Clinical trial NCT03135548
Conditions: Psoriasis
Sponsor: Boehringer Ingelheim
Start date: 2017-05-30; Completion date: 2018-11-14
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the safety and efficacy of BI 655130 in patients with PPP following multiple intravenous administrations compared to placebo.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Spesolimab (low dose) intervention 2: Placebo intervention 3: Spesolimab (high dose)
Intervention descriptions: intervention 1: 12 weeks treatment intervention 2: 12 weeks treatment intervention 3: 12 weeks treatment

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c09935708-03
EudraCT No.:
2016-004573-40
BI Trial No.:
1368.15
BI Investigational 
Product(s):
BI 655130
Title:
Multi-center, double-blind, randomised, placebo-controlled, phase 
IIa study to investigate efficacy, safety, tolerability, 
pharmacokinetics and pharmacogenomics of multiple intravenous 
doses of BI 655130 in patients with Palmoplantar Pustulosis (PPP)
Lay Title:
Initial Dosing of BI 655130 in Palmoplantar Pustulosis patients
Clinical Phase:
IIa
Trial Clinical 
Monitor:
Phone: 
Fax:
Coordinating 
Investigator:
 
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on Global Amendment 
No. 1 and No. 2))
Version and Date:
Version: 3.0
Date: 08 May 2018
Page 1 of 76
Proprietary confidential information.
2018 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
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not Applicable
Name of active ingredient:
BI 655130
Protocol date:
03 February 2017
Trial number:
1368.15
Revision date:
08 May 2018
Title of trial:
Multi-center, double-blind, randomised, placebo-controlled, phase IIa
study to investigate efficacy, safety, tolerability, pharmacokinetics
and pharmacogenomics of multiple intravenous doses of BI 655130 in 
patients with Palmoplantar Pustulosis (PPP)
Coordinating
Investigator
Phone: 
Fax: 
Trial site(s):
Multi-centre study
Clinical phase:
IIa
Objective(s):
The primary objective of this trial is to investigate the safety and 
efficacy of BI 655130 in patients with PPP following multiple 
intravenous administrations of either 900 mg or 300 mg compared to 
placebo
Methodology:
Randomised, parallel-design, multiple-doses, placebo-controlled, 
double-blind
No. of patients: 
total entered:
60 patients
each treatment:
20 patients per treatment 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
Main criteria
for inclusion:

Male or female patients, aged 18 to 65 years at screening

Diagnosed with Palmoplantar Pustulosis with a minimum 
ppPASI score of 12 and pppPGA of at least moderate severity 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not Applicable
Name of active ingredient:
BI 655130
Protocol date:
03 February 2017
Trial number:
1368.15
Revision date:
08 May 2018
at baseline

Patients with associated plaque psoriasis ≥ 10% of the body 
surface area are excluded
Test product
BI 655130
dose:
900 mg and 300 mg every 4 weeks at Day 1, 29, 57 and 85
mode of 
administration:
Intravenous (i.v.)
Comparator products:
placebo
dose:
0 mg (placebo) every 4 weeks at Day 1, 29, 57 and 85
mode of 
administration:
i.v.
Duration of treatment:
12 weeks
Endpoints
Primary Endpoint

Efficacy: ppPASI50 at week 16

Safety: Number of patients with drug-related AEs
Secondary Endpoint(s)

Treatment success defined as achieving a clinical response of 
0 or 1=clear/almost clear via PPP Physicians Global 
Assessment (pppPGA) at week 16

ppPASI75 at week 16

Percent change from baseline in the ppPASI at week 16
Safety criteria:
Physical examination, vital signs, 12-lead Electrocardiogram (ECG), 
laboratory tests, adverse events, serious adverse events and 
tolerability. The intensity grading of AEs and abnormal laboratory 
values will be performed according to Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0.
Statistical methods:
Randomisation will be stratified by the presence or absence of plaque 
psoriasis. For the primary endpoint, the unadjusted risk difference 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not Applicable
Name of active ingredient:
BI 655130
Protocol date:
03 February 2017
Trial number:
1368.15
Revision date:
08 May 2018
based on the observed proportion of patients with ppPASI50 at week 
16 for BI 655130 and placebo will be assessed descriptively, for the 
Full Analysis Set (FAS), and 95% Wilson confidence intervals (CIs) 
will also be provided. The FAS comprises all participants who were 
randomised, received at least one dose during the trial, and had a 
baseline measurement for the primary endpoint. The influence of the 
stratification variable on the primary endpoint will be characterized in 
exploratory analyses.
Safety data will be presented using descriptive methods.


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FLOW CHART
Trial Periods
Screen-
ing1
Randomised Treatment Period
Post treatment 
follow-up
Visit 
1
22
3
4
5
6
7
8
9
10
11 PE3
12
13 EOT4
Week
-4 to -1
2
4
6
8
10
12
16
24
32
Day 
-28 to-7
1
4±2
8±3
15±3
29±3
43±3
57±3
71±3
85±3
113±3
169±
7
225±7
Informed Consent
X
Inclusion/exclusion criteria
X
X
Demographics, Medical History
X
Physical Examination
X12,C
XT
XT
XT
XT
XT
XT
XT
XT
XT
XC
XT
X12,C
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testing5
Xs
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Xu,(s)
Safety Laboratory tests
X
X
X
X
X
X
X
X
X
X
X
X
X


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Trial Periods
Screen-
ing1
Randomised Treatment Period
Post treatment 
follow-up
Visit 
1
22
3
4
5
6
7
8
9
10
11 PE3
12
13 EOT4
Week
-4 to -1
2
4
6
8
10
12
16
24
32
Day 
-28 to-7
1
4±2
8±3
15±3
29±3
43±3
57±3
71±3
85±3
113±3
169±
7
225±7
Assign/Administer study drug
X
X
X
X
Palmoplantar Pustular Psoriasis Area 
and Severity Index (ppPASI)
X
X
X
X
X
X
X
X
X
X
X
X
X
PPP Physician Global Assessment 
(pppPGA)
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
Local Tolerability
X
X
X
X
Adverse events
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
Completion of participation4
X
Footnotes:
1 The time window for Visit 1 may be extended at the discretion of the Local Clinical Monitor (CML) in conjunction with the TCM (Trial Clinical Monitor) on a case by case basis.


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2 Day of Randomisation / Day of first administration of randomised medication.
3 PE – Primary Endpoint Visit.
4 EOT End of Trial. If the patient withdraws from the trial prematurely following randomisation, instructions in Sections 3.3.4 and 6.2.3 should be followed.
5 Only applicable for women of childbearing potential. S – serum pregnancy test (performed at screening). U – urine pregnancy tests will be performed at all other visits indicated in 
  the Flow chart. Urine pregnancy testing should be done prior to administration of study drug in case there is dosing at study visits. 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. Women who underwent tubal ligation are still considered of childbearing
potential and pregnancy testing is necessary just as for other women of childbearing potential.
C=complete physical examination; T=targeted physical examination. At the screening physical examination, patient height and weight will be collected (see Section 5.3.1).
13 For the patients with concurrent plaque psoriasis, the percent body surface area (BSA) involved with plaque-type psoriasis lesions will be captured.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................11
1.0
INTRODUCTION...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
2.0
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....18
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................18
2.2
TRIAL OBJECTIVES........................................................................................18
2.3
BENEFIT - RISK ASSESSMENT.....................................................................19
3.0
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.1.1
Administrative structure of the trial .................................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................23
3.3
SELECTION OF TRIAL POPULATION .......................................................24
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................24
3.3.3
Exclusion criteria ................................................................................................25
3.3.4
Withdrawal of patients from therapy or assessments .....................................26
3.3.4.1
Withdrawal from trial treatment ...........................................................................26
3.3.4.2
Withdrawal of consent for trial participation........................................................27
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................27
4.0
TREATMENTS...................................................................................................28
4.1
INVESTIGATIONAL TREATMENTS ...........................................................28
4.1.1 
Identity of the Investigational Medicinal Products..........................................28
4.1.3
Method of assigning patients to treatment groups ...........................................30
4.1.4
Drug assignment and administration of doses for each patient......................30
4.1.5
Blinding and procedures for un-blinding .........................................................31
4.1.5.1
Blinding.................................................................................................................31
4.1.5.2
Unblinding and breaking the code ........................................................................32
4.1.6
Packaging, labelling, and re-supply...................................................................32
4.1.7
Storage conditions...............................................................................................32
4.1.8
Drug accountability.............................................................................................33
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................33


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4.2.1
Other treatments and emergency procedures..................................................33
4.2.1.1
Rescue medication ................................................................................................33
4.2.1.2
Emergency Procedures..........................................................................................34
4.2.1.3
Additional treatments............................................................................................34
4.2.2
Restrictions ..........................................................................................................34
4.2.2.1
Restrictions regarding concomitant treatment ......................................................34
4.2.2.2
Restrictions on diet and life style..........................................................................35
4.2.2.3
Restrictions regarding women of childbearing potential ......................................35
4.3
TREATMENT COMPLIANCE........................................................................35
5.0
VARIABLES AND THEIR ASSESSMENT ....................................................37
5.1
TRIAL ENDPOINTS..........................................................................................37
5.1.1
Primary Endpoint(s)...........................................................................................37
5.1.2
Secondary Endpoint(s) .......................................................................................37
............................................................................................37
5.2
ASSESSMENT OF EFFICACY........................................................................37
5.3
ASSESSMENT OF SAFETY.............................................................................40
5.3.1
Physical examination ..........................................................................................40
5.3.2
Vital Signs............................................................................................................40
5.3.3
Safety laboratory parameters ............................................................................41
5.3.4
Electrocardiogram ..............................................................................................43
5.3.5
Other safety parameters.....................................................................................44
5.3.5.1
Medical examination.............................................................................................44
5.3.5.2
Local tolerability ...................................................................................................44
5.3.6
Assessment of adverse events.............................................................................44
5.3.6.1
Definitions of AEs ................................................................................................44
5.3.6.2
Adverse event collection and reporting ................................................................47
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................49
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................52
6.0
INVESTIGATIONAL PLAN.............................................................................53
6.1
VISIT SCHEDULE.............................................................................................53
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................53


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6.2.1
Screening and run-in period(s)..........................................................................54
6.2.2 
Treatment period(s)............................................................................................54
6.2.3
Follow Up Period and Trial Completion...........................................................55
7.0
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................56
7.1
STATISTICAL DESIGN – MODEL ................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................56
7.3
PLANNED ANALYSES.....................................................................................57
7.3.1
Primary endpoint analyses.................................................................................57
7.3.2
Secondary endpoint analyses .............................................................................58
.................................................................................58
7.3.4
Safety analyses.....................................................................................................59
7.3.6.1
Analysis of cellular and biochemical biomarkers.................................................60
7.3.6.2
Pharmacogenomic analyses ..................................................................................60
7.4
INTERIM ANALYSES ......................................................................................60
7.5
HANDLING OF MISSING DATA ...................................................................62
7.6
RANDOMISATION ...........................................................................................62
7.7
DETERMINATION OF SAMPLE SIZE .........................................................63
8.0
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................65
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................65
8.2
DATA QUALITY ASSURANCE ......................................................................66
8.3
RECORDS...........................................................................................................66
8.3.1
Source documents ...............................................................................................66
8.3.2
Direct access to source data and documents.....................................................67
8.3.3
Storage period of records ...................................................................................67
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................67
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........67
8.6
TRIAL MILESTONES.......................................................................................68
9.0
REFERENCES....................................................................................................69
9.1
PUBLISHED REFERENCES............................................................................69
9.2
UNPUBLISHED REFERENCES......................................................................71
10.0
APPENDICES.....................................................................................................72
10.1
DIAGNOSIS OF ANAPHYLAXIS ...................................................................72
11.0
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................73


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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
AMP
Auxiliary Medicinal Product
API
Active Pharmaceutical Ingredient
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BSA
Body Surface Area
CDC
Complement-Dependent Cytotoxicity
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organisation
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DEDP
Drug Exposure During Pregnancy
DILI
Drug Induced Liver Injury
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
Desoxyribo Nucleid Acid
ECG
Electrocardiogram
EDTA
Ethylendiaminetetraacetic Acid
e.g.
Example given
ELISA
Enzyme Linked Immunosorbent Assay
EOT
End of Trial
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FcRn
Neonatal Fc receptor
FIH
First-in-human
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GPP 
Generalized Pustular Psoriasis
HIV
Human Immunodeficiency Virus
HV
Healthy Volunteer
IB
Investigator’s Brochure
IBD
Inflammatory Bowel Disease
i.e.
id est
IEC
Independent Ethics Committee
IgG
Immunglobulin G


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IL
Interleukin
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITE
Indirect Target Engagement
i.v.
Intravenous
kDA
Kilodalton
kg
Kilogram
LPDD
Last Patient Drug Discontinuation
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligram
mm
Millimeter
MMRM
Mixed Model Repeated Measures
MoA
Mode of action
MRD
Multiple rising dose
NCE
New chemical entity
NIMP
Non-Investigational Medicinal Product
NRI 
No Response Imputation
OPU
Operative Unit
PD
Pharmacodynamics
PGA
Physicians Global Assessment
PK
Pharmacokinetics
PoCC
Proof of Clinical Concept
PPP
Palmoplantar Pustulosis
pppPGA
Palmoplantar Pustulosis Physicians Global Assessment
ppPASI
Palmoplantar Pustular Psoriasis Area and Severity Index
PROs
Patient Reported Outcomes
PUVA
Psoralen plus UV-A
RCTC
Rheumatology Common Toxicity Criteria
RDC
Remote Data Capture
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RNA
Ribonucleid Acid  
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
s.c.
subcutaneous
SD
Standard Deviation
SOP
Standard Operating Procedures
SRD
Single rising dose
SUSARs
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TMDD
Target Mediated Drug Disposition
TNF
Tumor necrosis factor
TSAP
Trial Statistical Analysis Plan


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WBC
White Blood Count
WFI
Water For Injection
WOCBP
Women of Childbearing Potential


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1.0
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) is (are) a genetically distinct 
entity from chronic plaque psoriasis as the major genetic determinant PSORS1 for plaque 
psoriasis has not been found in the pustular forms of psoriasis (PPP and GPP) patients [R16-
3560; R16-3546]. Experimental and human genetic data imply that the IL36 pathway 
(targeted by BI 655130) drives the pustular psoriasis diseases of PPP and GPP.
PPP may be considered a rare disease. PPP is characterized by the presence of sterile pustules 
on palms and/or soles [R16-0927]. 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 further highlighting the high need for an effective 
treatment option. There are 2 subpopulations of patients with palmoplantar pustulosis. Those 
patients with pure pustulosis where patients only have the sterile pustules on the palms of 
their hands and/or soles of their feet and those patients in addition having plaque psoriasis 
which for this study would be on less than 10% of their body surface area. For the sake of 
clarity in this study both subpopulations of patients would be referred to as having 
palmoplantar pustulosis (PPP).
Genetic human studies have established a link between IL36R signaling 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 predominately expressed in keratinocytes in the 
skin. It acts downstream of the IL36 pathway and is a known activator of NF-kB signaling. 
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 
the AP-1 complex and could be linked to impaired Toll-like receptor 3 signaling 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. 
Currently there is no standard of care available for the treatment of PPP (i.e., no approved 
therapy). PPP is notoriously difficult to treat. Patients usually end up being treated with the 


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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.
Thus, there is high unmet medical need for PPP.
Secukinumab (anti-IL17A; EU) and guselkumab (anti-IL23; Japan) are the only treatments 
currently being tested in the clinic for the PPP indication. No data for palmoplantar pustulosis 
are currently available for these treatments. No anti-IL36R treatments are known to have 
been tested or are being tested in the clinic.
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.


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2.0
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
BI 655130 is in development for the treatment of Palmoplantar Pustulosis. The first trial to be 
conducted in PPP patients is a proof-of-concept, phase IIa trial. The rationale to perform this 
trial is based on the published human genetic linkage between the target disease PPP and the 
IL36 pathway targeted by BI 655130 [R16-0950; R16-3561], the functional linkage between 
the IL36 pathway and PPP [R16-3543] and the high unmet medical need in PPP.
There is currently no drug specifically approved for the treatment of PPP and it 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, the current treatment options are not effective in reducing 
duration and severity of PPP. Thus, there is high unmet medical need for PPP.
The results from this trial will enable the design of the further developmental program and in
case that positive efficacy signals can be confirmed the results will form the basis for
discussions with regulatory agencies.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and efficacy of BI 655130 in
patients with PPP following multiple intravenous administrations of either 900 mg or 300 mg
compared to placebo.
A description of the endpoints to be determined, and the observations along with specific
information as how to collect the data for that information, is provided in Section 5.


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2.3
BENEFIT - RISK ASSESSMENT
Procedure-related risks
The use of an indwelling venous catheter for the purpose of infusion may be accompanied by 
mild bruising and also, in rare cases, by transient inflammation of the wall of the vein and 
local infection. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply when drawing blood samples prior to the start of infusion.
Drug-related risks and safety measures
The clinical safety and tolerability profile of intravenous single doses of BI 655130 has been
comparable to placebo in male subjects with intravenous single doses up to 10 mg/kg body
weight. There have been no withdrawals for adverse events (AEs) or abnormal laboratory 
values. There have been no deaths or other serious adverse events (SAEs). The adverse 
events reported had no apparent dose or exposure relationship. There have been no dose or 
exposure related abnormalities in safety laboratory parameters, no clinically relevant 
laboratory abnormalities on treatment with BI 655130 and no safety or tolerability concerns 
that would preclude further clinical development of BI 655130.
Nonclinical studies support repeat-dose clinical trials of up to 13 weeks duration. In a 13-
week intravenous toxicity study of BI 674304 in mice, no adverse effects of IL36R
antagonism was 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.
Still, the
following safety measures are/will be applied in this study in order to minimize the risk for
the PPP patients:

The i.v. administration allows for immediate discontinuation of further drug 
administration should any safety concern arise (please refer to Section 4.1.4).

BI 655130 will be administered under close medical observation (see Section 6.2) during 
patient visits. 

Patients will be closely monitored for signs and symptoms of hypersensitivity reactions.
Hypersensitivity reactions should be treated according to medical standards.

Extensive safety laboratory testing will be performed (Table 5.3.3:1).


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Currently there are no data available to suggest interactions of BI 655130 with other drugs 
(c03320877).
In order to mitigate any safety signals as early as possible, an independent Data Monitoring 
Committee (DMC) will oversee this study (see Sections 3.1. and 7.4 for further details).
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.3.6.1.
Participation in this study may help generate future benefit for larger groups of patients with 
PPP if BI 655130 proves to be successful in treating this disease since an unmet medical need 
will be addressed as described in Section 1.1. 
Treatment with BI 655130 has the potential to provide benefit to patients with palmoplantar
pustulosis by reducing the severity and duration of disease-related symptoms. However, no 
direct benefit for all individual participants in this study can be assumed, because efficacy of 
BI 655130 has not been confirmed in palmoplantar pustulosis and because some patients will 
be randomised to the placebo arm. 
It is important to have a placebo control to address potential confounding factors, such as 
placebo effect, potential investigator bias in safety and efficacy assessment or regression to 
the mean in endpoint scoring as well as in order to characterize both the efficacy and safety 
background rates in this trial population. Currently there are no clinical trial data available in 
the published literature that describes a placebo response on the ppPASI50 in the population 
of patients with palmoplantar pustulosis. 


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Considering the medical need for development of an effective and well tolerated drug for the 
therapy of PPP, the benefit of this trial is considered to outweigh the potential minimal risks 
and justifies the administration of multiple doses of BI 655130 to patients with PPP to 
investigate efficacy, safety, tolerability and pharmacokinetics.


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3.0
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a randomised, double-blind, placebo-controlled, parallel-design study. This design is 
appropriate for providing proof-of-concept and assessing the efficacy and safety of BI 
655130 compared to placebo in patients with PPP.
There will be two active dosing arms in this study along with a placebo control arm as 
follows:
Figure 3.1: 1
Trial design
The final analysis of the efficacy and safety data collected up to week 16 will be performed 
once all randomised patients have completed the first 16 weeks of study; at that time-point, a 
database lock will be done. The final analysis of the entire trial data collected through week 
32 will be performed once all patients have completed the last scheduled trial visit.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to:

manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedures (SOPs),

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

order the materials as needed for the trial; and

ensure appropriate training and information of local clinical monitors (CMLs), Clinical 
Research Associates (CRAs), and Investigators of participating countries.


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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 internal 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.
A Coordinating Investigator is responsible to coordinate Investigators at different centers
participating in this multicenter trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators and other important
participants, including their curricula vitae, will be filed in the ISF.
A partially external Data Monitoring Committee will be established to assess the safety of BI 
655130 in this clinical trial at specified intervals through the final time-point (week 32). At 
least 3 members of this DMC will be independent of the sponsor, including the DMC 
Statistician and the Chair. Measures will be put in place to ensure blinding of the sponsor and 
all other trial participants. The tasks and responsibilities of the DMC will be specified in a 
charter. The DMC will maintain written records of all its meetings. In addition, an optional 
interim analysis, to be performed on the primary efficacy endpoint once 50% of the total 
required number of patients has completed 16 weeks of study, will be performed by the DMC
(see Section 7.4 for further details).
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service and an Interactive Response Technology (IRT) vendor will be 
used in this trial. Details will be provided in IRT Manual and Central Laboratory Manual, 
available in ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This phase IIa trial is the first study with BI 655130 to be conducted in PPP patients. Current 
safety data about BI 655130 were obtained from a previous first-in-man single dose phase I 
trial 1368.1 and the multiple raising dose trial 1368.2 both carried out in healthy volunteers. 
BI 655130 was safe and well tolerated in all dose groups tested in1368.1 and in all dose 
group tested so far in 1368.2 (10 mg/kg multiple dosing and 20 mg/kg single dose. 20 mg/kg 
multiple dose group has been approved and is currently ongoing. 
Non-clinical safety data are limited as BI 655130 could not be directly tested in preclinical
toxicity studies (a surrogate antibody specific to mouse was used instead). The main objective
of this phase IIa trial is to investigate proof of concept (safety and efficacy) and tolerability of 
BI 655130 in patients with PPP. Pharmacokinetics and pharmacogenomics will also be 
evaluated.


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Both patients who have a pure palmoplantar pustulosis (PPP) presentation and those patients 
with a mixed pustulosis and psoriasis presentation on less than 10% of the BSA will be 
included in this study. 
A placebo control group is necessary and is included in this trial because there are currently 
no clinical trial data available in the published literature that describes a placebo response on 
the primary efficacy endpoint in the population of patients with palmoplantar pustulosis.
3.3
SELECTION OF TRIAL POPULATION
3.3.1
Main diagnosis for trial entry
The study will be performed in adult patients diagnosed with Palmoplantar Pustulosis defined 
as presence of primary, persistent (> 3months duration), sterile, macroscopically visible 
pustules on the palms and/or soles, without or with plaque psoriasis.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
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.
Signed and dated written informed consent in accordance with Good Clinical Practice
(GCP) and local legislation prior to the start of any screening procedures.
2.
Male or female patients, 18 to 65 years of age at screening.
3.
Palmoplantar Pustulosis defined as presence of primary, persistent (> 3months duration),
sterile, macroscopically visible pustules on the palms and/or soles, without or with
plaque psoriasis on less than 10% of the body surface area.
4.
Presence of active pustulation (yellow pustules) on palms and /or soles.
5.
A minimum ppPASI score of 12 and pppPGA of at least moderate severity at baseline.
6.
Women of childbearing potential (WOCBP)1 and men able to father a child 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. A list of contraception 
methods meeting these criteria is provided in the patient information.
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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3.3.3
Exclusion criteria
1. Patients with associated plaque psoriasis ≥ 10% of the body surface area.
2.
Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
3.
Severe, progressive, or uncontrolled renal, hepatic, haematological, endocrine, 
pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms 
thereof.
4.
Presence or known history of anti-TNF-induced PPP-like disease.
5.
Patients with SAPHO (Synovitis–acne–pustulosis–hyperostosis–osteitis) syndrome.
6.
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).
7.
Known history of lymphoproliferative disease, including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy 
and/or splenomegaly.
8.
Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to the screening visit, except appropriately treated basal or squamous cell 
carcinoma of the skin or in situ carcinoma of uterine cervix.
9.
Patients who have previously undergone allergy immunotherapy for prevention of
anaphylactic reactions.
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 a systemically administered biologic 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 (patients with a positive 
QuantiFERON TB test are excluded. Patients with suspected false positive or 
undeterminable QuantiFERON TB result may be re-tested). 
15. Major surgery performed within 12 weeks prior to randomisation or planned within 32 
weeks after randomisation (e.g. hip replacement, aneurysm removal, stomach ligation), 
as assessed by the investigator.
16. 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.
17. 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.


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18. 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).
19. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable study subject or unlikely to complete the trial.
20. Previous randomisation in this trial.
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial 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 randomised patients in the trial: if possible on 
treatment, or at least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to randomization, as well as the
explanation of the consequences of withdrawal. 
The decision to withdraw from trial treatment or from the whole trial as well as the reason 
must be documented in the patient files and Case Report Form (CRF).
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication. Please refer to Section 4.2.2 for restricted medication during this 
trial.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

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 stick to the trial requirements in the future. 
Given the patient’s agreement, the patient will undergo the procedures for the remaining 
scheduled visits and follow up as outlined in the Flow Chart.
Should the patient not agree to continue the remaining trial visits as scheduled after the 
premature treatment discontinuation, all efforts should be made to bring the patient to the 
primary endpoint visit at Week 16 (Day 113, V11), and/or at least to the End of Trial at Week 
32 (Day 225, V13).
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the CRF. These data will be included in the trial database and reported.


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3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment, please see Section 3.3.4.1
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 any of the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.0
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS 
The investigational product has been manufactured by BI Pharma GmbH & Co. KG. The BI
655130 molecule is a heterodimer with a molecular weight of approximately 146 kDa. BI
655130 drug product is formulated at a concentration of 20 mg/mL. Active Pharmaceutical
Ingredient (API) in a buffer consisting of 25 mM sodium citrate, 200 mM sucrose, 0.04% w/v
polysorbate 80 at pH 6 and water for injection (WFI). All excipients are of compendium
quality (e.g. USP, Ph.Eur.).
4.1.1 
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Table 4.1.1:1
Test product BI 655130:
Substance:
BI 655130
Pharmaceutical formulation:
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
150mg/7.5 mL
Posology:
900mg or 300 mg every 4 weeks at Day 1, 29, 57 and 85.
Route of Administration:
i.v. infusion
Duration of Use:
12 weeks
Table 4.1.1:2
Placebo
Substance
Placebo
Pharmaceutical formulation
A buffer of 25 mM sodium citrate, 200 mM sucrose,
0.04% w/v polysorbate 80 at pH 6 and water for 
injection.
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
0 mg/7.5 mL
Posology
0 mg every 4 weeks at day 1, 29, 57 and 85.
Route of Administration 
i.v. infusion
Duration of Use
12 weeks


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At the time of use the i.v. solutions for dosing will be prepared as detailed in the instruction 
in the ISF.


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4.1.3
Method of assigning patients to treatment groups
An Interactive Response Technology will be used to screen and randomise eligible patients,
perform subsequent drug assignment, manage initial/re-supply ordering of drug supplies and
handle emergency un-blinding. The investigator will receive all necessary instructions to
access IRT from the Sponsor or chosen provider. Detailed IRT functions and procedures will
be documented in the user requirement specifications mutually agreed to by the sponsor and
the IRT vendor. Patients will be randomly assigned to any of the treatment groups through the
assignment of medication which will be treatment group-specific (c.f. Section 3.1 for the
treatment groups of the trial). For technical and statistical features of the treatment allocation
process, please c.f. Sections 4.1.4 and 7.5.
4.1.4
Drug assignment and administration of doses for each patient
During visit 2 on Day 1 eligible patients will be randomised to receive one of three treatments
in a 1:1:1 ratio according to a randomisation plan. Randomisation will be stratified by the 
presence or absence of plaque psoriasis. The assignment will occur in a blinded fashion via
IRT.
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. Treatment will be
assigned to each patient after the completion of the screening visit and verification of all
inclusion and exclusion criteria.
For further details concerning the timing of dosing patients with investigation product see Flow 
Chart. Start and end time of the infusion will be recorded in eCRF.
Detailed instructions for the preparation of the infusion solution, the volume to be 
administered and the infusion rate is provided in the ISF. 
In case of safety concerns, e.g. due to infusion reactions, it is at the discretion of the
investigator or his/her designee to adapt the infusion scheme, including but not limited to
slowing down the infusion rate, stopping of the infusion and provided no further safety
concern exists restarting at a slower rate. Further based on his medical judgment he/she will
provide medications such as steroids, etc. as needed.


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The administration of the trial medication will be done under supervision of the investigating 
physician or a designee. The so-called four-eye principle (two-person rule) should be applied
for administration of trial medication and its preparation, if correct dosage cannot be ensured
otherwise. Prior to each administration of study drug, a urine pregnancy test will be 
performed on site. If this test has a positive result, the administration of study drug should not 
proceed and this urine test should be confirmed by a serum pregnancy test.
Table 4.1.4: 1
Schedule for dosing patients
Total BI 655130
Dose (mg)
Visit 2
Day 1
Visit 6 
Day 29
Visit 8 
Day 57
Visit 10
Day 85
Number of patients
900
20
20
20
20
300
20
20
20
20
0 (placebo)
20
20
20
20
4.1.5
Blinding and procedures for un-blinding
4.1.5.1
Blinding
Patients and investigators involved in trial conduct will remain blinded with regard to the 
randomised treatment assignments until after the final trial database lock. The randomisation 
code will be kept secret by Clinical Trial Support up to the final database lock. For the 
primary analysis which is to be performed at week 16 once all randomized patients have 
completed the 16-week visit, the blind status of study personnel through the remainder of the 
trial will be clarified in a logistics plan which is to be finalized prior to the unblind for the 
week 16 analysis. Please refer to Section 7.4 for further details.
A partially external DMC will perform an un-blinded safety and efficacy assessment at
specified intervals in order to ensure that patients are protected from potential harm, please 
refer to Section 3.1.1. An optional interim analysis, to be performed on the primary efficacy 
endpoint once 50% of the total required number of patients has completed 16 weeks of study, 
will also be performed by the DMC. Furthermore, an interim analysis on primary, secondary 
and selected further efficacy endpoints, to be performed by an external vendor once 75% of 
the total required number of patients has completed 16 weeks of study, will additionally be 
done. Please refer to Section 7.4 for further details.


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4.1.5.2
Unblinding and breaking the code
An emergency code break through IRT will be available to the Investigator / Pharmacist / 
investigational drug storage manager. This code break may only be opened 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. If the 
code break for a patient is opened, the sponsor must be informed immediately. The reason for 
opening the code break must be documented on the envelope and/or appropriate CRF page 
along with the date and the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’s
Pharmacovigilance group to access the randomisation code for individual patients during trial 
conduct. The access to the code will only be given to authorised Pharmacovigilance
representatives and not be shared further.
Formal treatment unblinding will be performed prior to each DMC meeting as a prerequisite 
for generation of the applicable DMC summaries required, as well as subsequent to database
lock for the interim analyses at week 16, subsequent to database lock for the week 16 primary
analysis, as well as subsequent to the final trial database lock. Treatment unblind will be 
officially released once the final trial database lock has been performed. Procedures to protect 
the integrity of the trial including the blind of patients, investigators, and study personnel 
through the final trial database lock will be implemented and are further described in Section 
7.4.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by Boehringer Ingelheim Pharma GmbH & Co. 
KG, Biberach, Germany. The investigational product consists of a carton holding a single vial 
of the trial medication. The required information according to the Annex 13/EU GMP 
Guideline is provided on the vial and carton. Each carton will have a unique medication 
number.
The investigational product 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 description of the label, refer to the ISF.
4.1.7
Storage conditions
Investigational Medicinal Product (IMP) will be kept in 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 sponsor must be 
contacted immediately. Refer to ISF. Trial medication must be securely stored, e.g. in a
locked refrigerator or at a pharmacy. The medication may only be dispensed to trial patients 


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according to the Clinical Trial Protocol (CTP) by authorized personnel as documented in the 
trial staff list. IMP will only be prepared for infusion just prior to infusion.
4.1.8
Drug accountability
The Investigator, Pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the Institutional Review Board (IRB) / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of 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
The Investigator, Pharmacist or investigational drug storage manager must maintain records 
of the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor or warehouse / drug distribution centre or alternative disposal of 
unused products. If applicable, the sponsor or warehouse / drug distribution centre will 
maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of disposal or
return to the sponsor, the investigator / pharmacist / investigational drug storage manager 
must verify that all unused or partially used drug supplies have been returned by the clinical 
trial staff 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
4.2.1.1
Rescue medication
The use of a rescue medication will be left at the discretion of the investigator and should be 
based on the severity and progression of the disease. It is recommended to wait until at least 
four weeks after the study drug administration (week 16) before prescribing a rescue 
medication in case no improvement or no change in disease condition is observed (stable 
disease). In case a rescue medication is prescribed, the patient will stay in the trial and will be
followed-up as initially planned until week 32 (End of Trial Visit). The sponsor will not supply
the sites with the rescue medication.


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4.2.1.2
Emergency Procedures
In case of infusion reactions emerging during or after infusion of study drug, the investigator 
should consider in accordance with severity of the reaction and local standard of care to
-
Immediately interrupt the infusion
-
Treat with systemic anti-histamines and intravenous steroids
Based on patient`s clinical course and medical judgment, the infusion may be re-initiated in 
case of mild or moderate reactions (according to RCTC grading in ISF) at lower speed with 
gradual increase to complete the infusion as detailed in the Instructions for Preparation and 
Handling of BI 655130/placebo in the Investigator Site File.
4.2.1.3
Additional treatments
No additional treatment is planned. However, in case of adverse events in need of treatment, 
the investigator can authorize symptomatic therapy. In those cases, patients will be treated as
necessary and, if required, kept under supervision at the trial site or transferred to a hospital 
until all medical evaluation results have returned to an acceptable level.
Background therapy is not allowed throughout the trial.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medications (or classes of medications) listed in Table 4.2.2.1:1 must not be taken for the
time periods as specified.
Table 4.2.2.1:1
Restricted Medications
Medication or class of medications
Restriction duration (through Primary
Endpoint Visit at Week 16)1
IL36R inhibitors other than the study drug
not allowed neither before nor during
trial participation
Secukinumab (Cosentyx®), ustekinumab 
(Stelara®), guselkumab, ixekizumab,
tildrakizumab, brodalumab
Adalimumab, infliximab
Natalizumab or agents that deplete B or T
cells (e.g. rituximab, alemtuzumab or 
visilizumab)
Investigational products for psoriasis
12 weeks or 5 half-lives, whichever is 
greater, prior to randomisation 


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Table 4.2.2.1:1 
Restricted Medications (cont’d)
Medication or class of medications
Restriction duration (through Primary 
Endpoint Visit at Week 16)1
Etanercept
Live virus vaccinations4
6 weeks prior to randomisation 
Other systemic immunomodulating treatments 
(e.g. corticosteroids2, 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 (e.g. corticosteroids3, vitamin D 
analogues, salicylic acid, tar, anthralin)
14 days prior to randomisation.
Anakinra
7 days prior to randomization
1 In case of worsening of the PPP and/or psoriasis, the use of a rescue medication is left at the discretion of the investigator 
(refer to Section (4.2.1.1)); In case of any other acute indication after the Primary Endpoint Visit at Week 16, the use of a 
restricted medication is permitted.
2 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).
3 Exception: topical steroids of US class 6 (mild, such as desonide) or US class 7 (least potent, such as hydrocortisone) for
use on the face, axilla, and/or genitalia with a restriction of use within 24 hours prior to trial visit in which ppPASI is
assessed.
4Live virus vaccination should be restricted until the end of the trial.
In the event a patient with prior use of systemic steroids, TNFa inhibitors, IL17/IL12/23
inhibitors, or anakinra 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.
4.2.2.2
Restrictions on diet and life style
No specific restrictions on diet or life style of the patients are required. 
4.2.2.3
Restrictions regarding women of childbearing potential 
Women of child bearing potential must maintain an adequate contraception throughout the 
course of the trial as described in patient information and up to 20 weeks after the last study 
drug infusion.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study center under
the supervision of the investigating physician or a designee. The measured plasma 
concentrations will provide additional confirmation of compliance.


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Patients who are non-compliant (for instance, who do not appear for scheduled visits) may be 
removed from the trial and the CRFs completed accordingly (for further procedures, please 
see Section 3.3.4.1).


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5.0
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint(s)

Efficacy: ppPASI50 at week 16

Safety: Number of patients with drug-related AEs
5.1.2
Secondary Endpoint(s)

Treatment success defined as achieving a clinical response of 0 or 1=clear/almost clear 
via PPP Physicians Global Assessment (pppPGA) at week 16

ppPASI75 at week 16

Percent change from baseline in the ppPASI at week 16
5.2
ASSESSMENT OF EFFICACY
Palmoplantar Pustulosis Physician Global Assessment (pppPGA)
pppPGA relies on clinical assessment of the patient’s skin presentation on the palms and 
soles and will be measured at the timepoints scheduled in the Flow Chart. The investigator 


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(or qualified site personnel) scores the lesions on the most severely affected palmoplantar 
surface from 0 – 4 as clear, almost clear, mild, moderate or severe (cf Table 5.2: 1; R17-
0324). Further practical guidance will be available in the ISF. 
Table 5.2:1 PPP Physician Global Assessment (pppPGA)
Score
Wording
Detailed description
0
Clear
No signs of PPP; no scaling or crusts or pustule remains
1
Almost clear Slight scaling and/or erythema and / or slight crusts; very few new 
(yellow) and / or old (brown) pustules
2
Mild
Scaling and/or erythema and/or crusts; visible new (yellow) and/or 
old (brown) pustules of limited number and extent
3
Moderate
Prominent scaling and/or erythema and / or crusting; prominent
new (yellow) and / or old (brown) pustules covering most of the area 
involved
4
Severe
Severe scaling and/or erythema and / or crusting; numerous new 
(yellow) or old (brown) pustules with and/or without major conflence 
covering the entire area of at least 2 palmoplantar surfaces
Palmoplantar Pustulosis Psoriasis Area and Severity Index (ppPASI)
The ppPASI 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, by 
Bhushan et.al [R16-5334] will be used in this trial (cf Table 5.2: 2).
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 ppPASI will be measured at the timepoints scheduled in the Flow Chart.
Table 5.2:2
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 
(%)*
0
<10
10<30
30<50
50<70
70<90
90 - 100
* where area assessed is glabrous skin on the palms/ soles 


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PPPASI = [(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)] 


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5.3
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:

Adverse events (including drug-related AEs)

Serious adverse events

Intensity of adverse events will be assessed by Rheumatology Common Toxicity Criteria 
(RCTC) version 2.0 (refer to ISF for details)

Safety laboratory tests

Physical examination

Vital signs (blood pressure, pulse rate, body temperature)

12-lead ECG
5.3.1
Physical examination
Complete and target physical examinations will be performed at visits as described in the 
Flow Chart. Height and weight of the patient will be recorded at the screening visit.
Complete physical examination will include vital sign assessment and general appearance as 
well as evaluation of all organ systems. Targeted physical examination will include vital sign 
assessment and evaluation of organ systems associated with AE(s) symptoms or laboratory
abnormalities.
Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
5.3.2
Vital Signs
Vital signs evaluations will be performed at visits as shown in the Flow Chart. This includes
measuring temperature, pulse rate, systolic/diastolic blood pressure and respiratory rate.
Respiratory rate, pulse rate, and blood pressure will be measured after patients have been 
sitting comfortably for at least five minutes. All recordings should be made using the same
type of blood pressure recording instrument on the same arm if possible.
Measurement of vital signs should precede blood sampling to avoid the impact of blood 
sampling on the vital measurements. At visits with study drug administration vital signs will 
be assessed pre-dose, at 5 minutes and approximately 120 minutes after study drug 
administration.


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Patients should be closely monitored for signs and symptoms of hypersensitivity reactions for 
approximately 2 hours after the study drug administration. Hypersensitivity reactions should 
be treated according to medical standards. Pre-medications for further injections might be
considered and will be agreed on between investigator and BI clinical monitor.
Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death [R11-
4890]. To be able to prospectively define and assess any potential cases of anaphylaxis, the 
clinical criteria for diagnosis of anaphylaxis defined in Section 10.1 are to be considered.
5.3.3
Safety laboratory parameters
The laboratory tests listed in Table 5.3.3: 1 will be performed at the central laboratory service 
provider. Samples will be taken and sent for testing at the central lab however in cases of 
immediate patient safety concerns a local laboratory may be used for selected testing.
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in ISF. For time points of laboratory sampling, see
Flow Chart.
Laboratory results (i.e. all safety laboratory and clinical laboratory data relevant for current 
clinical practice) of the patients will be available in real time to the respective investigator 
(via laboratory reports) and to the sponsor (via the central laboratory website) and selected 
abnormal laboratory alerts will be flagged to the site and sent to sponsor in real time.
Clinically relevant abnormal findings will be reported as baseline conditions or AE’s. A
clinically relevant value may be either in- or outside the reference range. Clinically relevant 
abnormal laboratory test results should be confirmed using an unscheduled visit laboratory kit 
and should be repeated until normalization or stabilization or until an alternative explanation 
has been found. Abnormal laboratory values will be also graded for intensity by using RCTC 
Version 2.0 criteria [R13-3515].
Table 5.3.3: 1
Laboratory tests
Category
Test name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)
Glycosylated Hbc (HbA1c) (only at screening)
Red Blood Cell Count
Reticulocyte Count
White Blood Cells / Leukocytes
Platelet Count/ Thrombocytes
Diff. Automatic
Neutrophils (relative count)
Eosinophils (relative count)
Basophils (relative count)
Monocytes (relative count)
Lymphocytes (relative count)


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Table 5.3.3: 1
Laboratory tests (cont`d)
Category
Test name
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 test 2. 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
Hormones (only at screening)
TSH (free T3 and free T4 in case of abnormal TSH
result)
Autoantibodies (only at screening)
Rheumatoid Factor
anti-CCP antibodies


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Table 5.3.3: 1
Laboratory tests (cont´d)
Category
Test name
Urinalysis (dipstick)
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/ Leucocytes
Urine (only at screening)
Albumin (quantitative)
Infections screening (only at screening)
Hepatitis B Surface Antigen (qualitative),
Hepatitis C Antibodies (qualitative),
HIV-1, and HIV-2 Antibody (qualitative),
QuantiFERON®
1performed only at the randomisation visit (visit 2).
2Urine and serum pregnancy testing will be performed as indicated in the Flow Chart.
3IgE will be taken in case of infusion reaction together with ADA (anti-drug antibodies) sample
5.3.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart.
ECGs will be recorded after the patients have rested for at least 5 minutes in a supine position 
and will always precede blood sampling to avoid impact of sampling on results. Six limb 
leads, as specified by Einthoven (I, II and III) and Goldberger (aVR, aVL, aVF), and six pre-
cordial leads (V1–V6), according to Wilson, will be used.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle
movements, electrode dislocation).
Additional ECGs may be collected for safety reasons. Clinically relevant, abnormal findings 
will be reported as AEs. 
The electronic version, if applicable, or dated and signed printouts of the ECG will be 
regarded as source data and stored in the patient’s medical file.


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5.3.5
Other safety parameters
5.3.5.1
Medical examination
At the screening visit, the medical examination will include documentation of patient
information, informed consent, demographics including height and body weight, smoking and
alcohol history, relevant medical history and concomitant therapy, review of inclusion and
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a physical
examination. Details about the timing of the examinations during the trial are included in the Flow 
Chart.
5.3.5.2
Local tolerability
Local tolerability will be assessed by the investigator according to ‘swelling’, ‘induration’,
‘heat’, ‘redness’, pain’, or other findings’ at the times indicated in the Flow Chart.
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of AEs
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which:

results in death,

is life-threatening, this 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,


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
results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
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. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
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 given 
above.
The latest list of “Always Serious AEs” can be found in the Remote Data Capture (RDC)
system. A copy of the latest list of “Always Serious AEs” will be provided upon request. 
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN


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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 RDC.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity grading of AEs will be performed according to 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
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:


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•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
5.3.6.2
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
Records of AEs and AESIs shall include data on the time of onset, end time, and intensity of 
the event as well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards through the residual effect period 
(REP), until individual patient’s end of trial:
•
All AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial:
•
The investigator does not need to actively monitor the patient for AEs but 
should only report relevant SAEs and relevant AESIs of which he may
become aware of.
If an individual patient discontinues trial medication prematurely but stays in the trial (i.e. if 
further visits are planned), the Investigator must report all AEs and all AESIs until the 
individual patient’s end of the trial.


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The follow-up period describes the period of time from the last administration of trial 
medication until the end of trial examination (last per protocol visit).
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication and any possible interactions between the investigational drug(s) and a 
Non-Investigational Medicinal Product (NIMP) / Auxiliary Medicinal Product (AMP).
The following should also be recorded as an (S)AE in the CRF and 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 pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.


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The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical 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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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and are to be
performed in order to monitor patients' efficacy, safety and other parameters in an appropriate
way. The scheduled measurements will allow monitoring of changes in vital signs, standard
laboratory values, and ECG variables that might occur as a result of administration of trial
medication. The safety assessments are standard, are accepted for evaluation of safety and
tolerability of an intravenously administered drug, and are widely used in clinical trials.
 
Efficacy and 
 parameters are outlined in Section 5.1


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6.0
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. Investigators 
are to encourage adherence by the patient to protocol specific activities. Each visit date (with 
its window) is to be counted from Day 1. The acceptable time windows for follow-up visits 
and end of trial examination are given in the Flow Chart. All deviations from the planned 
visit schedule will be documented. 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.
If a patient misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the last 
Blinded Report Planning Meeting.
Study measurements and assessments are scheduled to occur ‘before’ trial medication 
administration at dosing visits and are to be performed and completed prior to the trial drug 
administration
  For planned 
individual plasma concentration sampling times refer to the Flow Chart. At non-dosing visits 
sampling should be done after other study procedures have concluded. Sampling times will 
be recorded and used for determination of pharmacokinetic parameters.
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. Additional details on procedures at selected visits are provided below.
Measurement of vital signs should precede blood sampling and be assessed pre-dose at all 
dosing visits.
The following sequence of procedures at each visit (where applicable) is recommended:
2. AE/local tolerability and concomitant therapy collection
3. Physical examinations 
4. pppPGA, ppPASI
6. ECG
7. Blood sampling, 


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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 
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 study patient number by the RDC system once the consent 
is signed. 
Baseline conditions and medical history will be assessed during screening.
Screening (Visit 1) should normally take place no more than 28 days before Visit 2 and be 
completed no less than 7 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 CML in conjunction 
with the TCM on a case by case basis.
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).
Patients who fail screening following Visit 1 assessments should be registered as a screen 
failure in IRT. Re-screening is allowed in this trial.
For the comprehensive list of the trial procedures required at the Screening Visit (Visit 1) 
please refer to 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 Visit 2 to Visit 10, followed by the 
primary endpoint visit at week 16 (Visit 11). Procedures described in the Flow Chart for each 
visit should be performed.
At visits during the treatment period, venepuncture (i.e. safety laboratories, 
 
 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. Trial medication will be administered as i.v. infusion 
by the Investigator or his designee. Details and procedures of administration of study drug are 
described in Section 4.1.4 and in the ISF.


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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 randomized trial treatment regularly at week 16, safety follow-up 
visits will be performed at week 24 (FU1 visit) and at week 32 (End of Trial, EOT visit).
Early treatment discontinuation
Patients who discontinue treatment prematurely prior to the week 12 (last planned treatment 
visit), should follow the scheduled visits as defined in the Flow Chart until the End of Trial 
Visit at week 32.
Trial completion:
Trial completion is defined as a patient having reached the EOT visit (Week 32).


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7.0
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
This trial is a study of proof of concept in patients with palmoplantar pustulosis. It is 
designed as a randomised, double-blind, and placebo-controlled trial with 3 parallel groups (2 
doses of BI 655130 and placebo). 
The primary objective of this trial is to assess the safety and efficacy of BI 655130 in 
comparison to placebo in patients with palmoplantar pustulosis.
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 reduction from 
baseline of the primary endpoint, at all follow-up visits, is calculated as:
% ppPASI reduction from baseline = ((ppPASI at baseline – ppPASI at Visit X) / ppPASI at 
baseline) * 100. 
Achieving a response of X% or larger decrease from baseline in ppPASI score is denoted as 
ppPASIX (where X = 50). This trial is designed to demonstrate an increase in the proportion 
of patients who achieve a ppPASI50, the primary endpoint, for BI 655130 relative to Placebo 
via the unadjusted risk difference estimate at week 16.
Randomisation will be stratified by the presence or absence of plaque psoriasis. However, 
due to the low number of patients to be recruited into this trial, the effects of the stratification 
variable on the primary endpoint will be assessed only in exploratory analyses.
7.2
NULL AND ALTERNATIVE HYPOTHESES
There will be no formal hypothesis testing performed in this trial. As an exploratory Phase II 
trial in patients with palmoplantar pustulosis, inferences concerning the efficacy of BI 
655130 will be based on the magnitude of the observed difference(s) versus Placebo on the 
proportion of patients who achieve a 50% reduction from baseline in the ppPASI score 
(ppPASI50) at Week 16, as well as on other efficacy endpoints, such as the % change in 
ppPASI from baseline, ppPASI75, etc.
The study has 3 treatment arms (BI 655130 900 mg, BI 655130 300 mg and placebo), and 
there are 2 scenarios of interest, as described below:
(1) Scenario 1: Examines the maximum effect of (BI 655130 900 mg or 300 mg) versus 
Placebo
(2) Scenario 2: Examines the effect of BI 655130 300 mg versus Placebo
A sample size justification regarding the scenarios of interest and potential decision 
boundaries for comparison can be found in Section 7.7.


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7.3
PLANNED ANALYSES
The efficacy analyses will be performed for the FAS which is based on the intent-to-treat 
principle, and comprises all participants who were randomised, received at least one dose 
during the trial, and had a baseline measurement for the primary endpoint. Efficacy analyses 
will be based on the planned treatment (i.e., the treatment assigned at randomisation). Safety 
analyses on patients who were randomised and received at least one dose during the trial will 
be based on the actual treatment received at the randomisation visit; this set of patients is 
called the Safety Analysis Set (SAF). All efficacy analyses will be conducted on the FAS. All 
safety analyses will be conducted on the SAF.
Important violations of the protocol will include key inclusion and exclusion violations, 
incorrect medications taken, compliance with study medication, concomitant use of restricted 
medications, and any other violations of the protocol deemed important by the study team. 
All decisions concerning important protocol violations will be made prior to un-blinding of 
the database for the final week 16 analysis. A per-protocol set (PPS) will be defined as a 
subset of the FAS which excludes all patients with a violation that potentially affects the 
Week 16 efficacy assessment.
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.
For continuous secondary
 endpoints, mean changes from baseline will be analysed 
using a restricted maximum likelihood (REML)-based repeated measures approach. Analyses 
will include the fixed, categorical effects of treatment and visit, presence or absence of plaque 
psoriasis (yes/no), as well as the treatment-by-visit interaction, and continuous, fixed 
covariates of baseline “endpoint” and baseline-by-visit interaction. An unstructured 
covariance structure will be used to model the within-patient measurements. Exploratory 
confidence intervals will be based on least-squares mean differences to Placebo using a two-
sided α = 0.05.
This is an exploratory trial and formal confirmatory statistical testing will not be performed.
7.3.1
Primary endpoint analyses
The achievement of ppPASI50 at Week 16 is the primary endpoint in this trial and represents 
a binary variable with values of 0 (= non-response) or 1 (=response). Prior to treatment 
unblinding for the optional week 16 interim analysis, it may be decided to use the ppPASI75 
as the primary endpoint (instead of ppPASI50 which will then be considered as a secondary 
endpoint); if applicable, such decision will be documented in the Trial Statistical Analysis 
Plan (TSAP). 
The primary analysis of the unadjusted absolute risk difference versus Placebo will be 
calculated simply as the difference in the observed proportion of patients with ppPASI50 at 
week 16 for each treatment scenario, for the FAS. A 95% Wilson confidence interval around 
this difference will also be provided. In addition, a parametric bootstrap 95% confidence 
interval will be generated by sampling from the binomial distribution on each treatment with 


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number of patients and observed proportion of responders per treatment representing the 
sampling parameters. A hierarchical approach to the testing of both scenarios for BI 655130 
versus Placebo will, however, be performed for the primary analysis in order to control for 
multiplicity arising as a result of the multiple treatment comparisons.
Further details will be provided in the TSAP.
7.3.2
Secondary endpoint analyses
For the secondary binary endpoints, for the FAS, the unadjusted absolute risk difference 
versus Placebo will be calculated and a 95% Wilson confidence interval around this 
difference will also be provided. In addition, a parametric bootstrap 95% confidence interval 
will also be generated.
For secondary continuous endpoints, mean changes from baseline will be analysed using a 
restricted maximum likelihood (REML)-based repeated measures approach (see Section 7.3).


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7.3.4
Safety analyses
The safety set, described in Section 7.3, will be used to perform all safety analysis. In general, 
safety analyses will be descriptive in nature and will be based on BI standards. No hypothesis 
testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The REP is defined as
20 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’. Drug 
related AEs will be tabulated by system organ class and preferred term after coding according 
to the current version of the Medical Dictionary for Drug Regulatory Activities (MedDRA).
In addition, the frequency, severity, and causal relationship of adverse events will be 
tabulated by system organ class and preferred term after coding according to the current 
version of MedDRA.
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.


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7.4
INTERIM ANALYSES
In order to ensure the patient’s safety during the trial, a partially external DMC, independent 
of the trial and project teams, will be set-up to review all available un-blinded safety data as 
well as selected efficacy data at regular intervals following first-patient-in. A DMC SAP 
which describes the analyses required for assessment by the DMC will be produced and 
finalized prior to first patient randomized into the trial. Further details will be provided in a 
DMC charter.
An interim analysis, on the primary endpoint only, will be performed if the period for 
randomization of the entire patient population exceeds approximately 4 months. The purpose 
will be to facilitate further substance development and project planning. There will be no 
changes to the design of the trial as a result of the performance of this optional interim 
analysis. If performed, the interim database lock and subsequent analysis will be done once 
the first 50% of the total required number of patients has completed 16 weeks of study. The 
efficacy decision that will be communicated to the sponsor will be formulated with regard to 
the conditional probability for achieving at least a target difference in the treatment effect at 
week 16 based upon the primary endpoint and the decision boundary as described in DMC 


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charter. Further details on the communication strategy will be provided in the DMC charter. 
The interim analysis will be performed by the DMC, independent of the trial team, in order to
prevent the potential introduction of operational bias. Details regarding the analyses required 
for this interim, if required, will be described in the DMC SAP. An interim logistics plan, 
outlining the procedures to be implemented to ensure that all members of the trial team, 
including the investigators and patients, remain blinded to study treatments, will also be 
prepared and approved prior to achieving interim database lock in accordance with the 
sponsor’s SOP. This logistics plan will include a list of the sponsor representatives who will 
have access to the un-blinded interim data via knowledge of the interim results for subsequent 
project planning.
An additional interim analysis will be performed once the first 75% of patients have 
completed 16 weeks of the study for the purpose of planning the subsequent trial(s) in 
PPP. This analysis will include primary, secondary, and selected further efficacy endpoints 
and biomarkers as well as the PK concentration data, and details of the statistical analysis will 
be specified in the trial statistical analysis plan. In order to protect the integrity of the 
continuing trial, this 75% interim analysis will be performed by a team who are external and 
fully independent from the trial team. The information resulting from this analysis will not be 
shared with patients, investigators, or with sponsor-involved trial team members. An interim 
analysis logistics and access plan will be prepared which will outline the team who will 
perform the analysis, the procedures to protect the blind, the unblinding process, and the 
individuals who will have access to the results and to any individual unblinded data. There 
are no changes to the design of the trial planned as a result of the performance of this 
additional interim analysis.
Once all randomised patients have completed the first 16 weeks of study, a partial database 
lock may be performed in order that a fast track analysis of primary and selected secondary 
and safety endpoints be done; a second data lock would then be done for the remaining 
efficacy and safety data collected up to week 16. If fast-track analysis is not performed, a 
single database lock will be done for safety and efficacy data collected up to week 16. At this 
time, the final analysis of these data through week 16 will be performed. Since the study is 
planned to continue through an additional 16 weeks of further follow-up, and will remain 
blinded, a week 16 logistics plan will be developed in order to protect the integrity of the 
ongoing trial data and reporting subsequent to treatment un-blind for both the fast track and 
the complete week 16 primary analysis. Details of the analysis to be performed for the week 
16 data will be described in the TSAP which is planned to be finalized prior to achieving 
database lock for the optional week 16 interim analysis.
An analysis of the entire trial data will be performed once all randomized patients have 
completed the 32 weeks of study. At this time, the database will be locked, and official 
unblinding of the trial will be performed. Details of the analysis to be performed for the 
completed trial through 32 weeks (End of Trial Visit) will also be described in the TSAP 
which is planned to be finalized prior to achieving database lock for the optional week 16 
interim analysis.
All analyses are planned to be documented in a clinical trial report which is to be prepared at 
the end of the trial.


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7.5
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will 
still occur and approaches to handle this are proposed below.
With respect to safety evaluations, it is not planned to impute missing values.
For all binary endpoints (i.e. endpoints that are either 1 (patient responded) or 0 (patient did 
not respond)), the following will be performed:
•
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;
•
Otherwise, impute as a failure to achieve a response (i.e. NRI [No Response 
Imputation]).
If a patient takes a rescue medication for the treatment of palmoplantar pustulosis prior to 
observing the primary endpoint for this trial, then all data subsequent to the intake of such 
rescue will be considered to represent a failure to achieve a response. Further details on what 
constitutes a rescue intake with potential impact on efficacy outcomes will be described in the 
TSAP.
For secondary efficacy endpoints which are continuous in nature, the use of a restricted 
maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach 
will ensure that missing data are handled implicitly, via a missing at random assumption, by 
the statistical model.
7.6
RANDOMISATION
Patients will be randomised in blocks to double-blind treatment. Approximately equal 
numbers of patients will be randomised to each treatment group using a 1:1:1 allocation ratio. 
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 CTR. Access to the codes will be 
controlled and documented.
Randomisation will be stratified by the presence or absence of plaque psoriasis.


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7.7
DETERMINATION OF SAMPLE SIZE
The study is intended to show an increase for BI 655130 over placebo in terms of the 
proportion of patients achieving a ppPASI50 response at Week 16. There is currently no 
clinical trial data available in the published literature that describes a placebo response on the 
ppPASI50 in the population of patients with palmoplantar pustulosis. The success probability
for the primary endpoint on this PoCC trial has, therefore, been derived under the assumption 
that the difference between BI 655130 and Placebo is 0.30 and that a total N of 60 patients
(fixed according to feasibility considerations) will be studied in a 1:1:1 ratio (i.e. 20 patients 
per treatment group).
Simulations in SAS® were used to derive estimates of the probability that a single trial would 
demonstrate an observed difference in proportions between BI 655130 and Placebo that was 
equal or greater than a defined threshold under a positive scenario whereby the expected 
difference in proportions is 0.3 in favour of BI 655130. For identifying such a target 
threshold, a minimum probability of 0.80 was defined. For each trial simulation, the response 
for each patient on each treatment was generated using a binomial distribution utilizing the 
expected treatment response rates as noted in Table 7.7:1 below. The trial observed 
proportions for each treatment were calculated and then the treatment comparisons, according 
to scenario 1 and scenario 2, were each compared against a range of threshold values using a 
hierarchical approach. A total of 100,000 trial simulations were performed. In addition, the 
probability of a false positive declaration being made given the specified target threshold(s), 
so-called negative scenario, was also determined.


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Table 7.7:1
Probability to Achieve the Threshold Difference in Treatments given 
Expected Treatment Response Rates on ppPASI50 and a Total 
Sample Size of 60 Patients
Population Response Rate
Expected 
Response 
Difference
(BI vs PLC)
Threshold
(Observed 
Difference)
Probability
Threshold 
Exceeded1
False 
Positive 
Rate (%)2
Low
Dose BI
High 
Dose BI
Placebo
SCENARIO 1 (maximum of [BI 655130 900 mg or 300 mg] vs. Placebo)
0.45
0.45
0.15
0.3
0.20
93%
11%
0.50
0.50
0.20
0.3
0.20
92%
15%
0.55
0.55
0.25
0.3
0.20
91%
18%
0.60
0.60
0.30
0.3
0.20
91%
20%
SCENARIO 2 (BI 655130 300 mg vs. Placebo)
0.45
0.45
0.15
0.3
0.15
87%
7%
0.50
0.50
0.20
0.3
0.15
86%
10%
0.55
0.55
0.25
0.3
0.15
85%
12%
0.60
0.60
0.30
0.3
0.15
85%
14%
Hierarchical testing: scenario 2 only tested if outcome on scenario 1 ≥ specified threshold.
1 Positive scenario: Assuming the expected response rate difference, the probability that the 
   BI 655130 response rate exceeds that of Placebo by at least the threshold amount is 
   displayed.
2 Negative scenario: The probability that the BI 655130 response rate exceeds that of Placebo 
   by at least the threshold amount assuming that treatments are equal.
In summary, for a total N of 60 patients, a 1:1:1 allocation ratio to BI 655130 900 mg, BI 
655130 300 mg, and Placebo, then under the assumption of a target difference between each 
dose of BI 655130 and Placebo of 0.30 [positive scenario] for the proportion of responders on 
the primary endpoint at week 16, this trial will be able to show:

An observed difference in response rates of at least 0.20, for the maximum of (BI 655130 
900 mg and BI 655130 300 mg) versus Placebo, with 91% probability (assuming a 
Placebo response rate from 0.15 through 0.30). The false positive decision probability in 
this case ranges from approx. 11%-20% under the assumption of no treatment difference;

An observed difference in response rates of at least 0.15, for BI 655130 300 mg versus 
Placebo, with 85% probability (assuming a Placebo response rate from 0.15 through 
0.30). The false positive decision probability in this case ranges from approx. 7%-14% 
under the assumption of no treatment difference.
The hierarchical nature of the comparisons, with rejection of the maximum of (BI 655130 
900 mg or BI 655130 300 mg) versus Placebo (scenario 1) required prior to proceeding to the 
test of BI 655130 300 mg versus Placebo (scenario 2), warrants that the overall success 
probability is at least 85% while the overall false positive rate [under negative scenario] is 
controlled at 20% (one-sided).


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8.0
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in 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 subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective 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 a designee 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 designee obtains written consent 
of the patient’s own free will with the informed consent form after confirming that the patient 
understands the contents. The Investigator or designee must sign (or place a seal on) and date 
the informed consent form. 
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms 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 subject. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
Before providing any copy of patients’ 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 to ensure patient confidentiality.
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, date or 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))


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
Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-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). The CRA and auditor may review all CRFs and informed consents. The accuracy 
of the data will be verified by direct comparison with the source documents described in 
Section 8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
the national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below and in Section 5.5.3. 
Patient privacy will be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 


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processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD 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.
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).


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9.0
REFERENCES
9.1
PUBLISHED REFERENCES
R05-2548
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple
practical measure for routine clinical use. Joint Ann Mtg of the British 
Association of Dermatologists and the Canadian Dermatology Association, 
Oxford, 6 - 10 Jul 1993 Clin Exp Dermatol 1994. 19:210-216.
R10-6267
Wang DD, Zhang S, Zhao H, Men AY, Parivar K Fixed dosing versus body 
size-based dosing of monoclonal antibodies in adult clinical trials. J Clin 
Pharmacol 49, 1012 - 1024 (2009)
R11-4890
Sampson HA, et al
Second symposium on the definition and management of anaphylaxis: 
summary report - second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium.
2nd Symp of the National Institute of Allergy and Infectious Disease 
(NIAID)/Food Allergy and Anaphylaxis (FAA) Network on the Definition and 
Management of Anaphylaxis, Jul 2005
J Allergy Clin Immunol 117 (2), 391 - 397 (2006)
R13-3515
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V,
Tsuji W, Stevens R, Fries J, Witter J, Johnson K, Lassere M, Brooks
P. Standardizing assessment and reporting of adverse effects in rheumatology 
clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0. J 
Rheumatol 34 (6), 1401 - 1414 (2007)
R13-4749
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, Gupta M, Tang M, 
Allison DE, Lu D, Zhang Y, Joshi A, Dresser MJ
A guide to rational dosing of monoclonal antibodies.
Clin Pharmacokinet 51 (2), 119 - 135 (2012)
R13-4750
Joos B, Trkola A, Kuster H, Aceto L, Fischer M, Stiegler G, Armbruster C, 
Vcelar B, Katinger H, Guenthard HF
Long-term multiple-dose pharmacokinetics of human monoclonal antibodies 
(MAbs) against human immunodeficiency virus type 1 envelope gp120 (MAb 
2G12) and gp41 (MAbs 4E10 and 2F5).
Antimicrob Agents Chemother 50 (5), 1773 - 1779 (2006)
R13-4753
Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S
Projecting human pharmacokinetics of therapeutic antibodies from nonclinical 
data: what have we learned?
MAbs 3 (1), 61 - 66 (2011)


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R13-4754
Xin y, Gordon MS, Jin D, Wakshull E, Chen DS, Rosen LS, Munster PN, 
Naumovski L, Bai S
Population pharmacokinetic (PK) analysis supports fixed dosing for the 
humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) 
administered intravenously in patients with advanced solid tumors.
47th Ann Mtg of the American Society of Clinical Oncology (ASCO), 
Chicago, 3 - 7 Jun 2011
J Clin Oncol 29 (15) (Suppl),, Abstr 2586 (2011)
R16-0927
DeWaal, A.C. and Van De Kerkhof, P.C.M. Pustulosis palmoplantaris is a 
disease distinct from psoriasis. Journal of Dermatological Treatment.; 22:102–
105.(2011)
R16-0928
Setta-Kaffetzi, N. Simpson,M.A., Navarini,A.A.,Patel,V.M.,Lu,H., 
Allen,M.H.,Duckworth,M.,Bachelez, B.,Burden,A.D., 
Choon,S.,Griffiths,C.E.M.,Kirby,B.,Kolios,A.,Seyger,M.M.B.,Prins,C., 
Smahi,A.,Trembath,R.C.,Fraternali,F.,Smith,C.H.,Barker,J.N. and Capon, F.
AP1S3 Mutations Are Associated with Pustular Psoriasis
and Impaired Toll-like Receptor 3 Trafficking. The American Journal of 
Human Genetics 94, 790–797, (2014)
R16-0950
Setta-Kaffetzi N, Navarini AA, Patel VM, Pullabhatla V, Pink AE, Choon SE, 
Allen MA, Burden AD, Griffiths CEM, Seyger MMB, Kirby B, Trembath RC, 
Simpson MA, Smith CH, Capon F, Barker JN; Rare pathogenic variants in 
IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes; J 
Invest Dermatol 133, 1366 – 1369 (2013)
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 11 (5), 
e0155215 (2016)
R16-3544
R Mȫssner, 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 135, 
2538–2541 (2015)
R16-3546
Hashigucci, K. et al Polymorphism in the tumor necrosis factor B gene is 
associated with Palmoplantar pustulosis. Tissue Antigens 54: 288–290. (1999)
R16-3560
Kingo,K.,Mȫssner,R.,Koks,S.Ratsep,R.,Kruger,U.,Vasar,E.,Reich,K. and 
Silm, H. Association analysis of IL19, IL20 and IL24 genes in palmoplantar 
pustulosis. Brit. J. Dermatol 156:646-652 (2007)
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 
genotypephenotype correlation in pustular diseases; J Invest Dermatol (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(4):546-53.
R16-5360
Ge M, Durham LK, Meyer RD, Xie W, Thomas N Covariate-adjusted 
difference in proportions from clinical trials using logistic regression and 
weighted risk differences. Drug Inf J 45, 481 - 493 (2011)
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.
R17-0364
Mrowietz U, Bachelez H, Burden AD, Rissler M, Sieder C, Orsenigo R, et al, 
2PRECISE Study Group. Efficacy and safety of secukinumab regimens in 
moderate to severe pustular palmoplantar psoriasis; results from the largest 
multicenter, randomized, double-blind, placebo-controlled study (2PRECISE). 
25th Cong of the European Academy of Dermatology and Venereology 
(EADV), Vienna, 28 Sep - 2 Oct 2016 (Poster) 2016.
9.2
UNPUBLISHED REFERENCES
c03320877
 Investigator's Brochure BI 655130
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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10.0
APPENDICES
10.1
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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11.0
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1.0
Date of CTP revision
01 August 2017
EudraCT number
2016-004573-40
BI Trial number
1368.15 (1368-0015)
BI Investigational Product(s)
BI 655130
Title of protocol
Multi-center, double-blind, randomised, placebo-
controlled, phase IIa study to investigate efficacy, 
safety, tolerability, pharmacokinetics and 
pharmacogenomics of multiple intravenous doses 
of BI 655130 in patients with Palmoplantar 
Pustulosis (PPP)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
X
Section to be changed
Flowchart, Footnotes 10 and 12
Description of change
 
 
 
 


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Section to be changed
Description of change
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale for change
 
 
Section to be changed
Description of change
The following change was done (highlighted)
 
Rationale for change
Correction to align protocol description with the 
actual instructions given to the patients. 


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Number of global amendment
2.0
Date of CTP revision
08 May 2018
EudraCT number
2016-004573-40
BI Trial number
1368.15 (1368-0015)
BI Investigational Product(s)
BI 655130
Title of protocol
Multi-center, double-blind, randomised, placebo-
controlled, phase IIa study to investigate efficacy, 
safety, tolerability, pharmacokinetics and 
pharmacogenomics of multiple intravenous doses 
of BI 655130 in patients with Palmoplantar 
Pustulosis (PPP)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
X
Section to be changed
Section 4.1.5.1 Blinding
Description of change
Text highlighted in yellow was added: 
A partially external DMC will perform an un-
blinded safety and efficacy assessment at specified 
intervals in order to ensure that patients are 
protected from potential harm, please refer to 
Section 3.1.1. An optional interim analysis, to be 
performed on the primary efficacy endpoint once 
50% of the total required number of patients has 
completed 16 weeks of study, will also be 
performed by the DMC.
 
 
 
 
 
Please refer to Section 7.4 for 
further details.
Section to be changed
Section 4.1.5.2 Unblinding and breaking the code
Description of change
The following change was done (highlighted)


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Formal treatment unblinding will be performed 
prior to each DMC meeting as a prerequisite for 
generation of the applicable DMC summaries 
required, as well as subsequent to database lock for 
the 
interim analyse
at week 16, 
subsequent to database lock for the week 16 
primary analysis, as well as subsequent to the final 
trial database lock. Treatment unblind will be 
officially released once the final trial database lock 
has been performed. Procedures to protect the 
integrity of the trial including the blind of patients, 
investigators, and study personnel through the final 
trial database lock will be implemented and are 
further described in Section 7.4.
Section to be changed
Section 7.4 Interim Analyses
Description of change
The following has been added: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale for changes
In order to facilitate the project development and 
design planning of the subsequent trial in PPP.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09935708
3.0
clinical-trial-protocol-version-03
Multi-center, double-blind, randomised, placebo-controlled, phase IIa study to
investigate efficacy, safety, tolerability, pharmacokinetics and pharmacogenomics of
multiple intravenous doses of BI 655130 in patients with Palmoplantar Pustulosis
(PPP)
Approval-Therapeutic Area 
08 May 2018 13:23 CEST
Approval-Trial Clinical Monitor
08 May 2018 13:33 CEST
Approval-Team Member Medicine
08 May 2018 13:35 CEST
Author-Trial Clinical
Pharmacokineticist
08 May 2018 13:39 CEST
Approval-Biostatistics
08 May 2018 14:12 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09935708
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c17115152-02
BI Trial No.:
1368.15
Title:
Trial Statistical Analysis Plan (including Interim analysis after 75% 
of patients completed the primary endpoint; Primary analysis at 
Week 16; and, Final trial analysis).
Multi-center, double-blind, randomised, placebo-controlled, phase 
IIa study to investigate efficacy, safety, tolerability, 
pharmacokinetics and pharmacogenomics of multiple intravenous 
doses of BI 655130 in patients with Palmoplantar Pustulosis (PPP).
Including Protocol Amendment 2 [c09935708-03]
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone:
Fax:    
Date of statistical 
analysis plan:
23 May 2018 SIGNED
Version:
2.0 Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINT(S) ................................................................................10
5.2
SECONDARY ENDPOINT(S) ..........................................................................10
Key secondary endpoint(s).................................................................................10
5.2.1
.................................................................................10
................................................................................11
................................................................................12
............................................13
............................................13
............................................13
............................................14
............................................14
............................................14
............................................15
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................15
6.1
TREATMENTS...................................................................................................15
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................17
6.3
PATIENT SETS ANALYSED...........................................................................29
....................................................................................................32
6.5
POOLING OF CENTRES .................................................................................33
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................33
Withdrawals ........................................................................................................34
6.6.1
Efficacy data........................................................................................................34
6.6.2
Safety data ...........................................................................................................36
6.6.3
Time since first diagnosis ...................................................................................37
6.6.8
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................37
7.
PLANNED ANALYSIS......................................................................................41
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........44
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................45
7.3
TREATMENT COMPLIANCE........................................................................45
7.4
PRIMARY ENDPOINT .....................................................................................46


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7.5
SECONDARY ENDPOINTS.............................................................................48
Key secondary endpoint .....................................................................................48
7.5.1
Secondary endpoints...........................................................................................48
7.5.2
7.5.2.1
Secondary efficacy endpoints ...............................................................................48
...............................................................49
...............................................................49
...............................................................49
...............................................................51
...............................................................51
...............................................................52
7.7
EXTENT OF EXPOSURE.................................................................................52
7.8
SAFETY ANALYSIS..........................................................................................53
Adverse events.....................................................................................................53
7.8.1
Laboratory data ..................................................................................................54
7.8.2
Vital signs.............................................................................................................55
7.8.3
ECG......................................................................................................................56
7.8.4
Injection Site Reactions ......................................................................................56
7.8.5
Immunogenicity...................................................................................................56
7.8.6
7.9
HANDLING OF DMC ANALYSES .................................................................57
8.
REFERENCES....................................................................................................58
9.
ADDITIONAL SECTIONS ...............................................................................60
9.1
PPPASI AND RELATED ENDPOINTS ..........................................................60
9.2
THE PALMOPLANTAR PUSTULOSIS PHYSICIAN GLOBAL 
ASSESSMENT (PPPPGA).................................................................................63
10.
HISTORY TABLE..............................................................................................71


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases ...........................................................................15
Table 6.2: 1
Important protocol violations ...........................................................................18
Table 6.3: 1
Patient sets analysed .........................................................................................31
...................................32
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, and  
biomarker measurements to visits for statistical analysis.................................39
Table 7.1: 1
Categories for summary of continuous variables .............................................44
Table 9.1: 1 
Palmoplantar Pustulosis Psoriasis Area and Severity Index ............................60
Table 9.2: 1 
PPP Physician Global Assessment (pppPGA)..................................................63
Table 10: 1
History table .....................................................................................................71


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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
DBLM
Database lock meeting
DILI
Drug Induced Liver Injury
DLQI
Dermatology Life Quality Index
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram


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Term
Definition / description
eCRF
Electronic case report form
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
IPV
Important protocol violation
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
MQRM
Medical quality review meeting
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
NRI
No response imputation
NRI-IR
No response imputation including rescue medication
OC
Observed cases
OC-IR
Observed cases including values after rescue medication
OR
Original results
PD
Pharmacodynamic(s)
PG
Pharmacogenomic(s)


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Term
Definition / description
PGA
Physician Global Assessment
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PPP
Palmoplantar Pustulosis
pppPGA
Palmoplantar Pustulosis Physicians Global Assessment
ppPASI
Palmoplantar Pustular Psoriasis Area and Severity Index
PPS
Per protocol set
psvBSA
Plaque psoriasis vulgaris BSA
PT
Preferred Term
PV
Protocol Violation
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
TCM
Trial Clinical Monitor
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range
ULOQ
Upper limit of quantification


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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 CTP. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
A separate Biomarker Statistical Analysis Plan (BM-SAP) will complement this TSAP.
Study data will be stored in a trial database within the BRAVE system. 
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). SAS
calling R version 3.0.2 or later (12) may be used for calculation of Reeve's confidence 
intervals.
This TSAP will document the features of the primary week 16 analysis (to be performed once 
all randomized patients have completed through the week 16 visit), as well as the final trial 
analysis (to be performed once all patients have completed the trial). In addition, details 
regarding the interim analysis to be performed once 75% of patients have completed through 
the week 16 visit will also be described. Statistical features of an interim analysis performed 
once 50% of patients had completed through the week 16 visit are described in a separate 
SAP which was prepared by an external vendor.


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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.
The Safety Set as defined in the CTP is referred to as the SAF in this TSAP. In the
CTP, it is stated that patients will be analyzed for safety according to the actual treatment 
received at the randomization visit. Since at each dosing visit multiple vials will be 
administered for a single infusion - each vial with its own medication number – it is likely 
that analysis according to the randomized treatment itself may better reflect the fact that the 
majority of vials that a patient receives will represent the correct treatment assignment 
according to the randomization schedule. Hence, the analysis of the safety data will be 
performed according to the randomized treatment, and not the actual treatment received at the 
randomization visit.
The CTP states, e.g. Section 7.3.1, that a 95% Wilson confidence interval around the 
unadjusted absolute risk difference versus Placebo will be provided. This statement must be 
elaborated because the Wilson confidence interval was originally developed for single 
proportions (see (16)). Newcombe (17) transferred this method to risk differences. Therefore, 
the confidence interval for risk differences on binary endpoints used in this trial will be based 
on Newcombe and may correctly be referred to as a Newcombe confidence interval.
Change in plaque psoriasis BSA is listed as a further endpoint in CTP Section 5.1.3 and, for 
clarification this refers to the absolute change from baseline.  


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5.
ENDPOINTS
For all endpoints and unless explicitly specified otherwise, Week 16 refers to Visit V11 (PE
visit) using extended time windows as defined in .
For all endpoints and unless explicitly specified otherwise, Week 24 refers to Visit V12 
(Week 24) using extended time windows as defined in Table 6.7: 1.
For all endpoints and unless explicitly specified otherwise, Week 32 refers to Visit 13 
(EOT/Week 32) using extended time windows as defined in Table 6.7: 1.
For handling of missing data and corresponding sensitivity analyses, see Section 6.6.
5.1
  PRIMARY ENDPOINT(S)
Efficacy: ppPASI50 at Week 16
The achievement of ppPASI50 at Week 16 is the primary efficacy endpoint in this trial.
Derivation of the ppPASI and ppPASI50 is described in Section 9.1.
Safety: 
The number of patients with drug-related AEs is the primary safety endpoint in this trial. 
Further details are provided in Section 7.8.1.
5.2
SECONDARY ENDPOINT(S)
Key secondary endpoint(s)
5.2.1
Not applicable.
Secondary endpoint(s)
5.2.2
The secondary endpoints are listed below.

Treatment success defined as achieving a clinical response of 0 or 1=clear/almost clear 
via PPP Physicians Global Assessment (pppPGA) at Week 16
Derivation of pppPGA is described in Section 9.2.

ppPASI75 at Week 16
Derivation of ppPASI and ppPASI75 is described in Section 9.1.

Percent change from baseline in the ppPASI at Week 16
Derivation of ppPASI is described in Section 9.1.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on the treatment to be administered, assignment to treatment, and 
selection of dose, cf. Section 4 of the CTP.
All patients will receive either intravenous doses of 300mg or 900mg of BI 655130 solution 
for infusion (at weeks 0, 4, 8 and 12), or Placebo.
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 infusion of 
first study drug minus 1 minute.
Treatment phase & 
Residual effects 
period (REP)
On-treatment 
period
Date/time of start of 
infusion of first study drug 
(Day 1) 
Date of end of infusion of last 
study drug + 140 days at 11:59 
p.m.
Follow-up1 phase
Off-treatment 
period
Date of end of infusion of 
last study drug + 141 days at 
12:00 a.m.
Latest of: i) Date of EOT visit 
(Week 32 visit); ii) end date on 
trial termination page at 11:59 p.m.
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements associated 
with a specific date are assigned to a study analysis phase according to the rules specified in the table. An analysis phase 
will not extend beyond the start date of the following phase. 
1 The off-treatment period (i.e. Follow-up phase) only exists if the trial completion date is after the date of end of last 
infusion + 140 days.


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For the interim analysis to be performed once 75% of patients have completed the planned 
first 16 weeks of trial, the following data will be used:

The 16-week data will be summarized up to the minimum of the (analysis-specific 
data cut-off; study day 141), unless otherwise specified.

The 24-week data will be summarized up to the minimum of (the analysis-specific 
data cut-off; study day 197), unless otherwise specified.
The date of the analysis-specific data cut-off will be presented in a Data Cleaning Plan to be 
developed for the interim analysis on the week 16 data.
For the primary analysis to be performed once all patients have completed through the 
planned first 16 weeks of trial, the following data will be used:

The 16-week data will be summarized up to the minimum of the (analysis-specific 
data cut-off; study day 141), unless otherwise specified.

The 24-week data will be summarized up to the minimum of (the analysis-specific 
data cut-off; study day 197), unless otherwise specified.

The 32-week (EoS) data will be summarized up to the analysis-specific data cut-off.
The date of the analysis-specific data cut-off will be presented in a Data Cleaning Plan to be 
developed for the primary analysis on the week 16 data. 
For the final analysis of the trial to be performed once all patients have completed through the 
planned 32 weeks of trial, results will be summarized including applicable data from the on-
treatment period (Treatment phase plus REP). The selection of data for presentation in this 
analysis is described in Table 6.7: 1.
Treatment groups for the analysis will be labelled as follows:

"300 mg BI "

"900 mg BI"

"Placebo"

"BI Total" (i.e., across 300mg and 900mg arms)

"Overall Total" (across treatments), where appropriate.
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 VIOLATIONS
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 
BRPM/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 IPV. For definition of IPVs, and for 
the process of identification of these, refer to the BI reference document "Protocol Violation 
Handling Definitions" (2).
If any IPVs are identified, they are to be summarised into categories and will be captured in 
the BRPM/DBLM/MQRM minutes via an accompanying Excel spreadsheet (3). The 
following table contains the categories which are considered to be IPVs in this trial. If the data 
show other IPVs, this table will be supplemented accordingly by the time of the 
BRPM/DBLM/MQRM. Not all IPVs will lead to exclusion from analysis sets. IPVs leading 
to exclusion from analysis sets are indicated as such in Table 6.2: 1.
IPVs will be summarised and listed.


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Table 6.2: 1
Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
Signed and dated written informed 
consent in accordance with GCP and 
local legislation prior to admission to the 
trial
LABEL:
IC not in accordance with legislation.
IC01  (i.e., Inclusion 
criterion 1)
Note that IC obtained late 
(but available at time of 
analysis) may not lead to 
exclusion. See section B 
"Informed consent" for 
details.
All analyses
A1.02
18-65 years, males or females at 
Screening
LABEL:
Age beyond 18-65, not male or female.
IC02
Also check versus derived
age for patient.
None
A1.03
Palmoplantar Pustulosis defined as 
presence of primary, persistent (> 3
months duration), sterile, macro-
scopically visible pustules on the palms 
and/or soles, without or with plaque 
psoriasis on less than 10% of the body 
surface area.
LABEL:
No presence of PPP.
IC03
Also check versus ppPASI 
that pustule severity > 0 on 
at least one region
PPS
A1.04
Presence of active pustulation (yellow 
pustules) on palms and /or soles.
LABEL:
No active pustulation on palms/soles.
IC04
PPS
A1.05
A minimum ppPASI score of 12 and 
pppPGA of at least moderate severity at 
baseline.
LABEL: 
ppPASI < 12, pppPGA not at least mod.
IC05. Also check versus 
reported pppPGA and 
derived ppPASI at baseline.
PPS


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Table 6.2: 1 (cont’d) Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
A1.06
Women of childbearing potential 
(WOCBP)a and men able to father a 
child 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. A list of contraception 
methods meeting these criteria is 
provided in the patient information.
LABEL:
Contraception methods not used.
IC06
None
A2
Exclusion criteria violated 
General Exclusion Criteria
A2.01
Patients with associated plaque psoriasis 
≥ 10% of the body surface area.
LABEL: 
Plaque psoriasis >= 10% of body 
surface.
EC01. 
Also check versus derived 
psvBSA at screening
PPS
A2.02
Women who are pregnant, nursing, or 
who plan to become pregnant while in 
the trial.
LABEL: 
Pregnant or nursing.
EC02
None
A2.03
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.
EC03
PPS
                                                
a A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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Table 6.2: 1 (cont’d) Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
A2.04
Presence or known history of anti-TNF-
induced PPP-like disease.
LABEL:
Anti-TNF-induced PPP-like disease.
EC04
PPS
A2.05
Patients with SAPHO (Synovitis–acne–
pustulosis–hyperostosis–osteitis) 
syndrome.
LABEL:
SAPHO syndrome.
EC05
PPS
A2.06
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).
LABEL:
Transplanted organ or cell therapy.
EC06
PPS
A2.07
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.
EC07
None
A2.08
Any documented active or suspected 
malignancy or history of malignancy 
within 5 years prior to the screening 
visit, except appropriately treated basal 
or squamous cell carcinoma of the skin 
or in situ carcinoma of uterine cervix.
LABEL:
Malignancy within last 5 years.
EC08
None


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Table 6.2: 1 (cont’d) Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
A2.09
Patients who have previously undergone 
allergy immunotherapy for prevention of 
anaphylactic reactions.
LABEL:
Previous Allergy immunotherapy.
EC09
None
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.
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 a 
systemically administered biologic 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


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Table 6.2: 1 (cont’d) Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
A2.14
Chronic or relevant acute infections 
including human immunodeficiency 
virus (HIV), viral hepatitis and (or) 
active or latent tuberculosis (patients 
with a positive QuantiFERON TB test 
are excluded. Patients with suspected 
false positive or undeterminable 
QuantiFERON TB result may be re-
tested). 
LABEL:
Chronic or relevant acute infections.
EC14
None
A2.15
Major surgery performed within 12 
weeks prior to randomisation or planned 
within 32 weeks after randomisation (e.g. 
hip replacement, aneurysm removal, 
stomach ligation), as assessed by the 
investigator.
LABEL:
Recent or planned major surgery.
EC15
None
A2.16
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. 
EC16
Also check versus screen 
Lab values
None
A2.17
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.
EC17
Also check versus screen 
Lab values (medical review 
for Gilbert Syndrome)
None


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Table 6.2: 1 (cont’d) Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
A2.18
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.
EC18
PPS
A2.19
Chronic alcohol or drug abuse or any 
condition that, in the investigator’s 
opinion, makes them an unreliable study 
subject or unlikely to complete the trial.
LABEL:
Alcohol or drug abuse.
EC19
PPS
A2.20
Previous randomisation in this trial.
LABEL:
Previous randomisation in this trial.
EC20
PPS
B
Informed consent
B1
Informed consent not available
LABEL:
IC not available.
Based on direct assessment, 
not simply the tick box 
(which is A1.01).
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 analyses
#
B2
Informed consent too late
LABEL:
IC too late.
Informed consent date was 
after Visit 1
None


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Table 6.2: 1 (cont’d) Important protocol violations
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.
PPS, FAS, 
SAF
C1.02
Patient skipped an intermediate dose
LABEL:
Patient skipped an intermediate dose.
Patient missing a dose at an 
intermediate visit when dose 
at a later scheduled visit has 
been taken.
PPS
C2
Incorrect Dosing
C2.01
Actual administered dose above planned
LABEL:
Actual dose above planned
Can only be finally judged 
after DBL since unblinding 
information is required. 
Placebo patient who 
receives ≥100mg of verum 
overall 
or receives ≥100mg of 
verum on at least one 
specific visit
will be considered to be an 
IPV.
A BI 300mg patient who 
jointly fulfils all of the 
following:
Is randomized to the 
300mg group
At least one of the 
following:
o
received ≥ 20% 
above planned 
amount of verum 
overall 
o
received ≥ 50% 
above planned 
amount of verum 
on at least one 
specific visit 
will be considered to be an 
IPV. Here, the planned 
amount of verum on a 
PPS


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Table 6.2: 1 (cont’d) Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
specific visit is 300mg. The 
planned amount of verum 
overall is 

300mg if discon-
tinuation before visit 
V6

2*300mg if discon-
tinuation before  V8

3*300mg if discon-
tinuation before V10

4*300mg if discon-
tinuation on or after 
V10
A BI 900mg patient who 
jointly fulfills all of the 
following:
Is randomized to the 
900mg group 
At least one of the 
following:
o
received ≥20% 
above planned 
amount of verum 
overall 
o
received ≥ 20% 
above planned 
amount of verum 
on at least one 
specific visit 
will be considered to be an 
IPV. Here, the planned 
amount of verum on a 
specific visit is 900mg. The 
planned amount of verum 
overall is 

900mg if discon-
tinuation before visit 
V6

2*900mg if discon-
tinuation before  V8

3*900mg if discon-
tinuation before V10

4*900mg if discon-
tinuation at or after 
V10


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Table 6.2: 1 (cont’d) Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
C2.02
Actual administered dose below planned
LABEL:
Actual dose below planned
Can only be finally judged 
after DBL since unblinding 
information is required. 
A Placebo patient can not be 
below planned.
A BI 300mg patient who 
jointly fulfills all of the 
following:
Is randomized to the 
300mg group
At least one of the 
following:
o
received 20% 
below planned 
amount of verum 
overall 
o
received 50% 
below planned
amount of verum 
on at least one 
specific visit 
will be considered to be an 
IPV. Here, the planned 
amount of verum on a 
specific visit is 300mg. The 
planned amount of verum 
overall is 

300mg if discon-
tinuation before visit 
V6

2*300mg if discon-
tinuation before  V8

3*300mg if discon-
tinuation before V10

4*300mg if discon-
tinuation on or after 
V10
A BI 900mg patient who 
jointly fulfills all of the 
following:
Is randomized to the 
900mg group
At least one of the 
following:
o
received 20% 
below planned 
amount of verum 
PPS


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Table 6.2: 1 (cont’d) Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
overall 
o
received 50% 
below planned
amount of verum 
on at least one 
specific visit 
will be considered to be an 
IPV. Here, the planned 
amount of verum on a 
specific visit is 900mg. The 
planned amount of verum 
overall is 

900mg if discon-
tinuation before visit 
V6

2*900mg if discon-
tinuation before  V8

3*900mg if discon-
tinuation before V10

4*900mg if discon-
tinuation at or after
V10
C3
Randomization not followed
C3.01
Treated without randomisation
LABEL:
Treated without randomisation.
Patient treated according to 
eCRF, but not randomised 
according to IVRS.
RS, SAF, 
FAS, PPS
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
#
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
#


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Table 6.2: 1 (cont’d) Important protocol violations
Category / 
Code
Description
Comments
Excluded 
from1
D
Concomitant medication
D1
Previous medication
D1.01
Washout of previous medication too 
short
LABEL:
Washout too short.
PPS
#
D2
Prohibited medication use
D2.01
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 treatment to 
stabilize a worsening disease condition –
prior to or up to Week 16
LABEL:
Restricted medication prior to week 16.
PPS
#
D3
Mandatory medication not taken
<not applicable>
E
Missing data
<not specified>
F
Study specific analysis
<not specified>
F1
Other trial specific violation
F1.01
PE assessment more than 1 week before 
planned day
LABEL:
PE assessment > 1 week before planned.
PPS
F2
Certain violations of procedures used 
to measure primary or secondary 
efficacy data
<not specified>
G
Other safety related violations
G1.01
Pregnancy test not done for woman of 
child bearing potential
LABEL:
Pregnancy test not done.
Pregnancy test not done at 
any visit where such is 
scheduled and the patient did 
not yet complete follow-up.
None
# PV will be detected manually; PE = Primary endpoint
Source: BI reference document 'Protocol Violation Handling Definitions' [001-MCS-50-413_RD-01] (2).
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 into the trial. 
It will be used for display of patient analysis sets and patients with IPVs.

Safety analysis set (SAF)
This patient set includes all randomized patients who received at least one dose of 
study drug. It will be the main analysis set for presentation of safety. Treatment 
assignment will be as randomized.
For the interim analysis once 75% of patients have completed through the week 16 visit, the 
following additional patient sets will be defined.

Full analysis set week 16 - 75 (FAS wk 16 - 75)
This patient set includes all patients in the SAF who had a baseline measurement 
available for the primary endpoint and who were randomized more than 99 days 
before the data cut-off date (specific for the 75% interim); qualifying patients who did 
not provide any primary endpoint data, even partial data of the primary endpoint, for 
any visit post day 99, and who had not discontinued the trial post day 99, will be 
excluded. Treatment assignment will be as randomized. This is the main analysis set 
for presentation of efficacy up to week 16.

Full analysis set week 24 - 75 (FAS wk 24 - 75)
This patient set includes all patients in the SAF who had a baseline measurement 
available for the primary endpoint and who were randomized more than 141 days 
before the data cut-off date (specific for the 75% interim); qualifying patients who did 
not provide any primary endpoint data, even partial data of the primary endpoint, for 
any visit post day 141, and who had not discontinued the trial post day 141, will be 
excluded. Treatment assignment will be as randomized. This is the main analysis set 
for presentation of efficacy data up to week 24.
For the primary analysis to be performed once all patients have completed through the week 
16 visit, the following additional patient sets will be defined.

Full analysis set (FAS)
This patient set includes all patients in the SAF who had a baseline measurement 
available for the primary endpoint. Treatment assignment will be as randomized. This 
is the main analysis set for presentation of efficacy up to week 16.

Per protocol set (PPS)
This patient set includes all patients in the FAS who adhered to the CTP without any 


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IPV which was flagged for exclusion from the PPS in the table above.
This set will be used for sensitivity analysis on the primary efficacy endpoint.

Full analysis set week 24 (FAS wk 24 - primary)
This patient set includes all patients in the SAF who had a baseline measurement 
available for the primary endpoint and who were randomized more than 141 days 
before the data cut-off date (specific for the week 16 primary analysis); qualifying 
patients who did not provide any primary endpoint data for any visit post day 141, and 
who had not discontinued the trial post day 141, will be excluded. Treatment 
assignment will be as randomized. This is the main analysis set for presentation of 
efficacy data up to week 24.

Full analysis set week 32 (FAS wk 32 - primary)
This patient set includes all patients in the SAF who had a baseline measurement 
available for the primary endpoint and who were randomized more than 197 days 
before the data cut-off date (specific for the week 16 primary analysis); qualifying 
patients who did not provide any primary endpoint data for any visit post day 197, and 
who had not discontinued the trial post day 141, will be excluded. Treatment 
assignment will be as randomized. This is the main analysis set for presentation of 
efficacy data up to week 32.
For the final trial analysis, the definition of FAS and PPS will be identical to those analysis 
sets derived for the week 16 primary analysis. Additional analysis sets to be defined for the 
final trial analysis include:

Pharmacokinetic parameter set (PKS)
This patient set includes all patients in the SAF who provide at least one evaluable 
observation for the BI 655130 concentration, which was not flagged for exclusion. 
This patient set will be used for the display of concentrations.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at latest at the DBLM.
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 set1
RS
ES
SAF
FAS wk 16 – 75
FAS wk 24 – 75
FAS
FAS wk 24 -
primary
FAS wk 32 -
primary
PPS
PKS
Disposition
OR
OR
Compliance 
OR
OR
Exposure
OR
OR
IPVs
OR
Demographic/baseline characteristics
OR
OR
Primary efficacy endpoint
NRI, 
NRI-IR, OC,
OC-IR, LOCF
NRI, 
OC
Primary safety endpoint
OR
Secondary efficacy endpoints (Binary)
NRI,
OC, LOCF
Secondary efficacy endpoints 
(Continuous)
LOCF,
OC
Further safety parameters
OR,
OC-IR
1 Patient set as applicable to the particular time-point of the analysis (75% of patients with week 16, primary analysis on 
week 16, or final trial analysis).
For explanation of the different approaches with regard to missing data see Section 6.6.
OR = Original results (i.e., ignoring visit windows)
NRI = No Response Imputation
NRI-IR = No Response Imputation including rescue medication
OC = Observed cases
OC-IR = Observed cases including also values after rescue medication
LOCF = Last observation carried forward


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6.5
POOLING OF CENTRES
Given the low number of patients per centre and the primarily descriptive nature of the 
statistical analysis, separate analyses by centre are not meaningful and not desirable. All 
patients from all centres will be pooled for statistical analysis.
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). 


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OR analysis will be performed on parameters and endpoints that are either not affected by 
patients’ rescue medication use (e.g. plasma concentration level of BI 655130, rescue 
medication 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 at the interim analysis once 75% of patients have completed the 
week 16 visit, as well as at the primary analysis of week 16 once all patients have achieved 
the week 16 visit, will be performed using all available on-treatment data observed up to the 
respective analysis cut-off date.
Binary efficacy endpoints
The primary endpoint in this study, ppPASI50, is a binary outcome derived from the ppPASI 
score, which itself is regarded as a continuous endpoint. The ppPASI may be missing (e.g. if 
one of its components is missing). Imputation approaches as described in this section for the
binary endpoints will be applied to impute the binary outcome directly as opposed to imputing 
on any underlying, i.e. continuous, distribution.
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);

Otherwise, impute as a failure to achieve a response 
If a patient takes a rescue medication (as defined in Section 5.4.4) for the treatment of PPP, 
then all data subsequent to the intake of such rescue will be considered to represent a failure 
to achieve a response. 
A sensitivity analysis on this approach will be performed whereby data collected after rescue 
intake will be included (i.e. not set to failure); analysis type: NRI-IR.


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Further approaches to the handling of missing data will be performed as follows:
Observed cases (analysis type: OC) approach will be used as a sensitivity analysis and 
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 medication 
(i.e. such values will be set to missing).
Observed cases including rescue (analysis type: OC-IR) approach will be used as a 
further sensitivity analysis and is an extension of the OC approach which includes 
additionally all values which were measured after rescue medication intake.
Last observation carried forward (analysis type: LOCF) will be used for selected binary 
endpoints. For LOCF, carrying forward of baseline information is allowed. Where 
applicable, LOCF carries last value prior to any use of rescue medication forward
within the on-treatment period. 
Missing data after premature discontinuation will not be imputed when following the OC and 
OC-IR approach. 
Categorical efficacy endpoints with more than two outcomes
Some endpoints or their subscores are categorical with more than two potential outcomes (e.g. 
PGA, DLQI). As a general, rule imputation will only be applied on the complete score. 
However, if a subscore  is presented by itself, application of, e.g., LOCF may be applied 
within the subscore.  Imputed subscores will not be combined to provide a complete score. 
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, if applicable, 
will ensure that missing data are handled implicitly, via a missing at random assumption, by 
the statistical model.
The primary technique for the handling of missing data of continuous endpoints will therefore 
be the OC approach (described above for the binary efficacy endpoints). Last observation 
carried forward (LOCF) may, however, also be used for some continuous secondary or further 
endpoints (analysis type: LOCF). These endpoints include % change in the ppPASI, 
 
For LOCF, carrying forward of baseline information is allowed.
For sensitivity analysis, an MMRM may be fit after application of the LOCF approach. This 
approach may be referred to as: LOCF-MMRM. 


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Safety data
6.6.3
From CTP Section 7.5: 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.
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 (see 001-MCG-156_RD-01 (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 medication, where the first dosing day will be used if first dosing happened in 
the same month).

If the day and month of the start date are missing then the start date is set to 1st January of 
the year (except for rescue medication, 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.


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Time since first diagnosis
6.6.8
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows:

If the year of first diagnosis is unknown, time since first diagnosis will be set to missing.

If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th June of that year.

If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Measurements reported with date and time and taken prior to start of administration of trial 
treatment will be considered pre-treatment values. Measurements reported with a date only 
(and no time) and taken on the day of first administration of trial treatment will also be 
considered pre-treatment values. These pre-treatment values will be assigned to visits 
according to the nominal visit number as recorded on the eCRF or as provided by the 
laboratory.
Baseline, unless otherwise specified, is defined as the last measurement collected prior to the 
start of administration of the trial treatment.
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.


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Analysis of AE data, concomitant medication or non-drug therapies, as well as use of rescue 
medication will not be based on visits. Frequency tables for these data will be using on-
treatment data only. Therefore, no assignment to time windows will be necessary for such 
data.
For derivation of the last value on treatment, minimum value on treatment, and maximum 
value on treatment, all on-treatment values (whether or not selected in any time window; see 
Table 6.1: 1 for definition of the on-treatment period) will be considered; these will be 
derived for analysis of laboratory and vital signs data. For identification of potentially 
clinically significant abnormal laboratory values, all values (whether or not selected in any 
time window) before the off-treatment period will be considered.
A graphical analysis of the ALT and total bilirubin will be performed (so called eDISH plot) 
based on the available data obtained during the on-treatment period.
All other safety, efficacy and biomarker measurements will be assigned to visits based on
extended time windows around the planned visit dates, defined relative to the day of first trial 
treatment (which is scheduled for Visit V2). These extended time windows are defined in
Table 6.7: 1.


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Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs,
 
 to visits for statistical analysis
Visit 
number
/ 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 -7
n/a
V2
Day 1
Day 1
n/a
1 A
1
1 A
1
V3
Day 4
Day 4
+/- 2 
2
6
2
5
V4
Day 8
Day 8
+/- 3 
5
11
6
11
V5
Week 2
Day 15
+/- 3 
12
18
12
22
V6
Week 4
Day 29
+/- 3 
26
32
23
36
V7
Week 6
Day 43
+/- 3 
40
46
37
50
V8
Week 8
Day 57
+/- 3 
54
60
51
64
V9
Week 10
Day 71
+/- 3 
68
74
65
78
V10
Week 12
Day 85
+/- 3 
82
88
79
99
For 75% Interim analysis and for Primary analysis (Week 16)
V11
PE
Day 113
+/- 3 
110
116
100
Minimum
of (cut-off, 
141)
B
V12
Week 24
Day 169
+/- 7 
162
176
142
Minimum
of (cut-off,  
 197)
B
V13D
EOT/Wee
k 32/FU
Day 225
+/- 7  
218
232
198
Minimum
of (cut-off,  
 LD
C + 
 140)
B
For final trial analysis 
V11
PE/Week 
16
Day 113
+/- 3 
110
116
100
141
V12
Week 24
Day 169
+/- 7 
162
176
142
197
V13
EOT/Wee
k 32/FU
Day 225
+/- 7  
218
232
198
LDC + 140
For On-/Off- treatment displays (final trial analysis only)
EOT/Wee
k 32/FU
Day 225
+/- 7  
198
Day of last
f-up valueB
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 The cut-off date will be specified in the data cleaning plan for the 75% interim analysis or 16-week analysis.
C LD = Day of Last dose/infusion received
D V13 will additionally be presented for the primary analysis at week 16 (but not for the interim analysis)


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Repeated and unscheduled efficacy, safety and biomarker measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date of measurement. 
Only one observation per time window will be selected for statistical analysis at a particular
visit – the value which is closest to the protocol planned visit day will be selected. If there are 
two observations which have the same difference in days to the planned day, the later value 
will be selected. If there are two observations on the same day, the worst value will be 
selected.
Assignment of efficacy observations to visits based on time windows will be based on the 
non-imputed (observed) data after setting values after rescue medication intake to missing (if 
applicable, i.e. for the "NRI" and the "OC" approaches defined in Section 6.6). 
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 obtained during the on-treatment period, 
irrespective of whether the observation was selected in any time window.


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7.
PLANNED ANALYSIS
All efficacy analyses will be purely exploratory in nature. The following analyses are planned
at different stages throughout the trial.
o
75% Interim analysis (Week 16)
This analysis is performed when 75% of patients have completed 16 weeks of the study (75% 
interim analysis). 
The cut-off date for inclusion of data into the analysis of efficacy, based upon the planned 
date of attendance of the 44th patient (i.e. approximately 75% of the 60 planned patients) to 
the PE visit, will be described in a separate data cleaning plan, which will include details on 
the degree to which trial data will be cleaned prior to performing the analysis. The individual 
patient cut-off date for inclusion of data into the analysis is described in Table 6.7: 1.
Main efficacy analyses will display visits up to Week 16 only based on the FAS wk 16 – 75.
Additional displays of the efficacy will present data up to week 24 only based on the FAS wk 
24 – 75. All available data will be used for imputation purposes prior to data truncation for the 
analysis.
Selected outputs for the following endpoints will be generated. Details on the planned 
analyses are provided in Section 9.6:

Disposition

Demographic and baseline characteristics

Concomitant medication use

Exposure

ppPASI50

ppPASI, change from baseline and percent change from baseline

pppPGA ≤ 1 (yes/no) 
No safety data will be analyzed
 
Details on the 75% interim analysis specified above will be done by an external vendor.
 
 


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Only selected individuals will be unblinded. Since the study is planned to continue in a 
blinded manner through Week 32, a logistics (and access) plan will be developed in order to 
describe the processes to be implemented to protect the integrity of the ongoing trial through 
the final trial analysis. 
No separate report is planned to be written for this analysis. 
o
Primary Analysis (Week 16)
This analysis is performed when all patients have completed 16 weeks of the study (primary
analysis). 
The cut-off date for inclusion of data into the analysis of efficacy, based upon the planned 
date of attendance of the last randomized patient to the PE visit, will be described in a 
separate data cleaning plan, which will include details on the degree to which trial data will be 
cleaned prior to performing the primary week 16 analysis. The individual patient cut-off date 
for inclusion of data into the analysis is described in Table 6.7: 1. 
Main efficacy analyses will display visits up to Week 16 only based on the FAS. Additional 
displays of the efficacy will present data up to week 24 only based on the FAS wk 24, and up 
to week 32 (EoS) based on the FAS wk 32.
All CRF (efficacy and safety) data as well as further data related to safety such as the central 
Lab data files will be summarized at the time of the week 16 primary analysis. Other selected 
data that may be displayed at this time includes:
The primary analysis will be performed by the sponsor. Only selected individuals will be 
unblinded for this analysis. Since the study is planned to continue through an additional 16 
weeks of further blinded follow-up, 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. 
No separate report is planned to be written for the primary analysis. All analyses are planned 
to be documented in a clinical trial report which is to be prepared at the end of the trial.


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o
Final analysis (Week 32)
The analysis of the entire efficacy, safety, and biomarker data collected through the full 32
weeks of follow-up will be performed once all entered patients have completed the trial (up to 
EOT/Week 32 Visit); at that time point, a final database lock will be done and all on-
treatment data through week 32 will be reported. 
General Remarks
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (001-MCG-159) (10).
The individual values of all patients will be listed, 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
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.
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. However, for selected displays of endpoints 
presented by-visit, additional outputs which include both on- and off-treatment data will also 
be produced. Disposition of the patient population participating in the trial will be 
summarised by presentation of the frequency of patients screened, entered, screened but not 
entered, treated, entered but not treated, who completed all doses of trial medication as 
planned, who completed the PE visit (Visit 11), who completed the EOT visit, and who were 
prematurely discontinued, by reason. Disposition will be listed by country.


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The frequency of patients with IPVs will be presented for the RS by treatment. The IPVs will 
be listed per patient indicating whether or not the IPV led to exclusion from patient sets 
analyzed. 
The frequency of patients in each of the different analysis sets will also be presented by 
treatment.
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. 
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 to < 75 years
≥ 75 years
< 65 years
≥ 65 years
< 65 years
65 to < 75 years
75 to < 85 years
≥ 85 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 DISEASES AND MEDICATION
Analyses of concomitant diseases and medication will be based on the SAF.
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication 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, as well as characteristics of the 
trial disease, will be descriptively summarized by treatment. 
A medication will be considered concomitant to treatment, if it

is ongoing at the start of trial treatment or

starts within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
Concomitant medication use (excluding rescue medication) will be summarised with 
frequency and percentage of patients by ATC3 class and preferred name. Summaries will be 
presented for

concomitant medication taken any time prior to Day 1 (the day of start of trial treatment)

concomitant medication taken any time during the on-treatment period (cf. Section 6.1).
The frequency and percentage of patients with previous medication for PPP will be displayed. 
Use of rescue medication will be summarised separately (see Section 7.6.5).
Concomitant use of non-drug therapies will be summarized with frequency and percentage. 
Summaries will be presented for

concomitant non-drug therapies taken any time prior to Day 1 (the day of start of trial 
treatment)

concomitant non-drug therapies taken any time during the on-treatment period (cf. Section
6.1).
7.3
TREATMENT COMPLIANCE
Treatment compliance will be summarised overall and by visit via total volume infused (as a 
% of planned) for the FAS and SAF using descriptive statistics (N, mean, SD, minimum, 
median, maximum). The volume infused (as a % of planned) is defined as the volume infused 
at a visit (in ml as recorded in the eCRF), divided by 60 ml (the volume the 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.


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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".
The number of patients who received a dose will be tabulated per visit.
7.4
PRIMARY ENDPOINT
This binary primary efficacy endpoint will be described using patient frequencies and 
percentages for the FAS (or its derivatives - see Section 6.3). 
The analysis of the primary endpoint will be based on Section 7.3.1 of the CTP: 
From CTP Section 7.3.1: The primary analysis of the unadjusted absolute risk difference 
versus Placebo will be calculated simply as the difference in the observed proportion of 
patients with ppPASI50 at week 16 for each treatment scenario, for the FAS. A 95% Wilson
confidence interval around this difference will also be provided. In addition, a parametric 
bootstrap 95% confidence interval will be generated by sampling from the binomial 
distribution on each treatment with number of patients and observed proportion of responders 
per treatment representing the sampling parameters. A hierarchical approach to the testing of 
both scenarios for BI 655130 versus Placebo will, however, be performed for the primary 
analysis in order to control for multiplicity arising as a result of the multiple treatment 
comparisons.
The method to provide confidence intervals for single proportions will be based on Wilson 
(16).  The method to provide confidence intervals for unadjusted risk differences is derived 
from the Wilson method by Newcombe (17).
As described in Section 7.2 of the CTP, there will be no formal hypothesis testing performed 
in this trial.
From CTP Section 7.3.1: Exploratory analyses of the primary endpoint will include, in the 
absence of model convergence issues due to occurrence of low cell frequencies, the difference 
in the proportion of patients with a ppPASI50 between BI 655130 and placebo being 
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 presence or 
absence of plaque psoriasis (yes/no). 
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.
Confidence intervals to support the logistic regression of the primary endpoint will be 
calculated using the cumulative distribution function method of Reeve (14), instead of the 
delta method that was originally proposed in the CTP. More specifically, as suggested in 


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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 Appendix 9.5.


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7.5
SECONDARY ENDPOINTS
Analysis of secondary endpoints is described in Section 7.3.2 of the CTP.
Key secondary endpoint
7.5.1
This section is not applicable as no key secondary endpoint has been specified.
Secondary endpoints
7.5.2
7.5.2.1
Secondary efficacy endpoints
From CTP Section 7.3.2: For the secondary binary endpoints, for the FAS, the unadjusted 
absolute risk difference versus Placebo will be calculated and a 95% Wilson confidence 
interval around this difference will also be provided. In addition, a parametric bootstrap 95% 
confidence interval will also be generated.
As defined for the primary endpoint, the method to provide confidence intervals for single 
proportions will be based on Wilson (16), and for unadjusted risk differences is derived from 
the Wilson method by Newcombe (17).
For secondary continuous endpoints, mean changes from baseline will be analysed using a 
restricted maximum likelihood (REML)-based repeated measures approach (see [CTP] 
Section 7.3).
From CTP Section 7.3: [REML-based] analyses will include the fixed, categorical effects of 
treatment and visit, presence or absence of plaque psoriasis (yes/no), as well as the 
treatment-by-visit interaction, and continuous, fixed covariates of baseline “endpoint” and 
baseline-by-visit interaction. An unstructured covariance structure will be used to model the 
within-patient measurements. Exploratory confidence intervals will be based on least-squares 
mean differences to Placebo using a two-sided α = 0.05.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
Patients will be analysed according to the stratum (presence or absence of plaque psoriasis) as 
indicated on the eCRF.
SAS code for the above model will be based on the following structure:
PROC MIXED DATA=alldat cl method=reml; 
  CLASS visit trt stratum subject; 
  MODEL ept = base visit trt 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;
For handling of non-convergence see Section 9.7.


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7.7
EXTENT OF EXPOSURE
The number of subjects who received a dose of trial drug will be tabulated. The duration of 
infusion [in minutes], the amount of treatment received (actual and weight based), as well as 
the volume infused [% of planned] will be summarised by descriptive statistics (N, mean, SD, 
minimum, median, maximum) per visit and overall. 


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7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the SAF following BI standards. No 
hypothesis testing is planned.
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 two BI arms.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the start date of the second, later occurrence is the same or one day 
later than the end date of the first occurrence)
For further details on summarization of AE data, please refer to "Handling and summarization 
of adverse event data for clinical trial reports and integrated summaries" (7) [001-MCG-156] 
and "Handling of missing and incomplete AE dates" (4) [001-MCG-156_RD-01]. 
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 BI 655130 administration will be assigned to the on-treatment phase.
An overall summary of AEs will be presented by treatment. 
This overall summary will include summary statistics for the class of other significant AEs 
(sponsor definition based on ICH E3) and for the class of AESIs.
The following is considered an AESI in this trial:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.


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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’.
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 (primary safety endpoint of this trial). Separate tables will also 
be provided for patients with SAEs, patients with AESIs, patients with AE leading to 
discontinuation of the trial, 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 will also be summarised.
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.
Only patients with at least one available post-baseline value will be included in the analysis of 
an individual laboratory parameter. All individual laboratory data will be listed. Values 
outside the reference range will be flagged.
Descriptive statistics of laboratory values over time and for the difference from baseline (see
Section 6.7) will be based upon standardized values and provided by visit, including 
summaries of the last value on treatment, the minimum value on treatment and maximum 
value on treatment.


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Laboratory values will be compared to their reference ranges; shift tables will be provided for 
the number of patients with a specific RCTC grade at baseline versus the grade at the last 
measurement on treatment, as well as the worst grade on treatment. These analyses will be 
based on standardized laboratory values.
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on 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 
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, respiratory rate and 
body weight) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see Section
6.7) will be provided by treatment, including summaries of the last value during on-treatment
period, the minimum value during on-treatment period, and the maximum value during on-
treatment period (see Table 6.1: 1 for definition of the on-treatment period).


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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.
Injection Site Reactions
7.8.5
Injection site reactions will be summarized, by visit as well as overall, with the frequency and 
percentage of patients who experienced any injection site reaction, both overall and by type of 
reaction.


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7.9
HANDLING OF DMC ANALYSES
A partially external DMC, independent of the trial and project teams, was 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 was produced and finalized prior to first patient randomised into the trial. Further 
details were 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-50-413_RD-01: "Protocol Violation Handling Definitions", current 
version; IDEA for CON
3
001-MCS-50-413_RD-02: "Important Manual Protocol Violations Spreadsheet", 
current version; IDEA for CON
4
001-MCG-156_RD-01: "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-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD 
Data Files”, 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
001-MCG-157: "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
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON
11
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON
12
R Development Core Team (2013): R: A language and environment for statistical 
computing. R Foundation for Statistical Computing, Vienna, Austria (2013);
website: R-project.org
13
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) - a simple practical 
measure for routine clinical use. Joint Ann Mtg of the British Association of 
Dermatologists and the Canadian Dermatology Association, Oxford, 6 - 10 Jul 
1993 Clin Exp Dermatol 1994. 19:210-216. [R05-2548]


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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. 


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9.
ADDITIONAL SECTIONS
9.1
ppPASI AND RELATED ENDPOINTS
The Palmoplantar Pustulosis Psoriasis Area and Severity Index (ppPASI) 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). 
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 
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 (ppPASI)
The ppPASI is calculated as follows as a weighted sum of the scores obtained for E, P, D and 
A in Table 9.1: 1:
ppPASI = [(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 ppPASI score will also be considered to be missing. However, 
individual items and subscores may be presented as applicable.


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Achievement of Decrease in ppPASI ≥ xx% (ppPASIxx)
Achieving a response of xx% or larger decrease from baseline in ppPASI score is denoted as 
ppPASIxx. The ppPASIxx 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  
xx
BL
ppPASI
current
ppPASI
BL
ppPASI







100
)
(
)
(
)
(
then ppPASIxx = 1,
else ppPASIxx = 0.
The modified (precise) ppPASI
A modified ppPASI score (precise ppPASI) will be calculated based on the absolute 
number/percent affected area rather than using the ranges. Therefore, the calculation will 
include a factor 0.06 to scale to the same range (0 to 72) as the ppPASI described above. It is
based on the following calculation: 
Modified ppPASI = [(E+P+D) x (0.06 x Area affected (expressed in %) in right palm) x 0.2] 
      + [(E+P+D) x (0.06 x Area affected (expressed in %) in left palm)   x 0.2] 
      + [(E+P+D) x (0.06 x Area affected (expressed in %) in right sole)   x 0.3] 
      + [(E+P+D) x (0.06 x Area affected (expressed in %) in left sole)     x 0.3]
Missing values for severity or area of involvement will not be imputed. If at least one of these 
values is missing, then the modified ppPASI score will also be considered to be missing. 
However, individual items and subscores may be presented as applicable.
ppPASI 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)”.


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ppPASI severity (by palms or soles)
Among the two palms only, calculate the ppPASI (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):
ppPASI (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 ppPASI (palms) score will be 
missing.
Repeat for the ppPASI (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)”.
PPSI-proxy (using most severely affected area at baseline)
Within each area (right palm, left palm, right sole, left sole) sum the severities of components 
E, P and D; select the worst area at baseline among the four (highest score).
If there are more than one body regions with highest severity at baseline, select the first area 
in following order: Right Sole, Left Sole, Right Palm, Left Palm from these multiple body 
regions as the worst affected area. The sum score for the worst area represents the PPSI-proxy
(range 0 to 12).


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9.2
THE PALMOPLANTAR PUSTULOSIS PHYSICIAN GLOBAL 
ASSESSMENT (pppPGA)
Palmoplantar Pustulosis Physician Global Assessment (pppPGA) relies on clinical assessment 
of the patient’s skin presentation on the palms and soles. The investigator (or qualified site 
personnel) scores the lesions on the most severely affected palmoplantar surface from 0 – 4 as 
clear, almost clear, mild, moderate or severe. 
Scoring of pppPGA is described in Table 9.2: 1 below.
Table 9.2: 1
PPP Physician Global Assessment (pppPGA)
Score
Wording
Detailed description
0
Clear
No signs of PPP; no scaling or crusts or pustule remains
1
Almost clear Slight scaling and/or erythema and / or slight crusts; very few new 
(yellow) and / or old (brown) pustules
2
Mild
Scaling and/or erythema and/or crusts; visible new (yellow) and/or 
old (brown) pustules of limited number and extent
3
Moderate
Prominent scaling and/or erythema and / or crusting; prominent
new (yellow) and / or old (brown) pustules covering most of the area 
involved
4
Severe
Severe scaling and/or erythema and / or crusting; numerous new 
(yellow) or old (brown) pustules with and/or without major conflence 
covering the entire area of at least 2 palmoplantar surfaces


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1.0 Initial
24-May-2017
None
This is the initial TSAP with necessary
information for trial conduct. First 
approved version before first patient in.
2.0 Final
23-May-2018
(all)
This is the final TSAP, approved
before database snapshot for the 75% 
interim analysis. It is also intended to 
be the final TSAP before database lock 
for the primary analysis.