such an OC approach will exclude all values measured after intake of a 
rescue therapy.

Observed cases (OC-IR) approach will include all collected data, without imputation for 
any missing data. Such approach will be used as a sensitivity method for data display and 
is an extension of the OC approach which includes additionally all values which were 
measured after rescue therapy. Will also include all values measured after any use of 
investigator prescribed SoC.
Binary efficacy endpoints
Primary Imputation Approach – No Response Imputation [NRI]:
For all binary endpoints (i.e. endpoints that are either 1 (patient responded) or 0 (patient did 
not respond)), the following will be performed as the primary imputation approach (analysis 
type): 

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 no rescue treatment has been given during this 
period).

Otherwise, impute as a failure.
Other Imputation Approaches:

OC method will be also used to display the binary data.

Multiple Imputation (MI) approach:
For selected secondary binary endpoint, i.e., achievement of HiSCR at Week 12, multiple 
imputation (MI) will be used to handle missing data as a sensitivity analysis. Use baseline 
and on-treatment data only and impute HiSCR as binary variables with values 0, 1. The 


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imputation will be done using OC data as the input dataset, and will follow the steps 
outlined below:
1.
Multiple Imputation of Missing data: use SAS procedure PROC MI with the Fully
Conditional Specification (FCS) method and corresponding options/statements (SAS 
manual). Discriminant function method is used to impute missing values by using the 
ordering of the class level in each variable.
PROC MI DATA= hiscr_mi2 seed= 136852 nimpute=100 out=mi_fcs;
CLASS HiSCR_base- HiSCR_12 trt stratum;
VAR HiSCR_base- HiSCR_12 trt stratum;
FCS DISCRIM (HiSCR_base- HiSCR_12 trt stratum /CLASSEFFECTS=include);
RUN;
Note that the seed 136852 will be used throughout. If a second seed is required, 136853
will be used, and so on as necessary.
2.
Analysis of Completed Datasets: The imputed complete dataset will be used to calculate 
the response rate for each arm. The risk difference will be also calculated together with 
the standard error based on the normal approximation.
3.
Combine Results: Separate approach will be applied to the combination of the response 
rate for each arm and the difference between them. 
•
For the response rate of each arm, the distributions are not expected to be 
approximately normal, so Rubin’s rules (13) should not be used. Instead, the point 
estimate will be calculated as the mean of individual imputations and the 95% 
confidence interval for each arm will implement the MIWilson(14) approach.
•
For the risk difference, the distribution is approximately normal, so Rubin’s rules can 
be used. Accordingly, PROC MIANALYZE is used to combine the analysis results 
from step 2 and generate valid statistical inferences by accounting for the variability 
introduced by the MI process.
6.6.3
Safety data
With respect to safety evaluations, it is not planned to impute missing values. For safety data 
that are displayed by time point (or visit) of measurement, the OC-IR approach will be used. 
For safety data that are not displayed by visit such as AE and possibly clinically significant 
laboratory abnormality, OR will be used. 
The only exceptions where imputation might be necessary for safety evaluation are AE dates 
and start and stop dates for concomitant medications. Missing or incomplete AE dates are 
imputed according to BI standards. (4)
Partial start and stop dates for concomitant medications, rescue, and historical medication for 
HS will be imputed to enable subsequent calculation (but not for display) by the following 
"worst case" approach:


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
If the day of the end date is missing, then the end date is set to last day of the month (or to 
the patient's trial completion date, if it is earlier than the last day of the month).

If the day and month of the end date are missing then the end date is set to 31st of 
December of the year (or to the patient's trial completion date, if it is earlier than the 
31st of December of the year).

If the day of the start date is missing then the start date is set to first day of the month 
(except for rescue therapy, where the first dosing day will be used if first dosing happened 
in the same month).

If the day and month of the start date are missing then the start date is set to 1st January of 
the year (except for rescue therapy, where the first dosing day/month will be used if first 
dosing happened in the same year).

All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance.
If a concomitant medication was ticked to be ongoing, it is expected that the end date is 
missing and will not be imputed for display purposes.
6.6.4
PK data
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-36-
472_RD-01) (5). 
6.6.5
Biomarker data
The handling of other biomarkers e.g. RNA expression will be specified in a separate 
document.
6.6.6
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
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.
Baseline, unless otherwise specified, is defined as the last measurement collected prior to the 
start of administration of the trial treatment.


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Measurements taken after start of administration of trial treatment will be considered either 
on- or off-treatment values based on the definition in Section 6.1, and will be assigned to 
visits for statistical analysis, if applicable, as defined below.
Analysis of AE data, potentially clinically significant abnormal laboratory values, 
concomitant medication or non-drug therapies, as well as use of rescue therapy will not be 
based on visits. Frequency tables for these data will be using on-treatment data and 
categorized based on their occurring/starting dates. Therefore, no assignment to time windows 
will be necessary for such data.
The derivation of the last value, minimum value and maximum value of laboratory and vital 
signs data will consider all on-treatment values (whether or not selected in any time window; 
see Table 6.1: 1 for definition of the on-treatment period) within the period of interest; these 
will be derived for analysis of laboratory and vital signs data.
All other safety, efficacy and biomarker measurements will be assigned to visits based on 
extended time windows around the planned visit dates, defined relative to the day of first trial 
treatment (which is scheduled for Visit 2). These extended time windows are defined in Table 
6.7: 1.
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs and biomarker 
to visits for statistical analysis
Visit number
Visit 
label
Planned day
Time window
Window 
(per CTP)
Start
(per CTP)
End
(per CTP)
Start
(extended)
End
(extended)
1
screening
-28 to-1
2
Week0
Day1
none
1 A
1
1 A
1
3
Week1
Day 8
+-1
7
9
2
11
4
Week2
Day15
+-1
14
16
12
22
5
Week4
Day29
+-3
26
32
23
36
6
Week6
Day43
+-3
40
46
37
50
7
Week8
Day57
+-3
54
60
51
64
8
Week10
Day71
+-3
68
74
65
78
9C
Week12
(EoT)
Day85
+-3
82
88
79
92
10
Week20
(FUP1)
Day141
+-7
134
148
93
169
11
Week 28
(EOS)
Day197
+-7
190
204
170
211
For patients who discontinue the treatment early and are not willing to follow the whole visit schedule:
-
EOS       LD B +112
-
-
-
All days are counted relative to the day of randomized 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 trial treatment) via assessment on date & time (i.e. safety laboratory) will not be assigned to Day 1. 
Such data will be listed only.
BLD= Last dose.
C For the patients who enter extension trial, the EOT will be the last visit (i.e., V10 and V11 are not required). 
The EOS (=individual end of the study) will be the first administration of the trial drug in extension trial.


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Repeated and unscheduled efficacy, safety and biomarker measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date of measurement.
Only one observation per time window will be selected for statistical analysis at a particular 
visit – the value which is closest to the protocol planned visit day will be selected. If there are 
two observations which have the same difference in days to the planned day, the later value 
will be selected. If there are two observations on the same day, the worst value will be 
selected.
Assignment of observations to visits based on time windows will be based on the non-
imputed (observed) data after the implement of estimand concept. For example, for EC and 
OC methods, values after rescue therapy intake should be censored first before assignment of 
efficacy endpoints.
For visits without an assigned value based on time windows, a value will thereafter be 
imputed as defined in Section 6.6. Imputation of efficacy endpoints, when applicable, will be 
performed based on all available observations meeting the imputation rules, irrespective of 
whether the observation was selected in any time window.


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7.
PLANNED ANALYSIS
The following analyses of this trial protocol are planned:
Primary Analysis
The primary analysis will be performed once all patients have either 1) completed the 12 
weeks treatment period or 2) have reached the 12 weeks after starting of treatment if early 
discontinued the trial treatment; for this assessment a first database lock (before the final 
database lock) will be performed. 
The primary analysis will be performed by the sponsor. The project and trial team members 
will be un-blinded for treatment information and this analysis. 
Note that biomarker data may be reported in a separate biomarker report at this time. If 
applicable, details of these analyses will be provided in a separate Biomarker Statistical 
Analysis Plan.
Final analysis 
Final trial analysis will be performed once all randomized patients have completed the trial; at 
that time point, a final database lock will be done. 
If separate primary analysis and final analysis, comprehensive analysis will be performed in 
the primary analysis. All data up to the cut-off date will be included for analysis. In final 
analysis, only concomitant medication/therapy and safety listings will be provided for these 
ongoing patients before trial completion at the time of database lock for primary analysis. A 
final clinical trial report will be written for all data from primary analysis and final analysis.
The primary analysis and final analysis may be performed as a single analysis (at the time of 
trial completion), if insufficient time interval between the two planned analysis and agreement 
by the trial team not to perform two separate analyses before the time of the primary analysis. 
For example, majority of patients enter the extension study and no patient is ongoing under 
REP at time of DBL of primary analysis.
The decision will be described and documented in final CTR.
General Remarks
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
Clinical Trials and Project Summaries " (BI-KMED-BDS-HTG-0045) (10) and those 
generated for PK are based on 001-MCS-36-472 (5).
The individual values of all patients will be listed. Listings will generally be sorted by 
country, center number, patient number and visit (if visit is applicable in the respective 
listing). AE listings will be sorted by assigned treatment (see Section 7.8.1 below for details).
The listings will be contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:


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N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Q1
lower quartile
Median 
median
Q3
upper quartile
Max 
maximum
For PK analyte concentrations, the following descriptive statistics will additionally be 
calculated: variables:
CV: 
arithmetic coefficient of variation
gMean: 
geometric mean
gCV: 
geometric coefficient of variation
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations.
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline "Standards for Reporting of Clinical Trials and Project Summaries." (10)
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if there actually are missing values. Percentages will be based on 
all patients in the respective patient set whether they have non-missing values or not.
Disposition of the patient population participating in the trial will be summarized by the 
presentation of the frequency of patients screened, randomized, screened but not randomized, 
randomized but not treated, randomized and treated, who completed randomized medication, 
who withdrew from the trial before EOT visit, by reason, who were prematurely discontinued
from trial medication, by reason, who received rescue therapy for HS worsening and who 
entered the extension trial 1368.67.
The frequency of patients with iPDs, also summarized by whether or not the iPD led to 
exclusion from the PPS, will be presented. 
The frequency of patients in each of the different analysis sets will also be presented.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. 
Descriptive statistics will be presented by treatment for demographic parameters and baseline 
characteristics, based on the RS.
For the continuous variables described below, the following categories will be defined in 
Table 7.1: 1, 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
< 30 years
30 to < 65 years
≥65 years
Weight
≤60 kg
>60 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 year
> 5 to ≤10 years
> 10 years
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Analyses of concomitant 
diseases and medication will be based on the RS.
Concomitant diseases (i.e. baseline conditions) 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.
Concomitant diseases which are present at start of the study will be descriptively summarized 
by treatment.
A medication/non-drug therapy will be considered concomitant to treatment, if it

is ongoing at the start of randomized trial treatment or

starts within the on-treatment period (see Section 6.1 for a definition of study 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 at any time prior to the start of randomized trial 
treatment.
Concomitant medication use (excluding rescue therapy) will be summarized with frequency 
and percentage of patients by preferred name. Summaries will be presented for 

concomitant medication starting any time prior to Day 1 (the day of start of trial 
treatment)

concomitant medication starting any time during the on-treatment period (cf. Section 6.1)


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Concomitant use of non-drug therapies (excluding rescue therapy) taken any time during the 
on-treatment period (cf. Section 6.1) will be summarized with frequency and percentage. 
Summaries will be presented for 

concomitant non-drug therapies starting any time prior to Day 1 (the day of start of trial 
treatment)

concomitant non-drug therapies starting any time during the on-treatment period (cf. 
Section 6.1).
The frequency and percentage of patients with historical medication for HS will be displayed, 
including presentation by type of historical medication (preferred name), and by reason for 
discontinuation.
Use of rescue therapy will be summarized separately (see Section 7.6.3). 
7.3
TREATMENT COMPLIANCE
Treatment compliance (see Section 5.4.4 for the definition and calculation) will be 
summarized for the SAF using descriptive statistics (N, mean, SD, minimum, median, 
maximum). The number and percentage of patients with the following overall compliance 
categories will be presented: 

"< 80% of planned", 

"80 to 120% of planned" and 

"> 120% of planned".
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
The primary analysis will implement the Hybrid strategy (EC-H) of handing intercurrent 
event defined in Section 5.4.6. Any data collected after the intercurrent event will be censored 
for the timepoint afterwards, i.e., only data prior to the ICE will be considered.
For the primary endpoint analysis, a restricted maximum likelihood (REML) based approach 
using a mixed model with repeated measurements (MMRM) is calculated to compare the 
adjusted relevant difference between the two arms. 
MMRM analysis
The % change in total abscess and inflammatory nodule count from baseline (Visit 2), at 
Visits 3, 4, 5, 6, 7, 8 and 9 (Weeks 1, 2, 4, 6, 8, 10 and 12) will be evaluated using an MMRM 
accounting for the following sources of variation: fixed, categorical effects of treatment at 
each visit, the effect of stratum (stratification according to TNFi-naive population vs. TNFi-
failure population) and the fixed continuous effects of baseline at each visit. The unstructured 
covariance structure will be used to model the within patient measurements. To estimate 
denominator degrees of freedom the Kenward-Roger approximation will be used.
In the event of model non-convergence, the methods described in Section 10.2 will be utilized 
to resolve this.


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SAS code for MMRM: 
The following SAS code will be used to calculate the MMRM. 
PROC MIXED DATA=alldat cl method=reml;
CLASS visit trt stratum subject; 
MODEL ept = stratum visit*trt base*visit / ddfm=kr s CL; 
REPEATED visit / subject= subject type=un r rcorr; 
LSMEANS visit*trt / pdiff=all om cl alpha=0.05 slice=visit; 
RUN;
Results of the MMRM (N, mean, SE and 95% CI per dose group and timepoint) will be 
presented in tables and displayed graphically. 
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint(s)
Sensitivity analysis
As one sensitivity analysis for the primary endpoint, the observed data will be augmented 
with historical data. The 1368.52 placebo group will be combined with prior historical data 
for the placebo group from Humira Pioneer I and Pioneer II trials to derive the respective 
posterior distribution of the primary endpoint. A comparable population according to 
inclusion criteria in the current trial is obtained by trimming the historical data to patients 
with baseline total AN count no less than 5 and baseline total draining fistula count no larger 
than 20. A meta-analytic predictive (MAP) prior will be derived from the trimmed data. 
Similarly, the observed data of spesolimab group will be combined with a non-informative 
prior to derive the respective posterior distribution for spesolimab treatment. These posterior 
distributions will be used to evaluate the posterior treatment difference in primary endpoint 
between spesolimab and placebo. The posterior median and 95% credible intervals will be 
reported.
Furthermore, as the historical placebo data is from TNFi-naïve population, an additional 
sensitivity analysis will only consider the combination of the historical data with the observed 
data from TNFi-naïve patients in the placebo arm of the current study to derive the respective 
posterior distribution. The observed data from TNFi-failure patients in the placebo arm of the 
current study will be combined with a non-informative prior to derive the corresponding 
posterior distribution. The information from the strata will be weighted per sample size to 
obtain an overall estimate.
The MAP prior derivations for placebo arm obtained from Humira Pioneer I and Pioneer II 
trials, as well as posterior distribution for the treatment difference will be implemented 
following Section 10.3.1.
In addition, the following sensitivity analysis for MMRM may be done: 

Sensitivity analyses utilizing MMRM model on different patients sets (such as the 
PPS) 
Supplementary analysis


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The analysis based on supplementary strategy (EC-S) of handling intercurrent event defined 
in Section 5.4.5 may be done if the interested event occurs. Any data collected after the 
intercurrent event will be censored for the timepoint afterwards.
Subgroup analysis
Subgroup analysis will use similar MMRM model as described for primary analysis of
primary endpoint. A single MMRM model will be fitted involving all terms from the primary 
analysis model except replacing the treatment-by-visit term by the treatment-by-subgroup-by-
visit term. Considering the exploratory nature of the study with small sample size, no test will 
be carried out to compare the treatment effect between spesolimab and placebo within 
subpopulation. The variables used for subgroup analysis is defined in Section 6.4. If the 
model cannot converge, the level with smallest sample size will be excluded.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified.
7.5.2
(Other) Secondary endpoint(s)
For each of the secondary endpoint described below, hybrid strategy will be used to handle 
intercurrent events which lead to data censoring as described for the primary endpoint. 
Continuous secondary endpoints
The continuous secondary endpoints up to Week 12 will be analysed using a MMRM 
approach based upon the model specification as described for the primary endpoint.
Additionally, subgroup analysis will be performed for variables as described in Section 6.4.
Binary secondary endpoints
The binary secondary endpoints will be evaluated descriptively by treatment arm via 
frequency tables (with 95% confidence interval based on the Wilson score for each group and 
based on the Chan and Zhang method for risk difference). As in the case of the primary 
estimand, any binary data collected after use of any rescue therapy will be censored and then 
imputed using the NRI method as described in CTP section 7.3 “Handling of Missing Data”.
Example SAS code for CI of proportion difference by Chan and Zhang method is as follows:
PROC FREQ DATA=data;
<WHERE treat IN (’Treatment_1’,’Treatment_2’) ;>
TABLES treat*endpoint_bin / RELRISK RISKDIFF.
EXACT RELRISK (METHOD=SCORE column=2) RISKDIFF (METHOD=SCORE
column=2);
RUN;
For selected binary endpoint, e.g., achievement of HiSCR at Week 12, following additional 
analyses are planned.
Logistic regression analysis


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The difference in the proportion of patients with a response between Spesolimab and placebo 
will be analysed using predictive margins in a binary logistic model via %Margins in SAS®. 
Fixed classification effects will include treatment and stratification factor (TNFi-naive 
population versus TNFi-failure population). 
Example SAS code:
%Margins(data= data,         
class    = treat stratum,       
response = endpoint_bin, 
roptions = event='1', 
dist     = binomial,         
model    = treat stratum,       
margins  = treat,
options  = cl diff)
Stratified risk difference
A Mantel-Haenszel type weighted average of differences will be implemented with 
corresponding Wald confidence intervals based on the variance formula provided by Sato.
Example SAS code:
Proc freq data=data;
tables stratum*treat*endpoint_bin/cmh commonriskdiff(cl=mh);
quit;
In addition, sensitivity analyses utilizing MAP Bayesian method for achievement of HiSCR at 
Week 12, will be considered. For the process, please refer to section 7.4.2 as described for the 
primary endpoint. The MAP prior derivations for placebo arm obtained from Humira Pioneer 
I and Pioneer II trials, as well as posterior distribution for the treatment difference will be 
implemented following Section 10.3.2.
Please refer to Section 7.8.1 for the analysis of safety endpoint as a secondary endpoint, 
which is defined as the occurrence of Treatment Emergent Adverse Events (TEAEs).


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7.7
EXTENT OF EXPOSURE
An overall table will be summarized for the entire maintenance treatment period. The number 
of subjects who received a dose of trial drug will be tabulated. Treatment exposure will be 
assessed as the total dose of randomized treatment [mg] administrated for the loading stage, 
the maintenance stage, as well as the overall dose across the two stages, which will be 
summarised by descriptive statistics (N, mean, SD, minimum, median, maximum). The total 
duration of exposure [days] will also be displayed.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the safety analysis set.
All safety analyses will be performed following BI standards. No hypothesis testing is 
planned. OC-IR and OR methods will be used for safety reporting. All safety analysis will be 
performed for on-treatment period.
AE and possibly clinically significant laboratory abnormalities will be analyzed under OR (as 
defined in Section 6.6.3); the safety data by visit, i.e., laboratory, vital signs and local 
tolerability, will be analysed under OC-IR (as defined in Section 6.6.3).
As the onset time of an AE will not be collected in the trial, any AE which occurs on the same 
day as a treatment dose will be assigned to the “post treatment”. For safety assessments by 
visits, if time is not collected, data on the same day of a treatment dose will be treated to be 
“prior treatment” except for scheduled local tolerability and post-dose vital signs assessments.
Off-treatment data will be listed only.
Additional analyses on AE will be also included:
AE within loading stage


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For AE, the additional safety tables for loading dose stage will be produced by grouping 
patients based on their loading doses (1200 mg, Placebo) using SAF. The outputs will include 
on-treatment data up to the first maintenance dose at or post week 4. If patients discontinued 
from treatment prior to receiving first maintenance dose, then the safety data up to the date of 
last loading dose + 112 days will be included.
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. System organ classes (if 
applicable) will be sorted according to the standard sort order specified by the EMA, preferred 
terms (if applicable) will be sorted by total frequency (within system organ class).
For details on summarization of AE data, please refer to "Handling and summarization of
adverse event data for clinical trial reports and integrated summaries" (15) and "Handling of
missing and incomplete AE dates" (4).
The analysis of AEs will be based on the concept of treatment-emergent AEs. This means that 
all AEs will be assigned to the screening period, loading treatment phase, maintenance period 
(i.e. maintenance treatment phase plus REP) or off-treatment period (i.e. follow up) as defined 
in Section 6.1. Since only the start date of an AE is collected (without start time), any AE 
occurrence on the same day as the first Spesolimab administration will be assigned to the on-
treatment phase. 
An overall summary of AEs will be presented by treatment. This overall summary will 
include summary statistics for the class of other significant AEs (sponsor definition based on 
ICH E3) and for the class of AESIs.
The following is considered an AESI in this trial:
Systemic hypersensitivity including infusion reaction and anaphylactic reaction
Severe infections (according to RCTC grading)
Opportunistic and mycobacterium tuberculosis infections
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine Aminotransferase)
≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold ULN measured in the 
same blood draw sample, or in samples drawn within 30 days of each other
OR
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.


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In addition, user defined adverse event concepts (UDAEC) identified through specific search 
criteria will be reported separately (see Table 7.8.1:1).
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events Concepts
User-defined AE category
Label 
Description
Hypersensitivity
Hypersensitivity ALL
Combined search strategy based on the three 
individual UDAECs described below
Anaphylactic reaction, 
narrow
Narrow SMQ “Anaphylactic reaction”
Angioedema, narrow
Narrow SMQ “Angioedema”
Hypersensitivity, 
narrow
Narrow SMQ “Hypersensitivity”
Infections 
(serious/severe, 
opportunistic)
Infections 'ALL'
terms from combined search with sort order # 
in (20, 30, 40, 21, 22)
Sort order if applicable to project or trial
Opportunistic 
infections
SMQ "Opportunistic infections", narrow
Tuberculosis infections
sub-BIcMQ “Tuberculosis related terms”, 
narrow
BIcMQ "Infections", sub-search 8.2 
“Tuberculosis related terms” narrow
Severe infections
SOC "Infections and infestations" with  
AETOXGR >= 3 OR AESEV = 'Severe'. Not 
derived for studies where both severity 
variables are collected.
SOC "Infections and infestations" of at least 
severe RCTC grade (>= 3) or any severe 
events
Serious infections
SOC “Infections and infestations” with 
[AECOND: AESER = 1]
SOC “Infections and infestations” with 
"intensity= serious"
Malignancies
Malignant tumours
sub-SMQ “Haematological malignant 
tumours”, narrow,
sub-SMQ “Non-Haematological malignant 
tumours”, narrow
Malignancies excluding 
NMSC
sub-SMQ 
“Malignant tumours” excluding terms from 
search with sort order #=340
Sub-SMQ 
“Malignant tumours” excluding NMSC, 
where NMSC is defined above
Torsades de 
Pointes
Torsades de Pointes
Broad sub-SMQ “Torsade de pointes/QT 
prolongation”


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Depression
Depression
sub-SMQ "Depression (excl suicide and self-
injury)", broad
Suicidal 
ideation and 
behavior (SIB)
sub-SMQ "Suicide/self-
injury"
DRESS
DRESS (Drug reaction 
with eosinophilia and 
systemic symptoms 
syndrome), broad
SMQ "Drug reaction with eosinophilia and 
systemic symptoms syndrome", broad
Algorithm:
A or (B and C and D) or (B and C and E) or 
(B and D and E)
DRESS (Drug reaction 
with eosinophilia and 
systemic symptoms 
syndrome), narrow
SMQ "Drug reaction with eosinophilia and 
systemic symptoms syndrome", narrow
Only category A
* this is achieved by retrieving all cases found either by running subsearch 1 in narrow scope (BIcMQ search ID 32019093 ) or
subsearch 2 (BIcMQ serach ID 32019094)
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 
will be summarised separately. Separate tables will also be provided for patients with SAEs, 
patients with AESIs, patients with AE leading to discontinuation of the trial medication, and 
patients with other significant AEs (as described previously). AEs will also be summarized by 
maximum intensity.
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary system organ class and preferred term. The frequency of patients with 
SAEs and drug related SAEs will also be summarised respectively.
For disclosure of AE data in the EudraCT register, the frequency of non-serious AEs with an 
incidence of greater than 5 % (in preferred terms) and the frequency of SAEs will be 
summarised.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(16). Note that data from the central Laboratory will be used for all displays described below, 
unless otherwise specified.
For continuous safety laboratory parameters, normalized values will be derived. 
Normalisation means transformation to a standard unit and to a standard reference range. The 
process of normalisation, handling of repeat values at the same visit for by-visit displays, as 
well as standard analyses for safety laboratory data are described in the BI guidance for the 
Display and Analysis of Laboratory Data (16). All analyses considering multiple times of the 
ULN (as described below) will be based on standardized and not normalized values. For 
continuous safety laboratory parameters, differences to baseline will be calculated. For all 
outputs, the last assessment before the first treatment at Day 1 is chosen as the baseline value.


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Only patients with at least one available post-baseline value will be included in the analysis of 
an individual laboratory parameter. All individual laboratory data will be listed. Values 
outside the reference range will be flagged.
For derivation of the last value, the minimum value, and the maximum value, all values 
during the entire treatment period will be considered under OR. These will be derived for 
analysis of laboratory, vital signs and local tolerability data. For identification of potentially 
clinically significant abnormal laboratory values, all values during entire treatment period will 
also be considered under OR.
Descriptive statistics of laboratory values over time and for the difference from baseline on-
treatment (see Section 6.7) will be based upon normalized values and provided by visit 
(including follow up) under OC-IR, including summaries of the last value on treatment, the 
minimum value on treatment and the maximum value on treatment. Graphical displays via 
box plots will be produced for the change from baseline, over tie, for each continuous 
laboratory endpoint.
Laboratory values will be compared to their reference ranges; shift tables will be provided for 
the number of patients with a specific RCTC grade at baseline versus the grade at the last 
measurement on treatment, as well as the worst grade on treatment. These analyses will be 
based on standardized laboratory values.
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on converted lab values, i.e. using SI units. These rules will be listed in the 
SDL appendix of the CTR. Frequency tables will summarize the number of patients with 
potentially clinically significant abnormalities. Patients having an abnormal lab value at 
baseline will be presented separately. A separate listing will present potentially clinically 
significant abnormal lab values; for each functional lab group all patient’s lab values will be 
listed, if there exists at least one lab value with clinically significant abnormality within the 
group.
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥ 10xULN, and 
≥ 20xULN will be displayed based on standardized laboratory values. To support analyses of 
liver related adverse drug effects, the frequency of patients with AST and/or ALT ≥ 3xULN 
combined with a total bilirubin ≥ 2xULN in a 30 day period after AST/ALT elevation will be 
displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a patient can potentially 
be in both alkaline phosphatase strata in case of multiple AST/ALT and bilirubin elevations). 
The start of the 30 day time span is triggered by each liver enzyme elevation above the 
defined thresholds. This analysis will be based on standardized laboratory values. 
A graphical analysis of the ALT, AST and total bilirubin during the on-treatment period will 
also be performed; the so called eDISH plot. In the graph, for each subject, the peak total 
bilirubin is presented as a fold increase over the ULN against the peak ALT as a fold increase 
over the ULN, on a log10 scale. The measurements displayed or total bilirubin and ALT may, 
or may not, occur on the same date. Two reference lines, 2xULN for total bilirubin and 
3xULN for ALT, are drawn onto the graph in order to divide the plane into four quadrants. 
Normal cases are in the lower left quadrant, potential DILI cases are in the upper right 
quadrant (Hy’s Law quadrant), while the lower right quadrant is known as the Temple’s 
corollary range (ALT ≥ 3xULN and total bilirubin < 2xULN).


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Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate, body temperature, respiratory rate) and 
body weight will be descriptive in nature. Descriptive statistics of vital signs over time and for 
the difference from baseline (see Section 6.7) will be provided, including the last value, the 
minimum value and the maximum value during on-treatment period. 
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
Abnormal findings in 12-lead ECG will be reported as baseline conditions (at screening) or as 
AEs (during the trial) if judged clinically relevant by the investigator, and will be analysed as 
such.
No separate listing or analysis of ECG data will be prepared.
7.8.5
Local tolerability
Local tolerability will be summarized by visit under OC-IR, with the frequency and 
percentage of patients who experienced any symptoms by severity/intensity.
7.8.6
Others
Not applicable.
7.9
ANALYSIS OF COVID19 IMPACT
There is currently an outbreak of respiratory disease, COVID-19 worldwide which has 
impacted the conduct of this trial. This public health emergency has raised more difficulties 
for patients to meet protocol-specified procedures, including administering or using the 
investigational product or adhering to protocol-mandated visits and laboratory/diagnostic 
testing. Site personnel or trial subjects are also under the risk to get infection with COVID-19. 
Consequently, there are unavoidable protocol deviations due to COVID-19 illness and/or 
COVID-19 public and individual health control measures. To assess the impact on patients’ 
safety and drug efficacy in this trial, the following analyses are planned:
Disposition and iPD:
Frequency of the patient with missing visits or early discontinuation due to COVID-19 will be 
listed. iPDs related to COVID-19 will be also listed if any. 
Identification of SARS-CoV-2 infections


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If patients get SARS-CoV-2 infection while on treatment with study drug, AE frequency 
analysis for subgroup of subjects with SARS-CoV-2 infection while on treatment with study 
drug will be provided, based on the narrow BIcMQ SARS-CoV-2 infections.. 
AE based on the periods of COVID-19 disruption
•
Overall summary of AEs 
•
AEs by SOC and PT
•
AEs leading to d/c by SOC and PT
•
SAEs by SOC and PT
7.10
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. A separate DMC SAP which describes the analyses required for assessment 
by the DMC will be produced. Further details are provided in a DMC charter.
7.11
OTHERS
7.11.1
Biomarkers
The following biomarkers will be analysed and reported as a part of the CTR:

HS-CRP
Results on other biomarkers (e.g. RNA expression, serum and plasma biomarkers) may or 
may not be reported in the CTR, depending e.g. on the availability of the data. In case they are 
reported outside the CTR the analysis will be defined in a separate document (otherwise the 
analysis will be described in the CTR). 
For the analysis of biomarkers, log transformed data will be used where deemed necessary.
7.11.2
Immunogenicity
The ADA status and titer as well as frequency of patients with ADA to Spesolimab will be 
presented by visit. Descriptive statistics of ADA titer (for ADA positive patients, when 
available) will be provided by visit. The number of subjects with ADA status 
positive/negative at any time will also be presented. ADA parameters (e.g. treatment-induced 
ADA positive subjects, transient ADA response and persistent ADA response) will also be 
presented by visit and cumulatively for the overall study duration. Further exploratory 
assessments of the ADA data will be performed once data is available and these will be 
described, if done, in the CTR.
Further analyses based on ADA data may be performed such as 
-
efficacy-based subgroup analysis as described in Section 7.4.2 for the 2 groups
•
ADA positive and ADA negative subjects (at Week 12), or


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•
NAb positive and NAb negative subjects (at Week 12)
-
Safety-based subgroup analysis (using e.g. hypersensitivity safety events) for the 2 
groups
•
ADA positive and ADA negative subjects (at any time), or
•
NAb positive and NAb negative subjects (at any time), or before ADA 
development (including subjects with events either before their first ADA 
positive sample or without ADA positive sample throughout) and after ADA 
development (including subjects with events from the time point of their first 
ADA positive sample onwards). This approach takes into account the time when 
ADA actually developed and when the safety event occurred in relationship to 
ADA.
7.11.3
Pharmacokinetics
No PK parameters will be calculated.
The descriptive analysis of Spesolimab plasma concentrations will be based on the SAF.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains 
columnvariables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a 
concentration and an analysis flag comment (ACEXCO). Exclusion of a concentration 
depends on the analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL 
CALC’, the value will be excluded for all types of analyses based on concentrations. If 
ACEXCO is set to ‘DESC STATS’ the value will be excluded from descriptive evaluations 
per planned time point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ 
or ‘TIME DEVIATION’ the value can be used for further analyses based on actual times. If 
ACEXCO is set to ‘HALF LIFE’ the value will be excluded from half-life calculation only; 
the value is included for all other analyses.
Further details are given in (5).
No formal analysis of pharmacokinetic/pharmacodynamic relationships is planned. The
relationship between PK and selected efficacy endpoints, biomarkers and AEs may be
assessed. Any further exploratory analyses, if done, will be described in the CTR or in a 
separate report.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
As the discussion in Section 7, if the primary analysis and the final analysis are planned to be
performed separately, then a database lock for the primary analysis will be done and treatment 
will be unblinded to trial and project team members.
Then we will follow Fast-track approach: Once the last patient has completed their End-of-
Treatment (EOT) visit and all corresponding data has been entered and cleaned to the level 
documented in the “Data Delivery Request” (DDR) form, the data will be declared ready to 
be unblinded via the “Data Ready to be Unblinded and/or Final Trial Closure Notification” 
(RUN) form. Then the treatment information will be released for analysis.
The data collection for the off-treatment residual effect period until the End-of-Study (EoS)/ 
Follow-Up visit will continue into the unblinded trial database. Once trial data collection has 
been completed and all data has been entered and cleaned as documented on the RUN form, 
a final data lock will be performed.
After the release of treatment information, it is expected that only trial data related to the off-
treatment residual effect period will be entered and changed. Therefore, after the timepoint of 
release of treatment information, all changes affecting trial data up to the End-of-Treatment 
(EoT) visit will be documented and summarized in the CTR.
If the primary analysis and final analysis are combined as a single analysis (at the time of trial 
completion), if insufficient time interval between the two planned analysis and agreement by 
the trial team not to perform two separate analyses before the time of the primary analysis. 
Then we will follow Standard approach: The treatment information will be released to 
unblind the trial database after the last patient has completed their End-of-Study/Follow-up 
visit and all data has been entered and cleaned as defined in the “Data Ready to be 
Unblinded and/or Final Trial Closure Notification” (RUN) form.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-50-415_RD-03: “Clinical Trial Analysis Decision Log (template) Decision 
Log”, current version, Group “Biostatistics & Data Sciences”, IDEA for CON.
3.
BI-KMED-COPS-TMP-0001: "Important Protocol Deviation (iPD) log", current 
version; IDEA for CON
4.
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies”, current version; IDEA for CON
6.
001-MCS-40-106_RD-03: “Clinical Trial Protocol general template for Phase I-IV”, 
current version, Group “Clinical Operations”, IDEA for CON.
7.
001-MCS-80-606: “Management of Non-Compliances”, current version, Group 
“Quality Medicine”, IDEA for CON.
8.
001-MCS-40-413: Identify and Manage Important Protocol Deviations (iPD)”, current 
version, Group “Clinical Operations”, IDEA for CON.
9.
001-MCS-40-135_RD-01: “Integrated Quality and Risk Management Plan”, current 
version, Group “Clinical Operations”, IDEA for CON.
10. BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; IDEA for CON.
11. 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, EMA webpage.
12. 001-MCS-40-413_RD-00: "List of References to SOP Identify and Mange Important 
Protocol Deviations (iPD)", current version; IDEA for CON
13. Rubin, D. B. (1976), “Inference and Missing data” (with discussion),
Biometrika, 63, 581–592.[109]
14. Anne Lott & Jerome P. Reiter (2020) Wilson Confidence Intervals for Binomial
Proportions With Multiple Imputation for Missing Data, The American Statistician, 
74:2, 109-115,
DOI: 10.1080/00031305.2018.1473796
15. 001-MCG-156: "Handling and summarisation of adverse event data for clinical
trial reports and integrated summaries", current version; IDEA for CON


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16. BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data",
current version; IDEA for CON
17. Kirby et al. The Hidradenitis Suppurativa Quality of Life (HiSQoL) score: development 
and validation of a measure for clinical trials. British Journal of Dermatology (2020) 
183, pp340–348
18. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – a simple practical 
measure for routine clinical use. Joint Ann Mtg of the British Association of 
Dermatologists and the Canadian Dermatology Association, Oxford, 6 - 10 Jul 1993. 
Clin Exp Dermatol 1994; 19; 210-216.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
28-DEC-21
None
This is the final TSAP.