Clinical trial NCT02978690
Conditions: Psoriasis
Sponsor: Boehringer Ingelheim
Start date: 2016-12-19; Completion date: 2018-01-10
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase I, open label, single group study that is being performed to assess the safety, tolerability, Pharmacokinetics (PK) , Pharmacogenomics (PGx) and efficacy of a single dose of spesolimab in adult patients with active Generalized Pustular Psoriasis (GPP).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Spesolimab
Intervention descriptions: intervention 1: Solution for infusion

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08910926-02
EudraCT No.:
BI Trial No.:
2016-001236-35
1368.11
BI Investigational
Product:
BI 655130
Title:
Multi-centre, open-label, single arm, phase I study to investigate 
safety, tolerability, pharmacokinetics, pharmacogenomics and efficacy 
of a single intravenous dose of BI 655130 in patients with active 
generalized pustular psoriasis.
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:
Co-ordinating
Investigator:
Phone: 
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date:
Version: 2.0
Date: 09 Nov 2016
Page 1 of 82
Proprietary confidential information
© 2016 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:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 655130
Protocol date:
Trial number:
Revision date:
09 Nov 2016
22 July 2016
1368.11
Title of trial:
Multi-centre, open-label, single arm, phase I study to investigate safety, 
tolerability, pharmacokinetics, pharmacogenomics and efficacy of a single 
intravenous dose of BI 655130 in patients with active generalized pustular 
psoriasis.
Co-ordinating 
Investigator:
Phone: 
Fax: 
Trial site(s):
Multi-centre trial conducted in 7 countries
Clinical phase:
I
Objectives:
To investigate safety, tolerability, pharmacokinetics, pharmacogenomics and 
efficacy of a single intravenous dose of BI 655130 in patients with active 
generalized pustular psoriasis.
Methodology:
Multi-centre, open-label, single arm, single dose
No. of subjects: 
total entered:
Up to 10
each treatment:
Up to 10 (single arm study)
Diagnosis:
Active Generalized Pustular Psoriasis (active GPP)
Main criteria
for inclusion:
Main criteria for inclusion:

Male or female patients, aged 18 to 75 years at screening (V2)

A known and documented history of Generalized Pustular Psoriasis 
regardless of the IL36RN mutation status, with previous evidence of 
fever, and/or asthenia, and/or myalgia, and/or elevated C-reactive 
protein, and/or leucocytosis with peripheral blood neutrophilia
(above ULN)

Presenting with a flare of GPP with at least 10% BSA with 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 655130
Protocol date:
Trial number:
Revision date:
09 Nov 2016
22 July 2016
1368.11
erythema and pustules

A GPPGA score of at least moderate severity

GPP patients receiving maintenance treatment with retinoids and/or 
methotrexate for at least 4 weeks or GPP patients not receiving any 
maintenance therapy at screening visit 2 (V2)

Male and female patients must agree to use an effective birth 
control method
Main exclusion criteria:

Immediate life-threatening GPP flare or requiring intensive care 
treatment, according to the investigator’s judgement. Life-
threatening complications mainly include, but are not limited to, 
cardiovascular/cytokine driven shock, pulmonary distress.

Identified, ongoing serious/severe infection

Acute generalized exanthematous pustulosis (AGEP)

Patient’s clinical presentation being considered due to the 
differential diagnosis of toxic epidermal necrosis or Stevens-
Johnson syndrome

Use of restricted medication (see Table 4.2.2.1:1)

Patients with dose escalation of their maintenance therapy with 
methotrexate and/or retinoids within the 4 weeks preceding V2 
(second screening visit)

Background therapy with ciclosporin within the last 30 days 
preceding the second screening visit (V2)

Severe, progressive, or uncontrolled renal, hepatic, haematological, 
endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric 
disease, or signs and symptoms thereof, as judged by the 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 655130
Protocol date:
Trial number:
Revision date:
09 Nov 2016
22 July 2016
1368.11
investigator. Patients with less than 3-fold ULN increase in AST 
and/or ALT and/or alkaline phosphatase and/or with less than 2-fold 
ULN increase in total bilirubin on infusion day (V3) may be 
included, provided that no other cause of liver damage than GPP 
has been identified
Test product:
BI 655130 solution for infusion
dose:
10 mg/kg
mode of admin.:
Intravenous 
Comparator product:
Not applicable
Duration of treatment: Single dose
Primary endpoint:
The primary endpoint to assess safety and tolerability of BI 655130 
administered intravenously, is the number [(N (%)] of patients with adverse 
reactions, defined as drug-related AEs.
Secondary endpoints:

Percent change from baseline in GPPASI total score at Week 2

Proportion of patients with GPPGA total score of 0 (clear) or 1 (almost 
clear) at Week 2

Change from baseline in FACIT-Fatigue scale score at Week 2

Change from baseline in Pain VAS score at Week 2
The following pharmacokinetic parameters will be determined as secondary 
endpoints:
Cmax, AUC0-∞


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 655130
Protocol date:
Trial number:
Revision date:
09 Nov 2016
22 July 2016
1368.11
Further endpoints and 
parameters of interest:
 
 
 
 
 
 
Criteria for safety:
AEs and SAEs, safety laboratory tests, 12-lead electrocardiogram (ECG), vital 
signs (blood pressure [BP], pulse rate [PR], body temperature, body weight), 
injection site reactions, immunogenicity (ADA)
Statistical methods:
Descriptive statistics for safety, PK, and efficacy endpoints


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FLOW CHART
Trial periods
Screening
Treatment
Observation
End of 
Trial
(EOT)
Week
1
1
2
3
4
8
12
16
20
Visit
11
2
32,11
4
5
6
7
8
9
10
11
12
12pc3
13
13pc3
14
Days from the day of treatment
Day-1
Day 1
D2
D3
D4
D5
D6
D7
D14
D21
D28
D56
D84
D112
D140 
Time window for visits
±1d
±2d
±2d
±2d
±7d
±7d
+7d 
Informed consent
X
Patient’s confirmation of 
participation4
X4
Infection screening5
X
IL36RN mutation status6
X
Demographics
X
Medical history
X
X
Alcohol and smoking history
X
X
Physical examination7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test8
X
X
X
X
X
X
12 lead-ECG9
X
X
X
X
X
X
X
Safety laboratory tests10
X
X
X
X
X
X
X
X
Review of in-/exclusion criteria
X
X
X
PK Sampling12
X
X
X
X
X
X
X
X
X
X
X
X
X
Photographs of skin lesions13
X
X
X
X
X
X
X
X
X
X
Skin biopsies14
X
X
X14
 
 
 
X
X
X
GPPGA and GPPASI
X
X
X
X
X
X
X
X
X
X
X


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Trial periods
Screening
Treatment
Observation
End of 
Trial
(EOT)
Week
1
1
2
3
4
8
12
16
20
Visit
11
2
32,11
4
5
6
7
8
9
10
11
12
12pc3
13
13pc3
14
Days from the day of treatment
Day-1
Day 1
D2
D3
D4
D5
D6
D7
D14
D21
D28
D56
D84
D112
D140 
FACIT-fatigue, pain VAS, and PSS
X
X
X
X
CGI-I
X
X
X
Presence of edema (yes/no)
X
X
X
X
X
X
Pustular BSA
X
X
X
X
X
X
IRT call
X
X
X
X16
Dispense/administration study
drug17
X
Compliance check
X
Local tolerability
X
X
Adverse events18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Completion of patient 
participation19
X
Vital status collection
X
X20
1
The first screening visit can be performed on any day following the study and trial site initiation
2
Visit 3 (infusion day) should be performed the day after Visit 2 (day of admission for the flare)
3
Visits 12pc and 13pc are phone calls and will only be performed by women of childbearing potential: the patient will inform the site team of the result of the urinary 
pregnancy test. The result will not be recorded in the eCRF but only in the patient’s file
4
Informed consent will be signed at the first screening visit. As several weeks may elapse until the occurrence of a flare (qualifying event), the patient will be asked to 
confirm his/her consent to participate in the trial at the second screening visit when he/she is admitted for a GPP flare
5
Infection screening will include tuberculosis, hepatitis B, hepatitis C and HIV testing
6
IL36RN mutation status from historical patient’s data
7
Physical examination will include vital signs assessment (BP, PR, body weight and temperature) and general appearance as well as evaluation of all relevant organ 
systems
8
For all female patients of childbearing potential. In case the urine pregnancy test at Visit 2 (Day -1) is positive, it should be repeated for confirmation.
9
ECG measurements should always precede blood sampling. Triple ECG will be performed at second Screening Visit (V2) and will be considered as baseline. Single 
ECG will be recorded at other time points.
10
Safety laboratory tests include clinical chemistry, haematology, coagulation, and urinalysis, and will be performed locally. On Day 1, the results of the laboratory tests, 
except tryptase, must be available before the study drug administration.


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11
On Day 1, all baseline blood (plasma, serum, whole blood) and skin biopsy samplings must be performed before trial drug administration. As well, photographs of skin 
lesions and measurements of GPPGA, GPPASI, FACIT-Fatigue scale, pain VAS, PSS, pustular BSA scores and presence of edema must also be performed before trial 
drug administration.
12
Please refer to PK Flow Chart on next page for details.
13
Photographs of skin lesions should always precede skin biopsies and study drug administration
14
Baseline skin biopsies on Day 1: two lesional and two non-lesional skin biopsies of 3 mm punch each, for IHC and RNASeq, should be collected prior to receiving 
treatment; On Day 7: two lesional skin biopsies of 3 mm punch each should be collected; On Day 14 (optional): two lesional skin biopsies of 3 mm punch each would be 
collected. See sections 5.6.1 and 5.6.3
15
DNA banking is optional and will only be performed in patients who give their consent
16
EOT IRT call must also be performed in case of premature withdrawal
17
Start- and end-time of infusion will be recorded in the CRF.
18
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points indicated in the Flow Chart above.
19
Completion of patient participation also needs to be completed if the patient withdraws prematurely following inclusion (see Section 3.3.4).
20
For treated patients leaving the study before the planned EOT, then vital status should be collected at the planned day 140


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................6
 
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................18
1.2.4
Nonclinical pharmacokinetics..............................................................20
1.2.5
Clinical experience................................................................................20
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 25
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................25
2.2
TRIAL OBJECTIVES.......................................................................................25
2.3
BENEFIT - RISK ASSESSMENT ...................................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 29
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................29
3.1.1
Administrative structure of the trial...................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................32
3.3.1
Main diagnosis for study entry............................................................32
3.3.2
Inclusion criteria...................................................................................32
3.3.3
Exclusion criteria ..................................................................................33
3.3.4
Removal of subjects from therapy or assessments.............................34
3.3.4.1
Removal of individual subjects................................................34
3.3.4.2
Discontinuation of the trial by the sponsor..............................36
3.3.5
Replacement of subjects .......................................................................36
4.
TREATMENTS........................................................................................ 37
4.1
TREATMENTS TO BE ADMINISTERED....................................................37
4.1.1
Identity of BI investigational product and comparator product......37
4.1.2
Method of assigning subjects to treatment groups ............................37


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4.1.3
Selection of doses in the trial................................................................37
4.1.4
Drug assignment and administration of doses for each subject .......37
4.1.5
Blinding and procedures for unblinding ............................................39
4.1.5.1
Blinding....................................................................................39
4.1.5.2
Procedures for emergency unblinding .....................................39
4.1.6
Packaging, labelling, and re-supply ....................................................39
4.1.7
Storage conditions.................................................................................39
4.1.8
Drug accountability ..............................................................................40
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................41
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................41
4.2.1.1
Rescue medication ...................................................................41
4.2.1.2
Emergency procedures.............................................................41
4.2.1.3
Additional treatments...............................................................41
4.2.2
Restrictions............................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment .........................42
4.2.2.2
Restrictions on diet and life style.............................................43
4.3
TREATMENT COMPLIANCE.......................................................................44
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 45
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................45
5.1.1
Endpoints of efficacy.............................................................................45
5.1.2
Assessment of efficacy...........................................................................46
5.2
SAFETY..............................................................................................................47
5.2.1
Endpoints of safety................................................................................47
5.2.2
Assessment of adverse events...............................................................48
5.2.2.1
Definitions of adverse events...................................................48
5.2.2.2
Adverse event and serious adverse event reporting.................49
5.2.3
Assessment of safety laboratory parameters......................................51
5.2.4
Electrocardiogram................................................................................53
5.2.4.1
12-lead resting ECG.................................................................53
5.2.5
Assessment of other safety parameters...............................................54
5.2.5.1
Vital signs ................................................................................54
5.2.5.2
Medical examinations..............................................................54
5.2.5.3
Local tolerability......................................................................55
5.3
OTHER...............................................................................................................55
5.3.1
Photographs of skin lesions..................................................................55
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................55
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................55
5.5.1
Pharmacokinetic endpoints..................................................................56
5.5.1.1
Secondary endpoints................................................................56


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5.5.2
Methods of sample collection...............................................................56
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................57
5.5.2.2
Plasma sampling for ADA assessment ....................................57
5.5.3
Analytical determinations ....................................................................57
5.5.3.1
Analytical determination of BI 655130 plasma concentration 57
5.6
BIOMARKER(S) ...............................................................................................57
5.6.3
Methods of sample collection...............................................................59
5.6.4
Analytical determinations ....................................................................59
5.7.1
Pharmacodynamic endpoints...............................................................60
5.7.2
Methods of sample collection...............................................................60
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....60
6.
INVESTIGATIONAL PLAN.................................................................. 61
6.1
VISIT SCHEDULE............................................................................................61
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................61
6.2.1
Screening period....................................................................................62
6.2.1.1
Screening Visit 1......................................................................62
6.2.1.2
Screening Visit 2......................................................................63
6.2.2
Treatment Visit (V3) and observation period ....................................63
6.2.3
Early trial termination .........................................................................64
6.2.4
End-Of-Trial (Visit 14).........................................................................64
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 65
7.1
STATISTICAL DESIGN – MODEL ...............................................................65
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................65
7.3
PLANNED ANALYSES....................................................................................65
7.3.1
Primary analyses...................................................................................65
7.3.2
Secondary analyses ...............................................................................65
7.3.3
Further analyses....................................................................................66
7.3.4
Safety analyses.......................................................................................66
7.3.5
Interim analyses ....................................................................................67
7.3.6
Pharmacokinetic analyses ....................................................................67
7.4
HANDLING OF MISSING DATA ..................................................................69
7.4.1
Safety......................................................................................................69
7.4.2
Plasma drug concentration - time profiles..........................................69


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7.4.3
Pharmacokinetic parameters...............................................................69
7.4.4
Biomarker assessment ..........................................................................69
7.4.5
Efficacy...................................................................................................69
7.5
RANDOMISATION ..........................................................................................70
7.6
DETERMINATION OF SAMPLE SIZE ........................................................70
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 71
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................71
8.2
DATA QUALITY ASSURANCE .....................................................................72
8.3
RECORDS..........................................................................................................73
8.3.1
Source documents .................................................................................73
8.3.2
Direct access to source data and documents.......................................73
8.3.3
Storage of records .................................................................................73
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................73
8.4.1
Listedness...............................................................................................73
8.4.2
Expedited reporting to health authorities and IECs/IRBs................74
8.5
STATEMENT OF CONFIDENTIALITY.......................................................74
8.6
COMPLETION OF TRIAL..............................................................................74
8.7
PROTOCOL VIOLATIONS ............................................................................74
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................74
9.
REFERENCES......................................................................................... 75
9.1
PUBLISHED REFERENCES...........................................................................75
9.2
UNPUBLISHED REFERENCES.....................................................................77
10. APPENDICES .......................................................................................... 78
10.1
CLINICAL EVALUATION OF LIVER INJURY .........................................78
10.1.1 Introduction...........................................................................................78
10.1.2 Procedures .............................................................................................78
10.2
RECONSTITUTION INSTRUCTION(S).......................................................79
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 80


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ABBREVIATIONS
ACD
Acid Citrate Dextrose
ADA
Anti-Drug Antibodies
AE
Adverse event
AESI
Adverse events of special interest
ALT/GPT
Alanine transaminase
AP
Alkaline phosphatase
AST/GOT
Aspartate transaminase
AUC0-168h
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 168 hours
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMS
BioMarker Set
BP
Blood pressure
BSA
Body Surface Area
b.w.
Body weight
CA
Competent authority
CK
Creatine kinase
CL
Total clearance of the analyte in plasma after intravascular administration
Cmax
Maximum measured concentration of the analyte in plasma
CML
Local Clinical Monitor
CRA
Clinical Research Associate
CRF
Case report form
CGI-I
Clinical Global Impression – Improvement
CRP
C-reactive protein
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supply Unit
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
FACIT-F
Functional Assessment of Chronic Illness Therapy Fatigue
FAS
Full analysis set
FIH
First-In-Human
GGT
Gamma-glutamyl transferase
GPP
Generalized Pustular Psoriasis


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GPPASI
Generalized Pustular Psoriasis Area and Severity Index
GPPGA
Generalized Pustular Psoriasis Physician Global Assessment
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HPLC-MS/MS
High performance liquid chromatography with tandem mass spectrometry
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IL
Interleukin
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator site file
ITE
Indirect target engagement
IV
Intravenous
z
Terminal rate constant of the analyte in plasma
LDH
Lactate dehydrogenase
LLOQ
Lower limit of quantification
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRT
Mean residence time of the analyte in the body after intravenous bolus 
administration
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PGx
Pharmacogenomics
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PoCC
Proof-of-Clinical-Concept
PR
Pulse rate
PSS
Psoriasis Symptom Scale
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTcF
QT interval corrected for heart rate using the method of Fridericia
RDC
Remote data capture
REP
Residual effect period
SAE
Serious adverse event
SOC
System Organ Class
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 


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analyte in plasma
TB
Tuberculosis
TDMAP
Trial Data Management and Analysis Plan
TEAE
Treatment-emergent adverse event
TMF
Trial master file
TMM
Team Member Medicine
TNFi
Tumor necrosis factor inhibitor
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAS
Visual Analog Scale
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
WOCBP
Woman Of Childbearing Potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Generalized Pustular Psoriasis (GPP) is a life-threatening orphan disease characterized by 
systemic inflammation affecting the skin and internal organs. It manifests as repeated flares 
of widespread sterile pustules and diffuse erythema causing significant morbidity and even 
mortality to GPP patients [R16-0933]. Systemic symptoms include fever, marked 
leucocytosis with neutrophilia and elevated serum levels of C-reactive protein. Skin is often 
painful and tender. Patients are usually uncomfortable, and often febrile.
While GPP flares may be self-limiting (without treatment), the flare duration usually lasts for
weeks to months. Over a 2-week period, self-resolution of the flare would not be typically 
expected (Reference: Expert feedback). In contrast, GPP patients presenting with flares may 
rather progress to a life-threatening status without treatment. The mean duration of a treated
flare is 16 days (range 7-60 days) and mean duration of hospital stay in the acute phase of 
disease is 10 days (range 3-44 days) [R16-0933] [R16-2960]. Complications include sepsis 
and renal, hepatic, respiratory, and cardiac failure [R16-0933]. Triggers for GPP flares 
include infection, corticosteroid use, steroid withdrawal, stress and pregnancy [R16-0933]. 
Experts report that the frequency of flares (e.g., annual rate of flares) for an individual patient 
is unpredictable as well as the pattern i.e., clinical manifestations and rapidity of onset for an 
individual patient.
Mortality rates up to 7% have been reported but is likely an underestimate [R16-0933] [R16-
2698] [R16-1463] due to lack of reported data.
Limited data exist in the literature about treatment of GPP and up to date no gold standard or 
standard of care is recognized for it. GPP flares are notoriously difficult to treat, and current 
treatment options for controlling the acute phase of disease are limited and include 
ciclosporin, retinoids and methotrexate [R16-0933]. The current treatment options did not 
show clear efficacy in reducing duration and severity of flares in all patients. Flare 
recurrences appear to be the norm and occur promptly on withdrawing systemic therapy. 
Biologics (i.e. TNFi such as Infliximab) have been used and positive case reports have been 
reported but more robust data on their efficacy is lacking and more information is necessary 
for conclusions in a non-biased manner and to guide clinical use. Secukinumab (Cosentyx®) 
and infliximab (Remicade®) have been studied in low patient numbers in Japan and are 
registered for the treatment of GPP in Japan, but not specifically for the treatment of flares 
(primary endpoint of the open label studies were at week 16 assessing CGI-Improvement).
The partial response of GPP to currently available agents and their limitations (i.e. safety of 
ciclosporin and its limitation for long term maintenance treatment) indicate that there is high 
unmet clinical need for a more effective and tolerated targeted therapy that might overcome 
current treatment limitations. 
IL36R signaling drives skin inflammation in several animal models providing support for the 
strong link between IL36R biology and skin disorders based on human genetics [R14-5158].


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Genetic human studies established a strong link between IL36R signaling and skin 
inflammation, as demonstrated by occurrence of familial generalized pustular psoriasis (GPP) 
in patients with a loss of function mutation in IL36RN (the naturally occurring receptor 
antagonist to IL36R) which results in uncontrolled IL36R signaling [R14-5158]. Deficiency 
of IL-36Ra has been associated with familial and sporadic GPP. Further genetic linkage 
between GPP and the IL36 pathway has been recently disclosed. For example, mutations in 
other genes linked to the IL36 pathway such as CARD14 [R16-0929] may also lead to GPP. 
BI 655130 is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R 
signalling. IL36R is a novel member of the IL1R family. The IL36R is formed as a 
heterodimeric complex of IL36R and the IL1R accessory protein. The heterodimeric IL36R 
system with stimulating (IL36α, IL36β, IL36γ) and inhibitory ligands (IL36Ra) shares a 
number of structural and functional similarities to other members of the IL1/IL1R family, 
such as IL1, IL18 and IL33. All IL1 family members (IL1α, IL1β, IL18, IL36α, IL36β, 
IL36γ, and IL38) signal through a unique, cognate receptor protein which, upon ligand 
binding, recruits the common IL1RacP subunit and activates NFB and MAP kinase 
pathways in receptor-positive cell types, leading to enhanced production of downstream 
inflammatory cytokines/chemokines among which include IL8, IL6, and TNF. BI 655130 
could provide benefit as targeted therapy to GPP patients presenting with a flare of GPP by 
blocking the IL36 pathway and potentially reducing the severity and duration of disease-
related symptoms.
Of note, it has been shown recently in children from families who had neonatal onset of 
sterile multifocal osteomyelitis, periostitis, and pustulosis that the absence of interleukin-1–
receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening 
systemic inflammation with skin and bone involvement which responded to empirical 
treatment with the recombinant interleukin-1–receptor antagonist anakinra [P09-07583].
Strikingly, the patients showed an early response to targeted treatment of Anakinra with 
pustulosis resolving after days and even bone changes after only weeks. This latter disease 
model validates the relevance of therapeutic strategies relying on targeted inhibition of a 
unopposed, pathogenic IL1 family pathway.
1.2
DRUG PROFILE
 


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1.2.4
Nonclinical pharmacokinetics
The pharmacokinetics of BI 655130 were studied in cynomolgus monkeys. In mice, 
pharmacokinetics were performed with the mouse-specific anti-IL36R antibody, BI 674304 
[c03320876-01].
1.2.5
Clinical experience
A FIH (first-in-human) trial [c03361085-07] has been conducted according to a single-blind,
partially randomized, single rising dose and placebo-controlled (within dose groups) design.
The study explored safety, tolerability, pharmacokinetics and pharmacodynamics of
intravenously administered BI 655130 in healthy male subjects. Subjects were to receive
single ascending IV doses of 0.001 mg/kg, 0,003 mg/kg, 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg,
0.3 mg/kg, 1 mg/kg, 3 mg/kg, 6 mg/kg and 10 mg/kg body weight or placebo. The first 3
subjects of dose group 5 received only half of the planned dose of BI 655130 (0.05 mg/kg 
instead of 0.1 mg/kg) due to a calculation error. This led to an additional intermediate dose
group of 0.05 mg/kg for which data is available.
Overall the study included 78 male subjects with 59 subjects treated with BI 655130 and
19 subjects treated with placebo.
Safety and Tolerability
Based on preliminary evaluation, in the FIH study 27 of 78 subjects (34.6%) reported at least
1 treatment-emergent AE (TEAE). This included 19 of 59 subjects (32.2%) following
administration of BI 655130 and 8 of 19 subjects (42.1%) following administration of
placebo. Results are summarized in Table 1.2.5:1 below. There was no apparent relationship 
between the frequency of AEs and the dose. AEs categorized as related to treatment were 
observed in 3/19 (15.8%) subjects in the placebo group and in 7/59 (11.9%) subjects treated 
with BI 655130.
AEs were reported most frequently in the system organ classes (SOC) ‘gastrointestinal
disorders' (4/59 subjects [6.8%] on BI 655130 and 1/19 subjects [5.3%] on placebo), 'nervous
system disorders' (5/59 subjects [8.5%] on BI 655130 and 2/19 subjects [10.5%] on placebo),
‘infections and infestations’ (4/59 subjects [6.8%] on BI 655130 and 0/19 subjects [0%] on
placebo), and ‘general disorders and administration site reaction’ (4/59 subjects [6.8%] on BI
655130 and 1/19 subjects [5.1%] on placebo). AEs reported most frequently were headache
(5/59 subjects [8.5%] on BI 655130 and 2/19 subjects [9.5%] on placebo), and
nasopharyngitis (3/59 subjects [5.1%] on BI 655130 and 0/19 subjects [0%] on placebo).
There were two AEs of moderate intensity, both considered non related to the study drug,
(injection site hematoma, headache), all remaining AEs were of mild intensity. 


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Table 1.2.5: 1
Frequency [N (%)] of subjects with related adverse events by 
treatment and preferred term
Plac
BI 655130, Dose mg/kg body weight
0.001
0.003
0.01
0.03
0.1
0.3
1
3
6
10
0.05*
Number of 
subjects (%)
19 
(100.
0)
6 
(100
.0)
6 
(100
.0)
6 
(100
.0)
6 
(100
.0)
5 
(100
.0)
4 
(100
.0)
6 
(100
.0)
6 
(100
.0)
6 
(100
.0)
4
(100
.0)
3 
(100
.0)
Total with 
related AEs
3 
(15.8
)
1 
(16.
7)
1 
(16.
7)
1 
(16.
7)
0 
(0.0)
0 
(0.0)
0 
(0.0)
1 
(16.
7)
0 
(0.0)
2 
(33.
3)
0 
(0.0)
1 
(33.
3)
Conjunctiva 
l
hyperaemia
1 
(5.3)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
Nausea
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
1 
(16.
7)
0 
(0.0)
1 
(33.
3)
Vomiting
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
1 
(16.
7)
0 
(0.0)
0 
(0.0)
Injection
site reaction
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
1 
(16.
7)
0 
(0.0)
0 
(0.0)
Headache
2 
(10.5
)
1
(16.
7)
1 
(16.
7)
1
(16.
7)
0 
(0.0)
0 
(0.0)
0 
(0.0)
1 
(16.
7)
0 
(0.0)
0 
(0.0)
0 
(0.0)
0 
(0.0)
*Subjects were planned to receive treatment of 0.1 mg/kg but received an actual treatment of 0.05 mg/kg
There were no relevant changes compared to placebo for laboratory safety, including clinical 
chemistry, hematology, coagulation parameters, and urinalysis. No clinically relevant 
changes were observed in 12 lead ECGs, vital signs, physical exams and cardio-monitoring.
Pharmacokinetics
PK data for all dose groups are available.  PK parameters and the mean concentration-time 
plot are shown in Table 1.2.5:2 and Figure 1.2.5:1 below. In dose group 3, 2 subjects had PK 
concentrations that were below the limit of quantitation, resulting in n= 4. 


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Table 1.2.5: 2
Preliminary geometric mean (geometric CV%) PK parameters of 
BI655130 after IV Infusion
Dose
Group#
#1
#2
#3
#4
#5A
#5
Dose
0.001
mg/kg
N=6
0.003
mg/kg
N=6
0.01 mg/kg
N=4
0.03 mg/kg
N=6
0.05 mg/kg
N=3
0.1 mg/kg
N=5
AUC0-tz 
(h•µg/m L)
NC
NC
0.00652
(121)
2.08
(29.0)
9.57
(5.90)
25.1
(15.5)
Cmax
(µg/mL)
NC
NC
0.0228
(33.5)
0.413
(21.2)
0.998
(15.7)
1.96
(11.9)
t1/2
(day)
NC
NC
0.787
(150)
4.97
(17.3)
19.2
(23.0)
15.6
(24.0)
Dose
Group#
#6
#7
#8
#9
#10
Dose
0.3 mg/kg
N=4
1.0 mg/kg
N=6
3.0 mg/kg
N=6
6.0 mg/kg
N=6
10.0 mg/kg
N=4
AUC0-tz 
(h•µg/m L)
113
(5.86)
420
(13.3)
1050
(7.26)
2610
(11.7)
4130
(12.1)
Cmax
(µg/mL)
6.63
(3.28)
20.3
(13.6)
60.6
(7.17)
153
(12.7)
235
(2.79)
t1/2
(day)
20.4
(11.9)
33.5
(55.4)
25.8
(13.3)
33.9
(18.7)
29.3
(26.3)


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
BI 655130 is in development for the treatment of Generalized Pustular Psoriasis. The first 
trial to be conducted in GPP patients is an early stage development, proof-of-concept, phase I 
trial.
The rationale to perform this trial is based on the strong published human genetic linkage 
between the target disease GPP and the IL36 pathway targeted by BI 655130 [R15-1421] 
[R14-5158] and the high unmet clinical need in GPP. There is currently no drug specifically 
approved for the induction treatment of GPP flares. Patients presenting with a flare may 
progress to a life-threatening status without treatment and the current treatment options are 
not effective in reducing duration and severity of flares in GPP patients. 
Recently, a FIH trial has been completed (see section 1.2.5) which explored safety,
tolerability, pharmacokinetics, and pharmacodynamics of BI 655130 following IV infusions
of single rising doses of 0,001 mg/kg up to 10 mg/kg body weight in a healthy male
population. BI 655130 was safe and well tolerated.
The objective of the first GPP trial is to evaluate safety, tolerability, PK and 
pharmacogenomics as well as exploratory efficacy of a single dose of BI 655130 
administered to patients with a flare of GPP. 
The results from this trial will be the basis for health authority interactions to discuss and 
design the further developmental program with this compound in this rare and high unmet 
clinical need indication.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 655130
following the intravenous administration of a single dose of 10 mg/kg in patients with a flare
of GPP.
Secondary objectives are the assessment of the pharmacokinetics (PK) of BI 655130 after 
single dosing and the exploration of the efficacy in patients with a flare of GPP to establish 
proof-of-clinical-concept.
 
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
Treatment with BI 655130 has the potential to provide benefit to patients with a flare of GPP 
by reducing the severity and duration of disease-related symptoms.
The patients are exposed to the risks related to the exposure to the trial medication and the 
risks of the study procedures.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling 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 to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study should not exceed 400 mL per 
patient. This is less than the volume of a normal blood donation (500 mL). No health-related
risk to the patients is expected from this blood withdrawal.
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 or abnormal laboratory values. 
There has been no death or other serious adverse events. The adverse events reported had no 
apparent dose or exposure relationship. There have been no dose or exposure related 
abnormalities in safety laboratory parameters 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


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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.
We selected for the first trial in GPP patients 1368.11 a single dose of 10 mg/kg which was 
well tolerated in the previous single rising dose study and considered to be safe.
Based on the preceding FIH study, no specific drug-related risks are anticipated. Still, the
following safety measures are/will be applied in this study in order to minimize the risk for
the GPP patients:

The IV administration allows to immediately discontinue further drug administration 
should any safety concern arise (please refer to Section 4.1.4).

BI 655130 will be administered in a hospital setting and patients will be under close 
medical observation during their hospitalization (see section 6.2), as well as after their 
discharge and until the end of observation period. Safety will be closely monitored 
during site visits.

Patients will be closely monitored for signs and symptoms of hypersensitivity 
reactions for 4 hours after the infusion at Visit 3. Hypersensitivity reactions should be 
treated according to medical standards.

Extensive safety laboratory testing will be performed (Table 5.2.3:1).

The investigator will have the possibility to treat the patient with a rescue medication 
of his/her choice. The decision to use a rescue medication will be based on the 
severity and progression of the disease (please refer to section 4.2.1). 
Currently there are no data available to suggest interactions of BI 655130 [c03320876-01].
Retinoids (such as acitretin) and methotrexate will be permitted as background therapy 
(please refer to section 4.2.1). 
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of alterations in selected liver laboratory parameters to ensure patients´ safety.
 
 
 
Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of women of childbearing potential in this 
study is justified [c03320876-01]. To minimize the risk of unintentional exposure of an 
embryo or fetus to the investigational drug, women of childbearing potential must agree to 


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the requirements for pregnancy testing (the day before the study drug administration, and 
every 4 weeks thereafter until the EOT Visit) and contraceptive methods described in the 
patient information. Male patients will be asked to use condoms to avoid exposure of the 
partner via seminal fluid and prevent the partner to become pregnant if she is of childbearing 
potential. Birth control methods must be used for 20 weeks after the infusion (corresponding 
to five BI 655130 half-lives).
Considering the medical need of the development of an effective and well tolerated drug for 
the therapy of GPP flares, the benefit of this trial is considered to outweigh the potential 
minimal risks and justifies the administration of a single dose of BI 655130 10 mg/kg to
patients with a flare of GPP to investigate safety, tolerability, pharmacokinetics, and efficacy.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single dose trial is designed as open label, exploratory, phase I, multi-centre, multi-
national, single arm.
A maximum of 10 patients with a flare of GPP are planned to participate. Approximately 7
study sites in 7 countries worldwide will participate. They are all specialized referral centres 
experienced in the management of GPP.
Each patient will receive the active drug. Only one dose will be tested (10 mg/kg) and will be
administered intravenously at Visit 3.
Patients will be hospitalized during at least 4 days following the study drug administration. 
Thereafter, the decision of patient’s discharge will be left at the discretion of the investigator 
and based on the evolution of the GPP flare and the patient’s health status.
Overall, 14 visits are planned. The observation period will last 20 weeks to cover the whole 
Residual Effect Period (refer to section 5.2.2.2; Figure 3.1:1). Women of childbearing 
potential will performed two additional visits (phone calls) to inform the site team of the 
result of the urine pregnancy test at Day 56 (Visit 12pc) and Day 112 (Visit 13pc).
Figure 3.1: 1
Study design
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
BI 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 SOPs,
V4
D2
V6
D4
V3
D1
V10
D14
V11
D21
V12
D28
V8
D6
V9
D7
V5
D3
Infusion of BI 
655130
Observation period
Week 1
Weeks 2 to 4
V7
D5
V2
D-1
Screening 2
Admission of 
patient with a flare
Chronic
GPP
V1
Screening 1
Discharge from hospital
possible after Day 4
V14
D140
EOT
V13
D84
Weeks 5 to 20
Pregnancy test


D56
D112


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-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany. An IRT vendor will be used in this trial. Details will
be provided in IRT Manual available in ISF.
The trial will be conducted in each selected centre under the supervision of the Principal 
Investigator. A Coordinating Investigator is responsible to coordinate investigators at 
different centres participating in this multicentre 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 central laboratory service (except for safety laboratory tests, which will be performed at the
local laboratory of each site) and vendors for photodocumentation (skin lesions) and IRT 
(interactive response technology) will be used in this trial. Details will be provided in the 
applicable manuals available in the ISF.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI. Data management and statistical evaluation will be done by BI according to BI SOPs.
The organization of the trial in the participating countries will be performed by the respective 
local BI-organization (Operation Unit (OPU) or by a Contract Research Organization (CRO) 
with which the responsibilities and tasks will have been agreed and a written contract filed 
before initiation of the clinical trial. For each OPU participating in this study, a CML will be 
appointed responsible for coordinating the activities required in order to manage the trial in 
accordance with applicable regulations and internal SOPs in the countries covered by the 
respective BI OPU.
Tasks and functions assigned in order to 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.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This phase I trial is the first study with BI 655130 to be conducted in GPP patients. 
Current safety data about BI 655130 were obtained from a previous first-in-man phase I trial 
carried out in healthy volunteers. BI 655130 was safe and well tolerated in all dose groups 
tested in this trial up to the 10 mg/kg dose.
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 I trial is to investigate safety and tolerability of BI 655130 in patients with a 
flare of GPP.


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As a phase I trial, endpoints also include pharmacokinetics and pharmacogenomics. 
Efficacy is an exploratory endpoint at this early stage of the development. Final data will be 
compared to baseline.
For the first trial in GPP (1368.11) it is planned to include patients with active disease 
regardless of the mutation status (while the status will be investigated during the trial) for the 
following reason:

In addition to the described IL36RN mutation, other mutations in the same gene and 
other genes linked to the IL36 pathway (please see section 1.1 “Medical Background” 
above) have been described pointing to a general role of the IL36 pathway (and not 
only the IL36RN mutation) as disease trigger/driver

Patients can be included without need for screening for mutation status (critical as 
onset of treatment, treatment of acute flares has to be fast)
No active control group is included in this trial as there is currently no drug approved for the 
induction treatment of flares. Secukinumab (Cosentyx®) and infliximab (Remicade®) are 
registered for the treatment of GPP in Japan, but not specifically for flares. For secukinumab, 
authorization was granted on the basis of long-term treatment data (52 weeks) derived from 
one clinical trial conducted in patients with chronic GPP, not necessarily presenting with a 
flare episode at the time of inclusion. This study did not specifically evaluate the efficacy of 
secukinumab during flares (primary endpoint was proportions of patients who achieved 
treatment success at week 16) [R16-1462].
In trial 1368.11, GPP patient with a known history of GPP presenting with a flare will be 
included with a condition in need of immediate treatment to prevent progression (disease may 
progress to a life threatening condition). Of note, it has been reported that flare recurrences 
appear to be the norm and occur promptly on withdrawing systemic therapy or even on stable 
maintenance treatment (with current treatment options such as retinoids or methotrexate). A 
placebo design (with BI 655130 as add-on to current treatment options as comparison) is 
considered not feasible (expert feedback) due to the objectives listed above and the fact that 
GPP is an extremely rare disease.
Ongoing background treatment with methotrexate or retinoids will be continued during the 
trial participation.
Seven countries have been invited to participate in order to minimize the risk of under 
recruiting and to meet the goal of a maximum of 10 patients enrolled within 6 months.
Recruitment will be challenging due to the rareness of the disease and because patients must 
be included during a flare, which is difficult to predict. Moreover, the study will be 
performed in a competitive landscape. The selected countries seem to be the most appropriate 
countries to recruit.
The 10 mg/kg dose administered in this study was carefully selected on the basis of the first-
in-man Single Rising Dose (SRD) study conducted in healthy volunteers (BI Trial No. 
1368.1). This was the maximum dose administered in the SRD trial. This dose was safe and 
well tolerated and has been selected in this subsequent PoCC trial 1368.11 to maximize the 


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chance for a positive efficacy signal and treatment benefit for the patients. Please refer to 
section 4.1.3 for further details.
3.3
SELECTION OF TRIAL POPULATION
The objective is to enter a minimum of 6 patients but allow for a maximum of 10 patients. 
Once 6 patients have been included, the TMM can decide whether recruitment should be 
stopped or continued, dependent upon for example the rate at which patients are recruited 
into the trial.
A log of all patients enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in patients with a GPP flare.
3.3.2
Inclusion criteria
Patients will only be included into the trial, if they meet the following criteria:
1. Male or female patients, aged 18 to 75 years at screening (V2)
2. A known and documented history of Generalized Pustular Psoriasis regardless of the 
IL36RN mutation status, with previous evidence of fever, and/or asthenia, and/or 
myalgia, and/or elevated C-reactive protein, and/or leucocytosis with peripheral blood 
neutrophilia (above ULN)
3. Presenting with a flare of GPP with at least 10% of Body Surface Area (BSA) with 
erythema and pustules
4. A GPPGA score of at least moderate severity
5. GPP patients receiving maintenance treatment with retinoids and/or methotrexate for at 
least 4 weeks or GPP patients not receiving any maintenance therapy, at screening visit 
2 (V2)
6. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
7. Women of childbearing potential1 must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% 
per year when used consistently and correctly. A list of contraception methods meeting 
these criteria is provided in the patient information. 
Male patients must be ready and able to use condoms.


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1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming 
postmenopausal unless permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
Birth control method must be continued up to 20 weeks after BI655130 administration.
3.3.3
Exclusion criteria
Patients will not be allowed to participate if any of the following general criteria apply:
1. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
Women who stop nursing before the study drug administration do not need to be 
prevented from participating. They should refrain from breastfeeding up to 20 weeks after 
the study drug administration (see section 4.2.2.2).  
2. Immediate life-threatening flare of GPP or requiring intensive care treatment, according 
to the investigator’s judgement. Life-threatening complications mainly include, but are 
not limited to, cardiovascular/cytokine driven shock, pulmonary distress.
3. Identified, ongoing serious/severe infection
4. Acute generalized exanthematous pustulosis (AGEP)
5. Patient’s clinical presentation being considered due to the differential diagnosis of toxic 
epidermal necrosis or Stevens-Johnson syndrome
6. Currently involved in or intending to participate in another investigational study during 
the course of this trial.
7. Previous enrolment in this trial
8. 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
9. Patients with dose escalation of their maintenance therapy with methotrexate and/or 
retinoids within the 4 weeks preceding V2 (second screening visit)
10. Background therapy with ciclosporin within the last 30 days preceding the second 
screening visit (V2)
11. Previous exposure to an IL36R inhibitor
12. Severe, progressive, or uncontrolled renal, hepatic, haematological, endocrine, 
pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms 
thereof, as judged by the investigator. Patients with less than 3-fold ULN increase in AST 
and/or ALT and/or alkaline phosphatase and/or with less than 2-fold ULN increase in 
total bilirubin at infusion day (V3) may be included, provided that no other cause of liver 
damage than GPP has been identified.
13. Known chronic or relevant acute infections including active tuberculosis, HIV or viral 
hepatitis; QuantiFERON® TB test will be performed at screening. If the result is positive, 
patients may participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that the patient has no evidence of active 
tuberculosis. If presence of latent tuberculosis is established, then treatment should have 
been initiated and maintained according to local country guidelines.
14. Patient with a transplanted organ (with exception of a corneal transplant > 12 weeks prior 
to screening V2) or who have ever received stem cell therapy (e.g., Prochymal).


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15. Known history of lymphoproliferative disease, including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy 
and/or splenomegaly.
16. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to second screening visit (V2), except appropriately treated basal or squamous cell 
carcinoma of the skin or in situ carcinoma of uterine cervix.
17. Evidence of a current or previous disease, medical condition (including chronic alcohol or 
drug abuse) other than GPP, surgical procedure (i.e., organ transplant), medical 
examination finding (including vital signs and ECG), or laboratory value at the second 
screening visit (V2) outside the reference range, that is in the opinion of the investigator, 
is clinically significant and would make the study participant unreliable to adhere to the 
protocol or to complete the trial, compromise the safety of the patient, or compromise the 
quality of the data
18. History of allergy/hypersensitivity to a systemically administered biologic agent or its 
excipients
19. Patient’s refusal to be hospitalized for 4 days following the infusion
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
All patients have the right to withdraw from the study at any time without the need to justify 
their decision. The investigator has the right to remove patients from the study for non-
compliance, administrative or other reasons. An excessive withdrawal rate can have a severe 
negative impact on the scientific value of the trial. Every effort should be made to keep 
patients in the trial as scheduled. This includes careful patient selection and appropriate 
explanation of the trial requirements and procedures prior to enrolment as well as an 
explanation of the consequences of premature withdrawal.
Removal from trial
An individual patient is to be removed from the trial if:
1. The patient withdraws consent for trial participation, without the need to justify the 
decision
An individual patient may be removed from the trial if:
1. The patient is no longer able to participate for other medical reasons
2. Development of a toxicity or adverse event which warrants BI 655130 discontinuation 
including but not limited to SAEs or SUSARs


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In addition to these criteria, the physician may discontinue patients at any time based on his 
or her clinical judgment.
In case a patient has an elevation of AST and/or ALT and/or AP ≥3-fold ULN plus 2 time the 
baseline combined with an elevation of total bilirubin ≥2-fold ULN plus 1.5 time the baseline 
measured in the same blood sample (DILI, see section 5.2.2.1), it will be up to the discretion 
of the investigator to keep the patient in the trial as long as 
 considers he/she can perform 
all planned procedures.
As there is only one drug administration, patients may be less motivated to adhere to the 
study visit schedule.
Investigator and site staff should work to detect early signs of lost interest and strongly 
encourage the patients to continue to attend regularly scheduled study visits until the trial 
ends. Should that not be acceptable to the patient, the following alternatives should be offered 
to the patient in a descending order:
reduce the number of visits, with only the observation visits at Week 1 (Day 7, V9), Week 2 
(Day 14, V10), Week 4 (Day 28, V12), and the End-Of-Trial assessment at Week 20 (Day 
140, V14).
conduct only the Visits 9, 10 and 12 in person and V14 over the phone.
conduct all remaining study visits over the phone
discontinue participation in remaining trial activities but collect vital status at V12 and the 
end of the trial.
Participation in the trial must be stopped if the patient withdraws his consent.
If a patient is removed from or withdraws from the trial prior to the administration of trial 
medication, the reason for withdrawal will be entered in the case report form (CRF) and trial 
database and will be reported in the clinical trial report (CTR). If a patient is removed from or 
withdraws from the trial after the administration of trial medication, this will be documented 
and the reason for discontinuation must be recorded in the CRF. The data will be included in 
the CRF/trial database and will be reported in the CTR.  A complete V12 examination will be 
performed at the time of discontinuation and the information will be recorded in the CRFs. If 
the withdrawal occurs after V12, the patient should complete the EOT procedures. These 
discontinuations will be discussed in the CTR.
If a patient experiences a worsening of GPP during the course of the trial, he/she can receive 
rescue treatment and will be followed up as initially planned (refer to section 4.2.1.1). If a 
treated patient receives a prohibited treatment during the trial, he/she will continue the trial as 
initially planned and the prohibited treatment should be recorded as concomitant treatment.
If it is known that a patient becomes pregnant during the trial, she has to be followed until she 
has given birth or until the end of pregnancy. The patient’s data are to be collected until the 
end of the trial (last visit of last patient) and reported in the clinical trial report. For reporting 
of pregnancy and all related events refer to Section 5.2.2.2.
Removal from treatment
In case the infusion of study drug is permanently discontinued before the whole amount of 
prepared solution has been administered to the patient, every effort should be made to keep 


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the patient in the trial and perform all study assessments. If not possible, assessments at Week 
1, Week 2, Week 4, and Week 20 should be proposed to the patient. If still not possible, a 
complete V12 examination will be performed at the time of discontinuation and the 
information will be recorded in the CRFs. If the withdrawal occurs after V12, the patient 
should complete the EOT procedures. The discontinuation will be discussed in the CTR.
3.3.4.2
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. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 
50% of the patients show drug-related and clinically relevant adverse events of 
moderate or severe intensity, or if at least one drug-related serious adverse event is 
reported that is considered to be unacceptable.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP by a trial site or investigator, disturbing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
3.3.5
Replacement of subjects
The objective is to enter a minimum of 6 patients but allow for a maximum of 10 patients. 
Once 6 patients have been included, the TMM can decide whether recruitment should be 
stopped or continued, dependent upon for example the rate at which patients are recruited 
into the trial.
A patient who has performed the first screening visit (V1) will not necessarily have a flare 
before the end of recruitment. Therefore, all screened patients will not necessarily have the 
possibility of receiving the study drug.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured by BI Pharma GmbH & Co. KG. 
 
 
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are given below:
Substance:
BI 655130
Pharmaceutical formulation: Solution for infusion
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
1-0-0
Route of administration:
IV infusion
Duration of use:
Single dose
At the time of use, the IV solution for dosing will be prepared as detailed in the instruction
given in the ISF.
There is no reference product in this non comparative trial.
4.1.2
Method of assigning subjects to treatment groups
There is only one treatment group in this trial.
4.1.3
Selection of doses in the trial
The dose of 10 mg/kg for this trial was selected for trial 1368.11 on the basis of the data 
obtained in the FIH single rising dose trial 1368.1. In this study, the intravenous dose of 10 
mg/kg b.w. was safe and well tolerated. This support testing this dose in the subsequent 
PoCC trial 1368.11 to maximize the chance for a positive efficacy signal and treatment 
benefit for the patients.
All patients will receive a single dose of BI 655130 (10 mg/kg). 
4.1.4
Drug assignment and administration of doses for each subject
The treatment to be evaluated is outlined in Table 4.1.4: 1 below. It will be assigned to each 
patient after the completion of the inclusion visit and verification of all inclusion and 


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exclusion criteria. The assignment will occur in an open label fashion via Interactive 
Response Technology (IRT).
All included patients will receive the BI 655130 on Day 1. For further details concerning 
timing see Flow Chart. Start- and end time of the infusion will be recorded.
Detailed instructions for the preparation of the infusion solution, the volume to be 
administered and the infusion rate is provided in the ISF. 
After preparation, the solution for infusion may be stored at 2 - 8°C for up to 24 hours. After 
removal from 2 - 8°C storage or preparation, the solution must be administered within 60 
minutes if stored at ≤ 25°C. Do not freeze. 
Chemical and physical in-use stability has been demonstrated for 60 minutes at room 
temperature ≤ 25°C. In addition the time for infusion must not exceed 240 minutes at ≤ 25°C.
From a microbiological point of view the drug should be used immediately. If not used 
immediately, the in-use storage times and conditions prior to use are the responsibility of the 
user, and would normally not be longer than 24 hours at 2 - 8°C (36 - 46°F), unless 
preparation has taken place in controlled and validated aseptic conditions.
.
In all patients, the infusion solution will be intravenously administered over a period of 60
minutes. Infusion time can be extended up to 240 minutes provided that the maximum time 
between the start of preparation and completion of administration of the solution to the 
patient does not exceed 300 minutes (5 hours).
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. In any case, the total duration of infusion should not 
exceed 240 minutes (4 hours). Further based on 
 medical judgment he/she will provide 
medications such as steroids, etc. as needed.
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 – if applicable – its preparation, if correct dosage 
cannot be ensured otherwise. 
Table 4.1.4: 1
Preparation of final infusion solution containing BI 655130
Dose of BI 
655130 (mg/kg)
In-line filter 
used?
Approximate 
pre-flush 
volume [mL]
Concentration of 
the ready to use IV 
bag BI 655130 
[mg/mL]
Volume delivered 
[mL/kg b.w.]
Infusion time 
[min]
10
Yes
15
20
0.5
60 *
*
Can be extended up to 240 minutes, provided that the maximum time between the start of preparation and completion 
of administration of the solution to the patient does not exceed 300 minutes (5 hours)
Patients will be kept under close medical surveillance during the 4 days of hospitalization
following the study drug administration. 


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct, 
including data cleaning and preparation of the analysis). 
4.1.5.2
Procedures for emergency unblinding
As this trial will be conducted open-label, the treatment information will be known. 
Therefore, no emergency envelopes/procedure will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the Annex 13/EU GMP 
Guideline will be provided on the containers. Smaller boxes within the clinical trial supply
containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use only’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Patient or medication number

Batch number

Investigator
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the patient information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the patient information and informed consent forms.
Examples of the labels will be available in the ISF.
No re-supply is planned. Each site will receive trial medication kits with the initial release 
and will have the possibility to request additional medication shipment from central/local 
depots.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. A temperature log must be 
maintained for documentation. If the storage conditions are found to be outside the specified 


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range, the local clinical monitor (as provided in the list of contacts) is to be immediately 
contacted.
The medication may only be dispensed to trial patients according to the CTP by authorized 
personnel as documented in the trial staff list.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the study protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre

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 or immediately imminent 
signing of the clinical trial protocol 
Only authorized personnel as documented in the form ‘Trial Staff List’ may administer 
medication to trial patients. The trial medication must be administered in the manner 
specified in the CTP. All unused trial medication must be returned to the sponsor. All used 
and partially used medication must be destroyed locally by the trial site. Receipt, usage and 
return or disposal must be documented on the respective forms. Account must be given for 
any discrepancies. 
The investigator / pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use for each patient, and 
the return to the sponsor of unused products or disposal by the site of used or partially used 
products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products 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 that
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 drug supplies have been returned by the clinical trial staff and all 
used or partially used supplies have been destroyed by the trial site, and that no remaining 
supplies are in the investigator’s possession.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
Stable doses of concomitant therapies for chronic conditions, for which neither the condition 
nor the treatment are judged to exclude the patient from participation (see Section 3.3), are 
permissible. All concomitant medications should be carefully evaluated by the investigator 
and the CML should be contacted when there are questions regarding concomitant 
medications.
4.2.1.1
Rescue medication
The use of a rescue medication should be based on the severity and progression of the disease 
and will be left at the discretion of the investigator in case of a worsening of the flare. It is 
recommended to wait until two weeks after the study drug administration before prescribing a 
rescue medication in case no improvement or no change in disease condition is observed 
(stable disease). 
Even if the patient is dispensed rescue medication, he/she should stay in the trial and be 
followed-up as initially planned until Day 140. 
The choice of the rescue medication will be left at the discretion of the investigator. The 
sponsor will not supply the sites with the rescue medication.
4.2.1.2
Emergency procedures
No special emergency procedures are to be followed.
4.2.1.3
Additional treatments
No additional treatment is planned. 
However, in case of AEs in need of treatment, the investigator can authorise symptomatic 
therapy. In those cases, patients will be treated as necessary and, if required, kept under 
supervision at the trial site or transferred to a hospital until all medical evaluation results have 
returned to an acceptable level.
All concomitant and/or rescue therapies will be recorded on the appropriate pages of the 
eCRF.
Background treatment allowed
Patients receiving methotrexate or retinoids as background therapy for at least 4 weeks at 
second screening visit V2 can be included, if no escalation of dose occurred within the 4 
weeks preceding V2. The therapy must be continued at the same dose during the study 
participation. Any change of dose is not permitted throughout the trial participation.


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Patients who are not receiving methotrexate or retinoids at second screening visit V2 are not 
allowed to start such treatments during the trial (except in situations described in section 
4.2.1.1).
Background treatment not allowed
Background therapy with ciclosporin or other biologics is not allowed throughout the trial. A
patient with history of background treatment with ciclosporin can be included if the last 
intake was at least 30 days before Screening Visit 2. In this case, the dose that had been 
administered should be recorded in the eCRF.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medications (or classes of medications) listed in Table 4.2.2.1:1 must not have been 
taken before inclusion for the time periods as specified, and are not permitted throughout the 
study participation.
Table 4.2.2.1: 1
Restricted medications
Medication or class of medications
Restriction duration (through EOT Visit 1)
natalizumab, efalizumab, or agents that deplete B or 
T cells (e.g., rituximab, alemtuzumab, or 
visilizumab), briakinumab, secukinumab 
(Cosentyx®), ustekinumab (Stelara®), guselkumab, 
tildrakizumab
6 months prior to screening V2
IL36R inhibitors
not allowed neither before nor during trial 
participation
brodalumab, ixekizumab
4 months prior to screening V2
adalimumab (Humira®), infliximab (Remicade®) 
investigational products for psoriasis (non biologics)
12 weeks prior to screening V2
etanercept (Enbrel®) 
live virus vaccinations
6 weeks prior to screening V2
any investigational device or product (excludes 
psoriasis products) 
other systemic immunomodulating treatments except 
background therapy with methotrexate (e.g. 
ciclosporin A, corticosteroids2, cyclophosphamide), 
tofacitinib (Xeljanz®), apremilast (Otezla®) 
other systemic psoriasis treatments except 
background therapy with retinoids (e.g. fumarates, 
any other drug known to possibly benefit psoriasis) 
photochemotherapy (e.g., PUVA).
30 days prior to screening V2


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Table 4.2.2.1: 1
Restricted medications (Cont.)
phototherapy (e.g., UVA, UVB) topical treatment for 
psoriasis or any other skin condition (e.g. 
corticosteroids3, vitamin D analogues, vitamin A 
analogues, pimecrolimus, retinoids, salicylvaseline, 
salicylic acid, lactic acid, tacrolimus, tar, urea, 
anthralin, α-hydroxy, fruit acids)
14 days prior to screening V2
Anakinra
7 days prior to screening V2
1 In case of worsening of the flare, 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 setting after Day 28, 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 GPPASI is 
assessed
In the event a patient with prior use of restricted medications (refer to Table 4.2.2.1:1) is
enrolled, past medical records are required to document when these treatments were stopped.
All background, concomitant or rescue therapies will be recorded on the appropriate pages of 
the CRF. 
4.2.2.2
Restrictions on diet and life style
Male and female patients of child bearing potential must maintain an adequate contraception 
throughout the course of the trial and up to 20 weeks after the study drug infusion.
Adequate birth control methods for female patients are:

hormonal methods of contraception associated with inhibition of ovulation, 

intrauterine devices (IUD) or intrauterine hormone releasing systems (IUS), 

bilateral tubal ligation, 

vasectomized sexual partner (with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate and provided that partner is the sole sexual partner 
of the WOCBP participant), 

complete sexual abstinence as further described in the patient’s information.
As monoclonal antibodies can be secreted in milk, women should refrain from breastfeeding 
once they receive the study drug and up to 20 weeks after, i.e. until BI 655130 is eliminated 
(approximately 5 half-lives). They can start nursing again after this period.  


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4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study center under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
will provide additional confirmation of compliance. 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
Efficacy endpoints are secondary or further endpoints in this trial. 
Secondary efficacy endpoints will be:

Percent change from baseline in GPPASI total score at Week 2

Proportion of patients with GPPGA total score of 0 (clear) or 1 (almost clear) at Week 
2

Change from baseline in FACIT-Fatigue scale score at Week 2

Change from baseline in Pain VAS score at Week 2 
 
 
 
 


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5.1.2
Assessment of efficacy
The skin condition will be assessed by using the Generalized Pustular Psoriasis Area and 
Severity Index (GPPASI), Generalized Pustular Psoriasis Physician Global Assessment 
(GPPGA) and the CGI-Improvement (CGI-I). Patients’ questionnaires will also be used, 
fatigue scale (FACIT-Fatigue), Pain VAS, Psoriasis Symptom Scale (PSS) and other relevant 
scores as described in Section 5.1.1.
Methodological details for the evaluation of the scores/index are described in the ISF.
Generalized Pustular Psoriasis Area and Severity Index (GPPASI) 
The GPPASI is an adaptation for GPP patients of the PASI, an established measure of 
severity and area of psoriatic lesions in patients with psoriasis [R96-3541]. Similar adaptions 
have been used for PPP [R16-3360]. In the GPPASI, induration component has been 
substituted by pustules component. It is a tool which provides a numeric scoring for patients 
overall GPP disease state, ranging from 0 to 72. It is a linear combination of percent of 
surface area of skin that is affected and the severity of erythema, pustules, and scaling 
(desquamation) over four body regions.
GPPASI score will be measured at Visits 3 (before study drug administration) to 10, 12 (Day 
28), 13 (Day 84), and 14 (Day 140).
Generalized Pustular Psoriasis Physician Global Assessment (GPPGA)
GPPGA relies on clinical assessment of the GPP patient’s skin presentation. It is a modified 
PGA, a physician’s assessment of psoriatic lesions, which has been adapted to the evaluation 
of GPP patients [R15-5200]. The investigator (or qualified site personnel) scores the 
erythema, pustules and scaling of all psoriatic lesions from 0 - 4. Each component is graded 
separately, the average is calculated and the final GPPGA is determined from this composite 
score. A lower score then indicates a lesser severity, with 0 being clear and 1 being almost 
clear. To receive a score of 0 or 1, the patient should be afebrile, in addition to skin 
presentation requirements.
GPPGA score will be measured at Visits 3 (before study drug administration) to 10, 12 (Day 
28), 13 (Day 84), and 14 (Day 140).
FACIT-Fatigue scale
The FACIT-Fatigue scale is a brief and reliable instrument for monitoring fatigue and its 
effects on patients. It is a comprehensive compilation of questions that measure health-related 
quality of life in patients with chronic illnesses. It comprises 13 questions, the responses to 
which are each recorded on a 5-point Likert scale. Scores range from 0 to 52, with lower 
scores representing greater fatigue.


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The FACIT fatigue scale score will be measured at Visits 3 (before study drug 
administration), and 9, 10, and 12 (Day 28).
Pain VAS
The pain VAS is a unidimensional measure of pain intensity. It is a continuous scale 
comprised of a horizontal or vertical line, usually 10 centimeters (100 mm) in length, 
anchored by word descriptors at each end (“no pain”, “very severe pain”). The pain VAS is 
self-completed by the respondent. The respondent is asked to place a line perpendicular to the 
VAS line at the point that represents their pain intensity. Using a ruler, the score is 
determined by measuring the distance (mm) on the 10-cm line between the “no pain” anchor 
and the patient's mark, providing a range of scores from 0–100. A higher score indicates
greater pain intensity.
Pain VAS will be completed at Visits 3 (before study drug administration), and 9, 10, and 12 
(Day 28).
Psoriasis Symptom Scale (PSS)
The PSS is a four-item patient-reported outcome (PRO) instrument that assesses the severity 
of pain, redness, itching and burning from psoriasis. Current symptom severity is assessed 
using a 5-point Likert-type scale ranging from 0 (none) to 4 (very severe) and a total score is 
calculated by adding all subscores. The PSS was developed based on published evidence 
supporting the development of two similar, proprietary patient-reported outcome instruments: 
the Psoriasis Symptom Inventory and the Psoriasis Symptom Diary. These measures were 
developed in accordance with FDA PRO Guidance and have published evidence of 
reliability, validity, and ability to detect change [R14-3562, R14-3559, R15-1219, R15-1410, 
R15-1411].
The PSS will be self-administered by the patient at Visits 3 (before study drug 
administration), and 9, 10, and 12 (Day 28).
CGI-Improvement
The CGI-I is an observer-rated scale which measures illness global improvement (CGI-I). It 
is rated on a 7-point scale, with the improvement of illness scale using a response ranging 
from 1 (very much improved) to 7 (very much worse).
The CGI-I test measure will be performed at Visits 9, 10, and 12.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 655130 is the number [N (%)] of 
patients with adverse reactions, defined as drug-related AEs.


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Further safety criteria of interest: 

AEs and SAEs

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate, body temperature, body weight)

Frequency and severity of injection site reactions
 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately
life-threatening, results in persistent or significant disability or incapacity, requires or 
prolongs hospitalisation, 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.
Cancers with new histology or exacerbation of an existing cancer are always considered 
serious.
For Japan: An AE which possibly leads to disability will be reported as an SAE. Every new 
occurrence of cancer will be reported as a SAE regardless of the duration between 
discontinuation of the drug and the occurrence of the cancer.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 


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confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the eCRFs.
Yes: 
there is a reasonable causal relationship between the investigational product 
administered and the AE
No:
there is no reasonable causal relationship between the investigational product 
administered and the AE
Worsening of the underlying disease or pre-existing condition
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF.
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination, and laboratory test results will be 
recorded as an (S)AE in the eCRF, if they are judged clinically relevant by the investigator.
Protocol-specified adverse events of special interest (AESIs)
Protocol-specified AESIs are events of medical concern requiring monitoring and rapid 
communication.
The following are defined as protocol-specified AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters:
-
an elevation of AST and/or ALT and/or AP ≥3-fold ULN plus 2 time the 
baseline, combined with an elevation of total bilirubin ≥2-fold ULN plus 1.5 time 
the baseline, measured in the same blood sample.
      Any patients with these lab abnormalities need to be followed up according to Section 
10.1.2 of this CTP and the ‘DILI checklist’ provided in the ISF. In case of a DILI, it will be 
up to the investigator to keep the patient in the trial as long as 
considers he/she can 
perform all planned procedures.
Protocol-specified AESI can be classified as serious or non-serious but all AESI must be 
reported in an expedited manner similar to serious adverse events on a SAE form (i.e. non 
serious AESI must be reported on the SAE form and follow serious timelines).
5.2.2.2
Adverse event and serious adverse event reporting
Upon enrolment into a trial, the patient’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Patients will be required to report spontaneously any AEs and AESI as well as the time of 
onset, end, and intensity of these events. In addition, each patient will be regularly assessed 
by the medical staff throughout the clinical trial and whenever the investigator deems 
necessary. As a minimum, patients will be questioned for AEs, AESI (and concomitant 


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therapies) at the time points indicated in the Flow Chart. Assessment will be made using non-
specific questions such as “How do you feel?” Specific questions will be asked wherever 
necessary in order to more precisely describe an AE.
A careful written record of all AEs and AESIs shall be kept by the investigator in charge of 
the trial. 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.
SAEs which occurred during the screening period are to be reported according to standard 
procedures.
All AEs, serious and non-serious, as well as AESI occurring during the course of the clinical 
trial (i.e., from signing the informed consent onwards through the End-Of-Trial visit) will be 
collected, documented and reported to the sponsor by the investigator on the appropriate 
CRF(s) / SAE reporting forms.
Reporting will be done according to the specific definitions and instructions detailed in the 
‘Adverse Event Reporting’ section of the ISF. 
The residual effect period (REP) for BI 655130, when measurable drug levels or PD effects 
are still likely to be present, is 140 days (five half-lives). Therefore, all AEs reported within
140 days of the last trial medication will be considered on treatment.
For each AE, the investigator will provide the onset, end, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug. The investigator will 
determine the relationship of the investigational drug to all AEs as defined in Section 5.2.2.1.
If not stipulated otherwise in the ISF, the investigator must report the following events via 
telephone/fax using the SAE form immediately (within 24 hours of awareness) to the 
sponsor: SAEs, AESIs, and non-serious AEs relevant to a reported SAE or AESI. 
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterised, or no further information can be 
obtained.
If the investigator becomes aware of an SAE that occurred after the patient completed the 
clinical trial (including any protocol required residual effect period and/or follow-up), it 
should be reported by the investigator to the sponsor if considered relevant by the 
investigator.
A list of AEs which are defined to be always serious is provided in the ICF. These events 
should always be reported as SAEs. In order to support the investigator in identifying these 
‘always serious AEs’, if a non-serious AE is identified to be serious per BI definition, a query 
will be raised. The investigator must verify the description and seriousness of the event.
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. SAEs, AESI and non-serious AEs must include a causal relationship assessment 
made by the investigator.
The SAE form is to be forwarded to the defined unique entry point identified (specific 
contact details will be provided in the ISF). This immediate report is required irrespective of 
whether the investigational product has been administered or not and irrespective of causal 


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relationship. It also applies if new information to existing SAEs or protocol-specified AESIs 
becomes available. 
For Japan: All SAEs and AESIs must be reported immediately to the head of the trial site.
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.
Pregnancy
In the rare case that a female patient participating in this clinical trial becomes pregnant after 
having taken trial medication, the investigator must report immediately any drug exposure 
during pregnancy to the sponsor. Drug exposure during pregnancy has to be reported 
immediately (within 24 hours of awareness) to the defined unique entry point for SAE forms 
of the respective BI OPU (country-specific contact details will be provided in the ISF). The 
outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical 
Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart. On Day 1 (Treatment Visit), the 
results must be available before the study drug infusion, with the exception of serum tryptase.
The parameters that will be determined are listed in Table 5.2.3: 1. The laboratory tests will 
be performed at the local laboratory of each participating site. 


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
White blood cell count (WBC)
Platelet count
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if 
automatic differential WBC is 
abnormal)
Neutrophils (stabs), eosinophils, basophils, monocytes, 
lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Serum tryptase1
Substrates
C-Reactive Protein (CRP)
Serum albumin
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Total cholesterol 
Triglycerides
Plasma glucose
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Infection screening2
Hepatitis B Surface Antigen (qualitative)
Hepatitis C Antibodies (qualitative)
HIV-1, and HIV-2 Antibody (qualitative)
QuantiFERON®-TB


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Table 5.2.3: 1
Routine laboratory tests (Cont.)
Pregnancy test
Urine pregnancy test
Urine sediment (microscopic 
examination if urine analysis 
abnormal) (qualitative)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1
Only at inclusion/treatment visit (V3)
2
Only at first screening visit (V1)
A urine pregnancy test will be performed on all females of child-bearing potential at pre-
treatment visit, and every 4 weeks thereafter (please refer to the flow chart). The patient will 
give the result by phone on Day 56 (Visit 12pc) and Day 112 (Visit 13pc). In case of a 
positive result at baseline, the test should be repeated for confirmation.
In case of potential systemic allergic reaction, blood samples for determination of serum 
tryptase will be collected 0.5 h, 2 h, 6 h, 24 h after onset of the event.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
ECG measurements will always precede blood sampling to avoid impact of sampling on the 
ECG results.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for a 10-sec duration after the patients 
have rested for at least 5 min in a supine position. The site personnel will be instructed to
assure a relaxed and quiet environment so that all patients are at complete rest during the 
recordings. ECG assessment will always precede all other study procedures of the same time 
point (except blood drawing from an intravenous cannula which is already in place) to avoid 
impact of sampling on the ECG quality.
Electrode placement will be performed according to the method of Wilson, Goldberger and 
Einthoven.
Triple ECGs (recorded within 180 sec) will be recorded at the second screening visit (V2). At 
all other time points single ECGs will be recorded.
All locally printed ECGs will be evaluated by the investigator or a designee.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation). For time point with triple ECGs, all three single ECGs 
will be repeated. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. 
For the inclusion or exclusion (see Section 3.3) of a patient and for the assessment of cardiac 
safety during the study, the QT and QTcF according to Fridericia’s formula
(QTcF = QT / RR1/3), and generated by the ECG machines or their manual corrections by the 
investigators will be used. 


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Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at pre-
treatment) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the patient will be removed from the trial and will 
receive the appropriate medical treatment. 
Assessed ECGs will comply with the ICH E14 guidance document and supplements 
[R05-2311, R13-0801, R13-4095] as well as the FDA requirements for annotated digital 
ECGs [R09-4830].
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Vital signs evaluations will be performed at visits as shown in the flow chart. This includes 
body weight, temperature, pulse rate, systolic/diastolic blood pressure. 
Body weight measurements should be done on the same scale for each patient. In order to get 
comparable body weight values, it should be performed in the following way:
•
fasting (except for the screening visits)
•
after the urine sampling (body weight after bladder voiding)
•
shoes and coat/jackets should be taken off
•
pockets should be emptied of heavy objects (i.e. keys, coins etc.)
Body temperature will be measured using a standard device. All recordings for a given 
patient should be made using the same instrument and at the same area (ear, mouth…).
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 dosing visit (V3), vital signs evaluations will be performed pre-dose.
5.2.5.2
Medical examinations
At the inclusion visit, the medical examination will include documentation of patient
information, informed consent, demographics including height, smoking and alcohol history, 
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR, body weight and temperature), 12-lead ECG, laboratory tests, 
and a physical examination. At the End-Of-Trial examination, it will include review of vital 
signs, 12-lead ECG,  physical examination, assessment of psoriatic lesions, and of the 
presence of edema.


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Physical examinations will be performed at visits as described in the Flow Chart. Physical 
examination will include general appearance as well as evaluation of all relevant organ 
systems. Clinically relevant abnormal findings will be reported as baseline conditions or AEs.
Patients should be closely monitored for signs and symptoms of hypersensitivity reactions for
approximately 4 hours after the infusion at Visit 3. Hypersensitivity reactions should be 
treated according to medical standards.
5.2.5.3
Local tolerability
Local tolerability will be assessed by the investigator according to ‘swelling’, ‘induration’, 
‘heat’, ‘redness’, ‘pain’, or ‘other findings’.
5.3
OTHER
5.3.1
Photographs of skin lesions
Photography of skin lesions will be performed in all patients for additional documentation. 
Front and back trunk, legs and arms, as well as target lesions photographs will be taken 
preferably at the time points specified in the flow chart per instructions in the ISF. The 
patient’s consent must be obtained prior to take the photographs. Patients must be 
unrecognizable on the photos (refer to the procedure in the ISF).
5.4
APPROPRIATENESS OF MEASUREMENTS
The scheduled measurements will allow monitoring of changes in vital signs, standard 
laboratory values, and ECG variables that might occur as a result of administration of trial 
medication. The safety assessments are standard, are accepted for evaluation of safety and 
tolerability of an intravenously administered drug, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.5 are generally used
assessments of drug exposure. The biomarkers, pharmacogenomic and efficacy parameters 
and measurements outlined in Sections 5.1, 5.6, and 5.7 are of exploratory nature only.
Information about race should be obtained from all study participants as allowed by local 
regulations. This is because the prevalence and characteristics of psoriasis may differ 
between patients of different racial origin. It will thus be worthwhile to assess if patients of 
different race will respond differently to the study treatment.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs.
Exact time points of plasma sampling will be documented in the CRFs by the site personnel 
or sent as electronic files to the trial data manager. The actual sampling times will be used for 
determination of pharmacokinetic parameters.


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5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
 
 
 
 
 
 
5.5.2
Methods of sample collection
Optional use of plasma aliquots: Plasma samples may be used for further methodological 
investigations (ex: for future stability testing). However, only data for measuring the analyte 
and antibody responses to the analyte will be generated by these investigations. The PK study 
samples will be discarded after completion of the investigations but not later than 3 years 
after the final study report has been signed. Following the finalization of the ADA 


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bioanalytical report, ADA aliquots will be transferred to long term storage for 
possible/optional ADA characterization in the future.
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 655130 plasma concentrations, blood will be taken from an
antecubital or forearm vein into a K2EDTA (ethylenediaminetetraacetic acid)-anticoagulant 
blood drawing tube at the time points indicated in the Flow Chart under PK plasma. Blood 
will be withdrawn by means of either an indwelling venous catheter or by venipuncture with 
a metal needle. Procedure for handling can be found in the Lab Manual (ISF).
5.5.2.2
Plasma sampling for ADA assessment
For ADA assessment, blood will be taken from an antecubital or forearm vein into a 
K2EDTA anticoagulant blood-drawing tube at the time points listed in the Flow Chart under 
plasma ADA.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 655130 plasma concentration
BI 655130 concentrations will be determined by a validated Enzyme Linked Immunosorbent 
Assay (ELISA). 
5.6
BIOMARKER(S) 
 
 
 
 
 
 
 
 
 
 


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5.6.3
Methods of sample collection
Biomarkers sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK/PD data), including addition of samples 
and visits, as long as the total blood volume taken from each patient does not exceed 500 mL. 
Such changes would be implemented via non-substantial CTP Amendments. 
 
Lesional skin biopsies (for histopathologic, immunohistopatholic and RNASeq) will be 
performed at baseline prior to receiving treatment (Day 1) and on Day 7 (Visit 9). Optional 
skin biopsies may be performed on Day 14 (Visit 10). They will be collected at the site of 
most inflammatory (deepest red erythema) lesion. Paired non-lesional skin biopsies will also 
be collected at baseline. Instructions on the skin biopsy samples preparation will be reviewed 
by site staff prior to the first biopsy (refer to ISF).
 
 
 
 
 
 
 
5.6.4
Analytical determinations
For histopathological evaluation, a histopathological score of the skin biopsies will be based
on hematoxylin and eosin staining as the degree of parakeratosis, psoriasiform papillary
pattern, vessel density, and dilation in the papillae, lymphocyte infiltration around the
superficial plexes of vessels, and granulocyte infiltration in stratum corneum. The
histopathologic score for each of the five patterns will be graded on a scale of Positive,
Negative and Positive/Negative. At least one representative digital picture of each biopsy will
be collected and provided to BI. For other endpoints, all sections stained with markers for
presence of cytokines, leukocyte subsets, lymphocyte subsets, blood vessels, and other 
markers will be evaluated semi-quantitatively. Based on a semi-quantitative evaluation under 
the discretion of a consultant dermatologist, the staining level of each marker will be assessed 


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and reported. Characteristics of the analytical methods for the analysis of skin, serum and 
plasma biomarkers will be given in detail in the clinical trial report or in an accompanying
technical/biomarker report.
Serum, plasma proteins and cell populations by flow cytometry will be analyzed using 
established parameters for each analyte (protein) and the corresponding matrix (serum and 
plasma) and cell subsets (flow cytometry).
Targeted re-sequencing and gene expression will be analyzed using standard molecular 
genetic methods and technologies such as Next Generation Sequencing (for whole genome 
sequencing) and TaqMan Real Time PCR and/or RNA sequencing for expression analysis.
 
 
5.7.1
Pharmacodynamic endpoints
Cf. section 5.6.1.
5.7.2
Methods of sample collection
Cf. section 5.6.3.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the flow chart. Investigators 
should encourage patient adherence to protocol specific activities. Each visit date (with its 
window) is to be counted from Day 1. The acceptable time windows for observation visits
and End-Of-Trial 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.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of pharmacokinetic parameters.
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 Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the flow chart and the respective 
protocol sections. Refer to Section 5 for explanations of procedures. Additional details on 
procedures at selected visits are provided below.
Included patients must be hospitalized for at least 4 days following the study drug 
administration. Patients will perform Visits 2 to 7 as inpatients. Visits 8 to 14 can be 
ambulatory or as inpatient if the patient is still hospitalized.
Measurement of vital signs should precede blood sampling and be assessed pre-dose at 
dosing visit.
The following sequence of procedures at each visit (where applicable) is recommended:
1. FACIT-Fatigue scale, pain VAS, and PSS
2. AE/local tolerability (at V3, local tolerability will be evaluated after the infusion) and 
concomitant therapy collection
3. Physical examinations / Vital signs / Body weight and temperature
4. GPPGA, GPPASI, CGI-I, presence of edema, pustular BSA
5. Photographs of skin lesions
6. ECG
7. Blood sampling for safety laboratory tests, PK, ADA, and biomarkers
8. Skin biopsies


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Evaluation of GPPASI, GPPGA, CGI-I, presence of edema, and pustular BSA for a given 
patient should be performed by the same physician throughout the study.
The patient’s questionnaires (FACIT-Fatigue, PSS, pain VAS) should be completed by the 
patient himself without any help. In case of impossibility, they should not be completed.
6.2.1
Screening period
6.2.1.1
Screening Visit 1
The 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 have started 
screening. The patient should be recorded on the enrolment log and be registered in IRT as a 
screened patient.
Screening (Visit 1) should normally take place several days, weeks before a flare of GPP, and 
be terminated the day before the treatment administration at Visit 3 (a second screening visit 
will take place the day the patient is admitted for a flare of GPP (Visit 2)). 
Infection screening
Refer to exclusion criteria Section 3.3.3 with study participation directive for patients with a 
positive QuantiFERON®TB test TB.
Mutation status
Information on the presence or absence of IL36RN mutation will be collected in patient’s 
historical data and reported in the eCRF.
Demographics
Informed consent date, gender, ethnicity and race (if allowed by local law) will be collected 
and reported in the eCRF.
Baseline Conditions
Chronic diseases, current observable conditions, any new clinically relevant findings 
discovered from the physical examination, ECG, safety labs, and any condition requiring 
therapy (excluding GPP) will be reported on the Baseline Condition eCRF page.
Review of inclusion/exclusion criteria
Selection criteria will be reviewed carefully.
IRT
All patients that are screened must be registered with IRT. If the patient results in a screen 


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failure, IRT should be notified as soon as possible. Details of IRT procedures can be found in 
the IRT manual located in the ISF.
6.2.1.2
Screening Visit 2
The patient will be asked to confirm that he/she is still willing to participate in the trial. 
Eligibility will be assessed during this visit.
Re-screening will not be permitted: patients who fail screening following Visits 1 or 2 
assessments should be registered as a screen failure in IRT. Details of IRT procedures can be 
found in the IRT manual located in the ISF.
All procedures described in the Flow Chart for this visit will be performed. 
6.2.2
Treatment Visit (V3) and observation period
Treatment Visit 3 should be performed the day after Visit 2. 
The BI655130 will be administered only at Visit 3. The observation period is from Visit 4 to 
EOT Visit (V14).
All procedures described in the Study Flow Chart and PK Flow Chart for this visit will be 
performed.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 4 h-period prior to the
trial drug administration (including blank values for PK, ADA and biomarkers).
For information regarding laboratory tests, ECG, vital signs, and physical examination, refer 
to Sections 5.2.3 to 5.2.5.
Fasting condition is not required for blood sampling. Pharmacogenomic genotyping for 
targeted GPP causing mutations (IL36RN, CARD14, AP1S3) will be performed in all
patients (for details see Sections 5.6.2 and 5.6.3). DNA banking is optional and will only be 
performed in patients who give their consent for it.
Skin lesions photographs will be taken at all visits on site except visits 7 and 8. Skin biopsies 
will be performed at visits 3, and 9 (one additional biopsy at visit 10 is optional). For 
indications, refer to ISF.
Skin biopsies and venipuncture (i.e. safety laboratories, PK, ADA, biomarkers) should be the 
last procedure prior to study drug administration.
Study drug allocation via IRT and administration of study medication should be the last 
activity at Visit 3.
A urine pregnancy test will be performed at Day 28 (Visit 12), Day 56, Day 84 (Visit 13), 
Day 112, and Day 140 (Visit 14). The patient will inform the site of the results of the tests 
performed at Day 56 and Day 112 by phone.


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All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved.
6.2.3
Early trial termination
Trial termination should be completed at EOT visit. In case a patient prematurely 
discontinues the treatment or the trial, every effort should be made to perform assessments at 
Day 7 (Visit 9), Day 14 (Visit 10), Day 28 (Visit 12), and Day 140 (EOT Visit) as initially 
planned (please refer to section 3.3.4.1).
If a patient cannot or will not continue in the trial as defined above, then the patient should 
complete V12 procedures at the time of discontinuation. If the withdrawal occurs after V12, 
the patient should complete the EOT procedures.
For Japan: In the case of a patient’s discontinuation from the trial, the patient will be 
followed-up until the investigator or sub-investigator is convinced of the patient’s safety. 
When follow-up is not possible or comes to an end, it should be formally completed after 
discussion with the sponsor. If a patient stops attending trial assessments, the investigator 
should assess the patient’s status as comprehensively as possible and the well-being of the 
patient should be monitored. However, if the patient withdraws from the trial, it is the 
patient’s choice whether or not to participate; he or she cannot be compelled.
6.2.4
End-Of-Trial (Visit 14)
Completion is defined as a patient having reached the EOT visit within the specified window 
per the Flow Chart.
Adverse events persisting after trial completion must be monitored until they have normalised 
or have been sufficiently characterised.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The study design is described in Section 3 and trial objectives are listed under Section 2.2. 
The safety, efficacy and PK endpoints will be evaluated descriptively; for efficacy endpoints 
95% confidence intervals may be presented in addition.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in a confirmatory sense. Instead, the 
endpoints will be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified in the TSAP.
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.4.
7.3.2
Secondary analyses
The continuous secondary efficacy endpoints, such as GPPASI total score, Pain VAS, and 
FACIT-Fatigue score at week 2, will be evaluated descriptively, including the original as well 
as change from baseline values where applicable, along with exact 95% confidence intervals, 
if feasible. For the GPPASI total score, the percentage change from baseline at week 2 will be 
displayed.
The binary efficacy endpoint, GPPGA response of 0 (clear) or 1 (almost clear), will be 
described using patient frequencies and percentages. Exact 95% confidence intervals will 
additionally be provided for the proportion of patients with a response, if feasible.
The patient set for the evaluation of efficacy endpoints (FAS) will include all treated patients
who had a baseline and at least one post-baseline measurement available for either GPPASI 
or GPPGA. Baseline is defined as the last measurement collected prior to administration of 
the trial treatment.


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The secondary PK parameters (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). Analyses will be 
performed for parent drug.
Pharmacokinetic parameters of a patient will be included in the analysis unless the patient has 
an important protocol violation relevant for the evaluation. Whether a protocol violation is 
important will be decided no later than in the Report Planning Meeting. 
Reasons for exclusion of single pharmacokinetic parameters may be:

Time deviations

Use of restricted medications 
The patient set for the evaluation of PK endpoints (PKS) will include all treated patients that 
provide at least one observation for at least one secondary PK endpoint without important 
protocol violations with respect to the statistical evaluation of PK endpoints. It will be 
decided in the Report Planning Meeting which patients are to be included in the PKS.
Excluded patients will be listed with their individual plasma concentrations and individual 
pharmacokinetic parameters, however, will not be included in descriptive statistics for plasma 
concentrations, pharmacokinetic parameters or other statistical PK assessment.
7.3.3
Further analyses
Analysis of the further efficacy endpoints will be performed using similar methods to those 
described in section 7.3.2 for the secondary analyses. Patient frequencies and percentages 
will be used to describe each category of the CGI-I at each visit.
7.3.4
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated patients (that is, 
all patients who received at least one dose of the study drug), will be included in the safety 
evaluation. Safety analyses will be descriptive in nature and will be based on BI standards.
Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatment (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to intake of trial medication will be 
assigned to 'screening', and those between trial medication intake until the end of REP will be 
assigned to the treatment period. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, intensity and causal relationship of AEs will be tabulated by 
treatment, primary system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) 
and other significant AEs (according to ICH E3) will be listed separately. 


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Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be flagged. Additionally, differences from baseline will be evaluated.
For vital signs, the differences from baseline will be evaluated.
Relevant ECG findings will be reported as AEs.
7.3.5
Interim analyses
The analysis of the efficacy and safety data collected up to week 4 will be performed once all 
entered patients have completed the first 4 weeks of study (through visit 12); at that time-
point, a preliminary database lock will be done. Since the study is planned to continue 
through an additional 16 weeks of further follow-up, a logistics plan will be developed in 
order to describe the processes to be implemented for protecting the integrity of the ongoing 
trial through the final week 20 analysis. Details of the analyses to be performed for the final 
week 4 data, as well as for the completed study through 20 weeks, will be described in the 
trial statistical analysis plan (TSAP). Both the TSAP and logistics plan will be finalized prior 
to database lock for the final week 4 analysis.
Efficacy and safety data will be reviewed on an ongoing basis at the Medical Quality Review 
Meeting to ensure data quality and patient’s safety.
7.3.6
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 655130 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Patients who are not included in the PKS (refer to Section 7.3.1.) will be reported with their 
individual plasma concentrations and individual pharmacokinetic parameters; however, they 
will not be included in descriptive statistics for plasma concentrations, pharmacokinetic 
parameters or other statistical PK assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
If a predose concentration value is greater than 5% of Cmax, the patient’s pharmacokinetic 
data will be not included in any PK statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a patient will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the patient’s Cmax value, the patient’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
 


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7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analyzed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values).
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be set to missing. The 
lag phase is defined as the period between time zero and the first time point with a 
concentration above the quantification limit.
7.4.4
Biomarker assessment
No imputations are planned for any missing biomarker data.
7.4.5
Efficacy
The following rules will be used to impute for missing data:
•
For continuous endpoints, and for the CGI-Improvement, under the assumption that 
the disease is self-limiting and will gradually improve over time, the Last Observation 
Carried Forward (LOCF) approach is intended to be used;
•
For binary endpoints, the following will be performed: 


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o If there are data at visits both before and after the visit with a missing outcome, 
then impute as success only if both neighboring visits also represent a success;
o Otherwise, impute as a failure to achieve a response (i.e. NRI [No Response 
Imputation]).
For patients that take a rescue medication during the course of the study, efficacy outcomes 
subsequent to the time-point at which the medication was taken will be set to missing and 
will be imputed using the steps described above.
For continuous endpoints, the data will additionally be displayed in the original form without 
any imputation for missing data performed.
Details on the handling of missing item scores for the FACIT will be based on FACIT 
Administration and Scoring Guidelines (version 4) and provided in the TSAP.
Further imputation strategies for missing data will be considered in the TSAP.
7.5
RANDOMISATION
No randomisation is planned in this trial, as it is an open-label trial with one treatment arm. 
All patients will receive the same treatment. A (medication) randomisation list will only be 
provided for logistical reasons with a block size of 1, i.e., a list of consecutive numbers is 
provided.
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to enter a minimum of 6 patients but allow for a maximum of 10 patients. The 
planned sample size is not based on a power calculation but on feasibility and practical 
considerations to explore safety and tolerability as well as PK and efficacy of BI 655130 in 
GPP patients.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs, and for Japan, the Japanese GCP 
regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remain the 
responsibility of the patient’s treating physician.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study patients against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP, and for Japan, the Japanese GCP regulations (Ministry of 
Health and Welfare Ordinance No. 28, March 27, 1997).
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the
CTR.
According to local requirements: The terms and conditions of the insurance coverage must be 
given to each patient and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a patient’s 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 are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional patient information must be 
given to each patient or the patient’s legally accepted representative.
For Japan: 
The investigator must give a full explanation to trial patients including the items listed below 
in association with the use of the patient information form, which is prepared avoiding the 
use of technical terms and expressions. The patient is given sufficient time to consider 
participation in the trial. The investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the 
contents. The investigator must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent. Re-consenting may become necessary 


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when new relevant information becomes available and should be conducted according to the 
sponsor’s instructions. The consent and re-consenting process should be properly 
documented in the source documentation.
The following items need to be included:
1.
That the clinical trial is aimed at testing.
2.
Objectives of the trial.
3.
The name, title, and address of the investigator to contact.
4.
Trial procedures.
5.
Anticipated benefits of the investigational products and anticipated disadvantages to
the patient.
6.
Matters concerning other therapeutic measures.
7.
Duration of participation in the clinical trial.
8.
That the patient may withdraw from the trial at any time.
9.
That patient’s refusal of or withdrawal from participation in the trial does not cause 
any disadvantage to him or her.
10.
That the monitors, the auditors, and the institutional review board are given access 
to the relevant source documents on condition that confidentiality of the patient is 
fully secured.
11.
That privacy of the patient is kept.
12.
The office of the medical institution to contact in the event of trial-related injury.
13.
That necessary treatment is available to the patient in the event of trial-related 
injury.
14.
Matters concerning compensation in the event of any trial-related injury.
15.
The type of the IRB which is used for the reviews and deliberations on the matters 
such as appropriateness of conducting the clinical trial, the matters to be reviewed 
and deliberated by each IRB, and other matters concerning the IRBs involved in the 
clinical trial.
16.
Other necessary matters concerning the clinical trial.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, 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.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.


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8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained. 
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage of records
Trial sites:
The trial sites 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
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular AE is ‘listed’, i.e. is a known side effect of the drug. Therefore, a unique 
reference document for the evaluation of listedness needs to be provided. For BI 655130 this 
is the current version of the Investigator’s Brochure [c03320876-01]. The current version of 
this reference document is to be provided in the ISF. No AEs are classified as listed for study 
design, or invasive procedures.


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8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
The sponsor will take measures to protect the confidentiality and security of patients’ 
pharmacogenomics samples and patient’s data and privacy in accordance with current local
laws. Samples collected for the purpose of potential future genetic research will be labelled 
with the same unique code number as used for patient’s data in the main clinical trial. This
number will be used in place of patient’s name and other personally identifiable information 
that directly and easily identifies the patient, for example, his/her name and birth date. Only 
the trial site will have the link between patient’s name and the code number. 
Treatment data may be provided 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, i.e. the CA.
8.6
COMPLETION OF TRIAL
For Japan: when the trial is completed, the investigator should inform the head of the trial site 
of the completion in writing, and the head of the trial site should promptly inform the IRB 
and sponsor of the completion in writing.
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient/patient out, unless specified differently in Section 6.2.5 of the 
CTP) or early termination of the trial.
8.7
PROTOCOL VIOLATIONS
For Japan: The investigator should document any deviation from the protocol regardless of 
their reasons. Only when the protocol was not followed in order to avoid an immediate 
hazard to trial subjects or for other medically compelling reason, the principal investigator 
should prepare and submit the records explaining the reasons thereof to the sponsor, and 
retain a copy of the records.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
For Japan: in the event of health injury associated with this trial, the sponsor is responsible 
for compensation based on the contract signed by the trial site.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P09-07583
Aksentijevich I, et al. An autoinflammatory disease with deficiency of the 
interleukin-1-receptor antagonist. N Engl J Med 2009. 360(23):2426-2437.
R05-2311
ICH E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonised 
tripartite guideline, recommended for adoption at step 4 of the ICH process 
on 12 May 2005 by the ICH Steering Committee). www.emea.eu.int 
2005:1-14.
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R13-0801
E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs - Questions and 
Answers (R1). October 2012. 
website.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/ucm323656.htm
R13-4095
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): ICH guideline E14 - questions and answers: step 
5 (May 2012, EMA/CHMP/ICH/310133/2008). 
website.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2009/09/WC500002878.pdf
R14-3559
Revicki DA, Jin Y, Wilson HD, Chau D, Viswanathan HN. Reliability and 
validity of the psoriasis symptom inventory in patients with moderate-to-
severe psoriasis. J Dermatol Treat 2014. 25(1):8-14.
R14-3562
Bushnell DM, Martin ML, McCarrier K, Gordon K, Chiou CF, Huang X, 
Ortmeier B, Kricorian G. Validation of the Psoriasis Symptom Inventory 
(PSI), a patient-reported outcome measure to assess psoriasis symptom 
severity. J Dermatol Treat 2013. 24(5):356-360.
R14-5158 
Marrakchi S, et al; Interleukin-36-receptor antagonist deficiency and 
generalized pustular psoriasis; N Engl J Med 365 (7), 620 -628 (2011)
R15-1219
Martin ML, McCarrier KP, Chiou CF, Gordon K, Kimball AB, Voorhees 
AS van, Gottlieb AB, Huang X, Globe D, Chau D, Viswanathan HN, 
Kricorian G. Early development and qualitative evidence of content validity 
for the Psoriasis Symptom Inventory (PSI), a patient-reported outcome 
measure of psoriasis symptom severity. J Dermatol Treat 2013. 24(4):255-
260.
R15-1399 
Blumberg H1, Dinh H, Dean C Jr, Trueblood ES, Bailey K, Shows D, 
Bhagavathula N, Aslam MN, Varani J, Towne JE, Sims JE.; IL-1RL2 and 
its ligands contribute to the cytokine network in psoriasis.; J Immunol. 2010 
Oct 1;185(7):4354-62. doi: 10.4049/jimmunol.1000313. Epub 2010 Sep 10


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R15-1410
Lebwohl M, Swensen AR, Nyirady J, Kim E, Gwaltney CJ, Strober BE. 
The psoriasis symptom diary: development and content validity of a novel 
patient-reported outcome instrument. Int J Dermatol 2014. 53(6):714-722
R15-1411
Strober BE, Nyirady J, Mallya UG, Guettner A, Papavassilis C, Gottlieb 
AB, Elewski BE, Turner-Bowker DM, Shields AL, Gwaltney CJ, Lebwohl 
M. Item-level psychometric properties for a new patient-reported psoriasis 
symptom diary. Value Health 2013. 16(6):1014-1022.
R15-1420 
Towne JE, Sims JE.; IL-36 in psoriasis; Curr Opin Pharmacol. 2012 
Aug;12(4):486-90. doi: 10.1016/j.coph.2012.02.009. Epub2012 Mar 5. 
Review
R15-1421 
Onoufriadis A1, Simpson MA, Pink AE, Di Meglio P, Smith CH, 
Pullabhatla V, Knight J, Spain SL, Nestle FO, Burden AD, Capon F, 
Trembath RC, Barker JN.; Mutations in IL36RN/IL1F5 are associated with 
the severe episodic inflammatory skin disease known as generalized 
pustular psoriasis; Am J Hum Genet. 2011 Sep 9;89(3):432-7. doi: 
10.1016/j.ajhg.2011.07.022. Epub 2011 Aug 11
R15-1432 
Blumberg H1, Dinh H, Trueblood ES, Pretorius J, Kugler D, Weng N, 
Kanaly ST, Towne JE, Willis CR, Kuechle MK, Sims JE, Peschon JJ.; 
Opposing activities of two novel members of the IL-1 ligand family 
regulate skin inflammation; J Exp Med. 2007 Oct 29;204(11):2603-14. 
Epub 2007 Oct 1
R15-1447 
Tortola L1, Rosenwald E, Abel B, Blumberg H, Schäfer M, Coyle AJ, 
Renauld JC, Werner S, Kisielow J, Kopf M.; Psoriasiform dermatitis is 
driven by IL-36-mediated dc-keratinocyte crosstalk; J Clin Invest. 2012 
Nov;122(11):3965-76. doi: 10.1172/JCI63451. Epub 2012 Oct 15
R15-5200
Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. 
The 5-point Investigator's Global Assessment (IGA) Scale: A modified tool 
for evaluating plaque psoriasis severity in clinical trials. J Dermatolog 
Treat. 2015 Feb;26(1):23-31. 
R16-0929
Berki DM, Liu L, Choon SE, Burden AD, et al. Activating CARD14 
mutations are associated with generalized pustular psoriasis but rarely 
account for familial recurrence in psoriasis vulgaris. J Invest Dermatol 
2015. 135:2964-2970
R16-0933
Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. 
Clinical profile, morbidity, and outcome of adult-onset generalized pustular 
psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, 
Malaysia. Int J Dermatol. 2014 Jun;53(6):676-84. doi: 10.1111/ijd.12070. 
Epub 2013 Aug 22.
R16-1461
Varman KM, Namias N, Schulman CI, Pizano LR. Acute generalized 
pustular psoriasis, von Zumbusch type, treated in the burn unit. A review of 
clinical features and new therapeutics. Burns. 2014 Jun;40(4).


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R16-1462
Imafuku S, Honma M, Okubo Y, Komine M, Ohtsuki M, Morita A, Seko 
N, Kawashima N, Ito S, Shima T, Nakagawa H. Efficacy and safety of 
secukinumab in patients with generalized pustular psoriasis: A 52-week 
analysis from phase III open-label multicenter Japanese study. J Dermatol. 
2016 Feb 26. doi: 10.1111/1346-8138.13306. [Epub ahead of print]
R16-1463
Borges-Costa J, Silva R, Gonçalves L, Filipe P, Soares de Almeida L, 
Marques Gomes M. Clinical and laboratory features in acute generalized 
pustular psoriasis: a retrospective study of 34 patients. Am J Clin Dermatol. 
2011 Aug 1;12(4):271-6.
R16-2698
Augey F, Renaudier P, Nicolas JF. Generalized pustular psoriasis
(Zumbusch): a French epidemiological survey. Eur J Dermatol. 2006 Nov-
Dec;16(6):669-73.
R16-2960
Viguier M, Aubin F, Delaporte E, Pagès C, Paul C, Beylot-Barry M,
Goujon C, Rybojad M, Bachelez H; Groupe de Recherche sur le Psoriasis 
de la Société Française de Dermatologie. Efficacy and safety of tumor 
necrosis factor inhibitors in acute generalized pustular psoriasis. Arch 
Dermatol. 2012 Dec;148(12):1423-5
R16-3360
Brunasso AM, Salvini C, Massone C. Efalizumab for severe palmo-plantar 
psoriasis: an open-label pilot trial in five patients. J Eur Acad Dermatol 
Venereol. 2009 Apr;23(4):415-9. 
R95-0013
Broom C. Design of first-administration studies in healthy man. Early 
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R96-3541
Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a new
retinoid. Dermatologica. 1978;157(4):238-44.
9.2
UNPUBLISHED REFERENCES
c03320876-01
 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, 
harmacokinetics and pharmacodynamics of single rising intravenous doses 
of BI 655130 in healthy male volunteers; 27 January 2016
001-MCS-36-472 Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics


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10.
APPENDICES
10.1
CLINICAL EVALUATION OF LIVER INJURY
10.1.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-specified 
AESIs), are to be further evaluated using the following procedures:
10.1.2
Procedures
Repeat the following laboratory tests: ALT, AST, AP, and bilirubin (total and direct) - within 
48 to 72 h. If it is confirmed that AST and/or ALT and/or AP ≥3-fold ULN plus 2 time the 
baseline occurs in conjunction with an elevation of total bilirubin ≥2-fold ULN plus 1.5 time 
the baseline, the laboratory parameters listed below (clinical chemistry, serology, hormones, 
haematology) must be determined and made available to the investigator and to BI as soon as 
possible.
In addition, 

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the ‘DILI checklist’ provided in the ISF 

obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the ‘DILI checklist’ provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and 
work place exposure) according to the ‘DILI checklist’ provided in the ISF;
and report these via the CRF.
Clinical chemistry
Alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-
HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody 
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody
Hormones, tumormarker
TSH
Haematology
Thrombocytes, eosinophils


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
Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology, e.g. bile duct stones or neoplasm.

Initiate close observation of patients by repeat testing of ALT, AST, AP and total 
bilirubin (total and direct) at least weekly until the laboratory ALT and/or AST 
abnormalities stabilize or return to normal, then monitor further as specified in the 
CTP. Depending on further laboratory changes, additional parameters identified e.g. 
by reflex testing will be followed up based on medical judgement and Good Clinical 
Practices (GCP).
10.2
RECONSTITUTION INSTRUCTION(S)
Please refer to ISF for details about the preparation of the infusion solution.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
09 Nov 2016
EudraCT number
2016-001236-35
BI Trial number
1368.11
BI Investigational Product(s)
BI 655130
Title of protocol
Multi-centre, open-label, single arm, phase I 
study to investigate safety, tolerability, 
pharmacokinetics, pharmacogenomics and 
efficacy of a single intravenous dose of BI 
655130 in patients with active generalized 
pustular psoriasis.
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
Section to be changed
1. Flow charts, sections 2.3, 3.1, 5.1.1, 5.1.2, 
5.2.1, 5.2.2.2, 5.2.3, 5.2.5.2, 6.1, 6.2.2, 
6.2.4
2. Section 1.2.5
3. Synopsis, section 3.3.3
4. Synopsis, section 5.2.1
5. Section 3.3.2
6. Sections 3.3.2, 4.2.2.2
7. Sections 3.3.3, 4.2.2.2
8. Section 4.1.4
9. Section 4.1.4
10. Flow Chart, section 4.1.4
11. Section 6.2
12. Section 7.3.5
13. Section 7.3.2


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Number of global amendment
1
14. Sections 4.2.1.3, 5.2.3, 6.2
15. Sections 3.3.4.1, 6.2.3
16. Synopsis, 3.1, 3.2
Description of change
1. Update of study flow charts
Observation period was extended until 20 weeks 
after study drug administration (End of Trial visit 
is now at Week 20)
Additional visit at Week 12 with time-window 
was included
Additional urinary pregnancy tests were included
(due to extended observation period, results will 
be provided by phone)
2. PK data of FIH trial have been updated
3. Exclusion criteria n°4 was clarified
4. The primary endpoint was specified
5. The definition of women of childbearing 
potential was added
6. Period of use of birth control method was 
extended until 20 weeks after study drug 
administration. Birth control methods 
were updated
7. Information that women who stop 
breastfeeding can participate in the trial 
has been added. The time when they can 
start nursing again after their participation 
has also been specified.
8. In-use stability data were updated
9. Infusion time was prolonged to 60 minutes
10. Weight of infusion set before and after 
study drug administration was deleted
11. Statement that patient’s questionnaires 
should be completed by the patient 
himself was added
12. Interim analysis was added
13. The definition of FAS was specified
14. Correction of inconsistencies and typing 
errors in safety lab tests and others 
sections were performed
15. Statements regarding removal of patients 
were rephrased for better understanding
16. One country was removed (UK)
Rationale for change
1. PK results from 1368.1 trial suggest a 
 


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Number of global amendment
1
for doses tested in the study. The 
evaluation is ongoing. However as 
precautionary measure we have extended 
the observation period to Day 140 to cover
2. PK data for all dose groups are available
3. Exclusion criteria n°4 was clarified for
better understanding
4. The definition of an adverse reaction was 
specified for clarification
5. Information was missing
6. We have extended the period of use of 
contraception methods to cover the 
residual effect period 
 We 
have updated the birth control methods 
according to the new BI SOP
7. Information was missing
8. Updated In-Use Stability Data with date 
from 26 Sept 2016
9. Updated In-Use Stability Data with date 
from 26 Sept 2016
10. After Pre-Trial Contact Visits, the 
procedure seemed to be less reliable than 
collecting the infused volume indicated on 
infusion pump 
11. Statement was missing
12. The final analysis of the efficacy and 
safety data collected up to Week 4 will be 
performed once all entered patients have 
completed the first 4 weeks of study 
(through Visit 12); at that time-point, a 
preliminary database lock will be done
13. The definition of FAS was specified for 
clarification
14. A few inconsistencies and typing errors 
were corrected
15. Text about removal of patients has been 
rephrased to avoid misunderstanding
16. Investigator was excluded because 
moved to another site


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08910926
2.0
clinical-trial-protocol-version-2
Multi-centre, open-label, single arm, phase I study to investigate safety, tolerability,
pharmacokinetics, pharmacogenomics and efficacy of a single intravenous dose of BI
655130 in patients with active generalized pustular psoriasis
Approval-Team Member Medicine
09 Nov 2016 17:26 CET
Author-Trial Clinical Monitor
09 Nov 2016 17:49 CET
Approval-Therapeutic Area 
09 Nov 2016 18:58 CET
Author-Trial Statistician
10 Nov 2016 15:35 CET
Verification-Paper Signature
Completion
10 Nov 2016 17:23 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08910926
2.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
C13709701-02
BI Trial No.:
1368.11
Title:
Multi-centre, open-label, single arm, phase I study to investigate 
safety, tolerability, pharmacokinetics, pharmacogenomics and 
efficacy of a single intravenous dose of BI 655130 in patients with 
active generalized pustular psoriasis
Final Protocol (including protocol revision 1 (c08910926-02))
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone:
Fax:
Phone: 
Fax: 
Date of statistical 
analysis plan:
06 NOV 2017 REVISED
Version:
Revised
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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....................11
5.
ENDPOINTS .......................................................................................................13
5.1
PRIMARY ENDPOINT .....................................................................................13
5.2
SECONDARY ENDPOINTS.............................................................................13
5.2.1
Key secondary endpoint .....................................................................................13
5.2.2
Secondary endpoints...........................................................................................13
5.2.2.1
Secondary efficacy endpoints ...............................................................................13
5.2.2.2
Secondary pharmacokinetic endpoints..................................................................13
..................................................................................13
...........................................13
...........................................14
...........................................14
...........................................15
...........................................15
...........................................16
...........................................16
...........................................16
...........................................16
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................18
6.1
TREATMENTS...................................................................................................18
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................19
6.3
PATIENT SETS ANALYZED...........................................................................25
.....................................................................................................28
6.5
POOLING OF CENTRES .................................................................................28
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................28
6.6.1
Withdrawals ........................................................................................................28
6.6.2
Efficacy data........................................................................................................29
6.6.3
Safety data ...........................................................................................................31
6.6.4
PK data.................................................................................................................31
6.6.8
Time since first diagnosis ...................................................................................32
6.6.9
Disease characteristics........................................................................................33
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................34
7.
PLANNED ANALYSIS......................................................................................37


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........38
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................38
7.3
TREATMENT COMPLIANCE........................................................................39
7.4
PRIMARY ENDPOINTS...................................................................................40
7.5
SECONDARY ENDPOINT ...............................................................................40
7.5.1
Key secondary endpoint .....................................................................................40
7.5.2
Secondary endpoints...........................................................................................40
7.5.2.1
Secondary efficacy endpoints ...............................................................................40
7.5.2.2
Secondary pharmacokinetic endpoints..................................................................41
..............................................................42
..............................................................42
..............................................................43
..............................................................43
..............................................................43
..............................................................44
..............................................................44
..............................................................44
..............................................................45
7.7
EXTENT OF EXPOSURE.................................................................................45
7.8
SAFETY ANALYSIS..........................................................................................46
7.8.1
Adverse events.....................................................................................................46
7.8.2
Laboratory data ..................................................................................................47
7.8.3
Vital signs.............................................................................................................48
7.8.4
ECG......................................................................................................................49
7.8.5
Injection site reactions........................................................................................49
8.
REFERENCES....................................................................................................50
...........................................51
...........................................51
...........................................51
...........................................51
...........................................53
...........................................53
...........................................53
...........................................53
...........................................54
...........................................54
...........................................54
...........................................55
10.
HISTORY TABLE..............................................................................................56


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for efficacy, biochemical and cellular 
biomarkers, AEs, laboratory tests and vital signs ............................................18
Table 6.2: 1
Important protocol violations...........................................................................20
Table 6.3: 1
Patient sets analyzed.........................................................................................27
...................................28
Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, biomarker, 
and RNA sequencing measurements to visits for statistical analysis...............35
Table 7.1: 1
Categories for summary of continuous variables.............................................38
Table 10: 1
History table .....................................................................................................56


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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 the upper limit of quantification
AP
Alkaline phosphatase
AST
Aspartate aminotransferase
ATC3
Anatomical-Therapeutic-Chemical classification level 3
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
BMS
Biomarker set
BSA
Body surface area
CARE
Clinical data analysis and reporting environment
CGI
Clinical Global Impression
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CRP
C-reactive protein
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
ES
Enrolled set


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Term
Definition / description
EudraCT
European union drug regulating authorities clinical trials
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full analysis set
gCV
Geometric coefficient of variation
gMean
Geometric mean
GPP
Generalized pustular psoriasis
 
 
 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IL
Interleukin
IPV
Important protocol violation
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analyzed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
NRI
No response imputation
OC
Observed cases
OC-IR
Observed cases including values after rescue medication
OR
Original results
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter set
PPS
Per protocol set


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Term
Definition / description
PSS
Psoriasis symptom scale
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
REP
Residual effect period
RNA
Ribonucleic acid
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SI
Système international d’unités
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range
VAS
Visual analogue scale


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the CTP and its amendments, 
and to include detailed procedures for executing the statistical analysis of the primary and 
secondary variables and other data.
This TSAP assumes familiarity with the revised CTP. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, and planning of sample size.
Study data will be stored in a trial database within the Oracle ClinicalTM 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). 
PK parameters will be calculated using WinNonlinTM software (professional Network version 
5.2, Pharsight Corporation, Mountain View, CA 94041-1530, USA).
R version 3.0.2 or later (12), Biconductor version 2.13 or later, and the limma-package 
version 3.18.13 or later will be used in the analyses of gene expression data. Genome version 
hg38/GRCh38 will be used in conjunction with Ensembl version 84 or later.
This TSAP fully specifies the planned analyses for the analysis of the 4-week data. It also 
specifies the planned analyses for the complete trial data through Week 20 as far as possible;
prior to the final DBL, updates will be required for the analyses of further endpoints related 
to biomarker and RNA sequencing data.
 
 
 
 
 
 
 
 
Final Analysis of the 4-week data
It is planned to keep sites open through at least the end of September 2017 in order to 
potentially achieve a total of 8 to 10 patients who are treated with BI 655130. Once a decision 


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has been made to stop further recruitment into the study then steps will be taken to prepare 
for the final analysis of the 4-week data.
The final analysis of the efficacy and safety data collected up to Week 4 will be performed 
once all entered patients have completed the first 4 weeks of study (i.e. through Visit 12); at 
that time point, a database lock will be done. The individual patient cut-off date for inclusion 
of data into the 4-week analysis will be the minimum of (actual cut-off date; date of dosing 
plus 38 days [representing the upper boundary of the time window for the Week 4 visit]); the 
actual cut-off date used for data cleaning purposes will be specified in the data cleaning plan 
for the 4-week analysis and will typically represent the date of attendance of the last patient 
to the Week 4 visit (i.e. date of performance of last Visit 12). Since the final analysis of the 
efficacy and safety data up to week 4 in this open-label trial will be complete, and because no 
further patient dosing visits are planned, the week 4 results may be made available and 
published to support enrolment into subsequent trials in this and potentially other indications 
of BI 655130. Analyses of the data described in the sections listed below will be performed at 
the time of database lock for the 4-week data:

Section 7 (Analyses of disposition, IPVs and analysis sets, up to Week 4)

Section 7.1 (Demographics and other baseline characteristics)

Section 7.2 (Historical medications, background medications, concomitant medication 
use, and medical/disease history)

Section 7.5.2.1 (Secondary efficacy endpoints up to Week 4, based on FAS and PPS)

Section 7.6.1 (Further efficacy endpoints up to Week 4, based on FAS)

Section 7.6.4 (Use of rescue medication up to Week 4, based on TS)

Section 7.7 (Extent of exposure)

Section 7.8.1 (Adverse events up to Week 4)

Section 7.8.2 (Laboratory data up to Week 4)

Section 7.8.3 (Vital signs including body temperature up to Week 4)

Section 7.8.5 (Injection site reactions)
Other selected data that will be displayed at time of the 4-week database lock includes:

Plasma concentrations data
 
 
 
Some of the analyses performed at the time of the 4-week database lock may also be repeated 
following database lock for the entire trial (once all patients have completed the trial). The 
results for such endpoints obtained following the 4-week database lock should be considered 
the main source for interpretation on treatment effects over the first 4 weeks of study for the 
CTR; any differences in the outcomes obtained following the final database lock, if 
applicable, should be described.


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Analysis of the complete trial data through Week 20
The analysis of the entire efficacy and safety, as well as biomarker, data including those data 
collected through the full 20 weeks of follow-up will be performed once all entered patients 
have completed the trial (up to Visit 14); at that time point, a final database lock will be done
and all trial data will be reported.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The following analyses described in this TSAP are new/adapted analyses from those 
specified in the revised CTP.

For secondary efficacy endpoints of a continuous nature, it was specified in the CTP that 
exact 95% confidence intervals around the mean will be produced. Per specification in 
Section 7.5.2.1, the 95% confidence intervals for continuous data will be based on the t-
distribution.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In the CTP it is stated that analyses of immunohistochemistry and flow cytometry will be 
conducted. These analyses will not be carried out for the CTR, but may be done at a later 
time point (depending on the obtained results). In case they are performed at a later time 
point, the analysis details will be described in a separate document.
 
 
 
In the CTP, it was noted that a logistics plan will be developed to protect the integrity of the 
trial data once the week 4 analyses has been performed. However, since at this time the final 
analysis of the efficacy and safety data up to week 4 will be complete, and because no further 
patient dosing visits are planned, the week 4 results may be made available and published to 
support enrolment into subsequent trials in this and potentially other indications of BI 
655130.
The following analyses described in this TSAP are new/adapted analyses from those 
specified in the signed version of the TSAP, dated 4 OCT 2017:

Section 6.2
Definition of IPV: exclusion criteria 8 (i.e. use of restricted medication prior to the 
study) was modified from a programmatic to a manual assessment. This was done in 
order to ensure that medical decision could be made on whether such occurrence of an 
IPV would or would not affect the assessment on efficacy.
Same consideration was also applied to IPV D2.01 (and D2.02) representing 
prohibited medication use during the study.

Section 6.6.2 
LOCF imputation was clarified to confirm that the baseline value would be carried 
forward in the event of no available post-baseline data (and not just in the case when 
missing post-baseline data was driven by rescue medication taken immediately after 
the first dose).

Section 6.6.9
Additional imputation strategies, for summary reporting only, are presented for the 
handling of cases where incomplete data are reported for previous GPP flare 
occurrences.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
CTP: Primary endpoint to assess safety and tolerability of BI 655130 is the number [N (%)] 
of patients with adverse reactions, defined as drug-related AEs.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
5.2.2.1
Secondary efficacy endpoints
CTP: Secondary efficacy endpoints will be:

Percent change [calculated as "reduction"] from baseline in GPPASI total score at Week 
2

Proportion of patients with GPPGA total score of 0 (clear) or 1 (almost clear) at Week 2

Change from baseline in FACIT-Fatigue scale score at Week 2

Change from baseline in Pain VAS score at Week 2
For details on calculating these scores at each visit, cf. Section 9.1.
5.2.2.2
Secondary pharmacokinetic endpoints 
Secondary PK endpoints are AUC0-∞and Cmax of BI 655130 in plasma, as defined in 
Section 5.5.1.1 of the CTP.


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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 one intravenous dose of 10 mg/kg of BI 655130 solution for 
infusion.
The following separate study phases are defined for analyses of efficacy, biochemical and 
cellular biomarkers, AEs, laboratory tests and vital signs:
Table 6.1: 1
Flow chart of analysis phases for efficacy, biochemical and cellular 
biomarkers, AEs, laboratory tests and vital signs
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 study drug minus 1 minute
Treatment 
phase1
On-treatment 
period
Date/time of start of infusion of 
study drug (Day 1)
Date of end of infusion of 
study drug + 28 days at 11:59 
p.m.
REP
On-treatment 
period
Date of end of infusion of study 
drug + 29 days at 12:00 a.m.
Date of end of infusion of 
study drug +140 days at 11:59 
p.m.
Follow-up2
phase
Off-treatment 
period
Date of end of infusion of study 
drug + 141 days at 12:00 a.m.
Latest of: i) Date of End-of-
Trial visit (Week 20); 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 subsequent phase.
1 For the analysis of AEs, any AE occurrence on the same day as start of infusion of study drug will be assigned to the 
treatment phase.
2 The follow-up phase only exists if the trial completion date is after the date of end of infusion + 140 days.
For the final analysis to be performed once all patients have completed through the planned 
first 4 weeks of trial, results will be summarized for the on-treatment period, unless otherwise 
specified. The selection of data for presentation in this analysis is described in Table 6.7: 1.
For the entire analysis of the trial to be performed once all patients have completed through 
the planned 20 weeks of trial, results will be summarized for the on-treatment period, as well 
as for the off-treatment period, if applicable.


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Analysis phases will be labelled as follows in statistical analyses:

Screening phase: Screening

On-treatment period: BI 655130

Follow-up: Follow-up

Total over the screening, on-treatment and follow-up periods: Total
CTR Section 15, Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 AE displays will present 
results for the on-treatment period. Screening and follow-up phases will not be included in 
this analysis.
CTR Appendix 16.1.9.2.8.1 displays will present results for the screening phase, on-treatment 
period, follow-up period, and total.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
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 
RPM/DBLM. At this meeting, it will be decided whether a discrepant data value can be used 
in analyses or whether it must be queried in the clinical database. Each protocol deviation 
must be assessed to determine whether it is an 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 summarized into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet (3). The following table 
contains the categories which are considered to be IPVs in this trial. If the data show other 
IPVs, this table will be supplemented accordingly by the time of the RPM/DBLM. 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 summarized and listed.


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Table 6.2: 1
Important protocol violations
Category / 
Code
Description
Comments
Excluded from
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
Age out of range
Inclusion criterion 1, also 
check versus derived age
None
A1.02
"A known and documented history of 
GPP" not confirmed
Inclusion criterion 2
PPS, PKS, 
BMS, DSS, 
RSS
A1.03
"Presenting with a flare of GPP with at 
least 10% of BSA with erythema and 
pustules" not confirmed 
Inclusion criterion 3
PPS
A1.04
GPPGA score showing a severity less 
than moderate
Inclusion criterion 4, also 
check calculated GPPGA at 
Visit 3
PPS
A1.05
For GPP patients receiving maintenance 
treatment with retinoids and/or 
methotrexate: maintenance treatment 
was received for less than 4 weeks prior 
to Visit 2.
For other GPP patients: patient received 
any maintenance therapy other than 
retinoids and methotrexate at Visit 2.
Inclusion criterion 5
PPS
A1.07
Women of childbearing potential did not 
agree to use effective method of birth 
control; male patients did not agree to 
use condoms 
Inclusion criterion 7
None
A2
Exclusion criteria violated
A2.01
Pregnancy 
Exclusion criterion 1
None
A2.02
Immediate, life-threatening flare of GPP
Exclusion criterion 2
None
A2.03
Identified, ongoing serious/severe 
infection
Exclusion criterion 3
PPS
A2.04
Acute generalized exanthematous 
pustulosis (AGEP)
Exclusion criterion 4
PPS, PKS, 
BMS, DSS, 
RSS
A2.05
Differential diagnosis of toxic
epidermal necrosis or Stevens-Johnson 
syndrome
Exclusion criterion 5
PPS, PKS, 
BMS, DSS, 
RSS
A2.06
Involved in or intending to participate in 
another investigational study during the 
course of this trial
Exclusion criterion 6
PPS, PKS, 
BMS, DSS, 
RSS
# PV will be detected manually.
Source: BI reference document 'Protocol Violation Handling Definitions' [001-MCS-50-413_RD-01] (2).


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Comments
Excluded from
A2.07
Previous enrolment in this trial
Exclusion criterion 7
FAS1, PPS1, 
PKS, BMS1, 
DSS1, RSS1
A2.08a
Use of restricted medication with 
potential influence on efficacy data
Exclusion criterion 8, 
manual assessment of 
potential influence at 
RPM/DBLM
PPS, PKS, 
BMS, DSS, 
RSS
#
A2.08b
Use of restricted medication without 
potential influence on efficacy data
Exclusion criterion 8, 
manual assessment of 
potential influence at 
RPM/DBLM
None
#
A2.09
Patients with dose escalation of their 
maintenance therapy with methotrexate 
and/or retinoids within the 4 weeks 
preceding Visit 2
Exclusion criterion 9
PPS
A2.10
Background therapy with ciclosporin 
within the last 30 days preceding Visit 2 
Exclusion criterion 10
PPS
A2.11
Previous exposure to an IL36R inhibitor
Exclusion criterion 11
PPS, PKS, 
BMS, DSS, 
RSS
A2.12
Severe, progressive or uncontrolled 
disease 
Exclusion criterion 12
PPS
A2.13
Chronic or relevant acute infections
Exclusion criterion 13
PPS
A2.14
Patients with transplanted organ or who 
have ever received stem cell therapy
Exclusion criterion 14
PPS
A2.15
History of lymphoproliferative disease
Exclusion criterion 15
PPS
A2.16
Active or suspected malignancy or 
history of malignancy within 5 years 
prior to Visit 2
Exclusion criterion 16
PPS
A2.17
Evidence of a current or previous disease 
or medical condition other than GPP
Exclusion criterion 17
PPS
A2.18
History of allergy/hypersensitivity to a 
systemically administered biologic agent 
Exclusion criterion 18
PPS
A2.19
Refusal to be hospitalized for 4 days 
following the infusion
Exclusion criterion 19
None
1 The data reported during the second enrolment of the patient in the trial will be excluded.
# PV will be detected manually.
Source: BI reference document 'Protocol Violation Handling Definitions' [001-MCS-50-413_RD-01] (2).


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Comments
Excluded from
B
Informed consent
B1
Informed consent not available
Date of informed consent 
missing or no signature on 
patient’s “Declaration of 
Informed Consent”
In this case: Patient’s data 
will not be used at all.
All
B2
Informed consent too late
Informed consent date was 
after Visit 1
None
C
Trial medication
C1
Incorrect trial medication
C1.01
Study drug medication not taken 
Patient entered but no study 
drug taken
TS, FAS, PPS, 
PKS, BMS, 
DSS, RSS
C2
Non-compliance
C2.01
Non-compliance with study drug intake-
- administered dose too high
Study medication dose is 
greater than 120% of the 
planned dose
PPS
C2.02
Non-compliance with study drug intake-
- administered dose too low
Study medication dose is 
less than 70% of the planned 
dose
PPS, BMS, 
DSS, RSS
D
Concomitant medication
D1
Previous medication
D1.01
Washout of previous medication too 
short
Washout period too short -
See Table 4.2.2.1: 1 in CTP
PPS, PKS
#
D1.02
Rescue use on or after Visit 2 but prior 
to administration of study drug
Rescue medication taken on 
the day of Visit 2 or on the 
day of Visit 3 (clock time 
will not be reported)
FAS, PPS
D2
Prohibited medication use
D2.01a
Use of prohibited med. on or after V2 or 
during the on-trt. period, unless rescue 
trt. to stabilize a worsening disease cond.
– prior to or on D14, with potential 
influence on eff. data
See the list of restricted 
medication in CTP, Table 
4.2.2.1: 1, manual 
assessment of potential 
influence at RPM/DBLM
PPS, 
PKS, BMS, 
DSS, RSS
#
# PV will be detected manually.
Source: BI reference document 'Protocol Violation Handling Definitions' [001-MCS-50-413_RD-01] (2).


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Comments
Excluded from
D2.01b
Use of prohibited med. on or after V2 or 
during the on-trt period, unless rescue 
trt. to stabilize a worsening disease cond. 
- prior to or on D14, without potential 
infl. on eff. data
See the list of restricted 
medication in CTP, Table 
4.2.2.1: 1, manual 
assessment of potential 
influence at RPM/DBLM
None
#
D2.02
Use of prohibited medication during 
treatment period when not provided as a 
rescue treatment to stabilize a worsening 
disease condition – after Day 14
See the list of restricted 
medication in CTP, Table 
4.2.2.1: 1 
None
#
D3
Mandatory medication not taken
D3.01
Any dose change in background 
medication on or after Visit 2 – prior to 
or on Day 14
Dose escalation of 
background therapy 
(methotrexate or retinoids) 
is not allowed within 4 
weeks before Visit 2 (dose 
decrease is permitted). From 
Visit 2 to Visit 14 no change 
in dose of retinoids or 
methotrexate is allowed. 
PPS, PKS, 
BMS, DSS, 
RSS
D3.02
Any dose change in background 
medication – after Day 14
Dose escalation of 
background therapy 
(methotrexate or retinoids) 
is not allowed within 4 
weeks before Visit 2 (dose 
decrease is permitted). From 
Visit 2 to Visit 14 no change 
in dose of retinoids or 
methotrexate is allowed. 
None
E
Missing data
None
Missing visits, evaluations, 
and tests will be considered 
missing data, not protocol 
violations
F
Study specific analysis
F1
Other trial specific violation
F1.01
Study drug intake outside time window 
Infusion period takes longer 
than 240 minutes.
None
# PV will be detected manually.
Violations F2.01 and F2.02 can only be detected at the trial site.
Source: BI reference document 'Protocol Violation Handling Definitions' [001-MCS-50-413_RD-01] (2).


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Table 6.2: 1
Important protocol violations (continued)
Category / 
Code
Description
Comments
Excluded from
F2
Certain violations of procedures used 
to measure secondary efficacy data
F2.01
Evaluation of GPPASI or GPPGA for a 
given patient not performed by the same 
physician up to Week 2
GPPASI, GPPGA 
assessments up to Week 2 
for a given patient are not 
performed by the same 
physician.
PPS
#
F2.02
Evaluation of GPPASI or GPPGA for a 
given patient not performed by the same 
physician throughout the study
GPPASI, GPPGA for a 
given patient is not 
performed by the same 
physician throughout the 
study.
None
#
F2.03
Temperature recordings for a given 
patient not made at the same area
throughout the study
Not all recordings for a 
given patient made in ear or 
oral cavity, respectively.
None
G
Other safety related violations
G1
Pregnancy test not done for woman of 
child bearing potential at Visit 12, 12pc, 
13, 13pc, or 14 
None
#
# PV will be detected manually.
Violations F2.01 and F2.02 can only be detected at the trial site.
Source: BI reference document 'Protocol Violation Handling Definitions' [001-MCS-50-413_RD-01] (2).


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6.3
PATIENT SETS ANALYZED
The following analysis sets will be defined for this trial:

Enrolled set (ES)
This patient set includes all patients who signed informed consent. 
It will be used for analyses of patient disposition.

Entered set (ENT-S):
This patient set includes all entered patients (as identified by the investigator in the 
eCRF), whether treated or not.
It will also be used for analyses of patient disposition.

Treated set (TS):
This patient set includes all patients in the ENT-S who received study drug at Visit 3. 
It will be used for analysis of safety data.

Full analysis set (FAS):
This patient set includes all patients in the TS who had a baseline and at least one 
post-baseline measurement available for GPPASI or GPPGA without any IPV flagged 
for exclusion from the FAS in the table above.
This is the main analysis set for presentation of efficacy.

Per protocol set (PPS):
This patient set includes all patients in the FAS who adhered to the CTP without any 
IPVs which are flagged for exclusion from the PPS in the table above.
The PPS will be used for sensitivity analysis of secondary efficacy endpoints.

Pharmacokinetic parameter set (PKS): 
This patient set includes all patients in the TS who provide at least one observation for 
at least one secondary PK endpoint, which was not flagged for exclusion. PK 
parameters (and blood and plasma concentrations) can be flagged for exclusion due to 
a protocol violation relevant to the evaluation of PK (to be decided no later than in the 
RPM) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a patient’s data will be documented in the 
CTR.
Relevant IPVs are documented in Table 6.2: 1 above.
Plasma and blood concentrations and/or parameters will be considered as non-
evaluable, if e.g. a pre-dose concentration is >5% of the Cmax value of that patient, or 
if relevant time deviations occurred (as identified no later than in the RPM), or due to 
use of restricted medications (as identified no later than in the RPM).
CTP: It will be decided in the Report Planning Meeting which patients are to be 
included in the PKS.
This patient set will be used for the descriptive analysis of concentrations and PK 
parameters.


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The discussion of all exceptional cases and problems and the decisions on the allocation of 
patients to populations will be made at latest at the RPM/DBLM.
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 analyzed
Patient set
Class of 
endpoint
ES
ENT-S
TS
FAS
PPS
PKS
Disposition
OR
OR
OR
Compliance 
and exposure
OR
OR
IPVs
OR
Demographic/
baseline 
characteristics
OR
Primary 
endpoint
OR
Secondary 
efficacy 
endpoints
LOCF1,
NRI1,
OC-IR2, 
OC2
LOCF2, 
NRI2,OC2
Secondary PK 
endpoints
OR
 
 
 
 
1 secondary analysis
2 sensitivity analysis
3 only for percent reduction from baseline in GPPASI total score, change from baseline in FACIT-Fatigue scale score and 
change from baseline in Pain VAS
4 only for proportion of patients with GPPGA total score of 0 or 1
For explanation of the different approaches with regard to missing data see Section 6.6.
"LOCF" and "NRI" means analyses involving imputed data, cf. Section 6.6.2.
OC = observed cases, OC-IR = observed cases including also values after rescue medication, OR = original results.


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6.5
POOLING OF CENTRES
It is planned that up to 10 patients in approx. 7 centres in 7 countries will be entered in this 
trial, i.e., it can be expected that 1 or 2 patients only will be entered per centre. All endpoints 
will be evaluated by descriptive statistical methods, unless otherwise specified. 
Given the low number of patients per centre and the primarily descriptive nature of statistical 
analysis, separate analyses by centre are not meaningful and not desirable. All patients from 
all centres will be pooled for statistical analysis.
Listings, sorted by centre, will however be displayed.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Withdrawals
CTP: If a patient is removed from or withdraws from the trial prior to the administration of 
trial medication, the reason for withdrawal will be entered in the case report form (CRF) and 
trial database and will be reported in the clinical trial report (CTR). If a patient is removed 
from or withdraws from the trial after the administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. The data will 
be included in the CRF/trial database and will be reported in the CTR.


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6.6.2
Efficacy data
Handling of missing item scores for the FACIT will be based on FACIT Administration and 
Scoring Guidelines (Version 4): If there are missing items in the FACIT-Fatigue, the FACIT-
Fatigue scale score can be prorated. This is done by multiplying the sum of the FACIT-
Fatigue scores by 13 (i.e. the number of items in the FACIT-Fatigue scale), then dividing by 
the number of items actually answered. When there are missing data, prorating in this way is 
acceptable as long as more than 50% of the items were answered, i.e., if the number of 
answered questions is 7 or higher. Cf. Section 9.1 for details regarding the derivation of the 
FACIT-Fatigue scale score.
For the GPPASI, GPPGA and PSS total scores, a missing item or component score will lead 
to a missing total score. However, individual items and subscores may be presented as 
applicable. Cf. Section 9.1 for further details regarding the derivation of efficacy endpoints.
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.
Note that Visit 14 (i.e. the Week 20 (follow-up)) is intended to report follow-up data, i.e., 
data collected after the end of the on-treatment period (as defined in Table 6.1: 1). Therefore, 
no imputation based on data from the on-treatment period will be used to impute missing data 
at Visit 14 in order to avoid the mixing of on- with off-treatment data.
For the final analysis on the 4-week data, missing data imputations will be performed using 
only the data cleaned and planned to be reported at this time (Table 6.7: 1); data from later 
time-points will be excluded.
Binary efficacy endpoints
Some efficacy endpoints are defined in terms of the proportion of patients with a particular 
binary outcome, i.e. achievement of a GPPGA total score of 0 or 1. For those binary 
outcomes, the different methods for handling of missing data, presented below, will be 
performed as presented in Table 6.3: 1. Please note that some of these binary outcomes are 
derived from other parameters, but imputation is planned to take place only at the binary 
level, i.e., the GPPGA total score itself will not be imputed, but the binary endpoints derived 
based on these scores will be imputed.


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The following primary imputation strategy ("NRI") will be performed:
o If there are data at the visits both immediately before and immediately after the visit 
with a missing outcome, then impute as success only if both the preceding and the 
following observations 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);
o Otherwise, impute as a failure to achieve a response (i.e. no response imputation 
[NRI]).
For patients who take a rescue medication (as defined in Section 5.3.4) during the 
course of the study, all efficacy outcomes measured after the day of first use of rescue 
medication will be set to missing and, during the on-treatment period, will be imputed 
using the steps described above.
Observed cases (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 (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.
Continuous efficacy endpoints
For continuous efficacy endpoints, such as the pain VAS, FACIT-Fatigue scale score, and 
GPPASI total score, the different methods for handling of missing data, presented below, will 
be performed as presented in Table 6.3: 1:
Imputation technique ("LOCF"): Under the assumption that the disease is self-limiting 
and will gradually improve over time, the LOCF approach will be used as the primary 
imputation strategy to replace missing values either at intermediate visits or due to early 
withdrawal from the trial. The last available value, including baseline, will be carried 
forward to all subsequent visits within the on-treatment period at which a measurement 
is missing. Values measured after the day of first rescue medication intake (as defined 
in Section 5.3.4) will be set to missing and the missing values within the on-treatment 
period will be imputed by LOCF.
In addition, as sensitivity approaches, the OC and OC-IR will also be performed.
Rescue medication use
The original results (OR) approach implies the presentation of data exactly as observed (not 
using time windows as described in Section 6.7 and not setting values to missing). 
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 


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medication use itself), or, if it is not meaningful to apply any imputation rule for the 
replacement of missing values.
6.6.3
Safety data
CTP: With respect to safety evaluations, it is not planned to impute missing values.
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 and historical medication for GPP
will be imputed to enable subsequent calculation (but not for display) by the following "worst 
case" approach:

If the day of the end date is missing, then the end date is set to last day of the month (or to 
the patient's trial completion date, if it is earlier than the last day of the month).

If the day and month of the end date are missing then the end date is set to 31st of 
December of the year (or to the patient's trial completion date, if it is earlier than the 
31st of December of the year).

If the day of the start date is missing 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 will be used if 
first dosing happened in the same year).

All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance.
If a concomitant medication or historical medication was ticked to be ongoing, it is expected 
that the end date is missing and will not be imputed for display purposes.
For safety data that are displayed by time point (or visit) of measurement, the OC-IR 
approach will be used.
6.6.4
PK data
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5). CTP: Drug concentration data identified with NOS (no sample 
available), NOR (no valid result), NOA (not analyzed), BLQ (below the lower limit of 
quantification), or NOP (no peak detectable) will be displayed as such and not replaced by 
zero at any time point (this rule also applies […] to the lag phase, including the predose 
values).
CTP: For the non-compartmental analysis, concentration data identified with NOS, NOR or 
NOA will generally not be considered. Concentration values in the lag phase identified as 
BLQ or NOP will be set to zero. All other BLQ/NOP values of the profile will be set to 


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missing. The lag phase is defined as the period between time zero and the first time point with 
a concentration above the quantification limit.
PK data will be presented using the OR approach described in Section 6.6.2.
 
 
 
 
 
6.6.8
Time since first diagnosis
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows:

If the year of first diagnosis is unknown, time since first diagnosis will be set to missing.

If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th June of that year.

If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month.


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6.6.9
Disease characteristics
Incomplete information regarding disease characteristics will be imputed as follows:

If the "number of flares of GPP that resolved spontaneously without treatment" is >0 and 
equal the "number of resolved flares of GPP (total)" in previous 12 months, and 
information is missing whether the shortest flare resolved spontaneously without 
treatment, this information will be imputed with "Yes". This will be analogously done for 
the longest flare, but only if "number of resolved flares of GPP (total)" in previous 12 
months is reported to be > 1.

For calculation of "time since start of last flare of GPP before the trial to Visit 2", partial 
dates for "start date of symptoms of last flare" will be replaced with the first day of the 
month (if month and year are available). Otherwise, the dates will not be replaced. 
Replacement will only be done for calculation; the "start date of symptoms of last flare" 
will not be imputed.

If the actual "start date of symptoms of last flare" is unknown but "before the 12 months 
that precede the trial", then the "time since start of last flare of GPP before the trial to 
Visit 2" will be set to "> 1 year" for the statistical summary of disease characteristics.

If the actual "start date of symptoms of last flare" is unknown but "during the 12 months 
that precede the trial", then the "time since start of last flare of GPP before the trial to 
Visit 2" will be set to "<= 1 year" for the statistical summary of disease characteristics. If 
additionally no information was provided regarding the date of resolution of last flare of 
GPP before the trial (i.e. no date and no time interval relative to start of trial), this will be 
imputed with the information that the flare stopped "during the 12 months that precede 
the trial".


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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 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 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 values 
of the on-treatment period or follow-up values, based on the definition in Section 6.1, and 
will be assigned to visits for statistical analysis, if applicable, as defined below.
The assessment of injection site reactions (scheduled for Visit 3 and Visit 4) will be handled 
differently to other by-visit endpoints, because the Visit 3 assessment is not a pre-treatment 
assessment, but is planned after injection of trial treatment, therefore representing an on-
treatment measurement (i.e., both assessments are on-treatment assessments). Assessments at 
or after start of administration of trial treatment will be assigned to the nominal visit number 
as recorded on the eCRF, i.e. no time windows will be applied for analysis of this data.
Analysis of AE data and of rescue use will not be based on visits, therefore, no assignment to 
time windows will be necessary.
All other safety, efficacy and biomarker measurements will be assigned to visits based on 
time windows around the planned visit dates, defined relative to the day of trial treatment
(which is scheduled for Visit 3). These time windows are defined in Table 6.7: 1.


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Table 6.7: 1
Time windows for assignment of efficacy, safety lab, vital signs, biomarker, 
and RNA sequencing measurements to visits for statistical analysis
Visit 
number
Planned 
day
Time window
Visit label
Window
Start (inclusive)
End (inclusive)
4
Week 1, Day 2
Day 2
exact day
Day 2A
Day 2
5
Week 1, Day 3
Day 3
exact day
Day 3
Day 3
6
Week 1, Day 4
Day 4
exact day
Day 4
Day 4
7
Week 1, Day 5
Day 5
exact day
Day 5
Day 5
8
Week 1, Day 6
Day 6
exact day
Day 6
Day 6
9
Week 1, Day 7
Day 7
+ 3 days
Day 7
Day 10
10
Week 2
Day 14
+/- 3 days
Day 11
Day 17
11
Week 3
Day 21
+/- 3 days
Day 18
Day 24
For final Week 4 analysis
12
Week 4
Day 28
- 3 days/+ 10 days
Day 25
Minimum of (cut-
offB; Day 38)
For final analysis of entire trial
12
Week 4
Day 28
- 3 days/+ 10 days
Day 25
Day 38
13
Week 12
Day 84
+/- 14 days
Day 70
Day 98
14
Week 20
(follow-up)
Day 
142D
exact day to last value
Day 142
Day of last valueC
All days are counted relative to the day of 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, GPPASI, 
GPPGA) will not be assigned to Visit 4. Such data will be listed only.
B The cut-off date will be specified in the data cleaning plan for the 4-week analysis.
C Note that measurements assigned to the Week 20 (follow-up) visit are intended to represent follow-up 
measurements, i.e., made after the end of the on-treatment period (as defined in Table 6.1: 1).
D Planned day per CTP is Day 140, which would still be during the on-treatment period, as REP is defined to be 
140 days.
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, but which are 
not measured on the same day, the later value will be selected. If there are two observations 
on the same day, the worst value will be selected.
Assignment of 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 "LOCF" and "NRI" approaches and the "OC" approach defined in 
Section 6.6.2). Visits which were not assigned a value based on time windows will thereafter 
be imputed for the NRI and LOCF approaches defined in Section 6.6.2. Imputation of 
efficacy endpoints (binary as well as continuous) will be performed based on all available 
observations, irrespective of whether the observation was selected in any time window. For 
example, for LOCF imputation, the last observed value during the on-treatment period will be 
carried forward, whether or not it was the selected value in a time window. For more details 
on LOCF refer to Section 6.6.2.


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For derivation of the last value during the on–treatment period, the minimum value during the 
on–treatment period, and the maximum value during the on–treatment period, all values 
during the on-treatment period (whether or not selected in any time window) 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) will be considered.
Tables and figures with results of the statistical analysis will only display visits at which the 
respective parameter was planned to be collected according to the CTP.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (001-MCG-159) (10).
The individual values of all patients will be listed. Listings will generally be sorted by 
country, centre number, patient number and visit (if visit is applicable in the respective 
listing). AE listings will be sorted by assigned treatment (see Section 7.8.1 below for details).
The listings will be contained in Appendix 16.2 (SDL) of the CTR.
Analyses of secondary and further PK endpoints will be performed by BI and presented in 
Section 15.6 of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Q1
lower quartile
Median 
median
Q3
upper quartile
Max 
maximum
For plasma concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
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.
Disposition of the patient population participating in the trial will be summarized by 
presentation of the frequency of patients screened, entered, screened but not entered, treated, 
entered but not treated, who completed the trial through planned visit at Week 4, who 
completed planned observation time, who completed trial medication, and who were 
prematurely discontinued, by reason. A patient is defined to have completed the trial through 
the planned visit at Week 4 if the patient did not discontinue the trial at any time prior to the 
lower bound of the week 4 time window (cf. Table 6.7: 1). The vital status of prematurely 


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discontinued patients at Week 20 will also be summarized. Disposition will be listed by 
country.
The frequency of patients with IPVs, also summarized by whether or not the IPV led to 
exclusion from the FAS, PPS, PKS, BMS, DSS or RSS, will be presented for the ENT-S. The 
frequency of patients in each of the different analysis sets will also be presented.
Baseline, for applicable analyses, refers to the last measurement collected prior to the start of 
administration of the trial treatment.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
Descriptive statistics will be presented for demographic parameters and baseline 
characteristics, based on the FAS. The presence of IL36RN mutation, as recorded in the 
eCRF at Visit 1 based on historical data, will only be listed.
For the continuous variables described below, the following categories will be defined and 
presented according to the number and percentage of patients in each category:
Table 7.1: 1
Categories for summary of continuous variables
Variable
Categories
Age
< 50 years
50 to < 65 years
≥ 65 years
Weight
≤70 kg
>70 to ≤80 kg
>80 to ≤ 90 kg
>90 kg
BMI
< 25 kg/m2
25 to < 35 kg/m2
≥ 35 kg/m2
Time since first diagnosis
≤ 1 year
> 1 to ≤ 5 years
> 5 to ≤ 10 years
> 10 years
7.2
CONCOMITANT DISEASES AND MEDICATION
Analyses of concomitant diseases and medication will be based on the FAS.
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.


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Signs/symptoms of the trial disease (as identified on the eCRF) will be summarized 
separately from other concomitant diseases, by system organ class and preferred term.
Other characteristics of the trial disease, such as the frequency and percentage of resolved 
flares within the last 12 months, as well as details on the shortest, longest, and last GPP flare 
which occurred prior to admission into this trial, will be displayed. The duration (up to start 
of treatment) and likely cause of the current flare of GPP will also be presented. The "number 
of flares of GPP that resolved with treatment" will be calculated as the number of resolved 
flares of GPP in previous 12 months minus the number which resolved spontaneously 
without treatment.
A medication will be considered concomitant to treatment, if it

is ongoing at the start of trial treatment or

starts within the analysis phase of the trial treatment (see Section 6.1 for a definition of 
treatments and analysis phases).
Concomitant medication use (excluding rescue medication on or after Visit 2 and before end 
of the on-treatment period, historical medication for GPP and background medication) will be 
summarized with frequency and percentage of patients by ATC3 class and preferred name. 
Summaries will be presented for 

concomitant therapies taken any time prior to Day 1 (the day of start of trial treatment),

concomitant therapies initiated on Day 1, and

concomitant therapies taken any time during the on-treatment period (cf. Section 6.1).
The frequency and percentage of patients with previous treatment on methotrexate, retinoids, 
ciclosporin, and other historical medication for GPP will be displayed, and will include an 
assessment of those patients who continue to take methotrexate or retinoids as background 
medication in this trial. Here, background medication is defined as any administration of 
methotrexate or retinoids which is ongoing on the day of administration of BI 655130. In 
addition, the time since last dose relative to Visit 2 for patients who have discontinued prior 
methotrexate or retinoid use will be listed.
Rescue medication use on or after Visit 2 and before end of the on-treatment period will be 
summarized separately, as described in Section 7.6.4.
7.3
TREATMENT COMPLIANCE
Treatment compliance will be summarized for the FAS by descriptive statistics (N, mean, 
SD, minimum, median, maximum) for the amount of medication taken [% of planned], and 
by the number and percentage of patients with 

"< 70% of planned", 

"70 to 120% of planned" and 

"> 120% of planned".


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7.4
PRIMARY ENDPOINTS
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis 
of the number [N (%)] of patients with adverse reactions, defined as drug-related AEs, which 
is the primary endpoint of this trial.
7.5
SECONDARY ENDPOINT
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
7.5.2.1
Secondary efficacy endpoints
Analysis of secondary efficacy endpoints will be based on the FAS; an analysis based on the 
PPS will be performed as a sensitivity analysis. The analysis of imputed values (cf. 
Section 6.6.2) will be considered the main approach for secondary efficacy analyses of this 
trial. Other analysis approaches based on the FAS (and on the PPS) will be considered 
sensitivity analyses to assess the impact of missing data, intake of rescue medication, and 
IPVs on the efficacy outcomes.
The GPPASI total score and the percent reduction from baseline in GPPASI total score will 
be summarized descriptively by visit as will the FACIT-Fatigue scale total score and pain 
VAS score; the changes from baseline at each post-baseline visit will also be displayed. For 
the percent reduction from baseline in GPPASI total score as well as the change from 
baseline in FACIT-Fatigue scale total score and pain VAS at each visit, 95% confidence 
intervals around the mean will be presented and are calculated as follows:
 −
; .

√ ;  + 
; .

√,
where "mean" denotes the sample mean, "SD" denotes the sample standard deviation, "n" 
denotes the number of non-missing values in the sample, and "tn-1: 0.975" denotes the 0.975 
quantile of the t-distribution with n-1 degrees of freedom.
Graphical presentations of the mean and 95% confidence interval by visit will be provided for 
percent reduction from baseline in GPPASI total score, change from baseline in FACIT-
Fatigue scale total score and change from baseline in pain VAS score. Additionally, for 
percent reduction from baseline in GPPASI total score, 95% confidence intervals for the 
median will be calculated based on the SAS procedure PROC UNIVARIATE with option 
CIPCTLDF, and graphical presentations of the median and 95% confidence interval by visit 
will be provided.
For the FACIT-Fatigue scale, frequencies of patients with each score for each of the 
individual questions will additionally be summarized by visit.


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The proportion of patients with a GPPGA total score of 0 (clear) or 1 (almost clear) will be 
summarized descriptively by visit, presenting patient frequencies and proportions together 
with exact 95% Wilson score confidence intervals. Additional displays of the patient 
frequencies and percentages for the individual GPPGA total scores (0, 1, 2, 3, 4), as well as 
for each subscore on the underlying characteristics (‘erythema’, ‘pustules’, and 
‘scaling/crusting’), will also be produced. Bar charts over time will be displayed.
The time of first achievement of a GPPGA total score of 0 (clear) or 1 (almost clear), relative 
to the day of start of infusion of trial treatment, will be summarized with patient frequencies 
and percentages for the following categories:

No response

Response on or after Visit 2 but prior to treatment start

Response from treatment start to Day 4 

Response from Day 5 to Day 7

Response from Day 8 to Day 14 (Week 2)

Response from Day 15 to Day 28 (Weeks 3 and 4).
7.5.2.2
Secondary pharmacokinetic endpoints
CTP: The secondary PK parameters (refer to [CTP] Section 5.5.1) will be calculated 
according to the BI Standard Operating Procedure (SOP) ‘Standards and processes for 
analyses performed within Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-
472 [(11)]). Analyses will be performed for parent drug.
Descriptive statistics will be presented for secondary PK endpoints, based on the PKS.
Exclusion of PK parameters
The ADS "ADPP" contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS will include parameters if they are not flagged for exclusion, 
i.e. APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS "ADPC" (PK concentrations per time point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the 
value will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE" the value will be excluded from half-life calculation only; the value is 
included for all other analyses.


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Excluded concentrations, and concentrations and parameters of excluded patients will be 
listed in the clinical trial report, associated with an appropriate flag.
Further details are given in 001-MCS-36-472_RD-01 "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies" (5) and 001-MCS-36-472_RD-03 
"Description of Analytical Transfer Files and PK/PD Data Files" (6).


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7.7
EXTENT OF EXPOSURE
Exposure [as amount administered in mg/kg as well as in mg] and duration of infusion [in 
minutes], for the TS, will be summarized by descriptive statistics (N, mean, SD, minimum, 
median, maximum) and by the number and percentage of patients classified according to the 
following categories:
Exposure [mg] categories

Exposure "< 500 mg" BI 655130,

Exposure "500 mg to < 700 mg" BI 655130,

Exposure ">= 700 mg" BI 655130,
Duration of infusion [min] categories

Duration "< 60 min",

Duration ">=60 min to < 120 min",

Duration ">=120 min to < 240 min",

Duration ">= 240 min".


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7.8
SAFETY ANALYSIS
All safety analyses will be performed based on the TS.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs. System organ classes (if 
applicable) will be sorted according to the standard sort order specified by the EMA, 
preferred terms (if applicable) will be sorted by total frequency (within system organ class).
For 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. This means that 
all AEs will be assigned to the screening phase, treatment phase or follow-up phase as 
defined in Section 6.1. Since only the start date of an AE is collected (without start time), any 
AE occurrence on the same day as BI 655130 administration will be assigned to the on-
treatment period.
An overall summary of AEs will be presented. This overall summary will include summary 
statistics for the class of other significant AEs according to ICH E3 and for the class of 
AESIs.
CTP: The following are defined as protocol-specified AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory parameters: 
--
an elevation of AST and/or ALT and/or AP ≥3-fold ULN plus 2 times the baseline,
combined with an elevation of total bilirubin ≥2-fold ULN plus 1.5 time the baseline, 
measured in the same blood sample.
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.


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According to ICH E3 (9), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked hematological or other lab abnormalities, or
(ii) which were reported with ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of patients with AEs will be summarized by treatment, primary system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 
will be summarized separately (primary endpoint of this trial). Separate tables will also be 
provided for patients with SAEs, patients with AEs leading to study drug discontinuation, 
patients with AESIs and patients with other significant AEs (according to ICH E3 (9)). 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 summarized 
by treatment, primary system organ class and preferred term. The frequency of patients with 
SAEs will also be summarized.
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 
summarized.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (8). For continuous safety laboratory parameters, normalized values will be 
derived. Normalization means transformation to a standard unit and to a standard reference 
range. The process of normalization, handling of repeat values at the same visit for by-visit 
displays, as well as standard analyses for safety laboratory data are described in the BI 
guidance for the Display and Analysis of Laboratory Data (8). All analyses considering 
multiple times of the ULN (as described below) will be based on standardized and not 
normalized values. For continuous safety laboratory parameters, differences to baseline (see 
Section 6.7) will be calculated.
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 provided by visit (including follow-up), including the last value on 
treatment, the minimum value on treatment, and maximum value on treatment. Since safety 
laboratory tests will be performed at the local laboratory of each site, this analysis will be 
based on normalized laboratory values only.
Laboratory values will be compared to their reference ranges; a shift table will be provided 
for the number of patients within and outside the reference range at baseline and at the last 


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measurement on treatment. This analysis will be based on standardized laboratory values and 
reference ranges as provided by the local laboratory of each site.
Values of categorical laboratory parameters will only be listed.
Potentially clinically significant abnormalities will be identified based on BI standard rules
which are based on normalized converted lab values, i.e. using SI units. These rules will be 
listed in the SDL appendix of the CTR. Frequency tables will summarize the number of 
patients with potentially clinically significant abnormalities. Patients having an abnormal lab 
value at baseline will be presented separately. A separate listing will present potentially 
clinically significant abnormal lab values; for each functional lab group all patients' lab 
values will be listed, if there exists at least one lab value with clinically significant 
abnormality within the group.
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥10xULN, and 
≥20xULN will be displayed based on standardized laboratory values.
To support analyses of liver related adverse drug effects, the frequency of patients with AST 
and/or ALT ≥3xULN plus 2 times the baseline with concomitant or subsequent total 
bilirubin ≥2xULN plus 1.5 times the baseline in a 30 day period after AST/ALT elevation 
will be displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a patient can 
potentially be in both alkaline phosphatase strata in case of multiple AST/ALT and bilirubin 
elevations). The start of the 30 day time span is triggered by each liver enzyme elevation 
above the defined thresholds. This analysis will be based on standardized laboratory values.
A graphical analysis of ALT and total bilirubin during the on-treatment period will 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 for total bilirubin and ALT may, or may 
not, occur on the same date. Two reference lines, 2xULN for total bilirubin and 3xULN for 
ALT, are drawn onto the graph in order to divide the plane into four quadrants. Normal cases 
are in the lower left quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law 
quadrant), while the lower right quadrant is known as the Temple’s corollary range (ALT ≥ 
3xULN and total bilirubin < 2xULN).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate), body temperature, and body weight 
will be descriptive in nature. Descriptive statistics of vital signs over time and for the 
difference from baseline (see Section 6.7) will be provided, including the last value on 
treatment, the minimum value on treatment, and the maximum value on treatment.
The number and percentage of patients with a body temperature of ≥37.5 degree C will be 
presented by means of shift tables for post-baseline visits vs. baseline.


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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 analyzed as such.
7.8.4
ECG
Abnormal findings in 12-lead ECG will be reported as baseline conditions (at screening) or as 
AEs (during the trial) if judged clinically relevant by the investigator, and will be analyzed as 
such. No separate listing or analysis of ECG data will be prepared.
7.8.5
Injection site reactions
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.
Frequency and percentage of patients will also be summarized, by visit, for the intensity of 
each injection site reaction (mild, moderate, severe), and for the maximum intensity across all 
types of reaction.
 
 


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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


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
04-OCT-2017
None
This is the final TSAP without any 
modification
Revised
06-NOV-2017
6.2
Split important protocol violation 
regarding "use of restricted medication"
(acc. to exclusion criterion 8) into such 
violations with and without potential 
influence on secondary efficacy data. 
Split important protocol violation 
regarding "use of prohibited medication
on or after Visit 2 or during the on-
treatment period when not provided as a 
rescue treatment to stabilize a 
worsening disease condition – prior to 
or on Day 14" into such violations with 
and without potential influence on
secondary efficacy data.
6.6.2
Clarified regarding LOCF approach that 
baseline value can be carried forward
into the on-treatment period in case of 
missing data, irrespective of whether the 
data is missing or was set to missing 
due to intake of rescue medication.
6.6.9 
(new)
Added imputation rules for disease 
characteristics data.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15503343
2.0
8-01-tsap-core
8-01-tsap-core
Approval-Project Statistician
06 Nov 2017 16:45 CET
Approval-Trial Clinical Monitor
06 Nov 2017 16:49 CET
Approval-Medical Writer
07 Nov 2017 16:11 CET
Approval-Biostatistics
08 Nov 2017 12:51 CET


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c15503343
2.0