Clinical trial NCT04015518
Conditions: Palmoplantar Pustulosis (PPP)
Sponsor: Boehringer Ingelheim
Start date: 2019-07-31; Completion date: 2021-07-28
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to provide dose-ranging data for 4 dose regimens of BI 655130 compared to placebo on the primary endpoint of percentage change from baseline in PPP ASI at Week 16. The target dose(s) will be estimated from the model by incorporating information on the minimum clinically relevant effect and accounting for safety.

Supportive dose-ranging assessments will also be done on pre-specified secondary endpoints.

Detailed description:

Arms: arm 1: Subcutaneous injections of placebo matching Spesolimab, with subcutaneous injections of Spesolimab starting at week 16, for a total treatment time of 52 weeks. arm 2: Subcutaneous injections of Spesolimab in a low dose scheme for a total treatment time of 52 weeks. arm 3: Subcutaneous injections of Spesolimab in a medium-low dose scheme for a total treatment time of 52 weeks. arm 4: Subcutaneous injections of Spesolimab in a medium-high dose scheme for a total treatment time of 52 weeks. arm 5: Subcutaneous injections of Spesolimab in a high dose scheme for a total treatment time of 52 weeks.
Interventions: intervention 1: Spesolimab intervention 2: Placebo intervention 3: Spesolimab intervention 4: Spesolimab intervention 5: Spesolimab intervention 6: Spesolimab
Intervention descriptions: intervention 1: Subcutaneous injections of Spesolimab starting at week 16, for a total treatment time until week 52. intervention 2: Subcutaneous injections of placebo matching Spesolimab from week 0 to 16. intervention 3: Subcutaneous injections of Spesolimab in a low dose scheme for a total treatment time of 52 weeks. intervention 4: Subcutaneous injections of Spesolimab in a medium-low dose scheme for a total treatment time of 52 weeks. intervention 5: Subcutaneous injections of Spesolimab in a medium-high dose scheme for a total treatment time of 52 weeks. intervention 6: Subcutaneous injections of Spesolimab in a high dose scheme for a total treatment time of 52 weeks.

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (16.0) / Saved on: 30 Aug 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c18863881-01
EudraCT No.
EU Trial No.
2018-003078-28
BI Trial No.
1368-0016
BI Investigational
Medicinal Product(s)
BI 655130
Title
Multi-center, double-blind, randomised, placebo-controlled, phase 
IIb dose-finding study to evaluate efficacy and safety of different 
subcutaneous doses of BI 655130 in patients with moderate to 
severe Palmoplantar Pustulosis (PPP)
Lay Title
A study to test how effective and safe different doses of BI 655130 
are in patients with a moderate to severe form of the skin disease 
Palmoplantar Pustulosis
Clinical Phase
Phase IIb
Clinical Trial Leader
Phone: 
Fax: 
Coordinating 
Investigator
Phone: 
Fax: 
Status
Final Protocol
Version and Date
Version: 1.0
Date: 03 Apr 2019
Page 1 of 112
Proprietary confidential information.
2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
03 Apr 2019
Revision date
BI trial number
1368-0016
Title of trial
Multi-center, double-blind, randomised, placebo-controlled, phase IIb 
dose-finding study to evaluate efficacy and safety of different 
subcutaneous doses of BI 655130 in patients with moderate to severe 
Palmoplantar Pustulosis (PPP)
Coordinating 
Investigator
Trial site(s)
Multi-center trial
Clinical phase
IIb
Trial rationale
The trial rationale is to demonstrate proof-of-concept with respect to a 
non-flat dose response curve and to define a suitable dose range for 
BI 655130 regarding efficacy and safety for further pivotal testing in 
Phase III in patients with PPP.
Trial objective(s)
The primary objective is to provide dose-ranging data for 4 dose 
regimens of BI 655130 (with each regimen consisting of a loading 
and a separate maintenance subcutaneous dose) compared to placebo. 
The target dose(s) will be estimated from the model by incorporating 
information on the minimum clinically relevant effect and accounting 
for safety.
The additional objectives are to explore long-term efficacy, safety and 
tolerability of multiple dose regimens of BI 655130 in patients with 
PPP.
Trial endpoints
The primary endpoint to assess efficacy of BI 655130 is % change in 
PPP ASI (Palmoplantar Pustulosis Area and Severity Index) from 
baseline at Week 16.
Secondary endpoints:

Change from baseline in Pain Visual Analogue Scale (VAS) score 
at Week 4 and 16

PPP SI change from baseline at Week 16

PPP ASI50 at Week 16

PPP ASI75 at Week 16

PPP PGA clear/almost clear at Week 16

PPP PGA pustules clear/almost clear at Week 16

Percent change in PPP ASI from baseline at Week 52


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Trial design
Placebo-controlled, double-blind, randomised, parallel-design 
comparison of 5 arms over 52 weeks
Total number of patients
randomised
140
Number of patients on 
each treatment
40/20/20/20/40 per arm
Diagnosis
Palmoplantar Pustulosis defined as primary, persistent (>3months 
duration), sterile, macroscopically visible pustules on the palms 
and/or soles, without or with plaque psoriasis elsewhere on the body
Main in- and exclusion 
criteria

Male or female patients, 18 to 75 years of legal age (according to 
local legislation) at screening

Diagnosed with Palmoplantar Pustulosis with a minimum 
PPP ASI score of 12 and PPP PGA of at least moderate severity
(≥3), both at screening and baseline

Presence of white or yellow pustules on palms and/or soles at 
screening and baseline

Pustular severity score ≥2 in at least one region and ≥10 well-
demarcated pustules (white or yellow pustules) across all regions 
at screening and baseline 

Patients with a reduction in PPP ASI total score ≥ 5 from 
screening (Visit 1) to baseline (Visit 2) are excluded
Test product(s)
BI 655130
dose
Arm 1:
Arm 2:
Arm 3:
Arm 4:
mode of 
administration
Subcutaneous (s.c.)
Comparator product(s)
Placebo
dose
Arm 5:
mode of
administration
Subcutaneous (s.c.)


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Duration of treatment
52 weeks
Statistical methods
The primary analysis consists of a combination of MCPMod-based 
testing (with respect to a non-flat dose response curve) and an 
evaluation of the dose-wise benefit at Week 16. As a basis for the
MCPMod analysis a mixed effect model for repeated measurements 
(MMRM) is used. 
The MCPMod procedure allows for simultaneous evaluation of 
different potential dose response patterns, whilst protecting the 
overall probability of Type I error. The pre-specified models and their 
parameters used for this test are outlined in Section 7.2.2.


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FLOW CHART
Trial Periods
Screen-
ing1
Randomised Treatment Period
Post 
Treatment 
FU
Loading
Maintenance
Visit
1
22
3
4
5
6
7
8
9
PE3
10
11
12
13
14
15
16
17
18
EOT4
19
20
EOS4
Week
-4 to -2
1
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
60
68
Day
-28 to
-14
1
8
±2
15
±2
22
±2
29
±2
57
±7
85
±7
113
±7
141
±7
169
±7
197
±7
225
±7
253
±7
281
±7
309
±7
337
±7
365
±7
421 
±7
477
±7
Informed Consent
x
In/exclusion criteria
x
x
Demographics, BC 
/Medical History5
x
x
Physical Examination6
xC
xT
xT
xT
xT
xT
xT
xT
xT
xT
xT
xT
xT
xT
xT
xT
xT
xC
xT
xC
Height and weight
x
x
Vital Signs7
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Smoking Status / History
x
x
x
12-lead ECG
x
x
x
x
x
x
x
x
Pregnancy Testing8
xs
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
x
u,(s)
Safety Laboratory
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Infections Testing9
x
x
ADA / Nab11
x
x
x
x
x
x
x
x
x
x
x
x
x
DNA banking (optional)12
x


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Trial Periods
Screen-
ing1
Randomised Treatment Period
Post 
Treatment 
FU
Loading
Maintenance
Visit
1
22
3
4
5
6
7
8
9
PE3
10
11
12
13
14
15
16
17
18
EOT4
19
20
EOS4
Week
-4 to -2
1
2
3
4
8
12
16
20
24
28
32
36
40
44
48
52
60
68
Day
-28 to
-14
1
8
±2
15
±2
22
±2
29
±2
57
±7
85
±7
113
±7
141
±7
169
±7
197
±7
225
±7
253
±7
281
±7
309
±7
337
±7
365
±7
421 
±7
477
±7
PPP ASI / PPP SI14
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
PPP PGA, 
 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Photos of skin lesions
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Pain VAS, 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Skin biopsy (optional)18
x
x
IRT call19
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Administer study drug20
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Local tolerability
x
x
x
x
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
x
x
x
x
x
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Study completion
x4


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1 The time window for Visit 1 may be extended at the discretion of the Clinical Trial Manager (CT Manager) in conjunction with the Clinical Trial Leader (CT Leader) on a case by case basis.
2 Day of Randomisation / Day of first administration of randomised trial medication.
3 PE = Primary Endpoint Visit.
4 EOT = End of Treatment; EOS = End of Study. If the patient withdraws from the trial prematurely following randomisation, instructions in Sections 3.3.4 and 6.2.3 should be followed. 
5 Demographics, BC = Baseline Conditions and Medical History. For details please see Section 6.2.1.
6 Physical examination; C = complete; T = targeted (focus on evaluation of organ systems associated with AE(s) symptoms or laboratory abnormalities). For details please see Section 5.2.1.
7 Vital signs will be assessed predose and at dosing visits additionally 10 mins postdose and 1 hour after the end of study drug administration. For details please see Section 5.2.2.
8 Pregnancy testing is applicable only for women of childbearing potential (WOCBP; for the definition please refer to Section 3.3.3). S = serum pregnancy test (performed at screening).
U = urine pregnancy tests will be performed at all other visits. Urine pregnancy testing should be done prior to administration of study drug. Study drug should only be administered in case of 
a negative test result. (S) - in case of a positive urine pregnancy test, a serum pregnancy test will be done.
9 For details on infections testing at baseline and EOT visit (or early discontinuation visit, if applicable) please refer to Table 5.2.3: 1.
10 All
 samples will be collected within approximately 2 hour period prior to the study drug administration. For details please see Section 5.3.
11 ADA / Nab = Anti-Drug Antibody / Neutralizing Antibody
12 Desoxyribo Nucleid Acid (DNA) banking sample is optional. This sampling is only possible if the patient agreed by signing a separate informed consent. For details please see Section 5.5.
13 If not possible at Visit 2, the whole blood sampling for DNA re-sequencing may also be collected during a later visit. For details please see Section 5.4.
14 PPP ASI = Palmoplantar Pustulosis Area and Severity Index. Additionally, Palmoplantar Pustulosis Severity Index (PPP SI) will be calculated based on PPP ASI components. For details 
please see Sections 5.1.1 and 5.1.10, and Appendices 10.1.1 and 10.1.10.
18 Skin biopsy is an optional procedure and not a prerequisite for the participation in this trial. Skin biopsy is only allowed for patients who have consented for this procedure. For details please 
refer to Section 5.4.1 and the skin biopsy manual.
19 Interactive Response Technology (IRT) call at the screening visit indicates that a patient is in screening. IRT calls at dosing visits assign medication numbers.
20 Administration of the study drug must be performed by a healthcare professional. Drug will be administered after PPP assessments. For the sequence of procedures please see Section 6.2. For 
details on the 4 subcutaneous injections (prefilled syringes) per dosing visit please refer to Section 4.1.5.1.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
DRUG PROFILE................................................................................................16
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................21
1.4
BENEFIT - RISK ASSESSMENT.....................................................................22
1.4.1
Benefits.................................................................................................................22
1.4.2
Risks .....................................................................................................................22
1.4.3
Discussion.............................................................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........26
2.1.1
Main objectives....................................................................................................26
2.1.2
Primary endpoint(s)............................................................................................26
2.1.3
Secondary endpoint(s) ........................................................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................28
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................28
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................29
3.3
SELECTION OF TRIAL POPULATION .......................................................30
3.3.1
Main diagnosis for trial entry ............................................................................30
3.3.2
Inclusion criteria .................................................................................................30
3.3.3
Exclusion criteria ................................................................................................31
3.3.4
Withdrawal of patients from treatment or assessments..................................32
3.3.4.1
Discontinuation of trial treatment .........................................................................32
3.3.4.2
Withdrawal of consent to trial participation .........................................................33
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................33
4.
TREATMENTS...................................................................................................34
4.1
INVESTIGATIONAL TREATMENTS ...........................................................34
4.1.1
Identity of the Investigational Medicinal Products..........................................34
4.1.2
Selection of doses in the trial and dose modifications......................................34
4.1.3
Method of assigning patients to treatment groups...........................................36
4.1.4
Drug assignment and administration of doses for each patient......................36


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4.1.5
Blinding and procedures for unblinding...........................................................36
4.1.5.1
Blinding.................................................................................................................36
4.1.5.2
Unblinding and breaking the code ........................................................................37
4.1.6
Packaging, labelling, and re-supply...................................................................37
4.1.7
Storage conditions...............................................................................................38
4.1.8
Drug accountability.............................................................................................38
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................38
4.2.1
Other treatments and emergency procedures..................................................38
4.2.2
Restrictions ..........................................................................................................39
4.2.2.1
Restrictions regarding concomitant treatment ......................................................39
4.2.2.2
Restrictions on diet and life style..........................................................................41
4.2.2.3
Contraception requirements..................................................................................41
4.3
TREATMENT COMPLIANCE........................................................................42
5.
ASSESSMENTS..................................................................................................43
5.1
ASSESSMENT OF EFFICACY........................................................................43
5.1.1
Palmoplantar Pustulosis Area and Severity Index (PPP ASI)........................43
5.1.2
Palmoplantar Pustulosis Physician Global Assessment (PPP PGA)..............43
5.1.3
Pain VAS (Visual Analogue Scale) ....................................................................43
5.1.10
Palmoplantar Pustulosis Severity Index (PPP SI) ...........................................46
5.2
ASSESSMENT OF SAFETY.............................................................................47
5.2.1
Physical examination ..........................................................................................47
5.2.2
Vital signs.............................................................................................................48
5.2.3
Safety laboratory parameters ............................................................................48
5.2.4
Electrocardiogram ..............................................................................................50
5.2.5
Other safety parameters.....................................................................................51
5.2.6
Assessment of adverse events.............................................................................51
5.2.6.1
Definitions of AEs ................................................................................................51
5.2.6.1.1
Adverse event........................................................................................................51
5.2.6.1.2
Serious adverse event............................................................................................51
5.2.6.1.3
AEs considered “Always Serious”........................................................................52
5.2.6.1.4
Adverse events of special interest.........................................................................52
5.2.6.1.5
Intensity (severity) of AEs....................................................................................53
5.2.6.1.6
Causal relationship of AEs....................................................................................53
5.2.6.2
Adverse event collection and reporting ................................................................54


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5.2.6.2.1
AE Collection........................................................................................................54
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................54
5.2.6.2.3
Pregnancy..............................................................................................................55
5.5
BIOBANKING ....................................................................................................57
5.6
OTHER ASSESSMENTS...................................................................................57
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................57
6.
INVESTIGATIONAL PLAN.............................................................................58
6.1
VISIT SCHEDULE.............................................................................................58
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................58
6.2.1
Screening and run-in period(s)..........................................................................58
6.2.2
Treatment period(s)............................................................................................60
6.2.3
Follow-up period and trial completion..............................................................60
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................61
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................61
7.2
PLANNED ANALYSES.....................................................................................62
7.2.1
General considerations .......................................................................................62
7.2.2
Primary endpoint analyses.................................................................................63
7.2.3
Secondary endpoint analyses .............................................................................65
7.2.5
Safety analyses.....................................................................................................67
7.2.7
Interim Analyses .................................................................................................68
7.3
HANDLING OF MISSING DATA ...................................................................68
7.4
RANDOMISATION ...........................................................................................69
7.5
DETERMINATION OF SAMPLE SIZE .........................................................69
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........73
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................73
8.2
DATA QUALITY ASSURANCE ......................................................................74
8.3
RECORDS...........................................................................................................74
8.3.1
Source documents ...............................................................................................74


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8.3.2
Direct access to source data and documents.....................................................75
8.3.3
Storage period of records ...................................................................................75
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................76
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........76
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................76
8.6
TRIAL MILESTONES.......................................................................................76
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................77
9.
REFERENCES....................................................................................................79
9.1
PUBLISHED REFERENCES............................................................................79
9.2
UNPUBLISHED REFERENCES......................................................................82
10.
APPENDICES.....................................................................................................83
10.1
INSTRUCTIONS FOR USE..............................................................................83
10.1.1
Palmoplantar Pustulosis Area and Severity Index (PPP ASI)........................83
10.1.2
Palmoplantar Pustulosis Physician Global Assessment (PPP PGA)..............83
10.1.3
Pain Visual Analogue Scale (VAS) ....................................................................84
10.1.3.1
Pain VAS because of PPP on the palms and/or soles (PPP Pain VAS)................84
10.1.3.2
Pain VAS for muscular or joint pain.....................................................................84
10.2
DIAGNOSIS OF ANAPHYLAXIS .................................................................109
10.3
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (OMERACT) ......................................110
10.4
SMOKING HISTORY BASED ON CALCULATION OF PACK YEARS111
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................112


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ABBREVIATIONS
ADA
Anti-Drug Antibody
ADCC
antibody-dependent cellular cytotoxicity
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AS
Ankylosing Spondylitis
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
CDC
complement-dependent cytotoxicity
Cmax
Maximum Concentration
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Desoxyribo Nucleid Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOT
End of Treatment
EOS
End of Study
EudraCT
European Clinical Trials Database
FAS
full analysis set
FC
Flow Chart


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FU
Follow-up
GCP
Good Clinical Practice
GPP
Generalized Pustular Psoriasis
HIV
human immunodeficiency virus
i.v.
intravenous
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITE
indirect target engagement
LPLT
Last Patient Last Treatment
LOCF
Last observation carried forward
MCID
Minimal clinically important difference
MCPMod
multiple comparison procedure with modelling techniques
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
mixed effect model for repeated measurements
MRD
Multiple Rising Dose
Nab
Neutralizing Antibodies
PAO
Pustulotic arthro-osteitis
PBO
Placebo
PCS
Physical Component Summary
PD
Pharmacodynamics
PoC
Proof of Concept
PoCC
Proof of Clinical Concept
PPP
Palmoplantar Pustulosis
PPP ASI
Palmoplantar Pustulosis Area and Severity Index
PPP PGA
Palmoplantar Pustulosis Physician Global Assessment


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PPP SI
Palmoplantar Pustulosis Severity Index
PPS
per-protocol set
PRO
Patient Reported Outcome
q4w
every four weeks
q8w
every eight weeks
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
RNA
Ribo Nucleid Acid
s.c.
subcutaneous
SAE
Serious Adverse Event
SAF
safety analysis set
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TEAE
Treatment Emergent Adverse Events
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
VAS
Visual Analogue Scale 
vs
versus
WBC
white blood count
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
The target indication is Palmoplantar Pustulosis (PPP), a disease with a high unmet medical 
need. PPP is a chronic disease and a form of pustular psoriasis (as is Generalized Pustular 
Psoriasis, GPP). Recent evidence suggests that PPP and GPP are genetically distinct from 
chronic plaque psoriasis as the major genetic determinant PSORS1 for plaque psoriasis has 
not been found in PPP and GPP patients [R16-3560; R16-3546]. Gene expression [R16-3543]
and human genetic [R16-3553, R15-1421, R16-0950, R16-3544] and clinical data imply that 
the IL36 pathway (targeted by BI 655130) drives the pustular psoriasis diseases of PPP and 
GPP [P19-01888, R16-0950, R16-3561, R16-3544].
PPP may be considered a rare disease. PPP is characterised by the presence of sterile pustules 
on palms and/or soles [R16-0927], in some cases evolve from vesicles [R19-0961]. Despite 
the limited area of skin involvement in PPP, the disease is very debilitating with a large 
impact on quality of life including ability to work. PPP symptoms include pruritus, burning 
sensations, and pain. In severe cases, the skin affliction makes walking or other activities of 
daily living challenging if not impossible. No approved treatment is available for PPP except 
for guselkumab in Japan, further highlighting the high need for an effective treatment option. 
PPP can be associated with plaque psoriasis elsewhere on the body. 
Genetic human studies have established a link between IL36R signalling and PPP: The same 
hypomorphic missense mutation in IL36RN reported for GPP [R16-0950; R16-3561] has also 
been observed in PPP, albeit to a lesser extent as compared to GPP [R16-3544].
Further genetic linkage between PPP and the IL36 pathway has been recently disclosed. For 
example, mutations in other genes linked to the IL36 pathway such as CARD14 [R16-3544] 
and AP1S3 [R16-0928] have been linked to the pathogenesis of all forms of pustular psoriasis 
including PPP. CARD14 is specifically and predominantly expressed in keratinocytes in the 
skin. It acts downstream of the IL36 pathway and is a known activator of NF-kB signalling. 
Mutations in the coding sequence (c.11T>G and c.97C>T) in AP1S3 have been linked to the 
pathogenesis of all forms of pustular psoriasis including PPP. The gene encodes a subunit of 
the AP-1 complex. Functionally the occurrence of these rare mutations causes a destabilizing 
of the AP-1 complex and could be linked to impaired Toll-like receptor 3 signalling and 
subsequent expression of the anti-inflammatory mediator IFN-β [R16-0928].
It is planned to enroll PPP patients irrespective of their mutation status of these three genes. 
However the genotypes of all patients will be determined in order to investigate the influence 
of their genetic background on the result of BI 655130 treatment.
Currently there is no standard of care available for the treatment of PPP (i.e., no approved 
therapy except for guselkumab in Japan). PPP is notoriously difficult to treat. Patients usually
end up being treated with the currently available systemic treatment options including 
retinoids, PUVA, methotrexate, ciclosporine and topical corticosteroids. Unfortunately, these 
options are usually not effective in reducing duration and severity of PPP.


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Thus, there is high unmet medical need for PPP.
Secukinumab (anti-IL17A; EU), ANBO19 (IL36R mAb), along with BI 655130, are the only 
treatments currently being tested in the clinic for the PPP indication. Guselkumab has been 
recently approved for the treatment of PPP in Japan. No other anti-IL36R treatments are 
known to have been tested or are being tested in the clinic in PPP.
BI 655130 will target as a first in class compound the IL36 pathway which is genetically 
linked to PPP disease pathogenesis and will be investigated in the clinical program for 
treatment of PPP, a disease with significant unmet medical need.
1.2
DRUG PROFILE
Mode of action
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R
signalling. Binding of BI 655130 to IL36R is anticipated to prevent the subsequent activation 
of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-
inflammatory and pro-fibrotic pathways with the aim to reduce epithelial cell/ fibroblast/ 
immune cell-mediated inflammation and interrupt the inflammatory response that drives 
pathogenic cytokine production in inflammatory skin diseases including generalized pustular 
psoriasis (GPP), palmoplantar pustulosis (PPP) and atopic dermatitis, and inflammatory 
bowel disease (IBD).
Key pharmacokinetic characteristics
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. Overall, 
PK data so far suggests target-mediated drug disposition (TMDD) kinetics for BI 655130.
The effective half-life of BI 655130 is approximately 4 weeks in the linear dose range in 
healthy volunteers and approximately 3 weeks in GPP patients. For details please see the IB.
Drug interactions
There is no information available. A drug interaction study is planned within the ulcerative 
colitis program.
Residual Effect Period
The Residual Effect Period (REP) of BI 655130 is 16 weeks. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
The consideration behind the REP derivation is that the half-life of ~4 weeks for BI 655130 
was observed in the healthy volunteer SRD study of 1368.1. However, in the patient trial 
1368.11 where BI 655130 was tested in GPP patients, the effective half-life was 23.9 days, ie. 
~3.4 weeks. Therefore 16 weeks would correspond to approximately 5 half-lives in patients, 
after which time most drug will have been cleared and only less than 3.125% of BI 655130 
will still be available. 
Data from non-clinical studies


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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 peripheral blood mononuclear cells 
(PBMCs) 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 (haematology, 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.
Data from clinical studies
Studies in Healthy Volunteers
BI 655130 or placebo (PBO) was administered to 78 healthy volunteers at single ascending 
i.v. doses from 0.001 mg/kg to 10 mg/kg body weight (1368.1). Safety and tolerability of all 
tested i.v. doses was good. There were no drug-related Serious Adverse Events (SAEs). 
Adverse Events (AEs) categorized as related to treatment were observed in 3/19 (15.8%) 
subjects in the placebo group and in 7/59 (11.9%) subjects treated with BI 655130. The most 
frequent treatment-emergent AEs were nasopharyngitis (BI 655130: 21%; PBO: 15%), 
headache (BI 655130: 9%; PBO: 15%), influenza like illness (BI 655130: 7%; PBO: 10%), 


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and diarrhoea (BI 655130: 3%; PBO: 10%). There were two AEs of moderate intensity 
(injection site haematoma, headache), all remaining AEs were of mild intensity. There was no 
apparent relationship between the frequency of AEs and the dose. There were no relevant 
changes compared to placebo for laboratory safety, including clinical chemistry, 
haematology, coagulation parameters, and urinalysis. No clinically relevant changes were 
observed in 12-lead ECGs, vital signs, and cardio-monitoring. 
PK analysis showed that exposure (AUC0-tz and Cmax) to BI 655130 increased with 
increasing dose in an approximately dose-proportional manner from 0.3 to 10 mg/kg. The 
effective half-life of BI 655130 is approximately 4 weeks in the linear dose range. Overall, 
PK data so far suggests target-mediated drug disposition (TMDD) kinetics for BI 655130. 
Anti-drug antibodies (ADA) were detected in 8 patients, 3 of those had pre-existing levels. 
Pharmacodynamic effects in this first in human (FIH) single rising dose (SRD) trial 
[c03361085-07] were assessed by indirect target engagement (ITE) of IL36R by BI 655130 
using an ex-vivo whole blood stimulation assay. All doses higher than 0.001 mg/kg were 
biologically active, corresponding to the minimum anticipated biological effect level, 
MABEL. 
In a multiple rising dose (MRD) trial (1368.2), 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 once 
weekly (qw) for 4 weeks (i.e. 4 administrations) or a single dose of 20 mg/kg (8 subjects 
each, 3:1 on active or PBO). Overall, BI 655130 was well tolerated. There were no dose 
dependent AEs, AEs considered to be dose limiting and no SAEs. In all cases the AEs were 
of mild or moderate intensity. Furthermore, there were no clinically relevant abnormalities on 
treatment with BI 655130 with respect to safety laboratory, vital signs, or ECGs as assessed 
by a central reader. Importantly, based on the analysis of the ITE studies, more than 90% of 
peripheral IL36R was engaged for at least 22 weeks after the last application of four weekly
doses. For further details and most recent results refer to the current Investigator`s Brochure 
[c03320877].
Study 1368.3 explored pharmacokinetics as well as safety and tolerability of a subcutaneous 
formulation of BI 655130 at two different dose strengths of 150 mg (1 mL) and 300 mg 
(2 mL) using an open-label, single dose, parallel group, matched pair design to determine the 
relative bioavailability of the 300 mg s.c. compared to one single 300 mg i.v. dose of 
BI 655130. In this study, 36 healthy male and female subjects have been treated with 
BI 655130, with 12 subjects per dose group. 35 subjects completed the study per protocol, 
one subject discontinued for logistical reasons (work-related issues). 
Although the evaluation of the study is still ongoing, the local tolerability of the s.c. 
formulation can be considered as well tolerated. Following an s.c. injection of 150 mg of 
BI 655130, there were two cases of redness and one case of swelling at the injection site in 12 
subjects dosed. For the 300 mg s.c. dose there was one further report of redness in 12 subjects 
dosed. All local events were of mild intensity, occurred within 30 minutes after injection and 
completely resolved within 4 hours. There were no reports of injection site pain.
The type, intensity and duration of systemic adverse events were similar to what has been 
observed in the preceding SRD/MRD studies 1368.1 and 1368.2. Most of the AEs were of 
mild intensity, there were no AEs considered to be dose limiting, and no SAEs. One subject 
in the 300 mg i.v. group discontinued during the infusion due to a panic attack, another one in 


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the 300 mg i.v. group discontinued his participation two months after dosing for personal 
reasons.
In 1368.9 trial, 32 healthy Japanese male subjects were enrolled in 4 dose groups comprising 
8 subjects per group. The study consisted of three dose groups receiving single rising 
intravenous doses of BI 655130 (300 mg, 600 mg, and 1200 mg) and one dose group 
receiving single subcutaneous doses of BI 655130 (300 mg). In each dose group, 6 subjects 
received BI 655130 and 2 subjects placebo.
Treatments were administered in a double-blind fashion within dose groups. In total, 
24 subjects received BI 655130 and 8 subjects placebo. Three subjects in the 600 mg i.v. 
group (1 of them allocate to placebo) and 1 subject in the 1200 mg i.v. group discontinued the 
trial prematurely due to personal reasons.
A total of 3 out of 18 subjects (16.7%) on intravenous doses of BI 655130 (1 subject per i.v. 
dose level) were reported with an AE compared with 2 out of 8 subjects (25%) on placebo. 
No subject was reported with an AE following subcutaneous administration of BI 655130. 
Adverse events by preferred term reported on placebo were vomiting, chest comfort, and 
allergic rhinitis, while AEs reported on BI 655130 were upper respiratory infection (300 mg 
i.v.), contusion (600 mg i.v.), gastroenteritis (1200 mg i.v.), and temporomandibular joint 
syndrome (1200 mg i.v.). None of the observed AEs were judged by the investigator as 
related to the trial medication.
Studies in Patients
In a multi-center, open-label single arm phase I study (1368.11) to investigate safety, 
tolerability, pharmacokinetics, pharmacogenomics, and efficacy of a single intravenous dose
of BI 655130 (10 mg/kg) in patients with an acute flare of Generalized Pustular Psoriasis 
(GPP), 7 patients were treated. This trial could 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.
In a multi-center, double-blind, randomised, placebo-controlled, phase IIa study (1368.15) to 
investigate efficacy, safety, tolerability, pharmacokinetics and pharmacogenomics of multiple 
intravenous doses of BI 655130 in patients with Palmoplantar Pustulosis (PPP), 59 patients 
were randomised and treated with BI 655130 for 12 weeks. This trial showed a good safety 
and tolerability profile (see IB for details).
1368.15 was a double-blind, randomised and placebo-controlled trial with 59 patients that 
was intended to explore safety, tolerance, PK and efficacy in PPP patients. Patients were 
enrolled in Europe and Canada and randomised in a 1:1:1 allocation ratio and received either 
900 mg BI 655130, 300 mg BI 655130 or placebo intravenously every 4 weeks over a period 
of 12 weeks and were monitored for up to 32 weeks.
As there are currently no established nor validated endpoints available to specifically assess 
clinician- or patient reported outcomes in PPP, several endpoints were explored in this proof 
of concept trial. The endpoints included a PPP-specific PASI (ppPASI = PPP ASI in the 
nomenclature of trial 1368-0016) where induration was replaced with pustulation, as the 
sterile pustule is the primary component of PPP (as it is in GPP), while the scaling and 
erythema components remained unchanged. The primary efficacy endpoint was PPP ASI50 at 
Week 16. 


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As PPP is a neutrophilic dermatosis characterised by sterile pustules on palms and soles and 
in light of the rapid response observed on pustule clearance in trial 1368.11 (GPP), change 
from baseline in pustule severity was also included in the efficacy assessment. The focus on 
pustules allows to specifically address the impact and benefit of BI 655130 treatment on PPP 
disease. 
Overall, the baseline disease severity within the trial population was lower than expected 
because few patients with severe disease were enrolled in the trial. More specifically, half of 
the patients had a PPP ASI total score at baseline ≤16.70, which was close to the minimum 
required PPP ASI score of 12 for inclusion. The proportion of patients who achieved 
PPP ASI50 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). 
However, post-hoc subgroup analyses indicated efficacy of both doses of BI 655130 in 
patients with more severe PPP disease at baseline (above the median PPP ASI value of 16.7). 
In particular, the results on pustule severity were pronounced with a rapid reduction in 
pustule severity with evidence of a dose response relationship (Figure 1.2: 1). In the same 
subgroup, a mean percent reduction from baseline in PPP ASI has been observed. For details 
please see the current Investigator´s Brochure, c03320877.
Figure 1.2: 1: Mean of change from baseline (%) in pustule severity of PPP ASI (average 
across regions) by baseline PPP ASI score (> median of 16.7) over time – FAS (LOCF)
Summary
BI 655130 is an anti IL36R antibody with a high clinical activity to block IL36R signalling, 
as demonstrated in patients with GPP and PPP. IL36R inhibition shows a favorable
nonclinical safety profile in healthy volunteers and in patients tested. BI 655130 has been 


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tested in healthy volunteers with single or multiple dosing up to 4 weeks of 20 mg/kg i.v. qw, 
in GPP patients (1368.11 trial, N=7 in a single i.v. dose of 10 mg/kg) and in PPP patients 
(1368.15 trial, N=59, i.v. doses 300 mg and 900 mg every 4 weeks) which were all safe and 
well tolerated.
For a more detailed description of the BI 655130 profile, please refer to the current 
Investigator’s Brochure (IB) [c03320877].
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 655130 is in development for the treatment of Palmoplantar Pustulosis. The rationale of 
this trial is to demonstrate proof of concept with respect to a non-flat dose response curve and 
to define a suitable dose range for BI 655130 regarding efficacy and safety for further pivotal 
testing in phase III in patients with PPP. For this purpose, a multiple comparison procedure 
with modelling techniques (MCPMod) approach is considered.
The rationale to perform this trial is based on the proof-of-concept, phase IIa trial 1368.15. In 
this trial, the intravenous regimens proved activity. More pronounced clinical effects were 
seen in patients with higher disease activity (as shown in Fig 1.2: 1). By optimised inclusion 
criteria, it is intended to recruit in this trial patients with a higher disease intensity with a
focus on fresh pustulation and the requirement to have a certain threshold of fresh pustulation 
(see Inclusion criteria).
As there is high prevalence of PPP in Japan, evidence for phenotypic differences (clear 
pustular phenotype with no association with plaque psoriasis, focal infection as a trigger, and 
association with pustulotic arthro-osteitis, PAO) and treatment efficacy observed with 
guselkumab in Japan [R19-0861], a proof-of-concept is planned to be evaluated in Japan in 
this trial and therefore the trial will be stratified (Japan vs non-Japan).
Of note, the studies so far have a deficiency in being either exclusively Japan (guselkumab) 
or exclusively non-Japan (secukinumab) [R19-0676, R19-0677, and R19-0678]. 
We restrict further exploration of BI 655130 in this indication to a subcutaneous formulation
to better meet the needs of patients and a good alignment with the primary dermatology care 
treatment procedures. The pharmacokinetics and pharmacodynamics of different 
subcutaneous loading and maintenance dose regimens of BI 655130 in patients with PPP will 
be investigated.
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). 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.


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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Preclinical profiles of BI 655130 and clinical data from healthy volunteer and patient trials 
suggest that BI 655130 is safe, tolerable and may address an unmet medical need in PPP 
patients by an anti-inflammatory mechanism of action, cf. Section 1.2 and the IB 
[c03320877]. The data from the completed PoC trial 1368.11, in patients with an acute flare 
of generalized pustular psoriasis (GPP), 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. This and the data from 1368.15 indicates 
that BI 655130 inhibits IL36R signalling also in human disease and thus has the potential to 
be further investigated also in PPP patients (see Section 1.2 and IB).
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, please refer to the IB 
Section 5.1.2 [c03320877].
A total of more than 212 subjects have been exposed to single or multiple i.v. doses of 
BI 655130 as of September 2018 (see IB). BI 655130 was safe and well tolerated in four 
healthy volunteers trials evaluating the i.v. and s.c. formulation.
In trial 1368.15 there were no clinically relevant abnormalities on treatment with BI 655130 
with respect to safety laboratory and vital signs. BI 655130 was well tolerated and no safety 
signal was identified. For details refer to IB [c03320877].
1.4.2
Risks
There are no identified or potential risks for BI 655130, based on the toxicology program or 
any clinical trials conducted for this product to date (see also Section 1.2). No other IL-36 
receptor antagonist is currently approved, providing information on identified risks in 
molecules of this class.
The risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs.
In order to protect the patient’s safety during conduct of this trial, an independent Data 
Monitoring Committee has been established for the periodic review of clinical trial safety 
data.
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product
Drug-induced liver 
Rare but severe event, thus 
Timely detection, evaluation, and 


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injury (DILI)
under constant surveillance by 
sponsors and regulators.
follow-up of laboratory 
alterations in selected liver 
laboratory parameters to ensure 
patients´ safety. See also Section 
5.2.6, adverse events of special 
interest
Systemic 
hypersensitivity 
reaction
After administration of any 
biologic agent or protein, there 
is a possibility of occurrence of 
adverse immune reactions 
which can be local (e.g.
redness, pruritus, and or 
swelling at the injection site) or 
systemic (e.g. anaphylactic 
reactions).
Patients with a history of 
allergy/hypersensitivity to the 
systemically administered trial 
medication agent or its excipients 
are excluded from the trial.
In case of systemic 
hypersensitivity reactions 
including anaphylactic reaction 
emerging during or after 
administration of trial medication, 
the investigator should consider in 
accordance with severity of the 
reaction and local standard of care 
to interrupt and treat the 
condition. Systemic 
hypersensitivity reaction is 
defined as AESI. It is subject to 
close monitoring and 
investigators are requested to 
assess these conditions using the 
criteria discussed in the statement 
paper from Sampson HA [R11-
4890].
Infections
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of infections.
A recent characterisation of 
individuals with homozygous 
IL36R KO mutations revealed 
that normal immune function 
was broadly preserved 
suggesting that IL36 
signallingpathway inhibition 
does not compromise host 
defences [R17-3632].
Screening procedures for 
infections will be established for 
this trial. Patients with any 
relevant chronic or acute 
infections including human 
immunodeficiency virus (HIV), 
viral hepatitis or tuberculosis 
(including a positive Quantiferon 
test in early trials) are excluded 
from the trial. Treatment of 
infections should be initiated 
promptly according to standards 
of care.
Severe infections and 
opportunistic infections are 
considered AESI for this trial.
These conditions and serious 


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infections are subject to close 
monitoring.
An independent data monitoring 
committee (DMC) is in place to 
periodically evaluate clinical trial 
safety data.
Malignancies
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of a decreased 
immune defense against 
malignancies.
A recent characterisation of 
individuals with homozygous 
IL36R KO mutations revealed 
that normal immune function 
was broadly preserved 
suggesting that IL36 signalling 
pathway inhibition does not 
compromise host defences 
[R17-3632].
Patients with a recent history of 
malignancy will be excluded from 
participation in this trial.
In case of occurrence of 
malignant neoplasm other than
appropriately treated basal cell 
carcinoma or squamous cell 
carcinoma of the skin or in situ 
carcinoma of uterine cervix, the 
investigator should discontinue 
treatment with BI 655130.
Diagnostics and treatment have to 
be initiated according to local 
standard of care.
Malignancies represent always 
serious adverse events and are 
subject to close monitoring
Trial procedures
Blood Sampling 
As with all blood sampling, 
there is a risk of mild pain, 
local irritation, or bruising (a 
black or blue mark) at the 
puncture site. Furthermore, 
there is a small risk of light-
headedness and/or fainting. In 
rare cases, the puncture site can 
also become infected or nerves 
may be damaged, inducing 
long-lasting abnormal 
sensations (paresthesia), 
impaired sensation of touch and 
persistent pain.
These risks will be addressed by 
careful safety monitoring and risk 
mitigation measures such as
(a) close clinical monitoring for 
AEs;
(b) selection of experienced sites 
and site staff;
(c) training.
Skin Biopsy
Can cause local bruising, 
imflammation, nerve damage 
and pain.
These risks will be addressed by 
careful monitoring and risk 
mitigation measures such as 
(a) close clinical monitoring for 
AEs;


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(b) selection of sites with 
experienced site staff;
(c) training.
Other risks
Administration of 
Placebo
If the patient is randomised to 
receive a placebo, the patient´s 
condition could get worse 
during the course of the trial.
 
 
Please refer to 
Section 3.1.
Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of Women of Child Bearing Potential 
(WOCBP) in this study is justified. To minimize the risk of unintentional exposure of an 
embryo or fetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods described in Section 4.2.2.3.
1.4.3
Discussion
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 PPP patients will not be exposed to undue 
risks and adverse events in relation to the information that is expected to be gained from this 
trial. Considering the medical need of the development of an effective and well tolerated drug 
specifically and directly treating PPP, the benefit of this trial is considered to outweigh the 
potential risks for individual PPP patients participating in this trial. The benefit-risk profile is 
thus considered appropriate for an experimental therapy at this stage of clinical development.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The present trial will be performed to demonstrate proof of concept with respect to a non-flat 
dose response curve, and to define a suitable dose range for BI 655130 regarding efficacy and 
safety for further pivotal testing in Phase III in patients with PPP. For this purpose, a multiple 
comparison procedure with modelling techniques (MCPMod) approach is considered.
The primary objective is to provide dose-ranging data for 4 dose regimens of BI 655130 
(with each regimen consisting of a loading and a separate maintenance subcutaneous dose) 
compared to placebo on the primary endpoint of percentage change from baseline in PPP ASI 
at Week 16. The target dose(s) will be estimated from the model by incorporating 
information on the minimum clinically relevant effect and accounting for safety. Supportive 
dose-ranging assessments will also be done on pre-specified secondary endpoints.
The primary endpoint comparison will be performed for all randomised and treated patients 
who have a baseline value for the primary endpoint. The primary treatment comparison will
be performed as if all patients took randomised treatment for the duration of the trial that is 
excluding the effects of either treatment discontinuation or use of rescue therapy.
The additional objectives are to explore long-term efficacy, safety and tolerability of multiple 
dose regimens of BI 655130 in patients with PPP.
2.1.2
Primary endpoint(s)
The primary endpoint to assess efficacy of BI 655130 is % change in PPP ASI from baseline
at Week 16. Any data collected after use of any rescue therapy or after 6 weeks following 
discontinuation of treatment (to allow for incorporation of the continuing maximum treatment 
effect period) are censored for the purpose of the primary estimand.
2.1.3
Secondary endpoint(s)
Secondary endpoints are defined as described below. Note that for the secondary endpoints, 
any data collected after use of any rescue therapy or after 6 weeks following discontinuation 
of treatment (to allow for incorporation of the continuing maximum treatment effect period)
are censored for the purpose of the primary estimand.

Change from baseline in PPP Pain Visual Analog Scale (VAS) score at Week 4 and 16

PPP SI change from baseline at Week 16

PPP ASI50 at Week 16

PPP ASI75 at Week 16

PPP PGA clear/almost clear at Week 16

PPP PGA pustules clear/almost clear at Week 16

Percent change in PPP ASI from baseline at Week 52


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
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 randomised, double-blind, placebo-controlled, parallel-design dose-finding trial 
comprising of 4 active doses compared to placebo. Active treatment arms consist of active 
loading dose and active maintenance treatment. Two different loading doses and two 
different maintenance treatment doses are to be tested up to Week 16 (to give four different 
BI 655130 dose regimens). From Week 16 onwards, three different maintenance treatment 
doses are to be tested. The trial design is illustrated in Figure 3.1: 1.
Approximately 140 eligible patients with Palmoplantar Pustulosis will be randomised in a 
2:1:1:1:2 ratio to one of the 5 following treatment arms:
Arm 1: BI 655130
 (N=40) 
Arm 2: BI 655130 
(N=20)
Arm 3: BI 655130 
(N=20)
Arm 4: BI 655130 
(N=20)
Arm 5: Placebo
 
(N=40)
The randomisation will be stratified for Japan versus non-Japan and will be done to assure 
that sufficient patients per treatment arm are recruited specifically within each region (Japan 
vs non-Japan). Screening of patients into any single region (Japan or non-Japan) will be 
closed in order to ensure that not more than 91 patients are randomised into that region. The 
rationale is to allow for a thorough assessment in the Japanese population and to assess
whether there is a difference in treatment effect between Japanese vs non-Japanese patients 
(which is hypothesized based on clinical trials in Japan which tend to show larger treatment 
effects in PPP patients than have been observed in European clinical trials). This stratum will 
be included into the analyses of the primary endpoint.
 
This is required to keep the 
blinding. Please refer to Sections 4.1.1 and 4.1.5.1 for details.
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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The patients are followed-up until Week 68 which is 16 weeks after the last dose of the study 
drug at week 52 (Residual Effect Period of 16 weeks).
Figure 3.1: 1 Trial design
An independent Data Monitoring Committee will evaluate safety and efficacy data on a 
continuous basis. For details please refer to Section 8.7.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The selection of PPP patients is based on the high unmet medical need in these patients.The 
trial design has been chosen to aid in selecting the appropriate dose regimens for a 
subsequent Phase III trial in PPP. The doses to be studied in this trial are expected to generate 
sufficient information to allow the selection of a reasonable number of doses/dose regimens 
for the phase III trial. The loading dose is selected to maximize the treatment response, the 
duration of response, and to bring the effect earlier to steady state.
A MCPMod approach will be employed in a parallel group, double-blind, placebo controlled 
trial to select one or two doses for subsequent confirmation of the efficacy and safety of 
BI 655130 in Palmoplantar Pustulosis. As only limited treatment options are available for 
PPP patients in a global trial setting, the placebo control group in 1368-0016 is required to 
compare both the efficacy and safety of BI 655130 in this population. 


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The treatment duration of 52 weeks with BI 655130 (with primary endpoint at Week 16) was 
selected with the aim to maximize treatment efficacy (continued or improved efficacy after 
the primary endpoint) with this new mode of action and to explore the long-term efficacy and 
safety.
3.3
SELECTION OF TRIAL POPULATION
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients across the regions has been 
screened. Screening of patients into any single region (Japan or non-Japan) will be closed in 
order to ensure that not more than 91 patients are randomised into that region. Investigators
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
The trial will be performed in adult patients diagnosed with Palmoplantar Pustulosis defined 
as presence of primary, persistent (>3 months duration), sterile, macroscopically visible 
pustules on the palms and/or soles, without or with plaque psoriasis elsewhere on the body.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. 18 to 75 years of legal age (according to local legislation) at screening.
2. Diagnosis of Palmoplantar Pustulosis defined as presence of primary, persistent 
(>3 months duration), sterile, macroscopically visible pustules on the palms and/or soles, 
without or with plaque psoriasis elsewhere on the body.
3. Presence of white or yellow pustules on palms and/or soles at screening and baseline.
4. Pustular severity score ≥2 in at least one region and ≥10 well-demarcated pustules (white 
or yellow pustules) across all regions at screening and baseline.
5. PPP PGA of at least moderate severity (≥3) at screening and baseline.
6. A minimum PPP ASI score of 12 at screening and baseline.
7. Male or female patients. Women of childbearing potential (WOCBP)1 must be ready and 
able to use highly effective methods of birth control per ICH M3 (R2) that result in a low 
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.


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failure rate of less than 1% per year when used consistently and correctly. A list of 
contraception methods meeting these criteria is provided in the patient information and in 
Section 4.2.2.3.
8. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
3.3.3
Exclusion criteria
1. Reduction in PPP ASI total score ≥ 5 from screening visit (Visit 1) to baseline 
(randomisation visit, Visit 2).
2. Patients with plaque psoriasis with worsening of plaque psoriasis within the last 3 months 
prior to screening. 
3. Skin conditions that affect ability to score area and severity of PPP components (such as 
dyshidrotic eczema, calluses, tinea, xerotic scaling on heels, or maceration of interdigital 
areas).
4. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
5. Severe, progressive, or uncontrolled condition such as renal, hepatic, haematological, 
endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and 
symptoms thereof.
6. Presence or known history of anti-TNF-induced PPP-like disease.
7. Patient with a transplanted organ (with exception of a corneal transplant >12 weeks prior 
to screening) or who have ever received stem cell therapy (e.g., Prochymal).
8. Known history of lymphoproliferative disease, including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy 
and/or splenomegaly.
9. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin or in situ carcinoma of uterine cervix.
10. Use of 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.
11. Plans for administration of live vaccines during the study period or within 6 weeks prior 
to randomisation.
12. History of allergy/hypersensitivity to the systemically administered trial medication agent
or its excipients.
13. Active systemic infections during the last 2 weeks (exception: common cold) prior to 
randomisation, as assessed by the investigator.
14. Chronic or relevant acute infections including human immunodeficiency virus (HIV), 
viral hepatitis and (or) active or latent tuberculosis (TB):
QuantiFERON® 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.
                                                                                                                                                       
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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15. Major surgery (major according to the investigator’s assessment) performed within 
12 weeks prior to randomisation or planned within 52 weeks after randomisation (e.g. hip 
replacement, aneurysm removal, stomach ligation), as assessed by the investigator.
16. Patient has received surgical treatment of focal infection (e.g. tonsillectomy or dental 
therapy) within 6 months of randomisation.
17. Total white blood count (WBC) <3,000/μL, or platelets <100,000/μL or neutrophils 
<1,500/μL, or hemoglobin <8.5 g/dL at screening.
18. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2x the upper limit 
of normal, or total bilirubin >1.5x the upper limit of normal (patients with Gilbert’s 
syndrome are not excluded) at screening.
19. 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).
20. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
the patient an unreliable trial participant or unlikely to complete the trial Section 4.2.2.1.
21. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled.
22. Previous randomisation in this trial.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Sections 5.2.6.2.1 and 
5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.

The patient needs to take rescue therapy, see Section 4.2.2.1.

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).
Even if the trial treatment is discontinued, the patient remains in the trial and, given his/her 
agreement, ideally should follow the visits and procedures outlined in the Flow Chart, 
including the EOT and EOS visits. 


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If the patient is not willing to follow the whole visit schedule, at least the EOT should be 
conducted either immediately or as soon as possible followed by the EOS visit 16 weeks after 
the EOT visit.
The trial treatment discontinuation criteria apply from Week 24 onwards and require 
assessment and confirmation at 2 consecutive visits (discontinuation itself will apply at the 
second visit in the sequence)

No reduction in pustulation severity compared to baseline
AND

No reduction in PPP ASI of ≥ 5 points compared to baseline
A patient who meets the trial treatment discontinuation criteria may be discontinued from the 
trial treatment and administered rescue therapy as judged by the investigator.
The earliest trial treatment discontinuation timepoint according to this rule is at Week 28.
For individual stopping rules related to specific adverse events, please see Section 4.2.1
(Other treatments and emergency procedures).
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate 
conduct of the trial.
4. Termination of the development of the compound in this indication.
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 monocloncal 
antibody heterodimer with a molecular weight of approximately 146 kDa.
4.1.1
Identity of the Investigational Medicinal Products
The investigational product (test product and matching placebo) is provided in prefilled 
syringes of 1 mL volume.
Table 4.1.1: 1 Test product BI 655130
Substance:
BI 655130
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Chemical form:
Anti-human IL-36 Receptor mAb
Molecular weight:
146 kDa
Unit strength:
BI 655130 
Posology:
Mode of administration:
Subcutaneous injections
Table 4.1.1: 2 Test product Placebo to BI 655130
Substance:
Placebo to BI 655130
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Chemical form:
Not applicable
Molecular weight:
Not applicable
Unit strength:
Not applicable
Posology:
Method and route of administration:
Subcutaneous injections
4.1.2
Selection of doses in the trial and dose modifications
The aim of the trial 1368-0016 is to select dose regimens for a confirmatory phaseIII trial 
using a MCPMod based dose finding approach.
The BI 655130 subcutaneous dose regimens in 1368-0016 are selected to represent one 
subcutaneous dose in the range of the optimal i.v. dose identified in PoCC trial 1368.15, two 


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lower effective doses (different loading and different maintenance doses) and one dose with 
suboptimal efficacy for the Week 16 primary analysis. Additionally, the loading dose is 
selected to maximize the treatment response, the duration of response, and to bring the effect 
earlier to steady state.
Exposure response modelling was conducted on data from 1368.15 to support dose regimen 
selection in 1368-0016. Specifically, a graphical analysis of the average pustule severity 
(subcomponent of PPP ASI) suggested an increasing dose-exposure-response relationship in 
a severe subgroup of PPP patients in 1368.15 (presenting with a baseline PPP ASI > 16.7). A 
longitudinal PK/PD model linking plasma concentration to pustule severity was developed in 
this subgroup to describe the observed dose-exposure-response relationship and to predict the 
response to various subcutaneous dosing regimens.
The highest dose regimen
 
 chosen because it is the highest dose and 
frequency that can be conveniently administered subcutaneously without imposing undue 
burden on PPP patients. This regimen with a loading dose allows to maximize the dose, 
exposure and pustule severity response that can be obtained following extravascular 
administration of BI 655130. A loading dose may also allow for an earlier onset of response 
while also theoretically reducing the high inflammatory burden associated in patients with 
PPP.
The second dosing regimen 
 
 was chosen because a high loading dose along 
with a more convenient, lower maintenance subcutaneous regimen should also be therapeutic, 
and with an effect which is similar to that of the highest dose regimen over 16 weeks.
The third dosing regimen
 
 was chosen because a lower loading dose 
alongside the highest proposed maintenance dose, as well as being therapeutic, should have 
an effect over 16 weeks which is similar to but less than the effects of the two selected 
highest dosing regimens.
The lowest dose selected
 
 is considered to be a 
clinically subtherapeutic dose but is still expected to provide some relief in terms of reducing 
the average severity of pustules. For endpoints other than pustule severity (such as PPP ASI 
or pain VAS), this dose may not provide significant clinical benefit based on data from 
1368.15.
A longitudinal PK/PD model was also developed to describe the % change in PPP ASI at 
Week 16 (primary endpoint of this trial). Although the pustule severity model is used as the 
primary model for dose selection, the PPP ASI model supplemented the selection of the 
4 dosing regimens for 1368-0016. The predicted % change in PPP ASI at Week 16 is 
expected to show more separation between the 4 dose groups identified, albeit with lower 
overall drug effects compared to the pustule severity subcomponent.


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The pharmacokinetic profiles for the regimens selected are also expected to have a wide 
exposure range over the span of the trial duration. It is expected with the proposed 4 doses
that the PK and PD data obtained over the entire 52 weeks duration may provide a robust 
characterisation of the exposure-response relationship.
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised 
to blinded treatment arms according to a randomisation plan in a 2:1:1:1:2 ratio at Visit 2 via
Interactive Response Technology (IRT). This randomisation will be stratified according to 
region (i.e. Japan vs non-Japan).
Note that the medication number is different from the patient number (the latter is generated 
during screening via the IRT system). Each syringe will have an individual medication 
number for dispensation.
4.1.4
Drug assignment and administration of doses for each patient
Study drugs will be administered subcutaneously. Injections will be given in a double blind 
fashion.
At randomisation as well as at subsequent medication dispensation visits, IRT will assign 
medication numbers. Site personnel will enter the medication numbers in the eCRF.
BI 655130 will be administered as a subcutaneous injection by the investigator or authorized 
study personnel. The date and time of the administration will be recorded in the eCRF.
Details are described in the drug administration manual located in ISF.
The injection sites should avoid sites of psoriasis involvement as well as sites where the skin 
is tender, bruised, erythematous, or indurated, and should be alternated to other areas for 
subsequent doses.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients and investigators involved in the trial conduct will remain blinded with regard to the 
randomised treatment assignments until after database lock for the final trial analysis.
To maintain the treatment blind during the trial, all patients will receive 4 injections at all 
dosing visits in the every 4 weeks schedule, as indicated in the Flow Chart. 
 


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The primary analysis of the trial will be performed once all randomised patients have 
completed through 16 weeks of trial treatment. At this time, a database lock for the primary 
analysis will be done and treatment will be unblinded. In order to confirm the integrity of the 
treatment blind while the trial continues through to completion, a logistics plan will be 
developed to describe the mechanisms that are to be put in place to assure that the patients 
and investigators remain blinded to both individual patient data, as well to the primary 
analysis results. The blind status of trial and project team members at this time will also be 
clarified. The logistics plan will be finalized prior to the treatment unblind for the primary 
analysis.
The access to the randomisation code will be kept restricted until its release at the time of the 
final trial analysis once all patients have completed the trial.
A fully independent DMC will perform an un-blinded safety and efficacy assessment at
specified intervals in order to ensure that patients are protected from potential harm, please
refer to Section 8.7 for further details.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance (PV) group 
to access the randomisation code for individual patients during trial conduct. The access to 
the code will only be given to authorised Pharmacovigilance representatives for processing in 
the PV database system and not be shared further.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Trial 
Manager (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator (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.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor <and/or> appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies and that no remaining supplies are in the investigator’s 
possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Systemic hypersensitivity including anaphylactic reaction
In case of systemic hypersensitivity including anaphylactic reaction emerging during or after 
injection(s) of trial medication, the investigator should consider in accordance with severity 
of the reaction and local standard of care to

Stop further injection(s)


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
Treat with systemic anti-histamines, i.v. steroids, and in case of a severe allergic reaction 
(e.g., anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA as detailed in the laboratory manual (ISF) and 
consider the evaluation of histamine, serum tryptase, and complement components.
In case of systemic hypersensitivity, based on patient’s clinical course and medical judgment, 
injections may be cautiously re-initiated or continued in case of mild or moderate systemic 
hypersensitivity (according to RCTC grading, provided in the ISF).
In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.2, R11-4890) suspected to be caused by the trial medication, the 
investigator should discontinue treatment with study drug.
When a non-acute hypersensitivity reaction related to immune complexes (i.e., serum 
sickness) is suspected, please draw a sample for the laboratory assessment for circulating 
immune complexes.
Severe infections (according to RCTC grading in Appendix 10.3), serious infections, 
opportunistic or mycobacterium tuberculosis infection
Treatment of the infection should be initiated promptly according to local standard of care. 
No further trial medication should be administered until the active infection has resolved. 
Treatment with study drug may be restarted when the patient has recovered according to 
investigator’s assessment.
Malignancies
In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix, the 
investigator should discontinue treatment with study drug. Diagnostics and treatment have to 
be initiated according to local standard of care.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
This section provides information on restrictions regarding concomitant treatment before 
randomisation and during the trial (after randomisation), including a definition on rescue 
therapy for the treatment of worsening of PPP.
Restrictions regarding concomitant treatment before randomisation
The medications (or classes of medications) listed in Table 4.2.2.1: 1 must not be taken for 
the time periods as specified for washout.
Table 4.2.2.1: 1
Restricted Medications before randomisation
Medication or class of medications
Restriction duration
IL36R inhibitors other than the study drug
not allowed


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Table 4.2.2.1: 1 (cont.) Restricted Medications before randomisation
Medication or class of medications
Restriction duration
Biologic treatment, e.g.
Secukinumab (Cosentyx®), ustekinumab 
(Stelara®), guselkumab (Tremfya®), 
ixekizumab, tildrakizumab, brodalumab
Adalimumab, infliximab
Natalizumab or agents that deplete B or T cells
(e.g. rituximab, alemtuzumab or visilizumab)
12 weeks or 5 half-lives, whichever is 
greater, prior to randomisation
Investigational products for psoriasis
12 weeks or 5 half-lives, whichever is 
greater, prior to randomisation
Etanercept
Live virus vaccinations3
6 weeks prior to randomisation
Other systemic immunomodulating treatments 
(e.g. corticosteroids1, methotrexate, fumaric acid 
esters, acitretin, ciclosporin, apremilast)
Any investigational device or product (excludes 
psoriasis products)
4 weeks prior to randomisation
Phototherapy (e.g., UVA, UVB), topical 
treatment for psoriasis or any other skin 
condition affecting palms/soles (e.g. 
corticosteroids2, vitamin D analogues, salicylic 
acid, tar, anthralin)
14 days prior to randomisation
Anakinra
7 days prior to randomisation
1 There is no restriction on corticosteroids with only a topical effect (e.g. inhaled corticosteroids to treat asthma or
corticosteroids drops administered in the eye or ear).
2 Exception: topical steroids for use on the face, axilla, and/or genitalia with a restriction of use within 24 hours prior to
trial visit in which PPP ASI is assessed.
3 Live virus vaccination should be restricted until the end of the trial.
In the event a patient with prior use of biologic treatment, systemic steroids or 
immunomodulating treatments is enrolled, past medical records are required to document 
when these treatments were stopped. All concomitant or rescue therapies will be recorded 
(including time of intake and dose on study days) on the appropriate pages of the CRF.
Restrictions regarding concomitant treatment during the trial
Topical treatment


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Topical treatment for PPP is not allowed throughout the study. Topical treatment for other 
conditions is not restricted, however, the patient should avoid applying it with bare hands 
(e.g. use gloves) when the topical treatment is applied on affected body areas.
Topical corticosteroids
Topical corticosteroids for the treatment of PPP are not allowed during the trial unless they 
are needed as rescue therapy. Topical corticosteroids for body area other than palms and soles 
are allowed. The dose and mode of administration should be kept unchanged, if possible. The 
patient should avoid applying it with bare hands (e.g. use gloves).
Systemic immunomodulating treatments
Systemic corticosteroids and other immunomodulating agents (such as methotrexate, fumaric 
acid acitretin, ciclosporin, apremilast) for the treatment of PPP are not allowed unless they 
are needed as rescue therapy.
Biologic treatment
Biologic treatment is not allowed throughout the study, unless it is needed as rescue therapy.
Non-steroidal anti-inflammatory drugs (NSAIDs)
The use of NSAIDs is allowed, however it is recommended that a stable dose is maintained 
and the drug is not changed throughout the study up to at least the primary endpoint at 
Week 16.
Rescue therapy for the treatment of worsening of PPP
Rescue therapy is defined as both the use of medication such as topical corticosteroids or 
other topical treatment applied on the palms and/or soles, systemic immunomodulating 
treatments or biologics and therapy such as tonsillectomy, for the treatment of worsening of 
PPP.
The use of the rescue therapy leads to the discontinuation of the trial treatment, but the 
patient should remain in the trial observation.
4.2.2.2
Restrictions on diet and life style
No specific restrictions on diet or life style of the patients are required.
Emollients will be provided by the sponsor for the patient´s use during the trial. However, 
emollients must not be used on all visit days prior to the PPP assessments. Further details will 
be provided in ISF
4.2.2.3
Contraception requirements
Women of childbearing potential (for the definition of WOCBP, please refer to Section 3.3.3) 
must use highly effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and correctly during the trial, and 
for a period of at least 16 weeks after the last study drug administration. A double barrier 
method of contraception is not required. A list of contraception methods meeting these 
criteria is also provided in the patient information.


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Female Patients:
Acceptable methods of birth control for this trial are:

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal)

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomised sexual partner with documented absence of sperm
Or
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
Male Patients:
Contraception of male trial participants and female partners of male trial participants are not 
required.
4.3
TREATMENT COMPLIANCE
Treatment compliance will be calculated as shown in the formula below. Compliance will be 
verified by the Clinical Research Associate (CRA) authorised by the sponsor.
Treatment compliance (%) =
Number of actual injections 100
Number of per protocol planned injections
The measured plasma concentrations will provide additional information about compliance.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Palmoplantar Pustulosis Area and Severity Index (PPP ASI)
The Palmoplantar Pustulosis Area and Severity Index (PPP ASI) is an investigator 
assessment of the extent and severity of pustular and plaque lesions on the palms and soles 
presenting in PPP patients. The adaptation from 
 an established measure of severity and 
area of psoriatic lesions in patients with psoriasis, by Bhushan et.al [R16-5334] will be used 
in this trial.
This tool provides a numeric scoring for patients overall PPP disease state, ranging from 0 to 
72. It is a linear combination of the percent of surface area of skin that is affected on the 
palms and soles of the body and the severity of erythema, pustules, and scaling 
(desquamation).
The PPP ASI will be measured at the timepoints noted in the Flow Chart. The PPP ASI is 
provided in Appendix 10.1.1.
5.1.2
Palmoplantar Pustulosis Physician Global Assessment (PPP PGA)
The Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) relies on clinical 
assessment of the patient’s skin presentation on the palms and soles. The investigator scores 
the individual components (erythema, pustules and scaling/crusting) from 0 to 4 as clear, 
almost clear, mild, moderate or severe. 
PPP PGA is using severity scores for erythema, pustules, and scaling. The PPP PGA will be 
analyzed as PPP PGA total score including erythema, pustules and scaling, and as PPP PGA 
pustules score for pustules only. Further details and practical guidance will be available in the 
ISF.
The PPP PGA will be measured at the timepoints noted in the Flow Chart. The PPP PGA is 
provided in Appendix 10.1.2.
5.1.3
Pain VAS (Visual Analogue Scale)
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 patient.The patient 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 timepoints noted in the Flow Chart. The Pain VAS 
instrument to assess is provided in Appendix 10.1.3. Of note, there will be two pain VAS 
questionnaires, one specifically asking for pain on palms and/or soles (PPP Pain VAS) and 
one for muscular and joint pain.


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5.1.10
Palmoplantar Pustulosis Severity Index (PPP SI)
The Palmoplantar Pustulosis Severity Index (PPP SI) is based on the severity score of 
individual components (erythema, pustules, and scaling/desquamation) of PPP ASI
assessments. The most severe skin lesion location is identified by the investigator at baseline 
and assessed at all subsequent visits.
The PPP SI will be calculated by summing up the individual components of PPP ASI 
assessment (range 0-12) at each visit for the identified location.
PPP SI will be measured at the timepoints noted in the Flow Chart. Details are provided in 
Appendix 10.1.10.


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5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:

Adverse events (including drug-related AEs and AEs leading to discontinuation)

Adverse events of special interest (AESIs)

Serious adverse events (SAEs)

Intensity of adverse events will be assessed by Rheumatology Common Toxicity Criteria 
(RCTC) version 2.0 (refer to Appendix 10.3 and ISF for details)

Safety laboratory tests

Physical examination

Vital signs (blood pressure, pulse rate, body temperature, respiratory rate)

12-lead Electrocardiogram (ECG)

Local tolerability

Immunogenicity (ADA/Nab)
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin.


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Targeted physical examination will include vital sign assessment and evaluation of organ 
systems associated with AE(s) symptoms or laboratory abnormalities.
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart.
The results must be included in the source documents available at the site.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling. Measurements of vital signs should be assessed at screening. At dosing visits, vital 
signs evaluations will be performed pre-dose and additional evaluations will be taken at 
10 minutes post-dose and 1 hour after the end of the study drug administration.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest, and additionally 
temperature and respiratory rate. The results must be included in the source documents 
available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. For the sampling 
timepoints please see the Flow Chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF.
Patients do not have to be fasted for the blood sampling for the safety laboratory.
Instructions regarding blood and urine sample collection, sample handling/ processing and 
sample shipping are provided in the laboratory manual in the ISF.
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
Table 5.2.3: 1
Safety laboratory tests
Category
Test name
Haematology
Haematocrit (Hct)
Haemoglobin (Hb)
Glycosylated Hbc (HbA1c) (only at screening)
Red Blood Cell Count
Reticulocyte Count
White Blood Cells / Leukocytes
Platelet Count / Thrombocytes


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Table 5.2.3: 1 (cont.)
Safety laboratory tests
Category
Test name
Diff. Automatic
Neutrophils (relative and absolute)
Eosinophils (relative and absolute)
Basophils (relative and absolute)
Monocytes (relative and absolute)
Lymphocytes (relative and absolute)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils, bands (Stabs)
Neutrophils, polymorphonuclear (PMN)
Eosinophils
Basophils
Monocytes
Lymphocytes
Coagulation
Partial Thromboplastin Time (aPTT)
Prothrombin time (INR)
Fibrinogen
Enzymes
AST (GOT)
ALT (GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Amylase
Lipase
Serum Tryptase1
Electrolytes
Calcium Sodium
Potassium
Chloride
Bicarbonate
Substrates
Glucose
BUN (blood urea nitrogen)
Uric acid
Creatinine
eGFR (estimated by CKD-EPI formula) (only at
screening)
Bilirubin Total
Bilirubin Direct (if total is elevated)
Bilirubin Indirect (if total is elevated)
Troponin (Reflex, in case of elevated CK)
Protein, Total
Albumin
C-Reactive Protein (CRP) (high sensitivity)
Cholesterol, total
Triglycerides
LDL-Cholesterol 
HDL-Cholesterol
Specific gamma-globulin quantification
IgE3
Urine Pregnancy test2 (only for female patients of 
childbearing potential). At the drug administration 
visits, the test will be performed prior to the 
administration of study drug
Human Chorionic Gonadotropin in urine
Serum Pregnancy test2 (only for female patients
of childbearing potential)
Human Serum Chorionic Gonadotropin


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Table 5.2.3: 1 (cont.)
Safety laboratory tests
Category
Test name
Hormones (only at screening)
TSH (free T3 and free T4 in case of abnormal TSH
result)
Urinalysis
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC / Erythrocytes
Urine WBC / Leukocytes
Urine pH
Urine Creatinine
Urine-Sediment (microscopic examination, only
if urine analysis abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells
Urine Sed. Crys., Unspecified
Urine Sediment RBC / Erythrocytes
Urine Sediment WBC / Leukocytes
Urine (only at screening)
Albumin (quantitative)
Infections testing
Hepatitis B Surface Antigen (qualitative),
Hepatitis B core Antibody
HBV-DNA (quantitative) at screening (Visit 1) 
and EOT Visit4
Hepatitis C Antibodies (qualitative),
HIV-1, and HIV-2 Antibody (qualitative),
QuantiFERON®-TB5,6
1 Performed only at the randomisation visit (Visit 2).
2 Urine and serum pregnancy testing will be performed as indicated in the Flow Chart.
3 IgE will be taken in case of systemic hypersensitivity reaction together with ADA (anti-drug antibodies) sample.
4 A HBV-DNA should be conducted if Hepatitis B core Antibody is positive and Hepatitis B Surface Antigen is negative. 
These evaluations should be conducted at screening and at the EOT Visit.
5 If the 1st QuantiFERON®-TB test result is indeterminate, a retest should be performed
6 In patients with a negative QuantiFERON®-TB test, the test should be repeated at EOT visit.
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flow Chart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis. Additional ECGs may be recorded 
for safety reasons. Dated and signed printouts of ECG with findings should be documented in 
patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.


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5.2.5
Other safety parameters
All cases of malignancies that are detected during the trial will be reported as SAEs. Patients 
with a history of malignancy (except for specific cancers) will be excluded from this trial per 
the exclusion criteria (Section 3.3.3).
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:

results in death,

is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe,

requires inpatient hospitalisation or prolongation of existing hospitalisation

results in persistent or significant disability or incapacity,

is a congenital anomaly / birth defect,

is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse.
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.


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5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
Systemic hypersensitivity reactions including anaphylactic reaction
Any suspicion of severe systemic hypersensitivity reaction and of any potential cases of 
anaphylaxis should be defined and assessed using the criteria discussed in the statement paper 
from Sampson HA (Appendix 10.1, R11-4890).
Severe infections (according to RCTC grading in Appendix 10.2)
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, strongyloides (hyperinfection syndrome and disseminated forms only), 
paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only), shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression [R17-2617].
Hepatic injury


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A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity grading of AEs will be performed according to Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0 developed by OMERACT [R13-3515]. Refer to the 
ISF for intensity/severity classification. Intensity options are:
Grade 1 
mild
Grade 2 
moderate
Grade 3 
severe
Grade 4 
life-threatening
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

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 new AEs but should only 
report any occurrence of cancer and trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form (see 
Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.


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5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical 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 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements.
Unspecified DNA Banking:
An additional blood sample for DNA banking will be collected in PAXgene Blood DNA tube 
at Visit 2 (see Flow Chart). The DNA Banking sample, derived from the original blood 
sample, will be stored at Boehringer Ingelheim. The stored DNA may be retrospectively 
analysed.
5.6
OTHER ASSESSMENTS
Photographs of palmoplantar lesions
Photographs of palms and soles (with or without palmar or plantar lesions) and, if applicable, 
selected area with plaque psoriasis target lesion elsewhere on the body (in patients with 
concurrent plaque psoriasis only) will be taken at time points specified in the Flow Chart.
The images must not be identifiable to the patients (e.g. by tattoos). Photographs will be used 
for monitoring the study quality and explore diagnostic accuracy by clinical experts, Clinical 
Trial Physician or designated functions. The monitoring of images will not have any impact 
on patient selection by investigators and on data analyses. Details are described in the photo 
documentation instruction manual in the ISF.
5.7
APPROPRIATENESS OF MEASUREMENTS
The measurements performed during this trial are standard measurements in PPP treatment 
trials and will be performed in order to monitor safety aspects or assess treatment response in 
an appropriate way. The PROs included in this trial have been used and described in other 
diseases, including dermatologic conditions, where they have demonstrated adequate 
measurement properties. They were included because they explore concepts of PPP that 
patients and physicians have highlighted as relevant and important.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. Each visit data 
(with its window) up to EOS is to be counted from Day 1 (Visit 2). If any visit has to be 
rescheduled, subsequent visits should follow the original visit date schedule. Additional visits 
for the purpose of re-testing of laboratory parameters or AE monitoring may be included as 
deemed necessary by the investigator.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart and respective 
protocol sections.
Measurement of vital signs should precede blood sampling and be assessed pre-dose at all 
dosing visits.
Patient Reported Outcomes (PROs) such as
 Pain VAS, 
 
 should 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. This applies also to 
the randomisation visit (V2).
The following sequence of procedures at each visit (where applicable) is recommended:
1. PROs (prespecified order: 
 Pain VAS, 
2. AE and concomitant therapy collection; smoking status 
3. Physical examinations (including predose vital signs)
4. PPP PGA, PPP ASI, 
6. Photographs of skin lesions
7. ECG
8. Urine pregnancy testing (if applicable)
9. Blood and urine sampling, including 
 ADA/Nab,
10. Skin biopsies
11. Assign (IRT call) /Administer study drug
12. Local tolerability
13. Post-dose vital signs 
6.2.1
Screening and run-in period(s)
Screening Period
Study requirements, including the procedure for the follow-up of prematurely withdrawn 
patients must be fully explained to the patient and written informed consent obtained prior to 
initiating any study-related evaluation. The importance of staying in the trial until completion 


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of all study requirements will be emphasized. No trial procedures should be done unless the 
patient has consented to taking part in the trial.
Once consented, the patient is considered to be enrolled in the trial and has started screening. 
The patient should be recorded on the enrolment log and be registered in IRT as a screened 
patient. Patients will be assigned a patient number generated via the IRT system.
Screening (Visit 1) should normally take place no more than 28 days before Visit 2 and be 
completed no less than 14 days prior to Visit 2. Visit 1 procedures may be completed over 
multiple physical visits, if needed. The time window for Visit 1 may be extended at the 
discretion of the CT Manager in conjunction with the CT Leader on a case by case basis.
For the comprehensive list of the trial procedures required at the Screening Visit (Visit 1) 
please refer to Flow Chart. Patients who have a laboratory test value that makes their 
participation uncertain may have the test repeated to determine eligibility; however, the result 
must be available prior to Visit 2 (Day 1). Baseline conditions and medical history will be 
assessed during screening.
Demographics:
Informed consent date, gender, ethnicity and race (if allowed by local law) will be collected 
and reported in the eCRF.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding PPP, and if applicable concurrent plaque psoriasis) will be reported on the 
Baseline Condition eCRF page. The smoking status and history based on the calculation of 
pack-years will be collected as well; see Appendix 10.4 for details.
Infections screening
Infections testing will include tuberculosis, hepatitis B, hepatitis C, and HIV assessments (see 
Section 3.3.3 and Table 5.2.3: 1).
Medical History
Medical history of PPP, including the previous treatment, will be collected and reported in 
the eCRF.
Information on clinically significant previous and concomitant illnesses, other than PPP, or 
any clinically significant signs or symptoms that are present before informed consent, or pre-
existing conditions identified through findings from assessments and examinations done 
during the screening visits will be recorded as medical and surgical history at screening on 
the Baseline Condition page in the eCRF.
Patients who fail screening (i.e. does not meet the eligibility criteria) following Visit 1 
assessments should be registered as a screen failure in IRT.
Re-Screening


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If a patient results in a screen failure 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. 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.
6.2.2
Treatment period(s)
When eligibility of the patient to participate in the trial is confirmed, randomisation via IRT 
will be performed at Visit 2. The treatment period is from Day 1 to Week 52 (End of 
Treatment, EOT). Procedures described in the Flow Chart for each visit should be performed.
At visits during the treatment period, venepuncture (i.e. safety laboratories, 
 ADA, 
) and skin biopsies should be the last procedures performed prior to study drug 
administration. Only after all blood specimens are collected, will each eligible patient receive 
a dose of the assigned trial medication.
6.2.3
Follow-up period and trial completion
For all randomised patients termination of trial medication and trial completion must be
recorded on the corresponding CRFs.
For patients completing the randomised trial treatment regularly at Week 52 (EOT), safety 
follow-up visits will be performed at Week 60 (FU1 Visit) and at Week 68 (End of Study, 
EOS Visit).
Early treatment discontinuation
Patients who discontinue treatment prematurely prior to the planned EOT visit (Week 52, the
last planned treatment visit) should be registered as withdrawn from treatment in IRT.
Patients should follow the scheduled visits as much as possible as defined in the Flow Chart.
If the patient is not willing to follow the whole visit schedule, at least the EOT should be 
conducted either immediately or as soon as possible followed by the EOS visit 16 weeks after 
the EOT visit. All efforts should be made to keep the patient in the observation for at least 16 
weeks after the last dose of the study drug.
Treatment completion
Treatment completion is defined as a patient having completed treatments till planned EOT 
visit (Week 52).
Trial completion:
Trial completion is defined as a patient having reached the EOS Visit per protocol (Week 68).


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
This trial is designed as a randomised, parallel-group, double-blind, and placebo-controlled 
trial with 4 active doses of BI 655130 in patients with moderate to severe Palmoplantar 
Pustulosis.
The purpose of this trial is to demonstrate proof of concept of clinical activity of BI 655130 
on the primary endpoint of % PPP ASI change at Week 16. For the proof of concept a 
combined criterion of MCPMod testing (with respect to achieving a non-flat dose response 
curve) and evaluation of a minimum relevant benefit is implemented. In detail, for PoC, at 
first a statistically significant non-flat dose-response needs be detected. For this purpose, a 
multiple comparison procedure with modelling techniques (MCPMod) approach is applied.
Subsequently, at least one dose should show a benefit of at least 20% compared to placebo 
(i.e. the maximum benefit of BI 655130 for achieving the primary endpoint, based on 
modelled dose-response curve using model averaging across the statistically significant 
models (see Section 7.2.2), shows a ≥ 20% larger reduction compared to placebo).
Overall this approach is applied to define suitable dose regimens for BI 655130 regarding 
efficacy and safety for further pivotal testing in a subsequent study. Further assessment on the 
efficacy of BI 655130 at time-points after Week 16 will be performed in an exploratory 
manner.
Baseline refers to the measurement recorded at randomisation (Visit 2); if data at Visit 2 is 
missing, then data from Visit 1 will be considered baseline. The percent change from baseline 
of the PPP ASI score, at all follow-up visits (X), is calculated as:
% PPP ASI change from baseline = ((PPP ASI at Visit X – PPP ASI at baseline) / 
PPP ASI at baseline) * 100.
For the derivation of the primary endpoint, all measurements collected after treatment 
discontinuation, or after the use of rescue therapy for the purpose of disease worsening, will 
be censored. The primary endpoint is then evaluated based on the results of a mixed effect 
model for repeated measurements (MMRM) which assumes that missing data up to Week 16 
are handled via a missing at random approach. The estimated dose effects at Week 16 will 
then be analysed using the MCPMod approach techniques [R10-1424, R15-1961].
Randomisation will be stratified, and analysis will be performed, based on a stratification 
according to Japan versus non-Japan.
7.1
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis of the MCPMod test is that there is a flat dose response curve comparing 
the placebo and the BI 655130 dose groups on the primary endpoint of % PPP ASI change at 
Week 16. The alternative hypothesis is that there is a non-flat dose response curve indicating 
a (clinically relevant) benefit of BI 655130 over Placebo.


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The MCPMod procedure allows for simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of Type I error (one sided α of 
5%). The pre-specified models and their parameters used for this test are outlined in Section
7.2.2 and Section 7.5.
Additionally, the probability of making a positive decision to continue the program with a 
non-effective drug is further limited by requesting that an effect of at least “delta” relative to 
placebo is achieved (see Section 7.5 for details). This consequently leads also to a reduction 
of the probability for having a false positive decision.
7.2
PLANNED ANALYSES
7.2.1
General considerations
There will be 3 main patient populations in this trial for analyses: the full analysis set (FAS), 
the safety analysis set (SAF), and the per-protocol set (PPS).
Safety Analysis Set (SAF)
This patient set includes all patients who were randomised 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.
Full Analysis Set (FAS)
This patient set includes all patients in the SAF who had a baseline for the primary efficacy 
endpoint. Treatment assignment will be as randomised. This is the main analysis set for 
presentation of efficacy data.
Per-Protocol Set (PPS)
This patient set includes all patients in the FAS who adhered to the CTP without any IPDs 
(potentially affecting the study outcome) which lead to exclusion from the PPS. This set will 
be used for sensitivity analysis on the primary efficacy endpoint. Important deviations of the 
protocol will include violations of the key inclusion and exclusion criteria, incorrect 
medications taken, concomitant use of restricted medications, and any other deviations of the 
protocol deemed important by the study team. All decisions concerning important protocol 
deviations will be made prior to un-blinding of the database for the primary endpoint analysis 
at week 16, and a full list of such deviations will be provided in the trial Integrated Quality 
and Risk Management Plan (IQRMP).
Further analysis sets, 
, 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.
The following analyses of this trial protocol, in chronological order, are planned:
Week 16 Primary Analysis


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The primary analysis of the trial will be performed once all randomised patients have 
completed the first 16 weeks of the trial, and a database lock will be done. Details of the 
analysis to be performed will be described in the TSAP which is planned to be finalized prior 
to achieving database lock for this primary analysis. Treatment will be unblinded at this time. 
For further details regarding the maintenance and protection of the blind through the 
continuing trial subsequent to performance of the primary analysis, refer to Section 4.1.5.1.
Final Trial Analysis
The final analysis of the trial will be performed once all randomised patients have completed 
the trial. At this time, the treatment will be officially unblinded.
A Clinical Trial Report will be prepared at the end of the trial.
7.2.2
Primary endpoint analyses
The % change in PPP ASI at Week 16 is the primary endpoint of efficacy in this trial.
The primary analysis consists of a combination of MCPMod-based testing (with respect to a 
non-flat dose response curve) and an evaluation of the dose-wise benefit at Week 16. As a 
basis for the MCPMod analysis a mixed effect model for repeated measurements (MMRM) is 
used. 
MMRM model
The % change in PPP ASI from baseline (Visit 2), at Visits 6, 7, 8 and 9 (Weeks 4, 8, 12 and 
16 only) will be evaluated using an MMRM accounting for the following sources of 
variation: ‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification 
according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed 
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. In the event of model non-convergence 
(following application of suitable methods to attempt to resolve this – as will be specified in 
the TSAP), first, the strata for region will be dropped from the model, and then, if non-
convergence persists, an ANCOVA (Analysis of Covariance) model at Week 16 only will 
instead be performed. 
MCPMod analysis
The dose-response relationship of the Week 16 estimates from MMRM will then be analysed
using MCPMod [R10-1424, R15-1961]. Thereby, several possible dose response models 
(patterns) will be evaluated (while keeping full control of the type I error at 5%, one-sided) to 
identify the best-fitting model.
Dosing is planned to be administered in two phases, a loading phase followed by a 
maintenance phase (for details see Section 3.1). For modelling purposes the different active 
dose groups will be approximated by the planned total 
 
Consequently, the total doses which are 
included are BI 655130 
 (Arm 1: “high dose” regimen), 
 (Arm 2: “medium-


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high dose” regimen), 
 (Arm 3: “medium-low dose” regimen), 
 (Arm 4: “low 
dose” regimen) and placebo (Arm 5).
For the PoC testing and for the sample size calculation the following model assumptions and 
resulting graphs (see Figure 7.2.2: 1) have been selected to cover both the plausible and a 
diverse range of potential dose response patterns:

Linear

Emax: assumes 70% of the maximum effect is achieved at the “low dose” regimen
 

Exponential: assumes 25% of the maximum effect is achieved at the “medium-low dose”
regimen

Logistic: assumes 20% of the maximum effect is achieved at the “low dose” regimen
(Arm 4) and 95% of the maximum effect is achieved at “medium high dose” regimen
(arm 2, i.e.

Sigmoid Emax: assumes 10% of the maximum effect is achieved at “low dose” regimen
(Arm 4) and 80% of the maximum effect is achieved at the “medium-high dose” regimen
(Arm 2))
Figure 7.2.2: 1: Defined MCPMod shapes to be used.
The optimal contrasts corresponding to the candidate models will be shown in the TSAP. For 
the final evaluation, these contrasts will be updated using the expected model means from the 
candidate set and the estimated variance-covariance matrix extracted from the MMRM 
model.


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A non-flat dose response is established if at least one dose response pattern is statistically 
significant, rejecting the null hypothesis of a flat dose response relationship on % PPP ASI 
change at Week 16 jointly for each of the candidate dose response models, with a contrast 
test controlled for the family–wise type I error rate at a one sided α = 5%. If a non-flat dose 
response is established, the statistically significant model(s) from the above candidate set are 
refitted to the data to generate new estimates for all model parameters. The dose-response 
curve is then fitted based on model averaging across the statistically significant models.
If considered necessary and for the purpose of further model refinement, MCPMod might be 
repeated on the primary endpoint but with an extended set of shapes including the original 
candidates. 
 
Other analyses of the primary endpoint will include:
7.2.3
Secondary endpoint analyses
The following continuous secondary endpoints will be evaluated in the same manner as 
described for the primary endpoint:

Change from baseline in PPP Pain VAS score at Week 4

Change from baseline in PPP Pain VAS score at Week 16

PPP SI change from baseline at Week 16 
Hereby the same model shapes as for the primary endpoint will be used. The corresponding 
contrasts and further details will be described in the TSAP. 
For the continuous secondary endpoint of percent change in PPP ASI from baseline at Week
52, the following maintenance treatment comparisons will be performed using an MMRM
(incorporating weeks 4, 12, 20, 28, 36, 44, and 52) as well as descriptive methods:

Arm 1 vs Arm 2: to compare the effect of 
 q4w vs 
 q4w on a loading dose 
of

Arm 3 vs Arm 4: to compare the effect of 
 q4w vs 
 q8w on a loading dose 
of 

Arm 1 +Arm 3 +Arm 5 vs Arm 4: to compare the global effect of 
 q4w vs. 
 
q8w maintenance dose used after Week 16.


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
Arm 1 +Arm 3 +Arm 5 vs Arm 2: to compare the global effect of 
 q4w vs. 
 
q4w maintenance dose.

Arm 2 vs Arm 4: to compare the effect of 
 q4w vs.
 q8w maintenance dose 
used after Week 16.
For each of the binary secondary endpoints at Week 16, a MCPMod approach will also be 
used to evaluate the treatment effect of multiple doses of BI 655130 vs. placebo. This method 
will be implemented for MCPMod in a binary setting. The assessments will be performed 
using the identical dose response assumptions to those described for the primary endpoint 
analysis and will be done based upon the response proportions collected at Week 16 only. 
The contrasts applicable to each dose response shape for each of the binary secondary 
endpoints, will be specified, along with further details on the implementation of a binary 
MCP-Mod approach, in the TSAP. 
 
As a further analysis, a logistic regression model on each binary endpoint at Week 16 with 
fixed factors for ‘treatment’, and ‘region’ as strata will also be applied for the FAS. 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 in the treatment 
groups on the original scale, with the confidence interval calculated using the cumulative 
distribution function method of Reeve [R16-4414]; further details will be provided in the 
TSAP.


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7.2.5
Safety analyses
Adverse events will be coded using the current version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary. Standard BI summary tables and listings will be 
produced.
All randomised and treated patients will be included in the safety analysis. In general, safety 
analyses will be descriptive in nature and will be based on BI standards. No hypothesis 
testing is planned. Statistical analysis and reporting of adverse events will concentrate on 
treatment-emergent adverse events (TEAE). To this end, all adverse events occurring 
between start of treatment and end of the residual effect period will be considered ‘treatment-
emergent’; the residual effect period (REP) is defined as 16 weeks after the last dose of trial 
medication. Adverse events that start before first drug intake and deteriorate under treatment 
will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class (SOC) and preferred term after coding according to the current version of the 
MedDRA at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The 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.
Immunogenicity data will be analysed in a descriptive way.


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7.2.7
Interim Analyses
There are no interim analyses of this trial planned to be performed. 
Once all randomised patients have completed the first 16 weeks of study, a database lock will 
be done for safety and efficacy data collected up to Week 16. At this time, the primary
analysis of these data through Week 16 will be performed. Since the study is planned to 
continue, and will remain blinded, a logistics plan as described in Section 4.1.5.1 will be 
developed in order to protect the integrity of the ongoing trial data and reporting subsequent 
to treatment un-blind for the Week 16 primary analysis. Details of the analysis to be 
performed will be described in the TSAP which is planned to be finalized prior to achieving 
database lock for the Week 16 primary analysis. The primary analysis is planned to be 
described in a Clinical Trial Report (CTR).
A final analysis of the entire trial data will be performed once all randomised patients have 
completed the 68 weeks of study. The final analyses are planned to be documented in a CTR 
which is to be prepared at the end of the trial.
7.3
HANDLING OF MISSING DATA
For the primary efficacy endpoint which is continuous in nature, the use of a restricted 
maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach, in 
the primary analysis, will ensure that missing data are handled implicitly, via a missing at 
random assumption, by the statistical model.
In order to check the robustness of the primary MCPMod analysis to missing data, a 
sensitivity analysis will be performed using adjusted multiple imputation. Non-monotone 
missing data will initially be multiply imputed as missing-at-random. For monotone missing 
data, a Jump to Reference method will then be implemented via a sequential regression MI 
approach. For such missing data, patients in the active treatment groups are assumed to lose 
any treatment effect with their missing observations and to then assume a trajectory similar to 
that of the placebo group. For each imputed complete dataset, an ANCOVA (Analysis of 
Covariance) model for Week 16 data analogous to the primary MMRM model will be used
for the analysis. The results will be pooled using Rubin’s rules and the primary MCPMod 
analysis will be repeated on the summarized outcomes. Further details on the procedure will 
be included in the TSAP.
For secondary efficacy endpoints of a binary nature, a Non Response Imputation (NRI) 
approach, will be applied to the missing visits up to Week 52 that is, imputing as a failure to 
achieve a response in the visits with missing endpoint score, however:


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
If there are available data at the visits both before and after the visit with a missing 
outcome, then impute as a success only if both the preceding and the following 
measurement indicate success (that is, score of 1) and there is no use of rescue therapy for 
disease worsening within this imputation period;

Otherwise, impute as a failure to achieve a response (i.e. no response imputation).
Multiple imputation will be used as a sensitivity analysis to handle missing secondary binary 
data. Detailed description of multiple imputation will be included in the TSAP.
With respect to safety evaluations, it is not planned to impute missing values.
7.4
RANDOMISATION
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
Stratification of the randomisation will be performed for Japan versus non-Japan.
Within each stratum, patients will be randomised in a 2:1:1:1:2 randomisation ratio to receive 
either placebo or one of four BI 655130 dose regimens (“high dose” regimen; “medium-high 
dose” regimen; “medium-low dose” regimen; “low dose” regimen). The randomisation will 
be done in blocks to achieve balanced allocation.
The process of randomisation is done via an IRT. Practical aspects of the treatment allocation 
process are detailed in Section 4.1.3.
7.5
DETERMINATION OF SAMPLE SIZE
Calculations were performed using R Version 3.5.1.
The study is intended to show a benefit of BI 655130 over placebo in terms of the difference 
in % PPP ASI change at Week 16.
The aims of this study are two-fold. A first aim is to show a significant non-flat dose-
response curve across the different doses and placebo. Additionally to that at least one 
modelled dose within the dose range considered should show a benefit of at least "Delta" %
PPP ASI change compared to placebo. The probability of success of this trial is therefore 
defined as the probability to (1) obtain a significant test for non-flat dose-response curve and 
(2) to observe for at least one of the modelled doses an effect difference of at least delta 
compared to placebo.
The sample size calculation is based on an assumed maximum difference in % PPP ASI 
change of placebo vs. BI 655130 of 30%, as well as on the pre-specified models listed in 
Section 7.2.2. The standardized deviation of the % PPP ASI change is assumed to be 35%. 


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For placebo, a fixed rate of -25% PPP ASI change at Week 16 will be considered. These 
estimates are derived from trial 1368.15 in PPP.
Using a total sample size of 140 evaluable patients (40, 20, 20, 20 and 40 for placebo and low 
to high dose regimes respectively), the probability for a successful trial (as defined above) 
was estimated using simulations. For each dose group, samples of the required size were 
drawn from a normal distribution. Values smaller than -100% (which corresponds to 
complete recovery of a patient) were set to -100%. The expected values of the original 
normal distribution were chosen such that the expected dose group means after truncation 
correspond to the model assumptions. In the following, the reported dose means will always 
refer to dose means after truncation. The standard deviation of the untruncated normal 
distribution was set to 35% for all simulations. This will result in slightly reduced standard 
deviations after truncation (of approx. 30% for the highest dose group).
Based on these assumptions, the success probability under a delta of 25% (i.e. non-flat curve 
achieved, and at least one BI 655130 dose shows a difference to placebo of at least 25%) is 
approximately 77% when assuming a linear dose response curve (i.e. -25, -40, -44, -51 and -
55% PPP ASI change for placebo and low to high dose regimens, respectively). Assuming 
one of the other dose response curves listed in Section 7.2.2 the success probability is 
between 79% and 84%. For a delta of 20% the respective success probabilities are between 
93 and 96%.
If the difference between placebo and active doses is low, i.e. 10% (which is assumed to be 
clinically not relevant) the success probability is approximately 2% and 9% for a delta of 
25% and 20%, respectively (assuming a linear dose response curve). In the case that there is 
no treatment benefit, the false positive probability is limited by the α-level for the 
significance testing of the non-flat dose-response curve of 5% (one-sided). Additionally, this 
probability is further reduced by requesting an effect of at least delta. Thereby, the probability 
of a false decision for a non-effective drug is reduced to less then 1%.
The following Table 7.5: 1 provides success probabilities under different scenarios (i.e. 
different treatment effects and dose-response curves).
Table 7.5: 1 Probability of multiplicity-adjusted success probability given expected % change 
in PPP ASI at week 16 and a total sample size of 140 patients (with 
40/20/20/20/40 per dose group) based on MCPMod nominal alpha-level of 5% 
(one-sided) and additional treatment effect threshold (Delta).
(Assumed) 
True Model
Expected % change in PPP ASI (in %)
Exp. max. 
Response 
Difference
Delta
Multiplicity 
adjusted 
Success 
probability*
Placebo
Low 
dose 
BI
Medium-
low dose 
BI
Medium-
high 
dose BI
High 
dose 
BI
Linear30
-25
-40
-44
-51
-55
30
25
77,1%
Emax30
-25
-51
-52
-54
-55
30
25
80,7%
Exp30
-25
-29
-33
-42
-55
30
25
79,0%
Logistic30
-25
-31
-43
-54
-55
30
25
84,4%


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Table 7.5: 1 (cont.) Probability of multiplicity-adjusted success probability given expected % 
change in PPP ASI at week 16 and a total sample size of 140 patients 
(with 40/20/20/20/40 per dose group) based on MCPMod nominal alpha-
level of 5% (one-sided) and additional treatment effect threshold (Delta).
(Assumed) 
True Model
Expected % change in PPP ASI (in %)
Exp. max. 
Response 
Difference
Delta
Multiplicity 
adjusted 
Success 
probability*
Placebo
Low 
dose 
BI
Medium-
low dose 
BI
Medium-
high 
dose BI
High 
dose 
BI
SigEmax30
-25
-28
-37
-51
-55
30
25
83,6%
Linear40
-25
-45
-51
-59
-65
40
25
98,2%
Linear0
-25
-25
-25
-25
-25
0
25
<0,1%
Linear10
-25
-30
-31
-34
-35
10
25
1,8%
Linear30
-25
-40
-44
-51
-55
30
20
93,2%
Emax30
-25
-51
-52
-54
-55
30
20
94,6%
Exp30
-25
-29
-33
-42
-55
30
20
93,8%
Logistic30
-25
-31
-43
-54
-55
30
20
95,8,%
SigEmax30
-25
-28
-37
-51
-55
30
20
95,5%
Linear40
-25
-45
-51
-59
-65
40
20
99,8%
Linear0
-25
-25
-25
-25
-35
0
20
0,4%
Linear10
-25
-30
-31
-34
-25
10
20
8,7%
*Success probabilities under different efficacy assumptions for the defined success criteria of 1) Significant non-flat dose-
response achieved based on at least one of the candidate set models AND 2) Treatment benefit of at least ‘delta’ compared 
to placebo for at least one modelled dose within the considered dose range. Success probabilities have been calculated 
using R Version 3.5.1 based on simulations (10000 simulations per scenario). Thereby the calculations for the MCPMod
step have been performed using DoseFinding R-package 0.9-16 [R15-2001].
“Linear30: Main scenario reflecting the assumption of maximum effect difference of 30% 
compared to placebo assuming a linear dose-response curve as defined in Section 7.2.2.
“Emax30: Alternative scenario reflecting the assumption of maximum effect difference of 
30% compared to placebo assuming an Emax dose-response curve as defined in Section 
7.2.2.
“Exp30: Alternative scenario reflecting the assumption of maximum effect difference of 30% 
compared to placebo assuming an exponential dose-response curve as defined in Section 
7.2.2.
“Logistic30: Alternative scenario reflecting the assumption of maximum effect difference of 
30% compared to placebo assuming a logistic dose-response curve as defined in Section 
7.2.2.
“SigEmax30: Alternative scenario reflecting the assumption of maximum effect difference of 
30% compared to placebo assuming a sigmoid dose-response curve as defined in Section 
7.2.2.


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“Linear40: Alternative scenario reflecting the assumption of a higer maximum effect 
difference of 40% compared to placebo assuming a linear dose-response curve.
“Linear0: Alternative scenario reflecting the assumption of no difference compared to 
placebo assuming a linear dose-response curve.
“Linear10: Alternative scenario reflecting the assumption a clinically not relevant maximum 
effect difference of 10% compared to placebo assuming a linear dose-response curve.


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


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


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


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


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Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract.
A DMC will be established. Members of the DMC are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician.
The DMC will evaluate safety and efficacy data. The DMC will receive urgent significant 
safety concerns for immediate evaluation. While DMC members may be unblinded, measures 
are in place to ensure the blinding for everyone else involved in the trial. Regular DMC 
meetings will be held at specified intervals. The DMC will recommend continuation, 
modification or termination of the trial as detailed in the DMC charter. DMC 
recommendations as well as the final BI decision will be reported to the appropriate 
Regulatory Authorities (RAs)/Health Authorities (HAs), IRBs/IECs, and to investigators as 
requested by local law. The tasks and responsibilities of the DMC are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of Clinical Trial Managers (CT Managers), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.


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


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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. 2019. 380(10).
R08-5197
Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P. Relationship of the 
type of tobacco and inhalation pattern to pulmonary and total mortality. Eur 
Respir J. 1992. 5: 1111-1117.
R10-0936
Walters SJ, Brazier JE. Comparison of the minimally important difference 
for two health state utility measures: EQ-5D and SF-6D. Qual Life Res. 
2005. 14: 1523-1532.
R10-1424
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding 
studies combining multiple comparisons and modeling procedures. J 
Biopharm Stat. 2006. 16(5): 639-656.
R11-4890
Sampson HA, et.al. Second symposium on the definition and management 
of anaphylaxis: summary report - second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
2nd Symp of the National Institute of Allergy and Infectious Disease 
(NIAID)/Food Allergy and Anaphylaxis (FAA) Network on the Definition 
and Management of Anaphylaxis, Jul 2005. J Allergy Clin Immunol. 2006.
117(2): 391-397.
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, 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): 1401-1414.
R15-1421
Onoufriadis A, Simpson MA, Pink AE, Meglio P di, 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): 432-437.
R15-1961
Committee for Medicinal Products for Human Use (CHMP). Qualification 
Opinion of MCP-Mod as an efficient statistical methodology for model-
based design and analysis of Phase II dose finding studies under model 
uncertainty. European Medicines Agency (EMA). 23 January 2014.
R15-2001
Bornkamp B, Pinheiro J, Bretz F. Package ‘DoseFinding’. Comprehensive 
R Archive Network. 19 February 2015.


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R15-2620
Farley E, Masrour S, McKey J, Menter A. Palmoplantar psoriasis: A 
phenotypical and clinical review with introduction of a new quality-of-life 
assessment tool. J Am Acad Dermatol. 2009. 60(6): 1024-1031.
R15-5200
Langley RGB, Feldman SR, Nyirady J, Kerkhof P van de, Papavassilis C. 
The 5-point Investigator`s Global Assessment (IGA) Scale: A modified tool 
for evaluating plaque psoriasis severity in clinical trials. J Dermatol Treat. 
2015. 26(1): 23-31.
R16-0030
Pickard AS, Neary MP, Cella D. Estimation of minimally important 
differences in EQ-5D utility and VAS scores in cancer. Health and Quality 
of Life Outcomes. 2007. 5: 70.
R16-0927
DeWaal AC, Van De Kerkhof PCM. Pustulosis palmoplantaris is a disease 
distinct from psoriasis. Journal of Dermatological Treatment. 2011. 22(2):
102–105.
R16-0928
Setta-Kaffetzi N, Simpson MA, Navarini AA, Patel VM, Lu HC, Allen
MH, et.al. AP1S3 Mutations Are Associated with Pustular Psoriasis and 
Impaired Toll-like Receptor 3 Trafficking. American Journal of Human 
Genetics. 2014. 94: 790-797.
R16-0950
Setta-Kaffetzi N, et.al. Rare pathogenic variants in IL36RN underlie a 
spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol. 
2013. 133: 1366-1369.
R16-3543
Bissonnette R, Suarez-Farinas M, Li X, Bonifacio KM, Brodmerkel C, 
Fuentes-Duculan J, et.al. Based on Molecular Profiling of Gene Expression, 
Palmoplantar Pustulosis and Palmoplantar Pustular Psoriasis Are Highly 
Related Diseases that Appear to Be Distinct from Psoriasis Vulgaris. Plos 
One. 2016. 11(5): e0155215.
R16-3544
Moessner R, et al. Palmoplantar Pustular Psoriasis Is Associated with 
Missense Variants in CARD14, but Not with Loss-of-Function Mutations in 
IL36RN in European Patients. Journal of Investigative Dermatology. 2015.
135: 2538-2541.
R16-3546 
Hashigucci K, et.al. Polymorphism in the tumor necrosis factor B gene is 
associated with Palmoplantar pustulosis. Tissue Antigens. 1999. 54: 288-
290.
R16-3553
Wang TS, Chiu HY, Hong JB, Chan CC, Lin SJ, Tsai TF. Correlation of 
IL36RN mutation with different clinical features of pustular psoriasis in 
Chinese patients. Arch Dermatol Res. 2016. 308: 55-63.
R16-3560
Kingo K, Moessner R, Koks S, Raetsep R, Krueger U, Vasar E, et.al.
Association analysis of IL19, IL20 and IL24 genes in palmoplantar 
pustulosis. British Journal of Dermatology. 2007. 156: 646-652.
R16-3561
Tauber M, Bal E, Pei XY, Madrange M, Khelil A, Sahel H, et al. IL36RN 
mutations affect protein expression and function: a basis for genotype-
phenotype correlation in pustular diseases. J Invest Dermatol. 2016.
R16-4414
Reeve R. Confidence interval of difference of proportions in logistic 
regression in presence of covariates. Stat Methods Med Res. 2016.


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R16-5334
Bhushan M, Burden AD, McElhone K, James R, Vanhoutte FP, Griffiths 
CEM. Oral liarozole in the treatment of palmoplantar pustular psoriasis: a 
randomized, double-blind, placebo-controlled study. British Journal of 
Dermatology. 2001. 145: 546-553.
R16-5751
Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T 
cells: recognition and management. Blood. 2016. 127(26): 3321-3330.
R17-0324
PPP: physician's global assessment: the most severely affected 
palmoplantar surface. http://eraspen.eu/home/Further-
information/physicians-global-assessment0.html (access date: 27 January 
2017); European Rare and Severe Psoriasis Expert Network (ERASPEN) 
2015.
R17-2617
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen 
P, et.al. Opportunistic infections and biologic therapies in immune-
mediated inflammatory diseases: consensus recommendations for infection 
reporting during clinical trials and postmarketing surveillance. Ann Rheum 
Dis. 2015. 74: 2107-2116.
R17-3632
Mahil SK, Catapano M, Meglio P Di, Dand N, Ahlfors H, Carr IM, et.al. 
An analysis of IL-36 signature genes and individuals with IL1RL2 
knockout mutations validates IL-36 as a psoriasis therapeutic target. Sci 
Transl Med. 2017. 9: eaan2514.
R19-0483
Augustin M, Radtke MA, Zschocke I, Blome C, Behechtnejad J, Schäfer I, 
et.al. The patient benefit index: a novel approach in patient-defined 
outcomes measurement for skin diseases. Arch Dermatol Res. 2009. 301: 
561-571.
R19-0676
Terui T, Kobayashi S, Okubo Y, Murakami M, Hirose K, Kubo H. Efficacy 
and Safety of Guselkumab, an Anti-interleukin 23 Monoclonal Antibody, 
for Palmoplantar Pustulosis A Randomized Clinical Trial. JAMA 
Dermatology. 2018. 154(3): 309-316.
R19-0677
Terui T, Zheng R, Morishima H, Goto R, Kimura T. P0422 Interim results 
of phase 3 study demonstrating efficacy for guselkumab in subjects with 
palmoplantar pustulosis. EADV Congress. 12-16 September 2018.
R19-0678
Gottlieb A, Sullivan J, van Doorn M, Kubanov A, You R, Parneix A, et.al. 
Secukinumab shows significant efficacy in palmoplantar psoriasis: Results 
from GESTURE, a randomized controlled trial. J Am Acad Dermatol. 
2017. 76: 70-80.
R19-0861
Yamamoto T. Clinical Characteristics of Japanese Patients with 
Palmoplantar Pustulosis. Clinical Drug Investigation. 2019. 39: 241-252.


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R19-0961
Uehara M and Ofuji S. The morphogenesis of pustulosis palmaris et 
plantaris. Arch Dermatol. 1974. 109: 518-520.
R96-2382
The EuroQol Group. EuroQol - a new facility for the measurement of 
health-related quality of life. Health Policy. 1990. 16: 199-208.
R96-3541
Fredriksson T, Pettersson U. Severe Psoriasis – Oral Therapy with a New 
Retinoid. Dermatologica. 1978. 157: 238-244.
9.2
UNPUBLISHED REFERENCES
c03320877
Investigator's Brochure BI 655130. Current Version.
c03361085-07
Clinical Trial Protocol 1368.1 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; 27 January 2016.


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
10.1.1
Palmoplantar Pustulosis Area and Severity Index (PPP ASI)
Score
0
1
2
3
4
5
6
Erythema (E)
None
Slight
Moderate
Severe
Very 
severe
Pustules (P) 
(total)
None
Slight
Moderate
Severe
Very 
severe
Desquamation 
(D) (scaling)
None
Slight
Moderate
Severe
Very 
severe
Area affected 
(%)*
0
<10
10<30
30<50
50<70
70<90
90 - 100
* where area assessed is glabrous skin on the palms/ soles 
PPP ASI = [(E+P+D) Area x 0.2 (right palm)] + [(E+P+D) Area x 0.2 (left palm)] + [(E+P+D) Area x 0.3 (right 
sole)] + [(E+P+D) Area x 0.3 (left sole)]
10.1.2
Palmoplantar Pustulosis Physician Global Assessment (PPP PGA)
Components 
Erythema* 
0=Clear; 1=Almost Clear; 2=Mild, 3=Moderate, 4=Severe
Pustules 
0=Clear; 1=Almost Clear; 2=Mild, 3=Moderate, 4=Severe
Scaling/Crusting
0=Clear; 1=Almost Clear; 2=Mild, 3=Moderate, 4=Severe
*Do not score eroded area, physiological erythema, frictional hyperkeratosis and calluses
Each of the components (erythema, pustules, scaling/crusting) should be scored and recorded. 
The PPP PGA total score is derived as the mean of all individual components.
PPP PGA Total Score:
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


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10.1.3
Pain Visual Analogue Scale (VAS)
10.1.3.1
Pain VAS because of PPP on the palms and/or soles (PPP Pain VAS)
How much pain have you had because of your palmoplantar pustulosis (PPP) on the palms 
and/or soles in the past week?
Place a vertical (│) mark on the line to indicate the severity of the pain. 
No pain
Severe pain
0
100
10.1.3.2
Pain VAS for muscular or joint pain 
How much muscular or joint pain have you had 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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10.2
DIAGNOSIS OF ANAPHYLAXIS
Clinical Criteria for diagnosing anaphylaxis [R11-4890]
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 
1 year, less than (70 mm Hg +[2 x age] from 1 to 10 years, and less than 90 mm Hg from 11 
to 17 years.


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10.3
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (OMERACT)
1 - Mild
2 - Moderate
3 - Severe
4 - Includes Life 
Threatening
Asymptomatic, or
transient
Short duration (< 
1 week)
No change in life 
style 
No medication or 
OTC 
Symptomatic
Duration (1–2 
weeks) 
Alter lifestyle 
occasionally
Meds relieve. (may 
be prescription),
Study drug 
continued
Prolonged 
symptoms, 
reversible, major 
functional 
impairment
Prescription 
meds/partial relief
May be 
hospitalized<24h
Temporary study 
drug discontinuation, 
or/and dose reduced
At risk of death
Substantial disability, 
especially if 
permanent.
Multiple meds
Hospitalised >24h
Study drug 
discontinued
A.ALLERGIC/IMMUNOLOGIC
A1. Allergic 
reaction/
hypersensit-vity 
(including drug 
fever)
Transient rash; 
drug fever < 38° 
C, transient 
asymptomatic 
bronchospasm
Generalized 
urticaria responsive 
to meds; or drug 
fever > 38° C, or 
reversible 
bronchospasm
Symptomatic 
bronchospasm, 
requiring meds; 
symptomatic 
urticaria persisting 
with meds, allergy 
related 
oedema/angioedema
Anaphylaxis, 
laryngeal/ 
pharyngeal edema, 
requiring 
resuscitation
A2. 
Autoimmune 
reaction
Serologic or other 
evidence of 
autoimmune 
reaction but 
patient 
asymptomatic: all 
organ function 
normal and no 
treatment is 
required (e.g., 
vitiligo)
Evidence of 
autoimmune 
reaction involving a 
non-essential organ 
or functions, 
requiring treatment 
other than 
immunosuppressive 
drugs (e.g., 
hypothyroidism)
Reversible 
autoimmune reaction 
involving function of 
a major organ or 
toxicity requiring 
short term 
immunosuppressive 
treatment (e.g., 
transient colitis or 
anemia)
Causes major organ 
dysfunction, or 
progressive, not 
reversible, or 
requires long term 
administration of 
high dose 
immunosuppressive 
therapy
A3. Rhinitis 
(includes 
sneezing, nasal 
stuffiness, post 
nasal discharge)
Transient, non-
prescription meds 
relieve
Prescription med 
required, slow
Corticosteroids or 
other prescription 
med. with persistent 
disabling symptoms 
such as impaired 
exercise tolerance
NA


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10.4
SMOKING HISTORY BASED ON CALCULATION OF PACK YEARS 
Calculation of pack years based on number of cigarettes:
Pack years = Number of cigarettes/day   x   years of smoking
20
The following equivalents for the tobacco content should be used for smokers other than 
cigarettes smokers (R08-5197):
One plain or filter cigarette = 1 gram of tobacco
One cigar = 5 grams of tobacco
One cheroot or cigarillo = 3 grams of tobacco
One gram of pipe tobacco = 1 gram of tobacco
Calculation of pack years based on tobacco contents:
Pack years =
Number of grams/day  x years of smoking
20


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18863881
1.0
clinical-trial-protocol-version-01
Multi-center, double-blind, randomised, placebo-controlled, phase IIb dose-finding
study to evaluate efficacy and safety of different subcutaneous doses of BI 655130 in
patients with moderate to severe Palmoplantar Pustulosis (PPP)
Author-Clinical Trial Leader
04 Apr 2019 14:04 CEST
Approval-Team Member Medicine
04 Apr 2019 14:24 CEST
Author-Trial Clinical
Pharmacokineticist
04 Apr 2019 15:32 CEST
Author-Trial Statistician
05 Apr 2019 05:26 CEST
Approval-Therapeutic Area 
05 Apr 2019 10:10 CEST
Verification-Paper Signature
Completion
11 Apr 2019 14:53 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18863881
1.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c32614118-01
BI Trial No.:
1368-0016
Title:
Multi-center, double-blind, randomised, placebo-controlled, phase
IIb dose-finding study to evaluate efficacy and safety of different
subcutaneous doses of BI 655130 in patients with moderate to
severe Palmoplantar Pustulosis (PPP) [c18863881-01]
Investigational
Product:
Spesolimab (BI 655130)
Responsible trial 
statisticians:
Tel.:
Fax: 
Date of statistical 
analysis plan:
22 Jul 2020 SIGNED
Version:
1.0 Final
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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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................5
2.
LIST OF ABBREVIATIONS ..............................................................................6
3.
INTRODUCTION.................................................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY....................10
5.
ENDPOINTS .......................................................................................................11
5.1
PRIMARY ENDPOINT(S) ................................................................................11
5.2
SECONDARY ENDPOINT(S) ..........................................................................11
Key secondary endpoint(s)........................................................................11
5.2.1
Secondary endpoint(s) ...............................................................................11
5.2.2
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................16
6.1
TREATMENTS...................................................................................................16
6.2
IMPORTANT PROTOCOL DEVIATIONS ...................................................19
6.3
PATIENT SETS ANALYSED...........................................................................30
6.5
POOLING OF CENTRES .................................................................................35
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................36
Withdrawals ...............................................................................................36
6.6.1
Efficacy data...............................................................................................36
6.6.2
Safety data ..................................................................................................38
6.6.3


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Time since first diagnosis/tonsillectomy...................................................39
6.6.7
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................39
7.
PLANNED ANALYSIS......................................................................................42
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........44
7.2
CONCOMITANT DISEASE AND MEDICATION........................................45
7.3
TREATMENT COMPLIANCE........................................................................46
7.4
PRIMARY ENDPOINT .....................................................................................46
7.5
SECONDARY ENDPOINTS.............................................................................50
Key secondary endpoint ............................................................................50
7.5.1
Secondary endpoints..................................................................................50
7.5.2
Analysis of % change in PPP ASI from week 16 ....................................53
7.5.3
7.7
EXTENT OF EXPOSURE.................................................................................57
7.8
SAFETY ANALYSIS..........................................................................................58
Adverse events............................................................................................59
7.8.1
Laboratory data .........................................................................................62
7.8.2
Vital signs....................................................................................................63
7.8.3
ECG.............................................................................................................63
7.8.4
Local tolerability........................................................................................63
7.8.5
7.9
ANALYSIS OF COVID19 IMPACT ................................................................66
7.10
HANDLING OF DMC ANALYSES.................................................................67
8.
REFERENCES....................................................................................................68
9.
ADDITIONAL SECTIONS ...............................................................................71
9.1.1
PPP ASI and related endpoints ................................................................71
9.1.2
PPP PGA.....................................................................................................73
9.1.3
Pain VAS score...........................................................................................74


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10.
HISTORY TABLE..............................................................................................88


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LIST OF TABLES
Table 6.1: 1 
Flow chart of analysis phases ...........................................................................16
Table 6.2: 1
Important protocol deviations...........................................................................20
Table 6.3: 1
Patient sets analysed .........................................................................................32
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, and 
biomarker measurements to visits for statistical analysis.................................40
Table 7.1: 1
Categories for summary of continuous variables .............................................44
Table 7.4: 1
Total dose per treatment arm............................................................................48
Table 7.4: 2
Contrast coefficient...........................................................................................48
Table 7.5.2: 1 Contrast coefficient...........................................................................................52
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events 
Concepts ...........................................................................................................61
Table 10: 1
History table .....................................................................................................88


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug antibodies
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ALQ
Above limit of quantification
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
ATC3
Anatomical-Therapeutic-Chemical classification level 3
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BM-SAP
Biomarker Statistical Analysis Plan
BMI
Body mass index
BRAVE
BI RAVE®
BRPM 
Blinded Report Planning Meeting
BSA
Body surface area
CARE
Clinical data analysis and reporting environment
CI
Confidence interval
CRF
Case report form
CRP
C-reactive protein
CTC
Common Terminology Criteria
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBL
Database lock
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form


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Term
Definition / description
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOT
End of trial
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials
FAS
Full analysis set
F/U
Follow-up
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IHC
Immunohistochemistry
IL
Interleukin
IPD
Important protocol deviation
IRT
Interactive response technology
kg
Kilogram
LLOQ
Lower limit of quantification
LOCF
Last observation carried forward
LOQ
Limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures
mQC
Medical quality control
MQRM
Medical quality review meeting
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
NRI
No response imputation
OC
Observed cases
OC-IR
Observed cases including values after rescue therapy or treatment 
discontinuation
OR
Original results
PD
Pharmacodynamic(s), protocol deviation
PG
Pharmacogenomic(s)
PGA
Physician Global Assessment


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Term
Definition / description
PPP
Palmoplantar Pustulosis
PPP PGA
Palmoplantar Pustulosis Physicians Global Assessment
PPP ASI
Palmoplantar Pustular Psoriasis Area and Severity Index
PPS
Per protocol set
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual effect period
RS
Randomized set
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SD
Standard deviation
SDL
Subject data listing
SI
Système international d’unités
SMQ
Standardised MedDRA query
SOC
System Organ Class
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range
ULOQ
Upper limit of quantification
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 analyses described in the CTP and its amendments, 
and to include detailed procedures for executing the statistical analysis of the primary and 
secondary variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, and randomization.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 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).
This TSAP will document the features of the primary analysis for week 16 (to be performed 
once all randomized patients have completed through the week 16 of trial), as well as the final 
analysis (to be performed once all patients have completed the trial).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses stated in the CTP (latest version) will be performed as planned with the 
following adaptations.
In the CTP, MMRM model for % change in PPP ASI from baseline will include baseline 
visits, visits 6, 7, 8 and 9. In TSAP, the visits 3, 4 and 5 are also included.  
In the CTP, for the continuous secondary endpoint of percent change in PPP ASI from 
baseline at Week 52, the following maintenance treatment comparisons will be performed 
using an MMRM (incorporating weeks 4, 12, 20, 28, 36, 44, and 52). In TSAP, the visits 
including week 28, 40 and 52 will be included in addition to the visits included for primary 
analysis at week 16. 


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5.
ENDPOINTS
5.1
  PRIMARY ENDPOINT(S)
The % change in PPP ASI at Week 16 from baseline is the primary endpoint of efficacy in 
this trial.
Derivation of % change in PPP ASI is described in Section 9.1.1.
Any data collected after use of any rescue therapy or after 6 weeks following last drug 
administration if a patient discontinued treatment early (to allow for incorporation of the 
continuing maximum treatment effect period) are censored for the purpose of the primary 
estimand (EC).
5.2
SECONDARY ENDPOINT(S)
Key secondary endpoint(s)
5.2.1
Not applicable.
Secondary endpoint(s)
5.2.2
Secondary endpoints are defined as described below:

Change from baseline in PPP Pain Visual Analog Scale (VAS) score at Week 4 and 16

PPP SI change from baseline at Week 16

PPP ASI50 at Week 16

PPP ASI75 at Week 16

PPP PGA clear/almost clear (0 or 1) at Week 16

PPP PGA pustules clear/almost clear (0 or 1) at Week 16

Percent change in PPP ASI from baseline at Week 52.
Derivations of PPP ASI related endpoints and PPP SI are described in Section 9.1.1.
Derivation of PPP PGA related endpoints is described in Section 9.1.2.
Note that for the secondary endpoints, any data collected after use of any rescue therapy or 6 
weeks following last drug administration if a patient discontinued treatment early (to allow for 
incorporation of the continuing maximum treatment effect period) are censored for the 
purpose of the primary estimand (EC).


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
The occurrence of Treatment Emergent Adverse Events (TEAEs)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For more details of study information on the treatment to be administered, assignment to 
treatment, and selection of dose, refer to Section 4 of the CTP.
The following study phases are defined:
Table 6.1: 1
Flow chart of analysis phases
Study analysis 
phase
Description
Start (included)
End (included)
Screening phase
Screening
Earliest of (Date of 
informed consent, first 
screening procedure) 
Date/time of start of the first study
dose minus 1 minute.
Loading treatment 
phase
On-treatment 
period
Date/time of start of the first 
study loading dose (Day 1) 
Earlier of: i) Date/time of start of 
the first maintenance dose; or, ii) 
Date of end of last loading dose + 
112 days at 11:59 p.m. if patient 
early discontinued study treatment
before the first maintenance dose
Maintenance 
treatment phase 
(primary analysis at
week 16)
Date/time of start of the first 
study maintenance dose (if 
applicable)
Earlier of : i) Date/time of start of 
the first maintenance dose at or 
after week 16; or, ii) Date of end of 
last maintenance dose + 112 days 
at 11:59 p.m. if patient early 
discontinued study treatment 
before week 16
Maintenance 
treatment phase 
(post primary 
analysis at week 
16)
Date/time of start of the first 
maintenance dose at or after   
week 16 (if applicable)
Earlier of: i) Date/time of start of 
first dose in OLE 1368.24 trial; or,
ii) Date of end of last 
study maintenance dose + 112 days 
at 11:59 p.m.
Follow-up1 phase 
(if applicable)
Off-treatment 
period (if 
applicable)
Date of end of last study 
dose + 113 days at 0:00 a.m.
Latest of: i) Date of EOS visit; ii) 
end date on trial termination page 
at 11:59 p.m. iii) Date/time of start 
of first dose in OLE 1368.24 trial;
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase 
will not extend beyond the start date of the following phase. 
1 The off-treatment period (i.e. Follow-up phase) only exists if the trial completion date is after the date of end of last 
administration + 112 days.
The primary analysis is planned to be performed once all patients have completed through the 
planned first 16 weeks of trial or early discontinued. The primary analysis will focus on 
individual patient’s data up to treatment at week 16. If a patient early discontinued from 
treatment before week 16 or missed visit at week 16 but was still ongoing beyond week 16, all
on-treatment data up to Day 127 which is the right limit of the week 16 extended time
window (see Table 6.7: 1) will be included. In addition, for patients who missed visit at week 


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16 but was still ongoing beyond week 16, PPP Pain VAS, PPP ASI and PPP PGA 
assessments up to the first maintenance treatment after Week 16 (if available at time of 
primary analysis) will be included. They will not be reported in any outputs for primary 
analysis but might be used for imputation of endpoints related to PPP Pain VAS, PPP ASI and 
PPP PGA. See Section 6.6.2 for the details of imputation methods. 
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 trial 
analysis will include all trial data. 
Treatment groups for the analysis of Arm 1-4 will be labelled and sorted as follows:

"Speso Low": (i.e., Arm 4)

"Speso Medium-low": (i.e., Arm 3)

"Speso Medium-high": (i.e., Arm 2)

"Speso High": (i.e., Arm 1)

“Speso Total” (i.e., Arm 1, 2, 3 and 4), where appropriate for analysis up to Week 16
Treatment groups for Arm 5 will be labelled differently based on the data included in the 
analysis:

"Placebo & Speso": (i.e., Arm 5 if all trial data reported)

"Placebo": (i.e., Arm 5 if only data prior to the first Spesolimab treatment reported )

"Speso post placebo": (i.e., Arm 5 if only data post the first Spesolimab treatment
reported)
If needed, Arm 1-5 could be pooled using the following label:

“Overall Total”: (i.e., Arm 1, 2, 3, 4 and 5), where appropriate 
For the analysis on safety data post Week 16, the following treatments will be added in 
addition to original treatments as follows (see Section 7.8):

"Speso
 (i.e., Arm 1 + Arm 3 + Arm 5)
For the additional analysis on efficacy and safety data within loading stage, treatments will be 
re-grouped as follows (see Section 7.6.4 and Section 7.8):

"Placebo": (i.e., Arm 5)

"Speso 
 (i.e., Arm 3 + Arm 4)

"Speso 
 (i.e., Arm 1 + Arm 2)


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For the additional analysis on efficacy data post Week 16, treatments will be regrouped as 
follows (see Section 7.5.3):

"Speso 
 (i.e., Arm 4)

"Speso 
 (i.e., Arm 2) 

"Speso 
 (i.e., Arm 1 + Arm 3 + Arm 5)
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 violations of 
time windows) and a list of protocol deviations will be provided to be discussed at the 
RPM/DBLM/MQRM. At this meeting, it will be decided whether a discrepant data value can 
be used in analyses or whether it must be queried in the clinical database. Each protocol 
deviation must be assessed to determine whether it is an important Protocol Deviation (iPD). 
For definition of iPDs, and for the process of identification of these, refer to the BI reference 
document "Identify and Manage Important Protocol Deviations (iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM/MQRM minutes via an accompanying Excel spreadsheet (3). The following 
table contains the categories which are considered to be iPDs in this trial. If the data show 
other iPDs, for example, based on monitor visits to the sites, then this table will be 
supplemented accordingly by the time of the RPM/DBLM/MQRM. 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 summarised and listed for the randomized set.
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 
from1
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
Palmoplantar Pustulosis defined as 
presence of primary, persistent (>3 
months duration), sterile, 
macroscopically visible pustules on the 
palms and/or soles, without or with 
plaque psoriasis elsewhere on the body.
LABEL:
No presence of PPP.
IC02
Also check versus PPP ASI
that pustule severity > 0 on 
at least one region
PPS
A1.02
Presence of white or yellow pustules on 
palms and/or soles at screening and 
baseline
LABEL:
No presence of white or yellow pustules
on palms/soles.
IC03
PPS
A1.03
Pustular severity score ≥2 in at least one 
region and ≥10 well-demarcated pustules 
(white or yellow pustules) across all 
regions at screening and baseline
LABEL:
No pustular severity score ≥2 in any 
region or <10 well-demarcated pustules
IC04
Also check versus PPP ASI 
that pustule severity ≥2 on 
at least one region
PPS
A1.04
PPP PGA of at least moderate severity 
(≥3) at screening and baseline.
LABEL:
PPP PGA not at least moderate severity
IC05. Also check versus 
reported PPP PGA at 
baseline.
PPS
A1.05
A minimum PPP ASI score of 12 at 
screening and baseline 
LABEL: 
PPP ASI < 12
IC06. Also check versus 
derived PPP ASI at baseline.
PPS


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A1.06
Male or female patients. Women of 
childbearing potential (WOCBP)  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. 
LABEL:
Contraception methods not used.
IC07
None
A2
Exclusion criteria violated 
General Exclusion Criteria
A2.01
Reduction in PPP ASI total score ≥5 
from screening visit (Visit 1) to baseline 
(randomisation visit, Visit 2).
LABEL: 
Reduction in PPP ASI total score ≥5 
from V1 to V2
EC01
Also check versus PPP ASI 
at V1 and V2.
PPS
A2.02
Patients with plaque psoriasis with 
worsening of plaque psoriasis within the 
last 3 months prior to screening.
LABEL: 
Worsening of plaque psoriasis within the 
last 3 months
EC02
PPS
A2.03
Skin conditions that affect ability to 
score area and severity of PPP 
components 
LABEL: 
No ability to score are and severity of 
PPP components
EC03
PPS
A2.04
Women who are pregnant, nursing, or 
who plan to become pregnant while in 
the trial.
LABEL: 
Pregnant or nursing.
EC04
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A2.05
Severe, progressive, or uncontrolled 
renal, hepatic, haematological, 
endocrine, pulmonary, cardiac, 
neurologic, cerebral, or psychiatric 
disease, or signs and symptoms thereof. 
LABEL: 
Severe or uncontrolled disease.
EC05
None
A2.06
Presence or known history of anti-TNF-
induced PPP-like disease.
LABEL:
Anti-TNF-induced PPP-like disease.
EC06
PPS
A2.07
Patient with a transplanted organ or who 
have ever received stem cell therapy 
LABLE:
A transplanted organ or a stem cell 
therapy
EC07
None
A2.08
Known history of lymphoproliferative 
disease, including lymphoma, or signs 
and symptoms suggestive of possible 
lymphoproliferative disease, such as 
lymphadenopathy and/or splenomegaly.
LABEL:
Lymphoproliferative disease.
EC08
None
A2.09
Any documented active or suspected 
malignancy or history of malignancy 
within 5 years prior to screening, except 
appropriately treated basal cell 
carcinoma of the skin, squamous cell 
carcinoma of the skin or in situ 
carcinoma of uterine cervix.
LABEL:
Malignancy within last 5 years.
EC09
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A2.10
Use of any restricted medication as 
specified in CTP 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
LABEL:
Use of restricted medication interfering 
safety
EC10 – based on tick box 
only.
PPS
A2.11
Administration of live vaccines during 
the study period or within 6 weeks prior 
to randomisation.
LABEL:
Live vaccine within last 6 weeks.
EC11
None
A2.12
History of allergy/hypersensitivity to the 
systemically administered trial 
medication agent or its excipients.
LABEL:
History of allergy/hypersensitivity.
EC12
None
A2.13
Active systemic infections during the 
last 2 weeks (exception: common cold) 
prior to randomisation, as assessed by 
the investigator.
LABEL:
Systemic infections within last 2 weeks.
EC13
None
A2.14
Chronic or relevant acute infections 
including human immunodeficiency 
virus (HIV), viral hepatitis and (or) 
active or latent tuberculosis (TB):
LABEL:
Chronic or relevant acute infections.
EC14
None
A2.15
Major surgery performed within 12 
weeks prior to randomisation or planned 
within 52 weeks after randomisation, as 
assessed by the investigator.
LABEL:
Recent or planned major surgery.
EC15
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A2.16
Patient has received surgical treatment of 
focal infection (e.g. tonsillectomy or 
dental therapy) within 6 months of 
randomisation.
LABEL:
Surgical treatment of focal infection
EC16
None 
A2.17
Total white blood count (WBC) < 
3,000/μL, or platelets < 100,000/μL or 
neutrophils < 1,500/μL, or hemoglobin 
<8.5 g/dL at screening.
LABEL:
WBC, PLAT, NEU, HGB below limit. 
EC17
Also check versus screen 
Lab values
None
A2.18
Aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) > 2x the 
upper limit of normal, or total bilirubin > 
1.5x the upper limit of normal (patients 
with Gilbert’s syndrome are not 
excluded) at screening.
LABEL:
AST/ALT/TBIL above limits.
EC18
Also check versus screen 
Lab values (medical review 
for Gilbert Syndrome)
None
A2.19
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).
LABEL:
Recent enrollment in other study.
EC19
PPS


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
A2.20
Chronic alcohol or drug abuse or any 
condition that, in the investigator’s 
opinion, makes the patient an unreliable 
trial participant or unlikely to complete 
the trial.
LABEL:
Alcohol or drug abuse.
EC20
PPS
A2.21
Patients not expected to comply with the 
protocol requirements or not expected to 
complete the trial as scheduled.
LABEL:
No expectation to comply with the CTP 
or complete the trial.
EC21
PPS
A2.22
Previous randomisation in this trial.
LABEL:
Previous randomisation in this trial.
EC22
PPS
B
Informed consent
B1
Informed consent not available
LABEL:
IC not available.
IC01
Date of informed consent 
missing or no signature on 
patient’s “Declaration of 
Informed Consent”
In this case: Patient’s data 
will not be used at all.
All
#
B2
Informed consent too late
LABEL:
IC too late.
IC01
Informed consent date was 
after Visit 1
None


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
C
Trial medication and randomisation
C1
Incorrect trial medication
C1.01
Study drug medication not taken at all
LABEL:
Study drug medication not taken at all.
All except 
for ES and 
RS
C1.02a
Patient skipped an intermediate dose
prior to Week 16 for other reason
(all injections at one planned visit)
LABEL:
Patient skipped an intermediate dose
prior to Week 16 for other reason.
Patient missing a dose at an 
intermediate visit when dose 
at a later scheduled visit has 
been taken due to other 
reason.
PPS
C1.02b
Patient skipped an intermediate dose 
prior to Week 16 due to COVID 19
(all injections at one planned visit)
LABEL:
Patient skipped an intermediate dose 
prior to Week 16 due to COVID 19.
Patient missing a dose at an 
intermediate visit when dose 
at a later scheduled visit has 
been taken due to COVID 
19.
PPS
#
C1.03a
Patient skipped an intermediate dose at 
or after Week 16 for other reason
(all injections at one planned visit)
LABEL:
Patient skipped an intermediate dose at 
or after Week 16 for other reason.
Patient missing a dose at an 
intermediate visit when dose 
at a later scheduled visit has 
been taken due to other 
reason.
None
C1.03b
Patient skipped an intermediate dose at 
or after Week 16 due to COVID 19
(all injections at one planned visit)
LABEL:
Patient skipped an intermediate dose at 
or after Week 16 due to COVID 19.
Patient missing a dose at an 
intermediate visit when dose 
at a later scheduled visit has 
been taken due to COVID 
19.
None
#


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
C2
Incorrect Dosing
C2.01
Incorrect medication received prior to 
Week 16
LABEL:
Incorrect dose received prior to Week 16
Randomized patient who 
didn’t receive correct
planned total dose at any 
scheduled visit prior to 
Week 16.
Can only be finally judged 
after DBL since unblinding 
information is required
PPS
C2.02
Incorrect medication received at or after 
Week 16
LABEL:
Incorrect dose received at or after Week 
16
Randomized patient who 
didn’t receive correct 
planned total dose at any 
scheduled visit at or after 
Week 16
Can only be finally judged 
after DBL since unblinding 
information is required
None
C3
Randomization not followed
C3.01
Treated without randomisation
LABEL:
Treated without randomisation.
Patient treated according to 
eCRF, but not randomised 
according to IVRS.
All 
C3.02
Randomization order not followed
LABEL:
Stratification error
Stratification error
Programming check and also 
manual review after DBL
None
#
C4
Medication code broken
C4.01
Medication code broken before week 16 
without just cause
LABEL:
Code broken early without just cause.
Medication code was broken 
prior to DBL for the week 
16 analysis for no valid 
reason.
Final decision at the DBL 
meeting for the Week 16 
analysis based on medical 
judgment.
PPS
#


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
C4.02
Medication code broken after week 16 
without just cause
LABEL:
Code broken late without just cause.
Medication code was broken 
after DBL for the week 16 
analysis for no valid reason.
Final decision at final DBL 
based on medical judgment.
None
#
D
Concomitant medication
D1
Previous medication
D1.01
Washout of previous medication too 
short
LABEL:
Washout too short.
PPS
#
D2
Prohibited medication use
D2.01a
Use of restricted medication as per CTP 
Table 4.2.2.1: 1 on or after Screening or 
during the on-treatment period - when 
not provided as a rescue therapy to treat 
a worsening disease condition – prior to 
Week 16 primary analysis for other 
reason
LABEL:#
Restricted medication prior to week 16 
primary analysis for other reason.
PPS
#
D2.01b
Use of restricted medication as per CTP 
Table 4.2.2.1: 1 on or after Screening or 
during the on-treatment period - when 
not provided as a rescue therapy to treat 
a worsening disease condition – prior to 
Week 16 primary analysis due to 
COVID 19
LABEL:
Restricted medication prior to week 16 
primary analysis for COVID 19.
PPS
#


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Table 6.2: 1 (cont’d) Important protocol deviations
Category / 
Code
Description
Comments
Excluded 
from1
D2.02a
Use of restricted medication as per CTP 
Table 4.2.2.1: 1 on or after Screening or 
during the on-treatment period - when 
not provided as a rescue therapy to treat 
a worsening disease condition – after 
Week 16 primary analysis for other 
reason
LABEL:
Restricted medication after week 16 
primary analysis for other reason.
None
#
D2.02b
Use of restricted medication as per CTP 
Table 4.2.2.1: 1 on or after Screening or 
during the on-treatment period - when 
not provided as a rescue therapy to treat 
a worsening disease condition – after 
Week 16 primary analysis due to 
COVID 19
LABEL:
Restricted medication after week 16 
primary analysis due to COVID 19.
None
#
E
Missing data
<not specified>
F
Study specific analysis
<not specified>
G
Other safety related deviations
G1.01
Pregnancy test not done for woman of 
child bearing potential before IMP 
administration
LABEL:
Pregnancy test not done.
Pregnancy test not done at 
any visit before IMP was 
given.
None
#
# PD will be detected manually; 
Source: BI reference document ' Identify and Manage Important Protocol Deviations (iPD)' [001-MCS-50-413] (2,6).
1 See Section 6.3 for population definitions 


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6.3
PATIENT SETS ANALYSED
The following analysis sets will be defined for this trial:
Enrolled set (ES)
This patient set includes all patients who signed informed consent. It will be used for display 
of patient disposition.
Randomized set (RS)
This patient set includes all patients who were randomized in the trial. Treatment assignment 
will be as randomised. It will be used for display of disposition, IPD and etc.
Safety analysis set (SAF)
This patient set includes all patients who were randomised and received at least one dose of 
study drug. It will be the main analysis set for presentation of safety data. Patients will be 
analyzed according to the actual treatment.
Safety analysis set – Post Week 16 (SAF-post 16)
This patient set includes all patients in SAF who received at least one dose of study drug after, 
and including, Week 16. It will be the main analysis set for presentation of safety data after 
Week 16 only. Patients will be analyzed according to the actual treatment after week 16.
Full Analysis Set (FAS)
This patient set includes all patients who were randomised, received at least one dose of study 
drug and had a baseline for the primary endpoint. Treatment assignment will be as 
randomised. This is the main analysis set for presentation of efficacy data.
Full Analysis Set – Post Week 16 (FAS-post 16)
This patient set includes all patients in the FAS and had received at least one dose of study 
drug after, and including Week 16. Treatment assignment will be as randomised. This is the 
set for additional analysis of efficacy data post Week 16.
Per-Protocol Set (PPS)
This patient set includes all patients in the FAS 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 efficacy endpoint.
Modified FAS set (m-FAS)
This patient set includes all patients in the FAS set excluding pre-identified questionable 
cases (mild cases) based on mQC (medical quality control) review where the severity of PPP 
could not be clarified and confirmed based on the descriptive review and quality control of the 
photo documentation. The m-FAS will be used for sensitivity analysis on the primary efficacy 
endpoint and selected secondary endpoints.


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Handling of Treatment Misallocations in Analysis Sets
If a patient is randomized but not treated, they will not be included into efficacy or safety 
analysis according to FAS (including FAS-post 16), m-FAS, PPS and SAF (including SAF-
post 16).
If a patient is treated but not randomized, they will be excluded from both efficacy analysis 
and safety analysis by definition. However, patients under such circumstances will be 
described separately in the final clinical trial report.
If a patient is randomized but took incorrect treatment during the study, then:
-
For efficacy analyses according to FAS (including FAS-post 16), m-FAS and PPS, they 
will be reported under their randomized treatment groups. 
-
For safety analyses using the SAF,  
•
For Arm1-4: If a patient is planned to receive multiple dose administrations of 
Spesolimab, then patients will be reported under their randomized treatment group 
for safety analysis because the overall safety profile is expected to be driven by the 
amount of Spesolimab received in totality over the entire treatment duration. It is not
expected that the safety profile will deviate from the planned treatment regimen if the 
subject receives only a few vials of the incorrect medication at only some dosing 
occasions.
•
For Arm 5: If a patient is planned to receive multiple dose administrations of placebo 
(prior to Week 16 only), then patients will be reported under their randomized 
treatment group for safety analysis if the patient receives no dose of randomized 
Spesolimab during this treatment period (i.e., prior to Week 16). If the patient 
receives ≥1 syringe of randomized Spesolimab during this treatment period, then the 
patient will be assigned to Arm 4 (lowest dose of Spesolimab planned in the trial 
before week 16).
-
For safety analyses using the SAF-post 16, 
•
For Arm1-5: If a patient is planned to receive multiple dose administrations of 
Spesolimab, then patients will be reported under their randomized treatment group 
for safety analysis because the overall safety profile is expected to be driven by the 
amount of Spesolimab received in totality over the entire treatment duration. It is not
expected that the safety profile will deviate from the planned treatment regimen if the 
subject receives only a few vials of the incorrect medication at only some dosing 
occasions.
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. For explanation of the different methods 
of handling missing data, cf. Section 6.6.


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Table 6.3: 1
Patient sets analysed
Class of endpoint
Patient set
ES
RS
SAF
(includin
g SAF-
post 16)
FAS (including 
FAS-post 16, m-
FAS)
PPS
Disposition
OR
OR
Compliance and exposure
OR
iPD
OR
Demographic/baseline characteristics
OR
OR
CM
OR
Primary efficacy endpoint
EC-MMRM,
EC-MMRM1
EC-EP-MMRM1
EC-E19-MMRM1
EC-ID-MMRM1
EC-MI1, OC2,
OC-IR2
EC-
MMRM1
Secondary efficacy endpoints (Binary)
EC-NRI,
EC-NRI1,3
EC-EP-NRI1,3
EC-E19-NRI1,3
EC-ID-NRI1,3
EC-BRI1,3
OC2, OC-IR2
Secondary efficacy endpoints 
(Continuous)
EC-MMRM,
EC-MMRM1,3
OC2, OC-IR2
 ADA/Nab
OR
1 sensitivity analysis or subgroup analysis
2 descriptive display only
3 selected endpoints.


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EC: Primary estimand for binary and continuous efficacy endpoints. Any data collected after use of any rescue therapy or 
after 6 weeks following last drug administration if patient early discontinued treatment (to allow for incorporation of the 
continuing maximum treatment effect period) are censored.
EC-EP: Alternative estimand for binary and continuous efficacy endpoints. Any data collected after use of any rescue therapy 
or restricted therapy for other purpose or after 6 weeks following last drug administration if patient early discontinued 
treatment (to allow for incorporation of the continuing maximum treatment effect period) are censored. 
EC-E19: Alternative estimand for binary and continuous efficacy endpoints. Any data collected after use of any rescue 
therapy or after the first visit with missing treatment due to COVID-19 or after 6 weeks following last treatment before or at 
discontinuation (to allow for incorporation of the continuing maximum treatment effect period) are censored.
EC-ID: Alternative estimand for binary and continuous efficacy endpoints. Any data collected after use of any rescue therapy 
are censored.
"NRI", "MMRM” and "MI" represent analyses involving imputed data, cf. Section 6.6.2.
OC = observed cases excluding values after any use of rescue medication or 6 weeks following last drug administration if 
patient early discontinued treatment, OC-IR = observed cases including also values after any rescue medication or treatment 
discontinuation, OR = original results. 


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6.5
POOLING OF CENTRES
There is no plan to perform statistical analysis by pooling centers. 


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Section 7.5 of the CTP describes the handling of missing data.
The original results (OR) approach implies the presentation of data exactly as observed (not 
using time windows). 
OR analysis will be performed on parameters and endpoints that are either not affected by 
patients’ rescue therapy use (e.g. plasma concentration level of Spesolimab, rescue therapy
use itself), or, if it is not meaningful to apply any imputation rule for the replacement of 
missing values
Withdrawals
6.6.1
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.
Efficacy data
6.6.2
Based on the different reasons for patients’ data missing for different endpoints, various 
approaches will be used to assess the impact of missing data on the efficacy endpoints of this 
trial, depending upon the type of the endpoint (cf. Table 6.3: 1). Approaches to be applied are 
described below.
Missing data imputations of PPP Pain VAS, PPP PGA and PPP ASI related endpoints at the 
primary analysis of the trial may be performed using all data up to the first maintenance dose 
at or after week 16 if available. Missing data imputations of other endpoints at the primary 
analysis will be performed using all data up week 16.
Continuous efficacy endpoints
For efficacy endpoints which are continuous in nature, the use of a restricted maximum 
likelihood (REML)-based mixed model repeated measures (MMRM) approach as the primary 
method, if applicable, will ensure that missing data are handled implicitly, via a missing at 
random (MAR) assumption, by the statistical model. 
In order to check the robustness of MMRM method to missing data, a sensitivity analysis will 
be performed using Multiple imputation with jump to reference method (only for primary 
analysis at week 16):
As the first step, the non-monotone missing data of PPP ASI total score will be imputed using 
Markov Chain Monte Carlo (MCMC) simulation and standard techniques. 100 imputations 
will be performed to ensure adequate efficiency and stability of the estimation for missing 
data. In a second step, for each imputation, the monotone missing data of patients that were 
still ongoing in the trial will be imputed once by standard sequential linear regression MI 
including treatment as categorical covariate and PPP ASI from baseline up to week 16 as 


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continuous covariates (other missing values will also be imputed as a by-product but 
subsequently deleted).
In a third step, the monotone missing data of patients who early discontinued study treatment 
before week 16 will be imputed using a residual-based jump to reference method. The implicit 
assumption underlying this step is that patients in the active treatment groups are assumed to 
lose any treatment effect if they early discontinued from the trial treatment. Covariate-
adjusted differences between each treatment arm and placebo (i.e. 0 for those in the placebo 
arm) will be calculated for each visit of each imputed data set using ANCOVA (with 
treatment as categorical covariate and baseline PPP ASI as continuous covariates). The 
relevant treatment effects are then deducted from the measurements in each data set, i.e. the 
expected effects of treatment are removed. Sequential linear MI is then performed once per 
modified imputed data set, but only including patients in the placebo arm and those that 
require imputation at the visit being imputed, i.e. imputation will be solely based on the 
placebo distribution. The imputation model will include PPP ASI values at previous time 
points (including baseline) as covariates. After this imputation, all originally-observed values 
will be restored. All monotone missing data will therefore follow the distribution of the 
placebo arm, jumping from one arm’s distribution to the placebo’s at the point of start of the 
missingness, while still accounting for the past within-treatment performance (the residuals).
For each imputed complete dataset, an ANCOVA (Analysis of Covariance) model for Week 
16 data analogous to the primary MMRM model will be used for the analysis. The results will 
be pooled using Rubin’s rules across the 100 imputations and the primary MCPMod analysis 
will be repeated on the summarized outcomes. 
The following additional methods will be used to display the continuous data:
Observed cases (OC) approach will include all collected data, with no imputation 
performed on the missing data. Such an OC approach will exclude all values measured 
after intake of a rescue therapy or after 6 weeks following last drug administration if a 
patient discontinued treatment early. 
Observed cases including all observed data (OC-IR) will be used as a sensitivity method 
for data display and is an extension of the OC approach which includes additionally all 
values which were measured after rescue therapy or treatment discontinuation.
Binary efficacy endpoints
For all binary endpoints (i.e. endpoints that are either 1 (patient responded) or 0 (patient did 
not respond)), the following will be performed as the primary imputation approach (analysis 
type: No Response Imputation [NRI]):

If there are data at visits both before and after the visit with a missing outcome, then 
impute as success only if both neighbouring visits also represent a success (independent of 
whether the preceding and following observations were selected for analysis based on 
time windows described in Section 6.7 and no rescue treatment has been given during this 
period);

Otherwise, impute as a failure to achieve a response 


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Other imputation scheme will be also considered for analysis of the secondary binary efficacy 
endpoints.

Best response imputation (BRI): 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-missing data available (including 
baseline), then the missing value will be imputed as a failure.
OC and OC-IR methods will be also used to display the binary data.
Safety data
6.6.3
With respect to safety evaluations, it is not planned to impute missing values. For safety data 
that are displayed by time point (or visit) of measurement, the OC-IR approach will be used.
For safety data that are not displayed by visit such as AE and possibly clinically significant 
laboratory abnormality, OR will be used. 
The only exceptions where imputation might be necessary for safety evaluation are AE dates 
and start and stop dates for concomitant medications. Missing or incomplete AE dates are 
imputed according to BI standards (4).
Partial start and stop dates for concomitant medications, rescue, and historical medication for 
PPP 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 the start date is set to first day of the month (except 
for rescue therapy, where the first dosing day will be used if first dosing happened in the 
same month).

If the day and month of the start date are missing then the start date is set to 1st January of 
the year (except for rescue therapy, where the first dosing day/month of study medication 
will be used if first dosing happened in the same year).

All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance.
If a concomitant medication was ticked to be ongoing, it is expected that the end date is 
missing and will not be imputed for display purposes.


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Time since first diagnosis/tonsillectomy
6.6.7
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows:

If the year of first diagnosis is unknown, time since first diagnosis will be set to missing.

If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th June of that year.
If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month.
Time since tonsillectomy will be imputed in the same way. 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Measurements reported with date and time and taken prior to start of administration of trial 
treatment will be considered pre-treatment values. Measurements reported with a date only 
(and no time) and taken on the day of first administration of trial treatment will also be 
considered pre-treatment values. These pre-treatment values will be assigned to visits 
according to the nominal visit number as recorded on the eCRF or as provided by the 
laboratory. 
Baseline, unless otherwise specified, is defined as the last measurement collected prior to the 
start of administration of the trial treatment.
Measurements taken after start of administration of trial treatment will be considered either 
on- or off-treatment values based on the definition in Section 6.1, and will be assigned to 
visits for statistical analysis, if applicable, as defined below.
Analysis of AE data, potentially clinically significant abnormal laboratory values, 
concomitant medication or non-drug therapies, as well as use of rescue therapy will not be 
based on visits. Frequency tables for these data will be using on-treatment data and 
categorized based on their occurring/starting dates. Therefore, no assignment to time windows 
will be necessary for such data.
The derivation of the last value, minimum value and maximum value of laboratory and vital 
signs data will consider all on-treatment values (whether or not selected in any time window; 
see Table 6.1: 1 for definition of the on-treatment period) within the period of interest; these 
will be derived for analysis of laboratory and vital signs data. 
All other safety, efficacy 
 measurements will be assigned to visits based on
extended time windows around the planned visit dates, defined relative to the day of first trial 


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treatment (which is scheduled for Visit V2). These extended time windows are defined in
Table 6.7: 1.
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital 
measurements to visits for statistical analysis
Visit 
number
/ name
Planned 
day
Time window (Days)
Visit label
Window 
(per 
CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V1
Screening
- 28 to -
14
V2
Day 1
Day 1
1 A
1
1 A
1
V3
Week 1
Day 8
+/- 2 
6
10
2
11
V4
Week 2
Day 15
+/- 2
13
17
12
18
V5
Week 3
Day 22
+/- 2
20
24
19
25
V6
Week 4
Day 29
+/- 2
27
31
26
43
V7
Week 8
Day 57
+/- 7
50
64
44
71
V8C
Week 12
Day 85
+/- 7
78
92
72
99
V9
Week 16
Day 113
+/- 7
106
120
100
127
V10
Week 20
Day 141
+/- 7
134
148
128
155
V11
Week 24
Day 169
+/- 7
162
176
156
183
V12
Week 28
Day 197
+/- 7 
192
204
184
211
V13
Week 32
Day 225
+/- 7  
218
232
212
239
V14
Week 36
Day 253
+/- 7
246
260
240
267
V15
Week 40
Day 281
+/- 7 
274
288
268
295
V16C
Week 44
Day 309
+/- 7 
302
316
296
323
V17
Week 48
Day 337
+/- 7 
330
344
324
351
V18D
Week 52
(EoT)
Day 365
+/- 7 
358
372
352
393
V19
Week 60
Day 421
+/- 7
414
428
394
449
V20
Week 68
(EoS)
Day 477
+/- 7  
470
484
450
491
For patients who discontinue the treatment early and are not willing to follow the whole visit schedule:
-
EoS
LDB+112
-
-
-
Days are counted relative to the day of first treatment, which is defined as Day 1.
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made 
after start of infusion of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be 
assigned to Day 1. Such data will be listed only.
B LD=Last dose.
C Data within the extended time window of Week 8/16 but after the actual dose at Week 8/16 will not be selected 
to represent Week 8/16 except for local tolerability and post-dose vital sign assessments. 
D For the patients who enter OLE trial, the EOT will be the last visit (i.e., V19 and V20 are not required). The 
EOS (=individual end of the study) will be the first administration of the trial drug in OLE trial.
Repeated and unscheduled efficacy, safety 
 measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date of measurement. 
Only one observation per time window will be selected for statistical analysis at a particular
visit – the value which is closest to the protocol planned visit day will be selected. If there are 
two observations which have the same difference in days to the planned day, the later value 


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will be selected. If there are two observations on the same day, the worst value will be 
selected.
Note that data within the extended time window of Week 8/16 but after the actual dose at 
Week 8/16 will not be selected to represent Week 8/16 except for local tolerability and post-
dose vital sign assessments.
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 EC and 
OC methods, values after rescue therapy intake or 6 weeks following last treatment in case of 
discontinuation should be censored first before assignment of efficacy endpoints..
For visits without an assigned value based on time windows, a value will thereafter be 
imputed as defined in Section 6.6. Imputation of efficacy endpoints, when applicable, will be 
performed based on all available observations meeting the imputation rules, irrespective of 
whether the observation was selected in any time window.


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7.
PLANNED ANALYSIS
The following analyses of this trial protocol are planned:
Primary Analysis (Week 16)
This primary analysis will be performed when all patients have completed 16 weeks of the 
study or early discontinued and a database lock will be performed. 
Each patient’s available data up to the earlier time point of treatment at week 16 or Day 127, 
(i.e., the right limit of week 16 extended time window) will be considered in the primary 
analysis. 
The primary analysis will be performed by the sponsor. The selected project and trial team 
members will be un-blinded for this analysis. Since the study is planned to continue after the 
primary analysis in a blinded manner at sites (for investigators and patients), a logistics (and 
access) plan will be developed in order to describe the processes to be implemented in order 
to protect the integrity of the ongoing trial through the final analysis. 
Final analysis
The analysis of the entire efficacy, safety,
 data collected will be performed
once all randomized patients have completed the trial; at that time point, a final database lock 
will be done and all results of the trial will be reported.
A formal clinical trial report is planned for the primary analysis, and a separate clinical trial 
report will be prepared for the final analysis.
General Remarks
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (10)
 (5).
The individual values of all patients will be listed, including those collected during the off-
treatment period. Listings will generally be sorted by country, centre number, patient number 
and visit (if visit is applicable in the respective listing). AE listings will be sorted by treatment 
(see Section 7.8.1 below for details).
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N:
number of non-missing observations
Mean:
arithmetic mean


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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 
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 if there is 
no other particular specification.
Note that for the analysis of all data in this trial, the primary approach is to report only those 
data that fall within the on-treatment period. Disposition of the patient population 
participating in the trial will be summarised by presentation of the frequency of patients 
screened, randomized, treated, who completed the PE visit, who were prematurely 
discontinued study treatment before PE visit, by reason, who withdrew from the trial before 
PE visit, by reason (only for primary analysis), who completed all doses of treatment as 
planned (only for final analysis), who were prematurely discontinued study treatment, by 
reason  (only for final analysis), who completed the trial  (only for final analysis), and who 
withdrew from the trial, by reason (only for final analysis).
The frequency of patients with IPDs will be presented for the RS by treatment. The IPDs will 
be listed per patient indicating whether or not the IPD led to exclusion from patient sets 
analyzed. 
The frequency of patients in each of the different analysis sets will also be presented by 
treatment.


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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 SAF and FAS respectively. 
For the continuous variables described below, categories are defined in Table 7.1: 1. These 
variables will be presented according to the number and percentage of patients in each 
category.
Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
< 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


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7.2
CONCOMITANT DISEASE AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant diseases (i.e. baseline conditions) and concomitant non-drug therapies will be 
coded according to the most recent version of MedDRA. Concomitant medications will be 
coded according to the most recent version of the World Health Organisation – Drug 
Dictionary.
Concomitant diseases which are present at start of the study will be descriptively summarized 
by treatment. 
A medication/non-drug therapy will be considered concomitant to treatment, if it

is ongoing at the start of randomized trial treatment or

starts within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
A medication/non-drug therapy will be considered as prior medication/non-drug therapy, if 
the end date of the medication/therapy is at any time prior to the start of randomized trial 
treatment.
Concomitant medication use (excluding rescue therapy) will be summarised with frequency 
and percentage of patients by ATC3 class and preferred name. Summaries will be presented 
for

concomitant medication starting any time prior to Day 1 (the day of start of trial 
treatment)

concomitant medication starting any time during the on-treatment period (cf. Section 6.1).
Concomitant use of non-drug therapies (excluding rescue therapy) will be summarized with 
frequency and percentage. Summaries will be presented for

concomitant non-drug therapies starting any time prior to Day 1 (the day of start of 
trial treatment)


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
concomitant non-drug therapies starting any time during the on-treatment period (cf. 
Section 6.1).
For primary analysis of the trial, concomitant therapies/non-drug therapies starting up to the 
earlier time point of 1) Day 127 or 2) treatment at week 16 will be reported based on SAF.
For final analysis of the trial, concomitant therapies/non-drug therapies starting up to the first 
maintenance treatment at or after week 16 based on SAF (if applicable) and starting post the 
first maintenance at or after week 16 based on SAF-post 16 will be reported separately. 
The frequency and percentage of patients with historical medication for PPP will be displayed, 
including presentation by type of historical medication (preferred name), and by reason for 
discontinuation. 
Use of rescue therapy will be summarised separately (see Section 7.6.3).
7.3
TREATMENT COMPLIANCE
Treatment compliance will be summarised up to week 16, post week 16 (for final analysis 
only), and overall (for final analysis only) for the SAF (as a % of planned) using descriptive 
statistics (N, mean, SD, minimum, median, maximum). The volume injected (as a % of 
planned) is defined as the number of syringes injected at a visit (as recorded in the eCRF), 
divided by number of syringes that patient should have received, times 100.
For the patients who discontinued the study treatment prematurely only the visits on or before 
premature discontinuation will be used for the calculation of overall compliance.
The number and percentage of patients with the following overall compliance categories will 
be presented:

"< 80% of planned",

"80 to 120% of planned" and

"> 120% of planned".
7.4
PRIMARY ENDPOINT
For the primary endpoint analysis, first a mixed effect model for repeated measurements 
(MMRM) is calculated to estimate the treatment effects and the corresponding covariance 
matrix. Using the MCPMod approach (11, 12), these estimates are then further used to (1) test 
for a non-flat dose response curve and (2) to identify suitable dose-response shapes out of a 
selection of candidate models. The final model will then be calculated by averaging over all 
significant model shapes. 
Details on both the specification of the MMRM and the MCPMod approach are given in the 
CTP Section 7.2.2. Sample size calculations are described in CTP Section 7.5.
The primary analysis of primary endpoint will be based on the FAS. Any data collected after 
use of any rescue therapy or after 6 weeks following last drug administration if a patient 


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discontinued treatment early will be censored as the primary estimand (EC). 
MMRM analysis
The % change in PPP ASI from baseline (Visit 2), at Visits 3, 4, 5, 6, 7, 8 and 9 (Weeks 1, 2, 
3, 4, 8, 12 and 16) will be evaluated using an MMRM accounting for the following sources of 
variation: ‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification 
according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed 
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. 
In the event of model non-convergence, the methods described in Section 9.3 will be utilized 
to resolve this.
SAS code for MMRM:
The following SAS code will be used to calculate the MMRM.
PROC MIXED DATA=alldat cl method=reml; 
  CLASS visit trt stratum subject; 
  MODEL ept = stratum visit*trt base*visit / ddfm=kr s CL; 
  REPEATED visit / subject= subject type=un r rcorr; 
  LSMEANS visit*trt / pdiff=all om cl alpha=0.05 slice=visit; 
RUN;
Results of the MMRM (N, mean, SE and 95% CI per dose group and timepoint) will be 
presented in tables and displayed graphically.
MCPMod Analysis
For the primary analysis the dose-response relationship will be modeled using the total doses. 
Here, the total is the sum of all doses administered to the patient prior to the week 16 visit 
including both loading and maintenance phase. Thereby, it is assumed that the cumulative 
concentrations over time (AUC) and thus the cumulative total dose is the key driver of the 
efficacy response in the modelling part of MCPMod. Table 7.4: 1 shows the calculated total 
doses per treatment arm. 


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Table 7.4: 1
Total dose per treatment arm.
High dose regime 
(Arm 1)
Medium-high dose regime 
(Arm 2)
Medium-low dose regime 
(Arm 3)
Low dose regime 
(Arm 4)
Placebo
(Arm 5)
  W: Week.
The multiple comparison procedure will then be implemented using optimal contrast tests 
which control the family-wise type I error rate at a one-sided α = 0.05. For the MCPMod test, 
the optimal contrasts of each candidate model are calculated using the R-function optCont
using weights (w) proportional to the sample size of each dose group, respectively, and are 
shown in Table 7.4: 2. 
Table 7.4: 2
Contrast coefficient.
Contrast coefficients for (total) dose
Model
Placebo
Low dose:
Medium-
low dose:
Medium-
high dose:
High dose:
Linear
0.783
0.049
-0.049
-0.196
-0.587
Emax
0.869
-0.112
-0.151
-0.190
-0.416
Exponential
0.574
0.194
0.118
-0.106
-0.780
Logistic
0.706
0.220
-0.036
-0.279
-0.612
Sigmoid Emax
0.638
0.247
0.052
-0.256
-0.681
   BI: Spesolimab total dose,
 administered 
before week 16.
For the final evaluation, these contrasts will be updated using the expected model means from 
the candidate set and the estimated variance-covariance matrix extracted from the MMRM 
model. The updated contrast coefficients will be reported in the CTR. 
Once the significance of a dose-response signal is established, the dose-response profile and 
the target dose can be estimated using a model averaging approach. Here, the final model is 


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derived as a weighted average over all significant model shapes. Here, the weights for each 
significant model () are given by
() =
(.∙())
∑
(.∙())


,
where () is the Akaike Information Criterion (AIC) of model .
Estimates for each dose group will be calculated and will be based on the final dose-response 
model. The choice of the target dose to be investigated in Phase 3 will be based upon efficacy 
as well as considering safety and other relevant information. 
R code to perform the evaluations is available in Section 9.4.
The following displays are planned.
-
Table of the updated contrast coefficients per dose group and candidate model, together 
with the MCPMod test statistics and p-values for each model and the critical value
-
For averaging model, figure of the dose-response curve
-
For all significant model shapes, figures of the dose-response curve plus 95% 
confidence band (of the predicated shape) and 95% CI per dose (estimated from 
MMRM)
-
For all significant model shapes, figure with the placebo corrected dose-response curve 
plus 95% confidence band (of the predicated shape). 
R code is also available in Section 9.4.1.
Descriptive statistics 
Descriptive displays of percentage change from baseline in PPP ASI (with 95% CI) will be 
presented by treatment using OC and OC-IR methods respectively. The method to provide 
confidence intervals for each arm and unadjusted differences to placebo is derived from the 
Student’s t-distribution.


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7.5
SECONDARY ENDPOINTS
Key secondary endpoint
7.5.1
This section is not applicable as no key secondary endpoint has been specified.
Secondary endpoints
7.5.2
Continuous secondary endpoints
Continuous secondary endpoints up to week 16 will be evaluated using MMRM model and 
MCP-Mod in the same way as for the primary endpoint. 
For percent change in PPP ASI from baseline at Week 52, a similar setting to that described 
for the primary endpoint MMRM model (in Section 7.4) will be applied with the inclusion of 
the additional visits of Week 28, 40 and 52. 
Binary secondary endpoints
For each of the binary secondary endpoints at Week 16, a logistic regression and MCPMod
model will be used to evaluate the treatment effect of multiple doses of Spesolimab vs. 
placebo. This method will be implemented for MCPMod in a binary setting.
The primary analysis of binary secondary endpoints will be based on the FAS. Any data 
collected after use of any rescue therapy or after 6 weeks following last drug administration if 
a patient discontinued treatment early will be censored as the primary estimand (EC). 
Logistic regression analysis
For binary endpoints, the difference in the proportion of patients with a response between 
Spesolimab and placebo will be analysed, for the FAS, using a logistic regression approach 
with a logit link via PROC LOGISTIC in SAS®. Fixed classification effects will include 
treatment and region (Japan vs. Non-Japan). In case 0 event is observed in any of the 
combination of dose group and strata a penalized regression based on the Firth’s bias 
reduction method (19, 20) will be used.


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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 in the 
treatment groups on the original scale. Odds ratio will be also reported between each 
Spesolimab arm vs placebo
Confidence intervals will be calculated using the cumulative distribution function method of 
Reeve (14). More specifically, as suggested in Reeve (14), a numerical search algorithm will 
be employed to find the quantiles xA of the cumulative distribution function, F 
! , such that 
F 
! (x#) = A, where A = 2.5% and A = 97.5% and F 
! is given by equation (10) in Reeve 
(14). R code that will be used to implement this is provided in Section 9.2.
MCP-MOD analysis
The estimate of response rate from each dose group obtained via logistic regression or 
penalized regression based on the Firth’s bias reduction method (as described above) without 
intercept will be used as basis for the MCPMod analysis of the binary secondary endpoints. 
The subsequent MCP-Mod analyses are based on the response rates on the logit scale.
The multiple comparison procedure will be implemented using optimal contrast tests which 
control the family-wise type I error rate at a one-sided α = 0.05. The same candidate models 
as for the primary endpoint will be used for all secondary binary endpoints. For the MCPMod 
test, the optimal contrasts of each candidate model are calculated using the R-function 
optCont using weights (w) proportional to the sample size of each dose group, respectively, 
and are shown in Table 7.5.2: 1. These contrasts will be recalculated using the actual sample 
size of the dose groups (in case this differs from the planned numbers). The final contrasts
will be presented in the CTR.


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Table 7.5.2: 1 Contrast coefficient
Contrast coefficients for (total) dose
Model
Placebo
Low dose:
Medium-
low dose:
Medium-
high dose:
High dose:
Linear
-0.783
-0.049
0.049
0.196
0.587
Emax
-0.869
0.112
0.151
0.190
0.416
Exponential
-0.574
-0.194
-0.118
0.106
0.780
Logistic
-0.706
-0.220
0.036
0.279
0.612
Sigmoid Emax
-0.638
-0.247
-0.052
0.256
0.681
   BI: Spesolimab total dose, 
 administered 
before week 16.
The MCP-Mod test will be applied using these fixed contrasts. R code is also available in 
Section 9.4.2.
All significant dose-response models will be re-fitted to the data without any parameter 
assumptions to generate a set of new estimates of the model parameters from the data. The 
final model is derived as a weighted average over all significant model shapes obtained via 
the same averaging procedure as described for the primary endpoint. 
The following displays are planned.
-
Table of the contrast coefficients per dose group and candidate model, together with the 
MCPMod test statistics and p-values for each model and the critical value
-
For the average model, figure of the dose-response curve
-
For all significant model shapes, figures of the dose-response curve plus 95% 
confidence band (of the predicted shape) 
Descriptive statistics
Descriptive statistics and graphical displays (line plots) of the response on each binary 
endpoint will be produced using EC-NRI, OC and OC-IR methods respectively. The method 
to provide confidence intervals for single proportions will be based on Wilson (16).  The 
method to provide confidence intervals for risk differences is derived from the Wilson method 
by Newcombe (17). 


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Analysis of % change in PPP ASI from week 16
7.5.3
Analysis regarding the % change in PPP ASI will be performed, using the FAS-post 16 set, 
which focuses on the maintenance treatment period post primary endpoint (Week 16). Data 
starting from the first dose administered at Week 16 will be evaluated using the MMRM 
model where week 16 data will be used as baseline and visits at week 28, 40 and 52 will be 
included. Patients who didn’t receive treatment at week 16 will be excluded from this 
analysis. 
MMRM model accounts for the following sources of variation: ‘baseline’ (week 16) as a 
continuous covariate, and ‘visit’, ‘dose group’, ‘region’ (stratification according to Japan vs. 
non-Japan), ‘dose group*visit’ and ‘visit*baseline’ (week 16) interaction as fixed effects as 
well as the random ‘subject’ effect.  
In the event of model non-convergence, the methods described for the primary endpoint 
analysis in Section 9.3 will be repeated except that ANCOVA model at week 52 and not at 
week 16 will be instead performed.
Dose groups will be presented per the dose regimen administered post primary endpoint 
(Week 16) as follows:

 (i.e., Arm 4)

 (i.e., Arm 2)

 (i.e., Arm 1 + Arm 3 + Arm 5)
Results of the MMRM (N, adjusted mean, SE and 95% CI per dose groups and timepoint) 
will be presented in tables and displayed graphically. No statistical comparisons will be 
performed. Note that the results from this analysis need to be interpreted with caution as the 
efficacy outcomes post week 16 may also be impacted by treatments administered before 
week 16 and FAS-post 16 could not represent all population of the trial. 


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7.7
EXTENT OF EXPOSURE
The number of subjects who received a dose of trial drug will be tabulated. The amount of 
treatment received as well as the amount injected [% of planned] will be summarised by 
descriptive statistics (N, mean, SD, minimum, median, maximum) for the loading stage, the 
maintenance stage up to week 16, overall up to week 16 (primary analysis only), and the 
maintenance stage post week 16 (final analysis only), as well as the overall dose across all 
stages (final analysis only). 


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7.8
SAFETY ANALYSIS
All safety analyses will be performed following BI standards. No hypothesis testing is 
planned. OC-IR and OR methods will be used for safety reporting.
In primary analysis, AE and possibly clinically significant laboratory abnormalities up to 
week 16 will be analyzed. In final analysis, AE and possibly clinically significant laboratory 
abnormalities up to and post the first maintenance treatment at or after week 16 will be 
analyzed separately.
Primary analysis: AE and possibly clinically significant laboratory abnormalities up to week 
16
The analysis will include all on-treatment events up to the treatment at week 16 based on 
SAF. If patient early discontinued from treatment prior to week 16 or missed week 16 
treatment, then the on-treatment events up to Day 127 (the right limit of the extended week 16 
visit window) will be included. 
Final analysis: AE and possibly clinically significant laboratory abnormalities prior to the first 
maintenance at or after week 16
The analysis will include on-treatment events up to the first maintenance treatment at or after 
week 16 based on SAF. If a patient early discontinued from treatment prior to week 16, then 
the patient’s events up to the end of REP of the last treatment will be included.
One additional group will be reported for AE and possibly clinically significant laboratory 
abnormalities, which is the combination of Arm 1, 2, 3 and 4 (“Speso Total”).
Final analysis: AE and possibly clinically significant laboratory abnormalities post the first 
maintenance at or after week 16
The analysis will include on-treatment events post the first maintenance treatment at or after 
week 16 based on SAF-post 16. Only patients who have received at least one dose of 
treatment at or after week 16 will be included. 
For AE and possibly clinically significant laboratory abnormalities, except for 5 treatment 
arms of the trial, one additional group will be reported which is the combination of Arm 1, 3 
and 5 
As the onset time of an AE will not be collected in the trial, any AE which occurs on the same 
day as a treatment dose will be assigned to the “post treatment”. For safety assessments by 
visits, if time is not collected, data on the same day of a treatment dose will be treated to be 
“prior treatment” except for scheduled local tolerability and post-dose vital signs assessments. 
Off-treatment data will be listed only 
Additional analyses on AE will be also included:
AE within loading stage 
For AE, the additional safety tables for loading dose stage will be produced by re-grouping 
patients based on their loading doses 
 using SAF. The outputs 


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will include on-treatment data up to the first maintenance dose at week 8. If patient early 
discontinued from treatment prior to week 8 or missed treatment at week 8, then the safety 
data up to Day 71 (the right limit of the extended time window of week 8) will be included:

Overview on TEAE

TEAE by SOC, preferred term

Serious TEAE

All AESI

UDAEC
AE over on-treatment period
In the final analysis, the additional selected tables for the overall period will be produced 
based on SAF to report AE occurring during whole treatment period from Day 1. Note that 
only Arm 1-4 will be reported:

Overview on TEAE

TEAE by SOC, preferred term

Serious TEAE

All AESI

UDAEC
Adverse events
7.8.1
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs. System organ classes (if 
applicable) will be sorted according to the standard sort order specified by the EMA, preferred 
terms (if applicable) will be sorted by total frequency (within system organ class) across all 
treatment arms, or, if a total column across all arms is not foreseen in the table, by total 
frequency (within system organ class) across the BI arms.
For 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. Since only the 
start date of an AE is collected (without start time), any AE occurrence on the same day as the 
first Spesolimab administration will be assigned to the on-treatment phase.
An overall summary of AEs will be presented by treatment. This overall summary will 
include summary statistics for the class of other significant AEs (sponsor definition based on
ICH E3) and for the class of AESIs.
Based on the specification provided in 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’.


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The following is considered an AESI in this trial:
Systemic hypersensitivity reactions including anaphylactic reaction
Severe infections (according to RCTC grading in CTP Appendix 10.2)
Opportunistic and mycobacterium tuberculosis infections
Hepatic injury
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
In addition, user defined adverse event concepts (UDAEC) identified through specific search 
criteria will be reported separately (see Table 7.8.1: 1). 


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Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events Concepts
User Defined AE Concepts
Categories
Infusion/Systemic 
hypersensitivity reactions 
including anaphylactic 
reactions
Narrow SMQ “Anaphylactic reaction”
Narrow SMQ “Angioedema”
Narrow SMQ “Hypersensitivity”
Opportunistic infections
Narrow SMQ “Opportunistic infections”:
Tuberculosis infections 
BIcMQ Narrow sub-search 8.2 “Tuberculosis related 
terms” 
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-BIcMQ “Skin Malignancies excluding 
melanomas”
Malignancies excluding 
NMSC
Sub-SMQ “Malignant tumours”
excluding broad sub-BIcMQ “Skin Malignancies 
excluding melanomas”
3-point MACE
BIcMQ 3-MACE with subsearch 1.1 narrow and subsearch 
1.2 narrow *”
Torsades de pointes
Broad SMQ “Torsades de pointes/QT prolongation”
Severe infections (according 
to RCTC grading)
SOC Infections and infestations of at least severe RCTC 
grade, by HLGT
* this is achieved by retrieving all cases found either by running subsearch 1 in narrow scope (BIcMQ search ID 32019093 ) or 
subsearch 2 (BIcMQ serach ID 32019094 )
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 
will be summarised separately. Separate tables will also be provided for patients with SAEs, 
patients with AESIs, patients with AE leading to discontinuation of the trial medication, and 
patients with other significant AEs (as described previously). AEs will also be summarized by 
maximum intensity.
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary system organ class and preferred term. The frequency of patients with 
SAEs and drug related SAEs will also be summarised respectively.


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For disclosure of AE data in the EudraCT register, the frequency of non-serious AEs with an 
incidence of greater than 5 % (in preferred terms) and the frequency of SAEs will be 
summarised.
Laboratory data
7.8.2
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.
Normalisation means transformation to a standard unit and to a standard reference range. The 
process of normalisation, handling of repeat values at the same visit for by-visit displays, as 
well as standard analyses for safety laboratory data are described in the BI guidance for the 
Display and Analysis of Laboratory Data (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 will be calculated. For all 
outputs, the last assessment before the first randomized treatment at Day 1 is chosen as the 
baseline value.
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 and for the difference from baseline on-treatment
(see Section 6.7) will be based upon standardized values and provided by visit. In primary 
analysis, all visits up to week 16 will be reported including summaries of the last value, the 
minimum value and the maximum value up to week 16 based on SAF. In final analysis, all 
visits will be reported including summaries of the last value, the minimum value and the 
maximum value on treatment period for Arm 1-4 and, up to and post the first treatment at or 
after week 16 respectively for Arm 5 based on SAF. 
Laboratory values will be compared to their reference ranges; shift tables will be provided for 
the number of patients with a specific RCTC grade at baseline versus the grade at the last 
measurement, as well as the worst grade. In particular, for shift tables in final analysis, the last 
measurement and the worst graded will be counted by the period up to and post the first 
treatment at or after week 16 respectively for Arm 5. 
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 patient’s lab 
values will be listed, if there exists at least one lab value with clinically significant 
abnormality within the group.
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥ 10xULN, and 
≥ 20xULN will be displayed based on standardized laboratory values. To support analyses of 


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liver related adverse drug effects, the frequency of patients with AST and/or ALT ≥ 3xULN 
combined with a total bilirubin ≥ 2xULN in a 30 day period after AST/ALT elevation will be 
displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a patient can potentially 
be in both alkaline phosphatase strata in case of multiple AST/ALT and bilirubin elevations). 
The start of the 30 day time span is triggered by each liver enzyme elevation above the 
defined thresholds. This analysis will be based on standardized laboratory values. A graphical 
analysis of the ALT and total bilirubin during the on-treatment period will also be performed; 
the so called eDISH plot. In the graph, for each subject, the peak total bilirubin is presented as 
a fold increase over the ULN against the peak ALT as a fold increase over the ULN, on a 
log10 scale. The measurements displayed or total bilirubin and ALT may, or may not, occur 
on the same date. Two reference lines, 2xULN for total bilirubin and 3xULN for ALT, are 
drawn onto the graph in order to divide the plane into four quadrants. Normal cases are in the 
lower left quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law quadrant), 
while the lower right quadrant is known as the Temple’s corollary range (ALT ≥ 3xULN and 
total bilirubin < 2xULN).
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.
Vital signs
7.8.3
The analyses of vital signs (blood pressure, pulse rate), body temperature, and body weight 
will be descriptive in nature. In primary analysis, descriptive statistics of vital signs and for 
the difference from baseline (see Section 6.7) up to week 16 will be provided based on SAF, 
including the last value, the minimum value and the maximum value up to week 16. In final 
analysis, descriptive statistics of vital signs and for the difference from baseline (see Section 
6.7) for all visits will be provided based on SAF, including the last value, the minimum value
and the maximum value on treatment for Arm 1-4 and, up to and post the first treatment at or 
after week 16 respectively for Arm 5. 
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
ECG
7.8.4
Abnormal findings in 12-lead ECG will be reported as baseline conditions (at screening) or as 
AEs (during the trial) if judged clinically relevant by the investigator, and will be analysed as 
such.
No separate listing or analysis of ECG data will be prepared.
Local tolerability 
7.8.5
Local tolerability will be summarized by visit, with the frequency and percentage of patients 
who experienced any symptoms by severity/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. 
Consequently, there are unavoidable protocol deviations due to COVID-19 illness and/or 
COVID-19 public and individual health control measures. To assess the impact on patients’ 
safety and drug efficacy in this trial, the following analyses are planned:
Disposition and iPD:
Frequency of the patient with missed relevant visits or early discontinued from study 
treatment due to COVID-19 and related iPDs will be listed. 
Efficacy endpoints:
To evaluate the impact of COVID-19 on efficacy analysis, the following estimand is 
implemented. 
-
Alternative estimand (EC-E19) whereby any data collected after use of any rescue 
therapy or after the first visit with missing treatment due to COVID-19 or after 6 weeks 
following last treatment before or at discontinuation (to allow for incorporation of the 
continuing maximum treatment effect period) are censored. 
For the percent change in PPP ASI, a similar MMRM model to that used in the primary 
analysis will be performed.
For PPP ASI50, PPP ASI75 and PPP PGA clear/almost, descriptive statistics will be 
displayed.
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, during the disruption and post the disruption (for final 
analysis only) will be reported separately. It will include the following AE tables, 

Overview on TEAE

TEAE by SOC, preferred term

Serious TEAE
The start date for the COVID-19 disruption is chosen to be 1st March 2020 and the end date 
will be updated in future revision for final analysis. 
In addition, if there is any case, AE related to COVID-19 infection will be reported 
separately. 


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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_RD-01: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; IDEA for CON
6
001-MCS-40-413_RD-00: "List of References to SOP Identify and Mange 
Important Protocol Deviations (iPD)", current version; IDEA for CON
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
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding studies 
combining multiple comparisons and modelling procedures. J Biopharm Stat 16 
(5), 639-656 (2006). [R10-1424]
12
Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding under model 
uncertainty using general parametric models. Stat Med 33 (10), 1646 – 1661 
(2014). [R15-4293]


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14
Reeve R. Confidence interval of difference in proportions in logistic regression in 
presence of covariates. Statistical Methods in Medical Research: 27 issue: 2, 451-
465, 2016. [R16-4414]
15
SAS/STAT(R) 9.2 User's Guide, Second Edition. 
http://support.sas.com/documentation/cdl/en/statug/63033/HTML/default/viewer.ht
m#statug_lifetest_a0000000260.htm (retrieved 16-May-2018)
16
Brown LD, Cai TT, DasGupta A. Confidence intervals for a binomial proportion 
and asymptotic expansions. Ann Statistics 30, 160-201, 2002 [R12-3710]
17
Newcombe R.G. Interval estimation for the difference between independent 
proportions: Comparison of eleven methods. Stat Methods Med Res 17, 873-890  
1998. 
18
Carpenter, James R., James H. Roger, and Michael G. Kenward. "Analysis of 
longitudinal trials with protocol deviation: a framework for relevant, accessible 
assumptions, and inference via multiple imputation." Journal of biopharmaceutical 
statistics 23.6 (2013): 1352-1371.
19
Heinze G, Schemper M. A solution to the problem of separation in logistic 
regression. Statistics in Medicine 21: 2409-2419 (2002).
20
Firth D. Bias reduction of maximum likelihood estimates. Biometrika 80, 27–38
(1993)
21
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. 2011. 63: S240-S252.
22
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: 4.
24
Langley RGB, Feldman SR, Nyirady J, Kerkhof P van de, Papavassilis C. The 5-
point Investigator`s Global Assessment (IGA) Scale: A modified tool for 
evaluating plaque psoriasis severity in clinical trials. J Dermatol Treat. 2015. 26(1): 
23-31.


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25
Farley E, Masrour S, McKey J, Menter A. Palmoplantar psoriasis: A phenotypical 
and clinical review with introduction of a new quality-of-life assessment tool. J Am 
Acad Dermatol. 2009. 60(6): 1024-1031.
26
Augustin M, Radtke MA, Zschocke I, Blome C, Behechtnejad J, Schäfer I, et.al. The 
patient benefit index: a novel approach in patient-defined outcomes measurement 
for skin diseases. Arch Dermatol Res. 2009. 301: 561-571.
27
Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey: Manual and 
Interpretation Guide. Boston: The Health Institute, New England Medical Center. 
1993.
28
Ware JE. SF-36 Health Survey Update. Spine. 2000. 25(24): 3130-3139.
29
Frendl DM, Ware JE. Patient-reported Functional Health and Well-Being 
Outcomes with Drug Therapy: A Systematic Review of Randomized Trials Using 
the SF-36 Health Survey. Medical Care. 2014. 52(5): 439-445.


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9.
ADDITIONAL SECTIONS
9.1.1
PPP ASI and related endpoints
The Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPP ASI) is an investigator 
assessment of the extent and severity of pustular and plaque lesions on the palms and soles 
presenting in PPP patients. The adaptation from PASI, an established measure of severity and 
area of psoriatic lesions in patients with psoriasis, will be used in this trial (Table 9.1.1: 1). 
This tool provides a numeric scoring for patients overall PPP disease state, ranging from 0 to 
72. It is a linear combination of the percent of surface area of skin that is affected on the 
palms and soles of the body and the severity of erythema, pustules, and scaling 
(desquamation).
Table 9.1.1: 1 Palmoplantar Pustulosis Psoriasis Area and Severity Index
Score
0
1
2
3
4
5
6
Erythema (E)
None
Slight
Moderate
Severe
Very 
severe
Pustules (P) 
(total)
None
Slight
Moderate
Severe
Very 
severe
Desquamation 
(D) (scaling)
None
Slight
Moderate
Severe
Very 
severe
Area affected
(in%)* (A)
0
<10
10<30
30<50
50<70
70<90
90 - 100
* where area assessed is glabrous skin on the palms/ soles 
The Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPP ASI)
The PPP ASI is calculated as follows as a weighted sum of the scores obtained for E, P, D and 
A in Table 9.1.1: 1:
PPP ASI = [(E+P+D) x A x 0.2 (right palm)] 
  + [(E+P+D) x A x 0.2 (left palm)] 
  + [(E+P+D) x A x 0.3 (right sole)] 
  + [(E+P+D) x A x 0.3 (left sole)]
Missing values for severity or area of involvement will not be imputed. If at least one of these 
values is missing, then the PPP ASI score will also be considered to be missing. However, 
individual items and subscores may be presented as applicable.
Achievement of Decrease in PPP ASI ≥ xx% (PPP ASIxx)


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Achieving a response of xx% or larger decrease from baseline in PPP ASI score is denoted as 
PPP ASIxx. The PPP ASIxx represents a binary variable with values of 0 (= non-response) or 
1 (=response). 
It is calculated based on the following approach (with xx typically taking a value of 50, 75 or 
90):
If  
then PPP ASIxx = 1,
else PPP ASIxx = 0.
PPP ASI severity (by component)
Within each component (E, P or D), the mean severity across all body areas (both palms and 
both soles) is calculated and presented for each component separately. For example, for 
Erythema, present (Eright palm + Eleft palm + Eright sole + Eleft sole)/4 .
Within a component, a missing value in one body area leads to a missing value for the 
component.
Present the results separately “(by component)”.
PPP ASI severity (by palms or soles)
Among the two palms only, calculate the PPP ASI (palms) score via the components E, P, or 
D as well as the area (A) but replacing the region factor of 0.2 with a factor of 0.5 (total range
combining both palms of 0 to 72):
PPP ASI (palms) = 0.5 * {  [(Eright palm+Pright palm+Dright palm) x Aright palm] +
  [(Eleft palm+Pleft palm+Dleft palm) x Aleft palm]  } 
If at least one of the two palms has a missing value, then the PPP ASI (palms) score will be 
missing.
Repeat for the PPP ASI (soles) score but replacing the region factor of 0.3 with a factor of 0.5.
Present results separately for each of “(palms or soles)”.
Palmoplantar Pustulosis Severity Index (PPP SI)
PPP SI will be based on severity scores of individual components of PPP ASI assessments.
The most severely affected area based on pustules is identified by the investigator at baseline 
and the same area is assessed in all subsequent visits.
xx
BL
PPP ASI
current
PPP ASI
BL
PPP ASI









100
)
(
)
(
)
(


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Table 9.1.1: 2 Palmoplantar Pustulosis Severity Index (PPP SI)
Score
0
1
2
3
4
Erythema (E)
None
Slight
Moderate
Severe
Very 
severe
Pustules (P) 
(total)
None
Slight
Moderate
Severe
Very 
severe
Desquamation (D) 
(scaling)
None
Slight
Moderate
Severe
Very 
severe
PPP SI total score = E+P+D
Missing values for any subscore will not be imputed. If at least one of these values is missing, 
then the PPP SI score will also be considered to be missing. However, individual subscores 
may be presented as applicable.
The sum score for the worst area represents the PPP SI (range 0-12).
9.1.2
PPP PGA
The Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) relies on clinical 
assessment of the patient’s skin presentation on the palms and soles. The investigator scores
the individual components (erythema, pustules and scaling/crusting) from 0 to 4 as clear,
almost clear, mild, moderate or severe.
PPP PGA is using severity scores for erythema, pustules, and scaling. The PPP PGA will be
analyzed as PPP PGA total score including erythema, pustules and scaling, and as PPP PGA
pustules score for pustules only. Further details and practical guidance will be available in the
ISF.
The PPP PGA total score is derived as the mean of all individual components:
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
Missing component scores on erythema, pustules, scaling/crusting will not be imputed and the 
PPP PGA total score will be considered to be missing for a patient. Individual component 
scores may be presented, as applicable.
A lower PPP PGA score indicates a lesser severity, with 0 being clear and 1 being almost 
clear.


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9.1.3
Pain VAS score
There will be two pain VAS questionnaires, one specifically asking for pain on palms and/or 
soles (PPP Pain VAS) and one for muscular and joint pain.
The pain VAS is a unidimensional measure of pain intensity (21). 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 patient. The patient 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.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
     1
22-JUL-20
None 
This is the final TSAP