Conditions: Generalized Pustular Psoriasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
To evaluate efficacy, safety, and tolerability of spesolimab (BI 655130) compared to placebo in patients with Generalized Pustular Psoriasis (GPP) presenting with an acute flare of moderate to severe intensity.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Spesolimab intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for infusion intervention 2: Solution for infusion

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c15875404-04
EudraCT No.:
EU Trial No:
2017-004231-37
BI Trial No.:
1368-0013
BI Investigational 
Product(s):
Spesolimab (BI 655130)
Title:
Effisayil™ 1: Multi-center, double-blind, randomized, placebo-
controlled, Phase II study to evaluate efficacy, safety and 
tolerability of a single intravenous dose of BI 655130 in patients 
with Generalized Pustular Psoriasis (GPP) presenting with an acute 
flare of moderate to severe intensity
Lay Title:
  A study to test BI 655130 in patients with a flare-up of a skin      
disease called Generalized Pustular Psoriasis
Clinical Phase:
II
Clinical Trial Leader:
Phone:
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on Global Amendment 2)
Version and Date:
Version:  3.0
Date: 26 Jun 2020
Page 1 of 149
Proprietary confidential information.
2020 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 
Finished product name
N/A
Active ingredient name:
Spesolimab (BI 655130)
Protocol date
27 June 2018
Revision date
26 Jun 2020
Trial number
1368-0013 
Title of trial:
Effisayil™ 1: Multi-center, double-blind, randomized, placebo-
controlled, Phase II study to evaluate efficacy, safety and tolerability of 
a single intravenous dose of BI 655130 in patients with Generalized 
Pustular Psoriasis (GPP) presenting with an acute flare of moderate to 
severe intensity
Coordinating 
Investigator:
Phone: 
; FAX: 
Trial site(s):
Multi-center trial conducted in 11 to 20 countries. 
Clinical phase:
II
Objective(s):
To evaluate efficacy, tolerability and safety of BI 655130 compared to 
placebo in patients with Generalized Pustular Psoriasis (GPP) presenting 
with an acute flare of moderate to severe intensity.
Methodology:
Multi-center, placebo-controlled, randomized, double blind 
Number of patients 
entered: 
51 patients 
Number of patients on 
each treatment:
34 patients on BI 655130 and 17 patients on placebo
Diagnosis:
Patients with Generalized Pustular Psoriasis (GPP) presenting with an 
acute flare of moderate to severe intensity.
Main in- and exclusion 
criteria
Main inclusion criteria:
Patients will be enrolled (screened) into the trial, if they meet the 
following criteria:

1a) Patients with GPPGA of 0 or 1 and a known and documented 
history of GPP per European Rare And Severe Psoriasis Expert 
Network (ERASPEN) criteria regardless of IL36RN mutation status, 


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with previous evidence of fever, and/or asthenia, and/or myalgia, 
and/or elevated C-reactive protein, and/or leucocytosis with 
peripheral blood neutrophilia (above ULN).
OR

1b) Patients with an acute flare of moderate to severe intensity 
meeting the (ERASPEN) criteria of GPP with a known and 
documented history of GPP (per ERASPEN criteria) regardless of 
IL36RN mutation status, with previous evidence of fever, and/or 
asthenia, and/or myalgia, and/or elevated C-reactive protein, and/or 
leucocytosis with peripheral blood neutrophilia (above ULN).
OR

1c) Patients with first episode of an acute GPP flare of moderate to 
severe intensity with evidence of fever, and/or asthenia, and/or 
myalgia, and/or elevated C-reactive protein, and/or leucocytosis with 
peripheral blood neutrophilia (above ULN). For these patients the 
diagnosis will be confirmed retrospectively by a central external 
expert/committee.

Patients may or may not be receiving background treatment with 
retinoids and/or methotrexate and/or cyclosporine. Patients must 
discontinue retinoids/methotrexate/cyclosporine prior to receiving 
the first dose of BI 655130/ placebo.

Male or female patients, aged 18 to 75 years at screening.

Signed and dated written informed consent prior to admission to the 
study in accordance with ICH-GCP and local legislation prior to 
start of any screening procedures.

Women of childbearing potential 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. Note: A woman is considered of 
childbearing potential, i.e. fertile, following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent 
sterilisation methods include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. Tubal ligation is not a method of 
permanent sterilization. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause.\
Main Exclusion Criteria:

Patients with SAPHO (Synovitis–acne–pustulosis–hyperostosis–
osteitis) syndrome.

Patients with primary erythrodermic psoriasis vulgaris.

Patients with primary plaque psoriasis vulgaris without presence of 
pustules or with pustules that are restricted to psoriatic plaques.


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
Drug-triggered Acute Generalized Exanthematous Pustulosis 
(AGEP).

Immediate life-threatening flare of GPP or requiring intensive care 
treatment, according to the investigator’s judgement. Life-
threatening complications mainly include, but are not limited to, 
cardiovascular/cytokine driven shock, pulmonary distress syndrome, 
or renal failure. 

Severe, progressive, or uncontrolled hepatic disease, defined as >3-
fold Upper Limit of Normal (ULN) elevation in AST or ALT or 
alkaline phosphatase, or >2-fold ULN elevation in total bilirubin.

Patients with dose escalation of their maintenance therapy with 
cyclosporine and/or methotrexate and/or retinoids within the 2 
weeks prior to receiving the first dose of BI 655130/ placebo.

The initiation of systemic agents such as cyclosporine and/or 
retinoids and/or methotrexate 2 weeks prior to receiving the first 
dose of BI 655130/ placebo.
Treatment (Visit 2) will be initiated immediately in patients:

Who meet the inclusion criteria above

Who are presenting with an acute GPP flare of moderate to severe 
intensity, defined by emergence of:
a) Generalized Pustular Psoriasis Physician Global Assessment
(GPPGA) score of at least 3 (moderate), and
b) presence of fresh pustules (new appearance or worsening of 
pustules), and
c) GPPGA pustulation sub score of at least 2 (mild), and
d) at least 5% of Body Surface Area (BSA) covered with erythema 
and the presence of pustules

And who do not meet any of the exclusion criteria above.
Test product(s):
BI 655130 solution for infusion 60 mg/ml 
dose:
900 mg, single dose 
mode of 
administration:
i.v.
Comparator products:
Placebo comparator
dose:
Not applicable
mode of 
administration:
i.v.
Duration of treatment:
Single dose
Endpoints 
Primary Endpoint:


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The primary endpoint of the study is:

A Generalized Pustular Psoriasis Physician Global Assessment 
(GPPGA) pustulation subscore of 0 indicating no visible pustules at 
Week 1.
Key Secondary Endpoint:
The Key secondary endpoint of the study is: 

A GPPGA score of 0 or 1 at Week 1.
Secondary Endpoints: 
Secondary Endpoints of the study at Week 4 which are included in the 
statistical testing strategy in a hierarchical manner subsequent to 
performance of the tests on the primary endpoint and key secondary 
endpoint are:

A Psoriasis Area and Severity Index for Generalized Pustular 
Psoriasis (GPPASI) 75 at Week 4.

Change from baseline in Pain Visual Analog Scale (VAS) score at 
Week 4.

Change from baseline in Psoriasis Symptom Scale (PSS) score at 
Week 4.

Change from baseline in Functional Assessment of Chronic Illness 
Therapy (FACIT) Fatigue score at Week 4.
Secondary endpoints of the study which are not included in the 
statistical testing hierarchy are:

A GPPGA 0 or 1 at Week 4.

A GPPGA pustulation subscore of 0 indicating no visible pustules at 
Week 4.

A GPPASI 50 at Week 1.

A GPPASI 50 at Week 4.

The percent reduction in GPPASI from baseline at Week 1.

The percent reduction in GPPASI from baseline at Week 4.


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The following safety endpoint is also defined:
∀
The occurrence of Treatment Emergent Adverse Events (TEAEs).
Safety criteria:
AEs and Serious Adverse Events (SAEs), AEs of Special Interest, 
intensity of AEs per the Rheumatology Common Toxicity Criteria 
(RCTC) version 2.0, safety laboratory tests, 12-lead electrocardiogram 
(ECG), vital signs (blood pressure [BP], pulse rate [PR], body 
temperature, body weight), physical examination, infusion  site 
reactions,
Statistical methods:
The trial is designed to demonstrate superiority of BI 655130 in the 
primary endpoint, achievement of pustule clearance at week 1, and the 
key secondary endpoint, GPPGA (0, 1) at Week 1, relative to placebo. 
The primary analysis, on each of the primary and key secondary 
endpoints, will use a Suissa-Shuster test (pooled method) to compare the
proportion of patients who achieve a response on BI 655130 versus 
placebo at week 1. 
A further hypothesis on the secondary endpoints, GPPASI 75 at Week 4, 
Pain VAS score at Week 4, PSS score at Week 4 and FACIT Fatigue 
Score at Week 4, will be tested in a hierarchical manner if the test of the 
null hypotheses for both primary and key secondary endpoints has 
previously been rejected. 
All safety data in this study will be descriptively summarized.


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FLOW CHART
Trial Period
Screening
Treatment 
Follow-up Period3,21
Visit
V11
V21
V3
V4
V5
V6
V7
V8
V9
V103
V113
V123
V133
V14/
EoS2, 3,24
V15/
EoS2,25
V16/
EoS2,26
Week*
1
2
3
4
8
12
13-18
16-28
Day
-6 months 
to  day -1
1**
2
3
45
55
65
75
8
15
22
29
57
85
92-127
113-197
Window
±3d
±3d
±3d
±7d
±7d
±7d
±7d
Informed consent
X6
X6
Infection testing
X7
X7
IL36RN mutation status9
X
Demographics
X
Medical history
X
Smoking history
X
Physical examination4
XC
XC,T,8
XT
XT
XT
XT
XT
XT
XC,T
XT
XT
XT
XT
XT
XT
XT
Vital signs10a,10b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fever Assessment11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test12
XS
XU,(S),8
XU,(S) XU,(S)
XU,(S)
XU,(S)
XU(S)
XU,(S)
XU,(S)
XU,(S)
12 lead-ECG13
X
X8
X
X
X
X
X
X
X
X
Safety laboratory tests14
X
X14,8
X
X
X
X
X
X
X14
X14
X14
X14
X14
X14
X
X
Review of in-/exclusion criteria
X
X
GPPGA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
GPPASI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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FLOW CHART (CONT’D.)
Trial Period
Screening
Treatment 
Follow-up Period3,21
Visit
V11
V21
V3
V4
V5
V6
V7
V8
V9
V103
V113
V123
V133
V14/
EOS2, 3, 24
V15/
EOS2,25
V16/
EoS2,26
Week*
1
2
3
4
8
12
13-18
16-28
Day
-6 months 
to  day -1
1**
2
3
45
55
65
75
8
15
22
29
57
85
92-127
113-197
Window
±3d
±3d
±3d
±7d
±7d
±7d
±7d
PSS, 
19
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 Pain VAS, FACIT-
fatigue19
X
X
X
X
X
X
X
X
X
IRT call
X
X
X
X
X
X
X
X
X
X
Dispense/administration study 
drug3,21
X
X22
Local tolerability20 – post dose
X
X22
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X29
X29
X
Concomitant therapy 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Completion
X
X
X
Open Label Extension Trial
X23
ADA, anti-drug antibody; C, complete physical examination; 
d, Day; 
 ECG, 
Electrocardiogram; EoS, end of study; FACIT-fatigue, Functional Assessment of Chronic Illness Therapy - Fatigue; Fup, Follow-up;  GPPASI, Generalized Pustular Psoriasis 
Area and Severity Index: GPPGA, Generalized Pustular Psoriasis Physician Global Assessment; 
; IHC, Immunohistocompatibility 
Complex; IRT, Interactive Response Technology; 
 
; Nab, neutralizing Antibodies; PK, pharmacokinetic; PRO, Patient Reported 
Outcome; PSS, Psoriatic Symptom Scale; RNASeq, RNA Sequencing; S, serum; T, Targeted physical examination; U, urine; V, Visit; VAS, Visual Analog Scale; Wk, week.
*Week in the flow chart represents the end of each week (e.g. End of Wk1=D8, End of Wk2 =D15, End of Wk3 = D22, End of Wk4 =D29 etc.).
**The day of first study drug administration = Day 1. All subsequent study Days are counted from this Day 1.
1Visit 1 and Visit 2 can be on the same day if required (see also footnote 8). Initiation of randomized treatment at Visit 2 can only begin if the patient meets the criteria for Initiation 
of Treatment (see Section 3.3.4).
2 Should a patient prematurely discontinue from the treatment, every effort should be made to keep the patient in the trial and complete all of the remaining study visits. If this is not 
possible, assessments at V9 (Wk1), V12 (Wk4), and EoS (V14 or V15 or V16 as applicable) should be completed or at a minimum an early EoS visit.
3 If a patient qualifies for rescue treatment with open label BI 655130 at either a scheduled or unscheduled visit from after Day 8 and up to and including Week 12, all 
procedures/measurements listed for V9 (with the exception of skin biopsy, Whole Blood for RNA sequencing, Soluble Protein Biomarkers in Serum and Whole Blood for Flow 
Cytometry) are to be performed prior to dosing and an IRT call is to be placed prior to dosing.
4 C = Complete Physical Examination; T = Targeted physical examination. Refer to Section 5.2.1 for additional details.
 P
19
1
 


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5Per physician’s assessment, Days 4 through 7 are optional if the patient has achieved complete pustular clearance (GPPGA pustulation sub score = 0) at the prior visit.
6Informed consent will be signed at the screening visit (V1). For patients completing V1 and V2 > 6 weeks apart, it is recommended that the patient is asked to re-confirm (verbally) 
his/her consent to participate in the trial at Visit 2. 
7Infection testing includes tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see Table 5.2.3: 1). EoS infection testing should only be done once at V14 or V15 or V16 as 
applicable.
8These procedures do not need to be repeated/performed when V1 and V2 are performed on the same day.
9 IL36RN mutation status is to be obtained from the patient’s historical data if available.
10Vital signs: a) On non-study–drug administration days, vital sign assessments are to be done prior to blood sampling; b) On study drug administration days, vital signs will be 
assessed at pre-dose, at approximately 5 minutes after the end of infusion, and 120 mins after the end of infusion.
11 Fever assessments will be recorded on dosing days at three time points. If the patient will receive medication for fever treatment, the fever assessment will be performed prior to 
taking the anti-fever treatment. These fever assessments must be taken whether or not the patient has an elevated temperature and whether or not the patient takes anti-fever 
treatment. The fever assessments times are to be separated by intervals of 2 to 4 hours on dosing days. At all other visits (non-dosing days), fever will be assessed once a day and 
will be completed prior to receiving medication for fever treatment, if anti-fever treatment is given.
12Only applicable for women of childbearing potential. S – serum pregnancy test (performed at screening). U – urine pregnancy tests will be performed on-site and only at study 
drug administration visits. Urine pregnancy testing should be done prior to study drug administration. Study drug should only be administered in case of a negative test result. In 
case of a positive urine pregnancy test, a serum pregnancy (S) test will be done. 
13ECG measurements should always precede blood sampling and drug administration (including visits for rescue treatment).
14 Safety laboratory tests include clinical chemistry, haematology, coagulation, and urinalysis, and will be performed centrally. Local Labs are to be used for dosing decisions prior 
to i.v. administration. Please refer to Section 5.2.3 for further details.
19These measurements are to be completed by the patient on his/her own, without any help from or interpretation by other people. If the patient is too sick to complete the 
questionnaires him/herself but is able to reply verbally, a member of the study team should read the instructions, questions, and response options aloud to the patient and collect the 
patient’s verbal response in as neutral and unbiased a manner as possible. If this is not possible either, the questionnaires are not to be completed. The order of completion for PROs 
is recommended to be as follows: PSS; 
 pain VAS; FACIT-Fatigue; 
20Local tolerability will be assessed during the study drug administration and for approximately 2 hours after the study drug administration. 
21 After Wk1/D8 and through the follow-up period, should a patient who previously achieved a clinical response (GPPGA 0 or 1) to initial treatment (either BI655130 or placebo or 
escape medication) experience a recurrence of a GPP flare (see Table 3.1:1), treatment with a single i.v. dose of 900 mg BI 655130 is to be administered. After D8, only one rescue 
dose with BI 655130 is permitted if a patient experiences a recurrence of a GPP flare. Subsequent flares are to be treated with escape treatment (SoC) per physician’s discretion.
22 Only applicable to patients who meet the qualification for treatment with Open Label (OL)  single i.v. dose of 900 mg BI 655130 at Wk1/D8 (see Table 3.1:1)
23Patients who achieved a clinical improvement to study treatment (not including escape treatment) and show no flare symptoms of moderate/severe intensity at V14 or V15 will be 
offered to enter into an open label extension (OLE) trial (1368-0025), if they have completed this study (EoS/V14 or V15) and meet the inclusion criteria for the OLE trial.
24Patients who receive rescue treatment with OL BI 655130 between Wk7-Wk12 will not have V14. See also footnote 25. 
25Only for patients who receive rescue treatment with OL BI 655130 between Wk7 – Wk12. V15 is to be conducted 6 weeks (+/-7days) after rescue treatment with OL BI655130 
and includes a response evaluation. If at V15, the patient qualifies to enter OLE trial, then V15 will be considered as EoS. If not, then the patient will have an additional 10 weeks 
follow-up and have an EoS at V16.
 
 p
 
19


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26Only for patients who do not qualify to enter into the OLE trial. V16 is to be conducted 16 weeks (+/-7days) after the last dose of trial medication (excluding the Escape 
treatment).
If the date of EOS visit for this trial is not the same as the date of first dose of trial medication on the OLE trial (1368-0025), the investigator must continue to capture the AEs in 
this trial until the patient receives 1st dose in the OLE trial. Please refer to section 5.2.6.2 for further details.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................7
TABLE OF CONTENTS ......................................................................................................11
LIST OF TABLES.................................................................................................................15
LIST OF FIGURES...............................................................................................................16
ABBREVIATIONS................................................................................................................17
1.
INTRODUCTION...............................................................................................19
1.1
MEDICAL BACKGROUND.............................................................................19
1.2
DRUG PROFILE................................................................................................21
1.2.1
Mode of action.....................................................................................................21
1.2.2
Nonclinical pharmacology..................................................................................22
1.2.3
Clinical experience..............................................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................25
1.4
BENEFIT - RISK ASSESSMENT.....................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................29
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY 
ENDPOINTS .......................................................................................................29
2.1.1
Main objectives....................................................................................................29
2.1.2
Primary endpoint................................................................................................29
2.1.3
Key Secondary endpoint.....................................................................................29
2.1.4
Secondary endpoints...........................................................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................33
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................33
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE 
CHOICE OF CONTROL GROUP(S) ..............................................................38
3.3
SELECTION OF TRIAL POPULATION .......................................................38
3.3.1
Main diagnosis for trial entry ............................................................................39
3.3.2
Inclusion criteria .................................................................................................39
3.3.3
Exclusion criteria ................................................................................................40
3.3.4
Initiation of randomized treatment...................................................................42
3.3.5
Withdrawal of patients from therapy or assessments .....................................42
3.3.5.1
Withdrawal from trial treatment ...........................................................................43
3.3.5.2
Withdrawal of consent for trial participation........................................................43
3.3.5.3
Discontinuation of the trial by the sponsor...........................................................43
4.
TREATMENTS...................................................................................................44


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4.1
INVESTIGATIONAL TREATMENTS ...........................................................44
4.1.1
Identity of the Investigational Medicinal Products..........................................44
4.1.2
Selection of doses in the trial..............................................................................45
4.1.3
Method of assigning patients to treatment groups...........................................46
4.1.4
Drug assignment and administration of doses for each patient......................46
4.1.5
Blinding and procedures for unblinding...........................................................47
4.1.5.1
Blinding.................................................................................................................47
4.1.5.2
Unblinding and breaking the code ........................................................................48
4.1.6
Packaging, labelling, and re-supply...................................................................48
4.1.7
Storage conditions...............................................................................................49
4.1.8
Drug accountability.............................................................................................49
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................50
4.2.1
Other treatments and emergency procedures..................................................50
4.2.1.1
Emergency procedures..........................................................................................50
4.2.1.2
Additional treatments............................................................................................52
4.2.2
Restrictions ..........................................................................................................52
4.2.2.1
Restrictions regarding concomitant treatment ......................................................52
4.2.2.2
Restrictions on diet and life style..........................................................................54
4.2.2.3
Restrictions regarding women of childbearing potential......................................54
4.3
TREATMENT COMPLIANCE........................................................................55
5.
ASSESSMENTS..................................................................................................56
5.1
ASSESSMENT OF EFFICACY........................................................................56
5.2
ASSESSMENT OF SAFETY.............................................................................58
5.2.1
Physical examination ..........................................................................................59
5.2.2
Vital signs.............................................................................................................59
5.2.3
Safety laboratory parameters ............................................................................60
5.2.4
Electrocardiogram ..............................................................................................64
5.2.5
Local tolerability .................................................................................................64
5.2.6
Assessment of adverse events.............................................................................64
5.2.6.1
Definitions of Adverse Events..............................................................................64
5.2.6.2
Adverse event collection and reporting ................................................................68


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5.6
APPROPRIATENESS OF MEASUREMENTS..............................................74
6.
INVESTIGATIONAL PLAN.............................................................................75
6.1
VISIT SCHEDULE.............................................................................................75
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................75
6.2.1
Screening period..................................................................................................76
6.2.2
Randomization Visit and Treatments ...............................................................78
6.2.2.1
Clinical monitoring after study drug administration.............................................78
6.2.2.2
Unscheduled visits ................................................................................................79
6.2.3
Follow up period and trial completion..............................................................79
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE....................................................................................................81
7.1
STATISTICAL DESIGN – MODEL ................................................................81
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................81
7.3
PLANNED ANALYSES.....................................................................................83
7.3.1
Primary endpoint analyses.................................................................................84
7.3.2
Key Secondary endpoint analyses .....................................................................85
7.3.3
Secondary endpoint analyses .............................................................................85
7.3.5
Safety analyses.....................................................................................................87
7.4
INTERIM ANALYSES ......................................................................................89
7.5
HANDLING OF MISSING DATA ...................................................................89
7.6
RANDOMISATION ...........................................................................................93
7.7
DETERMINATION OF SAMPLE SIZE .........................................................93
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE.................................................................95
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................95
8.2
DATA QUALITY ASSURANCE ......................................................................96
8.3
RECORDS...........................................................................................................96
8.3.1
Source documents ...............................................................................................96
8.3.2
Direct access to source data and documents.....................................................97
8.3.3
Storage period of records ...................................................................................98
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................98
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT
PRIVACY ............................................................................................................98
8.5.1
Collection, storage and future use of biological samples and 
corresponding data .............................................................................................98
8.6
TRIAL MILESTONES.......................................................................................99
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................99


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9.
REFERENCES..................................................................................................101
9.1
PUBLISHED REFERENCES..........................................................................101
9.2
UNPUBLISHED REFERENCES....................................................................104
10.
APPENDICES...................................................................................................105
10.1
INSTRUCTIONS FOR USE............................................................................105
10.1.1
Physician’s Global Assessment for Generalized Pustular Psoriasis 
(GPPGA)............................................................................................................105
10.1.2
Psoriasis Area and Severity Index for Generalized Pustular 
Psoriasis (GPPASI) ...........................................................................................106
10.1.4
FACIT Fatigue Scale (Version 4) ....................................................................110
10.1.5
Psoriasis Symptom Scale ..................................................................................111
10.1.6
Diagnosis of Anaphylaxis..................................................................................112
10.1.9
Patient’s assessment of Pain VAS....................................................................115
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................118
11.1
GLOBAL AMENDMENT 1 ............................................................................118
11.2
GLOBAL AMENDMENT 2 ............................................................................142


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LIST OF TABLES
Table 3.1: 1
Study definitions ..............................................................................................35
Table 4.1.1: 1 Study compound...............................................................................................44
Table 4.1.1: 2 Placebo comparator..........................................................................................45
Table 4.1.4: 1 Treatments used in this trial. ............................................................................47
Table 4.2.2.1: 1
Restricted medications.............................................................................53
Table 5.2.3:1 Safety Laboratory Tests (Central Lab Assessment).........................................61
Table 5.2.3: 2 Laboratory tests to be assessed prior to i.v. administration at V2, V9 or for 
any rescue treatment (Local Labs) ...................................................................63
Table 7.5: 1 
Ranking rules for secondary continuous endpoint ...........................................91
Table 7.7: 1 
Power to achieve statistical significance for the primary endpoint and key 
secondary endpoint on BI 655130 versus Placebo under various scenarios 
for N=51 (2:1) ..................................................................................................94


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LIST OF FIGURES
Figure 3.1: 1
Study design ....................................................................................................37


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
AD
Atopic Dermatitis
ALT/GPT
Alanine transaminase
AP
Alkaline phosphatase
AST/GOT
Aspartate transaminase
BI
Boehringer Ingelheim
BP
Blood pressure
BSA
Body Surface Area
CML
Local Clinical Monitor
CRA
Clinical Research Associate
(e)CRF
(electronic) Case report form
CRP
C-reactive protein
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supply Unit
DILI
Drug induced liver injury
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EOS
End of Study
ERASPEN
European Rare And Severe Psoriasis Expert Network
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy - Fatigue
FIH
First-in-Human
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GGT
Gamma-glutamyl transferase
GPP
Generalized Pustular Psoriasis
GPPASI
Generalized Pustular Psoriasis Area and Severity Index
GPPGA
Generalized Pustular Psoriasis Physician Global Assessment
HV
Healthy Volunteers
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IL
Interleukin
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator site file
i.v.
Intravenous


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JDA
Japanese Dermatological Association
mAb
Monoclonal antibody
MCID
Minimal Clinically Important Difference
MedDRA
Medical Dictionary for Regulatory Activities
MIP
Macrophage Inflammatory Protein
Nab
Neutralizing Antibody
OL
Open label
OLE
Open label extension
PSS
Psoriasis Symptom Scale
PoC
Proof of Concept
PPS
Per-Protocol set
PRO(s)
Patient Reports Outcome(s)
REP
Residual effect period
RS
Randomized set
SAE
Serious adverse event
s.c.
Subcutaneous
SD
Single dose
SOC
System Organ Class
SoC
Standard of Care
SOP
Standard Operating Procedure
SRD
Single-rising dose
SS
Safety set
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
Tuberculosis
TCM
Trial Clinical Monitor
TEAE
Treatment-emergent adverse event
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAS
Visual Analog Scale
WOCBP
Woman Of Childbearing Potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Clinical Presentation of Generalized Pustular Psoriasis (GPP):
GPP is a severe skin disease characterized by the repeated occurrence of acute flares caused 
by systemic inflammation affecting the skin and internal organs (R15-1421, R16-0933). The 
classic presentation of acute GPP was first described as a recurrent pustular form of psoriasis 
by von Zumbusch in 1909 (R16-0932). While GPP and plaque psoriasis can occur at the 
same time in an individual patient (R17-3403), GPP is distinct from plaque psoriasis in 
clinical presentation, pathophysiology, histopathology, response to therapies, epidemiology 
and genetics.
The clinical presentation of GPP is quite different from psoriasis vulgaris (PV) in its’ 
episodic nature, often with normal appearing skin between very acute and severe disease 
flares. GPP is clinically characterized by the preponderance of pustules as the primary lesion 
on an erythematous base rather than red plaques covered with silvery scales representing the 
primary lesion of typical plaque psoriasis. In addition, the histopathological hallmarks of GPP 
are distinct spongiform pustules of Kogoj located in the subcorneal portion of the epidermis. 
GPP may be associated with systemic symptoms (fever, increased CRP and neutrophilia) and 
severe extra-cutaneous organ manifestations (liver, kidney failure, CV shock). While patients 
with GPP may have pre-existing or co-existing PV, it is possible to clinically distinguish 
patients with primary plaque disease (PV) who have a secondary pustular component from 
patients who have primary pustular disease (GPP) with a concomitant plaque component, 
based on the sequence of manifestations (primary lesion pustule rather than plaque) and the 
localization of a GPP pustule on an erythematous base rather than a PsO plaque.  
As descriptions for GPP are discordant among standard dermatology textbooks (R17-3403), 
the European Rare And Severe Psoriasis Expert Network (ERASPEN) has defined consensus 
criteria that include as key diagnosis criteria for acute GPP the presence of primary, sterile, 
macroscopically visible pustules on non-acral skin (excluding cases where pustulation is 
restricted to psoriatic plaques), with or without systemic inflammation, with or without 
plaque-type psoriasis, either relapsing (>1 episode) or persistent (>3 months).
Chronic GPP describes the state in between disease flares that may be characterized by the 
complete absence of symptoms or the persistence of residual skin symptoms such as 
erythema and scaling and minor pustulation.
Treatment options
Current treatment options for controlling acute flare of GPP and maintenance of response are 
limited and do not provide sustained efficacy (R16-0933). No treatments are currently 
approved for GPP in the US or centrally approved for GPP in the EU, though retinoids, oral 
steroids, cyclosporine or methotrexate are being recommended (R17-3600). Although these 
treatments are described to be effective in 70 – 84% of patients (R17-3600) these data 
observations are based on a retrospective cohort study from Japan without clearly defined 


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endpoints (R17-3626). Furthermore, these treatments cannot be used long-term due to side 
effects and contraindications (retinoids: teratogenicity, hair loss; cyclosporine: excessive hair 
growth, renal toxicity; MTX: liver toxicity).
Secukinumab (Cosentyx®), infliximab (Remicade®), ixekizumab (Taltz®), brodalumab 
(Lumicef®), adalimumab (Humira®), guselkumab (Tremfya®) and Risankizumab are only 
registered in Japan for the treatment of GPP and plaque psoriasis. For secukinumab, 
authorization was granted on the basis of long-term treatment data (52 weeks) derived from a 
single open label clinical trial conducted in 12 patients with chronic GPP and an endpoint at 
16 weeks (R16-1462). Treatment trials supporting licensing in Japan have treated residual 
disease for an extended period of time, providing no evidence of how to appropriately treat 
acute GPP flares.  
Biologics (mostly TNF inhibitors, occasionally IL-1 or IL-17 inhibitors) are increasingly used 
to treat more severe, extensive or treatment resistant patients with GPP, based on small 
published case series (R17-3603). However, these drugs are also associated with limitations 
in efficacy (incomplete and delayed responses are frequent) and safety as well as 
contraindications (infusion reactions, tuberculosis, cardiovascular disease). 
Unmet Medical Need 
Acute GPP flares of varying severity occur in most patients and may be idiopathic or 
triggered by external stimuli, such as infection, corticosteroid use or withdrawal, non 
adherence and dose reduction of current standard of care treatment, stress or pregnancy (R16-
0933). Moderate or severe GPP flares cause significant morbidity and mortality (R16-0933)
due to tender, painful skin lesions, extreme fatigue, high fever, peripheral blood neutrophilia 
and acute phase response and sepsis. The acute phase is associated with a mean duration of 
hospitalization of 10 days (range 3-44 days) (R16-0933). The observed mortality rate of 7% 
reported in a retrospective study (R16-0933) with 102 GPP cases seen in a tertiary hospital in 
Johor, Malaysia is likely an underestimate as not all GPP patients were included in the study. 
Mortality rates are also likely underestimated due to lack of identifying the cause of death as 
GPP and are largely driven by infectious complications and extra-cutaneous organ 
manifestations such as renal, hepatic, respiratory and cardiac failure (R16-0933). After 
responding to treatment or spontaneous flare cessation, it is estimated that up to 50% of 
patients may suffer from chronic GPP characterized by persistent erythema and scaling that 
may also include joint symptoms. 
Moreover, in countries with lower incidence of GPP, the differential diagnosis can be 
delayed.  This is partly due to the absence of a treatment protocol for GPP once it is 
diagnosed.
Based on the limitations described above, current therapeutic options are not suitable for life-
long treatment and do not provide sustained responses in most patients. Therefore, there is a 
high need to develop (i) a highly effective treatment with rapid onset of action for patients 
presenting with an acute GPP flare; and (ii) to develop an effective treatment of chronic GPP, 
which reliably prevents the occurrence of flares and is safe and tolerable for lifelong 
treatment.


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Role of IL-36R Signaling in GPP
The classic presentation of GPP flares as described by von Zumbusch is strongly correlated 
with polymorphisms in the IL36-R signaling pathway (R15-1421, R14-5158). Individuals 
with loss-of-function mutations of the IL36RN gene which encodes an endogenous IL36R 
antagonist (IL-36RN) have dramatically higher incidence of GPP, indicating that 
uncontrolled upregulation of IL36 signaling due to defective IL36RN antagonism leads to the 
inflammatory episodes observed in GPP. Genetic human studies have demonstrated the 
occurrence of GPP clusters in families with a loss of function mutation in IL36RN, which 
results in uncontrolled IL36R signaling (R14-5158).  Mutations in other genes linked to the 
IL36 pathway such as CARD14 (R16-0929) also lead to GPP. A recently published gene 
expression study indicates sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil 
chemokine expression, infiltration, and pustule formation, suggesting that the IL-1/ IL-36 
inflammatory axis is a potent driver of disease pathology in GPP (R17-3602). Moreover, a 
recent meta-analysis investigated 233 published GPP cases. They found that 49 (21.0%) of 
233 cases carried recessive IL36RN alleles. Those 49 recessive IL36RN alleles defined a 
GPP phenotype characterized by early onset and high risk of systemic inflammation (R16-
0930).
IL36R is a cell surface receptor involved in inflammatory responses in skin and gut. It is a 
novel member of the IL1R family that forms a heterodimeric complex with the IL1R 
accessory protein. The heterodimeric IL36R system with stimulating (IL36α, IL36β, IL36γ) 
and inhibitory ligands (IL36Ra) shares a number of structural and functional similarities to 
other members of the IL1/IL1R family, such as IL1, IL18 and IL33 (R17-3602). All IL1 
family members (IL1α, IL1β, IL18, IL36α, IL36β, IL36γ, and IL38) signal through a unique, 
cognate receptor protein which, upon ligand binding, recruits the common IL1RacP subunit 
and activates NFkB and MAP kinase pathways in receptor-positive cell types. In human skin 
tissues, IL36R is expressed in keratinocytes, dermal fibroblasts and infiltrating myeloid cells.  
IL36R activation in skin tissue drives the production of inflammatory mediators (e.g. CCL20, 
MIP-1β, TNF-α, IL12, IL17, IL23, TGF-β) and modulates the expression of tissue 
remodeling genes (e.g. MMPs, TGF-β). Therefore, the link between GPP and mutations in 
the IL36RN is somewhat analogous to the well-established neonatal onset of sterile 
multifocal osteomyelitis, periostitis, and pustulosis caused by absence of interleukin-1–
receptor antagonist. In this case, absence of the receptor antagonist allows unopposed action 
of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone 
involvement (R17-3602). These clinical features responded to empirical treatment with the 
recombinant interleukin-1–receptor antagonist anakinra (P09-07583). 
1.2
DRUG PROFILE
1.2.1
Mode of action
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R 
signaling. Binding of BI 655130 to IL36R is anticipated to prevent the subsequent activation 
of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-
inflammatory and pro-fibrotic pathways with the aim to reduce epithelial cell/ fibroblast/ 
immune cell-mediated inflammation and interrupt the inflammatory response that drives 


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pathogenic cytokine production in inflammatory diseases including generalized pustular 
psoriasis (GPP), palmoplantar pustulosis (PPP), Atopic Dermatitis (AD) and inflammatory 
bowel disease (IBD).
1.2.2
Nonclinical pharmacology
Preclinical Studies
BI 655130 binds to human IL36R with a binding avidity of less than 1 pM. BI 655130 
inhibits IL36 ligand-stimulated NF-B activation in HT29 and transformed epithelial cells 
and in primary human dermal fibroblasts or intestinal myofibroblasts with IC90 values in a 
consistent range of 0.7 to 3.7 nM. BI 655130 also inhibits IL8 release in primary human 
intestinal myofibroblasts and IFNγ secretion in human PBMC stimulated with IL36α, IL36β, 
or IL36γ combined with IL12. Mutations of two key residues (L234 and L235) to alanine 
were made to BI 655130 to abrogate FcR binding activity and function. Direct assessment of 
the impact of the mutations in the IgG1 FcR binding sites on both antibody-dependent 
cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effector 
functions revealed that the mutations abrogate both ADCC and CDC effector functions and 
indicate that BI 655130 will be a non-depleting therapy in vivo.
Toxicology studies
BI 655130 does not bind to IL-36R from common toxicology species. Therefore, meaningful 
toxicity studies of the molecule cannot be performed in any animal species with BI 655130. 
However, hazard identification studies of the mode-of-action (MoA) of IL-36R inhibition 
were performed in mice using a mouse specific anti-IL-36R monoclonal antibody (BI 
674304), which is a mouse IgG2a monoclonal antibody with rat variable regions. In a 13-
week intravenous toxicity study of BI 674304 in mice, no adverse effects of IL-36R 
antagonism were seen at a dose (50 mg/kg, twice weekly) that was 5 fold higher than the dose 
that was protective in an experimental mouse colonic inflammation model. In the 26-week 
toxicity study, male and female mice (20- 30/sex/group at 0, 10 and 50 mg/kg/day) were 
administered BI 674304 twice weekly for 26 weeks by intravenous injection via the caudal 
vein. There were no BI 674304-related changes in clinical observations, body weights, food 
consumption, ophthalmology, clinical pathology parameters (hematology, clinical chemistry), 
organ weights, macroscopic or microscopic examinations. The no-observed-adverse-effect 
level (NOAEL) was considered to be 50 mg/kg/day. The in vitro cytokine release and tissue 
cross-reactivity assays demonstrate that the risk of transient cytokine release in humans is 
low and that, as expected, BI 655130 stains epithelium in a variety of tissues. There were no 
signs of local irritation after single, 1 mL injections of the subcutaneous formulation in 
rabbits. These preclinical toxicology data support chronic BI 655130 dosing in humans.
1.2.3
Clinical experience
In the First-in-Human (FIH) study, BI 655130 or placebo (PBO) was administered to 78 
healthy volunteers with 58 subjects assigned to single ascending i.v. doses from 0.001 mg/kg 
to 10 mg/kg body weight and 20 subjects assigned to placebo. Safety and tolerability of all 
tested i.v. doses was good. There were no SAEs. AEs categorized as related to treatment were 
observed in 3/20 (15.0%) subjects in the placebo group and in 8/58 (13.8%) subjects treated 
with BI 655130. The most frequent treatment-emergent AEs were nasopharyngitis (BI 


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655130: 20.7%; PBO: 15.0%), headache (BI 655130: 8.6%; PBO: 15.0%), influenza like 
illness (BI 655130: 6.9%; PBO: 10.0%), and diarrhea (BI 655130: 3.4%; PBO: 10.0%). There 
were two AEs of moderate intensity (injection site haematoma, headache), all remaining AEs 
were of mild intensity. There were no serious AEs, no AEs that led to discontinuation of trial 
drug, no protocol-specified AEs of special interest and no other significant AEs according to 
ICH E3.
No relevant changes were observed in safety laboratory tests, vital signs, and 
electrocardiograms (ECGs). Importantly, there were no relevant differences in frequencies of 
subjects with treatment emergent AEs between the treatment groups, and no dose-
dependency was observed.
PK analysis showed that exposure (AUC0-tz and Cmax) to BI 655130 increased with 
increasing dose in an approximately dose-proportional manner from 0.3 to 10 mg/kg. The 
effective half-life of BI 655130 is approximately 4 weeks in the linear dose range. Overall, 
PK data so far suggests target-mediated drug disposition (TMDD) kinetics for BI 655130. 
Anti-drug antibodies (ADA) were detected in 9 subjects (8 subjects on BI 655130 and 1 
subject on placebo), 3 of those had preexisting levels. Pharmacodynamic effects in this FIH 
Single Rising Dose trial were assessed by indirect target engagement (ITE) of IL36R by BI 
655130 using an ex-vivo whole blood stimulation assay (c09985235-01).  The analyses 
indicate for doses of 3 mg/kg and above, the percent inhibition of macrophage inflammatory 
protein (MIP)-1β was at least 94% as compared to baseline during the entire time course up 
to 1680 hrs (10 weeks).
In a multiple rising dose trial, BI 655130 or placebo have been administered to healthy 
volunteers at multiple ascending i.v. doses of 3, 6,10 and 20 mg/kg given weekly for 4 weeks 
(i.e. 4 administrations) or a single dose of 20mg/kg (8 subjects each, 3:1 on active or PBO). 
Overall, multiple i.v. doses of 3 mg/kg, 6 mg/kg, and 10 mg/kg, as well as single and multiple 
doses of 20 mg/kg BI 655130 were found to be safe and well tolerated by the healthy male 
subjects in this trial. The incidence and intensity of drug related AEs appeared to be higher in 
the 20 mg/kg multiple dose BI 655130 treatment group than in the other treatment groups, 
mainly driven by headache. No dose-dependent AEs or other clinically relevant changes in 
safety laboratory tests, vital signs, or ECG were observed. For further details refer to the 
current Investigator`s Brochure (IB; c03320877).
The open-label, single group phase I study trial (1368.11) was conducted to investigate the 
safety, tolerability, pharmacokinetics, pharmacogenomics, and efficacy of a single 
intravenous dose of BI 655130 (10 mg/kg) in 7 patients with acute flare of generalized 
pustular psoriasis. The proof-of-concept (PoC) for IL36R inhibition in GPP was achieved in 
these patients who showed rapid clinical responses to single administrations of BI 
655130. Five of these 7 patients became clear or almost clear of GPP 1 week after the 
infusion, and all of them reached this status 4 weeks after treatment. Within 48 hours of 
treatment, pustules were completely cleared in 3 patients; pustules were cleared by Week 1 in 
5 patients, and by Week 2 in 6 patients. The early response in the skin was also accompanied 
by an early response in systemic components (C-Reactive Protein [CRP] approaching 
normalization within 4 weeks). A major improvement in GPPASI was observed in all patients 
very early with a mean (SD) percent change from baseline of 73.2% (16.2) at Week 2; by 


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Week 4, this was further reduced to 82.0%, and was maintained to Week 20 (83.6%). 
Additional improvements (mean [SD]) from baseline to Week 2 were observed in FACIT-F, 
12.3 (10.1); Pain-VAS, –45.9 (32.3); and PSS, –5.14 (3.18), all of which were also sustained 
through Week 4. For further details and most recent results refer to the current IB 
(c03320877) and published article in the New England
Journal of Medicine (P19-01888).
A placebo controlled Phase II study (1368-0015) has also been conducted in 59 patients with 
palmoplantar pustulosis (PPP), 38 of whom received infusions of BI 655130 at doses up to 
900 mg every 4 weeks (0, 4, 8 and 12 weeks) and were followed-up through week 32. Two
Serious AEs (SAEs) were reported (one patient each in the 300 mg BI 655130 and placebo
arm). While the majority of AEs were mild or moderate and expected for the population, a
severe AE was reported in 2 patients for each of the three study arms (300 mg BI 655130,
900 mg BI 655130 and placebo). Four AEs (10.5%) in patients treated with BI 655130 and
three AEs (14.3%) in patients treated with placebo led to discontinuation of trial medication.
Three patients in the 900 mg BI 655130 arm and two in the placebo arm experienced a
significant AE. No AEs of special interest (AESI) were reported. No clinically relevant
abnormalities with respect to safety laboratory and vital signs were observed.
While the proportion of patients who achieved ppPASI50 at Week 16 in the total population
was similar in all treatment groups (6 of 19 in 900 mg BI 655130 arm, 6 of 19 in 300 mg BI
655130 arm, and 5 of 21 in placebo arm) the baseline disease severity within the trial
population was lower than expected, with half of the patients having a baseline ppPASI total
score ≤ 16.70. In patients with baseline disease scores > 16.7, post-hoc subgroup analyses
indicated efficacy for both doses of BI 655130 relative to placebo. The mean percent 
reduction from baseline in ppPASI total score was 40%, 24% and 8%, at week 16 for BI 
655130 900 mg, BI 655130 300 mg, and placebo respectively in this subgroup. The mean 
percent reduction from baseline in pustular severity was 57%, 30% and 5% for the 900 mg BI 
655130, 300 mg BI 655130 and placebo groups respectively at week 16 of this subgroup, 
indicating a dramatic reduction in pustule severity with evidence of a dose response 
relationship.
Summary
BI 655130 is an anti-IL36R antibody with a high clinical activity to block IL36R signaling as 
demonstrated in patients with Generalized Pustular Psoriasis, a severe inflammatory skin 
disease driven by uncontrolled IL36 activity. BI 655130 has been tested in healthy volunteers 
who received multiple doses every week for 4 weeks. These weekly doses of 20 mg/kg i.v. 
were all found to be safe in the subjects treated. In addition, IL36R inhibition shows a 
favorable nonclinical safety profile. BI 655130 has also been tested in acute flare of GPP 
patients. In these patients, BI 655130 was well tolerated, with no serious adverse events or 
other clinically notable safety concerns. In a larger trial investigating patients with PPP no 
safety signals have been identified for BI 655130. While the primary endpoint was not 
successful, efficacy was demonstrated in a post-hoc analysis for both doses of BI 655130 
tested in patients with a baseline disease score > 16.7 based on the ppPASI.
For further details and most recent results refer to the current IB (c03320877).


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1.3
RATIONALE FOR PERFORMING THE TRIAL
Current treatment options for controlling acute flare of GPP, complete resolution of 
symptoms and prevention of reoccurrence of flares are limited and do not provide sustained 
efficacy (R16-0933). No treatments are currently approved for GPP in the US or centrally 
approved for GPP in the EU, though a combination of retinoids, cyclosporine or methotrexate 
has been recommended as primary options for controlling worsening of chronic GPP (R17-
3600). The use of these for acute flare of GPP is based on anecdotal retrospective case 
reports, making this trial prospectively testing a treatment that has shown efficacy for acute 
flare more important to conduct. In addition, long-term use of these treatments is limited due 
to side effects and contraindications (retinoids: teratogenicity, hair loss; cyclosporine: 
excessive hair growth, renal toxicity; MTX: liver toxicity). Side effects, such as hair loss, 
excessive hair growth and teratogenicity particularly limit the use of these treatments in 
women. Biologics (mostly TNF inhibitors, occasionally IL-1 or IL-17 inhibitors) are 
increasingly used to treat more severe, extensive or treatment resistant patients with GPP, 
based on small published case series (R17-3603, R16-2960). However, these drugs are also 
associated with limitations in efficacy (incomplete and delayed responses are frequent) and 
safety (risk of infections and infusion reactions). 
Based on the limitations described above, current therapeutic options are not suitable for life-
long treatment and do not provide sustained responses in most patients. Therefore, to address 
the high unmet needs in GPP there is a critical need to develop (i) a highly effective treatment 
with rapid onset of action for patients presenting with an acute GPP flare; and (ii) to develop 
an effective treatment that also reliably reduces the occurrence of flares and leads to complete 
resolution of manifestations such as widespread erythema and scaling, and is safe and 
tolerable for lifelong treatment. In addition, a search of the current literature did not yield any 
published studies focusing on moderate to severe GPP flares. Thus, our PoC approach 
(1368.11) and subsequent development plan (1368-0013) further address the need for GPP 
treatment options.
The strong genetic link between the IL36 signaling pathway and GPP and experimental data 
identifying IL-36 as the dominant cytokine driving GPP (R17-3602) suggest that inhibition of 
IL36R signaling with the humanized anti-IL36R antibody BI 655130 might be beneficial in 
treatment of GPP - similar to the strong responses seen in IL1R antagonist deficient patients 
with sterile multifocal osteomyelitis after treatment with Anakinra. In addition, 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).
Based on this rationale, an open-label, single arm study trial (1368.11) has been conducted to 
investigate proof-of-concept of a single dose of BI 655130 in patients with GPP. In total, 
seven patients have been treated with a single IV administration of 10mg/kg of BI 655130. 
As described in Section 1.2.3, inhibiting IL36R activity results in a rapid and sustained 
improvement in GPP clinical skin and systemic symptoms. In study 1368.11, 7 patients were 
randomised into this open label, single dose, single arm trial of BI 655130. All patients 
received a single intravenous dose of 10mg/kg BI 655130. AEs reported within 20 weeks 
after administration of the trial medication were considered on-treatment. 


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In total, 7 out of 7 patients (100%) were reported with at least 1 AE while on treatment. In 
4 patients (57.4%), AEs that were considered drug-related by the investigators were reported. 
None of the reported AEs was severe, serious, or led to discontinuation.
At the preferred term level, the most frequently reported treatment-emergent AE was 
arthralgia (3 out of 7 patients [42.9%]). Eosinophilia, chills, oedema peripheral, pyrexia, 
upper respiratory tract infection, and eczema were each reported in 2 patients (28.6%). 
In 1 patient, an infusion-related reaction was reported. The patient felt “heat” after the 
infusion of the trial medication during Visit 3. This event was not accompanied by other 
symptoms, in particular vital signs remained stable. This event was transient and did not
require any treatment.
There were no clinically relevant safety laboratory or vital signs abnormalities on treatment 
with BI 655130.
Overall, BI 655130 was well tolerated in the patients who participated in trial 1368.11.
Based on these results, the objective of this subsequent GPP trial is to evaluate efficacy, 
safety, and tolerability of BI 655130 compared to placebo in patients with GPP presenting 
with an acute flare of moderate to severe intensity. 
The results from this trial will support the first registration of BI 655130 in GPP patients.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see Section 5.4.3). If the patient agrees, banked 
samples may be used for future biomarker research and drug development projects, e.g. to 
identify patients that are more likely to benefit from a treatment or experience an adverse 
event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby 
better match patients with therapies.
1.4
BENEFIT - RISK ASSESSMENT
Patients who experience moderate to severe flares of GPP have a need for treatment to 
rapidly reverse the progressively worsening signs and symptoms of their condition.  The
completed PoC trial 1368.11 demonstrates that BI 655130 treatment rapidly stops the flare 
and clears pustules, the primary lesions in GPP.  As the first trial to investigate treatment of 
acute flares, in contrast to subacute residual/chronic GPP, the results support further 
development of treatment for this most dangerous aspect of GPP.  The trial design calls for 
screening for confirmed diagnosis of flaring GPP followed by monitoring for up to 6 months 
for the next acute flare.  The benefit of participation in this trial for qualifying patients is the 
opportunity to have their next GPP flare monitored prospectively and treated in a controlled 
setting with treatment targeted at the primary immune process driving the pathology of their 
disease.  BI 655130 treatment has successfully treated GPP flare rapidly resolving symptoms 
with sustained effect for at least 20 weeks subsequent to a single dose of BI 655130.  By 


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contrast current recommended treatment options are supported by anecdotal reports of GPP 
flare with improvement that can be expected to be lost without continued treatments.  
Preclinical profiles of BI 655130 and clinical data from healthy volunteer trials suggest that 
BI 655130 is safe, tolerable and may address an unmet medical need in GPP patients. Data 
from the completed PoC trial 1368.11 demonstrate that BI 655130 treatment rapidly stops the 
flare and clears pustules, the primary lesions in GPP, a disease closely linked to loss of 
function mutations in the natural IL36R antagonist (c03320877).
No relevant animal species is available for toxicology testing of the highly human specific 
antibody BI 655130. However, preclinical toxicology studies with a mouse surrogate 
antibody have demonstrated the safety of IL-36R inhibition in mice (c03320877).
As of September 2018, BI 655130 has been given to 212 subjects in ongoing and clinically 
completed trials. BI 655130 was well tolerated. Most reported adverse events were of mild or 
moderate intensity, but there have also been a small number of patients experiencing severe 
or serious adverse events in clinical trials. It is unknown whether these adverse events were 
caused by BI 655130. Overall adverse events observed in subjects who received BI 655130 
were comparable to adverse events observed in those who received placebo and no dose-
limiting adverse effects were observed (for details refer to IB; (c03320877)). 
As with any immune modulating agent, BI 655130 has the potential to impair immune 
function resulting in a risk of infection. 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). The role of IL-36 in tumor immunity is not well established at this 
time, but an increased risk of cancer from an IL-36R antagonist, though considered small, 
cannot be excluded. 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; (b) close 
clinical monitoring for AEs, including use of Rheumatology Common Toxicity Criteria 
(RCTC) for severity grading, definition of emerging malignancies, sepsis and disseminated 
intravascular coagulation as always-serious adverse events, definition of opportunistic 
infections and infusion and anaphylactic reactions as adverse events of special interest 
(AESI); (c) selection of sites experienced in treatment of GPP patients; and (d) 
implementation of a fully independent data-monitoring committee (DMC).
Other risks related to trial-specific procedures include blood sampling, intravenous infusion 
of study medication, and tissue biopsy, which can cause local bruising, inflammation, nerve 
damage and pain. In addition, the management of any latent Tuberculosis, and any untoward 
risks of placebo administration will be carefully monitored and addressed as described in 
Section 4.2.
Reactions to i.v. administered biologic agents represent the manifestations of systemic 
hypersensitivity reactions and include anaphylaxis, pruritus, hypotension and respiratory 
distress. Systemic hypersensitivity reactions are readily detectable, transient in nature, and 
manageable with standard medical treatment. Specific safety measures will be taken during 


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the trial. During and following the i.v. infusion, the patients will be monitored for systemic 
hypersensitivity including (See Section 4.2.1.1 for further details) infusion reactions at the 
site according to Instructions for Preparation and Handling of BI 655130.
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 on unintentional exposure of an 
embryo or fetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods described in the protocol. 
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure 
patients´safety, see also Section 5.2.6.
Summary of benefit-risk assessment
The trial presents a benefit for the patient of monitoring until the next GPP flare as well as 
monitoring and careful management during and after the occurrence of that flare.  
Considering the medical need of the development of an effective and well tolerated drug for 
treating GPP flares, the benefit of this trial is considered to outweigh the potential risks for 
and justifies the administration of BI 655130 to patients with Generalized Pustular Psoriasis 
(GPP) presenting with an acute flare of moderate to severe intensity. Due to the lack of 
mechanism- or compound-related safety signals and the antagonistic mode of action of BI 
655130 it is considered likely that GPP patients will not be exposed to undue 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 evaluate efficacy, safety, and tolerability of one single 
i.v. dose of BI 655130 compared to placebo in patients with Generalized Pustular Psoriasis 
(GPP) presenting with an acute flare of moderate to severe intensity.
2.1.2
Primary endpoint
The primary endpoint of the study is:

A GPPGA pustulation sub-score of 0 indicating no visible pustules at Week 1. 
For the estimand concept on the above-defined primary binary endpoint definition(s), any use 
of escape medication (see Section 3.1) prior to Week 1 will be considered to represent a non-
response at the Week 1 timepoint.
2.1.3
Key Secondary endpoint
The key secondary endpoint of the study is:

A Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 
at Week 1.
For the estimand concept on the above-defined key secondary binary endpoint definition(s), 
any use of escape medication (see Section 3.1) prior to Week 1 will be considered to 
represent a non-response at the Week 1 timepoint.
2.1.4
Secondary endpoints
Secondary Endpoints at Week 4:
Secondary Endpoints of the study at Week 4 which are included in the statistical testing 
strategy in a hierarchical manner subsequent to performance of the tests on the primary 
endpoint and key secondary endpoint (see Section 7.2) are:

A Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI) 75 at 
Week 4.

Change from baseline in Pain Visual Analog Scale (VAS) score at Week 4.

Change from baseline in Psoriasis Symptom Scale (PSS) score at Week 4.


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∀
Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) 
Fatigue score at Week 4.
Other secondary endpoints of the study at Week 4 are:
∀
A Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 
at Week 4.
∀
A GPPGA pustulation sub-score of 0 indicating no visible pustules at Week 4.
∀A GPPASI 50 at Week 4. 
∀The percent reduction in GPPASI from baseline at Week 4.
For the estimand concept on each of the above-defined binary secondary endpoint 
definition(s) at week 4,  any use of escape medication prior to Week 4, or OL BI 655130 use 
at D8, or any rescue medication with BI 655130 prior to Week 4 will be considered to 
represent a non-response at the Week 4 timepoint. For continuous endpoints, refer to Section 
7.3.3. 
Secondary Endpoints at Week 1:
Additional secondary endpoints of the study at week 1, where (for binary endpoint(s) only), 
any use of escape medication prior to week 1 will be considered to represent a non-response 
at the Week 1 timepoint, are: 
∀
A GPPASI 50 at Week 1.
∀
The percent reduction in GPPASI from baseline at Week 1.
Secondary Safety Endpoints:
The following safety endpoint is also defined:
∀
The occurrence of Treatment Emergent Adverse Events (TEAEs) 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multicenter, randomized, double-blind, placebo-controlled Phase II study with one 
dose of BI 655130/placebo in patients with GPP presenting with an acute flare of moderate to 
severe intensity. The primary objectives of this trial are to assess the efficacy, safety and 
tolerability of a single intravenous (i.v.) dose of BI 655130 in comparison to placebo in 
patients with generalized pustular psoriasis (GPP) presenting with an acute flare of moderate 
to severe intensity. 
Approximately 11 to 20 countries will participate by using sites/centers experienced in the 
management of GPP.
Fifty-one patients with generalized pustular psoriasis (GPP) presenting with an acute flare of 
moderate to severe intensity are required to be randomized to receive BI 655130/ placebo 
(2:1) into this trial. 
Patients are considered enrolled (screened) in the study once they have signed the informed 
consent. 
Patients eligible to receive treatment after screening will be able to participate in this study 
and will be randomized at a ratio of 2:1(BI 655130/Placebo) to one of two treatment groups 
as shown in Figure 3.1: 1. All patients will receive the first dose of study medication (900 mg 
i.v. BI 655130 or Placebo) on Day 1 of Week 1 (Randomization). Based on the subsequent 
treatment response patients will then be followed for 12 to 28 weeks (see Flow Chart). Study 
Week in the flow chart represents the end of each week (e.g. End of Wk1=D8, End of Wk2 
=D15, End of Wk3 = D22, End of Wk4 =D29 etc.).
During Week 1, D1, D2, D3 and D8 are mandatory visits, however, D4 – D7 are optional 
visits and need not be attended if a patient has already achieved complete pustular clearance 
(GPPGA pustulation sub score =0) at the previous visit. 
At the discretion of the investigator, patients may be hospitalized prior to, during or following 
first study drug administration. Thereafter, the decision to discharge a patient from the 
hospital will also be at the discretion of the investigator, based on the evolution of the GPP 
flare and the patient’s health status.
If the severity and progression of the disease worsens within the first week (Wk1/D2-D7) 
(see Table 3.1:1 for definition of disease worsening), the investigator can treat the patient 
with a Standard of Care (SoC) treatment of his/her choice (escape medication). If the disease 
condition is stable, it is recommended to wait until the primary endpoint visit (Wk1/D8) 
before prescribing an escape medication (SoC) since there will be an option to administer OL 
BI 655130 instead at this time. If escape medication is administered within the first week, the 
patient will not be eligible to receive treatment with OL single i.v. dose of 900 mg of BI 
655130 on D8. For escape medication use during the trial after Week 1, please refer to Table 
3.1:1.


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At the Week 1/Day8 visit, the primary endpoint and key secondary endpoint will be assessed. 
Patients who did not receive escape treatment and who have a GPPGA ≥ 2 at Wk1 and a 
GPPGA pustulation subscore of  ≥2 will be eligible to receive treatment with a single open 
label i.v. dose of  BI 655130 900 mg. All randomized patients will continue through the 
subsequent visits until the End of Study (EoS) as outlined in the Flow Chart. If patients 
receiving escape medication during Wk1 (D2-D7) are not willing to attend all subsequent 
visits then assessments at V9 (Wk1), V12 (Wk4) and EoS (V14 or V15 or V16 as applicable) 
should be encouraged or at the very minimum an early EoS visit. 
After Wk1/D8 and through the follow-up period, if a patient who previously achieved a 
clinical response (GPPGA 0 or 1), either with BI 655130 at D1 or placebo at D1 or escape 
medication or OL BI 655130 at D8, experiences a recurrence of a GPP flare (see Table 3.1: 1
for definition), a rescue treatment with a single i.v. dose of 900 mg BI 655130 is to be 
administered. This could occur at a scheduled or unscheduled visit anytime between after D8 
and Week 12. After D8, only one rescue dose with BI 655130 is permitted if a patient 
experiences a recurrence of a GPP flare. Subsequent flares are to be treated with escape 
treatment (SoC) per physician’s discretion.  
Patients who achieved a clinical improvement to BI 655130 and who show no flare 
symptoms of moderate/severe intensity at V14 or V15 visit will be offered to enter into an 
open label extension (OLE) trial (1368-0025), if they have completed this study (EoS/V14 or 
V15 visit, see below) and meet the eligibility criteria for the OLE trial.
For patients who qualify to enter OLE, prior to entering into the OLE trial:

Patients who do not require rescue treatment with OL BI 655130 are to be followed 
until Week 12 (V14/EoS). 

Patients who receive rescue treatment with OL BI 655130 between Wk2-Wk6 are to 
be followed until Week 12 (V14/EoS). 

Patients who receive rescue treatment with OL BI 655130 between Wk 7-Wk12 are to 
be followed for additional 6 weeks from administration of rescue treatment up to Wk 
13 –Wk18 (V15/EoS).
Patients who do not qualify to enter into the open label extension (OLE) trial (1368-0025), 
will be followed for 16 weeks (EoS/V16/Wk16-Wk28) after the last dose of trial medication, 
which is the latest timepoint of trial medication given during the study (i.e. the latest of V2, 
V9 if OL BI 655130 is given, rescue with OL BI 655130 if given). 
Individual patient participation is concluded when the patient has completed the last planned 
visit.  The “last-patient-last-visit-primary-endpoint” is the last scheduled primary endpoint 
visit (Week 1/D8) completed by the last patient.  The end of the trial is defined as “last 
patient out”, i.e. last scheduled visit (EoS) completed by last patient.  


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Table 3.1: 1
Study definitions
Criteria for 
Randomization/Initiation of 
Treatment
Randomized Treatment at Visit 2 will be initiated 
immediately in patients:

Who meet all of the inclusion/exclusion criteria at 
screening
And

With GPP presenting with an acute flare of moderate to 
severe intensity, defined by the emergence of:
a) a GPPGA score of at least 3 (moderate), and
b) presence of fresh pustules (new appearance or 
worsening of pustules), and
c) GPPGA pustulation sub score of at least 2 (mild), 
and
d) at least 5% of Body Surface Area (BSA) covered 
with erythema and the presence of pustules
Qualification for treatment 
with Open Label (OL) 
single i.v. dose of 900 mg BI 
655130 at Wk1/D8
Patients with a GPPGA ≥2 at Wk1 and pustular 
component of GPPGA ≥2 at Wk1 after receiving the first 
dose.
Recurrence of GPP Flare:
Criteria to receive rescue 
treatment with  Open Label 
(OL) single i.v. dose of 900 
mg BI 655130 after 
Wk1/D8 
After Wk1/D8 and through week 12, if there is ≥ 2 point 
increase in the GPPGA score and the pustular component 
of GPPGA ≥ 2 after achieving a clinical response 
(GPPGA 0 or 1) to initial treatment (either with BI 655130 
at D1 or placebo at D1 or escape medication or OL BI 
655130 at D8).
Note: Only one rescue dose with BI 655130 is permitted if 
a patient experiences a recurrence of a GPP flare. 
Subsequent flares are to be treated with Standard of Care 
(SoC) per physician’s discretion.  
Disease Worsening of GPP: 
Scenarios when Escape 
treatment in case of Disease 
Worsening may be given:
Disease worsening is defined as worsening of clinical status
or GPP skin and/or systemic symptoms as defined by the 
investigator. 
Escape treatment is the Standard of Care (physician’s 
choice) in the investigator’s opinion to treat the disease 
worsening of GPP. 
Note: The SoC options are multiple dose extended duration 
treatments.

Wk1/D2-D7: If the severity and progression of the 
disease worsens within the first week and requires 


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Table 3.1: 1
Study Definitions (cont’d.)
BSA, Body Surface Area; D, day; ERASPEN, European Rare And Severe Psoriasis Expert Network; GPP, Generalized 
Pustular Psoriasis; GPPGA, Generalized Pustular Psoriasis Physician Global Assessment; OL, open label; Pts, patients; Wk, 
week.
The study design is illustrated in Figure 3.1: 1.
immediate treatment, then the investigator can treat the 
patient with the escape medication of his/her choice. 
However, if the disease condition is stable, it is 
recommended to wait until the primary endpoint visit 
(Wk1/D8) before prescribing an escape medication since 
there will be an option to administer OL BI 655130 instead 
at this time.

After D8:
•
Patients who do not achieve a clinical response
(GPPGA 0 or 1) but have disease worsening
subsequent to D8 can receive an escape treatment 
chosen by the investigator.
•
Patients who have achieved a clinical response and 
later have disease worsening that is not severe enough 
to meet the criteria for recurrence for GPP flare can 
receive the escape medication. However, it is 
recommended to wait until the patient meets the 
criteria for recurrence of GPP flare since there will be 
an option to administer rescue medication with OL BI 
655130 instead at this time.
Note: Only one rescue dose with BI 655130 is 
permitted if a patient experiences a recurrence of a 
GPP flare. Subsequent flares are to be treated with 
Standard of Care (SoC) per physician’s discretion.


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Figure 3.1: 1
Study design
Refer to Table 3.1:1 for Key study definitions and Rescue criteria.
*Patients who do not require rescue treatment with OL BI 655130 are to be followed until Wk 12 (V14/EoS) prior to 
entering into OLE (1368-0025) trial. 
*Patients who receive rescue treatment with OL BI 655130 between Wk2-Wk6 are to be followed until Wk 12 (V14/EoS) 
prior to entering into the OLE trial. If at V14, they qualify to enter OLE trial, then V14 will be considered as EoS for these 
patients. If not, then the patients will have an additional 10 weeks follow-up and have an EoS at V16 (Wk16-28).
*Patients who receive rescue treatment with OL BI 655130 between Wk7 – Wk12 are to be followed for additional 6 weeks 
and have a response evaluation at V15 (Wk13-18). These patients will not have V14 visit. If at V15, they qualify to enter 
OLE trial, then V15 will be considered as EoS for these patients. If not, then the patients will have an additional 10 weeks 
follow-up and have an EoS at V16 (Wk16-28).
*Patients who do not qualify to enter into the OLE trial are to be followed for 16 weeks (EoS/V16/Wk16-28) after the last 
dose of trial medication, which is the latest time point of trial medication given during the study (i.e. the latest of D1, D8 if 
OL BI655130 is given, rescue with OL BI 655130 if given).
D, day; EoS, End of Study; Eps; Endpoints; Fup, Follow-up; GPP, generalized pustular psoriasis; GPPGA, generalized 
pustular psoriasis physician global assessment; i.v., intravenous; R, randomization; Scr, screening; SD, single dose; Wk, 
week.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This phase II trial with BI 655130 and placebo is to be conducted in patients with GPP 
presenting with an acute flare of moderate to severe intensity.
Based on data from 1368.11 which demonstrated rapid treatment onset of effect and flare 
resolution, a parallel group, randomized, double-blind and placebo controlled trial was 
considered most  appropriate to evaluate the efficacy and safety of BI 655130 in patients with 
GPP.  Also based on 1368.11 trial, the best option that can be offered for failing placebo 
patients is BI 655130. In the 1368.13 trial, any patients regardless of originally randomized 
treatment group, who experiences disease worsening and/or has recurrence of flare during the 
trial duration, will be offered escape treatment (SoC – physician’s choice) and/or rescue 
treatment with open label BI 655130. Refer to Section 3.1 for details regarding criteria for 
qualifying for escape treatment with SoC or rescue treatment with OL BI 655130.
No active control group is included in this trial as there is currently no drug approved for the 
induction treatment of acute flares of moderate to severe GPP. Secukinumab (Cosentyx®), 
infliximab (Remicade®), ixekizumab (Taltz®), brodalumab
(Lumicef®), adalimumab (Humira®), guselkumab (Tremfya®) and Risankizumab are only 
registered in Japan for the treatment of GPP and plaque psoriasis. For secukinumab, 
authorization was granted on the basis of long-term treatment data (52 weeks) derived from a 
single open label clinical trial conducted in 12 patients with chronic GPP and an endpoint at 
16 weeks (R16-1462). Moreover, due to the absence of approved drugs and a commonly 
accepted treatment algorithm, patients in this trial will have a very heterogenous pre-
treatment history as different SoC are available in different countries, which prevents the 
selection of suitable active comparator which is relevant for all patients. Considering an add-
on design in treatment-naïve patients or patients with a defined treatment history would make 
enrolment of this study non-feasible. In addition, given the lack of a known effect size for 
SoC treatments (e.g., biologics, retinoids, or cyclosporine), because these drugs have not been 
tested in clinical trials in acute GPP, the expected sample size would of necessity be much 
larger in an acute flare setting in order to account for potentially smaller treatment differences 
than might be observed in a comparable trial where placebo is used as the comparator.  This 
approach is not feasible in a rare disease such as GPP where recruitment is much slower and 
driven by a population with very few patients. 
Thus, study 1368-0013 will be a single-dose, placebo-controlled study of patients with acute 
GPP flares of moderate to severe intensity receiving 900 mg BI 655130 and then followed for 
an additional 12 weeks. Patients who satisfy the inclusion/exclusion criteria of subsequent 
open-label extension trial (1368-0025) will receive an option to continue receiving treatment 
for GPP with s.c. dosing. See Section 3.1 for additional details on the trial design.
Please also refer to Section 4.1.3 for further details.
3.3
SELECTION OF TRIAL POPULATION
Eleven to 20 countries have been invited to participate in order to minimize the risk of under 
recruiting and to meet the goal of 51 patients entered. Recruitment will be very challenging 


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due to the rareness of the disease and because GPP patients must have an acute flare of 
moderate to severe intensity in order to be randomized on the trial. 
For this trial, it is planned to include patients with active disease regardless of the mutation 
status (the status will be investigated during the trial) for the following reason:

Efficacy has been seen in GPP patients both with and without the IL36RN mutation (early 
response to flare treatment with BI 655130 in 1368.11).

In addition to the described IL36RN mutation, other mutations in the same gene and other
genes linked to the IL36 pathway have been described (please see Section 1.1 “Medical 
Background”).  This points to a general role of the IL36 pathway as disease trigger/driver.

Because rapid treatment of flares is critical, patients can be included without the need for 
screening for mutation status.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) at the investigational site irrespective of 
whether they have been treated with investigational drug or not.
3.3.1
Main diagnosis for trial entry
This study will assess treatment of patients with GPP presenting with an acute flare of 
moderate to severe intensity. 
At screening, the diagnosis of GPP is based on the consensus diagnostic criteria defined by 
the ERASPEN (R18-1705). 
These diagnosis criteria include:
Primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where 
pustulation is restricted to psoriatic plaques)

With or without systemic inflammation

With or without plaque-type psoriasis

Either relapsing (>1 episode) or persistent (>3 months) 
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
Patients will be enrolled (screened) into the trial, if they meet the following criteria. Please 
refer to Section 3.3.4 for criteria for initiation of randomized treatment:
1. a. Patients with GPPGA score of 0 or 1 and a known and documented history of GPP (per 
ERASPEN criteria) regardless of IL36RN mutation status, and in addition with previous 
evidence of fever, and/or asthenia, and/or myalgia, and/or elevated C-reactive protein, 
and/or leucocytosis with peripheral blood neutrophilia (above ULN)


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OR
b. Patients with an acute flare of moderate to severe intensity meeting the ERASPEN 
criteria of GPP with a known and documented history of GPP (per ERASPEN criteria) 
regardless of IL36RN mutation status, and in addition with previous evidence of fever, 
and/or asthenia, and/or myalgia, and/or elevated C-reactive protein, and/or leucocytosis 
with peripheral blood neutrophilia (above ULN).
OR
c. Patients with first episode of an acute GPP flare of moderate to severe intensity with 
evidence of fever, and/or asthenia, and/or myalgia, and/or elevated C-reactive protein, 
and/or leucocytosis with peripheral blood neutrophilia (above ULN). For these patients 
the diagnosis will be confirmed retrospectively by a central external expert/committee.
2. Patients may or may not be receiving background treatment with retinoids and/or 
methotrexate and/or cyclosporine. Patients must discontinue 
retinoids/methotrexate/cyclosporine prior to receiving the first dose of BI 655130 or 
placebo.
3. Male or female patients, aged 18 to 75 years at screening.
4. Signed and dated written informed consent prior to admission to the study in accordance 
with ICH-GCP and local legislation prior to start of any screening procedures.
5. Women of childbearing potential 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 Section 4.2.2.3 as well as in the patient information. Note: A 
woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming postmenopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Tubal ligation is not a method of permanent sterilization. A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause.
3.3.3
Exclusion criteria
Patients will not be screened or treated if any of the following criteria apply: 
1. Patients with SAPHO (Synovitis–acne–pustulosis–hyperostosis–osteitis) syndrome.
2. Patients with primary erythrodermic psoriasis vulgaris.
3. Patients with primary plaque psoriasis vulgaris without presence of pustules or with 
pustules that are restricted to psoriatic plaques.
4. Drug-triggered Acute Generalized Exanthematous Pustulosis (AGEP).
5. Immediate life-threatening flare of GPP or requiring intensive care treatment, according 
to the investigator’s judgement. Life-threatening complications mainly include, but are 
not limited to, cardiovascular/cytokine driven shock, pulmonary distress syndrome, or 
renal failure. 
6. Severe, progressive, or uncontrolled hepatic disease, defined as >3-fold Upper Limit of 
Normal (ULN) elevation in AST or ALT or alkaline phosphatase, or >2-fold ULN 
elevation in total bilirubin. 


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7. Treatment with:
a.
Any restricted medication as specified in Table 4.2.2.1: 1, or any drug considered 
likely to interfere with the safe conduct of the study, as assessed by the 
investigator.
b. any prior exposure to BI 655130 or another IL36R inhibitor
8. Patients with dose escalation of their maintenance therapy with cyclosporine and/or 
methotrexate and/or retinoids within the 2 weeks prior to receiving the first dose of BI 
655130/ placebo.
9. The initiation of systemic agents such as cyclosporine and/or retinoids and/or 
methotrexate 2 weeks prior to receiving the first dose of BI 655130/ placebo.
10. Patients with congestive heart disease, as assessed by the investigator.
11. Active systemic infections (Fungal and bacterial disease) during the last 2 weeks prior to 
receiving first drug administration, as assessed by the investigator.
12. Increased risk of infectious complications (e.g. recent pyogenic infection, any congenital 
or acquired immunodeficiency (e.g. HIV), past organ or stem cell transplantation), as 
assessed by the investigator. 
13. Relevant chronic or acute infections including HIV or viral hepatitis. For patients 
screened while having a flare (inclusion criteria 1b or 1c), if Visit 1 HIV or viral hepatitis 
results are not available in time for randomization, these patients may receive randomized 
treatment as long as the investigator has ruled out active disease based on available 
documented history (i.e. negative HIV and viral hepatitis test results) within 3 months 
prior to Visit 2.  A patient can be re-screened if the patient was treated and is cured from 
acute infection.  
14. Active or Latent TB: 
QuantiFERON® (or if applicable, T-Spot®) TB test will be performed at screening. If the 
result is positive, the patient may participate in the study if further work up (according to 
local practice/guidelines) establishes conclusively that the patient has no evidence of 
active tuberculosis. Active TB patients must be excluded. If presence of latent 
tuberculosis is established, then treatment should have been initiated and maintained 
according to local country guidelines. For patients screened while having a flare 
(inclusion criteria 1b or 1c), if the TB test results are not available in time for 
randomization, these patients may receive randomized treatment (provided they meet all 
other inclusion/exclusion criteria) as long as the investigator has ruled out active disease 
based on available documented history (i.e. negative for active TB) within 3 months prior 
to Visit 2.
15. History of allergy/hypersensitivity to a systemically administered trial medication agent 
or its excipients. 
16. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal or squamous cell carcinoma of the 
skin or in situ carcinoma of uterine cervix. 
17. Currently enrolled in another investigational device or drug study, or less than 30 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s).


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18. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
Women who stop nursing before the study drug administration do not need to be excluded 
from participating; they should refrain from breastfeeding up to 16 weeks after the study 
drug administration (see Section 4.2.2).
19. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to receiving first dose of study drug or planned during the study, e.g. hip 
replacement, aneurysm removal, stomach ligation), as assessed by the investigator.
20. Evidence of a current or previous disease, medical condition (including chronic alcohol or 
drug abuse or any condition) other than GPP, surgical procedure, psychiatric or social 
problems, medical examination finding (including vital signs and electrocardiogram 
(ECG)), or laboratory value at the screening outside the reference range that in the 
opinion of the investigator is clinically significant and would make the study participant 
unreliable to adhere to the protocol, comply with all study visits/procedures or to 
complete the trial, compromise the safety of the patient or compromise the quality of the 
data.
3.3.4
Initiation of randomized treatment
Treatment (Visit 2) will be initiated immediately in patients:

Who meet the inclusion criteria (Section 3.3.2).

Who are presenting with an acute GPP flare with moderate to severe intensity, defined by 
emergence of:
a) GPPGA score of at least 3 (moderate), and
b) presence of fresh pustules (new appearance or worsening of pustules), and
c) GPPGA pustulation sub score of at least 2 (mild), and
d) at least 5% of Body Surface Area (BSA) covered with erythema and the presence 
of pustules

And who do not meet any of the exclusion criteria (Section 3.3.3).
3.3.5
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole with 
different implications, please see Sections 3.3.5.1 and 3.3.5.2 below.
Every effort should be made to keep the treated 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 randomization, as well as the explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason 
must be documented in the patient files and Case Report Form.


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3.3.5.1
Withdrawal from trial treatment 
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision. 

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

If a hepatic injury alert (as defined in Section 5.2.6.1) is detected without identification of 
an alternative cause in the work-up according to the “DILI checklist”, the patient should 
not receive subsequent doses of OL BI 655130.

For individual stopping rules related to specific adverse events, please see Section 4.2.1.1
Emergency procedures. 
Patients who terminate study drug early should be encouraged to follow all study procedures 
per the Flow Chart and Sections 4.2.1 and 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the Case Report Form (CRF). These data will be included in the trial database 
and reported.
3.3.5.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision. Once a patient is withdrawn from the trial, no further information may be 
collected for the purpose of the trial. Furthermore, it may also mean that further patient 
follow-up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see Section 3.3.5.1
above.
3.3.5.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG, 
Biberach, Germany. The BI 655130 molecule is an anti-human IL-36 receptor monoclonal
antibody heterodimer with a molecular weight of approximately 146 kDa.
BI 655130 solution for infusion (i.v. administration) is formulated at 60 mg/mL presented in 
a 10 mL vial with a nominal fill volume of 7.5 mL (450 mg).
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Study compound
Substance:
Spesolimab (BI 655130)
Pharmaceutical formulation:
Solution for infusion
Source:
BI Pharma GmbH & Co. KG, Biberach, 
Germany
Unit strength:
BI 655130 450 mg/vial (60 mg/mL), 7.5 mL 
fill volume
Posology:
900 mg single i.v. dose at Day 1
Route of administration:
i.v. infusion 
Duration of use:
Single dose
At the time of use, the i.v. solution for dosing will be prepared as detailed in the instructions 
provided in the ISF.


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Table 4.1.1: 2
Placebo comparator
Substance:
Placebo to BI 655130
Pharmaceutical formulation:
Solution for infusion
Source:
BI Pharma GmbH & Co. KG, Biberach, 
Germany
Unit strength:
Placebo to BI 655130 450 mg/vial (60 
mg/mL), 7.5 mL fill volume
Posology:
0 mg on Day 1
Route of administration:
i.v. infusion
Duration of use:
Single Dose
4.1.2
Selection of doses in the trial
A fixed rather than weight-based dose regimen of single dose of 900 mg has been selected for 
the following reasons: 

Early trials of therapeutic monoclonal antibodies often investigate body-weight–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 pharmacokinetic (PK) 
and pharmacodynamic (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).

A dose of 10 mg/kg BI 655130 as a single i.v. infusion was chosen for the first trial in 
GPP (Proof of concept trial 1368.11) on the basis of the SRD trial 1368.1 that tested 
doses up to 10 mg/kg, which were all found to be safe and tolerable in the patient 
populations studied. The dose of 10mg/kg was chosen for Study 1368.11 as it was 
considered to provide greater assurance of achieving appropriate exposure levels in the 
skin and efficacy in GPP patients.  In Study 1368.11, no severe or serious adverse events 
were reported, this confirms that in the GPP patients enrolled (n=7), the selected dose of 
10mg/kg is safe and tolerable. 
Thus, based on these data from 1368.11, it was considered reasonable to continue with the 
dose of 10 mg/kg and to maintain the PK exposures observed in the trial 1368.11.  A fixed 
dose of 900 mg as a single IV infusion is recommended for flare treatment in the proposed 
trial (1368-0013) based on the evaluation of the PK data in GPP patients suggest that BI 
655130 exposure in patients was lower when compared to PK in Healthy Volunteers (HVs) 
and based on flexibility to recruit subjects with a body weight greater than 70 kg.


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Tests in healthy volunteers with doses up to 20 mg/kg (every week for 4 weeks in trial 
1368.2) indicated that BI 655130 was found to be safe (see Section 1.2.3 and IB for further 
details (c03320877)). Thus, the selected fixed dose (900 mg i.v.) is within safety limits for 
patients with a lower weight.
The intended dose for treatment of a moderate to severe flare which can be life-threatening is 
the maximum practical dose to deliver at one time. Experience with biologics has consistently 
led to concern about under-dosing leading to inadequate response.  In this trial those who 
have inadequate response at 1 week are allowed to receive a dose of BI 655130.  Thus, there 
will be a test of a second dose at an appropriate interval to evaluate under-dosing as the 
explanation for treatment failure.  Given (i) the rarity of the disease and in particular due to 
the rareness of flaring events precluding typical dose finding strategies, (ii) the serious and 
potentially life threatening nature of moderate/severe GPP and (iii) the favorable efficacy, 
safety and tolerability profile of BI 655130, exploration of lower doses in GPP patients 
presenting with a flare (trial 1368-0013) is considered to be not feasible or worthwhile.
4.1.3
Method of assigning patients to treatment groups
An Interactive Response Technology (IRT) will be used to screen eligible patients, perform 
drug assignment, manage initial/re-supply ordering of drug supplies and handle emergency 
un-blinding. The investigator will receive all necessary instructions to access the IRT from 
the Sponsor. Detailed IRT functions and procedures will be documented in the user 
requirement specifications mutually agreed to by the sponsor and the IRT vendor.
During Visit 2 and after the patient’s eligibility has been confirmed, the treatment will be 
assigned via IRT. Patients will be randomized to receive BI 655130 900 mg or placebo in a 
ratio of 2:1. The assignment will occur in a blinded fashion via IRT. The site is also required 
to register Visit 9 (Wk1/D8) in IRT. On registering the visit, IRT system will determine if a 
drug assignment (Treatment with open label BI 655130) is required. At the subsequent visits 
where study medication (Rescue with open label BI 655130) is to be administered (if 
applicable. i.e. in the event of recurrence of flare. Refer to Table 3.1:1), the site is required to 
complete the rescue medication module in the IRT. 
At randomization as well as subsequent medication administration visits (if applicable), IRT 
will assign medication numbers. Site personnel will enter the medication numbers in the 
eCRF.
4.1.4
Drug assignment and administration of doses for each patient
The treatment to be evaluated is outlined in Table 4.1.4: 1 below. It will be assigned to each 
patient after the completion of the randomization visit (Visit 2), verification of all inclusion 
and exclusion criteria and verification of criteria for initiation of treatment (see Section 
3.3.4).
Upon randomization, patients will receive the BI 655130 or placebo on Day 1. For further 
details concerning timing see the study Flow Chart. The start and end times of the infusion 
will be recorded.  Detailed instructions for the preparation of the infusion solution, the 
volume to be administered, and the infusion rate are provided in the ISF. 


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In all patients, the infusion solution is intended to be intravenously administered over a 
period of 90 minutes. In case of safety concerns, e.g. due to systemic hypersensitivity
including (See Section 4.2.1.1 for further details) infusion reactions, it is at the discretion of 
the investigator or his/her designee to adapt the infusion scheme, including but not limited to 
slowing down the infusion rate, stopping the infusion, and provided no further safety concern 
exists, restarting at a slower rate. Regardless, the total duration of infusion should not exceed 
180 minutes (3hours).  Further based on his/her medical judgment the investigator will 
provide medications as needed. 
The administration of the trial medication will be done under the supervision of the 
investigating physician or a designee. The so-called four-eye principle (two-person rule) is 
recommended for administration of trial medication and – if applicable – its preparation, if 
correct dosage cannot be ensured otherwise.
Table 4.1.4: 1
Treatments used in this trial.
Initial Treatment (Blinded)
Wk1/Day 1
900 mg SD i.v. BI 655130 
2 x BI 655130 450 mg/vial (60 mg/mL)
0 mg SD i.v. Placebo to BI 655130 
2 x Placebo to BI 655130 450 mg/vial 
(60 mg/mL)
Treatment with BI 655130 (Open Label)
Wk1/Day8
900 mg SD i.v. BI 655130
2 x BI 655130 450 mg/vial (60 mg/mL)
Rescue Treatment with BI 655130 (Open 
Label)
After Wk1/Day 8 through Wk12 
900 mg SD i.v. BI 655130 
2 x BI 655130 450 mg/vial (60 mg/mL)
SD, single dose; i.v., intravenous; Wk, week.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients and investigators involved in the trial conduct will always remain blinded with 
regard to the randomized treatment assignments until after database lock for the final trial 
analysis.
If the trial team agrees to perform the primary analysis and the final analysis separately (see 
Section 7.3), then a database lock for the primary analysis will be done and treatment will be 
unblinded to trial and project team members. 
If the trial team agrees to perform the primary analysis and final analysis as one single 
analysis (at the time of trial completion), then patients, investigators, and sponsor personnel 
involved in the trial conduct will be unblinded to the randomized treatment assignments after 
the database lock has been performed.


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The randomization codes will be provided to bio analytics prior to last patient out to allow for 
the exclusion from the analyses of PK samples taken from placebo patients. Bio analytics will 
not disclose the randomization code or the results of individual measurements until the trial 
has been officially unblinded to the sponsor. Sample drug levels and demographic data 
together with treatment assignments and dosing information may be made available to named 
individuals from bio analytics department for the purpose of PK dataset generation and 
analysis in accordance with sponsor’s standard procedures.
A fully external DMC will perform an unblinded safety and efficacy assessment at specified 
intervals in order to ensure that patients are protected from potential harm, please refer to 
Section 8.7 for further details.
Section 4.1.5.2 provides the rules surrounding breaking of the randomization code.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator / pharmacist / investigational drug 
storage manager via IRT (for Japan: only to the investigator).  It must only be used in an 
emergency situation when the identity of the trial drug must be known to the investigator in 
order to provide appropriate medical treatment or otherwise assure the safety of trial 
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page along with the date and the initials of the person who broke the code.
In case the automated unblinding option via the IRT system is malfunctioning, the IRT 
service provider can be contacted (24 hours a day coverage) and the treatment allocation can 
be obtained.  IRT support has direct access to the database and the treatment information can 
be manually obtained in case the automated process is not working properly.  Details about 
this process will be included in the ISF.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomization code for individual patients during trial conduct. The access to the 
code will only be given to authorized Pharmacovigilance representatives and not be shared 
further. 
Treatment unblinding will be performed prior to each DMC meeting as a prerequisite for 
generation of the applicable DMC summaries required, as well as subsequent to the primary 
analysis database lock (if applicable), and the final trial database lock at which time the final 
trial analyses will be performed. Treatment unblind for the study will be officially released 
once database lock for the final trial analysis has been performed.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by Boehringer Ingelheim Pharma GmbH & Co. 
KG, Biberach, Germany. They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice (GMP).  The investigational product consists of a 


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carton holding a single vial of the trial medication. Each carton will have a unique medication 
number.  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.
Trial medication must be securely stored, e.g. in a locked refrigerator or at a pharmacy.  If the 
storage conditions are found to be outside the specified range, the local clinical monitor (as 
provided in the list of contacts) must be contacted immediately. Refer to the ISF for 
additional information.
The trial medication must be administered in the manner specified in the CTP and 
instructions for IMP preparation handling and administration of BI 655130 or Placebo.
4.1.8
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB)/ethics 
committee 

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the Principal Investigator (if applicable)

Availability of FDA Form 1572 (if applicable)
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
All unused trial medication must be returned to the sponsor. All used and partially used 
medication must be destroyed locally by the trial site. Receipt, usage and return or disposal 
must be documented on the respective forms. Account must be given for any discrepancies.
The investigator and/or pharmacist and/or investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the sponsor or alternative disposal of unused products. 


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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 investigational product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor, the investigator / pharmacist / investigational drug storage manager must verify that 
all unused drug supplies have been returned by the clinical trial staff and all used or partially 
used supplies have been destroyed by the trial site, 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
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (see Section 3.3), are 
permissible. All concomitant medications should be carefully evaluated by the investigator 
and the Local Clinical Monitor (CML) should be contacted when there are questions 
regarding concomitant medications.
During the trial, if the severity and progression of the disease worsens, the investigator can 
treat the patient with Standard of Care (escape treatment) of his/her choice. Please refer to 
Table 3.1:1 for the details on the use of escape treatment during the trial. All efforts should be 
made to inform the patient of the importance of coming to the protocol specified visits (See 
Flow Chart) up to the EoS visit. Patients refusing to return to the study site (during the 
follow-up period) should at least provide safety information by phone at the respective visits.
Overall, the choice of the escape treatment i.e Standard of Care (SoC) treatment will be left at 
the discretion of the investigator. The sponsor will not provide/supply SoC treatment (s) to 
the sites.
4.2.1.1
Emergency procedures
Systemic hypersensitivity including Infusion reactions and anaphylactic reaction
In case of Systemic hypersensitivity including infusion reactions, and anaphylactic reaction, 
emerging during or after infusion of trial medication, the investigator should consider in 
accordance with severity of the reaction and local standard of care to
-
Immediately interrupt the infusion
-
Treat with systemic anti-histamines, i.v. steroids, and in case of a severe allergic 
reaction (erg, anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA/Nab as detailed in the Lab Manual (Central 
Laboratory). Consider also the evaluation of histamine, serum tryptase, and complement 
components.


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In case of systemic hypersensitivity including infusion reactions, based on patient’s clinical 
course and medical judgment, the infusion may be re-initiated in case of mild or moderate 
systemic hypersensitivity including infusion reactions (according to RCTC grading (R13-
3515) at lower speed with gradual increase to complete the infusion as detailed in the 
Instructions for Preparation and Handling of BI 655130 in the ISF.  Regardless, the total 
duration of infusion should not exceed 180 minutes (3hours).
In case of anaphylactic reactions based on published criteria (Appendix 10.1.6; (R11-4890)
that are suspected to be caused by the trial medication, the investigator should discontinue 
treatment with BI 655130.
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 potential systemic allergic reaction, blood samples for determination of serum 
tryptase will be collected 0.5 h, 2 h, 6 h, 24 h after onset of the event.
Severe infections (according to RCTC grading the ISF), serious infections, opportunistic or 
mycobacterium tuberculosis infections
Treatment of the infection should be initiated promptly according to local standard of care. 
No further trial medication should be administered until the active infection has resolved. 
Treatment with BI 655130 may be restarted when the patient has recovered according to 
investigator’s assessment.
Active/Latent TB:
QuantiFERON® (or if applicable, T-Spot®) TB test will be performed at screening. If the 
result is positive, the patient may participate in the study if further work up (according to 
local practice/guidelines) establishes conclusively that the patient has no evidence of active 
tuberculosis. Active TB patients must be excluded. If presence of latent tuberculosis is 
established, then treatment should have been initiated and maintained according to local 
country guidelines. For patients screened while having a flare (inclusion criteria 1b or 1c), if 
the TB test results are not available in time for randomization, these patients may receive 
randomized treatment (provided they meet all other inclusion/exclusion criteria) as long as 
the investigator has ruled out active disease based on available documented history (i.e. 
negative for active TB) within 3 months prior to Visit 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, 
treatment discontinuation is to be a consideration if deemed clinically appropriate by the
investigator. In addition, diagnostics and treatment are to be initiated according to local 
standard of care. 


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4.2.1.2
Additional treatments
No additional treatment is planned. 
However, in case of AEs in need of treatment, the investigator can authorize symptomatic 
therapy.  In those cases, patients will be treated as necessary and, if required, kept under 
supervision at the trial site or transferred to a hospital until all medical evaluation results have 
returned to an acceptable level.
All concomitant and/or rescue therapies will be recorded on the appropriate pages of the 
electronic CRF (eCRF).
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medications (or classes of medications) listed in Table 4.2.2.1: 1 must not have been 
taken before inclusion for the time periods as specified, and are not permitted throughout the 
study participation except in the following circumstances.
These drugs are permitted only when used as escape treatment in the event of disease
worsening and/or recurrence of GPP flare. Escape treatment with any of the drugs listed in 
the table will exclude the patient from qualification to receive a treatment dose with open 
label BI 655130 at D8. However after D8, these patients will qualify to receive treatment 
with open label BI 655130 if they experience a recurrence of GPP flare (see Table 3.1:1 for 
definition of recurrence of GPP flare).


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Table 4.2.2.1: 1
Restricted medications
Medication or class of medications
Restriction duration (through EoS Visit1)
secukinumab (Cosentyx®), Risankizumab
2 months prior to Visit 2
tildrakizumab
2 months prior to Visit 2
rituximab, ustekinumab (Stelara®)
2 months prior to Visit 2
natalizumab, alemtuzumab, guselkumab, 
ixekizumab, adalimumab (Humira®),
investigational products for psoriasis (non biologics)
2 months prior to Visit 2
brodalumab, efalizumab, visilizumab, briakinumab. 
infliximab (Remicade®)
2 months prior to Visit 2
IL36R inhibitors
not allowed before or during trial participation
etanercept (Enbrel®) 
live virus vaccinations
6 weeks prior to Visit 2
any investigational device or product (excludes 
psoriasis products) 
other systemic immunomodulating treatments (e.g. 
corticosteroids2, cyclophosphamide), tofacitinib 
(Xeljanz®), apremilast (Otezla®) 
other systemic psoriasis treatments (e.g. fumarates, 
any other drug known to possibly benefit psoriasis) 
photochemotherapy (e.g., PUVA).
GMA (Granulocytes and monocytes adsorptive 
apheresis)
30 days prior to Visit 2
                                              See Next Page (cont’d.)


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Table 4.2.2.1: 1
Restricted medications (cont’d.)
Medication or class of medications
Restriction duration (through EoS Visit1)
phototherapy (e.g., UVA, UVB) topical treatment 
for psoriasis or any other skin condition (e.g. topical 
corticosteroids, topical vitamin D analogues, tar, 
anthralin, topical retinoids
No treatment initiation of topical treatment 1 week 
prior to Visit 2, and use of these medications is not 
allowed Post Visit 2.
Anakinra
7 days prior to Visit 2
methotrexate, cyclosporine, retinoids
No treatment initiation 2 weeks prior to Visit 2
No dose escalation within 2 weeks prior to Visit 2
Must be discontinued prior to receiving the first dose 
of BI 655130/placebo and not allowed Post Visit 2
1 In case of worsening of the flare (disease worsening), please refer to Section 4.2.1 for the details on the use of escape 
treatment.
2 No restriction on inhaled corticosteroids to treat asthma or corticosteroid drops administered in the eye or ear.
4.2.2.2
Restrictions on diet and life style
No specific restrictions on diet or life style of the patients are required.
4.2.2.3
Restrictions regarding women of childbearing potential 
Women of child bearing potential (for the definition of WOCBP, please refer to Section 
3.3.2) must use a highly effective method of birth control per ICH M3 (R2) that results 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. 
Female Patients:
Acceptable methods of birth control for this trial are: 

Combined (estrogen and progestogen containing) hormonal birth control associated with 
inhibition of ovulation.

Progestogen-only hormonal birth control associated with inhibition of ovulation.

Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS). 

Bilateral Tubal occlusion (blocking of the fallopian tubes).

Vasectomy of sexual partner (proven effective by absence of sperm on the ejaculation).

Complete sexual abstinence (not to have male-female vaginal sex).
As monoclonal antibodies can be secreted in milk, women should refrain from breastfeeding 
once they receive the study drug and up to 16 weeks after, i.e. until BI 655130 is eliminated. 
They can start nursing again after this period.  


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4.3
TREATMENT COMPLIANCE
Administration of the trial medication will be done in the study center under the supervision 
of the investigator or a designee. The measured plasma concentrations will provide additional 
confirmation of compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The primary endpoint, the key secondary endpoint and the secondary endpoints, 
 
 are specified in Sections 2.1.2, 2.1.3, and 2.2.2, respectively.
Skin condition will be assessed by using the Generalized Pustular Psoriasis Physician Global 
Assessment (GPPGA), the Generalized Pustular Psoriasis Area and Severity Index 
(GPPASI), and the Psoriatic Symptom Scale (PSS), Patients’ questionnaires 
 
 Functional Assessment of Chronic Illness Therapy - Fatigue scale (FACIT-Fatigue), 
Pain VAS, 
 will be used as well. 
Additional details for these assessments are provided below.  Methodological details for the 
evaluation of the scores/index are described in the ISF.
Generalized Pustular Psoriasis Physician Global Assessment (GPPGA)
GPPGA relies on clinical assessment of the GPP patient’s skin presentation. It is a modified 
PGA, a physician’s assessment of psoriatic lesions, which has been adapted to the evaluation 
of GPP patients (R15-5200). The investigator (or qualified site personnel) scores the 
erythema, pustules, and scaling of all GPP lesions from 0 to 4. Each component is graded 
separately, the average is calculated, and the final GPPGA is determined from this composite 
score. A lower score indicates a lesser severity, with 0 being clear and 1 being almost clear. 
GPPGA is provided in Appendix 10.1.1; this score will be measured at the timepoint noted in 
the study Flow Chart.
Generalized Pustular Psoriasis Area and Severity Index (GPPASI)
The GPPASI is an adaptation for GPP patients of the PASI, an established measure of 
severity and area of psoriatic lesions in patients with psoriasis (R96-3541). Similar adaptions 
have been used for PPP (R16-3360). In the GPPASI, the induration component has been 
substituted with the pustules component. It is a tool that provides a numeric scoring for a 
patient’s overall GPP disease state, ranging from 0 to 72. It is a linear combination of percent 
of surface area of skin that is affected by erythema, pustules and scaling and the severity of 
erythema, pustules, and scaling (desquamation) over 4 body regions.
GPPASI is provided in Appendix 10.1.2; this score will be measured at the timepoint noted in 
the study Flow Chart.
 
 
 
 
w


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FACIT-Fatigue scale
The FACIT-Fatigue is a 13-item questionnaire (R10-6433, R07-4311, R16-0029) that 
assesses self-reported fatigue and its impact upon daily activities and function. Answers are 
based on a 5-point Likert scale. Responses of “not at all,” “a little,” “somewhat”, “quite a 
bit,” and “very much” are available for each question, and correspond to scores of 0, 1, 2, 3, 
and 4, respectively (total score range: 0-52). A minimal clinically important difference 
(MCID) of 3-4 points in change score has been reported (R16-0029). The recall period for 
items is 7 days.
The FACIT fatigue scale (Version 4) is provided in Appendix 10.1.4; this score will be 
measured at the timepoint noted in the study Flow Chart.
PSS
The PSS is a 4-item patient-reported outcome (PRO) instrument that was developed to assess 
the severity of psoriasis symptoms in patients with moderate to severe psoriasis (R18-1990). 
The symptoms included are:  pain, redness, itching, and burning. Current symptom severity is 
assessed using a 5-point scale ranging from 0 (none) to 4 (very severe). The symptom scores 
are added to an unweighted total score (range:  0 to 16).
The PSS instrument is provided in Appendix 10.1.5.
Pain VAS
The pain VAS is a unidimensional measure of pain intensity (R18-1989). It is a continuous 
scale comprised of a horizontal or vertical line, usually 10 centimeters (100 mm) in length, 
anchored by word descriptors at each end (“no pain”, “very severe pain”). The pain VAS is 
self-completed by the respondent. The respondent is asked to place a vertical ( | ) mark on the 
horizontal line to indicate the severity of the pain. Using a ruler, the score is determined by 
measuring the distance (mm) on the 10-cm line between the “no pain” anchor and the 
patient's mark, providing a range of scores from 0–100. A higher score indicates greater pain 
intensity.
Pain VAS will be measured at the timepoint noted in the study Flow Chart. The Pain VAS 
instrument is provided in Appendix 10.1.9.


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5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:
∀
Adverse events (including drug-related AEs)
∀
Adverse events of special interest (AESI)


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
Serious adverse events

Intensity of adverse events will be assessed by Rheumatology Common Toxicity Criteria
(RCTC) version 2.0 (refer to ISF for details)

Safety laboratory tests

Physical examination

Vital signs (blood pressure, pulse rate, body temperature)

12-lead Elecrocardiogram (ECG)

Infusion site reactions

Immunogenicity (ADA)
5.2.1
Physical examination
Complete and targeted physical examinations will be performed at visits as described in the 
Flow Chart. Height and weight of the patient will be recorded at the Screening Visit.
Complete physical examination will include vital sign assessment and general appearance as 
well as evaluation of all organ systems. Targeted physical examination will include vital sign 
assessment and evaluation of organ systems associated with AE(s) symptoms or laboratory 
abnormalities.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs. 
5.2.2
Vital signs
Vital signs evaluations will be performed at visits as shown in the Flow Chart. This includes 
measuring temperature, pulse rate, systolic/diastolic blood pressure and respiratory rate. 
Respiratory rate, pulse rate, and blood pressure will be measured after patients have been 
sitting comfortably for at least 5 minutes. All recordings should be made using the same type 
of blood pressure recording instrument on the same arm if possible. Measurement of vital 
signs should precede blood sampling to avoid the impact of blood sampling on the vital 
measurements. 
At visits with i.v. administration, vital signs will be assessed pre-dose, at approximately 5 
minutes after the end of infusion and 120 minutes after the end of infusion. On non-study–
drug administration days, vital sign assessments are to be done prior to blood sampling.
In addition to the temperature being measured along with the vital signs at time points shown 
in the Flow Chart, additional fever assessments will be recorded on dosing days at three time 
points. If the patient will receive medication for fever treatment, the fever assessment will be 
performed prior to taking the anti-fever treatment. These fever assessments must be taken 
whether or not the patient has an elevated temperature and whether or not the patient takes 
anti-fever treatment. The fever assessments times are to be separated by intervals of 2 to 4 
hours on dosing days. At all other visits (non-dosing days), fever will be assessed once a day 
and will be completed prior to receiving medication for fever treatment, if anti-fever 
treatment is given.
During i.v. drug administration, patients should be closely monitored for signs and symptoms 
of hypersensitivity reactions for approximately 2 hours after the study drug administration. 


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Hypersensitivity reactions should be treated according to medical standards. Pre-medications 
for further infusions might be considered and will be agreed on between investigator and BI 
clinical monitor.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart.  
The parameters that will be determined are listed in Table 5.2.3: 1. The laboratory tests will 
be performed at a central laboratory. 
However, local labs are to be used for dosing decisions at visits involving i.v. administration 
of BI 655130 or placebo. The labs listed in Table 5.2.3: 2 are to be collected and assessed by 
the investigator prior to study drug infusion to allow for immediate subject management; 
however, split or concurrent samples must be drawn and sent to the central laboratory for 
analysis. 
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 eDC 
system). The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.
Clinically relevant abnormal findings (e.g. anemia, hypoproteinemia, hypoalbuminemia, 
hypocalcemia etc.) will be reported as baseline conditions or AEs. A clinically relevant value 
may be either in- or outside the reference range. Clinically relevant abnormal laboratory test 
results must be confirmed using an unscheduled visit laboratory kit and should be repeated 
until normalization or stabilization or until an alternative explanation has been found. 
Abnormal laboratory values will be also graded for intensity by using RCTC Version 2.0 
criteria (R13-3515).
Instructions regarding sample collection, sample handling/processing and sample shipping 
are included in the laboratory manual in ISF.


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Table 5.2.3:1 
Safety Laboratory Tests (Central Lab Assessment)
Category
Test name
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
White blood cell count (WBC)
Platelet count
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if 
automatic differential WBC is 
abnormal)
Neutrophils (stabs), eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and International Normalized Ratio [INR])
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Serum tryptase
Amylase1
Lipase1
Substrates
C-Reactive Protein (CRP) 
Serum albumin 
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Total cholesterol 
Triglycerides 
Plasma glucose
BUN (blood urea nitrogen)
Uric acid
eGFR (estimated by CKD-EPI formula) (only at
screening)
Bilirubin Indirect (if total is elevated)
Troponin (Reflex, in case of elevated CK)
LDL-Cholesterol
HDL-Cholesterol
Electrolytes
Sodium
Potassium
Chloride
Calcium
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose 
Urine ketone 
Urobilinogen 
Urine bilirubin
Urine erythrocytes 
Urine leukocytes 
Urine pH


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Table 5.2.3:1 
Safety laboratory tests (Central Lab Assessment; cont’d.)
Category
Test name
Infection testing2
Hepatitis B Surface Antigen (qualitative)
Hepatitis B core Antibody
HBV-DNA (quantitative) at baseline and EoS Visit3
QuantiFERON® (or if applicable, T-Spot®)TB4,5
Hepatitis C Antibodies (qualitative)
HIV-1, and HIV-2 Antibody (qualitative)
Urine-Sediment (only
if urine analysis abnormal)
microscopic examination
Specific gamma-globulin 
quantification IgE
IgE6
Urine Pregnancy test7. At the 
drug administration
visits, the test will be performed 
prior to the
administration of study drug
Human Chorionic Gonadotropin in urine
Serum Pregnancy test7 (only for 
female
patients of childbearing 
potential)
Human Serum Chorionic Gonadotropin
1To be done at screening.
2Only at Visit 1(refer to exclusion criteria Section 3.3.3 for details regarding infection testing) and EoS (V14 or V15 or V16 
as applicable).
3An HBV-DNA test should be conducted if Hepatitis B core Antibody is positive and Hepatitis B Surface Antigen is 
negative. A positive HBV-DNA test at screening will exclude the patient. These evaluations should be conducted at 
screening and EoS (V14 or V15 or V16 as applicable).
4If the 1st QuantiFERON®(or if applicable, T-Spot®) TB test result is indeterminate, a retest should be performed.
<For Japan> T-Spot® TB test may be performed at local labs instead of QuantiFERON®TB test.
5In subjects with a negative QuantiFERON® (or if applicable, T-Spot®) TB test, the test should be repeated at EoS (V14 or 
V15 or V16 as applicable). <For Japan> T-Spot® TB test may be performed at local labs instead of QuantiFERON®TB 
test.
6IgE will be taken in case of systemic hypersensitivity including infusion reaction together with ADA (anti-drug antibodies) 
sample.
7Urine and serum pregnancy testing will be performed as indicated in the Flow Chart.


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Table 5.2.3: 2
Laboratory tests to be assessed prior to i.v. administration at V2, V9 
or for any rescue treatment (Local Labs)
Category
Test name
Haematology
Haematocrit, Haemoglobin, Red blood cell count (RBC), White blood 
cell count (WBC), Platelet count
Coagulation
Activated partial thromboplastin time (aPTT),Prothrombin time 
(Quick’s test and INR),Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT), Alanine transaminase 
(ALT/GPT), Alkaline phosphatase (AP)
Substrates
C-Reactive Protein (CRP) , Serum albumin, Creatinine, Total 
bilirubin 
Direct bilirubin, eGFR (preferably estimated by CKD-EPI formula)
Electrolytes
Sodium, Potassium
Urine Pregnancy test 1. 
Test will be performed prior to the administration 
of study drug
Human Chorionic Gonadotropin in urine
Serum Pregnancy test1 (only for female patients 
of childbearing potential)
Human Serum Chorionic Gonadotropin
1Urine and serum pregnancy testing will be performed as indicated in the Flow Chart.


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5.2.4
Electrocardiogram
ECG measurements will always precede blood sampling to avoid impact of sampling on the 
ECG results.  The 12-lead ECGs will be recorded and reviewed prior to dosing as scheduled 
in the Flow Chart. The investigator or a designee will evaluate whether the ECG is normal or 
abnormal and whether it is clinically relevant, if abnormal. ECGs may be repeated for quality 
reasons and the repeated recording used for analysis. No central laboratory will be used for 
ECG recording.
Additional ECGs may be recorded for safety reasons. The electronic version, if applicable, or 
dated and signed printouts of the ECG, will be regarded as source data and will be stored in 
the patient’s medical file.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
5.2.5
Local tolerability
Local tolerability will be assessed by the investigator according to ‘swelling’, ‘induration’, 
‘heat’, ‘redness’, pain’, or, other findings’ at the times indicated in the Flow Chart.  Local 
tolerability will be assessed during the IMP administration and for approximately 2 hours 
after the study drug administration. Grade the intensity of the local tolerability according to 
RCTC grading (cf. ISF).
Other Safety Parameters:
In case of an infusion reaction, monitor the patient per standard of care, grade the intensity of
the reaction according to RCTC grading (cf. ISF) and proceed as described in Section 4.2.1.1.
All cases of malignancies, sepsis or other serious infections and disseminated intravascular 
coagulation that are detected during the trial will be reported as SAEs. Please refer to the 
current list
of “Always Serious AEs” provided in eDC.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of Adverse Events 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.


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An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalization  
-
requires prolongation of existing hospitalization,
-
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 which, when 
based on appropriate medical judgement, may jeopardize 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 hospitalization or 
development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has developed a list of further AEs, which by their nature, can always 
be considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above. The latest list of “Always Serious AEs” can be found in the eDC system. 
These events should always be reported as SAEs as described above.


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Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:
Hepatic injury
Hepatic Injury, is defined by the following alterations of hepatic laboratory parameters:

An elevation of AST and/or ALT and/or AP ≥3-fold ULN plus 2 times the baseline, 
combined with an elevation of total bilirubin ≥2-fold ULN plus 1.5 times the baseline, 
measured in the
same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN
Any patients with these lab abnormalities need to be followed up according to the ‘Drug-
Induced Liver Injury (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 analyzed, if necessary in an unscheduled 
blood test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
Systemic hypersensitivity reactions including Infusion reactions and anaphylactic reaction
Any suspicion of severe systemic hypersensitivity including infusion reactions and any 
anaphylactic reaction should be defined and assessed using the criteria discussed in the 
statement paper from Sampson HA (Section 4.2.1.1 and Appendix 10.1.6; (R11-4890).
Severe infections (according to RCTC grading in the ISF)
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, strongyloides (hyperinfection syndrome and disseminated forms only), 


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paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only),  shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression (R17-2617).
Protocol-specified AESI can be classified as serious or non-serious but all AESI must be 
reported in an expedited manner similar to serious adverse events on a SAE form (i.e. non 
serious AESI must be reported on the SAE form and follow the same reporting timelines as 
for serious AEs).
Intensity of AEs
The intensity grading of AEs will be performed according to RCTC Version 2.0 developed 
by the Outcome Measures in Rheumatology (OMERACT) 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
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug. 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:


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
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files. 
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
For patients rolling over into open label extension trial (1368-0025):

From signing the informed consent of the parent trial onwards until the first dose of trial 
medication in the extension trial:

all AEs (non-serious and serious) and all AESIs.
For patients not rolling over into subsequent OLE trial (1368-0025):

From signing the informed consent onwards until the individual patient’s end of trial:

all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial:
the investigator does not need to actively monitor the patient for AEs but should only
report related SAEs and 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, but not on the CRF.
The follow-up period describes the period of time from the last administration of trial 
medication until the end of trial examination (last per-protocol contact).  
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 


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The same timeline applies if follow-up information becomes available. In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and, if applicable, the BI SAE form. The investigator should determine the 
causal relationship to the trial medication. 
The following should also be recorded as an (S)AE in the CRF and, if applicable, BI SAE 
form:
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 pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after a patient’s end of trial, must be followed up until they have resolved, have 
been  assessed as “chronic” or “stable” , or no further information can be obtained.
Pregnancy
Urine pregnancy testing should be done prior to study drug administration. 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. Women who underwent tubal ligation are still 
considered of childbearing potential and pregnancy testing is necessary as well. The testing 
schedule is specified in the Flow Chart.
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 immediately (within 24 
hours) report any drug exposure during pregnancy by means of Part A of the Pregnancy 
Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 


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is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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2016


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5.6
APPROPRIATENESS OF MEASUREMENTS
The scheduled measurements will allow monitoring of changes in vital signs, standard 
laboratory values, and ECG variables that might occur as a result of administration of trial 
medication. The safety assessments are standard, are accepted for evaluation of safety and 
tolerability of an intravenously administered drug, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used 
assessments of drug exposure. The biomarkers and pharmacogenomic parameters are 
outlined in Section 5.4 are of exploratory nature only.
Information about race should be obtained from all study participants as allowed by local 
regulations. This is because the prevalence and characteristics of psoriasis may differ 
between patients of different racial origin. It will thus be worthwhile to assess if patients of 
different race will respond differently to the study treatment.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule specified in the Flow Chart.  Each visit date 
(with its window) is to be counted from Day 1 (V2). 
All deviations from the planned visit schedule are to be documented.  If any visit has to be 
rescheduled, subsequent visits should follow the original visit date schedule. Additional visits 
for the purpose of retesting of laboratory parameters or AE monitoring may be included as 
deemed necessary by the investigator.
For detailed description of the trial procedures, please refer to the Flow Chart.
Details relating to study drug administration are provided in Section 4.1.4.  
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 
sections of this protocol.  Refer to Section 5 for explanations of the specified assessments and 
procedural details.
Based on the investigator’s clinical judgment, patients may be hospitalized prior to, during or 
following first study drug administration.  If so, patients will perform the needed visits as 
inpatients.  Subsequent visits will be conducted in accordance with the protocol and the 
investigator’s judgment (For details, see Flow Chart and Section 3.1).
The patients’ questionnaires (PSS, 
 pain VAS, FACIT-Fatigue, 
) are to 
be completed by the patient on his/her own in a pre-specified order in a quiet area/room 
before any other visit assessments or treatments, and, if possible, before any interaction with 
the investigator or other members of the study team, and, without any help from or 
interpretation by other people. If the patient is too sick to complete the questionnaires 
him/herself but is able to reply verbally, a member of the study team should read the 
instructions, questions, and response options aloud to the patient and collect the patient’s 
verbal response in as neutral and unbiased a manner as possible. If this is not possible either, 
the questionnaires are not to be completed. The mode of administration should be 
documented in the electronic Case Report Form (eCRF).
 
p
 
)


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At each applicable visit (see Flow Chart), the order of completion for PROs is recommended 
to be as follows:
∀
PSS
∀
∀
pain VAS
Separate from the PROs above, the evaluation of efficacy assessments (GPPGA, GPPASI, 
) for a patient are to be 
conducted by the same physician throughout the study.
6.2.1
Screening period
Screening (Visit 1):
After patients have been informed about the trial, written informed consent in accordance 
with GCP and the local legislation must be obtained prior to performing any study related 
procedures. 
Once consent is obtained, the patient is considered to have started the screening process, and 
is assigned a unique patient number by the IRT system.  The patient is to be recorded on the 
enrolment log and be registered in the IRT system as a screened patient.  Study requirements, 
including the procedure for the follow-up of prematurely withdrawn patients, must be fully 
explained to the patient and written informed consent obtained prior to initiating any study-
related evaluation. The importance of staying in the study until completion of all 
requirements is to be emphasized.  No study procedures are to be done unless the patient has 
provided consent to take part in the study.
Demographics:
Informed consent date, gender, ethnicity and race (if allowed by local law) will be collected 
and reported in the eCRF.
Baseline Conditions:
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding GPP) will be reported on the Baseline Condition eCRF page.  
)


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Infection screening:
Infection testing will include tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see 
Table 5.2.3:1). Please also refer to applicable exclusion criteria in Section 3.3.3 for details 
regarding handling of infection test results for patients screened while having a flare 
(inclusion 1b and 1c).
Medical History:
Information on clinically significant previous and concomitant illnesses, other than GPP, or 
any clinically significant signs or symptoms that are present before informed consent, or pre-
existing conditions identified through findings from assessments and examinations done 
during the screening visits will be recorded as medical and surgical history at screening. 
Regarding the GPP, a detailed history of the disease including evidence of systemic 
symptoms during a GPP flare in the past (i.e. fever, asthenia, myalgia, elevated C-reactive 
protein, leukocytosis with peripheral blood neutrophilia) and information of histopathological 
confirmation of diagnosis will be collected and reported in the eCRF. Also, previous and 
concomitant treatment for GPP will be recorded.
Mutation status:
Information on the presence or absence of IL36RN mutation (if available) will be collected in 
patient’s historical data and reported in the eCRF.
Review of inclusion/exclusion criteria:
Selection criteria will be reviewed carefully.
IRT:
All patients who are screened must be registered with IRT. 
Re-screening: 
If a patient results in a screen failure (i.e. does not meet the eligibility criteria, or does not 
flare within the 6 month screening period) the patient must be registered as a screen failure in 
IRT system.  However, re-screening of a previously screen failed patient will be permitted 
once. Upon re-screening, the patient will be assigned a new patient number. Details of IRT 
procedures can be found in the IRT manual located in the Investigator Site File (ISF). 
For the comprehensive list of the trial procedures required at the Screening Visit (Visit 1) 
please refer to the Flow Chart.


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6.2.2
Randomization Visit and Treatments
Patients will be randomized to receive a single dose of 900 mg BI 655130 or placebo (2:1) at 
Visit 2.
Please refer to Section 3.3.4 for details regarding criteria for initiation of treatment with BI 
655130.
In cases where Visit 1 and Visit 2 are greater than 6 weeks apart, it is recommended that 
patient is asked to re-confirm (verbally) his/her consent to participate in the trial and this 
verbal re-consent must be documented. The first study drug administration is at Visit 2 
Day 1).  
For information pertaining to PK, ADA/Nab, and biomarkers, see Sections 5.3 and 5.4.
For information pertaining to laboratory tests, ECG, vital signs, local tolerability, and 
physical examination, see Sections 5.2.1 to 5.2.5.
Fasting is not required for blood sampling.  Pharmacogenomic genotyping for targeted GPP-
causing mutations (IL36RN, CARD14, AP1S3) are to be performed for all patients (see 
Section 7.3.7.2).  DNA banking is optional and is only to be done for patients who have 
provided informed consent for this specific procedure.
Skin lesion photographs will be taken at all visits on site and are to be taken prior to any skin 
biopsies or study drug administration.  
Skin biopsies (if applicable) and venipuncture (i.e. safety laboratories, PK, ADA/Nab, 
biomarkers) should be the last procedures done prior to study drug administration.
Study drug allocation via the IRT system and administration of study drug should be the last 
activity at Visit 2 with the exception of local tolerability and post dose vital signs 
assessments.
For women of child-bearing potential, pregnancy testing will be done as specified in the Flow 
Chart.
6.2.2.1
Clinical monitoring after study drug administration
During i.v. drug administration, vital signs will be assessed pre-dose, at approximately 5 
minutes after the end of infusion, and 120 minutes after the end of infusion.  Patients should 
be closely monitored for signs and symptoms of hypersensitivity reactions for approximately 
2 hours after doses are administered.  Hypersensitivity reactions should be treated according 
to medical standards.  


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6.2.2.2
Unscheduled visits
During the treatment period patients may be seen at an unscheduled visit if they experience 
worsening of the disease, recurrence of GPP flare, or have AEs that in the opinion of the 
investigator need intervention (e.g. escape or rescue treatment) or repeated laboratory testing. 
The unscheduled visit may include additional collection of blood samples for safety reasons. 
The unscheduled visit may also include additional assessments deemed necessary by the 
investigator such as laboratory samples, ECGs, or other procedures that were missed at a 
previous visit. All unscheduled visits (including the reason for the visit) should be described 
and documented in the medical/source record, and in the eCRF.
6.2.3
Follow up period and trial completion
After receiving the single dose at Visit 2, patients will be followed for 12 -28 weeks 
depending on treatment response. Refer to Section 3.1 for details.
For all randomized patients termination of trial medication and trial completion must be 
recorded on the corresponding eCRF.  
For the comprehensive list of the trial procedures required during the follow-up period, please 
refer to Flow Chart.
Trial Completion:
Trial completion is defined as a patient having reached the EoS visit within the specified 
window per protocol.
Treatment Completion: 
Treatment completion is defined as a patient receiving the whole amount of prepared dose on 
D1. 
Early Treatment Discontinuation:
In case the infusion of study drug is permanently discontinued before the whole amount of 
prepared solution has been administered to the patient, every effort should be made to keep 
the patient in the trial and complete all of the remaining study visits. If this is not possible, 
assessments of the primary and key secondary endpoints at V9 (Wk1), V12 (Wk4) and EoS 
Visit (V14 or V15 or V16 as applicable) should be completed or at a minimum an early EoS 
visit. Please refer to the Flow Chart.


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Early Trial Discontinuation:
A patient not having reached the EoS visit within the specified window per protocol (e.g. due 
to withdrawal of consent, lost to follow-up, death etc.).
An open-label extension trial is planned, see Section 3.1 for details.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
This trial is designed as a randomized, parallel-group, double-blind, and placebo-controlled 
trial with one active dose of BI 655130 in patients with GPP presenting with an acute flare of 
moderate to severe intensity.
The primary objective of this trial is to evaluate the efficacy, safety and tolerability of a 
single i.v. dose of BI 655130 in comparison to placebo at Day 1. The primary analysis, on 
each of the binary, primary endpoint, achievement of a GPPGA pustulation subscore of 0 at 
Week 1, and key secondary endpoint, achievement of a GPPGA of (0, 1) at Week 1, where 
any use of escape medication prior to observing the endpoint is considered to be a non-
response, will compare the proportion of patients who achieve a response on BI 655130 to 
Placebo. Given the small sample size proposed to be used in this trial, an exact statistical test, 
the Suissa-Shuster Z-pooled test, will be used to perform the primary analysis. Confirmation 
of efficacy is then given if the proportion of patients achieving a response on the primary 
endpoint is statistically significantly higher for BI 655130 than for placebo. Formal statistical 
hypothesis testing will be performed at an overall 1-sided alpha level of 0.025.
Stratification of randomization will be performed in this trial for Japan versus non-Japan. 
This stratification is implemented for operational purposes only and is not intended to be used 
as an adjustment factor in the primary analyses of efficacy (see Section 7.6).
7.2
NULL AND ALTERNATIVE HYPOTHESES
The null and alternative hypotheses are described below. Statistical testing will be performed 
based on one-sided hypotheses and p-values. 
Test of the Primary Endpoint
The null hypothesis for the primary endpoint, the proportion of patients achieving a GPPGA 
pustulation subscore of 0, at Week 1 is
H01: Effect of BI 655130 on the proportion of patients achieving a GPPGA 
pustulation subscore of 0 at Week 1 (where any prior use of escape medication 
will be considered to represent a non-response) ≤ Placebo;
versus the alternative hypothesis
H02: 
Effect of BI 655130 on the proportion of patients achieving a GPPGA 
pustulation subscore of 0 at Week 1 (where any prior use of escape medication 
will be considered to represent a non-response) > Placebo.
Only if the null hypothesis, H01 of the primary endpoint is rejected, will the efficacy of BI 
655130 in the treatment of acute GPP flares be confirmed. 


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Test of the Key Secondary Endpoint
Further hypothesis will be tested on the key secondary endpoint in a hierarchical manner if
the null hypothesis of the primary endpoint H01 has been previously rejected.
The null hypothesis for the key secondary endpoint, the proportion of patients achieving a 
GPPGA score of (0, 1), at Week 1 is 
H11: 
Effect of BI 655130 on the proportion of patients achieving a GPPGA of 0 or 
1 at Week 1 (where any prior use of escape medication will be considered to 
represent a non-response) ≤ Placebo;
versus the alternative hypothesis
H12: 
Effect of BI 655130 on the proportion of patients achieving a GPPGA of 0 or 
1 at Week 1 (where any prior use of escape medication will be considered to 
represent a non-response) > Placebo.
No adjustment of the 1-sided alpha-level of 0.025 is necessary.
Test of the Secondary Endpoints
Further hypotheses will be tested on the following secondary endpoints in a hierarchical 
manner if  both null hypotheses of the primary endpoint and key secondary endpoint, H01 and 
H11, have been previously rejected. Note that the study is not further powered for the 
performance of these additional statistical comparisons. 
The null hypothesis for the secondary endpoint, the proportion of patients achieving a 
GPPASI 75 at Week 4 is 
H21: 
Effect of BI 655130 on the proportion of patients achieving a GPPASI 75 at 
Week 4 (where any prior use of escape medication/OL BI 655130 at 
D8/rescue medication with BI 655130 will be considered to represent a non-
response) ≤ Placebo;
versus the alternative hypothesis
H22: 
Effect of BI 655130 on the proportion of patients achieving a GPPASI 75 at 
Week 4 (where any prior use of escape medication/OL BI 655130 at 
D8/rescue medication with BI 655130 will be considered to represent a non-
response) > Placebo.
If the null hypothesis on GPPASI 75 at Week 4 has been previously rejected, then a test on 
the null hypothesis for the secondary endpoint, the pain VAS at Week 4, will be performed 
next in the testing hierarchy. The null hypothesis is: 
H31: 
Change from baseline in pain VAS at Week 4 for BI 655130 ≥ Placebo (where 
negative change indicates an improvement from baseline);


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versus the alternative hypothesis
H32: 
Change from baseline in pain VAS at Week 4 for BI 655130< Placebo (where          
negative change indicates an improvement from baseline).
If the null hypothesis on the pain VAS at Week 4 has been previously rejected, then a test on 
the null hypothesis for the secondary endpoint, the total score of PSS at Week 4, will be 
performed next in the testing hierarchy. The null hypothesis is: 
H41: 
Change from baseline in total score of the PSS at Week 4 for BI 655130 ≥ 
Placebo (where negative change indicates an improvement from baseline);
versus the alternative hypothesis
H42: 
Change from baseline in total score of the PSS at Week 4 for BI 655130< 
     
Placebo (where negative change indicates an improvement from baseline).
If the null hypothesis on the PSS at Week 4 has been previously rejected, then a test on the 
null hypothesis for the secondary endpoint, the total score on the FACIT-Fatigue at Week 4, 
will be performed next in the testing hierarchy. The null hypothesis is: 
H51: 
Change from baseline in the total score on FACIT-Fatigue at Week 4 for BI 
655130 ≤ Placebo;
versus the alternative hypothesis
H52: 
Change from baseline in the total score on FACIT-Fatigue at Week 4 for BI 
655130 > Placebo.
Each of the above secondary endpoints will be tested in a hierarchical manner subsequent to 
rejection of the null hypothesis on the previous secondary endpoint hence no adjustment to 
the 1-sided alpha-level of 0.025 is necessary.
7.3
PLANNED ANALYSES
The primary analysis of this trial is planned to be performed once all randomized patients 
have completed the 12 week period or early discontinued from the trial; a database lock for 
the primary analysis will then be performed. Final analysis is planned to be performed at the 
end of the trial once all randomized patients have completed the trial (including any follow-
up period) if applicable.
The primary analysis and final analysis may be performed as a single analysis (at the time of 
trial completion), if, prior to the time of the primary analysis, the trial team agrees that the 
expected time interval between the planned analyses is insufficient to justify the performance 
of separate analyses. 
Details of treatment unblinding for the primary analysis and final analysis are described in 
Section 4.1.5.1. Details of the analysis to be performed will be described in the TSAP.


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There will be 3 main patient populations in this trial for analyses: the randomized set (RS), 
the safety set (SS), and the per-protocol set (PPS).
Randomized Set 
This patient set includes all randomized patients. Treatment assignment will be as 
randomized. This is the main analysis set for presentation of efficacy. 
Safety Set 
This patient set includes all patients who were randomized and received at least one dose of 
study drug. It will be the main analysis set for presentation of safety. Patients will be 
analyzed according to the actual treatment.
Per-Protocol Set  
This patient set includes all patients in the RS who adhered to the CTP without any Important 
Protocol Violations (IPVs) potentially affecting the study outcome which lead to exclusion 
from the PPS. This set will be used for sensitivity analysis on the primary, key secondary, 
and secondary efficacy endpoints which are included in the testing hierarchy.
Important violations of the protocol will include violations of the key inclusion and exclusion 
criteria, incorrect medications taken, concomitant use of restricted medications, escape 
medication given without evidence for disease worsening, and any other violations of the 
protocol deemed important by the study team. All decisions concerning important protocol 
violations will be made prior to un-blinding of the database for the final trial analysis.
Further analysis sets, e.g. for the BM assessments, will be defined in the Trial Statistical 
Analysis Plan (TSAP).
Standard statistical parameters (number of non-missing values, mean, standard deviation 
(SD), median, quartiles, minimum and maximum) or frequency tables (including patient 
frequencies and percentages) will be calculated where appropriate.
7.3.1
Primary endpoint analyses
The analysis for the primary endpoint includes the evaluation of patients achieving a GPPGA 
pustulation subscore of 0 at Week 1. 
Any use of escape medication, e.g. use of restricted medication for disease worsening in 
Table 4.2.2.1: 1, prior to observing the primary endpoint is considered to reflect a failure to 
achieve the endpoint outcome, i.e. non-response (see primary endpoint definition in Section 
2.1.2).
Due to the small sample size of the trial, an exact statistical test will be used to assess the 
statistical significance of the treatment effect versus Placebo. Since the traditional Fisher’s 
exact test may be unnecessarily conservative, an alternative test, the Suissa-Shuster Z-pooled 
test, will be implemented in this trial. The Suissa-Shuster Z-pooled test always preserves the 
type I error level and is usually more powerful than the Fisher’s exact test. 


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The primary endpoint will be tested, for the RS, using the Suissa-Shuster Z-pooled test at a 1-
sided, alpha level of 0.025.
Secondary analysis of the primary endpoint will include:

A sensitivity analysis utilizing the PPS;

Analysis of an additional estimand whereby any use of escape medication prior to week 1 
will be considered to represent a non-response. For patients who use other restricted 
medication but not for disease worsening prior to Week 1, data will be censored for 
further analysis following the use and imputed using the methods described in Section 
7.5.

Sensitivity analyses which utilize alternative methods for the handling of missing data as 
described in Section 7.5. 

A subgroup assessment according to the Japan vs. non-Japan strata will be assessed 
descriptively

Sensitivity analyses to adjust for the covariates, IL36R mutation status (Yes vs. No) and 
baseline GPPGA total score (3 vs. 4) respectively using logistic regression.
Further analysis of the primary endpoint will include:

Analysis of the time to first achievement of a response on the primary endpoint via 
Kaplan-Meier methods.
7.3.2
Key Secondary endpoint analyses
The analysis for the key secondary endpoint, for patients achieving a GPPGA score 0 or 1 at 
Week 1, will be performed in the same manner as described for the analyses of the primary 
endpoint.
Any use of escape medication, e.g. use of restricted medication for disease worsening in 
Table 4.2.2.1: 1, prior to observing the key secondary endpoint is considered to reflect a 
failure to achieve the endpoint outcome, i.e. non-response (see key secondary endpoint 
definition Section 2.1.3).
7.3.3
Secondary endpoint analyses
The treatment effect on the following secondary endpoints, 1) the proportion of patients 
achieving a GPPASI 75 at Week 4, 2) the change from baseline in pain VAS at week 4, 3) the 
change from baseline in total PSS score at week 4, and 4) the change from baseline in the 
total FACIT-Fatigue score at Week 4, will be tested in a hierarchical manner as a part of the 
pre-specified testing strategy, subsequent to the test of the primary endpoint and key 
secondary endpoint, which is defined in Section 7.2. 
The analysis for the proportion of patients achieving a GPPASI 75 at Week 4 (where any use 
of escape medication/OL BI 655130 at D8/rescue treatment with BI 655130 prior to 
observing the endpoint(s) is considered to represent a failure to achieve the endpoint 
outcome, i.e. non-response) will be performed using the same approach as that defined for the 
primary endpoint analysis of the study based on the RS. 


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For the analysis of the continuous secondary endpoints which are included in the statistical 
testing strategy, the following estimand and testing approach will be implemented:
Any use of escape medication or OL BI 655130 at Day 8 or rescue medication with BI 
655130 prior to an assessment timepoint will be considered as a non-response at this 
timepoint and assigned worst treatment outcomes in the analysis.
The effect of BI 655130 vs placebo will be evaluated by a Wilcoxon rank test using the 
randomized set.  Any assessments after the use of escape medication or OL BI 655130 at D8 
or rescue medication with BI 655130 will be assigned worst case ranks for the testing. 
Missing data will be further imputed and handled via assignment of ranks. All details 
regarding the ranking rules for test are defined in Table 7.5:1.
Sensitivity analysis for secondary endpoints will be described in TSAP. 
Other secondary endpoints
For all patients who were treated with BI 655130 either through initial randomization, or 
through OL BI 655130 at D8, additional summaries of the following endpoints at Week 4 
will be done where any use of escape medication prior to Week 4 is considered to represent a 
non-response:
•
The proportion of patients with GPPGA 0 or 1 at Week 4, 
•
The proportion of patients with a GPPGA pustulation subscore of 0 indicating no 
visible pustules at Week 4
Other secondary endpoints will be presented in an exploratory manner using the methods 
described above. Frequencies and percentages will be presented for categorical endpoints; 
descriptive statistics will be used for continuous data. If applicable, 95% confidence intervals 
will also be displayed.
Analysis of treatment emergent AE will be described in Section 7.3.5.


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7.3.5
Safety analyses
Adverse events will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. Standard BI summary tables and listings will be 
produced.
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. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’; the residual effect 
period (REP) is defined as 16 weeks after the last dose of trial medication. Note that for 
patients who continue into the extension trial, TEAE up to the first dose in the extension trial 
will be available for display in the current study. Adverse events that start before first drug 
intake and deteriorate under treatment will also be considered as ‘treatment-emergent’.  For 
all subjects who received OL BI 655130 at D8 or rescue medication with BI 655130, safety 
assessments including adverse events, laboratories, vital signs etc. which occurred subsequent 
to such intake will be excluded from presentations according to the planned treatments; these 
data will, however, be included in summaries where all data after any use of BI 655130 are 
displayed.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class (SOC) and preferred term after coding according to the current version of the 
MedDRA. 
The exposure adjusted incidence rate (per 100 subject years) of a selected treatment emergent 
adverse event is defined as the number of subjects experiencing the adverse event per 
treatment group during time at risk divided by the total time of subjects at risk in that 
treatment group to contribute the event to the analysis multiplied by 100 (per 100 subject 
years), where: 
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 for patients who 
will not be rolled over to OLE study, the first dose of OLE study for patients who will be 
rolled over to OLE study, drug stop date + 112 days, date of Day 8 if OL BI 655130 is given, 
date of rescue medication if BI 655130 is given). For each selected treatment emergent AE, 
the exposure adjusted incidence rate will be calculated as: 


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Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with AE / 
Total AE-specific time at risk [subject years].
Laboratory data will be analyzed 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. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.


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7.4
INTERIM ANALYSES
No interim analysis is planned in this trial. 
In order to ensure the patient’s safety during the trial, a fully external DMC, independent of 
the trial and project teams, will review all available unblinded safety data as well as selected 
efficacy data at regular intervals following first-patient-in. A DMC SAP which describes the 
analyses required for assessment by the DMC will be produced. Further details will be 
provided in a DMC charter.
7.5
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will 
still occur and approaches to handle this are proposed below.
For primary and key secondary and secondary binary endpoints
With regards to the handling of missing data on the primary, key secondary and secondary 
binary efficacy endpoints, a Non Response Imputation will be applied as the primary 
imputation approach that is, imputing as a failure to achieve a response, however:
∀
If there are available data at the visits both before and after the visit with a missing 
outcome, then impute as a success only if both the preceding and the following 


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observations also represent a success and there is no use of escape medication, OL BI 
655130 at D8 or rescue medication with BI 655130 within this imputation period; 

Otherwise, impute as a failure to achieve a response (i.e. no response imputation [NRI]).
NRI is a conservative imputation scheme because it assumes that withdrawal (or missing data 
due to any other reason) is related to treatment failure. Other imputation schemes will 
therefore be considered for the primary, key secondary and secondary binary efficacy 
analyses including:

Best response imputation: impute all missing values based on the best response 
observed at visits prior to withdrawal/occurrence of missing data. If there is no non-
missing data available, then the missing value will be imputed as a failure.

If fewer than 3 patients have missing data on an endpoint at Week 1 then a list of all 
possible treatment differences will be generated whereby each of the potential 
responses (response, non-response) will be imputed for each patient in an exhaustive 
manner.
For secondary continuous endpoints
For secondary continuous endpoints at Week 4 which are included into the statistical testing 
strategy, the Wilcoxon rank test will be used. 
In test, worst case ranks will be assigned to those with prior escape medication or OL BI 
655130 at D8 or rescue medication with BI 655130 or death, and for patients with missing 
data at Week 4 for other reasons, LOCF method will be used for imputation.
The best possible baseline values are the lowest value 0 for Pain VAS and PSS and the 
highest value 52 for FACIT-Fatigue scale. The worst possible post-baseline values are the 
highest values 100 and 16 for Pain VAS and PSS and the lowest value 0 for FACIT-Fatigue 
scale.  Therefore, the maximum value for the worst possible change from baseline (i.e., the 
worst possible post-baseline value - best possible baseline value) is 100 for Pain VAS, 16 for 
PSS and -52 for FACIT-Fatigue scale.
The ranking rules are outlined in Table 7.5:1.


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Table 7.5: 1 
Ranking rules for secondary continuous endpoint
Category
Ranking
Case description
Imputed change 
from baseline for 
further ranking 
score*
1
Missing data at week 
4 but still alive and 
no use of either 
escape medication, 
OL BI 655130 at D8 
or rescue medication 
with BI 655130 prior 
to Week 4.
Ranked by 
imputed value
Patient has 
available data at 
visit prior to 
Week 4 
LOCF prior to 
Week 4
Patient has no 
post-baseline 
value
102 for Pain VAS
18 for PSS and 
-54 for FACIT-
Fatigue scale
2
Use of escape 
medication, OL BI 
655130 at D8 or 
rescue medication 
with BI 655130 prior 
to Week 4 but still 
alive.
Ranked by OL BI 
655130 at D8 or 
time to rescue 
medication or 
time to escape 
medication from 
randomization;
Patient has OL BI 
655130 at D8 and 
has no escape 
medication or 
rescue 
medication  prior 
to Week 4;
104 for Pain VAS
20 for PSS and 
-56 for FACIT-
Fatigue scale


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Table 7.5: 1 
Ranking rules for secondary continuous endpoint (cont’d.)
Category
Ranking
Case 
description
Imputed change 
from baseline for 
further ranking 
score*
Patient has 
rescue 
medication with 
BI 655130 x 
days from 
randomization 
and has no 
escape 
medication  prior 
to Week 4;
106-x/1000 for 
Pain VAS
22-x/1000 for PSS 
and 
-58+x/1000 for 
FACIT-Fatigue 
scale
Patient has 
escape 
medication y 
days after 
randomization 
and prior to 
Week 4;
108-y/1000 for 
Pain VAS
24-y/1000 for PSS 
and 
-60+y/1000 for 
FACIT-Fatigue 
scale
3
Patient died before 
the measurement at 
Week 4
Ranked by time 
to death from 
randomization
Patient died z 
days after 
randomization
110-z/1000 for 
Pain VAS
26-z/1000 for PSS 
and 
-62+z/1000 for 
FACIT-Fatigue 
scale
* Ranked values in this table are only for purpose of rank tests but not for any descriptive displays
 
With respect to safety evaluations, it is not planned to impute missing values.


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7.6
RANDOMISATION
BI will arrange for the randomization and the packaging and labeling of trial medication. The 
randomization list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. Access to the codes will be controlled and documented.
Stratification for Japan versus non-Japan will be done in order to assure that sufficient 
patients per treatment group are recruited specifically to support individual country 
submission in Japan; these strata will be treated as operational strata and will not be included 
into the analyses of efficacy endpoints. 
Within each stratum (Japan vs. non-Japan), patients will be randomized in a 2:1 ratio (BI 
655130 vs. Placebo). The randomization will be done in blocks to achieve balanced 
allocation. The block size of the randomization will be documented in the CTR.
The process of randomization is done via an IRT. Practical aspects of the treatment allocation 
process are detailed in Section 4.1.3.
7.7
DETERMINATION OF SAMPLE SIZE
Based on an application of the defined testing strategy (see Section 7.2), a simulation based 
power calculation has been performed for sample size assessment on both the primary and 
key secondary endpoints. For this purpose, the correlation of the two endpoints is set to be 
0.65 which is derived from efficacy data of POC study 1368.11. 
The effect of BI 655130 on the proportion of patients achieving a GPPGA pustulation 
subscore of 0 at Week 1 and separately on the proportion of patients achieving a GPPGA 
score of (0, 1) at Week 1 will be compared relative to placebo respectively. It is expected 
that, after one week of treatment with BI 655130, at least 60% of patients will have complete 
GPPGA pustulation subscore of 0 and at least 60% of patients will have a GPPGA score of 0 
or 1. In comparison, only 10% of patients on placebo are expected to have response to each 
of the primary endpoint and key secondary endpoint at Week 1. 
The power estimates below for detecting the clinically relevant differences, for the primary 
endpoint, the proportion of patients with a GPPGA pustulation subscore of 0 at Week 1 and 
the key secondary endpoint, a GPPGA score of 0 or 1 at Week 1, were derived using R 
version 3.3.2, for a sample size of 51 patients (2:1 ratio), and a 1-sided type I error of 0.025. 
The results are as given in Table 7.7: 1.  


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Table 7.7: 1 
Power to achieve statistical significance for the primary endpoint and 
key secondary endpoint on BI 655130 versus Placebo under various 
scenarios for N=51 (2:1)
Sample size:
BI 655130 vs. 
placebo
Primary 
endpoint/Key 
secondary endpoint:
Proportion of patients 
achieving GPPGA 
pustulation subscore 
of 0 at Week 1 [ BI 
655130 vs. placebo]/
Proportion of patients 
achieving GPPGA of 
(0 or 1) at Week 1  [ 
BI 655130 vs. 
placebo]
Power (%) to 
achieve primary 
endpoint 
Power (%) to 
achieve both 
primary endpoint 
and key secondary 
endpoint
34:17
0.5 vs 0.05/
0.5 vs 0.05
95.7%
92.9%
34:17
0.55 vs 0.05/
0.55 vs 0.05
98.1%
96.8%
34:17
0.6 vs 0.05/
0.6 vs 0.05
99.4%
98.8%
34:17
0.65 vs 0.05/
0.65 vs 0.05
99.9%
99.7%
34:17
0.5 vs 0.1/
0.5 vs 0.1
85.3%
78.1%
34:17
0.55 vs 0.1/
0.55 vs 0.1
92.0%
87.7%
34:17
0.6 vs 0.1/
0.6 vs 0.1
96.3%
93.9%
34:17
0.65 vs 0.1/
0.65 vs 0.1
98.5%
97.3%
Note:
if the rates of response for both primary endpoint and key secondary endpoint were 0.55 on BI 655130 and 0.1 on 
placebo, separately, then the overall power to achieve both endpoints would be approx. 87.7%.
Therefore, with an expected response rate of 0.6 on BI 655130 and 0.1 on placebo for each of 
the primary endpoint and key secondary endpoint and a type I error of <0.025 (1-sided), for a 
total sample size of 51 patients, this trial will be able to detect an effect of BI 655130 relative 
to placebo, for both primary endpoint and key secondary endpoint simultaneously, with an 
overall power of 93.9%.


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


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The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator or his/her 
delegate must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. Continuous risk review and assessment may lead to adjustments in 
trial conduct, trial design or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the investigator must make three documented attempts to retrieve 


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previous medical records. If this fails, a verbal history from the patient, documented in their 
medical records, would be acceptable. 
During the site visit the sponsor’s Clinical Research Associate (CRA) or auditor must be 
granted access to the original patient file (please see Section 8.3.2). The investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number or applicable national identification number or information as per local laws) 
have properly been removed or redacted from any copy of the patients’ source documents 
before sending them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example: 

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 


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must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
The rights of the trial patient to privacy and protection of the data / patient notes obtained 
during the trial have to be ensured in accordance with local laws and regulations. Procedures 
for data handling and data protection need to be described in the patient information and 
informed consent form.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular


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
Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, including audit trail for clinical 
data and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”). Early termination of the trial is defined as the premature termination 
of the trial due to any reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating all required 
activities, in order to:


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
manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedures (SOPs),

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of CMLs, CRAs, and participating trial sites.
The trial medication will be provided by the 
 
 
The trial will be conducted in each selected center under the supervision of the Principal 
Investigator. A Coordinating Investigator is responsible to coordinate investigators at 
different centers participating in this multicenter trial. Tasks and responsibilities are defined 
in a contract. Relevant documentation on the participating (principal) investigators and other 
important participants, including their curricula vitae, will be filed in the ISF.
A project-independent external Data Monitoring Committee (DMC) will be established to 
assess the safety and efficacy of BI 655130 in this clinical trial at specified intervals through 
the final timepoint (End of Study Visit). Measures will be put in place to ensure blinding of 
the sponsor and all other trial participants. The tasks and responsibilities of the DMC will be 
specified in a charter. The DMC will maintain written records of all its meetings. 
A central laboratory service and vendors for photo documentation (skin lesions) and IRT 
(interactive response technology) will be used in this trial. Details will be provided in the 
applicable manuals available in the ISF.
On-site monitoring will be performed by BI or a contract research organization appointed by 
BI. Data management and statistical evaluation will be done by BI according to BI SOPs.
The organization of the trial in the participating countries will be performed by the respective 
local BI-organization (Operative Unit [OPU] or by a Contract Research Organization [CRO]) 
with which the responsibilities and tasks will have been agreed and a written contract filed 
before initiation of the clinical trial. For each OPU participating in this study, a CML will be 
appointed responsible for coordinating the activities required in order to manage the trial in 
accordance with applicable regulations and internal SOPs in the countries covered by the 
respective BI OPU.
Tasks and functions assigned in order to organize, 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.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P09-07583
Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-
Kerkhoff A, et al. An autoinflammatory disease with deficiency of the 
interleukin-1-receptor antagonist. N Engl J Med. 2009;360(23):2426-37.
P19-01888
Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A, et al. 
Inhibition of the interleukin-36 pathway for the treatment of generalized 
pustular psoriasis. N Engl J Med 380 (10), 981 - 983 (2019)
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(9):1012-24.
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.
R11-4890
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock 
SA, Branum A, 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. J 
Allergy Clin Immunol. 2006;117(2):391-7.
R13-3515
Woodworth T, Furst DE, Alten R, Bingham CO, 3rd, Yocum D, Sloan V, et 
al. 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):1401-14.
R13-4749
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, et al. A guide to 
rational dosing of monoclonal antibodies. Clin Pharmacokinet. 
2012;51(2):119-35.


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R13-4750
Joos B, Trkola A, Kuster H, Aceto L, Fischer M, Stiegler G, et al. Long-
term multiple-dose pharmacokinetics of human monoclonal antibodies 
(MAbs) against human immunodeficiency virus type 1 envelope gp120 
(MAb 2G12) and gp41 (MAbs 4E10 and 2F5). Antimicrob Agents 
Chemother. 2006;50(5):1773-9.
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):61-6.
R13-4754
Xin Y, Gordon M, Jin D, Wakshull E, Chen D, Rosen L, et al. Population 
pharmacolinetic (PK) analysis supports fixed dosing for the humanized 
monoclonal antibody (huMab) anti-EGFL7 (MEGF-444A) administered 
intravenously in patients with advanced solid tumors. Journal of Clinical 
Oncology. 2011;29:15.
R14-5158
Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. 
Interleukin-36-receptor antagonist deficiency and generalized pustular 
psoriasis. N Engl J Med. 2011;365(7):620-8.
R15-1421
Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla 
V, et al. Mutations in IL36RN/IL1F5 are associated with the severe 
episodic inflammatory skin disease known as generalized pustular psoriasis. 
Am J Hum Genet. 2011;89(3):432-7.
R15-5200
Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. 
The 5-point Investigator's Global Assessment (IGA) Scale: A modified tool 
for evaluating plaque psoriasis severity in clinical trials. J Dermatolog 
Treat. 2015;26(1):23-31.
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):811-9.
R16-0929
Berki DM, Liu L, Choon SE, David Burden A, Griffiths CEM, Navarini 
AA, et al. Activating CARD14 Mutations Are Associated with Generalized 
Pustular Psoriasis but Rarely Account for Familial Recurrence in Psoriasis 
Vulgaris. J Invest Dermatol. 2015;135(12):2964-70.
R16-0930
Hussain S, Berki DM, Choon SE, Burden AD, Allen MH, Arostegui JI, et 
al. IL36RN mutations define a severe autoinflammatory phenotype of 
generalized pustular psoriasis. J Allergy Clin Immunol. 2015;135(4):1067-
70 e9.
R16-0932
von Zumbusch L. Psoriasis und pustuloses Exanthem. Archives of 
Dermatology and Syphilology. 1910;99:335-46.
R16-0933
Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. 
Clinical profile, morbidity, and outcome of adult-onset generalized pustular 
psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, 
Malaysia. Int J Dermatol. 2014;53(6):676-84.


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R16-1462
Imafuku S, Honma M, Okubo Y, Komine M, Ohtsuki M, Morita A, et al. 
Efficacy and safety of secukinumab in patients with generalized pustular 
psoriasis: A 52-week analysis from phase III open-label multicenter 
Japanese study. J Dermatol. 2016;43(9):1011-7.
R16-2960
Viguier M, Aubin F, Delaporte E, Pages C, Paul C, Beylot-Barry M, et al. 
Efficacy and safety of tumor necrosis factor inhibitors in acute generalized 
pustular psoriasis. Arch Dermatol. 2012;148(12):1423-5.
R16-3360
Brunasso AM, Salvini C, Massone C. Efalizumab for severe palmo-plantar 
psoriasis: an open-label pilot trial in five patients. J Eur Acad Dermatol 
Venereol. 2009;23(4):415-9.
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(12):2107-16.
R17-3403
Navarini AA, Burden AD, Capon F, Mrowietz U, Puig L, Koks S, et al. 
European consensus statement on phenotypes of pustular psoriasis. J Eur 
Acad Dermatol Venereol. 2017;31(11):1792-9.
R17-3600
Robinson A, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Bebo 
BF, Jr., et al. Treatment of pustular psoriasis: from the Medical Board of the 
National Psoriasis Foundation. J Am Acad Dermatol. 2012;67(2):279-88.
R17-3602
Johnston A, Xing X, Wolterink L, Barnes DH, Yin Z, Reingold L, et al. IL-
1 and IL-36 are dominant cytokines in generalized pustular psoriasis. J 
Allergy Clin Immunol. 2017;140(1):109-20.
R17-3603
Levin EC, Debbaneh M, Koo J, Liao W. Biologic therapy in erythrodermic 
and pustular psoriasis. J Drugs Dermatol. 2014;13(3):342-54.
R17-3626
Japanese Journal of Dermatology. 2010;120(4):815-39.
R17-3632
Mahil SK, Catapano M, Di Meglio P, 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 
R18-1705
Diagnostic Criteria: European Rare and Severe Psoriasis Expert Network 
(ERASPEN);  [May 17, 2017]. Available from: 
http://eraspen.eu/home/rfp/diagnostic-criteria.html.
R18-1989
Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: 
Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain 
(NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain 
Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-
36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and 


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Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 
2011;63 Suppl 11:S240-52.
R18-1990
Rentz AM, Skalicky AM, Burslem K, Becker K, Kaschinski D, Esser D, et 
al. The content validity of the PSS in patients with plaque psoriasis. J 
Patient Rep Outcomes. 2017;1(1):4.
R96-3541
Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a new 
retinoid. Dermatologica. 1978;157(4):238-44.
9.2
UNPUBLISHED REFERENCES
c03320877
Investigator's Brochure.  Current Version.
c09985235-01
 Single-blind, partially 
randomised, placebo-controlled Phase I study to investigate safety, 
tolerability, pharmacokinetics and pharmacodynamics of single rising 
intravenous doses of BI 655130 in healthy male volunteers, April 7, 2017.


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
10.1.1
Physician’s Global Assessment for Generalized Pustular Psoriasis (GPPGA)
PGA Score for GPP
0 = If mean=0 for all three components 
1 = If 0 < mean <1.5
2 = If (1.5 <= mean <2.5)
3 = If 2.5 <= mean <3.5
4 = If mean >=3.5
Source:  (R15-5200)
Erythema
0 = Clear:  
Normal or postinflammatory hyperpigmentation 
1 = Almost Clear:  
Faint, diffuse pink or slight red
2 = Mild:  
Light red
3 = Moderate:
Bright red 
4 = Severe:
Deep fiery red
Pustules
0 = Clear:
No visible pustules
1 = Almost Clear:
Low density occasional small discrete (non coalescent) pustules 
2 = Mild:
Moderate density grouped discrete small pustules (non coalescent) 
3 = Moderate:
High density pustules with some coalescence
4 = Severe:
Very high density pustules with pustular lakes
Scaling/crusting
0 = Clear:
No scaling and no crusting
1 = Almost Clear:
Superficial focal scaling or crusting restricted to periphery of lesions 
2 = Mild:
Predominantly fine scaling or crusting
3 = Moderate:
Moderate scaling or crusting covering most or all of lesions 
4 = Severe:
Severe scaling or crusting covering most or all lesions


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10.1.2
Psoriasis Area and Severity Index for Generalized Pustular Psoriasis 
(GPPASI)
Severity
AREA OF INVOLVEMENT
Provide the percentage of involved area in each body region (=area affected by pustules scaling [not the area 
for each component separately])
Source:  (R96-3541, R16-3360)
Erythema
Head
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Trunk
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Upper Limb
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Lower Limb
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Pustules
Head
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Trunk
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Upper Limb
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Lower Limb
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Scaling
Head
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Trunk
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Upper Limb
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Lower Limb
0=Clear
1=Almost clear
2=Mild
3=Moderate
4=Severe
Head
0=0%
1=1 to < 10%
2=10 to < 30%
3=30 to < 50%
4=50 to < 70%
5=70 to < 90%
6=90 to 100%
Trunk
0=0%
1=1 to < 10%
2=10 to < 30%
3=30 to < 50%
4=50 to < 70%
5=70 to < 90%
6=90 to 100%
Upper Limb
0=0%
1=1 to < 10%
2=10 to < 30%
3=30 to < 50%
4=50 to < 70%
5=70 to < 90%
6=90 to 100%
Lower Limb
0=0%
1=1 to < 10%
2=10 to < 30%
3=30 to < 50%
4=50 to < 70%
5=70 to < 90%
6=90 to 100%


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10.1.4
FACIT Fatigue Scale (Version 4)
Below is a list of statements that other people with your illness have said are important. Please
circle or mark one number per line to indicate your response as it applies to the past 7 days.
Not at 
all
A little
bit
Some-
what
Quite
a bit
Very
much
HI7
I feel fatigued.............................................
0
1
2
3
4
HI12
I feel weak all over....................................
0
1
2
3
4
An1
I feel listless (“washed out”)…....................
0
1
2
3
4
An2
I feel tired.................................................
0
1
2
3
4
An3
I have trouble starting things because I am 
tired..........................................................
0
1
2
3
4
An4
I have trouble finishing things because I am
tired ...........................................................
0
1
2
3
4
An5
I have energy..............................................
0
1
2
3
4
An7
I am able to do my usual activities..............
0
1
2
3
4
An8
I need to sleep during the day ……….............
0
1
2
3
4
An12
I am too tired to eat.....................................
0
1
2
3
4
An14
I need help doing my usual activities………....
0
1
2
3
4
An15
I am frustrated by being too tired to do the
things I want to do....................................
0
1
2
3
4
An16
I have to limit my social activity because I
am tired.......................................................
0
1
2
3
4
  Source:  (R16-0029)
English (Universal)
16 November 2007
Copyright 1987, 1997


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10.1.5
Psoriasis Symptom Scale 
Listed below are a set of problems that people with psoriasis have said are important. For each 
question, click on the circle that best describes the severity of your symptoms during the past 24 
hours. Please answer every question.
1. How severe was your pain from your psoriasis during the past 24 hours?
o
None
o
Mild
o
Moderate
o
Severe
o
Very severe
2. How severe was the redness from your psoriasis during the past 24 hours?
o
None
o
Mild
o
Moderate
o
Severe
o
Very severe
3. How severe was your itching from your psoriasis during the past 24 hours?
o
None
o
Mild
o
Moderate
o
Severe
o
Very severe
4. How severe was your burning from your psoriasis during the past 24 hours?
o
None
o
Mild
o
Moderate
o
Severe
o
Very severe
Source:  (R18-1990)
©2015, Boehringer Ingelheim International GmbH 


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10.1.6
Diagnosis of Anaphylaxis
Clinical criteria for diagnosing anaphylaxis (R11-4890).
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg 
+[2 x age] from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.


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10.1.9
Patient’s assessment of Pain VAS
How much pain have you had because of your generalized pustular psoriasis (GPP) in the 
past week? 
Place a vertical (│) mark on the line to indicate the severity of the pain. 
No pain               
Severe pain
0
100
Source:  (R18-1989).


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
19 Jul 2019
EudraCT number
EU number
Spesolimab (BI 655130)
BI Trial number
1368-0013
BI Investigational Product(s)
Spesolimab (BI 655130)
Title of protocol
Effisayil™ 1: Multi-center, double-blind, 
randomized, placebo-controlled, Phase II study to 
evaluate efficacy, safety and tolerability of a single 
intravenous dose of BI 655130 in patients with 
Generalized Pustular Psoriasis (GPP) presenting 
with an acute flare of moderate to severe intensity
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Title page: BI Investigational Medicinal Product
Table 4.1.1:1 Study Compound 
Description of change
Spesolimab (International Nonproprietary Name of 
BI 655130) was added.
Rationale for change
Updated information
Section to be changed
Title page and Synopsis
Description of change
Addition of Effisayil™ 1 to the trial title
Rationale for change
Administrative
Section to be changed
Clinical Trial Protocol Synopsis Table: Trial Site(s)
Description of change
Multi-center trial conducted in 8 11 to 15 20 
countries.
Rationale for change
Updated Information. Since the sample size has 
increased, it is likely that we may have to recruit 
more countries to meet the recruitment goal.
Section to be changed
Clinical Trial Protocol Synopsis Table: Number of 
patients entered 
Description of change
51 patients
Rationale for change
Updated information. Sample size has been 
increased from 27 patients to 51 patients. Per 
Health Authority recommendation, it is important 
that additional patients (i.e. beyond 27) be recruited 
into this trial in order to enhance the safety 
database in the acute GPP flare setting and, 
consequently, the assessment on benefit-risk. These 
additional patients also allow for a more robust 
assessment on the clinical efficacy, i.e. in a 


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situation where the placebo rate is unexpectedly 
higher than the original estimate for both primary 
and key secondary endpoints.
Section to be changed
Clinical Trial Protocol Synopsis Table: Number of 
patients on each treatment
Description of change
34 patients on BI 655130 and 17 patients on 
placebo
Rationale for change
Updated information. Since the sample size 
increased from 27 patients to 51 patients the 
patients on each treatment arm also increased.
Section to be changed
Clinical Trial Protocol Synopsis Table: Endpoints
Description of change
Co-primary endpoints have been converted into 
primary endpoint and key secondary endpoint.
The primary endpoint of the study is:

A Generalized Pustular Psoriasis Physician 
Global Assessment (GPPGA) pustulation 
subscore of 0 indicating no visible pustules at 
Week 1.
The Key secondary endpoint of the study is: 

A GPPGA score of 0 or 1 at Week 1.
Rationale for change
Updated Information. Per authority proposal, the 
co-primary endpoints have been adapted in this 
amended trial CTP to represent a primary endpoint 
reflecting the clearance of pustules at week 1, and a 
key secondary endpoint representing the overall 
improvement in GPP skin symptoms based on the 
achievement of a GPPGA score of 0 or 1 at week 1. 
The trial is still powered in order that success on 
both of these endpoints can be achieved.
Section to be changed
Clinical Trial Protocol Synopsis Table: Statistical 
Methods
Description of change
The trial is designed to demonstrate superiority of 
BI 655130 in each of the two co-primary 
endpoints, achievement of pustule clearance at 
week 1 and the key secondary endpoint GPPGA 
(0, 1) at Week 1, relative to placebo. The primary 
analysis, on each of the co-primary and key 
secondary endpoints, will use a Suissa-Shuster
test (unpooled method) to compare the proportion 
of patients who achieve a response on BI 655130 
versus placebo at week 1.
Confirmation of efficacy is then given only if the 


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proportion of patients with a response on BI 
655130 is statistically significantly higher than
the placebo for both of the co-primary endpoints.
A further hypothesis on the secondary endpoints, 
GPPASI 75 at Week 4, Pain VAS score at Week 4, 
PSS score at Week 4 and FACIT Fatigue Score at 
Week 4, will be tested in a hierarchical manner if 
the test of the null hypotheses for both primary co-
endpoints and key secondary endpoints has 
previously been rejected.
Rationale for change
Updated information to reflect the change from co-
primary endpoints to primary and secondary 
endpoints.
Section to be changed
Flow Chart 
Description of change
Removed Alcohol History
Rationale for change
Updated Information
Section to be changed
Flow Chart
Description of change
Moved footnote 3 from Wk 2, 3, 4, 8 and 12 and 
moved it to the corresponding visit numbers V10, 
V11, V12 and V13.
Rationale for change
Clarification
Section to be changed
Flow Chart
Description of change
Removed pregnancy test from V3 through V8 (non 
dosing days)
Rationale for change
Updated Information. Removed requirement of 
pregnancy test from V3 through V8 as these are 
non-dosing days and therefore pregnancy tests is 
not required.
Section to be changed
Flow Chart
Description of change
Moved Pain VAS and FACIT-fatigue to group 
together with DLQI for (at best) weekly 
measurement.
Rationale for change
Correction
Section to be changed
Flow Chart and Footnote # 28


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Section to be changed
Flow Chart
Description of change
Neutrophils will not be analyzed by flow cytometry 
from the whole blood sample. 
Rationale for change
Limited utility and technical feasibility.
Section to be changed
Flow Chart
Description of change
∀
Footnote #11 text was clarified to
Fever will be assessed at the day the patient 
presents to the clinic/hospital with GPP flare of 
moderate to severe intensity prior to receiving 
medication for fever treatment. Thereafter, fever 
must be assessed and recorded 2 times on that day, 
separated by intervals of 2 to 4 hours. At all other 
visits, fever will be assessed once a day prior to 
receiving medication for fever treatment (if 
applicable)assessments will be recorded on 
dosing days at three time points. If the patient 
will receive medication for fever treatment, the 
fever assessment will be performed prior to 
taking the anti-fever treatment. These fever 
assessments must be taken whether or not the 
patient has an elevated temperature and 
whether or not the patient takes anti-fever 
treatment. The fever assessments times are to 
be separated by intervals of 2 to 4 hours on 
dosing days. At all other visits (non-dosing 
days), fever will be assessed once a day and will 
be completed prior to receiving medication for 
fever treatment, if anti-fever treatment is given.
∀
Footnote # 12 text was clarified:
Only applicable for women of childbearing 
potential. S – serum pregnancy test (performed at 
screening). U – urine pregnancy tests will be 
performed on-site and at all other visits only at 
study drug administration visits. Urine 
pregnancy testing should be done prior to study 
drug administration. Study drug should only be 
administered in case of a negative test result. In 
case of a positive urine pregnancy test, a serum 


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pregnancy (S) test will be done. 
Rationale for change
Clarification
Section to be changed
Flow Chart
Description of change
Footnote 23 has been clarified to
Patients who achieved a clinical response
improvement to study treatment (not including 
escape treatment) and show no flare symptoms of 
moderate/severe intensity at V14 or V15 will be 
offered to enter into an open label extension (OLE) 
trial (1368-0025), if they have completed this study 
(EoS/V14 or V15) and meet the inclusion criteria 
for the OLE trial.
Rationale for change
Clarified that as long as the patients show clinical 
improvement or benefit from BI 655130, the 
patient may qualify to enter OLE trial. The patient 
does not have to have clinical response of GPPGA 
of 0 or 1 to qualify to enter in OLE trial. 
Section to be changed
Flow Chart
Description of change
Added footnote 29.
If the date of EOS visit for this trial is not the same 
as the date of first dose of trial medication on the 
OLE trial (1368-0025), the investigator must 
continue to capture the AEs in this trial until the 
patient receives 1st dose in the OLE trial. Please 
refer to section 5.2.6.2 for further details.
Rationale for change
Updated information to emphasize that if the date 
of EOS visit for this trial is not the same as the date 
of first dose of trial medication on the OLE trial 
(1368-0025), the investigator must continue to 
capture the AEs in this trial until the patient 
receives 1st dose in the OLE trial.
Section to be changed
Section 1.1 Medical Background
Description of change
Treatment options
Current treatment options for controlling acute 
GPP and maintenance of response are limited and 
do not provide sustained efficacy. No treatments
are currently approved for GPP in the US andor 
centrally approved for GPP in the EU, though 
retinoids, cyclosporine or methotrexate are being 
recommended.
Secukinumab (Cosentyx®), infliximab 
(Remicade®), ixekizumab (Taltz®), brodalumab
(Lumicef®), adalimumab (Humira®), 


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guselkumab (Tremfya®) and Risankizumab are 
only registered in Japan for the treatment of GPP 
and plaque psoriasis.
Rationale for change
Clarified the GPP treatment approval status in the 
EU.
Section to be changed
Section 1.2.1 Mode of action
Description of change
BI 655130 is a humanized antagonistic monoclonal 
IgG1 antibody that blocks human IL36R signaling. 
Binding of BI 655130 to IL36R is anticipated to 
prevent the subsequent activation of IL36R by 
cognate ligands (IL36 α, β and γ) and downstream 
activation of pro-inflammatory and pro-fibrotic 
pathways with the aim to reduce epithelial cell/ 
fibroblast/ immune cell-mediated inflammation and 
interrupt the inflammatory response that drives 
pathogenic cytokine production in inflammatory 
diseases including GPP, palmoplantar pustulosis 
(PPP), Atopic Dermatitis (AD) and inflammatory 
bowel disease (IBD).
Rationale for change
Updated the information from IB version 6
Section to be changed
Section 1.2.3 Clinical Experience
Description of change
Added clinical experience details of the placebo 
controlled Phase II study (1368-0015) 
palmoplantar pustulosis (PPP) patients.
Rationale for change
Updated the information from IB version 6
Section to be changed
Section 1.3 Rationale for Performing the Trial
Description of change
No treatments are currently approved for GPP in 
the US and or centrally approved for GPP in the
EU, though a combination of retinoids, 
cyclosporine or methotrexate has been 
recommended as primary options for controlling 
worsening of chronic GPP.
Rationale for change
Clarified the GPP treatment approval status in the 
EU
Section to be changed
Section 1.4 Benefit-Risk Assessment
Description of change
Included the following text based on IB V 6.0.
As of September 2018, BI 655130 has been given 
to 212 subjects in ongoing and clinically 
completed trials. BI 655130 was well tolerated. 
Most reported adverse events were of mild or 
moderate intensity, but there have also been a 
small number of patients experiencing severe or 
serious adverse events in clinical trials. It is 


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unknown whether these adverse events were 
caused by BI 655130. Overall adverse events 
observed in subjects who received BI 655130 
were comparable to adverse events observed in 
those who received placebo and no dose-limiting 
adverse effects were observed (for details refer 
to IB; (c03320877)). 
A total of 148 healthy volunteers have been 
exposed in phase I studies to single or multiple 
doses of BI 655130 with 118 subjects receiving up 
to dose levels of 20 mg/kg i.v., given once weekly 
(qw) for 4 weeks and 30 subjects receiving single 
s.c. injections of 150 mg or 300 mg. BI 655130 
was safe in 4 healthy volunteer 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 refer to IB; (c03320877)). Moreover, a 
total of 4 clinical studies are ongoing as of June 
2018: 1 trial with multiple doses (1368.15) 
exploring efficacy and safety in patients with 
Palmoplantar Pustulosis (PPP; target n=59), and 3 
(1368.4, 1368.5, 1368.10) clinical trials exploring 
efficacy and safety of BI 655130 in patients with
Ulcerative Colitis (UC; participant target n=10, 
550, and 30, respectively).
Rationale for change
Updated the information from IB version 6
Section to be changed
Section 1.4 Benefit-Risk Assessment
Description of change
During and following the i.v. infusion, the patients 
will be monitored for systemic hypersensitivity 
including (See Section 4.2.1.1 for further details)
infusion reactions at the site according to 
Instructions for Preparation and Handling of BI 
655130.
Rationale for change
Updated Information
Section to be changed
Section 2.1.2 Primary Endpoint
Description of change
The co-primary endpoint of the study is:

A Generalized Pustular Psoriasis Physician 
Global Assessment (GPPGA) score of 0 or 1 at 
Week 1.

A GPPGA pustulation sub-score of 0 indicating 
no visible pustules at Week 1. 
For the estimand concept on the above-defined co-
primary binary endpoint definition(s), death or any 
use of escape medication prior to Week 1 will be 


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considered to represent a non-response at the Week 
1 timepoint.
Rationale for change
Updated Information. Per authority proposal, the 
co-primary endpoints have been adapted to 
represent a primary endpoint reflecting the 
clearance of pustules at week 1, and a key 
secondary endpoint representing the overall 
improvement in GPP skin symptoms based on the 
achievement of a GPPGA score of 0 or 1 at week 1. 
The trial is still powered in order that success on 
both of these endpoints can be achieved.
Also, death was deleted because given short term 
nature of primary and secondary endpoints at week 
1 and 4 respectively, and the exclusion of patients 
with life-threatening flare of GPP, death is not 
expected to be a relevant outcome in this trial.
Section to be changed
Section 2.1.3 Key Secondary Endpoint
Description of change
The key secondary endpoint of the study is:

A Generalized Pustular Psoriasis Physician 
Global Assessment (GPPGA) score of 0 or 1 
at Week 1.
For the estimand concept on the above-defined 
key secondary binary endpoint definition(s), any 
use of escape medication prior to Week 1 will be 
considered to represent a non-response at the 
Week 1 timepoint.
Rationale for change
Updated Information. Per authority proposal, the 
co-primary endpoints have been adapted to 
represent a primary endpoint reflecting the 
clearance of pustules at week 1, and a key 
secondary endpoint representing the overall 
improvement in GPP skin symptoms based on the 
achievement of a GPPGA score of 0 or 1 at week 1. 
The trial is still powered in order that success on 
both of these endpoints can be achieved.
Section to be changed
Section 2.1.4 Secondary Endpoints
Description of change
Death has been removed from the estimand
concept of the endpoints.
Rationale for change
Updated Information. Given short term nature of 
primary and secondary endpoints at week 1 and 4 
respectively, and the exclusion of patients with life-
threatening flare of GPP, death is not expected to 
be a relevant outcome in this trial


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Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Approximately 8 11 to 15 20 countries will 
participate by using sites/centers experienced in the 
management of GPP.
Rationale for change
Updated Information. Since the sample size has 
increased, it is likely that we may have to recruit 
more countries to meet the recruitment goal. 
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Added the following updated text:
Fifty-one patients with generalized pustular 
psoriasis (GPP) presenting with an acute flare of 
moderate to severe intensity are required to be 
randomized to receive BI 655130/ placebo (2:1) 
into this trial.
Rationale for change
Updated Information reflecting the increase in 
sample size and/or recruitment period. Also, per 
Health Authority recommendation, it is important 
that additional patients (i.e. beyond 27) be recruited 
into this trial in order to enhance the safety 
database in the acute GPP flare setting and, 
consequently, the assessment on benefit-risk. These 
additional patients also allow for a more robust 
assessment on the clinical efficacy, i.e. in a 
situation where the placebo rate is unexpectedly 
higher than the original estimate for both primary 
and key secondary endpoints.
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Updated as following:
Patients who achieved a clinical response 
improvement to BI 655130 and who show no flare 
symptoms of moderate/severe intensity at V14 or 
V15 visit will be offered to enter into an open label 
extension (OLE) trial (1368-0025), if they have 
completed this study (EoS/V14 or V15 visit, see 
below) and meet the inclusion eligibility criteria 
for the OLE trial.
Rationale for change
Clarified that as long as the patients show clinical 
improvement or benefit from BI 655130, the 
patient may qualify to enter OLE trial. The patient 
does not have to have clinical response of GPPGA 
of 0 or 1 to qualify to enter in OLE trial.
Section to be changed
Table 3.1:1 Study Definitions (For Disease 
Worsening)
Description of change
Disease worsening is defined as worsening of 


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clinical status or GPP skin and/or systemic 
symptoms as defined by the investigator.  
Escape treatment is the Standard of Care 
(physician’s choice) in the investigator’s opinion 
to treat the disease worsening of GPP. 
Note: The SoC options are multiple dose extended 
duration treatments.
Wk1/D2-D7: If the severity and progression of the 
disease worsens within the first week and requires 
immediate treatment, then the investigator can 
treat the patient with a Standard of care treatment
the escape medication of his/her choice (escape 
medication). However, if the disease condition is 
stable, it is recommended to wait until the primary 
endpoint visit (Wk1/D8) before prescribing an 
escape medication (SoC) since there will be an 
option to administer OL BI 655130 instead at this 
time.
After D8:
•
Patients who do not achieve a clinical 
response (GPPGA 0 or 1) but have disease 
worsening subsequent to D8 can receive 
an escape treatment chosen by the 
investigator. (GPPGA 0 or 1) at D8 and 
who do not qualify for treatment with OL 
BI 655130 at D8 OR who have a 
subsequent flare after receiving one rescue 
dose of OL BI 655130 can receive an 
escape treatment chosen by the investigator.
•
Patients who have achieved a clinical 
response and later have disease 
worsening that is not severe enough to 
meet the criteria for recurrence for GPP 
flare can receive the escape medication. 
However, it is recommended to wait until 
the patient meets the criteria for 
recurrence of GPP flare since there will 
be an option to administer rescue 
medication with OL BI 655130 instead at 
this time.
Note: Only one rescue dose with BI 
655130 is permitted if a patient 
experiences a recurrence of a GPP flare. 
Subsequent flares are to be treated with 


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Standard of Care (SoC) per physician’s 
discretion.
Rationale for change
Clarified definition of disease worsening and 
scenarios when escape treatment may be given in 
case of disease worsening.
Section to be changed
Figure 3.1:1 Study Design
Description of change
Study design figure was updated to include 51
patients for sample size.
Rationale for change
Updated Information
Section to be changed
Section 3.2 Discussion of trial design, including the 
choice of control group (s)
Description of change
No active control group is included in this trial as 
there is currently no drug approved for the 
induction treatment of acute flares of moderate to 
severe GPP. Secukinumab (Cosentyx®), infliximab 
(Remicade®), ixekizumab (Taltz®), brodalumab 
(Lumicef®), adalimumab (Humira®),
guselkumab (Tremfya®) and Risankizumab are 
only registered in Japan for the treatment of GPP 
and plaque psoriasis.
Rationale for change
Updated information
Section to be changed
Section 3.3 Selection of Trial Population
Description of change
Eight Eleven to 15 20 countries have been invited 
to participate in order to minimize the risk of under 
recruiting and to meet the goal of 27 51patients 
entered. Recruitment will be very challenging due 
to the rareness of the disease and because GPP 
patients must have an acute flare of moderate to 
severe intensity in order to be randomized on the 
trial. 
Rationale for change
Updated Information. Since the sample size has 
increased, it is likely that we may have to recruit 
more countries to meet the recruitment goal.
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
Exclusion criteria # 14: Active or Latent TB: 
QuantiFERON® (or if applicable, T-Spot®) TB 
test will be performed at screening.
Rationale for change
Updated Information to allow TSPOT test to be 
performed in applicable country (i.e. Japan) instead 
of QuantiFERON.
Section to be changed
Section 3.3.3 Exclusion Criteria


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Description of change
Exclusion criteria # 16 has been deleted
Patients who have previously undergone allergy 
immunotherapy for prevention of anaphylactic 
reaction.
Rationale for change
This was removed from the exclusion criteria as it 
was felt that allergy immunotherapy is poorly 
defined (could be a desensitization to just anything) 
and would exclude a good number of patients 
unnecessarily. 
Section to be changed
Section 4.1.2 Selection of doses in the trial
Description of change
The intended dose for treatment of a moderate 
to severe flare which can be life-threatening is 
the maximum practical dose to deliver at one 
time. Experience with biologics has consistently 
led to concern about under-dosing leading to 
inadequate response.  In this trial those who 
have inadequate response at 1 week are allowed 
to receive a dose of BI 655130.  Thus, there will 
be a test of a second dose at an appropriate 
interval to evaluate under-dosing as the 
explanation for treatment failure.  Given (i) the 
rarity of the disease and in particular due to the 
rareness of flaring events precluding typical dose 
finding strategies, (ii) the serious and potentially 
life threatening nature of moderate/severe GPP and 
(iii) the favorable efficacy, safety and tolerability 
profile of BI 655130, exploration of other lower
doses in GPP patients presenting with a flare (trial 
1368-0013) is considered to be not feasible and is 
not planned or worthwhile.
Rationale for change
Provided additional details on the dose selected for 
this trial.
Section to be changed
Section 4.1.4 Drug assignment and administration
of doses for each patient
Description of change
In all patients, the infusion solution is intended to 
be intravenously administered over a period of 90
minutes. In case of safety concerns, e.g. due to 
systemic hypersensitivity including (See Section 
4.2.1.1 for further details) infusion reactions, it is 
at the discretion of the investigator or his/her 
designee to adapt the infusion scheme, including 
but not limited to slowing down the infusion rate, 
stopping the infusion, and provided no further 
safety concern exists, restarting at a slower rate.


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The administration of the trial medication will be 
done under the supervision of the investigating 
physician or a designee. The so-called four-eye 
principle (two-person rule) should be applied is 
recommended for administration of trial 
medication and – if applicable – its preparation, if 
correct dosage cannot be ensured otherwise.
Rationale for change
Updated information and added clarification. 
Previous trials with BI 655130 predominantly used 
intravenous route of administration. Sponsor 
decided to update the AESI term to expand the 
(previous) “infusion reaction including 
anaphylactic reaction” to include systemic 
hypersensitivity reactions that are not due to an 
infusion since there will be more trials which 
employ intravenous AND subcutaneous routes of 
administration of BI 655130.
Section to be changed
Section 4.1.7 Storage Conditions
Description of change
The medication may only be dispensed to trial 
patients according to the Clinical Trial Protocol 
(CTP) by authorized personnel as documented in 
the trial staff list
The trial medication must be administered in 
the manner specified in the CTP and 
instructions for IMP preparation handling and 
administration of BI 655130 or Placebo.
Rationale for change
Clarification
Section to be changed
Section 4.1.8 Drug Accountability
Description of change
Only authorized personnel as documented in the 
form ‘Trial Staff List’ may administer medication 
to trial patients. The trial medication must be 
administered in the manner specified in the CTP.
Rationale for change
Clarification. Removed the statement.
Section to be changed
Section 4.2.1.1   Emergency procedures
Description of change
Systemic hypersensitivity including Infusion 
reactions including and anaphylactic reaction
In case of Systemic hypersensitivity including
infusion reactions, including and anaphylactic 
reaction, emerging during or after infusion of trial 
medication, the investigator should consider in 
accordance with severity of the reaction and local 
standard of care to
-
Immediately interrupt the infusion


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Rationale for change
Previous trials with BI 655130 predominantly used 
intravenous route of administration. Sponsor 
decided to update the AESI term to expand the 
(previous) “infusion reaction including 
anaphylactic reaction” to include systemic 
hypersensitivity reactions that are not due to an 
infusion since there will be more trials which 
employ intravenous AND subcutaneous routes of 
administration of BI 655130.
Section to be changed
Section 4.2.1.1   Emergency procedures
Description of change
QuantiFERON® (or if applicable, TSPOT®) TB 
test will be performed at screening.
Rationale for change
Adjustment of the text following the changes in 
Section 3.3.3 exclusion criterion 14.
Section to be changed
Table 4.2.2.1:1 Restricted Medications
Description of change

Added Risankizumab as a restricted 
medication.

Reduced the washout period of all biologics to 
2 months.

Corrected a typo Natalizumab

Updated footnote 1 as following: 
In case of worsening of the flare (disease 
worsening), please refer to Section 4.2.1 for the 
details on the use of escape treatment i.e. standard 
of care (physician’s choice) is left at the discretion 
of the investigator (refer to Section 4.2.1).
Rationale for change
Updated Information
Section to be changed
Section 5.2.2 Vital Signs
Description of change
In addition to the temperature being measured 
along with the vital signs at time points shown in 
the Flow Chart, fever (temperature) will also be 
assessed at the day the patient presents to the 
clinic/hospital with GPP flare of moderate to 
severe intensity prior to receiving medication for 
fever treatment. Thereafter, fever must be assessed 
and recorded 2 times on that day, separated by 
intervals of 2 to 4 hours. additional fever 
assessments will be recorded on dosing days at 
three time points. If the patient will receive 
medication for fever treatment, the fever 
assessment will be performed prior to taking the 
anti-fever treatment. These fever assessments 
must be taken whether or not the patient has an 
elevated temperature and whether or not the 


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patient takes anti-fever treatment. The fever 
assessments times are to be separated by 
intervals of 2 to 4 hours on dosing days. At all 
other visits (non-dosing days), fever will be 
assessed once a day and will be completed prior to 
receiving medication for fever treatment, if anti-
fever treatment is given.
Rationale for change
Clarification
Section to be changed
Section 5.2.3 Safety Laboratory Parameters
Description of change
However, local labs may be used for dosing 
decisions at visits involving i.v. administration of
BI 655130 or placebo. The labs listed in Table 
5.2.3: 2 are recommended to be collected and 
assessed by the investigator prior to study drug 
infusion to allow for immediate subject 
management; however, split or concurrent samples 
will must be drawn and sent to the central 
laboratory for analysis. 
Rationale for change
Clarification
Section to be changed
Table 5.2.3:1 Safety Laboratory Tests (footnotes)
Description of change
Footnote 4: If the 1st QuantiFERON®(or if 
applicable, T-Spot®) TB test result is 
indeterminate, a retest should be performed. <For 
Japan> T-Spot® TB test may be performed at 
local labs instead of QuantiFERON®TB test.
Footnote 5: In subjects with a negative 
QuantiFERON® (or if applicable, T-Spot®)TB 
test, the test should be repeated at EoS (V14 or 
V15 or V16 as applicable). <For Japan> T-Spot®
TB test may be performed at local labs instead 
of QuantiFERON®TB test.
Footnote 6: IgE will be taken in case of systemic 
hypersensitivity including infusion reaction 
together with ADA (anti-drug antibodies) sample.
Rationale for change
Updated Information.
Section to be changed
Table 5.2.3:2 Laboratory tests to be assessed prior 
to i.v. administration at V2, V9 or for any rescue 
treatment (Local Labs)
Description of change
For Substrates: 
C-Reactive Protein (CRP) , Serum albumin, 


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Creatinine, Total bilirubin Direct bilirubin, eGFR 
(preferably estimated by CKD-EPI formula)
Rationale for change
Clarification
Section to be changed
Section 5.2.5 Local Tolerability
Description of change
Grade the intensity of the local tolerability 
according to RCTC grading (cf. ISF).
Rationale for change
Added Clarification as to what grading criteria 
should be used for grading local tolerability.
Section to be changed
Section 5.2.6.1 Definition of Adverse event 
Description of change
Hepatic injury
Hepatic Injury, is defined by the following 
alterations of hepatic laboratory parameters:

An elevation of AST and/or ALT and/or AP 
≥3-fold ULN plus 2 times the baseline, 
combined with an elevation of total bilirubin 
≥2-fold ULN plus 1.5 times the baseline, 
measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) 
elevations ≥ 10 fold ULN 
Rationale for change
Correction. To be consistent with the hepatic 
laboratory parameters to define hepatic injury in 
the preceding BI 655130 studies.
Section to be changed
Section 5.2.6.2 Adverse event collection and 
reporting
Description of change
AE collection period has been updated as 
following: 
For patients rolling over into open label 
extension trial (1368-0025):

From signing the informed consent onwards 
until the individual patient’s end of trial of the 
parent trial onwards until the first dose of 
trial medication in the extension trial:

all AEs (non-serious and serious) and 
all AESIs.
For patients not rolling over into subsequent 
OLE trial (1368-0025):

From signing the informed consent onwards 
until the individual patient’s end of trial:

all AEs (serious and non-serious) and 
all AESIs.


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Rationale for change
Updated Information
Section to be changed
Section 5.4.1 Biochemical and Cellular Biomarker 
(s)
Description of change
Serum will be collected to assess changes in 
protein levels of select IL-36 pathway and disease 
specific biomarkers such as but not limited to CRP, 
IL-1β, IL-1RA, IL1a, IL6, IL8, TNF, LCN2, and S-
100 proteins (A7, A8, A12), IL17A, IL17F, IL-10, 
IL-12p70, IL-18, IL-22, IFN-γ and VEGF pre and 
post treatment with BI 655130.
Rationale for change
To include analysis of all potential biomarkers of 
interest. 
Section to be changed
Section 5.4.1 Biochemical and Cellular Biomarker 
(s)
Description of change
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. The se 
biomarkers are considered exploratory biomarkers 
and respective assays will need to be qualified to 
meet the required performance criteria.
Rationale for change
Staged analysis ensures optimal allocation of 
resources. 
Section to be changed
Section 5.4.1 Biochemical and Cellular Biomarker 
(s)
Description of change
Cellular biomarkers will be assessed using flow 
cytometry and will include specific markers
of cells such as but not limited to Neutrophils,
Macrophages, and T lymphocytes in PBMC’s 
isolated from whole blood.
Rationale for change
Neutrophils will not be analyzed by flow cytometry 
from the whole blood sample due to limited utility 
and technical feasibility.
Section to be changed
Section 5.4.2 Pharmacogenomics Biomarker (s)
Description of change
In addition, skin biopsies and whole blood samples 
will be taken at time points indicated at the 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 


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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.
Rationale for change
Staged analysis ensures optimal allocation of 
resources. 
Section to be changed
Section 6.2 Details of trial procedures at selected 
visits
Description of change
∀
The patients’ questionnaires (PSS, 
, pain 
VAS, FACIT-Fatigue, and 
) are to 
be completed by the patient on himhis/herself
own in a pre-specified order in a quiet 
area/room before any other visit assessments 
or treatments, and, if possible, before any 
interaction with the investigator or other 
members of the study team, and, without any 
help from or interpretation by other people.
∀
At each applicable visit (see Flow Chart), the 
order of completion for PROs is recommended 
to be as follows: PSS, 
 Pain VAS, 
FACIT Fatigue, 
∀
Separate from the PROs above, the evaluation 
of efficacy assessments (GPPGA, GPPASI, 
 
for a patient are to be 
conducted preferably by the same physician 
throughout the study.
∀
Re-screening: If a patient results in a screen 
failure (i.e. does not meet the eligibility criteria, 
) 
 


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or does not flare within the 6 month 
screening period) the patient must be 
registered as a screen failure in IRT system.  
However, re-screening of a previously screen 
failed patient will be permitted once. Upon re-
screening, the patient will be assigned a new 
patient number. Details of IRT procedures can 
be found in the IRT manual located in the 
Investigator Site File (ISF). 
Rationale for change
Clarification and Updated Information
Section to be changed
Section 7.1 Statistical Design - Model
Description of change
The primary analysis, on each of the co-binary, 
primary endpoint, achievement of a GPPGA 
pustulation subscore of 0 at Week 1, and key 
secondary endpoint, achievement of a GPPGA of 
(0, 1) at Week 1, where death or any use of escape 
medication prior to observing the endpoint is 
considered to be a non-response, will compare the 
proportion of patients who achieve a response on 
BI 655130 to Placebo. Given the small sample size 
proposed to be used in this trial, an exact statistical 
test, the Suissa-Shuster Z-unpooled pooled test, 
will be used to perform the primary analysis. 
Confirmation of efficacy is then given if the 
proportion of patients achieving a response on each
the co-primary endpoints is statistically 
significantly higher for BI 655130 than for placebo. 
The final analysis of the trial, which will include 
all randomized patients, will be performed once 
all patients have completed the trial.
Rationale for change
Update of endpoints and clarification
Section to be changed
Section 7.2 Null and Alternative Hypothesis
Description of change
Test of the Co-Primary Endpoints
The null hypothesis for the co-primary endpoint, 
the proportion of patients achieving a GPPGA 
pustulation subscore of 0, at Week 1 is
H01: Effect of BI 655130 on the 
proportion of patients achieving a 
GPPGA pustulation subscore of 0 at 
Week 1 (where death or any prior 
use of escape medication will be 
considered to represent a non-
response) ≤ Placebo;
versus the alternative hypothesis


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H02: 
Effect of BI 655130 on the 
proportion of patients achieving a 
GPPGA pustulation subscore of 0 at 
Week 1 (where death or any prior 
use of escape medication will be 
considered to represent a non-
response) > Placebo.
Only if the null hypothesis, H01 of the primary 
endpoint is rejected, will the efficacy of BI 
655130 in the treatment of acute GPP flares be 
confirmed. 
Test of the Key Secondary Endpoint
Further hypothesis will be tested on the key 
secondary endpoint in a hierarchical manner if 
the null hypothesis of the primary endpoint H01
has been previously rejected.
The null hypothesis for the co-primarykey 
secondary endpoint, the proportion of patients 
achieving a GPPGA score of (0, 1), at Week 1 is 
H11: 
Effect of BI 655130 on the proportion of 
patients achieving a GPPGA of 0 or 1 at 
Week 1 (where death or any prior use of 
escape medication will be considered to 
represent a non-response) ≤ Placebo;
versus the alternative hypothesis
H12: 
Effect of BI 655130 on the proportion of 
patients achieving a GPPGA of 0 or 1 at 
Week 1 (where death or any prior use of 
escape medication will be considered to 
represent a non-response) > Placebo.
Only if both of the null hypotheses, H01 and H11, of 
the two co-primary endpoints are rejected, will the 
efficacy of BI 655130 in the treatment of acute 
GPP flares be confirmed.No adjustment of the 1-
sided alpha-level of 0.025 is necessary.
Test of the Secondary Endpoints
Further hypotheses will be tested on the following 
secondary endpoints in a hierarchical manner if  
both null hypotheses of the two co-primary 


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endpoint null hypothesesand key secondary 
endpoint, H01 and H11, have been previously 
rejected. Note that the study is not further powered 
for the performance of these additional statistical 
comparisons. 
The null hypothesis for the secondary endpoint, the 
proportion of patients achieving a GPPASI 75 at 
Week 4 is 
H21: 
Effect of BI 655130 on the proportion of 
patients achieving a GPPASI 75 at Week 4 
(where death or any prior use of escape 
medication/OL BI 655130 at D8/rescue 
medication with BI 655130 will be 
considered to represent a non-response) ≤ 
Placebo;
versus the alternative hypothesis
H22: 
Effect of BI 655130 on the proportion of 
patients achieving a GPPASI 75 at Week 4 
(where death or any prior use of escape 
medication/OL BI 655130 at D8/rescue 
medication with BI 655130 will be 
considered to represent a non-response) > 
Placebo.
Rationale for change
Update of endpoints and tests 
Section to be changed
Section 7.3.1 Primary Endpoint Analyses
Description of change
The analysis for the primary endpoint includes
the evaluation of patients achieving a GPPGA 
pustulation subscore of 0 at Week 1 and of patients 
achieving a GPPGA score 0 or 1 at Week 1 are the 
co-primary endpoints of this trial. 
Death or Any use of escape medication, e.g. use of 
restricted medication for disease worsening in 
Table 4.2.2.1: 1, prior to observing the primary 
endpoint is considered to reflect a failure to achieve 
the endpoint outcome, i.e. non-response (see 
primary endpoint definition in Section 2.1.2).
Due to the small sample size of the trial, an exact 
statistical test will be used to assess the statistical 
significance of the treatment effect versus Placebo. 
Since the traditional Fisher’s exact test may be 


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unnecessarily conservative, an alternative test, the 
Suissa-Shuster Z-unpooled pooled test, will be 
implemented in this trial. The Suissa-Shuster Z-
unpooled pooled test always preserves the type I 
error level and is usually more powerful than the 
Fisher’s exact test. 
Each of the co-The primary endpoints will be 
separately tested, for the RS, using the Suissa-
Shuster Z unpooled pooled test at a 1-sided, alpha 
level of 0.025.  Confirmation of efficacy is then 
given only if the null hypotheses on both of the co-
primary endpoints are simultaneously rejected.
Secondary analysis of both co-the primary 
endpoints will include:

A sensitivity analysis utilizing the PPS;

Analysis of an additional estimand whereby 
death or any use of escape medication prior to 
week 1 following onset of disease worsening will 
be considered to represent a non-response. For 
patients who use escape other restricted 
medication but not for disease worsening
prior to Week 1, without developing disease 
worsening, data will be censored for further 
analysis following the escape use and imputed 
using the methods described in Section 7.5.

Sensitivity analyses which utilize alternative 
methods for the handling of missing data as 
described in Section 7.5.

A subgroup assessment according to the 
Japan vs. non-Japan strata will be assessed 
descriptively.
Further analysis of the co-primary endpoints will 
include:
•
Analysis of the time to first achievement of 
a response on each of the co-primary 
endpoints via Kaplan-Meier methods.
Rationale for change
Update of endpoint and clarification 
Section to be changed
Section 7.3.2 Key Secondary Endpoint Analysis
Description of change

There is no key secondary endpoint defined in 
the trial.

The analysis for the key secondary 
endpoint, for patients achieving a GPPGA 


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score 0 or 1 at Week 1, will be performed in 
the same manner as described for the 
analyses of the primary endpoint.

Any use of escape medication, e.g. use of 
restricted medication for disease worsening 
in Table 4.2.2.1: 1, prior to observing the 
key secondary endpoint is considered to 
reflect a failure to achieve the endpoint 
outcome, i.e. non-response (see key 
secondary endpoint definition Section 2.1.3).
Rationale for change
Update of endpoint
Section to be changed
Section 7.3.3 Secondary Endpoint Analysis
Description of change

subsequent to the test of the primary endpoint 
and key secondary endpoint, which is 
defined in Section 7.2.

death or any use of escape medication…

Other secondary endpoints will be 
descriptively displayed only.presented in an 
exploratory manner using the methods 
described above.
Rationale for change
Clarification
Section to be changed
Section 7.5 Handling of Missing Data
Description of change

For primary and key secondary and
secondary binary endpoints
With regards to the handling of missing data on 
the primary, key secondary and secondary 
binary efficacy endpoints, a Non Response 
Imputation will be applied as the primary 
imputation approach that is, imputing as a 
failure to achieve a response, however:..

Worst case ranks will be assigned to those with 
death or prior escape medication or OL BI 
655130 at D8 or rescue medication with BI 
655130, and for patients with missing data at 
Week 4 for death or other reasons.
Rationale for change
Information update
Section to be changed
Section 7.7 Determination of Sample Size
Description of change

Update “co-primary endpoints” to “primary 
endpoint” and “key secondary endpoint”


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∀
The power estimates below for detecting the 
clinically relevant differences statistically 
significant differences, for both the co-primary 
endpoint, the proportion of patients with a 
GPPGA pustulation subscore of 0 at Week 1 
and the key secondary endpoint, a GPPGA 
score of 0 or 1 at Week 1, were derived using 
R version 3.3.2, for a sample size of 27 51 
patients (2:1 ratio), and a 1-sided type I error 
of 0.025. The results are as given in Table 7.7: 
1Note that the power can be reduced if by 
chance we end up with 28 patients are 
randomized among which 19 patients are on BI 
655130 treatment and 9 patients are on 
placebo. The resulting powers are also 
included in Table 7.7: 1.
∀
Updated Table 7.7: Power to achieve statistical 
significance for the co-primary endpoints and 
key secondary endpoint on BI 655130 versus 
Placebo under various scenarios for N=51 
(2:1)
∀
Therefore, for a total of 27 patients, with an 
expected response rate of 0.65 on BI 655130 
and 0.05 0.1 on placebo for each of the co-
primary endpoints and key secondary 
endpoint and a type I error of <0.025 (1-
sided), for a total sample size of 51 patients,
this trial will be able to detect an effect of BI 
655130 relative to placebo, for both primary 
endpoint and key secondary endpoint 
simultaneously, with a type I error of <0.025 
(1-sided) and  with an overall power of 
93.9%.
Rationale for change
Information update and clarification 
Section to be changed
Appendix 10.1.2    Psoriasis Area and Severity 
Index for Generalized Pustular Psoriasis (GPPASI)
Description of change
GPPASI Scoring has been updated from "none, 
slight, moderate, severe and very severe" to
"clear, almost clear, mild, moderate, severe".
Rationale for change
Correction
Section to be changed
Description of change
Rationale for change
Correction


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11.2
GLOBAL AMENDMENT 2
Date of amendment
26 Jun 2020
EudraCT number
EU number
Spesolimab (BI 655130)
BI Trial number
1368-0013
BI Investigational Product(s)
Spesolimab (BI 655130)
Title of protocol
Effisayil™ 1: Multi-center, double-blind, 
randomized, placebo-controlled, Phase II study to 
evaluate efficacy, safety and tolerability of a single 
intravenous dose of BI 655130 in patients with 
Generalized Pustular Psoriasis (GPP) presenting 
with an acute flare of moderate to severe intensity
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Several sections
Description of change
Administrative
Rationale for change
Correction of spelling errors
Section to be changed
Title page: Clinical Trial Leader
Description of change
Change name of  Clinical Trial Leader
Rationale for change
Updated Clinical Trial Leader
Section to be changed
Section 2.1.1 Main objectives
Description of change
Add wording to primary objective:
The primary objective of this trial is to evaluate 
efficacy, safety, and tolerability of one single i.v. 
dose of BI 655130 compared to placebo in patients 
with Generalized Pustular Psoriasis (GPP) 
presenting with an acute flare of moderate to severe 
intensity.
Rationale for change
To clarify the primary objective 
Section to be changed
Description of change
Rationale for change


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Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change


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Rationale for change
Description of change
Add wording in Table 3.1: 1 for treatment of 
recurrence of GPP flare:
After Wk1/D8 and through week 12, if there is ≥ 
2 point increase in the GPPGA score and the 
pustular component of GPPGA ≥ 2 after achieving 
a clinical response (GPPGA 0 or 1) to initial 
treatment (either with BI 655130 at D1 or placebo 
at D1 or escape medication or OL BI 655130 at 
D8).
Rationale for change
Clarify treatment option in case of recurrent flare
Section to be changed
Table 4.1.5.1 Blinding
Description of change
Update the blinding plans for primary analysis and 
final analysis:
Patients, investigators, as well as sponsor personnel 
involved in the trial conduct or analysis, will 
remain blinded with regard to the randomized 
treatment assignments until after the database lock 
for the final analysis of the trial has been 
performed. Once the database lock has been 
performed, all parties will be officially unblinded 
to the randomization details
Patients and investigators involved in the trial 
conduct will always remain blinded with regard 
to the randomized treatment assignments until 
after database lock for the final trial analysis.
If the trial team agrees to perform the primary 
analysis and the final analysis separately (see 
Section 7.3), then, a database lock for the 
primary analysis will be done and treatment will 
be unblinded to trial and project team members. 
If the trial team agrees to perform the primary 
analysis and final analysis as one single analysis 
(at the time of trial completion), then patients, 
investigators, and sponsor personnel involved in 
the trial conduct, will unblinded to the 
randomized treatment assignments after the 
database lock has been performed.
Rationale for change
To clarify the blinding plans of primary analysis 
and final analysis


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Section to be changed
Table 4.1.5.2 Unblinding and breaking code
Description of change
Add wording:
Treatment unblinding will be performed prior to 
each DMC meeting as a prerequisite for generation 
of the applicable DMC summaries required, as well 
as subsequent to the primary analysis database 
lock (if applicable), and the final trial database 
lock at which time the final trial analyses will be 
performed. Treatment unblind for the study will be 
officially released once database lock for the final 
trial analysis has been performed.
Rationale for change
To clarify the blinding plans of primary analysis 
and final analysis
Section to be changed
Section 5.2.3 Safety laboratory parameters
Description of change
Change wording:
However, local labs may are to be used for dosing 
decisions at visits involving i.v. administration of 
BI 655130 or placebo.
Rationale for change
To clarify local labs results are required for dosing 
decision at visits involving i.v. administration of BI 
655130 or placebo.
Section to be changed
Section 5.2.3 Safety laboratory parameters
Description of change
Add wording:
A positive HBV-DNA test at screening will 
exclude the patient.
Rationale for change
For clarification.
Section to be changed
Section 5.2.6.2 Adverse event collection and 
reporting
Description of change
Removal of figure 5.2.6.2:1
Rationale for change
Since there are different AE collection scenarios as 
described in paragraph 5.2.6.2 (with or without 
roll-over to extension trial), the figure did not cover 
the different scenarios and therefore it was 
removed.
Section to be changed
Section 7.1 Statistical Design - model
Description of change
Add wording:
The primary objective of this trial is to evaluate the 
efficacy, safety and tolerability of a single i.v. dose 
of BI 655130 in comparison to placebo at Day 1.
Rationale for change
To specify wording for primary objective.
Section to be changed
Section 7.1 Statistical Design - model


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Description of change
Delete wording:
The final analysis of the trial, which will include all 
randomized patients, will be performed once all 
patients have completed the trial.
Rationale for change
Information for primary/final analysis are 
described in Section 7.3.
Section to be changed
Section 7.3 Planned analyses
Description of change
Add the analysis timelines for primary analysis and 
final analysis:
The primary analysis of this trial is planned to 
be performed once all randomized patients have 
completed the 12 week period or early 
discontinued from the trial: a database lock for 
the primary analysis will then be performed. 
Final analysis is planned to be performed at the 
end of the trial once all randomized patients 
have completed the trial (including any follow-
up period) if applicable. 
The primary analysis and final analysis may be 
performed as a single analysis (at the time of 
trial completion), if, prior to the time of the 
primary analysis, the trial team agrees that the 
expected time interval between the planned 
analyses is insufficient to justify the 
performance of separate analyses. 
Details of treatment unblinding for the primary 
analysis and final analysis are described in 
Section 4.1.5.1. Details of the analysis to be 
performed will be described in the TSAP.
Delete wording:
The final trial analysis is planned to be performed 
at the end of the study once all randomized patients 
have completed the study (including any applicable 
follow-up period). The final analysis will include 
all trial data. Details of the analysis to be 
performed will be described in the TSAP.
Rationale for change
Clarify the time points of primary analysis and 
final analysis
Section to be changed
Section 7.3 Planned analyses
Description of change
Reference to CTR removed
A Clinical Trial Report will be prepared at the end 


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of the trial.
Rationale for change
Administrative.
Section to be changed
Section 7.3.1 Primary endpoint analyses
Description of change
Add sensitivity analysis:
Sensitivity analyses to adjust for the covariates, 
IL36R mutation status (Yes vs No) and baseline 
GPPGA total score (3 vs 4) respectively using 
logistic regression.
Rationale for change
It is of interest to check whether IL36R mutation 
status and baseline GPPGA total score are related 
to primary efficacy endpoints.
Section to be changed
Section 7.3.3 Secondary endpoint analyses
Description of change
Add primary estimand:
For the analysis of the continuous secondary 
endpoints which are included in the statistical 
testing strategy, the following estimand and 
testing approach will be done implemented:
Any use of escape medication or OL BI 655130 
at Day 8 or rescue medication with BI 655130 
prior to an assessment time point will be 
considered as a non-response at this time point 
and assigned worst treatment outcomes in the 
analysis.
Rationale for change
T clarify primary estimand for continuous 
endpoints
Section to be changed
Description of change


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Rationale for change
Section to be changed
Section 7.3.5 Safety analyses
Description of change
Update that for patients who continue into the 
extension trial, TEAE up to the first dose in the 
extension trial will be available for display in the 
current study. 
Note that for patients who continue into the 
extension trial, only TEAE up to the first dose in 
the extension trial will be available for display in 
the current study.
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 for patients who will not be rolled 
over to OLE study, the first dose of OLE study 
for patients who will be rolled over to OLE 
study, drug stop date + 112 days, date of Day 8 if 
OL BI 655130 is given, date of rescue medication 
if BI 655130 is given).
Rationale for change
Correct the wording for AE collection
Section to be changed
Section 7.5 Handling of missing data
Description of change
Remove “Multiple Imputation” method for 
analysis:
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 for patients who will not be rolled 
over to OLE study, the first dose of OLE study for 
patients who will be rolled over to OLE study, drug 
stop date + 112 days, date of Day 8 if OL BI 


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655130 is given, date of rescue medication if BI 
655130 is given).
Rationale for change
It is not needed for missing data imputation.
Section to be changed
Section 7.5 Handling of missing data
Description of change
LOCF method will be used for imputation of 
continuous endpoints:
In test, worst case ranks will be assigned to those 
with prior escape medication or OL BI 655130 at 
D8 or rescue medication with BI 655130 or death, 
and for patients with missing data at Week 4 for 
death or other reasons, LOCF method will be 
used for imputation.
The imputation and ranking rules are outlined in 
Table 7.5: 1.
Table 7.5: 1 
Imputation Ranking rules for 
missing secondary continuous endpoint
** Imputed Ranked values in this table are only 
for purpose of rank tests but not for any descriptive 
displays
Rationale for change
It has been mentioned in Table 7.5: 1. Further to 
clarify this method in contexts.


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Technical Version Number:
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Meaning of Signature  
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26514524-03
BI Trial No.:
1368-0013
Title:
Multi-center, double-blind, randomized, placebo-controlled, 
Phase II study to evaluate efficacy, safety and tolerability of a 
single intravenous dose of BI 655130 in patients with 
Generalized Pustular Psoriasis (GPP) presenting with an acute
flare of moderate to severe intensity 
Including Revised Protocol # 3 [c15875404-04]
Investigational
Product:
Spesolimab (BI 655130)
Responsible trial 
statisticians:
Tel.:
Fax: 
Date of statistical 
analysis plan:
  22 DEC 2020 SIGNED
Version:
Revised
Page 1 of 85
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS .....................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT.................................................................................10
5.2
SECONDARY ENDPOINTS.........................................................................10
6.
GENERAL ANALYSIS DEFINITIONS..........................................................16
6.1
TREATMENTS...............................................................................................16
6.2
IMPORTANT PROTOCOL DEVIATIONS ...............................................18
6.3
PATIENT SETS ANALYZED ......................................................................24
6.5
POOLING OF CENTRES .............................................................................28
6.6
HANDLING OF MISSING DATA AND OUTLIERS................................28
6.6.1
Withdrawals ................................................................................................29
6.6.2
Efficacy data................................................................................................29
6.6.3
Safety data ...................................................................................................37
6.6.7
Time since first diagnosis ...........................................................................38
6.6.8
Disease characteristics................................................................................40
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...............41
7.
PLANNED ANALYSIS......................................................................................44
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.....45
7.2
CONCOMITANT DISEASE AND MEDICATION....................................46
7.3
TREATMENT COMPLIANCE....................................................................47
7.4
PRIMARY ENDPOINT.................................................................................48
7.5
SECONDARY ENDPOINT...........................................................................49


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7.5.1
Key Secondary endpoint.............................................................................49
7.5.2
Secondary endpoints...................................................................................49
7.7
EXTENT OF EXPOSURE.............................................................................62
7.8
SAFETY ANALYSIS......................................................................................62
7.8.1
Adverse events.............................................................................................63
7.8.2
Laboratory data ..........................................................................................67
7.8.3
Vital signs.....................................................................................................69
7.8.4
ECG..............................................................................................................69
7.8.5
Local Tolerability........................................................................................69
7.9
ANALYSIS OF COVID19 IMPACT ............................................................72
7.10
HANDLING OF DMC ANALYSES.............................................................73
8.
REFERENCES....................................................................................................74
10.
HISTORY TABLE..............................................................................................84


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases of the study according to randomized 
treatment...........................................................................................................16
Table 6.2: 1
Important protocol deviations ..........................................................................19
Table 6.3: 1
Overview of use of patient analysis sets by class of endpoint and handling 
of estimand and missing data ...........................................................................26
Table 6.6.2: 1 Handling of estimand and missing data on binary efficacy endpoints in 
testing strategy..................................................................................................31
Table 6.6.2: 2 Ranking rules for Wilcoxon rank tests of secondary continuous endpoint on 
EN.....................................................................................................................33
Table 6.6.2: 3 Handling of estimand and missing data on continuous efficacy endpoints in 
testing strategy..................................................................................................36
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs and
biomarker to visits for statistical analysis ........................................................42
Table 7.1: 1
Categories for summary of continuous variables.............................................46
Table 7.8.1: 1 Project MedDRA search criteria for User Defined Adverse Event Concepts..66
Table 7.8.7:1 Summary of subgroups for selected AE data ....................................................72
Table 10: 1
History table .....................................................................................................84


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALQ
Above the upper limit of quantification
ALT
Alanine aminotransferase
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
ATC3
Anatomical-Therapeutic-Chemical classification level 3
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
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials


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Term
Definition / description
FACIT
Functional Assessment of Chronic Illness Therapy
gCV
Geometric coefficient of variation
gMean
Geometric mean
GPP
Generalized pustular psoriasis
GPPASI
Generalized Pustular Psoriasis Area and Severity Index
GPPASI 50
Achievement of a ≥ 50 % reduction in GPPASI total score compared to 
baseline
GPPASI 75
Achievement of a ≥ 75 % reduction in GPPASI total score compared to 
baseline
GPPASI 90
Achievement of a ≥ 90 % reduction in GPPASI total score compared to 
baseline
GPPGA
Generalized Pustular Psoriasis Physician Global Assessment
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IL
Interleukin
iPD
Important protocol deviation
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analyzed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
NRI
No response imputation
OR
Original results
PPS
Per protocol set
PSS
Psoriasis symptom scale
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator


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Term
Definition / description
REP
Residual effect period
RNA
Ribonucleic acid
RPM
Report planning meeting
RS
Randomized set
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SI
Système international d’unités
TS
Treated set
TSAP
Trial statistical analysis plan
UDAEC
User-defined Adverse Event Category
ULN
Upper limit of normal range
VAS
Visual analogue scale


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the CTP and its amendments, 
and to include detailed procedures for executing the statistical analysis of the primary and 
secondary variables and other data.
This TSAP assumes familiarity with the CTP. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, and planning of sample size, and randomization.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).
Study data will be stored in a trial database within the BRAVE system.
Analyses of the biomarker and gene expression data are described in a separate biomarker 
TSAP, unless otherwise specified in this document.
This is a multicenter, randomized, double-blind, placebo-controlled Phase II study with one 
dose of Spesolimab/placebo in patients with GPP presenting with an acute flare of moderate 
to severe intensity. In total, at least 51 patients will be randomized to receive Spesolimab/ 
placebo (2:1). All patients will receive the dose of study medication (900 mg i.v. Spesolimab
or Placebo) on Day 1 of Week 1. Based on the subsequent treatment response, patients will 
then be followed for 12 to 28 weeks (see Flow Chart of CTP). The primary and key 
secondary efficacy endpoints of the trial will be determined on Day 8. This TSAP fully 
specifies the analyses of the trial.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Following further endpoints are added to TSAP:

Change from baseline in GPPGA total score, by visit

Change from baseline in GPPGA pustulation subscore, by visit

GPPGA clear/almost clear (modified) defined as a GPPGA total score of 0 or 1 and 
with all subscores < 3, by visit

A GPPGA erythema sub-score of 0 or 1, by visit.

A GPPGA scaling sub-score of 0 or 1, by visit.

A GPPGA pustulation sub-score drop by at least 2 points from baseline, by visit.

A Pain VAS drop by at least 30 points from baseline.

Percentage change from baseline in each of GPPASI pustulation, erythema and 
scaling severities.


A PSS score of 0, by visit

A FACIT-Fatigue score improvement of at least 4 points, by visit
For time to first achievement of GPPGA pustulation score of 0 or GPPGA score of 0 or 1, the 
first day should be day of randomized treatment if it is different from randomization. For 
Wilcoxon testing, the calculations of ranks should be also relative to Day 1.
Percentage change from baseline in GPPASI will be calculated instead of percentage
reduction in GPPASI. For example, if there is 50% reduction in GPPASI score, it means % 
change from baseline in GPPASI is -50%. 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint of the study is: 

A GPPGA pustulation subscore of 0 indicating no visible pustules at Week 1. 
For the estimand concept (EN) on the above-defined primary binary endpoint definition, 
death or any use of escape medication prior to week 1 will be considered to represent a non-
response at the Week 1 timepoint.
See Section 9.1.2 for further details on the derivation of the GPPGA total score.
5.2
SECONDARY ENDPOINTS
Key Secondary Endpoint

A Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 
or 1 at Week 1. 
The same estimand concept (EN) used for primary endpoint will be used for key secondary 
endpoint. 
Secondary Endpoints at Week 4 (included in the statistical testing strategy): 
Secondary endpoints of the study at Week 4 which are included in the statistical testing 
strategy in a hierarchical manner subsequent to performance of the tests on the primary and 
key secondary endpoints are:

A Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI) 75 
at Week 4. 

Change from baseline in Pain Visual Analog Scale (VAS) score at Week 4. 

Change from baseline in Psoriasis Symptom Scale (PSS) score at Week 4. 

Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) 
Fatigue score at Week 4.
Secondary Endpoints at Week 4 (not included in the statistical testing strategy): 

A Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 
or 1 at Week 4. 

A GPPGA pustulation sub-score of 0 indicating no visible pustules at Week 4.

A GPPASI 50 at Week 4. 

The percent change from baseline in GPPASI at Week 4. 
Secondary Endpoints at Week 1: 

A GPPASI 50 at Week 1. 


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
The percent change from baseline in GPPASI at Week 1. 
For the estimand concept (EN) on each of the above-defined binary and continuous
secondary endpoint definition(s) at week 1/4, death or any use of escape medication prior to 
week 1/4, or OL Spesolimab use at D8 or any rescue medication with Spesolimab prior to 
week 4 will be considered to represent a non-response at the week 1/4 time-point.
For further details on the derivation of the GPPASI score, the PSS score, and the FACIT-
Fatigue score, refer to Sections 9.1.1, 9.1.5, and 9.1.3, respectively.
Secondary Safety Endpoints: 

The occurrence of Treatment Emergent Adverse Events (TEAEs).


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on the treatment to be administered, assignment to treatment, and 
selection of dose, cf. Section 4 of the CTP.
The study phases are defined relative to randomized dose at Day 1 as below:
Table 6.1: 1
Flow chart of analysis phases of the study according to randomized treatment
Study analysis 
phase
Description
Start (included)
End (included)
Screening phase
Screening
Earliest of (Date of informed 
consent, first screening procedure)
Date/time of start of infusion 
of randomized study treatment
minus 1 minute
Treatment phase
(including
Residual effect
period)2
On-treatment
period
Date/time of start of infusion of 
randomized study treatment (Day 1)
Earliest of: i) Date of end of 
infusion of randomized study 
treatment (Day 1) + 112 days 
at 23:59, ii) Date/time of first 
dose in OLE trial 1368.25., iii)
Date of end-of-study visit if 
there is no roll-over to 
1368.25
Follow-up 
phase12
Off-treatment
period
Date of end of infusion of 
randomized study treatment (Day 1)
+ 113 days at 0:00
Latest of: i) Date of End-of-
Study visit; ii) last contact 
date on End of Study page at 
23:59
Dates are defined individually per patient. 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 last contact date is after the date of end of infusion of 
randomized treatment + 112 days.
2 For primary safety purpose, safety data is censored for reporting following intake of (optional) open-label Spesolimab on 
Day 8, or intake of rescue medication with Spesolimab for treatment of a GPP flare.
Treatment groups for the analysis phases according to the randomized/actual treatment on 
Day 1 (see Table 6.1: 1) will be labelled as follows:

"Placebo" (i.e. randomized to receive /actual received Placebo on Day 1)

"Speso 900 mg IV SD" (i.e. randomized to receive /actual received Spesolimab on 
Day 1)

"Overall"(across treatments), where appropriate.
“Overall Total” is applicable in disposition, demographics and baseline characteristics, 
compliance summaries, AE, clinically significant abnormal lab values and others if needed. 
Where applicable, output columns should be arranged in the order as given above.


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For analysis on effects of OL Spesolimab at Day 8 following randomized treatment at Day 1, 
patients will be categorized into four different groups (see Section 7.6.2):

Arm 1, "Placebo only"(i.e. randomized to placebo treatment and not given OL
Spesolimab at D8)

Arm 2, "Placebo + OL D8"(i.e. randomized to placebo treatment and given OL 
Spesolimab at D8)

Arm 3, "Speso only"(i.e. randomized to Spesolimab treatment and not given OL 
Spesolimab at D8)

Arm 4, "Speso + OL D8"(i.e. randomized to Spesolimab treatment and given OL 
Spesolimab at D8)
For further analysis on safety data including REP of any non-randomized Spesolimab, 
individual patient’s data will be separated based on the use of randomized treatment at Day 1 
and non-randomized Spesolimab as follows (see Section 7.8.1):

“Prior non-rand. Speso ”(i.e. TEAE starting before use of any non-randomized 
Spesolimab are considered)

“Post OL Speso at D8” (i.e. TEAE starting post OL dose at Day 8 but before rescue 
medication with Spesolimab are considered)

“Post rescue with Speso” (i.e. TEAE starting post rescue medication with
Spesolimab are considered)
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
database (i.e., enrolled patients). Consistency check listings (for identification of deviations 
of time windows) and a list of protocol deviations will be provided to be discussed at the 
RPM/DBLM. At this meeting, it will be decided whether a discrepant data value can be used 
in analyses or whether it must be queried in the clinical database. Each protocol deviation 
must be assessed to determine whether it is an important Protocol Deviation (iPD). The 
categories of iPD are defined in the Integrated Quality and Risk Management plan (IQRMP). 
These categories are repeated below in order to ensure that those iPD which lead to exclusion 
from the PPS are suitably documented before unblinding and locking of data.
For definition of iPDs, and for the process of identification of these, refer to the BI reference 
document "Identify and Manage Important Protocol Deviations (iPD)" (2).
If any patients fulfil the iPD categories, then they are to be summarized and will be captured 
in the RPM/DBLM minutes via an accompanying Excel spreadsheet (3). The following table 
contains the categories which are considered to be iPDs in this trial. If the data show other 
iPDs, for example, based on monitor visits to the site(s), then this table will be supplemented 
accordingly by the time of the RPM/DBLM. Not all iPDs will lead to exclusion from analysis 
sets. iPDs leading to exclusion from analysis sets are indicated as such in Table 6.2: 1.
IPDs will be summarized and listed for the randomized set.


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Table 6.2: 1
Important protocol deviations
Category / 
Code
Description
Comments
Excluded from
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
GPP per CTP not confirmed
Inclusion criterion 1
PPS#
A1.02
Retinoids/methotrexate/cyclosporine not 
discontinued prior to first dose of study 
treatment
Inclusion criterion 2
PPS
A1.03
Age out of range
Inclusion criterion 3
Also programmatic check 
required
None
A1.04
Women of childbearing potential not to 
agree to use effective method of birth 
control; 
Inclusion criterion 5
None
A2
Exclusion criteria violated
A2.01
SAPHO syndrome
Exclusion criterion 1
PPS
A2.02
Primary erythrodermic psoriasis vulgaris
Exclusion criterion 2
PPS
A2.03
Primary plaque psoriasis vulgaris 
without presence of pustules or with 
pustules that are restricted to psoriatic 
plaques
Exclusion criterion 3
PPS
A2.04
Drug-triggered Acute Generalized 
Exanthematous Pustulosis (AGEP)
Exclusion criterion 4
PPS
A2.05
Immediate life-threatening flare of GPP 
or requiring intensive care treatment
Exclusion criterion 5
PPS
A2.06
Severe, progressive, or uncontrolled 
hepatic disease
Exclusion criterion 6
None
A2.07a
Any restricted medication, or any drug,
with potential influence on safe conduct 
of study
Exclusion criterion 7
PPS#
A2.07b
Any prior exposure to Spesolimab or 
another IL36R inhibitor
Exclusion criterion 7
PPS#
A2.08
Dose escalation of cyclosporine and/or 
methotrexate and/or retinoids within the 
2 weeks prior to first study treatment
Exclusion criterion 8
Also programmatic check 
required
PPS#
A2.09
The initiation of systemic agents 2 
weeks prior to first study treatment
Exclusion criterion 9
Also programmatic check 
required
PPS#


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Table 6.2: 1
Important protocol deviations (cont’d.)
Category / 
Code
Description
Comments
Excluded from
A2.10
Congestive heart disease 
Exclusion criterion 10
None
A2.11
Active systemic infections during the 
last 2 weeks prior to first study treatment
Exclusion criterion 11
None
A2.12
Increased risk of infectious 
complications 
Exclusion criterion 12
None
A2.13
Relevant chronic or acute infections 
including HIV or viral hepatitis.
Exclusion criterion 13
None
A2.14
Active or Latent TB
Exclusion criterion 14
None
A2.15
History of allergy/hypersensitivity to a 
systemically administered trial 
medication agent or its excipients
Exclusion criterion 15
None
A2.16
Any documented active or suspected 
malignancy or history of malignancy 
within 5 years prior to screening
Exclusion criterion 16
None
A2.17
Currently enrolled or less than 30 days 
since another investigational device or 
drug study
Exclusion criterion 17
PPS
A2.18
Pregnancy
Exclusion criterion 18
None
A2.19
Major surgery within 12 weeks prior to 
first study treatment
Exclusion criterion 19
None
A2.20
Clinical Evidence which would make the 
study participant unreliable to adhere to 
the protocol
Exclusion criterion 20
PPS
B
Informed consent
B1
Informed consent not available
Inclusion criterion 4; 
Date of informed consent 
missing or no signature on 
patient’s “Declaration of 
Informed Consent”
In this case: Patient’s data 
will not be used at all.
All#
B2
Informed consent too late
Informed consent date was 
after Visit 1
None


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Table 6.2: 1
Important protocol deviations (cont’d.)
Category / 
Code
Description
Comments
Excluded from
C
Trial medication and randomization
C1
Incorrect trial medication
C1.01
Missing medication or incorrect 
medication received by patients due to 
other reasons
At least one randomized vial 
was given wrongly or 
missing at Day 1 due to 
other reason.
Can only be finally judged 
after DBL since unblinding 
information is required
PPS
C1.02
Missing medication or incorrect 
medication received by patients due to 
COVID-19
At least one randomized vial 
was given wrongly or 
missing at Day 1 due to 
COVID-19.
Can only be finally judged 
after DBL since unblinding 
information is required
PPS
C2
Non-compliance
C2.01
Non-compliance with study drug intake-
- administered dose too low or too high
Study medication dose 
(based on infusion volume) 
is less than 80% or more 
than 120% of the total 
planned dose
PPS
C3
Randomization not followed
C3.01
Treated without randomisation
Patient treated according to 
eCRF, but not randomised 
according to IVRS.
PPS/RS/SAF
C3.02
Randomization order not followed
Stratification error
Programming check and 
also manual review after 
DBL
None#
C4
Medication code broken
C4.01
Medication code broken inappropriately
Medication code was broken 
prior to the DBL for no 
valid reason.
Final decision at the DBL 
meeting based on medical 
judgment.
PPS#


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Table 6.2: 1
Important protocol deviations (cont’d.)
Category / 
Code
Description
Comments
Excluded from
D
Concomitant medication
D1
Previous medication
D1.01
Washout of previous medication too 
short
Washout period too short -
See Table 4.2.2.1: 1 in CTP
PPS#
D2
Prohibited medication use
D2.01a
Use of prohibited med (with potential 
influence on eff. data) when not 
provided as an escape treatment to 
stabilize a worsening disease condition –
prior to or up to Week 1
See the list of restricted 
medication in CTP, Table 
4.2.2.1: 1, manual 
assessment at MQRM/
RPM/DBLM
PPS#
D2.01b
Use of prohibited med (with potential 
influence on eff. data) when not 
provided as an escape treatment to 
stabilize a worsening disease condition –
after Week 1
See the list of restricted 
medication in CTP, Table 
4.2.2.1: 1,manual 
assessment at MQRM/
RPM/DBLM
None#
D2.01c
Use of prohibited med (without potential 
influence on eff. data)
See the list of restricted 
medication in CTP, Table 
4.2.2.1: 1,manual 
assessment at MQRM/
RPM/DBLM
None#
D3
Change in Background medication
D3.01
Background medication (methotrexate, 
cyclosporine, or retinoids) not stopped 
prior to receiving first study treatment on 
Day 1
Background medication 
continues into the treatment 
period
PPS#
E
Missing data
F
Study specific analysis
F1
Other trial specific deviation
F1.01
Study drug intake outside time window 
Infusion period takes longer 
than 180 minutes.
None
F1.02
Patient was administered open-label 
treatment at Day 8 with Spesolimab but 
did not qualify for this treatment per 
CTP requirement. 
Patient was Spesolimab re-
treated but did not show a 
GPPGA of ≥2 and a pustular 
sub-score ≥2 at Day 8
None
F1.03
Patient was administered rescue 
treatment with Spesolimab but did not 
achieve flare qualification per CTP 
requirement. 
Flare qualification requires: 
≥2 point increase in GPPGA 
score & pustulation subscore 
of GPPGA ≥2 after 
achieving a clinical response
(GPPGA 0 or 1)
None#


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Table 6.2: 1
Important protocol deviations (cont’d.)
Category / 
Code
Description
Comments
Excluded from
G
Other safety related deviations
G1
Pregnancy test not done for woman of 
child bearing potential at days of IMP 
treatment and not prior the IMP 
administration
Pregnancy test not done 
before randomized treatment 
at Day 1, OL Spesolimab at 
Day 8 or rescue Spesolimab
None#
# PD will be detected manually;
Source: BI reference document ' Identify and Manage Important Protocol Deviations (iPD)' [001-MCS-50-413] (2, 12).


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6.3
PATIENT SETS ANALYZED
The following analysis sets will be defined for this trial:

Enrolled Set (ES)
This patient set includes all patients who signed informed consent. It will be used for 
analyses of patient disposition.

Randomized Set (RS):
This patient set includes all randomized patients. Treatment assignment will be as 
randomized. It will be used for analyses of patient baseline demographics and disease 
characteristics, and is the main set for the analyses of efficacy endpoints.

Safety Analysis Set (SAF):
This patient set includes all patients who were randomized and received at least one 
dose of study drug on Day 1. This is the main analysis set for safety. Patients will be 
analyzed according to the actual treatment received.

Per-Protocol Set (PPS):
This patient set includes all patients in the randomized set who adhered to the CTP 
without any iPDs which are flagged for exclusion from the PPS in the table above.
The PPS will be used for sensitivity analysis on the primary and key secondary 
endpoints.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at latest at the RPM/DBLM.
Handling of Treatment Misallocations in Analysis Sets
If a patient is randomized but not treated, they will be reported under their randomized 
treatment group for efficacy analysis according to RS and PPS (per the intent-to-treatment 
principle).  By definition, however, such patients are excluded from the safety analyses since 
no randomized study medication was taken.
If a subject is treated but not randomized, they will be excluded from the efficacy analysis 
and safety analysis by definition. However, subjects under such circumstances will be 
described in the final clinical trial report.
If a subject is randomized but took incorrect treatment during the study, then:

For efficacy analyses according to the RS and PPS, they will be reported under their 
randomized treatment group. 

For safety analyses using the SAF which are based on actual treatment: 
•
If a subject is planned to receive a single dose administration of Spesolimab
(randomized to 900 mg SD), then they will be reported under the Spesolimab 900 
mg SD group if the subject receives at least 1 vial of randomized Spesolimab on Day 


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1. A subject will be assigned to the placebo treatment group only if they are treated 
and receive no vials of randomized Spesolimab on Day 1.
•
If a subject is planned to receive placebo treatment, then they will be reported under 
the placebo arm if they are treated and receive no vial of randomized Spesolimab on 
Day 1. If the subject receives >= 1 vial of randomized Spesolimab on Day 1, then 
the patient will be reported as treated with Spesolimab 900 mg SD treatment group.
Table 6.3: 1 illustrates the data sets which are to be used for each category class of endpoints, 
and the approaches used with regard to missing data including estimand concepts. 


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Table 6.3: 1 Overview of use of patient analysis sets by class of endpoint and handling of 
estimand and missing data
Class of endpoint
ES
SAF
RS
PPS
Disposition
OR
OR
Compliance and exposure
OR
iPD
OR
Demographic/baseline 
characteristics
OR
Concomitant medication
OR
Primary endpoint and key 
secondary endpoint
EN-NRI, EN-NRI1
EN-BRI1, EN-EM1
EN-PC-NRI1
OC2, OC-IR2
EN-NRI1,
Secondary binary efficacy 
endpoints
EN-NRI, EN-NRI13
EN-BRI13
OC2, OC-IR2
Secondary continuous 
efficacy endpoints
EN-LOCF, EN-LOCF13
EC-MMRM1, EC-LOCF1
OC2, OC-IR2
Safety data
OR
OC-IE
OC-IR1
sensitivity/further analysis or subgroup analysis
2 descriptive display only
3 for secondary endpoints included in the testing strategy only
For explanation of the different approaches with regard to missing data see Section 6.6.
EN: Primary estimand for binary and continuous endpoints. Death or any use of escape medication, or OL Spesolimab use at 
D8, or rescue medication with Spesolimab, prior to observing the endpoint(s) is considered to represent a non-response in 
the analysis of this endpoint outcome.


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EN-PC: Alternative estimand for binary endpoints. Death or any use of escape medication, or OL Spesolimab use at D8, or 
rescue medication with Spesolimab, prior to observing the endpoint(s) is considered to represent a non-response in the 
analysis of this endpoint outcome. Any data after the use of restricted medication for other purpose will be censored. 
EN-ID8: Alternative estimand for binary and continuous endpoints. Death or any use of escape medication, or rescue 
medication with Spesolimab, prior to observing the endpoint(s) is considered to represent a non-response in the analysis of 
this endpoint outcome.
EC: Alternative estimand for continuous endpoint. Any data post escape medication use or OL Spesolimab use at D8, or 
rescue medication with OL Spesolimab will be censored.
EC-ID8: Alternative estimand for continuous endpoint. Any data post escape medication use or rescue medication with OL 
Spesolimab will be censored.
NRI, BRI, EM, LOCF and MMRM represent analyses involving imputed data, cf. Section 6.6.2.
OC = observed cases excluding values after any use of escape medication, or OL Spesolimab use at D8, or rescue 
medication with Spesolimab, OC-IR = observed cases including also values after any use of escape medication, or OL 
Spesolimab use at D8, or rescue medication with Spesolimab, OC-IE = observed cases excluding values after any use of OL 
Spesolimab use at D8, or any rescue medication with Spesolimab, OC-ID8 = observed cases excluding values after any use 
of escape medication, or rescue medication with Spesolimab.
OR = original results. 


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6.5
POOLING OF CENTRES
No particular analysis is planned.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Section 7.5 of the CTP describes the handling of missing data.


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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 for which 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. 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 in terms of the proportion of patients with a particular 
binary outcome, i.e. achievement of a GPPGA total score of 0 or 1. Then imputation is 
planned to take place only at the binary level, i.e., the GPPGA total score itself will not be 
imputed, but the binary endpoints derived based on these scores will be imputed, unless 
otherwise specified.
Binary efficacy endpoints for randomized dose at Day 1
The following primary imputation strategy ("NRI") will be performed after the 
implementation of the estimand concept:

For endpoints which are measured at multiple visits, if there are available data at the 
visits both before and after the visit with a missing outcome, then impute as a success 
only if both 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); 

Otherwise, impute as a failure to achieve a response (i.e. no response imputation).
Other imputation schemes will be also considered for the primary and secondary binary 
efficacy analyses included in the hierarchical testing procedure, including (see the footnote of 
Table 6.6.2: 1 for the definition of EN):

Best response imputation (BRI) after implementation of EN: impute all missing values 
based on the best response observed for the patient at visits prior to 
withdrawal/occurrence of missing data  (independent of whether the observations were 
selected for analysis based on time windows described in Section 6.7). If there is no non-


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missing data available (including baseline), then the missing value will be imputed as a 
non-response.

Exhaustive method (EM) (primary endpoint and key secondary endpoint only) for EN: If 
fewer than 3 patients have missing data on an endpoint at Week 1 then a list of all 
possible treatment differences will be generated whereby each of the potential responses 
(response, non-response) will be imputed for each patient in an exhaustive manner. The 
primary endpoint analysis will be repeated for each possible combination of imputed 
values on missing responses and the results will be summarized in a single table.   
In addition, the following methods will be implemented to display the data descriptively. 
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 any use 
of escape medication, or OL Spesolimab use at D8, or rescue medication with 
Spesolimab.
Observed cases including intercurrent events (OC-IR) approach is an extension of the 
OC approach which includes additionally all values which were measured after any use 
of escape medication, or OL Spesolimab use at D8, or rescue medication with 
Spesolimab.
With regard to the handling of missing data on the primary and key secondary binary efficacy 
endpoints at Week 1 and secondary binary efficacy endpoints at Week 4, which are included 
in the testing strategy, the following table gives an overview of the proposed estimand 
implementation and missing data imputation methods which are planned to be used.


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Table 6.6.2: 1 Handling of estimand and missing data on binary efficacy endpoints in testing 
strategy
Analysis 
or display 
method
Binary efficacy 
endpoint
observed or not
Estimand or display concept
Imputation 
method on 
missing data 
due to other 
reasons, i.e. 
withdrew 
consent, lost to 
follow up, data 
not collected,
etc.
[Week 1 and 4] 
Death, or use of 
escape medication, 
or [Week 4 only] 
OL Spesolimab use 
at D8 or rescue use 
with Spesolimab, 
prior to endpoint 
[Week 1 and 4] Use 
of restricted 
medication for other 
purpose 
EN-NRI
Observed/
Not observed
Non-response
Observed
NRI
EN-BRI
Observed/
Not observed
Non-response
Observed
BRI
EN-EM 
Observed/
Not observed
Non-response
Observed
EM
EN-PC-
NRI
Observed/ 
Not observed
Non-response
Censored and then 
imputed by NRI
NRI
OC
Observed 
Censored
Observed
n.a.
Not observed
No imputation
No imputation
No imputation
OC-IR
Observed 
Observed
Observed
n.a.
Not observed
No imputation
No imputation
No imputation
EN: Primary estimand for binary endpoint. For week 1, death or any use of escape medication, and, for week 4, death, or 
any use of escape medication, or OL Spesolimab use at D8, or any rescue medication with Spesolimab, prior to observing 
the endpoint(s) is considered to represent a non-response.
EN-PC: Alternative estimand for binary endpoint. For week 1, death or any use of escape medication, and, for week 4, death, 
or any use of escape medication, or OL Spesolimab use at D8, or any rescue medication with Spesolimab, prior to observing 
the endpoint(s) is considered to represent a non-response. Any data after the use of restricted medication for other purpose 
will be censored.
OC = observed cases excluding values after any use of escape medication, or OL Spesolimab use at D8, or any rescue 
medication with Spesolimab, OC-IR = observed cases including also values after any use of escape medication, or OL 
Spesolimab use at D8, or any rescue medication with Spesolimab.
"NRI", "BRI" and “EM” (Exhaustive method) mean analyses involving imputed data, cf. Section 6.6.2.
Continuous efficacy endpoints for randomized dose at Day 1
For the primary estimand of continuous endpoints, death or any use of escape medication, or 
OL Spesolimab at Day 8, or any rescue medication with Spesolimab, prior to observing the 
endpoint(s) is considered to represent a non-response. Here the outcome of “non-response” 
itself is not a missing value but is the worst possible outcome of the corresponding 


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continuous endpoint. See Section 7.5.2 for how to display continuous endpoint with both 
“non-response” outcome and other numeric continuous values.
The primary imputation strategy of missing values of continuous endpoints is LOCF after the 
implementation of estimand concept:

Impute the missing outcome as the last available value (including baseline) prior to the 
missing outcome; 
Wilcoxon rank test on secondary continuous endpoints:
For secondary continuous endpoints, a rank-based approach will be used for testing as below:
The best possible baseline values are the lowest value 0 for Pain VAS score and PSS score,
and the highest value 52 for FACIT-Fatigue scale score. The worst possible post-baseline 
values are the highest values 100 and 16 for Pain VAS score and PSS score respectively, 
and the lowest value 0 for the FACIT-Fatigue scale score. Therefore, the maximum value 
for the worst possible change from baseline (i.e., the worst possible post-baseline value –
the best possible baseline value) is 100 for Pain VAS, 16 for PSS, and -52 for the FACIT-
Fatigue scale. Furthermore, the maximum value for the worst percentage change from 
baseline in GPPASI at Week 1 and at Week 4 will be the highest observed percentage 
change from baseline of all patients with non-missing GPPASI at Week 1 or Week 4, 
which are denoted as PT1 and PT4 respectively. 
For Wilcoxon rank tests of the secondary continuous endpoints at week 1 or at week 4, worst 
case ranks will be assigned to those patients with death, or prior escape medication, or OL 
Spesolimab at D8, or rescue medication with Spesolimab cf. Section 7.5 of CTP. The ranking 
rules for the tests are outlined in Table 6.6.2: 2.


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Table 6.6.2: 2 Ranking rules for Wilcoxon rank tests of secondary continuous endpoint on 
EN
Category
Ranking
Case description
Imputed change
from baseline 
for further 
ranking score
1
Missing data at 
week 1/41 but still 
alive and no use of 
either escape
medication, OL
Spesolimab at D8 or 
rescue medication
with Spesolimab 
prior to Week 1/41.
Rank by imputed 
value
Patient has 
available data at 
visit prior to Week 
1/41
LOCF prior to 
Week 1/41
Patient has no 
prior available 
value
102 for Pain 
VAS
18 for PSS and 
-54 for FACIT-
Fatigue scale
PT1/PT4+2 for 
percentage 
change from 
baseline in 
GPPASI at Week 
1/4
2
Use of escape
medication, OL
Spesolimab at D8 or 
rescue medication
with Spesolimab 
prior to endpoint 
collection at Week 
1/41 but still alive.
Rank by OL
Spesolimab at D8 
or time to rescue 
medication or time
to escape 
medication from
randomized 
treatment.
Patient has OL 
Spesolimab at D8,
and has no escape 
medication, and no 
rescue medication 
prior to endpoint 
collection at Week 
4
104 for Pain 
VAS
20 for PSS 
-56 for FACIT-
Fatigue scale
PT4+4 for 
percentage 
change from 
baselines in 
GPPASI at Week 
4


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Table 6.6.2: 2 Ranking rules for Wilcoxon rank tests of secondary continuous endpoint on 
EN (cont’d.)
Category
Ranking
Case description
Imputed change
from baseline for 
further ranking 
score*
Patient has rescue 
medication with 
Spesolimab x 
days from 
randomized 
treatment., and 
has no escape 
medication prior 
to endpoint 
collection at 
Week 4
(independent of 
whether OL 
Spesolimab was 
administered at 
D8 or not)
106-x/1000 for 
Pain VAS
22-x/1000 for PSS 
-58+x/1000 for 
FACIT-Fatigue 
scale
PT4+6-x/1000 for 
percentage change 
from baseline in 
GPPASI at Week 
4
Patient has
escape 
medication y 
days after 
randomized 
treatment and 
prior to endpoint 
collection at
Week 1/41
(independent of 
whether OL 
Spesolimab was 
administered at 
D8 or not, or 
rescue 
medication was 
taken)
108-y/1000 for 
Pain VAS
24-y/1000 for PSS 
-60+y/1000 for 
FACIT-Fatigue 
scale
PT1/4+8-y/1000 
for percentage 
change from 
baseline in 
GPPASI at Week 
1/4


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Table 6.6.2: 2 Ranking rules for Wilcoxon rank tests of secondary continuous endpoint on 
EN (cont’d.)
Category
Ranking
Case description
Imputed change
from baseline for 
further ranking 
score*
3
Patient died before 
the measurement at 
Week 1/41
Ranked by time 
to death from 
randomized 
treatment.
Patient died z 
days after 
randomized 
treatment.
(independent of 
the occurrence of 
other events)
110-z/1000 for 
Pain VAS
26-z/1000 for PSS 
-62+z/1000 for 
FACIT-Fatigue 
scale
PT1/4+10-z/1000 
for percentage 
change from 
baseline in 
GPPASI at Week 
1/4
* Ranked values in this table are only for purpose of rank tests but not for any descriptive displays
1 For percentage change from baseline in GPPASI at week 1, the imputation rule is based on the data at week 1, but for other 
secondary continuous endpoints, it is based on the data at week 4. 
Other sensitivity analysis of continuous endpoints include an additional estimand (EC) 
whereby any data after use of escape medication/OL Spesolimab at D8/rescue treatment with 
Spesolimab will be censored. The following two methods may be used to handle the censored 
or missing data here:

A mixed effect model for repeated measurements (MMRM) will be used to handle
the missing cases implicitly. 

(For secondary continuous endpoints only) LOCF method will be used to impute the 
missing cases. 
In addition, OC and OC-IR methods will be implemented to display the data descriptively if 
needed. 
With regard to the handling of missing data on the secondary continuous efficacy endpoints 
at Week 4, which are included in the testing strategy, the following table gives an overview 
of the proposed estimand implementation and missing data imputation methods which are 
planned to be used.


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Table 6.6.2: 3 Handling of estimand and missing data on continuous efficacy endpoints in 
testing strategy
Analysis or 
display 
method
Continuous efficacy 
endpoint observed or not
Estimand or display 
concept
Imputation 
method on 
missing data 
due to other 
reasons, i.e. 
withdrew 
consent, lost 
to follow up, 
data not 
collected,
etc.
Death, or use of escape 
medication, or OL 
Spesolimab use at D8 or 
rescue use with 
Spesolimab, prior to 
endpoint 
EN-LOCF
Observed/ Not observed
Non-response
LOCF
EC-MMRM
Observed/ Not observed
Censored
MMRM
EC-LOCF
Observed/ Not observed
Censored then imputed 
by LOCF
LOCF
OC
Observed 
Censored
n.a.
Not observed
No imputation
No 
imputation
OC-IR
Observed 
Observed
n.a.
Not observed
No imputation
No 
imputation
EN: Primary estimand for continuous endpoint. Death or any use of escape medication or OL Spesolimab use at D8, or any 
rescue medication with Spesolimab, prior to observing the endpoint(s) is considered to represent a non-response. 
EC: Alternative estimand for continuous endpoint. Any data post escape medication use or OL Spesolimab at D8, or rescue 
medication with OL Spesolimab will be censored.  
OC-IR = observed cases including also values after any use of escape medication, or OL Spesolimab use at D8, or any 
rescue medication with Spesolimab
"LOCF” and “MMRM” mean analyses involving imputed data, cf. Section 6.6.2.


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6.6.3
Safety data
With respect to safety evaluations, it is not planned to impute missing values.
The following approaches will be used for the descriptive reporting. 

Observed cases including escape medication (OC-IE) approach will include all collected 
data after escape medication use, without imputation for any missing data. Such an OC-
IE approach will exclude all values measured after OL Spesolimab use at D8, or rescue 
medication with Spesolimab.

Observed cases including intercurrent (OC-IR) approach will be applied in the same 
manner as defined for the efficacy data (see Section 6.6.2).
The only exceptions where imputation might be necessary for safety evaluation are AE dates 
and, start and stop dates for concomitant medications. Missing or incomplete AE dates are 
imputed according to BI standards (4).
Partial start and stop dates for concomitant medications, and background, escape, as well as
historical medication for GPP will be imputed to enable subsequent calculation (but not for 
display) by the following "worst case" approach:

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 escape medication, 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 escape medication, 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.


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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.
Missing start dates of open-label treatment with Spesolimab on Day 8 will be set to date of 
the Day 8 visit (if consistent with any specification on the month and/or year), otherwise it 
needs to be assessed by the trial team on an individual basis. Missing end dates will be set to 
the same date as the start date.
Missing start dates of rescue treatment with Spesolimab for a GPP flare will be set to the date 
of occurrence of the applicable flare, the date being consistent with any specification on 
month and/or year of the rescue treatment; other situations need to be assessed by the trial 
team on an individual basis.
6.6.7
Time since first diagnosis
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows:


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
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.


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6.6.8
Disease characteristics
Incomplete information regarding disease characteristics will be imputed as follows:

For calculation of "date of diagnosis of most recent flare of GPP before the trial to Visit 
1", partial dates will be replaced with the first day of the month (if month and year are 
available, and not later than the month and year upon which Visit 1 was performed). 
Otherwise, the dates will not be replaced. Replacement will only be done for calculation.

For calculation of "start date of symptoms of current flare of GPP", partial dates will be 
replaced with the day of the first study treatment administration (if month and year are 
available, and are identical to the month and year upon which first study treatment 
administration was performed). Otherwise, the dates will not be replaced. Replacement 
will only be done for calculation.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline, unless otherwise specified, refers to the last measurement collected prior to the dose 
of randomized Spesolimab/placebo administered at Day 1 in the study. For the analysis of 
biomarkers (see Section 7.6.5) baseline refers to the last measurement prior to randomized 
treatment administered at Day 1 but not more than 5 days earlier.
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 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. 
Measurements taken after start of administration of trial treatment will be considered either 
on- or off-treatment values based on the definition in Section 6.1, and will be assigned to 
visits for statistical analysis, if applicable, as defined below.
Analysis of AE data, concomitant medications, recurrence of flares and of rescue/escape
medication use will not be based on visits therefore, no assignment to time windows will be 
necessary.
All other safety, efficacy 
 measurements will be assigned to visits based on 
time windows around the planned visit dates, defined relative to the day of first trial 
treatment, Day 1. These time windows are defined in Table 6.7: 1.


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Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs
to visits for statistical analysis
Visit 
number
Planned day
Time window
Visit label
Window (per CTP)
Start (extended)
End (extended)
2
Week 1, Day 1
Day 1
exact day
Day 1 A
Day 1 A
3
Week 1, Day 2
Day 2
exact day
Day 2
Day 2
4
Week 1, Day 3
Day 3
exact day
Day 3
Day 3
5 B
Week 1, Day 4
Day 4
exact day
Day 4
Day 4
6 B
Week 1, Day 5
Day 5
exact day
Day 5
Day 5
7 B
Week 1, Day 6
Day 6
exact day
Day 6
Day 6
8 B
Week 1, Day 7
Day 7
exact day
Day 7
Day 7
9E
Week 1, Day 8
Day 8
exact day
Day 8
Day 10
10
Week 2
Day 15
+/- 3 days
Day 11
Day 18
11
Week 3
Day 22
+/- 3 days
Day 19
Day 25
12
Week 4
Day 29
+/- 3 days
Day 26
Day 43
13
Week 8
Day 57
+/- 7 days
Day 44
Day 71
14
Week 12C
Day 85
+/- 7 days
Day 72
Day 99
Post Week 12 D
Day 100
Day 113
Off treatment D
Day 114
Day of last 
follow-up value
All days are counted relative to the day of randomized treatment, which is defined as Day 1.
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made 
after start of trial treatment) via assessment on date & time (i.e. safety laboratory) will not be assigned to Day 
1. Such data will be listed only.
B Since visits 5-8 are optional, the assessments (if any) will not be displayed in tables or figures only if 
otherwise specified.
C Patients who receive rescue treatment with OL Spesolimab between Wk7-Wk12 will not have scheduled V14, 
however if there is any unscheduled assessment between the defined extended time window for V14, it will be 
still used. 
D All tables and figures by visit will only report visits up to week 12 (if applicable). “Post Week 12” and “off 
treatment” won’t be used for any tables or figures.  
E For primary analysis visit (V9), only the assessments prior any non-randomized treatment will be used except 
for those pre-specified post-treatment assessments.  
Repeated and unscheduled efficacy, safety and other measurements will be handled similarly 
to scheduled measurements and will also be assigned to a time window depending upon the 
date of measurement. 
Notice that for EN, EN-PC and EN-ID8 estimands, any observation post intercurrent events 
of interests (i.e., death, escape medication or rescue medication with Spesolimab for all 3 
estimands or OL Spesolimab at D8 for EN and EN-PC only) will be set to be “non-response”. 
Further, within the extended time window of a visit, if the day of the intercurrent event is
prior to the date of planned visit, then a “non-response” observation will be assigned to that 
day. If the day of the intercurrent event is on or after the date of planned visit, then a “non-
response” observation will be assigned to that day only if there is no other observation on the 
same day, otherwise, no additional observation will be assigned. 


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Only one observation per time window will be selected for statistical analysis at a particular 
visit – the value which is closest to the protocol planned visit day will be selected. If there are 
two observations which have the same difference in days to the planned day, but which are 
not measured on the same day, the later value will be selected. If there are two observations 
on the same day, the worst value will be selected.
Assignment of observations to visits based on time windows will be based on the non-
imputed (observed) data after the implement of estimand concepts. For example, for EN 
estimand, values after death or use of escape medication, OL Spesolimab at Day 8 or rescue 
medication with Spesolimab should be set to be “Non-response” first before assignment of 
efficacy endpoints.
For visits without an assigned value based on time windows, a value will thereafter be 
imputed (if needed) as defined in Section 6.6. Imputation of efficacy endpoints, when 
applicable, will be performed based on all available observations meeting the imputation 
rules, irrespective of whether the observation was selected in any time window. 
Tables and figures presenting results of the statistical analysis will only display visits at 
which the respective parameter was planned to be collected according to the CTP. Note that 
Visits 5-8 are optional so they will not be displayed in tables and figures only if otherwise 
specified.


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7.
PLANNED ANALYSIS
Primary analysis of study will be performed once all patients have completed 12 weeks study 
period or early discontinue. A snapshot will be taken for the primary analysis and all patients’ 
data up to the cut-off date will be included into analysis. 
Final trial analysis is planned to be performed at the end of the study once all randomized 
patients have completed the study (including any follow-up period) if applicable. Additional 
but limited data after primary analysis snapshot will be listed in final analysis. 
A database lock for the primary analysis will be done and treatment will be un-blinded. In 
order to warrant the integrity of the treatment blind while the trial continues through 
completion, a logistics plan will be developed to describe the mechanisms that are to be put 
in place to assure that the patients and investigators remain blinded to both individual patient 
data, as well as the primary analysis results. The blind status of trial and project team 
members at this time will also be clarified. The logistics plan will be finalized prior to the 
treatment un-blind for the primary analysis. 
The primary analysis and final analysis may be performed as a single analysis (at the time of 
trial completion), if, prior to the time of the primary analysis, the trial team agrees that the 
expected time interval between the planned analyses is insufficient to justify the performance 
of separate analyses.
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (001-MCG-159) (10). The individual values of all patients will be 
listed. Listings will generally be sorted by country, center number, patient number and visit 
(if visit is applicable in the respective listing). AE listings will be sorted by assigned 
treatment (see Section 7.8.1 below for details). The listings will be contained in Appendix 
16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Q1
lower quartile
Median 
median
Q3
upper quartile
Max 
maximum
Statistical parameters will be displayed to a defined number of decimal places as specified in 
the BI guideline "Reporting of clinical trials and project summaries" (10). 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 


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respective treatment. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if there actually are missing values. Percentages will be based 
on all patients in the respective patient set whether they have non-missing values or not.
Disposition of the patient population participating in the trial will be summarized by the 
presentation of the frequency of patients screened, randomized, screened but not randomized, 
randomized but not treated, randomized and treated, who completed trial medication (on Day 
1), who were prematurely discontinued from trial medication (on Day 1), by reason, who 
completed participation in the trial, who were prematurely discontinued from trial, by reason, 
and who entered the extension trial 1368.25.
The frequency of patients with iPDs, also summarized by whether or not the iPD led to 
exclusion from the PPS, will be presented. The frequency of patients in each of the different 
analysis sets will also be presented.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. 
Descriptive statistics will be presented by treatment for demographic parameters and baseline 
characteristics, based on the RS. The presence of mutations (yes or no) in the following 
genotypes will be descriptively presented by treatment for the RS: IL36RN, CARD14, or, 
AP1S3 based on information collected via eCRF and the results for the DNA resequencing 
respectively.
Characteristics of the trial disease, including details on the current and past GPP flares prior 
to trial onset, will be displayed for randomized patients. Here the output for most recent flare 
will be based on “Disease Characteristics (Most Recent Flare prior to Consent)” eCRF page 
while other prior flares will be based on “Natural Medical History for GPP” eCRF page. 
For the continuous variables described below, the following categories will be defined, and 
presented according to the number and percentage of patients in each category:


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Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
< 50 years
50 to < 65 years
≧65 years
< 65 years
≧65 years
Weight
≤70 kg
>70 to ≤80 kg
>80 to ≤90 kg
>90 kg
BMI
< 25 kg/m2
25 to < 30 kg/m2
≧30 kg/m2
Time since first diagnosis
≤1 year
> 1 to ≤5 years
> 5 to ≤10 years
> 10 years
7.2
CONCOMITANT DISEASE AND MEDICATION
Only descriptive statistics are planned for this section of the report. Analyses of concomitant 
diseases and medication will be based on the RS.
Concomitant diseases (i.e. baseline conditions) and concomitant non-drug therapies will be 
coded according to the most recent version of MedDRA. Concomitant medications will be 
coded according to the most recent version of the World Health Organisation – Drug 
Dictionary.


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A medication/non-drug therapy will be considered concomitant to treatment, if it

is ongoing at the start of randomized trial treatment or

starts within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
A medication/non-drug therapy will be considered as prior medication/non-drug therapy, if 
the end date of the medication/therapy is at any time prior to the start of randomized trial 
treatment.
Concomitant medication use (excluding escape medications as defined in the CTP) will be 
summarized with frequency and percentage of patients by ATC3 class and preferred name. 
The frequency and percentage of patients with historical medication for GPP will be 
displayed, including presentation by type of historical medication (preferred name), and by 
reason for discontinuation. 
The frequency and percentage of patients taking either none or any background medication 
for GPP will be tabulated by type of background therapy (preferred name); a background 
therapy is assumed to be present if the medication is identified on the CONMED page of the 
CRF and is given for the purpose of disease under study (flagged as a background 
medication). 
Use of escape medication, treatment with OL Spesolimab at Day 8, or rescue treatment with 
Spesolimab will be summarised separately (see Section 7.6.3). An escape medication is
assumed if for any medication which is newly given for the disease under study and denoted 
for the purpose of escape use (disease worsening/not improved) per CONMED page of the 
CRF.
Concomitant use of non-drug therapies will be summarised with frequency and percentage. 
Summaries will be presented in the same manner as done for the concomitant medication use.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
Treatment compliance to the randomized study treatment will be summarised on Day 1 via 
dose intensity (as described in Section 5.4.6) for the SAF using descriptive statistics (N, 
mean, SD, minimum, median, maximum).
The number and percentage of patients with the following overall compliance categories will 
be presented:  
"< 80% of planned", 
">=80 of planned"


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7.4
PRIMARY ENDPOINT
The evaluation of patients achieving a GPPGA pustulation subscore of 0 at Week 1 is the 
primary endpoint of this trial. 
Death, or any use of escape medication prior to observing the primary endpoint(s) is 
considered to reflect a failure to achieve the endpoint outcome, i.e. non-response. In this 
concept, death, or any use of escape medication after the actual assessment time point of 
week 1 is not considered. If time is not collected, death or any use of escape medication on or 
after the actual assessment day of Week 1 is not considered.
The Suissa-Shuster Z-pooled test, will be implemented to test the treatment effect on the 
primary endpoint on the RS (estimand EN), at a 1-sided, alpha level of 0.025. Confirmation 
of efficacy is then given only if the null hypothesis on the primary endpoint is rejected. In the 
output, the result will be reported at 2-sided alpha level of 0.05 which is more common way 
in CTR but it is exactly same as 1-sided alpha level of 0.025. Confidence intervals (95%) 
around the risk difference will be produced using the Chan and Zhang method (6).
Example SAS code for Suissa-Shuster Z-pooled test is as follows:  
PROC FREQ DATA=data;
TABLES treat*endpoint_bin;
EXACT BARNARD (column=2); 
RUN;
Example SAS code for CI of proportion difference by Chan and Zhang method is as follows:
PROC FREQ DATA=data;
<WHERE treat IN (’Treatment_1’,’Treatment_2’);>
TABLES treat*endpoint_bin / RELRISK RISKDIFF;
EXACT RELRISK (METHOD=SCORE column=2) RISKDIFF (METHOD=SCORE 
column=2);
RUN;
Graphical displays (Line plots) of the response on primary endpoint will be produced over 
time (with 95% confidence intervals based on the Wilson score) up to, and including, Visit 14 
(Week 12).
Secondary analysis for the primary endpoint will include:

A sensitivity analysis utilizing the PPS;

Sensitivity analyses on the RS which utilize alternative methods for the handling of 
missing data as described in Section 6.6.2.

Analysis of an additional estimand (EN-PC) whereby death or any use of escape 
medication, prior to observing the week 1 primary endpoint will be considered to 


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represent a non-response. For patients who use restricted medication for other purpose 
prior to Week 1, data will be censored for further analysis following the restricted 
medication use and imputed using NRI method as described in Section 6.6.2.

Sensitivity analyses on the RS to adjust for the potential covariates, IL36R mutation 
status (Yes vs No) and baseline GPPGA total score (3 vs 4) respectively.
The proportion of patients with a response between Spesolimab and placebo will be 
analysed by IL36R mutation status and baseline GPPGA total score (3 vs 4) 
respectively, using a logistic regression approach with a logit link via PROC 
LOGISTIC in SAS®. Fixed classification effects will include treatment, subgroup and 
treatment-by-subgroup interaction term. 
The estimates from the logistic regression are on the logit scale, and the difference in 
proportions will be calculated as the difference between the predicted probabilities by 
subgroup level and treatment on the original scale.
Descriptive subgroup displays on the primary endpoint (via estimand EN) will be done for 
the applicable subgroups as defined in Section 6.4 using the RS. 
7.5
SECONDARY ENDPOINT
7.5.1
Key Secondary endpoint
The treatment effect on the key secondary endpoints will be tested in a hierarchical manner 
subsequent to the test of the primary endpoint. The key secondary endpoint on the patients 
achieving a GPPGA score 0 or 1 at Week 1 will be analyzed in the same way as primary 
endpoint. 
7.5.2
Secondary endpoints
Secondary endpoints included in the testing procedure
The treatment effect on the following secondary endpoint will be tested in a hierarchical 
manner as a part of the pre-specified testing strategy (see Section 7.2 of the CTP), subsequent 
to the test of the primary endpoint and key secondary endpoint:
1) The proportion of patients achieving a GPPASI 75 at Week 4, 
2) The change from baseline in pain VAS score at week 4, 
3) The change from baseline in PSS score at week 4, and,
4) The change from baseline in the total FACIT-Fatigue score at Week 4. 
GPPASI 75 at Week 4


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The primary analysis for the proportion of patients achieving a GPPASI 75 at Week 4 will be 
performed using the same approach as that defined for the primary analysis of the primary 
endpoint, based on the RS (estimand EN).
Graphical displays will be produced using the same method as described for the primary 
endpoint.
Sensitivity analysis for GPPASI 75 at Week 4 will include: 

Sensitivity analyses on the RS which utilize BRI respectively for the handling of missing 
data as described in Section 6.6.2.
Descriptive subgroup displays (via estimand EN) will be done for the applicable subgroups as 
defined in Section 6.4 using the RS. 
Pain VAS score, PSS score, and FACIT-Fatigue score at Week 4
For the analysis of each of the continuous secondary endpoints which are included in the 
statistical testing strategy, the following approach will be done:
Any assessments after death, or the use of escape medication, or OL Spesolimab at D8, or 
rescue medication with Spesolimab, will be considered as “non-response” and assigned with 
worst outcome for the analysis (estimand EN). In this concept, death, or any use of escape 
medication or OL Spesolimab at Day 8 or of rescue medication with Spesolimab after the 
actual endpoint assessment time point at week 4 is not considered. If time is not collected, 
death, or any use of escape medication or of rescue medication with Spesolimab on or after 
the actual assessment day of Week 4 is not considered. 
In primary analysis of the secondary continuous endpoints, “non-response” itself is not a 
missing value but the worst possible outcome of the endpoint. The mean of the endpoints 
could not be reported due to the mix of “non-response” outcomes and other numeric
continuous outcomes. The Q1, median and Q3 could be still reported, however, where “non-
response” will be treated as the worst outcome in the rank. If the proportion of “non-
response” is high enough, Q1, median and Q3 of the endpoint could all be reported as “non-
response”. For example, for a continuous endpoint where larger value indicates the better 
outcome, if the achieved data is (NR, NR, NR, NR, NR, NR, 2, 3, 3, 3, 5) where NR=”non-
response”, then Q1 is NR, median is NR and Q3 is 3.
For each secondary continuous endpoint, the effect of Spesolimab will be evaluated by a 
Wilcoxon rank test using the RS. All details regarding the ranking rules for Wilcoxon test are 
defined in Section 6.6.2.
Example SAS code for Wilcoxon rank test is as below:
proc NPAR1WAY data=data wilcoxon;
        class treatment;
        var endpoint;
        exact wilcoxon;


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   run;
The difference between treatments, based on the RS, will be displayed using a modified
Hodges-Lehmann (HL) estimate of the median difference (11). If a patient has died or used 
escape medication, or OL Spesolimab at D8, or rescue medication with Spesolimab prior to a 
timepoint (i.e., Week 4), then the patient’s assessment at that timepoint (i.e., Week 4) will be 
treated as “non-response” in HL estimation. Otherwise, missing data at that timepoint (i.e., 
Week 4) will be imputed using LOCF method. The modification of the HL estimate is that all 
NR-NR comparisons on a patient level will be excluded from the calculation since they do 
not provide any information about the numerical estimate and they have no clear 
‘positioning’ when calculating the median. Further the difference between a non-missing 
value and a non-response status should be ‘large positive’ or ‘large negative’, depending on 
the direction. A 95% confidence interval around the modified HL estimate of the median 
treatment difference will also then be calculated, adjusting for the reduced number of 
comparisons (due to exclusion of the NR-NR outcomes). Graphical displays of the modified 
HL estimate of the median treatment difference (with and without 95% confidence intervals) 
will be produced over time. For clarity, a full description of the modified HL method is 
defined as follows:
For each of the secondary continuous endpoints in the testing procedure, assume that the 
continuous response vector in Placebo arm is (x1, x2, …, xn) and the continuous response 
vector in Spesolimab arm is (y1, y2, …, ym), where n is the number of patients in Placebo 
arm and m is the number of patients in Spesolimab arm. 
Step 1, In line with the standard HL approach, calculate the difference between every 
possible pair of x’s and y’s; dij=yj-xi. There will be a total of m times n such differences. 
For the modified version, all NR-NR comparisons are then discarded from the calculation, 
that is, mn-l comparisons will be performed (where l is the number of NR-NR
comparisons). Note that all comparisons between a non-response and a measurement are 
still retained. The remaining values in the list of dij will then be ranked in ascending order 
and the median from the list will be picked as the modified HL estimate.
Step 2, Compute the rank of the lower confidence limit as 
RL=

 
−". $(&&)
 
where ".  is the z-value corresponding to a one sided 
97.5% confidence interval, m’= () −*)/, and n’=m’n/m and noting that m’n’=mn-l.
If RL is a non-integer, it needs to be rounded down. The rank of the upper confidence 
limit will be RU=m’n’-RL+1. If the obtained RL or RU is not a possible value, then it 
should be rounded to the nearest possible value. 
Step 3, Look up the values that corresponding to the ranks RL and RU in the remaining 
values in the ranked list of dij. These are the confidence limits for HL estimate. 
Note that if the overall non-response rate across two arms is too high (i.e., >30%), the 
modified HL estimate will be no longer robust and therefore will not be displayed. 


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Descriptive statistics, based on RS (OC) and RS (OC-IR), will be produced, and will include 
n, mean, SD, min, median, and max for the individual treatment groups.
Sensitivity analysis for each of the continuous secondary endpoints will include an additional 
estimand (EC) whereby any data post use of escape medication/OL Spesolimab at D8/rescue 
treatment with Spesolimab will be censored. Two methods will be used to handle the 
censored or other missing values respectively:

MMRM method (EC-MMRM),
Continuous endpoints up to week 4 will be evaluated using an MMRM model 
accounting for the following sources of variation: ‘baseline’, ‘visit’ and ‘treatment’ as 
covariates, ‘visit*treatment’ and ‘visit*baseline’ as interaction effects as well as the 
random ‘subject’ effect. The unstructured covariance structure will be used to model the 
within patient measurements. To estimate denominator degrees of freedom the 
Kenward-Roger approximation will be used. 
It is expected most of patients on placebo arm may receive escape medication up to Day 
8 or OL Spesolimab at Day 8. Based on “EC” estimand, then most placebo data post 
Day 8 may have been censored. To avoid achieving the estimates which are not robust, 
if from certain visits, the values of more than 70% patients are censored or missing for 
one treatment arm, then MMRM estimates won’t consider the data from that time point 
for that arm. 
In the event of any model non-convergence, the methods described in Section 9.2 will be 
utilized to resolve this. 
Example SAS code for MMRM is as below:
PROC MIXED DATA=alldat cl method=reml; 
  CLASS visit trt subject; 
  MODEL ept = visit*trt base*visit / ddfm=kr s CL; 
  REPEATED visit / subject= subject type=un r rcorr; 
  LSMEANS visit*trt / pdiff=all om cl alpha=0.05 slice=visit; 
RUN;
Results of the MMRM (N, mean, SE and 95% CI per dose group and timepoint) will be 
presented in tables and displayed graphically.

LOCF method (EC-LOCF).
In addition, subgroup displays will be done for the applicable subgroups as defined in Section 
6.4 using the RS in the following two ways:

Descriptive statistics using primary EN estimand and impute missing values using LOCF 
method. 

MMRM method using EC estimand,


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Subgroup analysis will use MMRM model based on the alternative estimand (EC). A 
single MMRM model will be fitted involving all terms from the above EC-MMRM 
model in the sensitivity analysis except replacing the treatment-by-visit term by the 
treatment-by-subgroup-by-visit term. 
To avoid achieving the estimates which are not robust, if from certain visits, the values 
of more than 70% patients are censored or missing across all subgroup levels for one 
treatment arm, then MMRM estimates won’t consider the data from that time point for 
all subgroups of that arm. 
In the event of any model non-convergence, the methods described in Section 9.2 will be 
utilized to resolve this. 
Secondary endpoints not included in the testing procedure
For the binary secondary endpoints (either at week 1 or at week 4) that, are not included into 
the statistical testing strategy, graphical displays and statistical testing using the Suissa-
Shuster Z-pooled test will be performed using the primary estimand and imputation strategy
(EN-NRI), as described for the primary endpoint in Section 7.4.
For the continuous secondary endpoints, the percentage change in GPPASI from baseline at 
Week 1 and Week 4, which are not included into the statistical testing strategy, the analysis 
will be performed using the same method as for the secondary continuous endpoints in the 
testing strategy. All details regarding the ranking rules for Wilcoxon rank tests are defined in 
Section 6.6.2 (and Table 6.6.2: 2).


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7.7
EXTENT OF EXPOSURE
The number of subjects who received a dose of randomized trial drug will be tabulated. The 
duration of infusion [in minutes] and the amount of treatment received [mg] will be 
summarised by descriptive statistics (N, mean, SD, minimum, Q1, median, Q3, maximum) on 
Day 1. 
The number and percentage of patients according to the duration of infusion will also be 
classified according to the following categories:
Duration of infusion [min] categories
Duration "< 60 min",
Duration ">=60 min to < 120 min",
Duration ">=120 min to < 240 min",
Duration ">= 240 min".
The above will also be summarized for the open-label treatment with Spesolimab provided on 
Day 8, as well as for the rescue treatment with Spesolimab.
7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the SAF following BI standards. No 
hypothesis testing is planned.
Primary analysis for safety data
The primary safety analysis will be done based on data through the first 12 weeks of 
treatment (i.e., up to Day 85)). 
In the primary safety analysis, OC-IE method will be used whereby data after actual time of 
intake of (optional) open-label Spesolimab on Day 8, or rescue medication with Spesolimab 
for treatment of a GPP flare will be censored for reporting. 
Since the onset time of an AE will not be collected in the trial, any AE which occurs on the 
same day as the first dose of randomized trial medication (Day 1) will be, conservatively, 
assigned to the on-treatment period. Any AE which occurs on the same day as the first dose 
of a non-randomized Spesolimab medication administration (i.e. for OL D8, or for rescue) 
will be assigned to the period commencing on the day of use of the non-randomized 
Spesolimab treatment. For safety assessments by visits (except for local tolerability or post-
treatment vital signs), if time is not collected, data on the same day of (optional) open-label 
Spesolimab on Day 8, or rescue medication with Spesolimab for treatment of a GPP flare will 
not be excluded.
In addition, all AE tables will be repeated up to Week 1 and up to the end of REP of the 
randomized treatment at Day 1 respectively.
Further analysis for safety data


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In further analysis of safety data, AEs of patients will be reported by treatments and their 
starting time periods relative to the use of randomized treatment at Day 1, OL Spesolimab at 
Day 8 and rescue medication with Spesolimab (see Section 6.1). That is to say, one patient 
may be counted in multiple treatment periods as defined below based on the use of 
randomized treatment at Day 1, OL Spesolimab at Day 8 and rescue medication with 
Spesolimab. In addition, AEs of patients post any use of randomized or non-randomized 
Spesolimab are summarized where two arms will be pooled:

“Prior non-rand. Speso ”(i.e. TEAE starting before use of any non-randomized 
Spesolimab are considered)

“Post OL Speso at D8” (i.e. TEAE starting post OL dose at Day 8 but before rescue 
medication with Spesolimab if applicable are considered)

“Post rescue with Speso” (i.e. TEAE starting post rescue medication with 
Spesolimab are considered)

“Post any Speso” (i.e. TEAE starting post any randomized or non-randomized 
Spesolimab are considered where two arms will be pooled)
Descriptive summaries of all AE and potentially clinically significant abnormal Lab values
will be repeated up to the end of REP of any of randomized treatment at D1 or non-
randomized Spesolimab.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA. Patients will be analyzed 
according to the actual treatment received.
The exposure adjusted incidence rate (per 100 subject years) of a selected treatment emergent 
adverse event is defined as the number of subjects experiencing the adverse event per 
treatment group during time at risk divided by the total time of subjects at risk in that 
treatment group to contribute the event to the analysis multiplied by 100 (per 100 subject 
years).
Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with AE / 
Total AE-specific time at risk [subject years].
For analysis up to Week 1, Week 12 and the end of REP of randomized drug:
Time at risk [subject years] = (date of onset of TEAE up to the end time of risk–
randomized study drug start date + 1) / 365.25
The end time of risk will be the min (day of death, randomized drug stop date + X days, the 
day prior to OL Spesolimab at Day 8, the day prior to rescue medication with Spesolimab, the 
day prior to first dose in the extension study if patient will be rolled over or last contact date 


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per EoS page if patient will not be rolled over). Here X equals to 6, 84 and 112 for analysis 
up to Week 1, Week 12 and the end of REP of randomized drug respectively. 
For the further analysis on safety data, 
Time at risk prior to non-randomized Spesolimab/ post OL Spesolimab at Day 8/post 
rescue medication with Spesolimab [subject years] = (date of onset of TEAE up to the 
end time of risk – randomized treatment date/Day 8 / date of rescue use of Spesolimab
+ 1) / 365.25
End of time at risk prior to any non-randomized Spesolimab will be the min of (Day 113 or 
the day prior to any non-randomized Spesolimab, last contact date per EoS page if patient 
will not be rolled over or the day prior to first dose in the extension study if patient will be 
rolled over). 
End of time at risk post OL Spesolimab at Day 8 will be the min of (Day 8 Spesolimab date
+112 or the day prior to the use of rescue medication with Spesolimab or the last contact date 
per EoS page if patient will not be rolled over or the day prior to first dose in the extension 
study if patient will be rolled over). 
End of time at risk post use of rescue medication with Spesolimab will be the min of (the day 
of rescue medication with Spesolimab in the trial +112 or the last contact date per EoS page 
if patient will not be rolled over or the day prior to first dose in the extension study if patient 
will be rolled over).
In addition, for overall period post use of any Spesolimab,
Time at risk overall post use of any Spesolimab [subject years] = (date of onset of 
TEAE up to the end time of risk – first use of any Spesolimab start date + 1) / 365.25
End of time at risk for overall post use of any Spesolimab will be min of (the day of last 
Spesolimab in the trial +112 or the last contact date per EoS page if patient will not be rolled 
over or the day prior to first dose in the extension study if patient will be rolled over).
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
exposure adjusted incidence rates (per 100 subject years), as well as the number of patients 
with AEs and not on the number of AEs. System organ classes (if applicable) will be sorted 
according to the standard sort order specified by the EMA, preferred terms (if applicable) will 
be sorted by total frequency (within system organ class) across all treatment columns, cf. 
Section 6.1.
For further details on summarization of AE data, please refer to "Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries" (7) 
and "Handling of missing and incomplete AE dates" (4). 
The analysis of AEs will be based on the concept of treatment emergent AEs. This means that 
all AEs will be assigned to the screening phase, treatment phase or follow-up phase as 


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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 randomized Spesolimab/placebo administration will be 
assigned to the on-treatment period.
An overall summary of AEs will be presented. This overall summary will include summary 
for the class of AESIs.
The following are considered as AESIs (see Sec 5.2.6.1 of CTP):

Hepatic injury

Systemic hypersensitivity reactions including Infusion reactions and anaphylactic 
reaction

Severe infections (according to RCTC grading in the ISF)

Opportunistic and mycobacterium tuberculosis infections
The investigator identified AESI will be captured from the eCRF and reported as 
“Investigator reported AESI” table. In addition, user defined adverse event concepts 
(UDAEC) identified through specific search criteria will be reported separately (cf. Table 
7.8.1: 1).


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Table 7.8.1: 1 Project MedDRA search criteria for User Defined Adverse Event Concepts
User-defined AE category
Label 
Description
Infections 
(serious/severe, 
opportunistic)
Infections ALL
Combined search strategy based on the individual 
UDAECs described below; the UDAEC “severe
infections (investigator-defined) will be disregarded 
for this search
Opportunistic 
infections
Narrow SMQ “Opportunistic infections”
Tuberculosis 
infections
BIcMQ “Infections”:
Narrow sub-search 8.2 “Tuberculosis related terms”
Serious 
infections
all serious events in SOC “Infections and
infestations”
Severe 
infections
all events in SOC “Infections and infestations” of at 
least severe RCTC grade, by HLGT
Hypersensitivity
Hypersensitivity 
ALL
Combined search strategy based on the three 
individual UDAECs described below
Anaphylactic 
reaction
Narrow SMQ “Anaphylactic reaction”
Angioedema
Narrow SMQ “Angioedema”
Hypersensitivity
Narrow SMQ “Hypersensitivity”
Malignancies
Malignant 
tumours
Narrow Sub-SMQ “Malignant tumours”
Narrow Sub-SMQ “Haematological malignant 
tumours”
Narrow Sub-SMQ “Non-Haematological malignant 
tumours”
Malignant skin 
tumours
Broad Sub-SMQ “Skin malignant tumours”
Skin melanomas
HLT Skin melanomas (excl. Ocular)
Non-melanoma 
skin cancer 
(NMSC) 
Broad Sub-SMQ “Skin malignant tumours”
excluding HLT Skin melanomas (excl. Ocular)


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Table 7.8.1: 1  Project MedDRA search criteria for User Defined Adverse Event Concepts
(cont’d.)
User-defined AE category
Label 
Description
Malignancies 
excluding 
NMSC 
Sub-SMQ “Malignant tumours”  excluding 
NMSC, whereas NMSC is defined above
3-point MACE
3-point MACE
BIcMQ “Major Adverse Cardiovascular Events” with  
  Narrow sub-search 1.1 “3-Point MACE (part 1/2)” 
  Narrow sub-search 1.2 “3-Point MACE (part 2/2)” *
Torsades de 
Pointes
Torsades de 
Pointes
Broad sub-SMQ “Torsade de pointes/QT 
prolongation”
* 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
According to ICH E3 (9), the sponsor has defined AEs which are to be classified as ‘other 
significant’. For the current trial, these will include those non-serious AEs which were 
reported with ‘action taken = Drug Withdrawn’ or ‘action taken = Dose Reduced’.
The exposure-adjusted incidence rate and frequency of patients with AEs will be summarized 
by treatment, primary system organ class and preferred term. AEs and serious AEs which 
were considered by the investigator to be drug related will be summarized separately. 
Separate tables will also be provided for patients with SAEs, patients with AEs leading to 
study drug discontinuation, patients with AEs leading to death, patients with AESIs, patients 
with other significant AEs (derived based upon ICH E3 (9)), UDAEC and serious UDAEC 
(cf. Table 7.8.1: 1) . AEs will also be summarized by maximum intensity.
For disclosure of AE data on ClinicalTrials.gov and EudraCT register respectively, the 
additional AE tables will be produced per requirements. 
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (8). 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.
Normalization means transformation to a standard unit and to a standard reference range. The 
process of normalization, 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 (8). All analyses considering multiple times of the 
ULN (as described below) will be based on standardized and not normalized values. For 
continuous safety laboratory parameters, differences to baseline (see Section 6.7) will be 
calculated.


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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.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be based upon normalized values and provided by visit (including follow 
up), including the last value on treatment, the minimum value on treatment and maximum 
value on treatment. Graphical displays via box plots will be produced for the change from 
baseline, over time, for each continuous laboratory endpoint.
Laboratory values will be compared to their reference ranges; a shift table will be provided 
for the number of patients with a specific RCTC grade at baseline and at the last 
measurement on treatment, as well as the worst grade on treatment. These analyses will be 
based on standardized laboratory values. Potentially clinically significant abnormalities will 
be identified based on BI standard rules which are based on normalized converted lab values, 
i.e. using SI units. These rules will be listed in the SDL appendix of the CTR. Frequency 
tables will summarize the number of patients with potentially clinically significant 
abnormalities. Patients having an abnormal lab value at baseline will be presented separately.
A separate listing will present potentially clinically significant abnormal lab values; for each 
functional lab group all patients' lab values will be listed, if there exists at least one lab value 
with clinically significant abnormality within the group.
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥10xULN, and 
≥20xULN will be displayed based on standardized laboratory values.
To support analyses of liver related adverse drug effects, the frequency of patients with AST 
and/or ALT and/or AP≥3xULN plus 2 times the baseline with concomitant or subsequent 
total bilirubin ≥2xULN plus 1.5 times the baseline 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.
Two graphical analyses of ALT and total bilirubin during the on-treatment period will be 
performed; the so-called eDISH plot. The first graph will include all patients in the SAF,
while the second graph will only include those patients who do not show ALT/AST values 
with changes from baseline <2 x baseline and bilirubin values with changes from baseline 
<1.5 x baseline in SAF. For each graph, the peak total bilirubin is presented as a fold increase 
over the ULN against the peak ALT as a fold increase over the ULN, on a log10 scale. The 
measurements displayed for total bilirubin and ALT may, or may not, occur on the same date.
Two reference lines, 2xULN for total bilirubin and 3xULN for ALT, are drawn onto the 
graph in order to divide the plane into four quadrants. Normal cases are in the lower left 
quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law quadrant), while the 
lower right quadrant is known as the Temple’s corollary range (ALT ≥ 3xULN and total 
bilirubin < 2xULN).


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Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate), body temperature, 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 during 
the on-treatment period, the minimum value during the on-treatment period, and the 
maximum value during the on-treatment period (see Table 6.1:1 for definition of the on-
treatment period). Graphical displays via box plots will be produced for the change from 
baseline, over time, for each continuous vital sign endpoint.
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 analyzed 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 analyzed as 
such. No separate listing or analysis of ECG data will be prepared.
7.8.5
Local Tolerability
Local Tolerability will be summarized, by visit, with the frequency and percentage of patients 
who experienced any symptom by type and intensity.


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7.9
ANALYSIS OF COVID19 IMPACT
There is currently an outbreak of respiratory disease, COVID-19 worldwide which has 
impacted the conduct of this trial. This public health emergency has raised more difficulties 
for patients to meet protocol-specified procedures, including administering or using the 
investigational product or adhering to protocol-mandated visits and laboratory/diagnostic 
testing. Site personnel or trial subjects are also under the risk to get infection with COVID-
19. 


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Consequently, there are unavoidable protocol deviations due to COVID-19 illness and/or 
COVID-19 public and individual health control measures. To assess the impact on patients’ 
safety and drug efficacy in this trial, the following analyses are planned:
Disposition, PD and iPD:
Frequency of the patient with missing visits or early discontinuation due to COVID-19 will 
be listed. PDs and iPDs related to COVID-19 will be also listed if any. 
AE based on the periods of COVID-19 disruption
To assess whether there was any potential change in AE assessment during the COVID-19 
disruption, AEs prior the disruption and post the disruption will be reported separately. It will 
include the following AE tables:

Overview on TEAE

TEAE by SOC, preferred term

SAE by SOC, preferred term

UDAEC
The start date for the COVID-19 disruption is chosen to be 1st March 2020. 
In addition, if there is any case, COVID-19 infection will be reported separately. 
7.10
HANDLING OF DMC ANALYSES
A fully external DMC, independent of the trial and project teams, will be set-up to review all 
available un-blinded safety data as well as selected efficacy data at regular intervals 
following first-patient-in. A separate DMC SAP which describes the analyses required for 
assessment by the DMC will be produced. Further details are provided in a DMC charter.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Statistical Principles for Clinical Trials, current 
version
2
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”,
current version; IDEA for CON
3
BI-KMED-COPS-TMP-0001: "Important Protocol Deviation (iPD) log", current
version; IDEA for CON
4
BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE dates",
current version; IDEA for CON
5
001-MCS-36-472: “Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics”, current version, Group “Biostatistics & 
Data Sciences”, IDEA for CON
6
Chan I S F, Zhang Z. “Test‐based exact confidence intervals for the difference of 
two binomial proportions”[J]. Biometrics, 1999, 55(4): 1202-1209.
7
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON
8
BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data",
current version; IDEA for CON
9
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
10
BI-KMED-BDS-HTG-0045: "Standards for Reporting of Clinical Trials and Project
Summaries", current version; IDEA for CON.
11
R20-2984: Hodges Jr J L, Lehmann E L. Estimates of location based on rank 
tests[J]. The Annals of Mathematical Statistics, 1963: 598-611.
12
001-MCS-40-413_RD-00: "List of References to SOP Identify and Mange
Important Protocol Deviations (iPD)", current version; IDEA for CON
13
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):811-9.
14
R18-1989: Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: 
Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS 
Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire 
(SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale 
(SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain 
(ICOAP). Arthritis Care Res (Hoboken). 2011;63 Suppl 11:S240-52.


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15
R18-1990: Rentz AM, Skalicky AM, Burslem K, Becker K, Kaschinski D, Esser 
D, et al. The content validity of the PSS in patients with plaque psoriasis. J Patient 
Rep Outcomes. 2017;1(1):4.
16
17
001-MCG-741: "Clinical subgroup analyses for local and regional Populations in 
Asia - Clinical Bridging Study Waiver (BSW) and Descriptive Subgroup Analysis 
(SGA) Reports”, current version; IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
Author
Sections 
changed
Brief description of change
1
18-JAN-19
None
This is the final TSAP.
2
10-NOV-20
All
Per CTP amendment 2, update primary 
and key secondary endpoints. 
All
Per CTP amendment 2, add sample size 
and update testing method.
All
Per CTP amendment 3, add further 
endpoints for randomized treatment 
All
Section 6.1
The first dose of OLE trial was 
considered to define the analyses phase of 
this trial.
Section 6.1
Section 7.8
Further analysis on safety data including 
REP of any non-randomized Spesolimab
are updated. 
Section 6.2
Minor changes on iPD categories. 
Section 6.6.2
Remove MI for missing data per CTP 
amendment 3. 
Update the ranking rules for Wilcoxon 
ranking tests for continuous endpoints.
Section 6.7
Update rules to assign the time windows. 
Section 7
Add the timeline for primary and final 
analyses per CTP amendment 3. 
Section 7.4
Add sensitivity analysis for primary 
endpoint per CTP amendment 3
Section 7.5.2
Add sensitivity analyses for continuous 
endpoints and refine the wording. 
Section 7.8.6
Elaborate analysis on Immunogenicity
Section 7.8.7
Add subgroup analysis of AE
Section 7.9
Add analysis for the impact of COVID 19


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Table 10.1        History table (cont’d.)
Version
Date
Author
Sections 
changed
Brief description of change
3
22-Dec-2020
Section 4
Section 4
If central lab are not available, the eCRF 
results will be used 
 
Section 6.7 
Section 7.8.1
Remove important risk as the UDAEC 
are not identified risks, and 3-point 
MACE and Torsades de Pointes are 
added