Conditions: Hidradenitis Suppurativa
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 45
Healthy volunteers: no

Brief summary:
This study is open to adults with hidradenitis suppurativa who took part in a previous clinical study of a medicine called spesolimab. Participants who completed treatment can join this study.

The purpose of this study is to find out how safe spesolimab is and whether it helps people with hidradenitis suppurativa in the long-term. Participants are in this study for about 2 years and 4 months. For 2 years, participants visit the study site every 2 weeks to get spesolimab injections under the skin. At study visits, doctors check the severity of participants' hidradenitis suppurativa and collect information on any health problems of the participants.

Detailed description:

Arms:
arm 1: Participants in the placebo arm of the 1368-0052 Proof of Concept Clinical (PoCC) trial received an initial 1200 mg intravenous (i.v.) loading dose of spesolimab plus subcutaneous (s.c.) placebo at Visit 1, followed by 600 mg s.c. doses of spesolimab every two weeks for the next 12 weeks. Further dosing was based on changes in HS-PGA grade assessment from baseline to week 12. arm 2: Participants in the active arm of the 1368-0052 Proof of Concept Clinical (PoCC) trial received an initial 600 mg subcutaneous (s.c.) loading dose of spesolimab plus intravenous (i.v.) placebo at Visit 1, followed by 600 mg s.c. doses of spesolimab every two weeks for the next 12 weeks. Further dosing was based on changes in HS-PGA grade assessment from baseline to week 12.

Interventions: intervention 1: Spesolimab 1200 mg intervention 2: Spesolimab 600 mg intervention 3: Placebo matching 600 mg Spesolimab intervention 4: Placebo matching 1200 mg Spesolimab
Intervention descriptions: intervention 1: Participants in the 1368-0052 PoCC trial's placebo arm received a 1200 mg intravenous (i.v.) loading dose at Visit 1, then 600 mg s.c. every two weeks for 12 weeks. intervention 2: Participants in the 1368-0052 PoCC trial's active arm received a 600 mg subcutaneous (s.c.) loading dose of spesolimab at Visit 1, followed by 600 mg s.c. every two weeks for 12 weeks. intervention 3: Participants from the placebo arm of the 1368-0052 PoCC trial will receive a subcutaneous (s.c.) administration of placebo matching 600 mg spesolimab at Visit 1. intervention 4: Participants from the active arm of the 1368-0052 PoCC trial will receive an intravenous (i.v.) infusion of placebo matching 1200 mg spesolimab at Visit 1

Protocol document:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019
Clinical Trial Protocol
TITLE PAGE
Document Number:
c33707086-02
EudraCT No.
EU Trial No.
2020-005587-55
BI Trial No.
1368-0067
BI Investigational
Medicinal Product(s)
Spesolimab, BI 655130
Title
An open-label, long-term extension trial of spesolimab treatment 
in adult patients with Hidradenitis Suppurativa (HS)
Lay Title
A study investigating long-term treatment with spesolimab in 
people with a skin disease called hidradenitis suppurativa who 
completed a previous clinical trial.
Clinical Phase
II
Clinical Trial Leader
Tel: 
Coordinating 
Investigator
Email:
Version and Date
Version:
Final Version 2.0
Date:
04 Jul 2022
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Proprietary confidential information.
2022 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
16 Dec 2020
Revision date
04 Jul 2022
BI trial number
1368-0067
Title of trial
An open-label, long-term extension trial of spesolimab treatment in adult 
patients with Hidradenitis Suppurativa (HS)
Coordinating 
Investigator
Trial site(s)
Multi-centre trial conducted in multiple countries
Clinical phase
II
Trial rationale
The main rationale of this extension trial is to collect additional long-term 
safety and efficacy data of spesolimab in HS patients.
Trial objective(s)
The primary objective of this trial is to assess the long-term safety of 
spesolimab in patients with HS who have completed the 1368-0052 PoCC 
trial and are qualified for entry into this trial. The secondary objectives are 
to evaluate efficacy at a lower dose than tested in PoCC trial.
Trial endpoints
The primary endpoint is the occurrence of treatment emergent adverse 
events (TEAEs) up to the end of the maintenance treatment period 
including REP (i.e., 16 weeks after the last study treatment).
Secondary Endpoints:
•
Percentage change in total abscess and inflammatory nodule (AN) 
count from baseline up to Week 
•
Percentage change in total draining fistula (DF) count from baseline up 
to Week 
•
Hidradenitis Suppurativa Clinical Response (HiSCR) up to Week 
•
Change from baseline in International Hidradenitis Suppurativa 
Severity Score System (IHS4) value up to Week 
•
Hidradenitis Suppurativa Physician Global Assessment (HS-PGA) 
score of 0 or 1 up to Week 
•
Absolute change from baseline in Hidradenitis Suppurativa Area and 
Severity Index (HASI) score up to Week 
•
Occurrence of at least one flare (defined as at least 
 in 
AN count with a minimum increase of 2 relative to baseline) up to 
Week 
•
Achievement of at 
 from baseline in Numerical 
Rating Scale (NRS30) in Patient’s Global Assessment of HS Pain up to 
Week 
Trial design
Open label, single-arm, multi-regimen, 2-year extension study in adult 
patients with HS who have completed their treatment in the 1368-0052 
PoCC trial.


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Total number of 
patients
randomised
Approximately 45 patients will enter this trial
Number of 
patients per group
Number of patients per group will depend on the number of patients 
completing the parent (1368-0052) trial in each arm. Patients from the 
placebo arm of the 1368-0052 trial will be given an initial 
 
dose of spesolimab, followed by 
 every 
 
weeks. Patients from the active arm of the 1368-0052 trial will be given a 
loading dose of placebo followed by
 spesolimab
 every 
 
weeks.
Diagnosis
Adult patients with HS who have completed their treatment in the 1368-
0052 trial.
Main in- and 
exclusion criteria
Main inclusion criteria (for a complete list see Section 3.3.2):

Patients who have completed treatment in the parent HS spesolimab 
trial (1368-0052) without premature discontinuation.
Main exclusion criteria (for a complete list see Section 3.3.3)
•
Patients who experienced study treatment-limiting adverse events 
during the 1368-0052 parent trial.
•
Use of any restricted medication or any drug considered by the 
investigator likely to interfere with the safe conduct of the study since 
the last visit of the 1368-0052 parent trial.
•
Any condition which in the opinion of the investigator affects the 
safety of the patient, the patient’s ability to participate in this trial or 
could compromise the quality of data.
Test product(s)
Spesolimab
dose
At Visit 1 patients from the placebo group in the parent 1368-0052 trial are 
given 
 of spesolimab plus 
 placebo 
followed by 
 spesolimab every  weeks. At Visit 1 patients 
from the active group in the parent 1368-0052 trial are given 
infusion of placebo plus 
. spesolimab followed by 
spesolimab every  weeks. Administration of study medication at Visit 1 is 
blinded. Refer to Section 4.1.2 for details. At Week 12, all patients will be 
assessed for total number of ANs and DF and HS PGA. Based on the 
individual responder status at baseline, decisions on further dosing will be 
taken as depicted in Table 3.1: 1.
mode of 
administration
at Visit 1 only, and s.c. at all visits
Duration of 
treatment
 weeks
Statistical methods Given the single arm and open-label nature of this trial, no hypothesis 
testing will be performed in the confirmatory sense. All statistical 
assessments will be performed in an explorative manner to better 
understand the efficacy and safety profile of spesolimab.


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FLOW CHART – UP TO W12
Trial Periods
Visit
1*
2
3
4
5
6
7
Week (W)
W0
W
W
W
W
W
Day
Time Window for Visits
n/a
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
±2 
days
Informed consent
X
Demographics
X
Medical history
X
Columbia-Suicide Severity Rating Scale (C-SSRS)
X
X
X
X
X
X
X
Physical examination1
-Complete (C) or Targeted (T)
C
T
T
T
T
T
T
Height
X
Weight
X
X
X
X
Vital Signs2
X2a
X2b
X2b
X
X
X
X
Safety Laboratory tests (blood and urine)3
X
X
X
X
Infection Testing4
X
12 lead-ECG (local)
X
X
X
X
Pregnancy testing5
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
Review of in-/exclusion criteria
X
Local tolerability assessment6
X
X
X
X
X
X
X
All AEs/SAEs/AESIs
X
X
X
X
X
X
X
Pain NRS
X
X
X
X
DLQI, PGI-S, PGI-C, HiSQOL7
X
X
X
X
FACIT Fatigue Scale7
X
X
X
X
HiSCR, HS-PGA, IHS4, HASI8
X
X
X
X
X
X
X
Abscess count. Inflammatory nodule count. Non-
inflammatory nodule count. Draining Fistula count.
X
X
X
X
X
X
X
Photography
X
X
X
X
hs-CRP
X
X
X
X
ADA/Nab9
X
X
X
X
X
PK Sampling9
X
X
X
X
X
Blood sample (Serum soluble protein biomarkers)
X
X
X
X
Blood sample for RNA sequencing
X
X
X
X
IRT contact
X
X
X
X
X
X
X
Administer study drug
X
X
X
X
X
X
X
*V1 of this extension trial should preferably be performed during the EoT visit of the parent 
PoCC trial (1368-0052). When the visits are performed on the same day duplicate procedures 
across studies are performed once during the EoT/V1. If these visits are not performed on the 
same day, then either all V1 procedures need to be performed at that visit or a modification of 
procedures will be considered after discussion with the sponsor (e.g., if V1 is within 2 days of 
the EoT visit of the PoCC trial, then certain visit procedures need not be repeated; however, if 
the gap is between 3-14 days, then align with the sponsor accordingly). If a patient is unable 
to roll over on the day of the EoT Visit of the 1368-0052 PoCC trial because of medical 
reasons, then they can be permitted to rollover within 2 weeks of the EoT Visit of the PoCC 
trial. During this gap, if required, patients can take systemic and topical antibiotics for disease 
worsening as per investigator discretion (see Section 4.2). However, biologics, 


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immunomodulators and opioid analgesics are not allowed for HS and non-HS indications.
Any further extensions beyond 2 weeks must be discussed with the sponsor.
** At Week 
 of this extension trial, all patients will be assessed for the change of HS-PGA 
grade. The change in HS-PGA grade will be compared with the assessment at baseline of this 
extension trial / Week 
 of the 1368-0052 PoCC trial. Based on the individual responder 
status, decisions on further dosing will be taken as depicted in Table 3.1:1.
1. Complete physical examination includes general appearance as well as evaluation of all 
organ systems; Targeted physical examination includes evaluation of organ systems 
associated with AE(s) symptoms or laboratory abnormalities
2. Vital signs will be assessed pre dose as well as approximately 10 minutes post dose. 
Measurement of pre-dose vitals should precede blood sampling. Vital signs include 
systolic and diastolic blood pressure, pulse rate, respiratory rate and temperature. Refer to 
Section 5.2.2 for further information.
a.
For the trial drug administrations at Visit 1, vitals should be captured 
approximately 5 minutes and 60 minutes post dose for i.v. administration and 
approximately10 minutes post-dose for s.c. administrations.
b. At Visit 2 and Visit 3 additional measurements will be performed approximately 
60 minutes after s.c. study drug administration.
3. Safety laboratory tests include clinical chemistry, haematology, coagulation, and 
urinalysis and will be performed by the Central Lab.
4. Infection testing includes tuberculosis, hepatitis B, hepatitis C, and HIV assessments.
Also refer to Table 5.2.3: 1 and Section 6.2.1.2 for further instructions.
5. Women of childbearing potential only. Pregnancy testing should be done prior to 
administration of study drug. Study drug should only be administered in case of a 
negative test result. In case of a positive urine pregnancy test, a serum pregnancy test will 
be done.
6. The investigator will assess local tolerability at the administration site of spesolimab 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”, 
“pain”, and any other findings should be reported as an adverse event.
7. Patient questionnaires should be completed before any other procedures on that day, 
before the physician assessments, and before study drug administration.
8. Physician assessments should be done after patient questionnaires are completed and 
before study drug administration. HiSCR is calculated automatically by comparing the 
lesion count from baseline. Further details are described in Section 5.1.1.
9. Pre-dose PK/ADA/Nab samples will be obtained approximately within one hour prior to 
start of study drug administration.


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FLOW CHART – W14 TO END OF STUDY
Trial Periods
Maintenance 
Treatment Period
(visits every 2 
weeks)
End of 
Treatment**
Follow-up 1
(2 weeks after 
last dose)
End of Study
(16 weeks 
after last 
dose)
Visit
8 to 52
EoT
FUP1
EoS15
Day
Week (W)
Time window for visits
±3 days
±3 days
±3 days
+10 days
IRT contact
X
X
Concomitant therapy
X
X
X
X
Columbia-Suicide Severity Rating 
Scale (C-SSRS)
X
X
X
X
Physical examination10
Targeted
Targeted
Complete
Targeted
Vital signs11
X
X
X
X
Weight
Every second visit
X
X
X
Safety Laboratory tests (blood and 
urine)12
Every second visit
X
X
X
Pregnancy testing13
X
X
X
X
Infection testing14
X14
X14
Local tolerability assessment
X
X
All AEs/SAEs/AESIs15
X
X
X
X15
Pain NRS
Every second visit
X
X
DLQI, PGI-S, PGI-C, HiSQOL16
Every second visit
X
X
FACIT Fatigue Scale16
Every second visit
X
X
HiSCR, HS-PGA, IHS4, HASI17
X17
X
X
Abscess count. Inflammatory nodule 
count. Non-inflammatory nodule 
count. Draining Fistula count.17
X17
X
X
Photography18
X18
X
X
ADA/Nab19
X19
X
X22
X
PK Sampling19
X19
X
X22
X
hs-CRP20
X20
X
12 lead-ECG (local)21
X21
X
X
X
Administer study drug (every 2 weeks)
X
X
**Patients who discontinue trial treatment prematurely should undergo the EoT visit as soon 
as possible, the Follow-up (FUP 1) visit two weeks after last dose, and the EoS visit 16 weeks 
after the last dose. If a patient discontinues the study during a scheduled treatment visit then 
the visit is considered an EoT visit.
***Week 
 Patients identified as a Non-responder AND up-titrated to 
 at Week 
 
must undergo a re-assessment of their HS-PGA. If there is no change or no improvement in 
their HS-PGA grade at Week 
 compared to Week 
 then the patient MUST be 
discontinued from the trial (Table 3.1: 1). The HS-PGA page and Abscess and Inflammatory 
Nodule count page are added as “unscheduled visits” at Week 
 to document the re-
assessment. This assessment is recommended to be performed at the start of the visit. If the 
patient is discontinued at the Week 
 visit, then this visit can be considered the EoT visit.
Every second visit = every other visit starting from W14.


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10. Complete physical examination includes general appearance as well as evaluation of all 
organ systems; Targeted physical examination includes evaluation of organ systems 
associated with AE(s) symptoms or laboratory abnormalities.
11. Vital signs will be assessed pre dose as well as 10 minutes post dose. Measurement of 
pre-dose vitals should precede blood sampling. Vital signs include systolic and diastolic 
blood pressure, pulse rate, respiratory rate and temperature.
12. Safety laboratory tests include clinical chemistry, haematology, coagulation, and 
urinalysis and will be performed by the Central Lab.
13. Women of childbearing potential only. Pregnancy testing should be done prior to 
administration of study drug. Study drug should only be administered in case of a 
negative test result. In case of a positive urine pregnancy test, a serum pregnancy test will 
be done.
14. Testing at EoT includes tuberculosis and hepatitis B. Also refer to Table 5.2.3: 1 for 
information on QuantiFERON testing at Weeks 
and 
Please also see Section 
6.2.1.2 for further information.
15. After the EoS visit (=individual patient’s end of the trial) the investigator should report 
only any cancers of new histology and exacerbations of existing cancer, trial treatment 
related SAEs and trial treatment related AESIs of which the investigator may become 
aware of and only via the BI SAE form, please see Section 5.2.6.2.1.
16. Patient questionnaires should be completed before any other procedures on that day, 
before the physician assessments, and before study drug administration.
17. Physician assessments should be done after patient questionnaires are completed and 
before study drug administration. Starting from Week 14, physician assessments, abscess 
counts, inflammatory nodule counts, non-inflammatory nodule counts, and draining 
fistula counts are completed every 4 weeks for the next six months, i.e., Weeks 14, 18, 
22, 26, 30, 34, 38, and then every 12 weeks thereafter, i.e., Weeks 50, 62 74, 86, 98.
HiSCR is calculated automatically by comparing the lesion count from baseline. Further 
details are described in Section 5.1.1.
18. Photography should be completed every 
 weeks starting from Week 
19. PK and ADA/Nab samples are collected at Weeks 
, EoT, 
and EoS. Pre-dose PK/ADA/Nab samples will be obtained approximately within 1 hour 
prior to start of study drug administration.
20. hs-CRP measurements should be completed every 
 weeks starting from Week 
21. ECG is required every 12 weeks starting from Week 
22. PK and ADA/Nab samples will only be collected if the patient missed the EoT visit
collection.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART – UP TO W12...............................................................................................4
FLOW CHART – W14 TO END OF STUDY ......................................................................6
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
DRUG PROFILE................................................................................................15
1.2.1
Mode of action.....................................................................................................15
1.2.2
Studies in Patients...............................................................................................17
1.2.3
Residual Effect Period ........................................................................................17
1.2.4
Summary..............................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................18
1.4
BENEFIT - RISK ASSESSMENT.....................................................................18
1.4.1
Benefits.................................................................................................................18
1.4.2
Risks .....................................................................................................................19
1.4.2.1
Reactions to Injections/Infusions..........................................................................24
1.4.2.2
Women of Child Bearing Potential.......................................................................24
1.4.2.3
COVID-19.............................................................................................................24
1.4.3
Discussion.............................................................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........26
2.1.1
Main objectives....................................................................................................26
2.1.2
Primary endpoint(s)............................................................................................26
2.1.3
Secondary endpoint(s) ........................................................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................28
3.1
OVERALL TRIAL DESIGN.............................................................................28
3.1.1
Trial Design Diagram .........................................................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................30
3.3
SELECTION OF TRIAL POPULATION .......................................................31
3.3.1
Main diagnosis for trial entry ............................................................................31
3.3.2
Inclusion criteria .................................................................................................31
3.3.3
Exclusion criteria ................................................................................................31
3.3.4
Withdrawal of patients from treatment or assessments..................................32
3.3.4.1
Discontinuation of trial treatment .........................................................................32


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3.3.4.2
Withdrawal of consent to trial participation .........................................................33
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................34
4.
TREATMENTS...................................................................................................35
4.1
INVESTIGATIONAL TREATMENTS ...........................................................35
4.1.1
Identity of the Investigational Medicinal Products..........................................35
4.1.2
Selection of doses in the trial and dose modifications......................................36
4.1.3
Method of assigning patients to treatment groups...........................................37
4.1.4
Drug assignment and administration of doses for each patient......................37
4.1.5
Blinding and procedures for unblinding...........................................................38
4.1.5.1
Blinding.................................................................................................................38
4.1.5.2
Unblinding and breaking the code ........................................................................39
4.1.6
Packaging, labelling, and re-supply...................................................................39
4.1.7
Storage conditions...............................................................................................39
4.1.8
Drug accountability.............................................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................40
4.2.1
Other treatments and emergency procedures..................................................40
4.2.1.1
Systemic hypersensitivity including infusion reaction and anaphylactic reaction40
4.2.1.2
Malignancies.........................................................................................................41
4.2.1.3
Suicidality .............................................................................................................41
4.2.1.4
Peripheral Neuropathy ..........................................................................................41
4.2.2
Restrictions ..........................................................................................................41
4.2.2.1
Restrictions Regarding Concomitant Treatment...................................................41
4.2.2.2
Rescue Treatment..................................................................................................43
4.2.2.3
Antibiotic Use During the Trial ............................................................................44
4.2.2.4
Analgesics Use During the Trial...........................................................................44
4.2.2.5
Lesion Intervention ...............................................................................................44
4.2.2.6
Restrictions on Diet and Life Style.......................................................................44
4.2.2.7
Contraception Requirements.................................................................................44
4.3
TREATMENT COMPLIANCE........................................................................45
5.
ASSESSMENTS..................................................................................................46
5.1
ASSESSMENT OF EFFICACY........................................................................46
5.1.1
Hidradenitis Suppurativa Clinical Response - HiSCR....................................46
5.1.2
International Hidradenitis Suppurativa Severity Score System - IHS4........46
5.1.3
Hidradenitis Suppurativa Physician Global Assessment - HS-PGA..............46
5.1.4
Hidradenitis Suppurativa Area and Severity Index - HASI...........................46
5.1.5
Pain Numerical Rating Scale – Pain NRS.........................................................47
5.1.6
Dermatology Life Quality Index........................................................................47
5.1.7
Hidradenitis Suppurativa Quality of Life – HiS-QoL.....................................47
5.1.8
FACIT-Fatigue Scale..........................................................................................48
5.1.9
Patient Global Impression of Change - PGI-C.................................................48
5.1.10
Patient Global Impression of Severity - PGI-S ................................................48
5.2
ASSESSMENT OF SAFETY.............................................................................48
5.2.1
Physical examination ..........................................................................................48
5.2.2
Vital signs.............................................................................................................48


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5.2.3
Safety laboratory parameters ............................................................................49
5.2.4
Electrocardiogram ..............................................................................................52
5.2.5
Other safety parameters.....................................................................................53
5.2.5.1
Malignancies.........................................................................................................53
5.2.5.2
Columbia-Suicide Severity Rating Scale (C-SSRS).............................................53
5.2.5.3
Local Tolerability..................................................................................................54
5.2.6
Assessment of adverse events.............................................................................54
5.2.6.1
Definitions of AEs ................................................................................................54
5.2.6.2
Adverse event collection and reporting ................................................................58
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................60
5.3.1
Assessment of pharmacokinetics .......................................................................60
5.3.2
Methods of sample collection .............................................................................60
5.3.2.1
Plasma sampling for PK analysis..........................................................................60
5.3.2.2
Sampling for ADA/Nab assessment .....................................................................60
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................61
5.4.1
Biochemical and cellular biomarkers................................................................61
5.4.2
Pharmacogenomics biomarkers.........................................................................61
5.4.3
Methods of sample collection .............................................................................61
5.5
BIOBANKING ....................................................................................................61
5.6
OTHER ASSESSMENTS...................................................................................62
5.6.1
Photographs.........................................................................................................62
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................62
6.
INVESTIGATIONAL PLAN.............................................................................63
6.1
VISIT SCHEDULE.............................................................................................63
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................63
6.2.1
Visit 1 – Start of Treatment ...............................................................................64
6.2.1.1
Informed Consent..................................................................................................64
6.2.1.2
Infection Testing ...................................................................................................65
6.2.2
Treatment period(s)............................................................................................65
6.2.3
Follow-up period and trial completion..............................................................65
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................67
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................67
7.2
PLANNED ANALYSES.....................................................................................67
7.2.1
General considerations .......................................................................................67
7.2.2
Primary endpoint analyses.................................................................................67
7.2.3
Secondary endpoint analyses .............................................................................68
7.2.5
Safety analyses.....................................................................................................68
7.2.6
Other Analyses ....................................................................................................69
7.2.7
Interim Analyses .................................................................................................70
7.3
HANDLING OF MISSING DATA ...................................................................70


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7.4
RANDOMISATION ...........................................................................................70
7.5
DETERMINATION OF SAMPLE SIZE .........................................................71
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........72
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................72
8.2
DATA QUALITY ASSURANCE ......................................................................73
8.3
RECORDS...........................................................................................................73
8.3.1
Source documents ...............................................................................................73
8.3.2
Direct access to source data and documents.....................................................74
8.3.3
Storage period of records ...................................................................................74
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................74
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........75
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................75
8.6
TRIAL MILESTONES.......................................................................................75
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................76
9.
REFERENCES....................................................................................................78
9.1
PUBLISHED REFERENCES............................................................................78
9.2
UNPUBLISHED REFERENCES......................................................................80
10.
APPENDICES.....................................................................................................81
10.1
DIAGNOSIS OF ANAPHYLAXIS ...................................................................81
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................82
11.1
GLOBAL AMENDMENT 1 ..............................................................................82


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ABBREVIATIONS
ADCC
Antibody-dependent Cellular Cytotoxicity
ADA
Anti-drug antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AN count
Abscess and Inflammatory Nodule
AST
Aspartate Aminotransferase
AUC0-tz 
Area Under the Concentration-time Curve
BI
Boehringer Ingelheim
CA
Competent Authority
CDC
Complement-dependent Cytotoxicity
Cmax
Maximum Plasma Concentration
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
C-SSRS
Columbia-Suicide Severity Rating Scale
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DCs
Dendritic Cells
DF
Draining Fistula
DILI
Drug Induced Liver Injury
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoT
End of Treatment
EoS
End of Study


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FACIT
Functional Assessment of Chronic Illness Therapy
FDA
U.S. Food & Drug Administration
GPP
Generalized Pustular Psoriasis
HASI
Hidradenitis Suppurativa Area and Severity Index
HBV
Hepatitis B virus
HiSCR
Hidradenitis Suppurativa Clinical Response
HiS-QoL
Hidradenitis Suppurativa Quality of Life
HIV
Human Immunodeficiency Virus
HS-PGA
Hidradenitis Suppurativa Physician Global Assessment
HS
Hidradenitis suppurativa
I&D
Incision and Drainage
i.v.
intravenous
IB
Investigator Brochure
ICH-GCP
ICH Harmonized Guideline for Good Clinical Practice
IEC
Independent Ethics Committee
IGRA
Interferon Gamma Release Assay
IHS4
International Hidradenitis Suppurativa Severity Score System
IL36
Interleukin 36
IL36R
Interleukin 36 Receptor
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
k.g.
Kilogram
LPLT
Last Patient Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
m.g.
Milligram
MoA
Mode-of-action
MMRM
Mixed Effect Model for Repeated Measurements
MRD
Multiple Rising Dose
Nab
Neutralizing Antibody
NRI
Non Response Imputation
NRS
Numerical Rating Scale


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OLE 
Open label extension
OPU
Operative Unit
PD
Pharmacodynamic
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PK
Pharmacokinetics
PoC
Proof of concept
PoCC
Proof-of-clinical-concept
PPD
Purified Protein Derivative
PPP
Palmoplantar Pustulosis
PROs
Patient Recorded Outcomes
q.w.
Every Week
RA
Regulatory Authorities
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
s.c.
subcutaneous
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SoC
Standard of Care
SOP
Standard Operating Procedure
SRD
Single Rising Dose
TB
Tuberculosis
TEAE
Treatment-Emergent Adverse Events
TSAP
Trial Statistical Analysis Plan
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 study 
methodology; however, the disease appears to be more common than was previously 
considered [R20-3176].
Treatment often begins with topical or oral antibiotics. 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 (s.c.) dosing.
When the medical management is ineffective, surgery is the 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.
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 primary human 
intestinal myofibroblasts and IFNγ secretion in human Peripheral Blood Mononuclear Cells 
PBMC stimulated with IL36α, IL36β, or IL36γ combined with IL12.


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Mutations of two key residues (L234 and L235) to alanine were made to 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 IL36R 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 IL36R inhibition 
were performed in mice using a mouse specific anti-IL36R monoclonal antibody (Boehringer 
Ingelheim (BI) 674304), which is a mouse IgG2a monoclonal antibody with rat variable 
regions. In a 13-week intravenous (i.v.) toxicity study of BI 674304 in mice, no adverse 
effects of IL36R 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 i.v. injection via the 
caudal vein. There were no BI 674304-related changes in clinical observations, body weights, 
food consumption, ophthalmology, clinical pathology parameters (haematology, clinical 
chemistry), organ weights, macroscopic or microscopic examinations. The no-observed-
adverse-effect level 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, 1mL 
injections of the s.c. formulation in rabbits. These preclinical toxicology data support chronic 
spesolimab dosing in humans.
Spesolimab or placebo was administered to 78 healthy volunteers at single ascending i.v. 
doses from 0.001 mg/kg to 10 mg/kg body weight. Safety and tolerability of all tested i.v. 
doses was good. There were no drug-related serious adverse events (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%; placebo: 15%), headache (spesolimab: 9%; placebo: 
15%), influenza like illness (spesolimab: 7%; placebo: 10%), and diarrhoea (spesolimab: 3%; 
placebo: 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 electrocardiogram (ECGs), vital signs, and cardio-
monitoring. Pharmacokinetics (PK) analysis showed that exposure (AUC0-tz and Cmax) to 
spesolimab increased with increasing dose in an approximately dose-proportional manner 
from 0.3 to 10 mg/kg.


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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 kinetics for spesolimab. 
Anti-drug antibodies (ADA) were detected in 8 patients, 3 of those had pre-existing levels. 
Pharmacodynamic (PD) effects in this First in Human Single Rising Dose (SRD) trial 
[c03361085] were assessed by indirect target engagement 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 (MRD) 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 20 mg/kg (8 subjects each, 3:1 on active or
placebo). 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) [c03320877-10].
1.2.2
Studies in Patients
Safety and efficacy data are available from a proof of concept (PoC) study in patients with 
GPP. In trial 1368-0011, seven patients received a single i.v. dose of 10 mg/kg spesolimab
and were monitored for 20 weeks. At week 1 after dosing, GPP Physician Global Assessment
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 
GPP Area and Severity Index 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%).
Further trials are ongoing in patients with GPP, PPP, AD, UC, or CD. An independent Data 
Monitoring Committee (DMC) is involved in the monitoring of these trials. As of September 
2020, an estimated 604 subjects have been exposed to spesolimab, out of a total of 693 
subjects in the clinical development programme. No safety signal of concern has been 
identified in any of the ongoing trials.
1.2.3
Residual Effect Period
The Residual Effect Period (REP) of spesolimab is 16 weeks. This is the period after the last 
dose with measurable drug levels and/or PD effects still likely to be present.
1.2.4
Summary
Spesolimab is an anti IL36R antibody with a high clinical activity to block IL36R signaling, 
as demonstrated in patients with GPP, 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 


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addition, IL36R inhibition shows a favourable nonclinical safety profile. Therefore, 
spesolimab might be a promising drug to treat patients suffering from HS.
For a more detailed description of the spesolimab profile, please refer to the current IB
[c03320877-10].
1.3
RATIONALE FOR PERFORMING THE TRIAL
Adalimumab 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 s.c. dosing. 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 IL36R antagonist currently in development for the treatment of GPP. HS 
and GPP may have similarity considering the presence of pustules, neutrophil infiltration, and 
psoriasiform hyperplasia. IL36 alpha, beta and gamma mRNA expression are upregulated in 
lesional skin in HS patients with a decrease in IL36RN expression [R20-3047]. Internal in 
situ hybridization staining of HS lesions also confirms the increased expression of ligands. 
IL36 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 dendritic cells (DCs) and monocytes can be activated by 
IL36 (internal data and published) to potentiate the antigen presenting cell function of DCs 
and also lead to secretion of chemokines and cytokines that can recruit more immune cells 
including neutrophils. IL36 is a potent activator of neutrophil infiltration and in the context of 
HS, neutrophils are shown to undergo NETosis leading to secretion of auxiliary medicinal 
products and type I Interferons [R20-3155]. Based on the role of IL36 driving TH17 and TH1 
responses in GPP (published and our internal data) the hypothesis is that IL36 is also a key 
driver of TH17 responses in skin of HS patients. To that end, we are conducting the 1368-
0052 proof-of-clinical concept (PoCC) study in moderate to severe HS patients.
The main rationale of this extension trial is to collect additional long-term safety and efficacy 
data of spesolimab in eligible HS patients from the 1368-0052 PoCC trial. Additional 
appreciable benefit for the patients of this extension study is the possibility to receive 
spesolimab as s.c. maintenance treatment with the aim to maintain their positive clinical 
response reached in the preceding PoCC trial, if they are eligible to receive further 
spesolimab treatment in this extension study.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Preclinical profiles of spesolimab and clinical data from healthy volunteers and patient trials 
suggest that spesolimab is safe, tolerable and may address an unmet medical need in patients 
with HS by an anti-inflammatory mechanism of action. Efficacy in HS has not been 
established. The data from the completed 1368-0011 PoC trial, in patients with an acute flare 
of GPP, demonstrate that spesolimab treatment rapidly stops the flare and clears pustules, the 


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primary lesions in GPP, a disease closely linked to loss-of function mutations in the natural 
IL36R antagonist. (see: spesolimab IB, document number c03320877-10) 
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 IL36R inhibition in mice (spesolimab IB, 
document number c03320877-10, Section 5.1.2). A recent publication has assessed the 
clinical phenotype and immune function in 12 healthy individuals harbouring an IL36R 
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 IL36 blockade is likely to 
represent a safe and well tolerated therapeutic concept.
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 20 mg/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 c03320877-10). Moreover, several 
clinical studies are ongoing as of May 2020, exploring efficacy and safety of spesolimab in 
different indications such as: Atopic Dermatitis, Ulcerative Colitis, Crohn’s Disease, GPP, 
and PPP. 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 no signal of a safety issue and 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.
Eligible patients completing the 1368-0052 PoCC trial will be offered to rollover into this 
trial to receive open-label active spesolimab maintenance treatment for up to 2 years. Patients 
will be re-assessed at week 12 to evaluate response and further dose modifications will be 
done accordingly. 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 (i.e., unbearable adverse events (AEs)) will be discontinued and switched to 
available standard of care (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
There are no identified or potential risks for spesolimab, based on the toxicology programme 
or any clinical trials conducted for this product to date. No other IL36 receptor antagonist is 
currently approved, providing information on identified risks in molecules of this class. The 


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risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs.
In order to protect the patient’s safety during conduct of this trial, an independent DMC has 
been established for the periodic review of clinical trial safety data. Refer to Section 8.7 for 
details.
Table 1.4.2:1 Overview over trial related risks 
Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product - spesolimab
Drug induced liver injury
(DILI)
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators.
Timely detection,
evaluation, and follow-up of 
laboratory alterations in 
selected liver laboratory 
parameters to ensure 
patients´ safety. Refer to 
Section 5.2.6.1.4.
Systemic Hypersensitivity
After administration of any 
biologic agent or protein, 
there is a possibility of 
occurrence of adverse 
immune reactions which can 
be local (e.g. redness, 
pruritus, and or swelling at 
the injection site) or 
systemic (e.g. anaphylactic 
reactions).
Patients with a history of 
allergy/hypersensitivity to 
the systemically 
administered trial 
medication agent or its 
excipients are excluded 
from the trial.
In case of systemic
hypersensitivity reactions
including anaphylactic
reaction emerging during or 
after administration of trial 
medication, the investigator 
should consider in 
accordance with the severity 
of the reaction and local 
SoC 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 and investigators 
are requested to assess these
conditions using the criteria 
discussed in the statement 


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Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
paper from Sampson HA 
[R11-4890]. Refer to 
Section 5.2.6.1.4.
Infections
Inhibition of the immune 
response with an 
immunomodulating biologic 
may increase the risk of 
infections.
A recent characterization of 
individuals with 
homozygous IL36R KO 
mutations revealed that 
normal immune function 
was broadly preserved 
suggesting that IL36 
signaling pathway inhibition 
does not compromise host 
defenses [R17-3632].
Infection testing procedures 
will be established for this 
trial. Treatment of infections 
should be initiated promptly 
according to standards of 
care.
Patients with infections such 
as human 
immunodeficiency virus 
(HIV), viral hepatitis or 
tuberculosis are 
discontinued from the trial. 
However, if latent 
tuberculosis is established
during the trial, then patients 
can receive anti-tuberculosis 
treatment as per investigator 
discretion and continue 
receiving study medication
as per investigator. Refer to 
Sections 3.3.4.1 and 6.2.1.2
Severe infections and 
opportunistic infections are 
considered AESIs for this 
trial. These conditions and 
serious infections are 
subject to close monitoring.
Refer to Section 5.2.6.1.4.
Malignancies
Inhibition of the immune 
response with an 
immunomodulating biologic 
may increase the risk of a 
decreased immune defense 
against malignancies.
A recent characterization of
individuals with 
homozygous IL36R KO 
mutations revealed that 
normal immune function 
Patients with a recent 
history of malignancy will 
be excluded from 
participation in this trial.
In case of occurrence of 
malignant neoplasm other 
than appropriately treated 
basal cell carcinoma or 
squamous cell carcinoma of 
the skin or in situ carcinoma 
of uterine cervix, the 


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Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
was broadly preserved 
suggesting that IL36 
signalling pathway 
inhibition does not 
compromise host defenses. 
[R17-3632].
investigator should 
discontinue treatment with 
spesolimab.
Diagnostics and treatment 
have to be initiated 
according to local SoC.
Malignancies represent 
always SAEs and are 
subject to close monitoring.
Refer to Section 5.2.6.1.3.
Peripheral Neuropathy
Three cases reported by the 
investigator as Guillain-
Barré syndrome (GBS) were 
received in ongoing clinical 
trials with spesolimab. A 
panel of independent 
neurologists and experts in 
the study of neuropathies 
assessed the 3 cases. Only 1 
met level 4 diagnostic 
certainty for the diagnosis of 
GBS (lowest level on 
Brighton scale of 1 to 4). In 
that case, there was a 
coincident infection with 
SARS-CoV-2. The other 2 
cases were assessed as not 
GBS. Observed cases 
showed a heterogenous 
pattern. A causal 
association to spesolimab 
was assessed to be unlikely.
As per assessment by the 
panel of external 
neurologists the nonspecific 
symptoms and findings in 
all three cases may best be 
referred to as peripheral 
neuropathy.
Timely detection, 
evaluation, and follow-up of 
suspected peripheral 
neuropathies to ensure 
patients´ safety.
Targeted Follow up 
questions to gather detailed 
information in case of any 
event during trial to ensure 
proper decision making.
Trial treatment 
discontinuation criteria as 
well as criteria for trial 
treatment restart are 
implemented for relevant 
cases. Refer to Section 
4.2.1.4.


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Possible or known risks of 
clinical relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Trial procedures
Blood Sampling
As with all blood sampling, 
there is a risk of mild pain, 
local irritation, or bruising 
(a black or blue mark) at the 
puncture site. Furthermore, 
there is a small risk of light-
headedness and/or fainting. 
In rare cases, the puncture 
site can also become 
infected or nerves may be 
damaged, inducing long-
lasting abnormal sensations 
(paraesthesia), 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 the laboratory 
manual.
Other risks
Suicidal ideation and 
behaviour
Increased risk of suicidal 
ideation and behaviour is 
present in the population of 
patients with HS.
‘Baseline/ screening’ 
version of Columbia-
Suicide Severity Rating 
Scale (C-SSRS) will be 
administered with the aim to 
exclude patients with active 
moderate or severe 
symptomatology present 
within a specified time prior 
to Visit 1. ‘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 
behaviour represent SAEs 
and are subject to close 
monitoring. Refer to Section 
5.2.5.1.


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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 AEs, 
definition of opportunistic infections and mycobacterium tuberculosis infections, severe 
infections and systemic hypersensitivity including infusion reaction and anaphylactic 
reactions as AESI; (c) selection of sites experienced in treatment of HS patients with 
biologics; and (d) implementation of a fully independent DMC.
1.4.2.1
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 Investigator Site File (ISF). Subcutaneous 
injection has been well tolerated in a small phase I study (1368-0003; see spesolimab IB, 
document number c03320877-10) and will be carefully monitored for local tolerability in this 
study. i.v. infusion, which occurs only at Visit 1, has been well tolerated in various clinical 
trials and will be monitored for tolerability.
1.4.2.2
Women of Child Bearing Potential
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 foetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods. Refer to Section 4.2.2.7.
1.4.2.3
COVID-19
Currently, information about the immune response in patients with COVID-19 is sparse and 
inconclusive. There are some reports suggesting high-levels of pro-inflammatory cytokines in 
the severe cases, with much of the morbidity associated with coronavirus infection, 
potentially related to immune activation and inflammation. To date, there is no reliable 
evidence suggesting a link between SARS-CoV-2 infections and the IL36 pathway targeted 
by spesolimab. According to the Centers for Disease Control and Prevention 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 not 
well 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 


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patients with increased risk of infections, close monitoring of AEs, as well as guidance on 
handling of acute infections occurring during the trial have been included in the clinical trial 
protocols (CTP). As any other acute infection a suspected or diagnosed COVID-19 infection 
should be treated according to the SoC 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 studied in trials with 
spesolimab are not believed to be at higher risk of COVID-19 due to their background or 
concomitant diseases. Protocol-defined procedures do not impose undue risk to study 
participants.
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 
required, will support the investigator in their decision finding. It is acknowledged that the 
investigator may decide to implement protocol deviations where this protects the safety, 
wellbeing, and/or is in the best interest of the patient.
1.4.3
Discussion
Due to the lack of mechanism- or compound-related safety signals of spesolimab, it is 
expected that patients with moderate or severe HS will not be exposed to unacceptable, undue 
risks and AEs.
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
The primary objective of this trial is to assess the long-term safety of spesolimab in patients 
with HS who have completed the 1368-0052 PoCC trial and are qualified for entry into this 
trial. The secondary objectives are to evaluate efficacy at a lower dose than tested in PoCC 
trial.
2.1.2
Primary endpoint(s)
The primary endpoint is the occurrence of treatment emergent adverse events (TEAE) up to 
the end of maintenance treatment period including REP (i.e., 16 weeks after the last study 
treatment).
2.1.3
Secondary endpoint(s)
•
change in 
 abscess and inflammatory nodule (AN) count from baseline up 
to Week 
.
•
change in total draining fistula (DF) count from baseline up to Week 
.
•
Hidradenitis Suppurativa Clinical Response (HiSCR) up to Week 
.
•
Change from baseline in International Hidradenitis Suppurativa Severity Score System 
(IHS4) value up to Week 
.
•
Hidradenitis Suppurativa Physician Global Assessment (HS-PGA) score of 0 or 1 up to 
Week 
.
•
 change from baseline in Hidradenitis Suppurativa Area and Severity Index 
(HASI) score up to Week 
.
•
Occurrence of at least one flare (defined as at least 
 in AN count with a 
minimum increase of 2 relative to baseline) up to Week 
.
•
Achievement of at least 
 from baseline in Numerical Rating Scale (NRS30) 
in Patient’s Global Assessment of HS Pain up to Week 
.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This open label, single-arm, multi-regimen, 2-year extension study investigates the long-term 
safety and efficacy of spesolimab in patients with HS who have completed their treatment in 
the 1368-0052 PoCC trial. BI trial 1368-0052 is the first trial from which patients will 
rollover into this extension trial. Patients rolling over into this trial must have completed the 
treatment period as required in the 1368-0052 PoCC trial. Ideally, the end of treatment (EoT) 
visit of the preceding trial is the baseline visit (V1) of this extension trial.
This extension trial consists of a 
 weeks treatment period followed by a 
 week safety 
follow-up period.
Approximately 
 patients from the 1368-0052 PoCC trial are planned to be rolled over into 
this open-label extension study.
Patients from the placebo arm of the 1368-0052 PoCC trial will be given an initial 
 
 dose of spesolimab plus
 placebo, followed by 
 spesolimab
 every 
 weeks
). Patients from the active arm of the 1368-0052 PoCC trial will be given an 
initial 
. placebo plus 
 spesolimab 
., followed by 
 spesolimab 
. every 
. Administration of trial medication at Visit 1 is blinded. See Section 3.1.1 for more 
details.
At Week 
of this extension trial, all patients will be assessed for the change of HS-PGA 
grade. The change in HS-PGA grade will be compared with the assessment at baseline of this 
extension trial / Week 
 of the 1368-0052 PoCC trial. Based on the individual responder 
status decisions on further dosing will be taken as depicted in Table 3.1: 1.


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Table 3.1: 1  Week 12 Dose Modification Management
Baseline
Assessment at Week 12
Management
Status from Week 12 of 
1368-0052 PoCC trial
HS-PGA grade change 
from baseline HS-PGA 
grade of this trial
Responder
(Achieved HiSCR 50)
No change or 
improvement in grade (i.e., 
reduction by at least 1 
grade)
Continue the same dose
Worsening in grade (i.e., 
increase by at least 1 
grade)
Option to increase the dose to 
Partial Responder
(Achieved HiSCR 25 but 
did not achieve HiSCR 
50)
Improvement in grade
Continue the same dose
No change or worsening in 
grade
Increase the dose to 
Non-responder
(Did not achieve HiSCR 
25)
Improvement in grade
Continue the same dose
No change or worsening in 
grade
Increase the dose to 
Re-assess HS-PGA grade at week 
 and discontinue, if no change or 
worsening observed compared to 
Week 
Responder is defined as achievement of HiSCR 50 in the1368-0052 PoCC trial, partial 
responders are defined as patients who did not achieve HiSCR 50, but achieved at least a 
 in AN count relative to baseline in the 1368-0052 PoCC trial, and non-
responders are defined as patients who have shown less than 
 in AN counts or 
have worsening of the disease in the 1368-0052 PoCC trial.


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3.1.1
Trial Design Diagram
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial will be conducted as a prospective, open-label design. The aim of the trial is to 
allow treatment continuation to individual patients who completed the 1368-0052 PoCC 
trial and evaluate the sustainability of response. Additionally, this trial provides opportunity 
for the patients who were on the placebo arm in the 1368-0052 PoCC trial to get access to 
the trial treatment. It is also designed to generate additional safety information.
Patients who prematurely discontinued the 1368-0052 PoCC trial are not eligible to 
participate in this study. For patients who terminate study drug prematurely in this 
extension study the subsequent visit will be replaced by an early EoT visit followed by an 
end of study (EoS) visit 16 weeks after the last study drug administration.
Interim analyses of PK, ADA, and clinical data may be performed throughout the conduct 
phase of this 2-year trial to support future trial applications, IB, regulatory documents and 
scientific publications. The final analysis of the entire trial data will start once the last patient 
has completed the EOT visit and final report will include all trial data. Individual patient 
participation is concluded when the patient has completed the last scheduled visit. The end of 
whole study is defined as “last patient out”; i.e., last scheduled visit completed by the last 
patient in the study. All the parameters will be assessed in a descriptive manner, since the 
trial is open-label.
An independent DMC will evaluate safety and efficacy data on a continuous basis.


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3.3
SELECTION OF TRIAL POPULATION
Patients in this long-term open label extension (OLE) trial will be rolled over from the 1368-
0052 PoCC trial. The total number of patients to be rolled over depends on how many 
eligible patients roll over from the 1368-0052 PoCC trial. The maximum number of patients 
eligible to rollover is approximately 45 from multiple countries and multiple sites. This OLE 
study aims to offer active long-term treatment to patients having completed treatment with 
spesolimab in the 1368-0052 PoCC trial, and an opportunity for patients on the placebo arm 
to get active treatment. This study will also help to characterize the safety and clinical 
outcome of spesolimab long-term treatment.
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.
3.3.1
Main diagnosis for trial entry
Patients with HS who have completed the treatment with spesolimab in the parent HS trial.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Patients who have completed treatment in the parent HS spesolimab trial (1368-0052) 
without premature discontinuation.
2. Signed and dated written informed consent in accordance with ICH Harmonized 
Guideline for Good Clinical Practice (ICH-GCP) and local legislation prior to admission 
to the trial.
3. 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. A list of contraception methods meeting these criteria is provided in the 
patient information and consent form and in Section 4.2.2.7.
3.3.3
Exclusion criteria
1. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
2. Patients who experienced study treatment-limiting adverse events during the 1368-0052 
parent trial.
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause.


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3. Severe, progressive, or uncontrolled condition such as renal, hepatic, haematological, 
endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and 
symptoms thereof.
4. Any new documented active or suspected malignancy except appropriately treated basal 
cell carcinoma, squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix.
5. Use of any restricted medication or any drug considered by the investigator likely to 
interfere with the safe conduct of the study since the last visit of the 1368-0052 parent 
trial.
6. History of allergy/hypersensitivity to the systemically administered trial medication agent 
or its excipients.
7. Major surgery (major according to the investigator’s assessment) planned during this
extension trial (e.g. hip replacement, aneurysm removal, stomach ligation), as assessed by 
the investigator.
8. Any condition which in the opinion of the investigator affects the safety of the patient, the 
patient’s ability to participate in this trial or could compromise the quality of data.
9. Any suicidal behaviour in the past 2 years (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour).
10. Any suicidal ideation of type 4 or 5 on the C-SSRS in the past 3 months (i.e. active 
suicidal thoughts with method and intent but without specific plan, or active suicidal 
thoughts with method, intent and plan).
11. Currently enrolled in another investigational device or drug trial, except for 1368-0052.
12. Previous participation in this trial.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below. Every effort should be made to keep the patients in the trial: if possible on
treatment, or at least to collect important trial data. Measures to control the withdrawal rate 
include careful patient selection, appropriate explanation of the trial requirements and 
procedures prior to trial enrolment, as well as the explanation of the consequences of 
withdrawal. The decision to discontinue trial treatment or withdraw consent to trial
participation and the reason must be documented in the patient files and Case Report Form
(CRF). If applicable, consider the requirements for Adverse Event collection reporting 
(please see Sections 5.2.6.2.1 and 5.2.6.2).
Patients withdrawn from the trial, independent of the underlying reason, should undergo the 
EoT visit as soon as possible, the FUP 1 Visit two weeks after the last dose, and the EoS Visit 
16 weeks after the last dose for safety reasons. This should also be proposed to patients who 
withdraw their informed consent.
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.


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•
The patient develops infections such as HIV, viral hepatitis or tuberculosis. However, if 
latent tuberculosis is diagnosed during the trial, patients can receive anti-tuberculosis 
treatment as per investigator discretion and continue receiving study medication as per 
investigator. Refer to Section 6.2.1.2
•
The patient needs to take concomitant medication such as immunosuppressive biologics, 
live vaccines, or other concomitant medication that interferes with the Investigational 
Medicinal Products (IMP) or other trial treatment. Also refer to Sections 4.2.1 and 4.2.2.
•
The patient can no longer receive trial treatment for medical reasons such as surgery, 
serious or severe Drug Induced Liver Injury attributable to the trial drug, other adverse 
events, other diseases, or pregnancy. Also refer to Sections 5.2.6.1.4 and 5.2.6.2.3.
•
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 behaviour (i.e. actual attempt, interrupted 
attempt, aborted attempt, or preparatory acts or behaviour). The patient should 
immediately be referred to a mental health professional for further work-up.
•
The patient is a Non-responder on 1200 mg of IMP and there is no change or no 
improvement in their HS-PGA grade at Week 24 compared to Week 12.
In addition, the principal investigator may discontinue subjects at any time based on his or 
her clinical judgment.
For individual stopping rules related to specific AEs, please see Section 4.2.1.
In case of a temporary reason, trial treatment should be restarted if medically justified, please 
see Section 4.1.4.
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.
If new efficacy/safety information becomes available, BI will review the benefit-risk-
assessment and, if needed, pause or discontinue the trial treatment for all patients or take any 
other appropriate action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a patient wants to withdraw consent, the investigator should be 
involved in the discussion with the patient and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.


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3.3.4.3
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.4.1.
3. Deviations from ICH-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 1 – BI 655130 (spesolimab) solution for injection
Substance:
BI 655130 (spesolimab)
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
/prefilled syringe 2mL (150mg/mL)
Posology:
 every  weeks, including at Visit 1 for 
subjects who were on spesolimab in the parent trial. 
An increase in dose at W
 to 
mg 
. every  
 if needed; Refer to Table 3.1: 1.
Method and route of administration:
Table 4.1.1: 2 
Test product 2 – BI matching placebo solution for injection
Substance:
Placebo matching BI 655130 (spesolimab)
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
placebo, 
 prefilled syringe
Posology:
Placebo matching 
 at Visit 1 only for subjects 
who were on placebo in the parent trial
Method and route of administration:


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Table 4.1.1: 3 
Test product 3 – BI 655130 (spesolimab) solution for infusion
Substance:
BI 655130 (spesolimab)
Pharmaceutical formulation:
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
Posology:
Visit 1 only for subjects who were on 
placebo in the parent trial (Loading Dose)
Method and route of administration:
Table 4.1.1: 4
Test product 4 – BI matching placebo solution for infusion
Substance:
Placebo matching to BI 655130 (spesolimab)
Pharmaceutical formulation:
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
Placebo 
Posology:
Placebo matching 
 in Visit 1 only for 
subjects who were on spesolimab in the parent trial
Method and route of administration:
4.1.2
Selection of doses in the trial and dose modifications
In the 1368-0052 PoCC trial, a fixed rather than weight-based dose regimen was selected. 
Early trials of therapeutic monoclonal antibodies often investigate bodyweight–based 
regimens to reduce the inter-subject variability in drug exposure. However, there is generally 
only a modest contribution of body weight to the overall PK and PD variability of 
monoclonal antibodies. Furthermore, monoclonal antibodies are highly target specific and 
offer a relatively large therapeutic window compared to new chemical entities. Therefore, 
most monoclonal antibodies are approved at fixed doses in antibody/target excess in order to 
cover target turnover and maximize efficacy [R10-6267; R13-4749; R13-4753; R13-4750; 
R13-4754].


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In this extension trial, patients from the active arm in the parent trial will be given 
 
 every 
, which is half the dose of the 1368-0052 PoCC trial. This is to evaluate 
whether these patients would be able to sustain efficacy at a lower dose. Patients who were in 
the placebo arm will be given a 
 dose of spesolimab, followed by 
 
. every
. The rationale is to give an opportunity to the patients from the placebo arm 
to be given active treatment and also to understand induction response after a placebo period. 
Additionally, this dose was also selected to evaluate efficacy of 
 dose. All 
the patients will be reassessed at Week 
 to evaluate the response and will have the option 
of either continuing the same dose or increasing the dose.
Data from the 1368-0052 PoCC trial will not be available prior to the 1st patient rolling over 
into this extension trial. When new data from the PoCC trial becomes available, the impact 
for this extension trial will be evaluated and if needed the dose would then be adjusted by 
amending this protocol.
4.1.3
Method of assigning patients to treatment groups
An Interactive Response Technology (IRT) system will be used in this trial in order to 
dispense medication kits as well as manage initial/re-supply ordering of medication kits. The 
study site will be required to complete the appropriate module within the IRT system. The 
investigator will receive all necessary instructions to access the IRT system from the sponsor 
or chosen provider. Detailed IRT transactions and procedures will be documented in the user 
requirement specifications mutually agreed to by the sponsor and the IRT provider. All 
medication kit assignments will occur in an open label fashion except for medications 
provided for Visit 1. Note that the medication number is different from the patient number.
4.1.4
Drug assignment and administration of doses for each patient
Patients will be treated with spesolimab as indicated in the Flow Chart and Section 3.1.1. The 
medication will be assigned via IRT.
At Visit 1 patients who were in the placebo arm of the 1368-0052 PoCC trial will be given an 
initial 
 dose of spesolimab plus 
placebo. Patients from the active arm 
of the 1368-0052 PoCC trial will be given
 placebo plus 
 spesolimab 
Detailed instructions for the preparation of the solution for infusion, the volume to be 
administered and the infusion rate as well as detailed instructions for use and handling of 
spesolimab syringes are provided in the ISF.
At all other visits all patients will receive 
 spesolimab 
 for the remainder of the 
trial unless an increase in dose to 
 is required at Week 
Refer to Table 3.1: 1.
Patients have to be closely monitored for local or systemic hypersensitivity reactions for one
hour following 
or 
 study drug administration. Patients should be closely monitored for 
signs and symptoms of injection site or systemic hypersensitivity reactions following study 
drug administration. 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. Study personnel should observe the injection site for signs 


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of redness, swelling or hardness. They should also ask patients about itching, dizziness or 
shortness of breath. Patients should be advised that if they experience redness, swelling or 
other changes at the injection site, they should notify site personnel. They should further be 
advised that if they experience itching all over or a feeling of being swollen, dizzy or short of 
breath, they should seek emergency medical attention immediately and notify site personnel.
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 his/her medical judgment he/she 
will provide medications such as steroids, etc., as needed (see Section 4.2.1 for handling of 
infusion reactions). Detailed instructions for handling of infusion reactions are also provided 
in the “Instructions for Pharmacist” document 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 Visit 1. 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. (See Section 3.3.4.1.)
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 the 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, investigators, central reviewers, and everyone involved in trial conduct or analysis
or with any other interest in this extension will remain blinded to the medication provided at 
Visit 1 at least until the last patient from the 1368-0052 trial completes
 weeks of treatment 
in this trial. The access to the randomisation code for Visit 1 will be kept restricted until its 
release for analysis.


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4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available for the blinded medication at Visit 1 only. Although,
all patients will receive spesolimab regardless at all visits. All patients at Visit 1 will be 
receiving placebo plus spesolimab.
4.1.6
Packaging, labelling, and re-supply
The IMP will be provided by BI or a designated contract research organization (CRO). They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice. 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. 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 CTP by authorized personnel as documented in the trial staff 
list.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
•
Approval of the CTP by the institutional review board (IRB) / independent ethics 
committee (IEC)
•
Availability of a signed and dated clinical trial contract between the sponsor or delegate 
and the investigational site,
•
Approval/notification of the regulatory authority (RA), e.g. competent authority (CA),
•
Availability of the curriculum vitae of the Principal Investigator,
•
Availability of a signed and dated CTP,
•
Availability of the proof of a medical license for the Principal Investigator, if applicable,
•
Availability of U.S. Food & Drug Administration (FDA) Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal.


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These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the IMP and trial patients. The investigator or 
designee will maintain records that document adequately that the patients were provided the 
doses specified by the CTP and reconcile all IMP 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 and that no remaining supplies are 
in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Systemic steroids dosed i.v. 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.
Any of the below 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.
4.2.1.1
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 SoC to:
•
Immediately interrupt the infusion (if i.v.) or stop further injections (if s.c.).
•
Treat with systemic anti-histamines, i.v. 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, i.v. 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 
Rheumatology Common Toxicity Criteria (RCTC) grading) at lower speed with gradual 
increase to complete the infusion as detailed in the Instructions for Pharmacist in the ISF. 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 systemic hypersensitivity 


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(according to RCTC grading) to complete the injections as detailed in the Instructions for Use 
of Spesolimab Pre-filled Syringes in the ISF. 
In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.1 [R11-4890]) suspected to be caused by the trial medication, the 
investigator should discontinue treatment permanently with spesolimab.
When a non-acute hypersensitivity reaction related to immune complexes (i.e., serum 
sickness) is suspected, please draw a sample for the laboratory assessment for circulating 
immune complexes.
In case of severe infections (according to RCTC grading), serious infections, opportunistic or 
mycobacterium tuberculosis (TB) infections, treatment of the infection should be initiated 
promptly according to local SoC. No further trial medication should be administered until the 
active infection has resolved. Treatment with spesolimab may be restarted when the patient 
has recovered according to investigator’s assessment.
4.2.1.2
Malignancies
In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix, the 
investigator should discontinue treatment with spesolimab. Diagnostics and treatment have to 
be initiated according to local SoC.
4.2.1.3
Suicidality
In case of signals of suicidal ideation or suicidal behaviour the patient should be referred to 
psychiatric work up. Overall, the choice of SoC treatment will be left at the discretion of the 
investigator. The sponsor will not provide/supply SoC treatment (s) to the sites. See Section 
5.2.5.2.
4.2.1.4
Peripheral Neuropathy
If peripheral neuropathy is suspected, treatment with spesolimab should be temporarily 
discontinued until a full neurological investigation has been conducted. 
After completion of the neurological investigation, treatment can be restarted based on 
medical judgement of the investigator.
4.2.2
Restrictions
4.2.2.1
Restrictions Regarding Concomitant Treatment
The medication (or classes of medications) listed in Table 4.2.2.1:1 are restricted for specific 
periods during the study (W0 - W12 and W12 through to EoT). As these restricted 
medications are consistent with the preceding 1368-0052 PoCC trial, patients must not have 
taken the medications (or classes of medications) through to the EoT Visit of the PoCC trial 
(which is the same day as Visit 1 in this trial). In the event that the EoT/V1 cannot be done on 


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the same day then a maximum 2-week gap can be allowed from the EoT Visit of the 1368-
0052 PoCC trial to Visit 1 of this extension trial, systemic and topical antibiotics can be used 
for disease worsening as per investigator discretion. However, biologics, immunomodulators 
and opioid analgesics are not allowed for HS and non-HS indications. See also footnote to 
Visit 1 in the Flow Chart.


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Table 4.2.2.1: 1 – Restricted Medications
Medication 
W0 - W12
W12* - EoT
Systemic antibiotics1
Restricted for HS
Permitted for HS-disease 
worsening 
Systemic corticosteroids2
Restricted for HS
Restricted for HS
Biologics causing 
immunosuppression
Restricted for HS and non-
HS indications
Restricted for HS and non-
HS indications
Other systemic 
immunomodulatory agents
Restricted for HS and non-
HS indications
Restricted for HS and non-
HS indications
Live vaccines3
Restricted 
Restricted
Opioid analgesics
Restricted for HS 
Restricted for HS
Spironolactone4
Restricted for HS and non-
HS indications
Restricted for HS
Metformin4
Restricted for HS and non-
HS indications
Restricted for HS
Topical cannabis oil5
Restricted for HS
Permitted
Systemic medicinal cannabis
Restricted for HS and non-
HS indications
Restricted for HS
Topical corticosteroids for HS
Restricted for HS6
Permitted 
*Following Week 
 dose modification management – See Table 3.1: 1
1. For more information on the use of systemic antibiotics please see Section 4.2.2.3.
2. Systemic corticosteroids as short courses, i.e., approximately 1- 2 weeks at the discretion 
of the investigator, can be used for indications other than HS.
3. Patients can receive seasonal influenza vaccines (excluding live attenuated vaccines).
4. Restricted if used for HS. Allowed for non-HS indications as a stable dose prior to V2 of 
the 1368-0052 PoCC trial.
5. Restricted if used over HS-affected areas. Other alternative therapies for HS are 
restricted, unless permitted after discussion with the PI and the sponsor.
6. Prior to Week 
, 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 defined as the treatment for disease worsening, and includes systemic 
antibiotics or immunosuppressive biologics such as TNF-inhibitors. The sponsor will not 
provide/supply these treatment(s) to the sites. As per Table 4.2.2.1: 1, immunosuppressive 
biologics are restricted during the entire trial. If a patient receives rescue treatment, the 
decision to maintain the patient on trial treatment is based on the investigator’s clinical 
judgement.


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4.2.2.3
Antibiotic Use During the Trial
Non HS use:
Systemic antibiotics can be used for indications other than HS. A maximum of 4 weeks of 
systemic antibiotics are allowed from Week 0 - Week 12 for non-HS indications.
HS disease worsening (as defined above in Section 4.2.2.2):
After Week 12, systemic antibiotics may be used for disease worsening as per investigator 
discretion.
4.2.2.4
Analgesics Use During the Trial
Opiate analgesics (except synthetic opioids such as tramadol) are restricted for HS. It can be 
allowed for non-HS indications as per investigator discretion.
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 from the 1368-0052 PoCC 
trial and is anticipated to remain stable throughout the study.
If a subject's pain (HS-related or non-HS-related) worsens after Visit 1, then non-opioid 
analgesic therapy may be initiated or increased.
Use of analgesics will be documented in 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, 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 from W0 – W12. An intervention can maximally occur 
on two different lesions at the same time or on the same lesion at two different study visits. 
There are no restriction in the number of lesion interventions from W12 – EoT.
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 list of contraception methods meeting these criteria 
is also provided in the patient information.


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Female Patients
Acceptable methods of birth control for this trial are: 
•
Combined (oestrogen 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 or intrauterine hormone-releasing system 
•
Bilateral tubal occlusion 
•
Vasectomised sexual partner with documented absence of sperm 
Or
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
Male Patients
Contraception of male trial participants and female partners of male trial participants are not 
required.
4.3
TREATMENT COMPLIANCE
Administration of the study medication will be done in the study centre 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
All assessments are measured at the time points noted in the Flow Chart and preferably 
completed prior to study drug administration.
5.1
ASSESSMENT OF EFFICACY
5.1.1
Hidradenitis Suppurativa Clinical Response - HiSCR
The HiSCR 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 AN count, with 
no increase in the abscess or draining fistula count. [R20-2976] HiSCR is calculated
automatically by comparing the lesion count from baseline.
5.1.2
International Hidradenitis Suppurativa Severity Score System - 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].
A nodule (inflammatory nodule) is a raised, three dimensional, 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.
5.1.3
Hidradenitis Suppurativa Physician Global Assessment - HS-PGA
This documents the physician’s assessment of the patient’s HS at a given time point. It scores 
patient disease severity as either clear or minimal or mild or moderate or severe or very 
severe, based on abscesses, draining fistulae, inflammatory nodule and non-inflammatory 
nodule.
5.1.4
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. 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).


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5.1.5
Pain Numerical Rating Scale – Pain NRS
The Pain NRS is an endpoint for the assessment of HS-related pain severity for clinical trials 
with patients with HS. It is a unidimensional measure of pain intensity and can be 
administered monthly at the site. Response is given by an 11-point scale ranging from 0 to 
10. The Pain NRS is completed by the patients during clinic visits. It will be used to assess 
the worst HS pain. Ratings will range from 0 (no HS pain) to 10 (HS pain as bad as one can 
imagine).
5.1.6
Dermatology Life Quality Index 
The 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 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.
5.1.7
Hidradenitis Suppurativa Quality of Life – HiS-QoL
The 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 


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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.
5.1.8
FACIT-Fatigue Scale
The FACIT-Fatigue Scale 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 of 3-4 
points in change score has been reported [R16-0029]. The recall period for items is 7 days.
5.1.9
Patient Global Impression of Change - PGI-C
The PGI-C is a 1-item tool assessing the change of HS since the start of taking the study 
medication by 5-point Likert-type scale. The tool is required for anchoring of other 
instruments and endpoints.
5.1.10
Patient Global Impression of Severity - 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.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin.
A targeted physical examination will be performed at the time points specified in the Flow 
Chart. It includes evaluation of organ systems associated with AE(s) symptoms or laboratory 
abnormalities.
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart.
The results must be included in the source documents available at the site.
5.2.2
Vital signs
This includes temperature, respiratory rate, systolic and diastolic blood pressure and pulse 
rate (electronically or by palpation count for 1 minute) in a seated position after 5 minutes of 
rest. 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. Additionally, vital signs will be measured approximately 10 min post-
dose after s.c. administration and approximately 5 and 60 min. post-dose in case of i.v. study 
drug administration. Also at Visit 2 and Visit 3 additional measurements will be performed 


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approximately 60 minutes after s.c. 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. For the sampling time 
points please see the Flow Chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. Patients do not have to be fasted for the blood sampling for the safety 
laboratory. If blood sampling for central lab is not possible because central laboratory
supplies are not available on time, safety lab analyses can be performed at a local laboratory. 
The results of the local lab tests must be reported to the investigator who ensures medical 
review and proper documentation in the eCRF.
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. The central laboratory will send reports to 
the investigator. It is the responsibility of the investigator to evaluate the laboratory reports. 
Clinically relevant abnormal findings as judged by the investigator will be reported as 
adverse events (please refer to Section 5.2.6).
In case the criteria for 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 and/or the
electronic data capture (eDC) system. The amount of blood taken from the patient concerned 
will be increased due to this additional sampling. The central laboratory will transfer the 
results of the analysis to the sponsor.
Table 5.2.3:1 
Infection testing at Visit 1 and EoT visit
Category
Test Name
Infection Testing 
Hepatitis B virus-DNA (quantitative) at Visit 1 and EoT Visit1
QuantiFERON®-TB-Gold Plus2, 3, 4
Hepatitis B Surface Antigen (qualitative)5
Hepatitis B core Antibody5
Hepatitis C Antibodies (qualitative) 5
HIV-1, and HIV-2 Antibody (qualitative) 5
T-spot TB test
1.
An 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 Visit 1 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 patients with a previously (i.e., in the previous PoCC trial or in this ongoing extension trial) negative 
QuantiFERON®-TB test, the test should be repeated every 52 weeks, as long as the results are negative.
5.
If determined as negative at Visit 1, then there is no need to retest at the EoT Visit.


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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)
Prothrombin time (INR)
Fibrinogen
Enzymes
AST (GOT)
ALT (GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Amylase
Lipase
Electrolytes
Calcium
Sodium
Potassium
Chloride
Bicarbonate


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Category
Test Name
Substrates
Glucose
BUN (blood urea nitrogen)
Uric acid
Creatinine4
eGFR (estimated by CKD-EPI formula) (only 
at Visit 1)
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 & hs-CRP) (high 
sensitivity)
Cholesterol, total
Triglycerides
LDL-Cholesterol
HDL-Cholesterol
Specific gamma-globulin quantification
IgE1, IgG
Urine Pregnancy test (only for WOCBP)
Human Chorionic Gonadotropin in urine
Serum Pregnancy test (only for WOCBP 
if urine pregnancy test is positive)
Human Serum Chorionic Gonadotropin
Urinalysis (dipstick)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes / Blood
Urine WBC/ Leukocytes
Urine pH
Specific gravity


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Category
Test Name
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 Visit 1)
Albumin (quantitative)
Interferon Gamma Release Assay 
(IGRA)
QuantiFERON®-TB or T-spot at EoT visit 2,3
1. Only in case of allergic reaction
2. Patients with indeterminate QuantiFERON or invalid/borderline T-spot may be retested 
with IGRA (once) and if inconclusive should have a PPD skin test. .
3. In subjects with a negative QuantiFERON®-TB-Gold Plus or PPD skin test, the test 
should be repeated every 52 weeks (including the test at the EoT visit) as long as the 
results are negative.
4. 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
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flow Chart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis. Additional ECGs may be recorded 
for safety reasons. Dated and signed printouts of ECG with findings should be documented in 
patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at Visit 1) or otherwise as AEs and will be followed up and/or treated as medically 
appropriate.


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5.2.5
Other safety parameters
5.2.5.1
Malignancies
All cases of malignancies that are detected during the trial will be reported as SAEs. Patients 
with a documented active or suspected malignancy (except for specific cancers) will be 
excluded from this trial per the exclusion criteria (Section 3.3.3).
5.2.5.2
Columbia-Suicide Severity Rating Scale (C-SSRS)
Considering the characteristics of spesolimab, no penetration of blood-brain-barrier is 
anticipated, and a central effect triggering suicidal events is considered unlikely. The 
available pre-clinical and clinical data do not indicate effects of spesolimab on the central 
nervous system.
Pro-active screening for SIB in the HS clinical development program will be implemented 
with the following objectives:
•
As a safety measure to exclude subjects at risk of suicidality and monitor for signs of 
suicidality.
•
Structured data collection that may help in future assessment of potential signals around 
suicidality.
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behaviour and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsellor, 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 behaviour, and may be expanded to up to 17 items in case of positive responses. The 
investigator has to directly evaluate the scale and confirm that they evaluated and reviewed 
the scale. The investigator documents their evaluation and review of the scale by either, 
•
writing at statement in the source notes, or
•
writing “reviewed” on questionnaire, signs, and dates the questionnaire.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at Visit 1 (using the ‘since last visit’ version) with the aim to exclude subjects 
with active moderate or severe symptomatology within a specified time prior to the baseline 
visit. The life time history of SIB will also be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed at each clinic or 
phone visit (‘since last visit’ version). 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 psychiatrist. If there is a confirmed positive report of 
suicidal behaviour or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the subject during the clinic visit, and/or is to consult a psychiatrist. If 


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the positive report is confirmed, appropriate actions for the subject’s safety have to be 
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behaviour must 
be reported as SAEs by the investigator. For ‘Self-injurious behaviour, no suicidal intent’ 
(Type 11) standard AE / SAE reporting rules are to be applied. For each negative report 
(suicidal ideation type 1, 2 or 3) after start of the trial, the investigator is to decide based on 
clinical judgment whether it represents an AE as defined in the CTP, and if it is considered an 
AE then it must be reported accordingly.
5.2.5.3
Local Tolerability
Local tolerability at the administration site of spesolimab will be assessed by the investigator 
during the trial 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”, “pain”, and any other findings should be reported as AEs 
(see Section 6.2.2).
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 electronic case report form (eCRF) only. However, 
if these abnormalities are AEs of the parent PoCC trial and still ongoing after the first dose in 
this extension trial, then they should not be recorded as baseline conditions. In such situations 
Section 5.2.6.2 should be followed.
5.2.6.1.2
Serious adverse event
A SAE is defined as any AE, which fulfils at least one of the following criteria:
-
results in death,


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-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI 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 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 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 10.1 [R11-4890]).
Severe infections
Refer to the RCTC grading in the ISF.


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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), TB, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, strongyloides (hyperinfection syndrome and disseminated forms only), 
paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only), shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), hepatitis C virus progression 
[R17-2617].
Potential Severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined by the 
following alterations of hepatic laboratory parameters: 
•
An elevation of AST (Aspartate Aminotransferase) and / or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold 
ULN measured in the same blood sample, or in samples drawn within 30 days of each 
other; or
•
ALT and / or AST elevations ≥10-fold ULN.
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. 
For patients with abnormal aminotransaminase levels between >1 and <3 x ULN at baseline: 
1. An elevation of AST and / or ALT ≥3-fold the baseline value combined with an elevation 
of bilirubin ≥2-fold ULN or ≥2-fold the baseline value (if bilirubin is elevated at baseline), 
measured in the same blood sample, or in samples drawn within 30 days of each other, or,
2. Aminotransferase elevations ≥5-fold the baseline value.
For patients with abnormal aminotransaminase levels between ≥3 x ULN and <5 x ULN at 
baseline: 
1. An elevation of AST and / or ALT ≥2-fold the baseline value combined with an elevation 
of bilirubin ≥2-fold ULN or ≥2-fold the baseline value (if bilirubin is elevated at 
baseline); measured in the same blood sample or in samples drawn within 30 days of each 
other, or,
2. Aminotransferase elevations ≥3-fold the baseline value.


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Peripheral NeuropathyAny event suspected or diagnosed as Peripheral Neuropathy would be 
considered as an AESI. For the treatment interruption rules, please see Section 4.2.1.4.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) grading of AEs will be performed according to RCTC Version 2.0 
developed by the Outcome Measures in Rheumatology organization [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.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the drug.
•
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.


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•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files. The 
following must be collected and documented on the appropriate CRF(s) by the Investigator
(special notes on SAE form reporting where needed):
•
From the time of the signing of the consent form in the extension trial until the end of 
the EoS visit all AEs (serious and non-serious) and all AESIs.
•
All AEs that started in the 1368-0052 PoCC (parent) trial (onset date in parent trial) 
and are still ongoing after 1st IMP administration in the extension trial:
•
Re-record the AE in the extension trial eCRF with the same information as it was 
recorded in the parent trial.
•
Should the AE end during the course of the extension trial,
update both - the extension trial eCRF and the parent trial eCRF. If the parent trial 
is already locked, update only the extension trial eCRF. In this case the update for 
the parent trial will be handled outside of the eCRF of the parent trial.
•
However, concerning reporting on the SAE form (if applicable), the follow-up report 
will still be sent on the parent trial SAE form, no new SAE form is to be completed 
for the extension trial.
•
If the intensity of an ongoing AE changes after 1st IMP administration in the extension 
trial:
update both - the extension trial eCRF and the parent trial eCRF- with the end date 
for the initial/previous intensity. If the parent trial is already locked, update only 
the extension trial eCRF. In this case the update for the parent trial will be handled 
outside of the eCRF of the parent trial.
The AE with the new intensity will be handled as new event; this means it is only 
recorded in the extension trial eCRF.
Example: If the intensity increased then the new AE name/term should 
contain “Worsening of….” or “Exacerbation of….”.
Considerations for reporting on the SAE form, when intensity change 
qualifies as worsening/exacerbation of an event that had already been 
reported on the SAE form:
- corresponding follow up report to be sent on the parent trial SAE form 
with date of worsening as event end date. 
- extension trial SAE form to be sent as initial report for the extension trial 
for new event “worsening/exacerbation of….” with date of worsening as 
onset date.


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Considerations for reporting on the SAE form, when intensity change 
qualifies as worsening/exacerbation of an event and requires for the first 
time reporting on the SAE form (meeting for the first time 
seriousness/AESI criteria):
- only extension trial SAE form to be sent - as initial report for the 
extension trial for new event “worsening/exacerbation of….” with date of 
worsening as onset date.
•
All AEs with an end date before the 1st IMP administration in the extension trial, even if 
Informed Consent of the extension trial was already signed:
•
Record only in the eCRF of the parent trial. 
•
In case of an AE reportable on the SAE form, send the update only on the SAE 
form of the parent trial. 
•
Do not re-record in the extension trial eCRF, do not complete a new SAE form for 
the extension trial.
•
After the EoS visit in the extension trial:
After a patient´s EoS Visit in the extension trial the investigator does not need to actively 
monitor the patient for new AEs but should only report new malignancies or the exacerbation 
of existing malignancies, trial treatment related SAEs and trial treatment related AESIs of 
which the investigator may become aware of by any means of communication, e.g. phone call. 
Those AEs should be reported on the BI SAE form (see Section 5.2.6.2.2) for the extension 
trial, but not on the CRF (neither on CRF for extension trial nor for parent trial).
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI immediately to the sponsor’s unique entry point (within 24 hours of 
becoming aware of the event) (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 send 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.


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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.
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, ADA and neutralizing antibody (Nab) will be measured 
and their impact on PK will be assessed. The relationship between PK and selected efficacy 
endpoints, biomarkers and AEs may be assessed. PK and demographic data together with 
treatment assignments and dosing information may be made available to individuals outside 
of the trial team for the purpose of PK dataset generation in accordance with sponsor’s 
standard procedures.
5.3.2
Methods of sample collection
Plasma/Serum samples may be used for further methodological investigations (ex: for future 
stability testing). However, only data for measuring the analyte and antibody responses to the
analyte will be generated by these investigations. After completion of the trial, the 
plasma/serum samples may be used for further methodological investigations, e.g. for 
stability testing. However, only data related to the analyte and data related to the ADAs will 
be generated by these additional investigations. The samples will be discarded after 
completion of the additional investigations but not later than  years upon the final study 
report has been signed.
5.3.2.1
Plasma sampling for PK analysis
For quantification of spesolimab plasma concentrations, blood will be taken from a forearm
vein into a K2EDTA (ethylendiaminetetraacetic acid) anticoagulant blood-drawing tube at 
the time points listed in the Flow Chart under plasma PK. Handling procedures can be found 
in the laboratory manual.
5.3.2.2
Sampling for ADA/Nab assessment
For ADA assessment, blood will be taken from a forearm vein into a K2EDTA anticoagulant 
blood-drawing tube at the time points listed in the Flow Chart under ADA/Nab. For Nab
assessment, blood will be taken from a forearm vein into a serum blood-drawing tube at the 


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time points listed in the Flow Chart under ADA/Nab. Handling procedures can be found in 
the laboratory manual (see ISF).
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.
5.4.1
Biochemical and cellular biomarkers
Serum will be collected as indicated in the Flow Chart to assess changes in protein levels of 
select IL36 pathway and disease related markers. The biomarker assay analysis of samples 
will be performed in a staged approach. The initial analysis will focus on selected time points 
and depending on these results a decision will be made about further analysis of all samples. 
This is due to the exploratory nature of the mechanism being tested and the timing of effect 
on candidate biomarkers in the study.
5.4.2
Pharmacogenomics biomarkers
Whole blood samples will be collected as indicated in Flow Chart 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. The biomarker analysis of samples will 
be performed in a staged approach. The initial analysis will focus on selected time points and 
depending on these results a decision will be made about further analysis of all samples. This 
is due to the exploratory nature of the mechanism being tested and the timing of effect on 
candidate biomarkers in the study.
5.4.3
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 Flow Chart.
5.5
BIOBANKING
Not applicable.


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5.6
OTHER ASSESSMENTS
5.6.1
Photographs
Subjects will have photographs taken of their disease response during the study. The
photographs will be taken at designated study visits listed in the Flow Chart. 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 Flow Chart. Each visit date 
(with its window) up to the EoS Visit is to be counted from Visit 1 (visit with first IMP 
administration). If any of these visits has to be rescheduled, the date of the subsequent visit 
should be calculated again from Visit 1. Additional visits (unscheduled visits) for the purpose 
of re-testing of laboratory parameters or AE monitoring may be included as deemed 
necessary by the investigator. If a visit was missed due to any reason, the Clinical Trial 
Leader (CT Leader) must be contacted to discuss if the visit must be skipped.
For detailed description of the visit schedule and the trial procedures, please refer to the Flow 
Chart and its footnotes.
Details relating to study drug administration and treatment interruptions are provided in 
Section 4.1.4.
Study measurements and assessments are scheduled to occur ‘before’ trial medication 
administration. For planned individual plasma concentration sampling times refer to the Flow 
Chart. Sampling times will be recorded and used for PK analysis.
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.
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this CTP may not be feasible at a site. With the consent of the 
patient, sponsor and investigator may agree on alternative, back-up or rescue methodology 
which may include but will not be limited to virtual patient visits and assessments, home 
healthcare nurse visits, and direct-to-patient shipments of trial treatment. Such alternative 
measures may be described in a specific Crisis Management Manual as part of the initial 
submission package, and will also be mentioned in the patient information leaflet. The 
implementation of these measures will depend on patient’s consent, operational feasibility, 
local law and regulations. If alternative methodology is implemented, the deviations from the 
original plan will be precisely documented.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart and respective 
CTP sections. Refer to Section 5 for explanations of the specified assessments and procedural 
details.


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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.
Separate from the PROs above, the evaluation of efficacy assessments are to be conducted 
preferably by the same qualified assessor, whenever possible, throughout the study.
PROs and assessments should preferably be done prior to any study drug administration.
6.2.1
Visit 1 – Start of Treatment
For the comprehensive list of the trial procedures required at Visit 1 please refer to the Flow 
Chart. Study drug will start at Visit 1.
Visit 1 should preferably be performed in one visit combined with the EoT visit of the 
preceding 1368-0052 PoCC trial. Any duplicate procedures across the two studies are 
performed only once when the visit is combined. When these two visits across both studies 
do not occur on the same day then a modification of procedures will need to be considered. 
Refer to the Flow Chart for procedures that are identical across the two visits and for further 
information on any modification of procedures.
If a patient performs the EoT visit in the 1368-0052 PoCC study and a newly observed 
medical finding, for example, prohibits the patient to immediately enrol into this study, then 
the patient can come back for Visit 1 at a later date per the opinion of the investigator and
after discussion with the sponsor. The maximum gap for enrolling into this trial is 2 weeks 
after the EoT in the 1368-0052 PoCC trial. During this gap, patients can take systemic and 
topical antibiotics for disease worsening as per the investigator discretion (see Section 4.2). 
However, biologics, immunomodulators and opioid analgesics are not allowed for HS and 
non-HS indications.
Refer to Section 4.1.4 for study drug assignment and administration. Administration of the 
study drug is blinded at Visit 1 only.
6.2.1.1
Informed Consent
The patient must be given sufficient time to consider participation in this extension trial. 
Therefore, to facilitate the logistics of Visit 1 and the consenting process, information about 
this extension trial should be discussed with potentially eligible patients in advance of Visit 1 
of this trial. A copy of the patient information and consent form of the extension trial should 
be provided to potentially eligible patients preferably no later than Visit 8 of the previous 
1368-0052 PoCC trial. This will provide potential patients with sufficient time to consider 
their possible participation in this extension trial. At Visit 1, 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. Also refer to Section 8.1.
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 evaluations. The importance of staying in the trial until 


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completion of all study requirements should be emphasized. No trial procedures can 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. Once informed consent is 
obtained, the IRT contact is to be performed by the site. IRT will assign a patient number at 
the time IRT registration. Collection of SAEs and AEs begins immediately after the patient 
has signed the consent form (please refer to Section 5.2.6.2.1). The patient should be 
recorded on the enrolment log.
6.2.1.2
Infection Testing
Infection testing will include TB, Hepatitis B, Hepatitis C, and HIV assessments (see Table 
5.2.3:1). The results of the Infection Testing will not be available until after the patient 
receives their first dose at Visit 1. See Section 3.3.4.1 for Discontinuation Rules.
Interferon Gamma Release Assay
Patients with indeterminate / suspected false-positive QuantiFERON TB or invalid/borderline 
T-spot test result may have the test repeated once. If after repeat testing the QuantiFERON 
TB result is “indeterminate”, a PPD skin test may be performed locally. A tuberculin skin test 
reaction ≥10mm (≥5mm if receiving ≥15mg/d prednisone or its equivalent) is considered 
positive.
In patients with a previously (i.e., in the previous PoCC trial or in this ongoing extension 
trial) negative IGRA for TB the test should be repeated every 52 weeks, as long as the results 
are negative. Refer to Table 5.2.3:1.
If latent tuberculosis is diagnosed during the trial, then patients can receive anti-tuberculosis 
treatment as per investigator discretion and continue receiving study medication as per 
investigator.
6.2.2
Treatment period(s)
The treatment period is from Visit 1 to the EoT Visit at Week 
. For the comprehensive list 
of the trial procedures required during these visits please refer to the Flow Chart and its 
footnotes. See also Section 5.2 for details of all safety assessments.
Refer to Section 4.1.4 for study drug administration.
For information on the collection of photographs of skin lesions, please see Section 5.6.1
6.2.3
Follow-up period and trial completion
For the comprehensive list of the trial procedures required at the EoT, FUP 1, and the EoS 
visits please refer to Flow Chart and its footnotes.
The FUP 1 Visit occurs 2 weeks after the EoT Visit; this is 2 weeks after the patient has 
received their last dose of trial medication.


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The EoS visit will take place at the end of the REP which is 16 weeks after last injection of 
trial medication. Please also refer to the REP in Section 1.2.3. After conclusion of trial the 
patients will be treated according to the standard of care.
Patients who discontinue trial treatment prematurely should undergo the EoT visit as soon as 
possible, the FUP 1 Visit two weeks after the last dose, and the EoS Visit 16 weeks after the 
last dose. If a patient discontinues the study during a scheduled treatment visit then the visit is 
considered an EoT visit.
In the event a patient discontinues treatment and the trial prematurely and is unable to 
perform both FUP 1 and EoS visits, (only willing or physically can only perform one visit) 
then the early FUP 1 Visit procedures should be followed.
For all patients, trial completion status must be recorded on the corresponding eCRFs.
Treatment completion is defined as a patient completing the EoT Visit after receiving 
approximately 2 years of treatment without early discontinuation of study treatment.
Trial completion is defined as a patient having reached the EoS Visit within the specified 
window per protocol.
If needed in the opinion of the investigator, after the EoS visit additional visits may be 
scheduled for continued safety monitoring.
Abnormal assessments or lab values judged clinically relevant by the investigator will be 
monitored until they are returned to a medically acceptable level.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The primary objective of this trial is to assess the long-term safety of spesolimab in patients 
with HS who have completed the 1368-0052 PoCC trial and are qualified for entry into this 
trial. The secondary objectives are to evaluate efficacy at a lower dose than tested in PoCC 
trial.
For primary analysis of the primary endpoint, all adverse events with an onset between start 
of treatment and end of the REP (i.e., 16 weeks after the last study treatment) will be included.
7.1
NULL AND ALTERNATIVE HYPOTHESES
Given the single arm and open-label nature of this trial, no hypothesis testing will be 
performed in the confirmatory sense. All statistical assessments will be performed in an
explorative manner to better understand the efficacy and safety profile of spesolimab.
7.2
PLANNED ANALYSES
7.2.1
General considerations
This trial is designed as a single arm, open-label trial in patients with HS who have 
completed the planned treatment period in spesolimab 1368-0052 PoCC trial.
The following patient population set will be defined in this trial for analyses:
Safety Analysis Set (SAF)
This patient set includes all patients who received at least one study treatment in this trial.
Further analysis sets will be defined in the trial statistical plan (TSAP) if necessary.
Important deviations of the protocol will include deviations of the key inclusion and 
exclusion criteria, 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 final database lock (DBL) for this extension trial.
Standard statistical parameters (number of non-missing values, mean, standard deviation, 
median, quartiles, minimum and maximum) or frequency tables (including patient 
frequencies and percentages) will be calculated where appropriate.
A Clinical Trial Report (CTR) will be prepared once the final DBL for this extension trial has 
been performed.
7.2.2
Primary endpoint analyses
Refer to Section 7.2.5 for the description of safety analyses for the primary endpoint. The 
primary endpoint will be summarized based on SAF.


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7.2.3
Secondary endpoint analyses
For binary endpoints, the efficacy data will be presented over time based on SAF where any 
data collected after the use of rescue therapy will be censored and then imputed using the 
Non Response Imputation (NRI) method as described in Section 7.3.
For continuous endpoints, the efficacy data will be presented over time based on SAF where 
any data collected after the use of rescue therapy will be censored and then may be handled 
by a mixed effect model for repeated measurements (MMRM).
Further, it is also of interest to explore week 12 efficacy performance of patients who were 
responders, partial responders and non-responders in the 1368-0052 trial respectively as 
defined in Table 3.1: 1.
Further details will be provided in the TSAP.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, (i.e., 16 weeks after last study 
treatment) will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned. 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of the first treatment and end of 
the REP of the last treatment. Adverse events that start before first drug intake and deteriorate 
under treatment will also be considered as ‘treatment-emergent’. Safety assessments 
including treatment emergent adverse events, laboratories, vital signs etc. based on SAF.
Frequency, severity, and causal relationship of treatment emergent adverse events will be 
tabulated by system organ class (SOC) and preferred term after coding according to the 
current version of the MedDRA at DBL. Exposure adjusted incidence rate of all treatment 
emergent adverse events will also be presented.


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The exposure adjusted incidence rate (per 100 subject years) of a selected treatment 
emergent adverse event is defined as the number of subjects experiencing the adverse event 
per treatment group during time at risk divided by the total time of subjects at risk in that 
treatment group to contribute the event to the analysis multiplied by 100 (per 100 subject 
year), where:
Time at risk [subject years] = (date of onset of TEAE – study drug start date + 1) / 365.25
If, for a subject, the selected treatment emergent adverse event didn’t occur then the time at 
risk will be censored at min (date of death, last contact date per EoS page, drug stop date + 
112 days, cut-off date if interim analysis performed). For each selected treatment emergent 
AE, the exposure adjusted incidence rate will be calculated as:
Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with TEAE / 
Total TEAE-specific time at risk [subject years].
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings.
Vital signs, physical examinations, or other safety-relevant data observed at 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
Pharmacokinetics
Please refer to Section 5.3.1 and further information available in the TSAP.
Biomarker Analysis
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. 
Thresholds for defining significantly up- and down-regulations will be given in the TSAP.
Further details will be discussed in the TSAP.


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7.2.7
Interim Analyses
In order to ensure the patient’s safety during the trial, an external DMC, independent of the 
trial and project teams, will be set-up to review all available un-blinded safety data as well as 
selected efficacy data at regular intervals following first-patient-in. A DMC Statistical 
Analysis Plan, which describes the analyses required for assessment by the DMC, will be 
produced. Further details will be provided in a DMC charter.
As the primary aim of this study is to collect long-term safety and efficacy data on the use of 
spesolimab in this population, multiple interim analyses may be done over the two-year 
conduct phase of this trial to support, for example, regulatory interactions, Clinical Trial 
Application and Marketing Authorisation Application/Biologics Licencing Application
submissions, but also to provide important safety and efficacy information to the sponsor to 
guide further development of the compound, and to the investigators via IB updates and 
publications. 
Since patients will be enrolled into this study over a time period of several weeks and in line 
with the exploratory nature and open label design of the study, such analyses will be 
performed on demand and are not feasible to be pre-defined. 
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will 
still occur and approaches to handle this are proposed below.
For the safety data, including the primary endpoint, no missing data imputations are planned.
For secondary binary efficacy endpoints, a NRI approach will be applied to the missing 
visits; that is, imputing as a failure to achieve a response in the visits with missing endpoint 
score, however:
-
If there are visits with available data 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).
For secondary continuous efficacy endpoints, MMRM method may be applied to handle the 
missing data.
Further analyses to assess the robustness of the results on efficacy endpoint will be described 
in the TSAP if necessary.
7.4
RANDOMISATION
This is an open-label and single arm study. No randomization of treatment group is required. 


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Treatment allocation of patients at Visit 1 is based on their previous treatment in the 1368-
0052 PoCC trial. Patients, investigators, central reviewers, and everyone involved in trial 
conduct or analysis or with any other interest in this extension will remain blinded to this 
medication by IRT system. Afterwards, all patients will receive open-label s.c. spesolimab 
starting at Visit 2 onwards where no blinding is required.
7.5
DETERMINATION OF SAMPLE SIZE
Given the descriptive nature of this trial, no sample size calculation has been performed. The 
sample size of this OLE is determined based on the sample size of the preceding parent trial 
(1368-0052).


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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-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 BI 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 IRB / EC and CA according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally 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 


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(or places a seal on) and dates the informed consent. Please also refer to Section 6.2.1.1 for 
special considerations prior to Visit 1.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions. The consent and re-consenting 
process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, 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 RA. The quality assurance auditor will have access to all 
medical records, the investigator’s trial-related files and correspondence, and the informed 
consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The current medical history of the patient may not be sufficient to confirm
eligibility for the trial and the investigator may need to request previous medical histories and 
evidence of any diagnostic tests. In this case, the investigator must make at least one 
documented attempt to retrieve previous medical records. If this fails, a verbal history from 
the patient, documented in their medical records, would be acceptable.
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))
•
SAEs (onset date (mandatory), and end date (if available))
•
Concomitant therapy (start date, changes)
•
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
•
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
•
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and ICH-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.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 


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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the World Health 
Organization ICH-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 RA.
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 – (Biobanking is not applicable in this trial).
•
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 – (Biobanking ICF is not applicable in this trial).
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 suspected unexpected 
serious adverse reactions occurring with the trial medication until 30 days after LPLT at their 
site.


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Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / CA in each participating EU member state will be notified about the trial
milestones according to the respective laws. A final report of the clinical trial data will be 
written only after all patients have completed the trial in all countries (EU or non-EU) to 
incorporate and consider all data in the report. The sponsor will submit to the EU database a 
summary of the final trial results within one year from the end of a clinical trial as a whole, 
regardless of the country of the last patient (EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim.
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 safety data and efficacy data. The DMC will receive urgent 
significant safety concerns and DILI for immediate evaluation. While DMC members may be 
unblinded, measures are in place to ensure the blinding for everyone else involved in the trial. 
Regular DMC meetings will be held at specified intervals. The DMC will recommend 
continuation, modification or termination of the trial as detailed in the DMC charter. DMC 
recommendations as well as the final BI decision will be reported to the appropriate 
RAs/Health Authorities, 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 CT Leader, responsible for coordinating all required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers, 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 


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regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service 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
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.
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. 
R10-6267
Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus 
body size-based dosing of monoclonal antibodies in adult clinical trials. 
J Clin Pharmacol 2009 ; 49; 1012-1024
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
R11-4311
United States Census projections: 2004 - 2030: by year, state, age and 
sex, produced by the Census Bureau in 2005 (this page last reviewed: 
Thursday, July 28, 2011). http://wonder.cdc.gov/population.html 
(access date: 13 September 2011) ; Atlanta: Centers for Disease 
Control and Prevention (CDC); 2011.
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 2006 ; 117(2) ; 391-
397.
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.
R13-4749
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, 
Tang M, Allison DE, Lu D, Zhang Y,. Joshi A, Dresser MJ. A guide to 
rational dosing of monoclonal antibodies. Clin Pharmacokinet 2012; 
51(2); 119-135.
R13-4750
Joos B, Trkola A, Kuster H, Aceto L, Fischer M, Stiegler G, 
Armbruster C, Vcelar B, Katinger H, Guenthard HF. Long-term 
multiple-dose pharmacokinetics of human monoclonal antibodies 
(MAbs) against human immunodeficiency virus type 1 envelope gp120 


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(MAb 2G12) and gp41 (MAbs 4E10 and 2F5). Antimicrob Agents 
Chemother 2006; 50(5); 1773-1779. 
R13-4753
Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. 
Projecting human pharmacokinetics of therapeutic antibodies from 
nonclinical data: what have we learned? MAbs 2011; 3(1); 61-66.
R13-4754
Xin y, Gordon MS, Jin D, Wakshull E, Chen DS, Rosen LS, Munster 
PN, Naumovski L, Bai S. Population pharmacokinetic (PK) analysis 
supports fixed dosing for the humanized monoclonal antibody (huMAb) 
anti-EGFL7 (MEGF0444A) administered intravenously in patients 
with advanced solid tumors. 47th Ann Mtg of the American Society of 
Clinical Oncology (ASCO), Chicago, 3 - 7 Jun 2011. J Clin Oncol 
2011 ; 29(15) (Suppl)
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.
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.
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 2017 ; 9; eaan2514
R20-2976
Kimball AB, Sobell JM, Zouboulis CC, Gu Y, Williams DA, Sundaram 
M, 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 2016 ; 30; 989-
994.
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 Score System (IHS4), a 
novel dynamic scoring system to assess HS severity. Br J Dermatol 
2017 ; 177; 1401-1409.
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. Br J Dermatol 2018 ; 178; 761-767.
R20-3155
Byrd AS, Carmona-Rivera C, O'Neil LJ, Carlucci PM, Cisar C, 
Rosenberg AZ, et al,. extracellular traps, B cells, and type I interferons 
contribute to immune dysregulation in hidradenitis suppurativa. Sci 
Transl Med 2019 ; 11; eaav5908
R20-3156
Kirby JS, Thorlacius L, Villumsen B, Ingram JR, Garg A, Christensen 
KB, et al,. The Hidradenitis Suppurativa Quality of Life (HiSQOL) 


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score: development and validation of a measure for clinical trials. Br J 
Dermatol 2020 ; 183; 340-348.
R20-3184
Zouboulis CC, Marmol V del, Mrowietz U, Prens EP, Tzellos T, 
Jemec. GBE Hidradenitis suppurativa/acne inversa: criteria for 
diagnosis, severity assessment, classification and disease evaluation. 
Dermatology (Basel) 2015 ; 231(2) ; 184-190.
R20-3176
Saunte DM, Boer J, Stratigos A, Szepietowski JC, Hamzavi I, Kim KH, 
et al,. Diagnostic delay in hidradenitis suppurativa is a global problem. 
Br J Dermatol 2015 ; 173(6) ; 1546-1549.
R20-3177
Zouboulis CC, Desai N, Emtestam L, Hunger RE, Ioannides D, Juhasz 
I, et al,. European S1 guideline for the treatment of hidradenitis 
suppurativa/acne inversa. J Eur Acad Dermatol Venereol 2015 ; 29; 
619-644
9.2
UNPUBLISHED REFERENCES
c03320877-10
Investigator’s Brochure, BI 655130 (spesolimab), version 10, dated 14
April 2022.
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 BI 655130 in 
healthy male volunteers. 1368.1. Version 6. 27 Jan 2016.


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10.
APPENDICES
10.1
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 than (70 mm Hg +[2 x age] from 1 to 10 years, and less than 90 
mm Hg from 11 to 17 years.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
04 July 2022
EudraCT number 
EU number
2020-005587-55
BI Trial number
1368-0067
BI Investigational Product(s)
BI 655130
Title of protocol
An open-label, long-term extension trial of 
spesolimab treatment in adult patients with 
Hidradenitis Suppurativa (HS)
Global amendment due to urgent safety reasons
No
Global amendment
X
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS, 
Trial Endpoints, 2.1.3 Secondary endpoints(s)
Description of change
Change the wording in two endpoints
FROM:
Number of patients having at least one flare 
(defined as at least 
 in AN count 
with a minimum increase of 2 relative to
baseline) up to Week 
Number of patients having at least 
 
 from baseline in Numerical Rating 
Scale (NRS30) in Patient’s Global Assessment 
of HS Pain up to Week 
TO:
Occurrence of at least one flare (defined as at 
least 
 in AN count with a minimum 
 of  relative to baseline) up to Week 
.
Achievement of at least
 from 
baseline in Numerical Rating Scale (NRS30) in 
Patient’s Global Assessment of HS Pain up to 
Week 
Rationale for change
To better clarify and to make these two 
secondary endpoints more informative.
Section to be changed
Flow Chart - Up to W
Description of change
Add footnote about dose modification at Week 
12
Rationale for change
To align with Table 3.1: 1 and instructions in 
section 3.1
Section to be changed
Flow Charts, Footnotes #8 and #17, Section 5.1.1
Description of change
Added information that the HiSCR value is 


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calculated automatically.
Rationale for change
To clarify that the HiSCR value is not required to 
be completed by the investigator.
Section to be changed
Flow Chart -W
to End of study, Section 3.3.4
Withdrawal of patients from treatment, 6.2.3
Follow-up period and trial completion
Description of change
Align wording FUP1 and EoS visit timelines 
with Flow Chart. FUP 1 is two weeks after last 
dose and EOS is 
 weeks after last dose.
Rationale for change
To have consistent wording
Section to be changed
Flow Chart – W
 to End of Study
Description of change
Add footnote ***. Clarification on re-assessment 
of Non-responders on 
 at Week 
Rationale for change
To align with the information in Table 3.1: 1.
Section to be changed
Table 1.4.2:1 Risks
Description of change
The risk “Peripheral Neuropathy” was added to 
Table 1.4.2:1 including a summary of data and 
mitigation strategy.
Rationale for change
Added to inform about the newly added potential 
risk “peripheral neuropathy” deriving from the 
three cases reported as Guillain-Barré syndrome 
by the investigator in Spesolimab trials (details 
in the CTP). The cases were considered as 
peripheral neuropathy by the external neurologist 
expert panel’s assessment.
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
Include the discontinuation of Non-responders 
on 
 at Week 
Rationale for change
To be consistent with Table 3.1: 1
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
The patient needs to take concomitant 
medication such as immunosuppressive 
biologics, systemic corticosteroids, other 
immunomodulators, opioid analgesics for HS, 
live vaccines, or other concomitant medication 
that interferes with the Investigational Medicinal 
Products (IMP) or other trial treatment.
Rationale for change
To be consistent with Table 4.2.2.1: 1 –
Restricted Medication.
Section to be changed
3.3.4.1 Discontinuation of trial treatment
Description of change
Added language in bold i.e. The patient can no 


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longer receive trial treatment for medical reasons 
such as surgery, serious or severe Drug 
Induced Liver Injury attributable to the trial 
drug, other adverse events, other diseases, or 
pregnancy. Also refer to Section 5.2.6.1.4.
Rationale for change
To use standard language.
Section to be changed
4.1.4, 7th paragraph
Description of change
Add the name of the exact document, i.e., 
Instructions for Pharmacist, which is found in the 
ISF.
Rationale for change
To clarify the name of the document in the ISF.
Section to be changed
4.2.1.4 Peripheral Neuropathy
Description of change
Following information was added: “Peripheral 
Neuropathy”
If peripheral neuropathy is suspected, treatment 
with Spesolimab should be temporarily 
discontinued until a full neurological 
investigation has been conducted. After 
completion of the neurological investigation, 
treatment can be restarted based on medical 
judgement of the investigator.
Rationale for change
Added as mitigation strategy to account for the 
three cases reported as Guillain-Barré syndrome 
in spesolimab trials. The cases were considered 
as peripheral expert panel’s assessment (details 
in the CTP).
Section to be changed
Table 4.2.2.1: 1 – Restricted Medications
Description of change
Move footnote #6 to “Restricted for HS”
Rationale for change
To clarify that topical corticosteroids are allowed 
prior to Week 
for non-HS areas only.
Section to be changed
4.2.1.1, 3rd paragraph
Description of change
Add the name of the exact document, i.e., 
Instructions for Pharmacist, which is found in the 
ISF.
Rationale for change
To clarify the name of the document in the ISF.
Section to be changed
4.2.1.1, 4th paragraph
Description of change
Add the name of the exact document, i.e., Use of 
Spesolimab Pre-filled Syringes, which is found 
in the ISF.
Rationale for change
To clarify the name of the document in the ISF.
Section to be changed
4.2.2.1


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Description of change
(W0 - W
and W
through to EoT).
Rationale for change
Change W
 to W
to match the headings in 
the Restricted Medications Table 4.2.2.1: 1
Section to be changed
4.2.2.2
Description of change
If a patient receives rescue treatment, the 
decision to maintain the patient on trial treatment 
is based on the investigator’s clinical 
judgement.
Rationale for change
To remove the need for the investigator to 
discuss their decision with the sponsor.
Section to be changed
4.2.2.4
Description of change
Opiate analgesics (except synthetic opioids 
such as tramadol) are restricted for HS. It can 
be allowed for non-HS indications as per 
investigator discretion
Rationale for change
This is a 2-year OLE trial with a primary 
endpoint of TEAE. Tramadol is added to allow 
for pain relief for HS or non-HS indications to 
help patients over this 2-year period.
Section to be changed
4.2.2.7 Contraception Requirements
Description of change
Remove the following sentence: A double barrier 
method of contraception is not required.
Rationale for change
Sentence is redundant and confusing. The 
acceptable methods of birth control are defined 
in this section.
Section to be changed
5.2.3 Safety laboratory parameters
Description of change
If blood sampling for central lab is not possible 
because central laboratory supplies are not 
available on time, safety lab analyses can be 
performed at a local laboratory. The results of 
the local lab tests must be reported to the 
investigator who ensures medical review and 
proper documentation in the eCRF.
Rationale for change
To prevent that an important safety laboratory 
analysis is not done and allow local safety 
analysis in emergency
Section to be changed
5.2.5.2 Columbia-Suicide Severity Rating Scale 
(C-SSRS)
Description of change
Remove reference to investigator having to write 
a report and instead confirm their review in the 
source notes or by writing reviewed on 
questionnaire, signs and dates the questionnaire
Rationale for change
To remove the requirement that required the 


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BI Trial No.: 1368-0067
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Clinical Trial Protocol
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investigator to write a report; not necessary.
Section to be changed
5.2.6.1.4 Adverse events of special interest
Description of change
Added Peripheral Neuropathy as an Adverse 
event of special interest.
Rationale for change
To update reporting requirements to ensure all 
cases of suspected peripheral neuropathy 
including non-serious ones are analyzed quickly.
Section to be changed
6.2.3 Follow-up period and trial completion
Description of change
After conclusion of trial the patients will be 
treated according to the standard of care.
Rationale for change
To include a statement of treatment after 
conclusion of trial
Section to be changed
Abbreviations; 7.2.1; 7.2.2; 7.2.5
Description of change
Treated Set (TS) replaced by SAFety analysis set 
(SAF)
Rationale for change
To be aligned with the Trial Statistical Analysis 
Plan


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
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c33707086
2.0
clinical-trial-protocol-version-01
An open-label, long-term extension trial of spesolimab treatment in adult patients
with Hidradenitis Suppurativa (HS)
Approval-Biostatistics
05 Jul 2022 17:10 CEST
Approval-Clinical Trial Leader
05 Jul 2022 17:39 CEST
Approval-Clinical Program 
07 Jul 2022 12:31 CEST
Approval-Principal Investigator
07 Jul 2022 15:51 CEST


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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
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c33707086
2.0

SAP_001.pdf: 
ABCD
BI-VQD-12681-S-G_50-415_AD-01 (5.0)
TRIAL STATISTICAL ANALYSIS PLAN
TITLE PAGE
Document No.:
c43847488-01
BI Trial No.:
1368-0067
Title:
An open-label, long-term extension trial of spesolimab treatment 
in adult patients with Hidradenitis Suppurativa (HS)
Investigational
Product(s):
Spesolimab, BI 655130
Responsible trial 
statistician(s):
Tel.: 
Fax: 
Tel.: 
Date of statistical 
analysis plan:
04 Jun 2024
Version:
2.0 Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS(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 ..........................................................14
6.1
TREATMENT(S)................................................................................................14
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................16
6.3
INTERCURRENT EVENTS .............................................................................16
6.4
SUBJECT SETS ANALYSED...........................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................19
6.6.1
Withdrawals ........................................................................................................19
6.6.2
Efficacy data........................................................................................................19
6.6.3
Safety data ...........................................................................................................20
6.6.4
PK data.................................................................................................................21
6.6.5
Biomarker data ...................................................................................................21
6.6.6
Time since first diagnosis ...................................................................................21
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................21
7.
PLANNED ANALYSIS......................................................................................26
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........28
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................28
7.3
TREATMENT COMPLIANCE........................................................................29
7.4
PRIMARY OBJECTIVE ANALYSIS..............................................................29
7.5
SECONDARY OBJECTIVE ANALYSIS........................................................29
7.5.1
Key secondary objective analysis.......................................................................29
7.5.2
Secondary objective analysis..............................................................................29
7.6
FURTHER OBJECTIVE ANALYSIS..............................................................30
7.6.1
Further efficacy endpoints .................................................................................30


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7.6.2
Use of rescue therapy..........................................................................................30
7.6.3
Other analysis......................................................................................................31
7.7
EXTENT OF EXPOSURE.................................................................................31
7.8
SAFETY ANALYSIS..........................................................................................31
7.8.1
Adverse Events ....................................................................................................31
7.8.2
Laboratory data ..................................................................................................34
7.8.3
Vital signs.............................................................................................................36
7.8.4
ECG......................................................................................................................36
7.9
OTHER ANALYSIS...........................................................................................36
7.9.1
Biomarker analyses.............................................................................................36
7.9.2
Immunogenicity...................................................................................................36
7.9.3
PK / PD analyses .................................................................................................37
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............39
9.
REFERENCES....................................................................................................40
11.
HISTORY TABLE..............................................................................................51


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases of the study .......................................................15
Table 6.4: 1
Overview of use of patient analysis sets by class of endpoint and handling of 
estimand and missing data................................................................................18
Table 6.7: 1
Time windows for assignment of vital signs to visits for statistical analysis...23
Table 6.7: 2
Time windows for assignment of DLQI, PGI-S, PGI-C, HiSQoL, Pain NRS 
safety lab, and biomarker to visits for statistical analysis ................................24
Table 6.7: 3
Time windows for assignment of all the other efficacy assessments except 
those mentioned in Table 6.7: 2 to visits for statistical analysis. .....................25
Table 7.1: 1
Categories for summary of continuous variables .............................................28
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events 
Concepts ...........................................................................................................33
Table 11: 1
History table .....................................................................................................51


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glosssary
Term
Definition / description
ADA
Anti-drug antibodies
ADS
Analysis dataset
AdT
total abscess, inflammatory nodule and draining tunnel
AE
Adverse event
AESI
Adverse event of special interest
ALQ
Above the upper limit of quantification
ALT
Alanine aminotransferase
AN
Abscess and inflammatory nodule
ANdT
Abscess, inflammatory nodule and draining fistula/tunnel 
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
ATC3
Anatomical-Therapeutic-Chemical classification level 3
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
CTA
Clinical Trial Application
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting


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Term
Definition / description
DMC
Data monitoring committee
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
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
m-HiSCR
Modified - Hidradenitis suppurativa clinical response
HS-CRP
High-Sensitivity C-Reactive Protein
IHS4
International Hidradenitis Suppurativa Severity Score System
IHS4-55
At least a 55% reduction from baseline in IHS4
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
i.v. 
intravenous
MAA/BLA
Market Authorization Application/Biologics Licence Application


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Term
Definition / description
MedDRA
Medical Dictionary for Regulatory Activities
DLQI
Dermatology Life Quality Index
Nab
Neutralising antibody
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
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
REP
Residual effect period
RNA
Ribonucleic acid
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SI
Système international d’unités
SOC
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, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, 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, 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).
Analyses of the biomarker and gene expression data are described in a separate biomarker 
TSAP, unless otherwise specified in this document.
Since the primary aim of this study is to collect long-term safety and efficacy data on the use 
of spesolimab (BI 655130) in adult patients with Hidradentis suppurativa (HS), 1 interim 
analysis when all the rolled over patients reach Week 12 in this trial will be done over the 2-
year conduct phase of this trial in order to support, for example, regulatory interactions, 
Clinical Trial Applications (CTA), and Market Authorization Application/Biologics Licence 
Application  (MAA/BLA)submissions, but also to provide important safety and efficacy 
information to the sponsor to guide further development of the compound, and to the 
investigators via IB updates and publications. Any data cut-off to be used for the reporting of 
trial data at interim will be presented in either a separate data cleaning plan, or in an appendix 
to this TSAP. If considered appropriate, an access plan may be developed at the time of the 
interim which describes those personnel who will be allowed access to the results of the 
interim data analysis. 


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4. CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses stated in the CTP (latest version) will be performed as planned with the 
following adaptations.
Considering the categorical nature of PGI-S and PGI-C, the frequency over time will be 
presented for these further endpoints instead of absolute change from baseline as planned in 
CTP.
The below further efficacy endpoints, which were not specified in the CTP, have been added:

Percent change from baseline (%) in total abscess and draining fistula (AdT) count 
over time.

Percent change from baseline (%) in total abscess, inflammatory nodule and draining 
fistula/tunnel (ANdT) count over time.

Proportion of patients with achievement of m-HiSCR response over time.

Proportion of patients with achievement of IHS4-55 response over time.

Percent change from baseline (%) in total inflammatory nodule count up over time.

Percent change from baseline (%) in total abscess count up to over time.

Achievement of complete elimination of draining fistulas over time.

Achievement of complete elimination of abscess over time.

Proportion of patients with achievement of HiSCR over time.

At least 30% reduction from baseline in Numerical Rating Scale (NRS30) in Patient’s 
Global Assessment of HS Pain over time.


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5.
ENDPOINTS(S)
For estimand and handling of missing data and the occurrence of inter-current events, unless 
otherwise specified, see Section 6.3, Section 6.4 and Section 6.6. For the specification of 
baseline definition, unless otherwise specified, see Section 6.7.
For the summary of all efficacy data, only those observations which were collected during the 
on-treatment period will be used.
Baseline for safety data, unless otherwise specified, is the last value prior to initiation of 
treatment in current 1368-0067 study.
Regarding the analyses of the change from baseline by visit or compared to baseline by visit 
for efficacy endpoints, unless otherwise specified, we will use last measurement collected 
prior to initiation of spesolimab as baseline. i.e.,
•
For prior spesolimab arm in 1368-0052, the baseline in parent trial is used, which 
refers to the last measurement collected prior to initiation of treatment in 1368-0052.
•
For prior placebo arm in 1368-0052, the baseline in current trial is used, which refers 
to the last measurement collected prior to initiation of treatment in 1368-0067.
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is the occurrence of treatment-emergent adverse events (TEAEs) up to 
the end of the maintenance treatment period including REP (i.e., 16 weeks after the last study 
treatment).
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)
Secondary endpoints are defined as described below:

Percent change in 
 abscess and inflammatory nodule (AN) count from baseline (%) 
up to Week 

Percent change in 
 draining fistula (DF) count from baseline (%) up to Week 
 
(Only patients with at least 1 draining fistula at baseline will be used for analysis).

Hidradenitis suppurativa Clinical Response (HiSCR) up to Week 

Change from baseline in International Hidradenitis suppurativa Severity Score System 
(IHS4) value up to Week 

Hidradenitis suppurativa Physician Global Assessment (HS-PGA) score of 0 or 1 up to 
Week 

Absolute change from baseline in Hidradenitis suppurativa Area and Severity Index
(HASI) score up to Week 

At least one flare (defined as at least 
 in AN count with a minimum 
 


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of  relative to baseline) up to Week 

At least 
 from baseline in Numerical Rating Scale (NRS30) in Patient’s 
Global Assessment of HS Pain up to Week 


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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 first dose at Day 1 as below:


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Table 6.1: 1
Flow chart of analysis phases of the study 
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 second.
Treatment phase 
& Residual 
effects period
On-treatment 
period
Date/time of start of 
the first study dose 
regardless of infusion 
or injection (Day 1)
Earliest of: i) Date of last study 
drug regardless of infusion or 
injection + 112 days at 23:59, 
ii) cut-off for interim analysis 
if applicable.
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. 
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.
Treatments will be labelled for final analysis as follows:
Tables will be displayed also by prior treatment from parent trial for final analysis:

“Prior Placebo” (applicable to analysis for whole on-treatment period, i.e., including 
infusion loading at Day 1 for placebo patients from parent trial]
-
“Prior Placebo + uptitration at Week 
 (applicable to analysis for whole on-
treatment period, i.e., including infusion loading at Day 1 for placebo patients from 
parent trial and after dose escalation]
-
“Prior Placebo + Other” (applicable to analysis for whole on-treatment period, i.e., 
placebo patients from parent trial who received 
 dose 
 during all 
 period or who were early discontinued before Week 
])


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
“Prior Speso” (applicable to analysis for whole on-treatment period, i.e., including 
 at Day 1 for speso patients from parent trial, before and post dose 
escalation)
-
“Prior Speso + uptitration at Week 
” (applicable to analysis for whole on-treatment 
period, i.e., including 
 at Day 1 for speso patients from parent trial 
and after dose escalation)
-
“Prior Speso + Other” (applicable to analysis for whole on-treatment period, i.e., 
speso patients from parent trial who received 
 during all 
 
 or who were early discontinued before Week 
)
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 violations of 
time windows) and a list of protocol deviations will be provided to be discussed at the 
RPM/DBLM/ CQM. 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). 
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)" (3).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM/CQM 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 sites, then this table will be 
supplemented accordingly by the time of the RPM/DBLM/CQM. Not all iPDs will lead to 
exclusion from analysis sets. Certain iPDs may lead patients to being excluded from all the 
analyses.
As this is an open label, long term safety trial, all analyses will be performed based on the 
treated population only. Since no confirmatory efficacy testing is planned, no efficacy related 
iPDs leading to exclusion from analysis set are defined.
6.3
INTERCURRENT EVENTS
The expected intercurrent events (ICEs) of interest in this trial are:

Use of rescue therapy (while still on treatment), as defined in Section 5.4.3

Treatment discontinuation without restricted medication, flagged by medical review if 
occurring

Treatment discontinuation with restricted medication, flagged by medical review if 
occurring
The strategies for handling intercurrent events in this trial are as follows:
Hybrid Strategy (EC-H): All intercurrent events except for the administration of rescue 
therapy will be handled using the treatment policy approach. Rescue therapy will be handled 


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using the hypothetical approach, under the scenario in which the intercurrent event would not 
occur. This will be used as the primary strategy of implementing the Estimand Concept 
(EC), allowing the effects of adherence, i.e., regardless of treatment discontinuation, but 
excluding the effects of rescue therapy. 
No deaths are expected in this trial. In the unlikely event of a death occurring, it will be 
handled using a hypothetical approach for each strategy.
6.4
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.
Safety Analysis Set (SAF):
This patient set includes all patients who received at least one dose of study drug in trial 
1368-0067. This is the main analysis set for efficacy and safety. Patients will be analyzed 
according to the actual treatment received.
Safety Set ADA (SAF-ADA)
This patient set includes all patients who received at least one dose of study drug and had at 
least one evaluable ADA sample in trial 1368-0067. This is the main analysis set for ADA 
impact on efficacy and safety. Patients will be analyzed according to the actual treatment 
received.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at the RPM/DBLM at the latest.


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Table 6.4: 1
Overview of use of patient analysis sets by class of endpoint and handling of 
estimand and missing data 
Class of endpoint
  
ES
SAF
Disposition
OR
Compliance and 
exposure
OR
iPD
OR
Demographic/baseline 
characteristics
OR
Concomitant 
medication
OR
Primary endpoint
OR
Secondary binary 
efficacy endpoints
OC-NRI: for binary 
efficacy endpoints
Secondary continuous 
efficacy endpoints
OC for continuous 
efficacy endpoints.
Further efficacy 
endpoints 
OC for continuous 
efficacy endpoints.
OC-NRI: for binary 
efficacy endpoints
Plasma concentration 
& ADA
OR
Efficacy endpoints by 
ADA impact
OC for continuous 
efficacy endpoints
OC-NRI for binary 
efficacy endpoints
AE
OR
Lab data, vital signs
OC-IR
For explanation of the different approaches with regard to missing data see Section 6.6.
OC = observed cases excluding values after any use of rescue medication.
OC-IR = observed cases including also values after any use of rescue medication.
OC-NRI = values after any use of rescue medication will be censored and impute with non-responder..
OR = original results. 
NRI = Non-Response Imputation, cf. Section 6.6.2.


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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 6.4: 1) Approaches to be applied are 
described below.
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 


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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 interim analysis planned at week 
 those efficacy endpoints up to Week 
 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. 
For final analysis, the efficacy endpoints during on-treatment period will 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.
Binary efficacy endpoints
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: No Response Imputation [NRI]):
•
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.
OC-NRI method will be used to display the binary data.
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 Observed cases (OC-IR: with 
no imputation for any missing data, which will include values after any rescue medication or 
treatment discontinuation.) approach will be used. 
For safety data that are not displayed by visit such as AE and possibly clinically significant 
laboratory abnormality, original results (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 (10). 
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 (11). 
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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For the baseline defined in efficacy endpoints like “change from baseline” or “compared to 
baseline”, unless otherwise specified, is defined as the last measurement before initiation of 
treatment (cf. Section 5). 
Baseline for time to event endpoints, is defined as the last measurement collected prior to the 
start of administration of the trial treatment in the current extension trial 1368-0067.
For analysis of anti-drug antibodies (ADA), 2 different baselines will be used for the clinical 
trial report (CTR). For the analysis of ADA impact on pharmacokinetic (PK), the entire course 
of treatment is to be considered and assessments prior to initial trial of the parent trial (1368-
0052)  is considered baseline. Details will be discussed on the trial CTR.
For the analysis of ADA impact on safety and efficacy endpoints, baseline is defined as the 
first evaluable sample collected prior to treatment administration at baseline of this trial 0067.
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 6.7:2, Table 6.7:3.


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Table 6.7: 1
Time windows for assignment of vital signs to visits for statistical analysis.
Visit number
Visit 
label
Planned day
Time window [day]
Window 
(per CTP)
Start 
(per CTP)
End
(per CTP)
Start
(extended)
End
(extended)
1
Week0
Day1
n/a
1 A
1
1 A
1
2
Week
Day
+-2
3
Week
Day
+-2
4
Week
Day
+-2
5
Week
Day
+-2
6
Week
Day
+-2
7
Week
Day
+-2
8
Week
Day
+-3
…
…
…
…
Planned 
date-3
Planned 
date+3
End of 
extended 
window of 
last 
visit+1 
Midpoint 
of planned 
days 
between 
current 
visit and 
next visit
53
Week
EoT
Da
+-3
54
Week
(FUP1)
Da
+-3
55
Week
(EOS)
Da
+-10
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 first treatment of current study, which is defined as Day 1.
* For the patients who enter OLE trial, V1 is strongly recommended to be performed during the EOT of 
the preceding parent trial.
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.


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Table 6.7: 2
Time windows for assignment of DLQI, PGI-S, PGI-C, HiSQoL, Pain NRS 
safety lab, and biomarker to visits for statistical analysis
Visit number
Visit label
Planned 
day
Time window [day]
Window 
(per CTP)
Start 
(per CTP)
End
(per CTP)
Start
(extended)
End
(extended)
1
Week0
Day1
n/a
1 A
1
1 A
22
3
Week
Day
+-2
5
Week
Day
+-2
7
Week
Day
+-2
8
10
12 
14
16
18
20
22
24
…
52
Week
Week
Week
Week
Week
Week
Week
Week
Week
…
Week
Day
Day
Day
Day
Day
Day
Day
Day
Day
Day
+-3
+-3
+-3
+-3
+-3
+-3
+-3
+-3
+-3
…
+-3
Midpoint 
of planned 
days 
between 
current 
visit and 
next visit
53
Week
EoT
Day
+-3
54
Week
(FUP1)
Day
+-3
55
Week
(EOS)
Day
+-10
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 first treatment of current study, which is defined as Day 1.
* For the patients who enter OLE trial, V1 is strongly recommended to be performed during the EOT of 
the preceding parent trial.
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.


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Table 6.7: 3
Time windows for assignment of all the other efficacy assessments except 
those mentioned in Table 6.7: 2 to visits for statistical analysis.
Visit number
Visit 
label
Planned day
Time window [day]
Window 
(per CTP)
Start 
(per CTP)
End
(per CTP)
Start
(extended)
End
(extended)
1
Week0
Day1
n/a
1 A
1
1 A
1
2
3
4
Week
Week
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 first treatment of current study, which is defined as Day 1.
* For the patients who enter OLE trial, V1 is strongly recommended to be performed during the EOT of 
the preceding parent trial.
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.


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7.
PLANNED ANALYSIS
Final trial analysis is planned to be performed at the end of the study once all patients have 
completed the study (including any follow-up period) if applicable. As specified in CTP in 
Section 7.2.7, multiple interim analyses may be done over the 2-year conduct phase of this 
trial. The corresponding snapshot will be taken for the interim analysis and data only up to the 
cut-off will be included into the analysis.
First interim analysis up to Week 
The interim analysis is planned after all patients in current study finishing their Week 
 visit 
or early discontinued before the visit, and a snapshot will be performed. All data collected up 
to Week 
 dosing will be included in this interim analysis. 
Final analysis
Final trial analysis will be performed once all patients have completed the trial; at that time point, 
a final database lock will be done. 
General Remarks
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
Clinical Trials and Project Summaries" (9) and those generated for PK will follow BI 
guideline " Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics" (11).
The individual values of all patients will be listed, including those collected during the off-
treatment period. Listings will generally be sorted by country, centre number, patient number 
and visit (if visit is applicable in the respective listing). 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:
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:


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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" (9).
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 treated patient set. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actual missing values. Percentages will be 
based on all patients in the respective patient set whether they have non-missing values or not 
unless there is another particular specification.
Disposition of the patient population participating in the trial will be summarised by 
presentation of the frequency of patients enrolled, treated, enrolled but not treated, who 
completed all doses of trial medication as planned, who completed the trial (EOS), who 
prematurely discontinued study treatment, by reason and who withdrew from the trial, by 
reason. Summary statistics of patients who did the dose modification at Week 12 and patients 
who discontinued due to no change observed at Week 24 after dose modification (according 
to Table 3.1: 1 in CTP) will be also displayed. The frequency of patients with iPDs will be 
presented; iPDs will be listed per patient.
To better illustrate the long-term disposition of entire maintenance treatment (cf. Section 6.1), 
a summary table regarding patient status over time will be added. The cumulative frequency 
of patients for the following categories will be displayed based on 
-week intervals:

Ongoing on study medication, i.e., without early treatment discontinuation by the time 
point
o
Intake of rescue medication
o
Up-titrate the dose to 
o
Any of the above

Pre-maturely stopped study medication, i.e., discontinued study medication by the 
time point
o
Intake of rescue medication
o
Up-titrate the dose to 
o
Any of the above

Ongoing but not achieved the visit, if due to the cut-off of interim analysis
o
Intake of rescue medication
o
Up-titrate the dose to 


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o
Any of the above
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive statistics will be presented for demographic parameters and baseline 
characteristics, based on the SAF.
Characteristics of the trial disease will be displayed for patients receiving at least 1 dose of 
study drug. 
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:
Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
<30 years
30 to <65 years
≥65 years
Body 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 SAF.
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.
A medication/non-drug therapy will be considered concomitant to treatment, if 

starting prior to day of first trial treatment OR on treatment in 1368-0052

ongoing at the start of trial treatment or


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
starting within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
Concomitant medication use (excluding rescue therapy) will be summarized with frequency 
and percentage of patients by preferred name. Summaries will be presented for 

starting prior to day of first trial treatment OR on treatment in 1368-0052

concomitant medication starting any time during the on-treatment period (cf. Section 6.1)
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 

starting prior to day of first trial treatment OR on treatment in 1368-0052

concomitant non-drug therapies starting any time during the on-treatment period (cf. 
Section 6.1).
Use of rescue therapy will be summarized separately (see Section 7.6.2). 
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) for day 1, maintain period and overall treatment period. 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 OBJECTIVE ANALYSIS
Refer to Section 7.8.1 for the description for adverse events including the primary endpoint.
7.5
SECONDARY OBJECTIVE ANALYSIS
7.5.1
Key secondary objective analysis
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary objective analysis
For continuous secondary endpoints, the primary analysis will implement the hybrid strategy 
(EC-H) of handing ICE defined in Section 6.3. Any data collected after the ICE will be 
censored for the timepoint afterwards, i.e., only data prior to the ICE will be considered. 


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Descriptive summaries and graphical displays (line plots) will be produced using OC method 
for continuous secondary endpoints and binary secondary endpoints respectively.
7.6
FURTHER OBJECTIVE ANALYSIS
Analysis of further endpoints is described in Section 7.2.4 of the CTP. All analyses of further 
endpoints will be performed for the SAF.
7.6.1
Further efficacy endpoints
For each of the further endpoint described below, hybrid strategy will be used to handle 
intercurrent events which lead to data censoring as described for the primary endpoint. 
Continuous further endpoints
The further continuous and binary endpoints will be evaluated in a descriptive manner using 
OC method as section 7.2.4 in CTP, by visit if applicable.
Questionnaires will be descriptively summarized by visit.
Binary further endpoints
Descriptive statistics will be displayed based on the OC-NRI approach for each of the binary
further endpoint, by visit if applicable.
7.6.2
Use of rescue therapy
Summary of use of rescue therapy
Frequency of use of rescue therapy, as identified on the eCRF, from Day 1 up to the end of 
reporting period, will be summarized with the number and percentage of patients by preferred 
name.
Time to first use of rescue therapy
The time to event will be defined as the start date of first rescue therapy use minus the date of 
first drug administration, plus 1 day. If patient has no rescue therapy, the time to first use of 
rescue therapy will be censored on the patient level at the last contact day up to the end of 
reporting period.
A Kaplan-Meier analysis of time to the first use of rescue therapy will be presented. KM-
estimates of the survival/failure probabilities at weekly intervals, as well as the median time-
to-event will be provided. Confidence intervals will be based on two-sided α= 0.05. 


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7.6.3
Other analysis
Since there’s dose modification at week 
 and and re-assessment week 
  according to the 
Table 3.1: 1 in CTP, descriptive summaries for the status of HS-PGA grade change at Week 
 and Week 
 by responder status at baseline will be provided.
7.7
EXTENT OF EXPOSURE
An overall table will summarize the entire 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 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 for overall on-treatment period. 
No hypothesis testing is planned. OC-IR and OR methods will be used for safety reporting.
AE and possibly clinically significant laboratory abnormalities will be analysed 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.
7.8.1 Adverse Events
AEs will be coded with the most recent version of MedDRA.
For AEs in current trial, we will summarize AEs start in 1368-0052 and still ongoing in 
current trial 1368-0067 plus new AEs start in current trial.
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 (SOC, if 
applicable) will be sorted according to the standard sort order specified by the EMA, preferred 
terms (PT, if applicable) will be sorted by total frequency (within SOC).
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" (10).


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The analysis of AEs will be based on the concept of TEAEs. This means that all AEs will be 
assigned to the screening period, on-treatment period (i.e. 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. 
Exposure-adjusted adverse event incidence rates for TEAE will be calculated using the 
following approach:
1)
The exposure adjusted incidence rate (per 100 subject years) of a selected TEAE is 
defined as the number of subjects experiencing the adverse event per treatment group 
during time at risk divided by the total time of subjects at risk to contribute the event to 
the analysis multiplied by 100 (per 100 subject years), where: 
Time at risk [subject years] = (date of onset of AE – first treatment start date in current 
study +1) / 365.25
2)
If, for a subject, the selected TEAE didn’t occur, then the time at risk will be censored at 
min (date of death, last contact date per EoS page, cut-off date for the interim analysis, or 
the end of on-treatment period). For each selected TEAE, the exposure adjusted incidence 
rate will be calculated as: 
Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with TEAE / 
Total TEAE-specific time at risk [subject years].
An overall summary of AEs will be presented. This overall summary will include summary 
statistics for the class of other significant AEs (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.
In addition, user defined adverse event concepts (UDAEC) identified through specific search 
criteria will be reported separately (see Table 7.8.1: 1)


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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”
Depression
Depression
sub-SMQ "Depression (excl suicide and self-
injury)", broad


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User-defined AE category
Label 
Description
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 prior treatment from parent trial, 
primary SOC and PT. 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 PTs) will be summarised by 
treatment, primary SOC and PT. 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 PTs) 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 
(12). 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 (12). 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 time, 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 1 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 4 quadrants. 
Normal cases are in the lower left quadrant, potential DILI cases are in the upper right 


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quadrant (Hy’s Law quadrant), while the lower right quadrant is known as the Temple’s 
corollary range (ALT ≥3xULN and total bilirubin <2xULN).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
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.
7.9
OTHER ANALYSIS
7.9.1 Biomarker analyses
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 (in case they are 
reported in the CTR, the analysis will be described in the CTR). 
For the analysis of biomarkers, log transformed data will be used where deemed necessary.
7.9.2 Immunogenicity
Analysis of ADA and assessments of ADA impact on PK  will be  performed based on the 
complete administration data of spesolimab from both 1368-0052 and this trial data 1368-
0067. Analysis of assessments of ADA impacts on safety and efficacy endpoints will be 
performed based on this 1368-0067 trial data only for the clinical trial report (CTR). 


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The ADA status and titre as well as frequency of patients with ADA to spesolimab will be 
presented by visit. Descriptive statistics of ADA titre (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 are available and these will be 
described, if done, in the CTR.
Further analyses based on ADA data will be performed for efficacy-based and safety-based 
analysis with the following ADA and neutralizing antibody (NAb) status and endpoints. 
Patient is considered ADA positive (+) if he/she had at least 1 positive ADA sample in the 
trial. Otherwise, patient is considered ADA negative (-). Patient is considered NAb positive 
(+) if he/she had ADA positive and at least 1 NAb positive sample in the trial. Patient is 
considered NAb negative (-) if he/she had ADA positive but no NAb positive sample OR if 
he/she is considered ADA negative.
-
efficacy-based subgroup analysis as described in Section 6.4
•
ADA positive and ADA negative subjects (at Week 12 or later time), or
•
Neutralising antibody (Nab) positive and NAb negative subjects (at Week 12 or 
later time)
-
Safety-based subgroup analysis (using e.g. hypersensitivity safety events)
•
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.
7.9.3 PK / PD analyses
No PK parameters will be calculated.
The descriptive analysis of spesolimab plasma concentrations will be based on the PKS.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 


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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 (11).
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
Due to the first dose of current study is blinded, the treatment information will be loaded into 
the trial database after the unblinding of parent trial 1368-0052.


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9.
REFERENCES
1.
BI-VQD-23790-S-G_50-415_AD-02 (v5.0): “Project Analysis Dataset (PADS) 
Template (template) “, current version, Group “Biostatistics & Data Sciences”, 
IDEA for CON.
2.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note for Guidance on Statistical Principles for Clinical Trials, current 
version.
3.
BI-VQD-12045_40-413 (v3.0): " Identify and 
Manage Important Protocol Deviations (iPD) ", current version; IDEA for CON
4.
BI-KMED-BDS-HTG-0041: “How to Guide: Analysis and Presentation of AE Data 
from Clinical Trials”, current version, KMED
5.
001-MCS-40-106_RD-03: “Clinical Trial Protocol general template for Phase I-
IV”, current version, Group “Clinical Operations”, IDEA for CON.
6.
001-MCS-80-606: “Management of Non-Compliances”, current version, Group 
“Quality Medicine”, IDEA for CON.
7.
001-MCS-40-135_RD-01: “Integrated Quality and Risk Management Plan”, current 
version, Group “Clinical Operations”, IDEA for CON.
8.
REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND 
OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for 
human use, and repealing Directive 2001/20/EC, European Commission webpage.
9.
BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project 
Summaries", current version; IDEA for CON.
10.
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON
11.
BI-KMED-TMCP-HTG-0025 (v1.0): “How to Guide: Standards and Processes for 
Analyses Performed within Clinical Pharmacokinetics/Pharmacodynamics”, current 
version, KMED.
12.
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data",
current version; IDEA for CON
13.
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.
14.
R20-3156: 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


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15.
001-MCG-156: "Handling and summarisation of adverse event data for clinical
trial reports and integrated summaries", current version; IDEA for CON
16.
R20-3045: The European Hidradenitis Suppurativa Foundation Investigator 
Group, Zouboulis C.C., TzellosT., 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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11. HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
12-Jan-2024
None
This is the final TSAP.
2.0
04-Jun-2024
Section 6.4 
Subject sets 
analysed 
Section 6.7 
Baseline, time 
windows and 
calculated visits
Section 7.9.2 
Immunogenicity
Following clarifications and 
changes and made on 
immunogenicity (anti-drug 
antibody (ADA)):
Section 6.4
Safety set ADA (SAF 
ADA) to be added
Section 6.7
Definitions of baseline of 
ADA is added 
Section 7.9.2
(1) data included in the 
ADA analysis
(2) Definitions of ADA 
and NAb (Neutralizing 
antibody) positive
are clarified.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c44454211
1.0
8-01-tsap-final ver2
An open-label, long-term extension trial of spesolimab treatment in adult patients
with Hidradenitis Suppurativa (HS)
Approval
04 Jun 2024 17:28 CEST
Approval-Clinical Program
04 Jun 2024 17:39 CEST
Approval
05 Jun 2024 13:29 CEST
Approval-Project Statistician
05 Jun 2024 16:12 CEST
Approval-Medical Writer
06 Jun 2024 09:56 CEST


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c44454211
1.0