Conditions: Palmoplantar Pustulosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 108
Healthy volunteers: no

Brief summary:
This study is open to people with palmoplantar pustulosis who took part in previous clinical studies of a medicine called spesolimab. Participants who benefited from spesolimab treatment in the previous studies can join this study.

The purpose of this study is to find out how safe spesolimab is and whether it helps people with palmoplantar pustulosis in the long-term. Participants are in this study for up to 5 years. During this time they visit the study site every month to get spesolimab injections under the skin.

At study visits, doctors check the severity of participants' palmoplantar pustulosis and collect information on any health problems of the participants.

Detailed description:

Arms:
arm 1: Up to 260 weeks

Interventions: intervention 1: Spesolimab
Intervention descriptions: intervention 1: Spesolimab

Protocol document:
Prot_000.pdf: 




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Number of patients on 
each treatment
Only one open label dose, 500 patients from parent trials expected
Diagnosis
Palmoplantar Pustulosis
Main in- and exclusion 
criteria
∀
Willing male or female patients who have completed treatment in 
one of the parent trials without premature discontinuation
∀
Patients who have obtained an individual health benefit, per 
investigator judgement (such as PPP PGA of 0 (clear) or 1 
(almost clear) or other clinical improvement), from treatment in 
the parent trial.
∀
Women of childbearing potential (WOCBP)  must be ready to 
use highly effective methods of birth control 
∀
Patients who experienced study treatment-limiting adverse events 
during their pre-ceding trial are to be excluded.
Test product(s)
Spesolimab, BI 655130
dose
600 mg every 4 weeks
mode of 
administration
subcutaneous (s.c.)
Comparator product(s)
Not applicable
dose
Not applicable
mode of
administration
Not applicable
Duration of treatment
260 weeks
Statistical methods
Descriptive statistics only






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1Visit V1 of this long-term extension study should be performed during the last treatment visit (EoT) 
of the preceding parent trial of Spesolimab (BI 655130). This is strongly recommended. 
Assessments done at the EoT-visit in the parent trial do not have to be repeated for Visit V1 in this 
extension trial. In case it is not possible to perform V1 of the extension trial at the EoT visit of the
parent trial, the maximum days allowed between EoT parent trial and V1 of this trial will be 28 days. 
The time window for Visit 1 may be extended at the discretion of the Clinical Trial Leader on a case 
by case basis.
Even in this case the procedures of V1 that were already performed at EoT of the parent trial will not 
be repeated if there are no clinically significant changes in PPP and clinical status of the patient.
Important: results of lab or any other assessment that needs to be repeated in the opinion of the 
investigator must be available prior to V2 (1st IMP administration in the extenstion trial
See Section 6.2.1 for detailed instructions.
2V2 (= 1st IMP administration in extension trial) must be performed on Day 28 (±7) from EoT of 
parent trial (last IMP administration). The time window between last IMP administration in the parent 
trial and the first IMP administration in the extension trial may be extended in exceptional cases at the 
discretion of the Clinical Trial Leader on a case by case basis.
3For patients who discontinue study medication in the extension trial before their scheduled end of 
treatment, an early EoT visit has to be scheduled. Subsequently EoS visit 16 weeks after the last dose 
of study medication has to be performed.
4The written informed consent (IC) must be obtained prior to performing any study related procedures. 
Date of IC will be reported in the eCRF. 
5Infection testing at screening includes tuberculosis (TB), hepatitis B (HBV), hepatitis C (HCV), and 
HIV assessments. In patients with negative TB result, repeat the test approx. once a year at visits in 
Wk48, 96, 144, 192, 240 and at EoT, as long as the TB result is negative. HBV (not HCV and HIV) to 
be repeated at EoT.
For details on infection testing please see Section 5.2.3 incl. table and important footnotes. See 
Section 3.3.4.3 for newly occurring infections during the trial.
6Physical examination: C=complete incl. weight, T=targeted (focus on evaluation of organ systems 
associated with AE(s) symptoms or laboratory abnormalities). For details please see Section 5.2.1
7Measurement of vital signs should precede blood sampling and will be assessed pre-dose at all 
dosing visits and at approx. 10 minutes after study drug administration. For details please see Section 
5.2.2
8ECG measurements should always precede blood sampling and drug administration. ECGs are taken 
approximately once a year: at screening (not to be repeated if done at EoT in parent trial) and at visits 
in Wk 48, 96, 144, 192, 240, EoT and EoS; For details please see Section 5.2.4
9Pregnancy testing is applicable only for women of childbearing potential (WOCBP). 
U - urine pregnancy tests will be performed at all visits. Urine pregnancy testing should be done
locally on-site prior to administration of study drug by using the urine-dipstick test provided by 
central lab. Study drug should only be administered in case of a negative test result. In case of a 
positive urine test result, the visit will be re-scheduled, IMP administration postponed and serum 
pregnancy test performed.
(S) - in case of a positive urine pregnancy test, a serum pregnancy test will be done and evaluated by 
the central lab. In case of a positive serum test, the patient must be discontinued from the trial. In case 




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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART VISIT 1-15....................................................................................................4
FLOW CHART VISIT 16-EOS..............................................................................................5
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................16
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
1.4.1
Benefits.................................................................................................................21
1.4.2
Risks .....................................................................................................................22
1.4.3
Discussion.............................................................................................................27
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................28
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........28
2.1.1
Main objectives....................................................................................................28
2.1.2
Primary endpoint(s)............................................................................................28
2.1.3
Secondary endpoint(s) ........................................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................30
3.1
OVERALL TRIAL DESIGN.............................................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................31
3.3
SELECTION OF TRIAL POPULATION .......................................................32
3.3.1
Main diagnosis for trial entry ............................................................................32
3.3.2
Inclusion criteria .................................................................................................32
3.3.3
Exclusion criteria ................................................................................................33
3.3.4
Withdrawal of patients from the trial...............................................................34
3.3.4.1
Wish to discontinue trial treatment, non-compleance of patient, medical reason 
and intake of restricted medication.......................................................................34
3.3.4.2
Implications due to loss of treatment response.....................................................34
3.3.4.3
Implications of specific adverse events ................................................................35
3.3.4.4
Withdrawal of consent to trial participation .........................................................36
3.3.4.5
Discontinuation of the trial by the sponsor...........................................................36
4.
TREATMENTS...................................................................................................37
4.1
INVESTIGATIONAL TREATMENTS ...........................................................37








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ABBREVIATIONS
ADA
Anti-Drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
CA
Competent Authority
Cmax
Maximum Concentration
CMV
Cytomegalovirus
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DSUR
Development Safety Update Report
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EoS
End of Study
EoT
End of Treatment
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FUP
Follow-up
GCP
Good Clinical Practice


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GMP
Good Manufacturing Practice
HA
Health Authority
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
i.v.
intravenous
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LPLT
Last Patient Last Treatment
LPLV
Last Patient Last Visit
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRD
Multiple Rising Dose
Nab
Neutralizing Antibody
OPU
Operative Unit
PFS
Pre-filled syringe
PK
Pharmacokinetics
PRO
Patient Reported Outcome
PVAN
Polyomavirus nephropathy
RA
Regulatory Authority
REP
Residual Effect Period
s.c.
subcutaneous
SAE
Serious Adverse Event
(S)AE
(Serious) Adverse Event – refers to both serious and non-serious AE
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SUSAR
Suspected Unexpected Serious Adverse Reactions


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TB
Tuberculosis
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
The target indication is Palmoplantar Pustulosis (PPP), a disease with a high unmet medical 
need. PPP is a chronic disease and a form of pustular psoriasis (as is Generalized Pustular 
Psoriasis, GPP). Recent evidence suggests that PPP and GPP are genetically distinct from 
chronic plaque psoriasis as the major genetic determinant PSORS1 for plaque psoriasis has 
not been found in PPP and GPP patients [R16-3560; R16-3546]. Gene expression [R16-3543] 
and human genetic [R16-3553, R15-1421, R16-0950, R16-3544] and clinical data imply that 
the IL36 pathway (targeted by Spesolimab, BI 655130) drives the pustular psoriasis diseases 
of PPP and GPP [P19-01888, R16-0950, R16-3561, R16-3544].
Genetic human studies have established a link between IL36R signalling and PPP: The same 
hypomorphic missense mutation in IL36RN reported for GPP [R16-0950; R16-3561] has also 
been observed in PPP, albeit to a lesser extent as compared to GPP [R16-3544].
Further genetic linkage between PPP and the IL36 pathway has been recently disclosed. For 
example, mutations in other genes linked to the IL36 pathway such as CARD14 [R16-3544] 
and AP1S3 [R16-0928] have been linked to the pathogenesis of all forms of pustular psoriasis 
including PPP. CARD14 is specifically and predominantly expressed in keratinocytes in the 
skin. It acts downstream of the IL36 pathway and is a known activator of NF-kB signalling. 
Mutations in the coding sequence (c.11T>G and c.97C>T) in AP1S3 have been linked to the 
pathogenesis of all forms of pustular psoriasis including PPP. The gene encodes a subunit of 
the AP-1 complex. Functionally the occurrence of these rare mutations causes a destabilizing 
of the AP-1 complex and could be linked to impaired Toll-like receptor 3 signalling and 
subsequent expression of the anti-inflammatory mediator IFN-β [R16-0928].
Currently there is no standard of care available for the treatment of PPP, i.e., no approved 
therapy except for Guselkumab in Japan. PPP is notorisouly difficult to treat. Patients usually 
end up being treated with the currently available systemic treatment options for plaque 
Psoriasis including retinoids, PUVA, methotrexate, cyclosporine and topical corticosteroids. 
Unfortunately, these options are usually not effective in reducing duration and severity of 
PPP. Thus, there is a high unment medical need for patients with PPP.
Spesolimab (BI 655130) will target as a first in class compound the IL36 pathway which is 
genetically linked to PPP disease pathogenesis and will be investigated in the clinical 
program for treatment of PPP, a disease with significant unmet medical need.
1.2
DRUG PROFILE
Please see current IB [c03320877] for all details of non-clinical and clinical studies 
conducted so far. Below a summary of important aspects regarding drug profile is given.


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Mode of action
Spesolimab (BI 655130) is a humanized antagonistic monoclonal IgG1 antibody that blocks 
human IL36R signalling. Binding of Spesolimab (BI 655130) to IL36R is anticipated to 
prevent the subsequent activation of IL36R by cognate ligands (IL36 α, β and γ) and 
downstream activation of pro-inflammatory and pro-fibrotic pathways with the aim to reduce 
epithelial cell/ fibroblast/ immune cell-mediated inflammation and interrupt the inflammatory 
response that drives pathogenic cytokine production in inflammatory skin diseases including 
generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP) and atopic dermatitis, 
and inflammatory bowel disease (IBD).
Key pharmacokinetic characteristics
PK analysis showed that exposure (AUC0-tz and Cmax) to Spesolimab (BI 655130) 
increased with increasing dose in an approximately dose-proportional manner from 0.3 to 
10 mg/kg. Overall, PK data so far suggests target-mediated drug disposition (TMDD) kinetics 
for Spesolimab (BI 655130). The effective half-life of Spesolimab (BI 655130) is 
approximately 4 weeks in the linear dose range in healthy volunteers and approximately 3 
weeks in GPP patients. For details please see the IB.
Drug interactions
Drug interaction studies have not been conducted to date. A drug interaction study is planned 
in a different indication. 
Residual Effect Period
The Residual Effect Period (REP) of Spesolimab (BI 655130) is 16 weeks. This is the period 
after the last dose with measurable drug levels and/or pharmacodynamic effects still likely to 
be present.
The median half-life for Spesolimab (BI 655130) observed in the healthy volunteer SRD 
study, 1368.1, was ~4 weeks.
However, in the patient trial 1368.11 where Spesolimab (BI 655130) was tested in GPP 
patients, the effective half-life was 23.9 days, ~3.4 weeks. Therefore 16 weeks would 
correspond to approximately 4 to 5 half-lives in patients, corresponding to 3% -5% of steady 
state Spesolimab (BI 655130) serum levels. 
Data from non-clinical studies
Toxicology studies
Spesolimab (BI 655130) does not bind to IL-36R from common toxicology species. 
Therefore, meaningful toxicity studies of the molecule cannot be performed in any animal 
species with Spesolimab (BI 655130). However, hazard identification studies of the mode-of-
action (MoA) of IL-36R inhibition were performed in mice using a mouse specific anti-IL-
36R monoclonal antibody (BI 674304), which is a mouse IgG2a monoclonal antibody with 
rat variable regions. In a 13-week intravenous toxicity study of BI 674304 in mice, no 
adverse effects of IL-36R antagonism were seen at a dose (50 mg/kg, twice weekly) that was 
5 fold higher than the dose that was protective in an experimental mouse colonic 
inflammation model. In the 26-week toxicity study, male and female mice (20-30/sex/group 
at 0, 10 and 50 mg/kg/day) were administered BI 674304 twice weekly for 26 weeks by 
intravenous injection via the caudal vein. There were no BI 674304-related changes in 


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clinical observations, body weights, food consumption, ophthalmology, clinical pathology 
parameters (haematology, clinical chemistry), organ weights, macroscopic or microscopic 
examinations. The no-observed-adverse-effect level (NOAEL) was considered to be 
50 mg/kg/day.
The in vitro cytokine release and tissue cross-reactivity assays demonstrate that the risk of 
transient cytokine release in humans is low and that, as expected, Spesolimab (BI 655130)
stains epithelium in a variety of tissues. There were no signs of local irritation after single, 
1 mL injections of the subcutaneous formulation in rabbits. These preclinical toxicology data 
support chronic Spesolimab (BI 655130) dosing in humans.
Data from clinical studies
Studies in Healthy Volunteers
Spesolimab (BI 655130) or placebo (PBO) was administered to 78 healthy volunteers (59 on 
Spesolimab (BI 655130) and 19 on PBO at single ascending i.v. doses from 0.001 mg/kg to 
10 mg/kg body weight (1368.1). Safety and tolerability of all tested i.v. doses was good. 
There were no drug-related Serious Adverse Events (SAEs). There was no apparent 
relationship between the frequency of AEs and the dose. There were no relevant changes 
compared to placebo for laboratory safety, including clinical chemistry, haematology, 
coagulation parameters, and urinalysis. No clinically relevant changes were observed in 
12-lead ECGs, vital signs, and cardio-monitoring. 
In a multiple rising dose (MRD) trial (1368.2), Spesolimab (BI 655130) or placebo have been 
administered to healthy volunteers at multiple ascending i.v. doses of 3, 6, 10 and 20 mg/kg 
given once weekly (qw) for 4 weeks (i.e. 4 administrations) or a single dose of 20 mg/kg 
(8 subjects each, 3:1 on active or PBO). Overall, Spesolimab (BI 655130) was well tolerated. 
There were no dose dependent AEs, AEs considered to be dose limiting and no SAEs. In all 
cases the AEs were of mild or moderate intensity. Furthermore, there were no clinically 
relevant abnormalities on treatment with Spesolimab (BI 655130) with respect to safety 
laboratory, vital signs, or ECGs as assessed by a central reader. Importantly, based on the 
analysis of the ITE studies, more than 90% of peripheral IL36R was engaged for at least 
22 weeks after the last application of four weekly doses. For further details and most recent 
results refer to the current Investigator`s Brochure [c03320877].
Study 1368.3 explored pharmacokinetics as well as safety and tolerability of a subcutaneous 
formulation of Spesolimab (BI 655130) at two different dose strengths of 150 mg (1 mL) and 
300 mg (2 mL) using an open-label, single dose, parallel group, matched pair design to 
determine the relative bioavailability of the 300 mg s.c. compared to one single 300 mg i.v. 
dose of Spesolimab (BI 655130). In this study, 36 healthy male and female subjects have 
been treated with Spesolimab (BI 655130), with 12 subjects per dose group. 35 subjects 
completed the study per protocol, one subject discontinued for logistical reasons (work-
related issues). 
The local tolerability of the s.c. formulation can be considered as well tolerated. 
The type, intensity and duration of systemic adverse events were similar to what has been 
observed in the preceding SRD/MRD studies 1368.1 and 1368.2. Most of the AEs were of 
mild intensity, there were no AEs considered to be dose limiting, and no SAEs. 


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In 1368.9 trial, 32 healthy Japanese male subjects were enrolled in 4 dose groups comprising 
8 subjects per group. The study consisted of three dose groups receiving single rising 
intravenous doses of Spesolimab (BI 655130) (300 mg, 600 mg, and 1200 mg) and one dose 
group receiving single subcutaneous doses of Spesolimab (BI 655130) (300 mg). In each 
dose group, 6 subjects received Spesolimab (BI 655130) and 2 subjects placebo.
The overall AE frequency following administration of single doses of 300 to 1200
mg i.v. or 300 mg s.c. Spesolimab (BI 655130) was comparable with placebo. None of the 
observed AEs were judged by the investigator as related to the trial medication.
Study 1368-0029 investigated the relative bioavailability, safety, and tolerability of 
subcutaneous injections (SC) of different doses of Spesolimab (BI 655130) and of different 
injection sites in healthy male and female subjects using a single dose, mono-centric, open-
label, matched-group (gender and weight) design.
A total of 48 subjects entered the trial and completed the planned observation time according 
to the clinical trial protocol. In total, 43 of the 48 treated subjects (89.6%) reported at least 1 
treatment-emergent AE. The frequency of subjects with treatment-emergent AEs was 
comparable between each treatment group. 
Investigator-assessed drug-related AEs were reported for 35 subjects (72.9%) and were 
reported with similar frequency in each treatment group. 
No ‘other significant AEs’ (according to ICH E3), AEs leading to discontinuation of trial 
medication, AEs of severe intensity, adverse events of special interest, deaths, or other SAEs 
were reported. 
Safety laboratory tests, physical examination, and the evaluation of vital signs, local 
tolerability, and electrocardiogram recordings revealed no clinically relevant findings. 
To sum up, Spesolimab (BI 655130) was safe and well tolerated by the healthy subjects and 
no safety signal was identified in trial 1368.29.
Studies in Patients
In a multi-center, open-label single arm phase I study (1368.11) to investigate safety, 
tolerability, pharmacokinetics, pharmacogenomics, and efficacy of a single intravenous dose 
of Spesolimab (BI 655130) (10 mg/kg) in patients with an acute flare of Generalized Pustular 
Psoriasis (GPP), 7 patients were treated. This trial could demonstrate that Spesolimab (BI 
655130) treatment rapidly stops the flare and clears pustules, the primary lesions in GPP, a 
disease closely linked to loss-of-function mutations in the natural IL36R antagonist.
Spesolimab (BI 655130) was well tolerated and no safety signal was identified in trial 
1368.11.
1368.15 was a double-blind, randomised and placebo-controlled trial with 59 patients that 
was intended to explore safety, tolerance, PK and efficacy in PPP patients. Patients were 
enrolled in Europe and Canada and randomised in a 1:1:1 allocation ratio and received either 
900 mg Spesolimab (BI 655130), 300 mg Spesolimab (BI 655130) or placebo intravenously 
every 4 weeks over a period of 12 weeks and were monitored for up to 32 weeks.
As there are currently no established nor validated endpoints available to specifically assess 
clinician- or patient reported outcomes in PPP, several endpoints were explored in this proof 
of concept trial. The endpoints included a PPP-specific PASI (ppPASI = PPP ASI in the 
nomenclature of trial 1368-0016) where induration was replaced with pustulation, as the 


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sterile pustule is the primary component of PPP (as it is in GPP), while the scaling and 
erythema components remained unchanged. The primary efficacy endpoint was PPP ASI50 at 
Week 16. 
As PPP is a neutrophilic dermatosis characterised by sterile pustules on palms and soles and 
in light of the rapid response observed on pustule clearance in trial 1368.11 (GPP), change 
from baseline in pustule severity was also included in the efficacy assessment. The focus on 
pustules allows to specifically address the impact and benefit of Spesolimab (BI 655130)
treatment on PPP disease. 
Overall, the baseline disease severity within the trial population was lower than expected 
because few patients with severe disease were enrolled in the trial. More specifically, half of 
the patients had a PPP ASI total score at baseline ≤16.70, which was close to the minimum 
required PPP ASI score of 12 for inclusion. The proportion of patients who achieved 
PPP ASI50 at Week 16 in the total population was similar in all treatment groups (6 of 19 in 
900 mg Spesolimab (BI 655130) arm, 6 of 19 in 300 mg Spesolimab (BI 655130) arm, and 5 
of 21 in placebo arm), the primary endpoint was not met. However, post-hoc subgroup 
analyses indicated efficacy of both doses of Spesolimab (BI 655130) in patients with more 
severe PPP disease at baseline (above the median baseline PPP ASI value of 16.7). In 
particular, the results on pustule severity were pronounced with a rapid reduction in pustule 
severity with evidence of a dose response relationship. In the same subgroup, a mean percent 
reduction from baseline in PPP ASI has been observed. For details please see the current 
Investigator´s Brochure [c03320877]. 
There were no clinically relevant abnormalities on treatment with Spesolimab (BI 655130)
with respect to safety laboratory and vital signs. Spesolimab (BI 655130) was well tolerated 
and no safety signal was identified in trial 1368.15.
Summary
Spesolimab (BI 655130) is an anti IL36R antibody with a high clinical activity to block 
IL36R signalling, as demonstrated in patients with GPP and PPP. IL36R inhibition shows a 
favorable nonclinical safety profile in healthy volunteers and in patients tested.
Spesolimab (BI 655130) has been tested in healthy volunteers with single or multiple dosing 
up to 4 weeks of 20 mg/kg i.v. qw, in GPP patients (1368.11 trial, N=7 in a single i.v. dose of 
10 mg/kg) and in PPP patients (1368.15 trial, N=59, i.v. doses 300 mg and 900 mg every
4 weeks) which were all safe and well tolerated.
1.3
RATIONALE FOR PERFORMING THE TRIAL
The target indication is Palmoplantar Pustulosis (PPP), a disease with a high unmet medical 
need. PPP is a chronic disease and a form of pustular psoriasis (as is Generalized Pustular 
Psoriasis, GPP). Recent evidence suggests that PPP and GPP are genetically distinct from 
chronic plaque psoriasis as the major genetic determinant PSORS1 for plaque psoriasis has 
not been found in PPP and GPP patients. Gene expression and human genetic and clinical 
data imply that the IL36 pathway (targeted by Spesolimab (BI 655130)) drives the pustular 
psoriasis diseases of PPP and GPP. PPP may be considered a rare disease. PPP is 
characterised by the presence of sterile pustules on palms and/or soles, in some cases evolve 
from vesicles. Despite the limited area of skin involvement in PPP, the disease is very 
debilitating with a large impact on quality of life including ability to work. PPP symptoms 


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include pruritus, burning sensations, and pain. In severe cases, the skin affliction makes 
walking or other activities of daily living challenging if not impossible. 
Spesolimab (BI 655130) is currently in development for the treatment of Palmoplantar 
Pustulosis (PPP). The main rationale of this extension trial is to collect additional longterm 
safety and efficacy data of Spesolimab (BI 655130) in PPP patients who have previously 
been treated with Spesolimab (BI 655130)
Additional appreciable benefit for the patients of this extension study is the possibility to 
receive Spesolimab (BI 655130) as s.c. maintenance treatment with the aim to maintain their 
positive clinical response reached in one of the preceding Spesolimab (BI 655130) PPP trials, 
if they are eligible to receive further Speesolimab (BI 655130) treatment in this extension 
study. If patients lose their benefit during the course of the extension trial in their personal 
opinion or in the opinion of the investigator, or a preferred treatment option becomes 
available patients can discontinue trial participation after a discussion with the investigator. 
As in any other clinical trial patients can also revoke their consent at any time without the 
need to justify the decision. For all details please see Section 3.3.4.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Preclinical profiles of Spesolimab (BI 655130) and clinical data from healthy volunteer and 
patient trials suggest that Spesolimab (BI 655130) is safe, tolerable and may address an 
unmet medical need in PPP patients by an anti-inflammatory mechanism of action. The data 
from the completed PoC trial 1368.11, in patients with an acute flare of generalized pustular 
psoriasis (GPP), demonstrate that Spesolimab (BI 655130) treatment rapidly stops the flare 
and clears pustules, the primary lesions in GPP, a disease closely linked to loss-of-function 
mutations in the natural IL36R antagonist. This and the data from 1368.15 indicates that 
Spesolimab (BI 655130) inhibits IL36R signalling also in human disease and thus has the 
potential to be further investigated also in PPP patients.
No relevant animal species is available for toxicology testing of the highly human specific 
antibody Spesolimab (BI 655130). However, preclinical toxicology studies with a mouse 
surrogate antibody have demonstrated the safety of IL-36R inhibition in mice, please refer to 
the IB.
An estimated number of 378 subjects have been exposed to single or multiple i.v. doses of 
Spesolimab (BI 655130) in ongoing or completed clinical trials as of Sep 2019. Spesolimab 
(BI 655130) was safe and well tolerated in five healthy volunteer trials evaluating the i.v. and 
s.c. formulation.
In trial 1368.15 for patients with PPP there were no clinically relevant abnormalities on 
treatment with Spesolimab (BI 655130) with respect to safety laboratory and vital signs. 
Spesolimab (BI 655130) was well tolerated and no safety signal was identified. For details 
refer to IB [c03320877].


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1.4.2
Risks
There are no identified or potential risks for Spesolimab (BI 655130), based on the 
toxicology program or any clinical trials conducted for this product to date. No other IL-36 
receptor antagonist is currently approved, providing information on identified risks in 
molecules of this class.
The risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs.
In order to protect the patient’s safety during conduct of this trial, an independent Data 
Monitoring Committee has been established for the periodic review of clinical trial safety 
data.
Table 1.4.2: 1 Risks
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product
Drug-induced 
liver injury 
(DILI)
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators.
Timely detection, evaluation, and follow-
up of laboratory alterations in selected 
liver laboratory parameters to ensure 
patients´ safety. See also Section 5.2.6, 
adverse events of special interest
Systemic 
hypersensitivity 
reaction
After administration of any 
biologic agent or protein, 
there is a possibility of 
occurrence of adverse 
immune reactions which can 
be local (e.g. redness, 
pruritus, and or swelling at 
the injection site) or systemic 
(e.g. anaphylactic reactions, 
see also Appendix 10.2).
Patients with a history of 
allergy/hypersensitivity to the systemically 
administered trial medication agent or its 
excipients are excluded from the trial.
In case of systemic hypersensitivity 
reactions including anaphylactic reaction 
emerging during or after administration of 
trial medication, the investigator should 
consider in accordance with severity of the 
reaction and local standard of care to 
interrupt and treat the condition. Systemic 
hypersensitivity reaction is defined as 
AESI. It is subject to close monitoring and 
investigators are requested to assess these 
conditions using the criteria discussed in 
the statement paper from Sampson HA 
[R11-4890].


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Table 1.4.2: 1 Risks (cont.)
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product
Peripheral 
Neuropathy
Three cases reported by 
the investigator as 
Guillain-Barré syndrome 
(GBS) were received in 
ongoing clinical trials with 
spesolimab. A panel of 
independent neurologists 
and experts in the study of 
neuropathies assessed the 
3 cases. Only 1 met level 4 
diagnostic certainty for the 
diagnosis of GBS (lowest 
level on Brighton scale of 
1 to 4). In that case, there 
was a coincident infection 
with SARS-CoV-2. The 
other 2 cases were 
assessed as not GBS. 
Observed cases showed a 
heterogenous pattern. A 
causal association to 
spesolimab to any of the 
reported cases was assessed 
to be unlikely.
As per assessment by the 
panel of external 
neurologists the 
nonspecific symptoms and 
findings in all three cases 
may best be referred to as 
peripheral neuropathy.
Timely detection, evaluation, and 
follow-up of suspected peripheral 
neuropathies to ensure patients´ safety. 
Use of dedicated questions to elicit 
neurologic history during screening 
and exclusion criteria to avoid selection 
of patients with acute demyelinating 
neuropathy.
Targeted Follow up questions to gather 
detailed information in case of any 
event during trial to ensure proper 
decision making. 
Trial treatment discontinuation criteria 
as well as criteria for trial treatment 
restart are implemented for relevant 
cases.


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Table 1.4.2: 1 Risks (cont.)
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product
Infections
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of 
infections.
A recent characterisation of 
individuals with 
homozygous IL36R KO 
mutations revealed that 
normal immune function was 
broadly preserved suggesting 
that IL36 signalling pathway 
inhibition does not 
compromise host defences 
[R17-3632].
Screening procedures for infections will be 
established for this trial. Patients with any 
relevant chronic or acute infections 
including human immunodeficiency virus 
(HIV), viral hepatitis or tuberculosis are 
excluded from the trial. Treatment of 
infections should be initiated promptly 
according to standards of care.
Severe infections and opportunistic 
infections are considered AESIs for this 
trial. These conditions and serious 
infections are subject to close monitoring.
Malignancies
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of a 
decreased immune defense 
against malignancies.
A recent characterisation of 
individuals with 
homozygous IL36R KO 
mutations revealed that 
normal immune function was 
broadly preserved suggesting 
that IL36 signalling pathway 
inhibition does not 
compromise host defences.
[R17-3632].
Patients with a recent history of 
malignancy other than appropriately 
treated basal cell carcinoma or squamous 
cell carcinoma of the skin or in situ 
carcinoma of uterine cervix will be 
excluded from participation in this trial.
In case of occurrence of malignant 
neoplasm other than appropriately treated 
basal cell carcinoma or squamous cell 
carcinoma of the skin or in situ carcinoma 
of uterine cervix, the investigator should
discontinue treatment with Spesolimab
(BI 655130).
Diagnostics and treatment have to be 
initiated according to local standard of 
care.
Malignancies represent always serious 
adverse events and are subject to close 
monitoring


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Table 1.4.2: 1 Risks (cont.)
Hypothetical risks 
of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Trial procedures
Blood Sampling 
As with all blood sampling, 
there is a risk of mild pain, 
local irritation, or bruising (a 
black or blue mark) at the 
puncture site. Furthermore, 
there is a small risk of light-
headedness and/or fainting. 
In rare cases, the puncture 
site can also become infected 
or nerves may be damaged, 
inducing long-lasting 
abnormal sensations 
(paresthesia), impaired 
sensation of touch and 
persistent pain.
These risks will be addressed by careful 
safety monitoring and risk mitigation 
measures such as
(a) close clinical monitoring for AEs;
(b) selection of experienced sites and site 
staff;
(c) training.
Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of Women of Child Bearing Potential 
(WOCBP) in this study is justified. To minimize the risk of unintentional exposure of an 
embryo or fetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods as described in Section 4.2.3.
Patients rolling over into the current open label extension study completed their treatment 
with the study drug in previous Spesolimab (BI 655130) trials. Even if the balance between 
safety and efficacy from the parent trials is still unknown at the timepoint the patients are 
rolled over into this open label extension trial, a long-term treatment is considered justifiable 
as there is currently no other suitable standard treatment that reliably controls PPP symptoms 
and is safe and tolerable for a long-term treatment. 
Benefit-Risk Assessment in context of COVID-19 pandemic for patients participating in 
clinical trials investigating Spesolimab:
A thorough assessment based on the data available as of 18 May 2020 has been conducted to 
evaluate whether spesolimab may pose a higher risk associated with COVID-19 infection. 
Additionally, the general risk of COVID-19 infection in context of the trial population’s 
underlying disease and common co-morbidities was assessed. The key aspects of the 
assessment are summarized below. 
Spesolimab is an immune-modulating humanized monoclonal antibody that blocks the human 
IL-36 receptor and thereby the pro-inflammatory IL-36 pathway. Available non-clinical and 
clinical data in 378 subjects (see current Investigators Brochure [c03320877]) have not 


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shown an increased risk of infections with spesolimab. However, as reflected in Table 1.4.2:1
above and the patient informed consent form, similar to other immune modulating biological 
treatments, spesolimab may hypothetically increase the risk of infections. Therefore, risk 
mitigation measures, such as exclusion of patients with increased risk of infections, close 
monitoring of adverse events, as well as guidance on treatment and handling of acute 
infections occurring during the trial have been included within this clinical trial protocol.
As any other acute infection, a suspected or diagnosed COVID-19 infection should be treated 
according to the standard of care and interruption of study medication should be considered.
Currently, information about the immune response in patients with COVID-19 is sparse and 
inconclusive. There are some reports suggesting high-levels of pro-inflammatory cytokines in
the severe cases, with much of the morbidity associated with coronavirus infection, 
potentially related to immune activation and inflammation. To date, there is no reliable 
evidence suggesting a link between SARS-CoV-2 infections and the IL-36 pathway targeted 
by spesolimab. Considering the current knowledge of COVID-19 and the implemented risk 
mitigation measures addressing the potential risk of infections, patients studied in trials with 
spesolimab are not believed to be at higher risk of COVID-19 due to their background or 
concomitant diseases. Protocol-defined procedures do not impose undue risk to study 
participants. 
The benefit-risk assessment of spesolimab remains favourable in the context of the COVID-
19 pandemic. Patients participating in trials with spesolimab are expected to benefit from trial 
treatment and interruption of treatment may worsen their disease. Published guidance for the 
use of biologics during the COVID-19 pandemic recommends to continue treatment with 
biologics (e.g. NICE COVID-19 rapid guideline: severe asthma [R20-2257], American 
College of Allergy, Asthma&Immunology [R20-2258], and National Psoriasis Foundation 
[R20-2256]). In line with this guidance no systematic testing for SARS-CoV-2 is required to 
be performed on the trial. However, the investigator may choose to perform the testing as per 
his/her discretion if useful based on individual medical consideration and in the case of 
suspected COVID-19 infection.
To address potential risks associated with operational aspects related to the participation in 
this clinical trial in context of COVID-19 pandemic, the following risk mitigation measures 
are to be considered based on local requirements and development of pandemic.
Every subject or patient will be assessed thoroughly, and individual benefit-risk assessments
are made prior to study entrance and during the study by the investigator in respect of SARS-
CoV-2 infection. A suspected or diagnosed, non-severe and non-serious COVID-19 infection 
should be treated according to the standard of care and interruption of study medication 
should be considered by the investigator. In case of a confirmed severe (according to RCTC 
grading in Appendix 10.3), and/or serious COVID-19 infection, trial treatment will be 
interrupted immediately and appropriate measures for monitoring, treatment and quarantine 
will be implemented. No further trial medication will be administered until the active 
infection has resolved. Treatment with study drug may be restarted when the patient has 
recovered according to investigator’s assessment.


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The investigators will take the totality of information related to each single patient and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. 
1.4.3
Discussion
Due to the lack of mechanism- or compound-related safety signals and the antagonistic mode 
of action of Spesolimab (BI 655130) it is considered likely that PPP patients will not be 
exposed to undue risks and adverse events in relation to the information that is expected to be 
gained from this trial. Considering the medical need of the development of an effective and 
well tolerated drug specifically and directly treating PPP, the benefit of this trial is considered 
to outweigh the potential risks and justifies the administration of Spesolimab (BI 655130) to 
patients with PPP. The benefit-risk profile is thus considered appropriate for an experimental 
therapy at this stage of clinical development.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
To evaluate the long-term safety and efficacy of Spesolimab (BI 655130) in patients with 
PPP, who have completed previous Spesolimab (BI 655130) trials and are qualified for entry 
in this trial. 
2.1.2
Primary endpoint(s)
The primary endpoint is the occurrence of treatment emergent adverse events (TEAEs) up to 
week 260 of maintenance treatment. 
Note: TEAEs are defined as all adverse events occurring between start of treatment in the 
extension trial and the end of its residual effect period. Adverse events that start before first 
drug intake in the extension trial and deteriorate under treatment during the extension trial
will also be considered as ‘treatment-emergent’.
2.1.3
Secondary endpoint(s)
The following secondary endpoints are defined as described below. Note that for the 
secondary endpoints, any data collected after use of any rescue therapy or after 6 weeks 
following discontinuation of treatment (to allow for incorporation of the continuing 
maximum treatment effect period) in current trial are censored for the purpose of the primary 
estimand.
∀
Percent change in PPP ASI from baseline in parent trial at week 48, 96, 144, 192, 240 and 
260
∀
Proportion of patients with PPP ASI50 compared to baseline in parent trial at week 48, 
96, 144, 192, 240 and 260
∀
Proportion of patients with PPP PGA of 0 (clear) or 1 (almost clear) at week 48, 96, 144, 
192, 240 and 260


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This open label, single-arm, multi-regimen, 5-year extension study investigates the long-term 
safety and efficacy of Spesolimab (BI 655130) in patients with PPP who have completed their 
treatment in previous Spesolimab (BI 655130) trials (´the parent/preceding/previous trial´). BI 
trial 1368-0016 is the first trial from which patients will roll over into this extension trial. At a 
later stage further patients may roll over from planned Phase III trials with Spesolimab (BI 
655130).
Approximately 500 patients from the parent trials are expected to meet the entry criteria and 
are planned to be rolled over into this open-label extension study. Enrollment period will not 
be expanded in case less than 500 patients can roll over. Patients rolling over into 1368-0024
trial must have completed the treatment period as required in the parent trial. Ideally, the EoT
visit of the preceding trial is the Screening visit (V1) of the extension trial. Procedures 
performed at the last visit of the preceding trial should not be repeated in 1368-0024 (see 
Section 6.2.1 for details).
If patients lose their benefit during the course of the extension trial in their personal opinion 
or in the opinion of the investigator, or a preferred treatment option becomes available 
patients can discontinue trial participation aftter a discussion with the investigator. As in any 
other clinical trial patients can also revoke their consent at any time without the need to 
justify the decision. For all details please see Section 3.3.4.
The extension study consists of a screening period lasting up to 28 days for patients rolling 
over from parent trials, followed by a 260 weeks treatment period and a 16 weeks safety 
follow-up period. 1st IMP administration in the extension trial should be done 28 days (±7
days visit window) after last IMP administration in preceding trial. The time window between 
last IMP administration in the parent trial and the first IMP administration in the extension 
trial may be extended in exceptional cases at the discretion of the Clinical Trial Leader on a 
case by case basis. Patients will receive open label Spesolimab (BI 655130) 600mg every 4 
weeks subcutaneously during the treatment period. This is the highest maintenance dose from 
the first preceding trial 1368-0016 as this is assumed to provide the optimal treatment effect. 
At the same time the dose is safe and well tolerated based on the available data so far (see 
Figure 3.1: 1). 


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Trial Design 
Figure 3.1: 1 One single arm: Spesolimab (BI 655130) 600mg s.c. q4w over 260 weeks 
For patients who terminate study drug prematurely in this extension study the subsequent 
visit will be replaced by an early EoT visit followed by an EoS visit 16 weeks after the last 
study drug administration (see Figure 3.1: 1). 
Interim analyses of 
and clinical data may be performed throughout the conduct 
phase of this 5-year study to support future trial applications, investigator brochures, 
regulatory documents and scientific publications. The final analysis of the entire trial data 
will be performed once all patients have completed the last scheduled trial visit. Individual 
patient participation is concluded when the patient has completed the last scheduled visit. 
The end of whole study is defined as “last patient out”; i.e. last scheduled visit completed by 
the last patient in the study. 
An independent Data Monitoring Committee will evaluate safety and efficacy data on a 
continuous basis.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This open label extension study aims to offer active long-term treatment to patients having 
benefited from treatment with Spesolimab (BI 655130) in the previous Spesolimab (BI 
655130) trials, and to characterize the safety of Spesolimab (BI 655130) long-term treatment. 
It will also characterize the clinical outcome over a long period of Spesolimab (BI 655130)
treatment. Spesolimab (BI 655130) as s.c. treatment is to be offered to maintain the clinical 
response in PPP that was reached in the parent trials. A control group is not planned in this 
extension study because there is no established standard of care for PPP and active treatment 
should be offered for this high unmet needs patient population.


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It is acknowledged that the reporting of data for this open-label trial will likely be biased due 
to, among others, selection and reporting bias. This is, however, deemed acceptable given 
that all patients who respond to previous treatment and who continue into this extension trial 
will be able to receive an active treatment with Spesolimab (BI 655130) for their ongoing 
disease.
3.3
SELECTION OF TRIAL POPULATION
Patients in this long-term open label extension trial will be rolled-over from previous trials 
with BI 651330. Patients must have completed the treatment of the previous trial and must 
meet the eligibility criteria for this open label extension trial. Patients must be willing and 
eligible to continue a long-term treatment with Spesolimab (BI 655130) for up to 5 years.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Patients with PPP who have completed and clinically responded to the treatment with study 
drug (Spesolimab) in previous trials with Spesolimab (BI 655130).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be included into the trial:
1. Signed and dated written informed consent for the current trial 1368-0024, in accordance 
with ICH-GCP and local legislation prior to admission to the current trial
2. Male or female patients who have completed the treatment period in one of the parent 
trials without premature discontinuation
3. Patients who have obtained an individual health benefit, per investigator judgement (e.g.
PPP PGA of 0 (clear) or 1 (almost clear) or other clinical improvement), from treatment 
in the parent trial.
4. Women of childbearing potential must be ready and able to use highly effective methods 
of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year 
when used consistently and correctly. A list of contraception methods meeting these 
criteria is provided in Section 4.2.3 and in the patient information. Note: A woman is 
considered of childbearing potential, i.e. fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is not 
a method of permanent sterilization. A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause.


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3.3.3
Exclusion criteria
Patients meeting any of these exclusion criteria must not be enrolled into the trial:
1. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
2. Patients who experienced study treatment-limiting adverse events during the parent trial.
3. Severe, progressive, or uncontrolled condition such as renal, hepatic, haematological, 
endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and 
symptoms thereof.
4. Patients with congestive heart disease, as assessed by the investigator.
5. Patient with a transplanted organ (with exception of a corneal transplant >12 weeks prior 
to screening in parent trial) or who have ever received stem cell therapy (e.g., 
Prochymal).
6. Known history of lymphoproliferative disease, including lymphoma, or signs and 
symptoms suggestive of possible lymphoproliferative disease (e.g. splenomegaly).
7. Any documented active or suspected malignancy or history of malignancy within 5 years
prior to screening in parent trial, except appropriately treated basal cell carcinoma of the 
skin, squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix.
8. Patients who have developed active or severe infective disease and opportunistic 
infections/infective diseases.
-
Patients with latent TB during preceding trial are allowed to be included in study 1368-
0024, provided they have received and/or receive currently appropriate treatment 
according to local guidelines. See Section 5.2.3 for more details.
9. Use of any restricted medication as specified in Section 4.2.1 or any drug considered by 
the investigator likely to interfere with the safe conduct of the study since the last visit of 
the previous Spesolimab (BI 655130) trial and during screening period for the current 
trial.
10. Plans for administration of live vaccines during the study period or since parent trial.
11. History of allergy/hypersensitivity to the systemically administered trial medication agent 
or its excipients.
12. Major surgery (major according to the investigator’s assessment) performed since the last 
visit of previous Spesolimab (BI 655130) trial or planned during the current trial (e.g. hip 
replacement, aneurysm removal, stomach ligation), as assessed by the investigator.
13. Patient has received surgical treatment of focal infection (e.g. tonsillectomy or dental 
therapy) since the last visit of previous Spesolimab (BI 655130) trial or planned during 
the current trial.
14. Total white blood count (WBC) <3,000/μL (SI unit <3.00 GI/L), or platelets <100,000/μL
(SI unit <100 GI/L) or neutrophils <1,500/μL (SI unit <1.5 GI/L), or hemoglobin 
<8.5 g/dL (SI unit <85 g/L) at screening.
15. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2x the upper limit 
of normal, or total bilirubin >1.5x the upper limit of normal (patients with Gilbert’s 
syndrome are not excluded) at screening.
16. Any condition which in the opinion of the investigator affects the safety of the patients,
the patients´ ability to participate in this trial or could compromise the quality of data. 
17. Previous participation in this trial.
18. Presence of acute demyelinating neuropathy


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3.3.4
Withdrawal of patients from the trial
Patients may discontinue the trial or withdraw consent to trial participation as a whole 
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
The decision to discontinue the trial or withdraw consent to trial participation and the reason
(if known) must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Section 5.2.6)
Patients withdrawn form the trial, independent of the underlying reason, should complete an 
early EoT-visit and the 16 week FUP period for safety reasons (please see Flow Chart and 
Section 6.2.3.1). This should also be proposed to patients who withdraw their informed 
consent.
3.3.4.1
Wish to discontinue trial treatment, non-compleance of patient, medical reason 
and intake of restricted medication
An individual patient will be withdrawn from the trial if:
∀
The patient wants to discontinue trial treatment, without the need to justify the decision.
This includes patients losing individual perceived health benefit or becoming aware of a 
preferred treatment option.
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
∀
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events – see also Section 3.3.4.3, other diseases, or pregnancy).The patient took 
restricted medication which is not allowed acc. to Section 4.2.1 and Table 4.2.1: 1.
3.3.4.2
Implications due to loss of treatment response
∀
Patients who need to take rescue medication must be discontinued from the trial. Rescue 
therapy is defined as the use of topical corticosteroids or other topical treatment, systemic 
immunomodulating treatments or biologics and therapy such as tonsillectomy, for the 
treatment of worsening of PPP. For the complete list and all details of restricted 
medication see Section 4.2.1 and Table 4.2.1: 1.
∀
The following additional trial treatment discontinuation criteria apply from Visit 2 
onwards:
-
Increase of pustulation severity compared to baseline (baseline (V1) of extension trial)
AND
-
Loss of PPP ASI by ≥ 5 points compared to baseline (baseline (V1) of extension trial)
A patient who meets the trial treatment discontinuation criteria at 2 consecutive visits must be 
discontinued from the trial treatment and administered standard of care therapy.


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3.3.4.3
Implications of specific adverse events
Systemic hypersensitivity including anaphylactic reaction
In case of systemic hypersensitivity including anaphylactic reaction emerging during or after 
injection(s) of trial medication, the investigator should consider in accordance with severity 
of the reaction and local standard of care to
∀
Stop further injection(s)
∀
Treat with systemic anti-histamines, i.v. steroids, and in case of a severe allergic reaction 
(e.g., anaphylactic reaction) epinephrine
Also draw a plasma sample for IgE and ADA as detailed in the laboratory manual (ISF) and 
consider the evaluation of histamine and complement components.
In case of systemic hypersensitivity, based on patient’s clinical course and medical judgment, 
injections may be cautiously re-initiated or continued in case of mild or moderate systemic 
hypersensitivity (according to RCTC grading, provided in the ISF).
In case of anaphylactic reaction based on the criteria discussed in the statement paper from 
Sampson HA (Appendix 10.2, R11-4890) suspected to be caused by the trial medication, the 
investigator should discontinue treatment with study drug.
When a non-acute hypersensitivity reaction related to immune complexes (i.e., serum 
sickness) is suspected, please draw a sample for the laboratory assessment for circulating 
immune complexes.
Severe infections (according to RCTC grading in Appendix 10.3), serious infections, 
opportunistic or mycobacterium tuberculosis infection
Treatment of the infection should be initiated promptly according to local standard of care. 
No further trial medication should be administered until the active infection has resolved. 
Treatment with study drug may be restarted when the patient has recovered according to 
investigator’s assessment.
∀
Latent TB must be treated according to local guidelines. Patient can continue the IMP 
treatment based on the discretion of the investigator. 
Malignancies
∀
In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix, 
the investigator should discontinue treatment with study drug and withdraw the patient 
from the trial. Diagnostics and treatment have to be initiated according to local standard 
of care. 
∀
In case of basal cell carcinoma or squamous cell carcinoma of the skin or in situ 
carcinoma of uterine cervix, diagnostics and treatment have to be initiated according to 
local standard of care. The treatment with study drug should be interrupted until 
confirmation that the event was treated successfully. Re-scheduling of any missed visit 
needs to be discussed with the Sponsor.
Peripheral Neuropathy
If peripheral neuropathy is suspected, treatment with spesolimab should be temporarily 
discontinued until a full neurological investigation has been conducted.


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After completion of the neurological investigation, treatment can be restarted based on 
medical judgement of the investigator.
3.3.4.4
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the importance to perform still the early EoT (eEoT) visit and to 
complete the 16 week FUP period to ensure patient´s safety. 
3.3.4.5
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 including but not limited to the following:
1. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment;
2. Potentially better treatment option becomes available;
3. Deviations from GCP, the trial protocol, or the contract that impairs conduct of the study, 
patient safety, or data integrity;
Further follow up of patients affected will occur as described in Section 3.3.4.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG, 
Biberach, Germany. The Spesolimab (BI 655130) molecule is an anti-human IL-36 receptor 
monocloncal antibody heterodimer with a molecular weight of approximately 146 kDa.
4.1.1
Identity of the Investigational Medicinal Products
The investigational product is provided in prefilled syringes of either 1 mL or 2 mL (PFS-1 or 
PFS-2) volume. The patients rolling over from the first parent trial 1368-0016 will all start 
with the PFS-2. However, depending on the availability of timely re-supply, there might be 
the need to switch to the PFS-1 at a later stage of the trial. Therefore, both PFS options are 
listed in the Table 4.1.1: 1 below and will also be covered in the Patient Information and 
Informed Consent Form.   
Table 4.1.1: 1 Test product Spesolimab (BI 655130)
Substance:
Spesolimab, BI 655130
Pharmaceutical formulation:
Solution for injection
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
150 mg in 1 mL solution
 300 mg/pre-filled syringe, 2 mL fill volume
 150 mg/ pre-filled syringe, 1 mL fill volume
Posology:
600 mg every 4 weeks
Mode of administration:
Subcutanous injections
4.1.2
Selection of doses in the trial and dose modifications
Patients will receive open label Spesolimab (BI 655130) 600mg every 4 weeks 
subcutaneously for up to 5 years. This is the highest maintenance dose from the first preceding 
trial 1368-0016 as this is assumed to provide the optimal treatment effect based on the data 
from the PoCC trial 1368-0015. Based on the available data so far this dose is also safe and 
well tolerated. Dose selection data from the parent trials will not be available prior to the 1st
patient rolling over to this open label extension trial. As soon as new data from other 
Spesolimab (BI 655130) trials will become available the impact for this extension trial will be 
evaluated and if needed the dose would then be adjusted by amendening this protocol (1368-
0024).


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4.1.3
Method of assigning patients to treatment groups
Not applicable, as all patients in this trial will receive the same treatment.
4.1.4
Drug assignment and administration of doses for each patient
An Interactive Response Technology (IRT) will be used to register the screening of patients, 
perform drug assignment, and manage initial/re-supply ordering of drug supplies. The 
investigator will receive all necessary instructions to access the IRT from the Sponsor. 
Detailed IRT functions and procedures will be documented in the user requirement 
specifications mutually agreed to by the sponsor and the IRT vendor.
Visit 1 of this extension trials is ideally the EoT visit of the parent trial. During this visit no 
medication assignment for the patients in this open label extension trial is assigned as they 
receive the last dose of the parent trial during this visit. 
At Visit 2 and at all subsequent medication administration visits, IRT will assign medication 
numbers. Each syringe will have an individual medication number for dispensation. The last 
dose of medication will be assigned at the EoT-Visit.
Site personnel will enter the medication numbers in the eCRF. Note that the medication 
number is different from the patient number (the latter is generated during screening via the 
IRT System).
Spesolimab (BI 655130) must be administered as a subcutaneous injection in thighs or 
abdomen by the investigator or authorized study personnel. The date and time of the 
administration of each syringe needs to be documentedby the investigator. Details are 
described in the drug administration manual located in ISF. If a dose was missed or trial 
treatment was temporary discontinued due to any reason, it must be discussed with the 
Clinical Trial Leader if the dose can be given later or if the treatment can be re-started.
The injection sites should avoid sites of psoriasis involvement as well as sites where the skin 
is tender, bruised, erythematous, or indurated, and should be alternated to other areas for 
subsequent doses.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open label, single arm trial; therefore, no blinding will be necessary. In this open-
label trial, treatment allocation will not be concealed throughout the trial.
4.1.5.2
Unblinding and breaking the code
Not applicable.


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4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Trial 
Manager, identified in the list of contacts, must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB / ethics committee 
∀
Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,
∀
Approval/notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated clinical trial protocol,
∀
Availability of the proof of a medical license for the Principal Investigator,
∀
Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor <and/or> appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.


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4.2
RESTRICTIONS
4.2.1
Restrictions on previous and concomitant medications
Restrictions regarding previous and concomitant treatment are summarized in Table 4.2.1: 1
Table 4.2.1: 1 Restrictions regarding previous and concomitant treatment
Medication or class of medications
Restriction duration
IL36R inhibitors other than the study drug
not allowed from screening (V1) until the 
EoS-visit;*
Biologic treatment, e.g.
Secukinumab (Cosentyx®), ustekinumab 
(Stelara®), guselkumab (Tremfya®), ixekizumab, 
tildrakizumab, brodalumab
Adalimumab, infliximab
Etanercept
Anakinra
Natalizumab or agents that deplete B or T cells 
(e.g. rituximab, alemtuzumab or visilizumab)
not allowed from screening (V1) until the 
EoS-visit;*
Investigational products for psoriasis
not allowed from screening (V1) until the 
EoS-visit;*
Live virus vaccinations
not allowed from screening (V1) until the 
EoS-visit;*
Other systemic immunomodulating treatments (e.g. 
corticosteroids, methotrexate, fumaric acid esters, 
acitretin, ciclosporin, apremilast) for the treatment 
of PPP
Any investigational device or product 
not allowed from screening (V1) until the 
EoS-visit;*


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Table 4.2.1: 1 Restrictions regarding previous and concomitant treatment (cont.)
Medication or class of medications
Restriction duration
Any topical treatment for PPP (e.g. 
corticosteroids, vitamin D analogues, salicylic 
acid, urea, tar, anthralin, keratolytic 
properties), Phototherapy (e.g. UVA, UVB). 
This includes all areas affected by PPP, even 
if extended beyond palms and /or soles (e.g. 
ankle).
not allowed from screening (V1) until the 
EoS-visit*
Emollients are allowed but must not be 
used within 24hrs prior to visits with
PPP assessments. For details see the skin 
care instructions in the ISF.
Conditions other than PPP:
Topical corticosteroids on palms and/or soles 
and all other regions also affected by PPP
Topical treatments other than topical 
corticosteroids that may affect the assessment 
of PPP
not allowed from screening (V1) until the 
EoS-visit*
Note: 
Patients should avoid applying topical 
treatments with bare hands on allowed 
body parts (e.g. use gloves).
Topical corticosteroids on allowed body 
parts not to be used within 24 hours prior 
to trial visits in which PPP ASI is 
assessed. 
Non-steroidal anti-inflammatory drugs (NSAIDs)
and acetaminophen/paracetamol
Allowed but recommended that a stable 
dose is maintained and the medication is 
not changed.
*if taken, the patient must be discontinued from the trial (see Section 3.3.4) and an early EoT- and 
regular EoS-visit need to be performed. If taken after an EoT-visit, the regular EoS-visit needs 
still to be performed. 
In the event a patient with prior use of biologic treatment, systemic steroids or 
immunomodulating treatments is enrolled, past medical records are required to document 
when these treatments were stopped. All concomitant or rescue therapies will be recorded on 
the appropriate pages of the CRF.
4.2.2
Restrictions on diet and life style
No specific restrictions on diet or life style of the patients are required. 
Emollients will be provided by the sponsor upon request for the patient´s use during the trial. 
However, emollients must not be used within 24hrs prior to the PPP assessments. Further 
details will be provided in ISF.


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4.2.3
Contraception requirements
Women of childbearing potential (for the definition of WOCBP, please refer to Section 3.3.3) 
must use highly effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and correctly during the trial, and 
for a period of at least 16 weeks after the last study drug administration. A double barrier 
method of contraception is not required. A list of contraception methods meeting these 
criteria is also provided in the patient information.


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


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


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5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on:
∀
Adverse events (including drug-related AEs and AEs leading to discontinuation)
∀
Adverse events of special interest (AESIs)
∀
Serious adverse events (SAEs)
∀
Intensity of adverse events will be assessed by Rheumatology Common Toxicity Criteria 
(RCTC) version 2.0 (refer to Appendix 10.3 and ISF for details)
∀
Safety laboratory tests
∀
Physical examination
∀
Vital signs (blood pressure, pulse rate, body temperature, respiratory rate)
∀
12-lead Electrocardiogram (ECG)
∀
Local tolerability
∀
Immunogenicity (ADA/Nab)
5.2.1
Physical examination
A complete physical examination incl. weight measurement will be performed at the time 
points specified in the Flow Chart. It includes at a minimum general appearance, neck, lungs, 
cardiovascular system, abdomen, extremities, and skin.
Targeted physical examination without weight measurement will include vital sign 
assessment and evaluation of organ systems associated with AE(s) symptoms or laboratory 
abnormalities.
The results must be included in the source documents available at the site.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling. At dosing visits, vital signs evaluations will be performed pre-dose and additional 
evaluation will be taken at approx. 10 minutes post-dose.


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This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest, and additionally 
temperature and respiratory rate. The results must be included in the source documents 
available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. For the sampling 
timepoints please see the Flow Chart.
All analyses (except for the urine pregnancy dipstick tests which are done locally at the 
investigational site) will be performed by a central laboratory, the respective reference 
ranges will be provided in the ISF.
Patients do not have to be fasted for the blood sampling for the safety laboratory but 
information of food intake before blood sampling must be collected in the source data of the 
patient.
Instructions regarding blood and urine sample collection, sample handling/ processing and 
sample shipping are provided in the laboratory manual in the ISF.
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
Table 5.2.3: 1
Safety laboratory tests
Category
Test name
Haematology
Haematocrit (Hct)
Haemoglobin (Hb)
Glycosylated Hbc (HbA1c) (at screening, and 
yearly from week 48 onwards)
Red Blood Cell Count
Reticulocyte Count
White Blood Cells / Leukocytes
Platelet Count / Thrombocytes
Diff. Automatic
Neutrophils (relative and absolute)
Eosinophils (relative and absolute)
Basophils (relative and absolute)
Monocytes (relative and absolute)
Lymphocytes (relative and absolute)
Diff. Manual (if Diff Automatic is abnormal)
Neutrophils, bands (Stabs)
Neutrophils, polymorphonuclear (PMN)
Eosinophils
Basophils
Monocytes 
Lymphocytes


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Table 5.2.3: 1
Safety laboratory tests (cont.)
Category
Test name
Coagulation
Partial Thromboplastin Time (aPTT)
Prothrombin time (INR)
Fibrinogen
Enzymes
AST (GOT)
ALT (GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Amylase
Lipase
Electrolytes
Calcium Sodium
Potassium
Chloride 
Bicarbonate
Substrates
Glucose
BUN (blood urea nitrogen)
Uric acid
Creatinine
Bilirubin Total
Bilirubin Direct (if total is elevated)
Bilirubin Indirect (if total is elevated)
Troponin (Reflex, in case of elevated CK)
Protein, Total
Albumin
C-Reactive Protein (CRP) (high sensitivity)
Cholesterol, total
Triglycerides 
LDL-Cholesterol 
HDL-Cholesterol
Specific gamma-globulin quantification
IgE2
Urine Pregnancy test1 (only for female patients of 
childbearing potential). At the drug administration 
visits, the test will be performed and checked at 
the investigational site prior to the administration 
of study drug
Human Chorionic Gonadotropin in urine
Serum Pregnancy test1 (only for female patients
of childbearing potential)
Human Serum Chorionic Gonadotropin
Hormones
TSH (free T3 and free T4 in case of abnormal TSH
result) (at screening, and yearly from week48 
onwards)


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Table 5.2.3: 1
Safety laboratory tests (cont.)
Category
Test name
Urinalysis
Dipstick (qualitative), test and analysis done by 
central lab:
∀Urine Nitrite
∀Urine Protein
∀Urine Glucose
∀Urine Ketone
∀Urobilinogen
∀Urine Bilirubin
∀Urine Blood
∀Urine Leukocytes Esterase
∀Urine pH
∀Urine Creatinine
Urine-Sediment (microscopic examination, only
if urine analysis abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epithelial Cells
Urine Sed. Crys., Unspecified
Urine Sediment RBC / Erythrocytes
Urine Sediment WBC / Leukocytes
Infections testing
Hepatitis B Surface Antigen (qualitative) 3
Hepatitis B core Antibody3
HBV-DNA (quantitative)3                                 
Hepatitis C Antibodies (qualitative)4
HIV-1, and HIV-2 Antibody (qualitative)4
QuantiFERON®-TB5,6
1 Urine and serum pregnancy testing will be performed as indicated in the Flow Chart.
2 IgE will be taken in case of systemic hypersensitivity reaction together with ADA (anti-drug antibodies) sample.
3 HBV at screening and EoT. A HBV-DNA should be conducted if Hepatitis B core Antibody is positive and Hepatitis B 
Surface Antigen is negative. 
4 HCV and HIV at screening only; not to be repeated if done at EoT in parent trial;
5 If the 1st QuantiFERON®-TB test result is indeterminate, a retest should be performed. If the restest QuantiFERON-TB 
test result is undetermined, a tuberculin skin test should be performed 
6 In patients with a previously (i.e. in parent trial or in ongoing extension trial) negative QuantiFERON®-TB test, the test 
should be repeated approx.once a year at visits in Wk48, 96, 144, 192, 240 and at EoT, as long as the results are negative. 
In case the QuantiFERON®-TB test result changes to indeterminate/positive further work up as a tuberculin-skin-test and 
x-ray should be inititated to exclude or confirm active TB. 
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flow Chart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis. Additional ECGs may be recorded 
for safety reasons. Dated and signed printouts of ECG with findings should be documented in 
patient’s medical record.
For AE reporting of clinically relevant abnormal findings please refer to Section 5.2.6.2.  


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5.2.5
Other safety parameters
All cases of malignancies that are detected during the trial will be reported as SAEs. Patients 
with a history of malignancy (except for specific cancers) will be excluded from this trial per 
the exclusion criteria (Section 3.3.3). For correct AE reporting in this extension trial refer to 
Section 5.2.6.2.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀
Worsening of the underlying disease or of other pre-existing conditions
∀
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
For AE reporting of abnormalities refer to Section 5.2.6.2. 
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
∀
results in death,
∀
is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe,
∀
requires inpatient hospitalisation or prolongation of existing hospitalisation
∀
results in persistent or significant disability or incapacity,
∀
is a congenital anomaly / birth defect,
∀
is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse.
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.


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5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the EDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in Section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
Systemic hypersensitivity reactions including anaphylactic reaction
Any suspicion of severe systemic hypersensitivity reaction and of any potential cases of 
anaphylaxis should be defined and assessed using the criteria discussed in the statement paper 
from Sampson HA (Appendix 10.2, R11-4890).
Severe infections (according to RCTC grading in Appendix 10.3)
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal leucoencephalopathy, 
bartonellosis (disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, 
histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, 
lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, strongyloides (hyperinfection syndrome and disseminated forms only), 
paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only), shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression [R17-2617].


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Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
∀
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or
∀
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Peripheral Neuropathy
Any event suspected or diagnosed as Peripheral Neuropathy would be considered as an AESI.
For the treatment interruption rules, please see Section 3.3.4.3 Implications of specific 
adverse events.
5.2.6.1.5
Intensity (severity) of AEs
The intensity grading of AEs will be performed according to Rheumatology Common 
Toxicity Criteria (RCTC) Version 2.0 developed by 
 [R13-3515]. Refer to the 
ISF for intensity/severity classification. Intensity options are:
Grade 1 
mild
Grade 2 
moderate
Grade 3 
severe
Grade 4 
includes life-threatening
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.


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∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-existing 
or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
∀
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).
∀
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the
Investigator (special notes on SAE form reporting where needed):
∀
From the time of first dose of trial drug administration in the extension trial until the
EoS-visit: 
all AEs (serious and non-serious) and all AESIs
∀
All AEs that started in the parent trial (onset date in parent trial) and are still ongoing 
after 1st IMP administration in the extension trial:
-
Re-record the AE in the extension trial eCRF with the same information as it was 
recorded in the parent trial. 
-
Should the AE end during the course of the extension trial (after 1st IMP 
administration in the extension trial), update only the extension trial 
eCRF;However, concerning reporting on the SAE form (if applicable), the follow-
up report will still be sent on the parent trial SAE form, no new SAE form is to be 
completed for the extension trial.


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-
If the intensity of an ongoing AE changes after 1st IMP administration in the 
extension trial:
 update only the extension trial eCRF;
 The AE with the new intensity will be handled as new event with 
the onset of the new intensity as start date; Example: If the intensity 
increased then the new AE name/term should contain “Worsening 
of….” or “Exacerbation of….”.
Considerations for reporting on the SAE form, when intensity change qualifies 
as worsening/exacerbation of an event that had already been reported on the 
SAE form:
- corresponding follow up report to be sent on the parent trial SAE form with 
date of worsening as event end date. 
- extension trial SAE form to be sent as initial report for the extension trial for 
new event “worsening/exacerbation of….” with date of worsening as onset 
date.
Considerations for reporting on the SAE form, when intensity change qualifies 
as worsening/exacerbation of an event and requires for the first time reporting 
on the SAE form (meeting for the first time seriousness/AESI criteria):
- only extension trial SAE form to be sent - as initial report for the extension 
trial for new event “worsening/exacerbation of….” with date of worsening as 
onset date.
∀
All AEs with an end date before the 1st IMP administration in the extension trial, even if 
Informed Consent of the extension trial was already signed:
-
Record only in the eCRF of the parent trial. 
-
In case of an AE reportable on the SAE form, send the update only on the SAE 
form of the parent trial. 
-
Do not re-record in the extension trial eCRF, do not complete a new SAE form for 
the extension trial.
After the EoS visit in the extension trial:
After a patient´s EoS-visit in the extension trial the investigator does not need to actively 
monitor the patient for new AEs but should only report new malignancies or the exacerbation 
of existing malignancies, trial treatment related SAEs and trial treatment related AESIs of 
which the investigator may become aware of by any means of communication, e.g. phone call. 
Those AEs should be reported on the BI SAE form (see Section 5.2.6.2.2) for the extension 
trial, but not on the CRF (neither on CRF for extension nor for parent trial).


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5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
For further details specific to the AE reporting of this extension trial see Section 5.2.6.2.1.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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5.4
ASSESSMENT OF BIOMARKER(S)


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5.4.3
Methods of sample collection
Sampling of whole blood and serum is described in the laboratory manual in the ISF.
5.5
BIOBANKING
Not applicable
5.7
APPROPRIATENESS OF MEASUREMENTS
The measurements performed during this trial are standard measurements in PPP treatment 
trials and will be performed in order to monitor safety aspects or assess treatment response in 
an appropriate way. The 
included in this trial have been used and described in other 
diseases, including dermatologic conditions, where they have demonstrated adequate 


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measurement properties. They were included because they explore concepts of PPP that 
patients and physicians have highlighted as relevant and important.
Therefore, the appropriateness of all measurements applied in this trial is given.




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Once consented, the patient is considered to be enrolled in the trial and has started screening. 
The patient should be recorded on the enrolment log and be registered in IRT as a screened 
patient. Patients will be assigned a patient number (different from the patient number in the 
parent trial) generated via the IRT system.
Screening Visit (Visit 1):
Visit 1 of the extension trial should be performed in one visit and in combination with the 
EoT visit of the preceding parent trial. 
The aim of V1 is 1) to evaluate the willingness and eligibility of the patient to take part in this 
open label extension trial and 2) to collect the baseline data for the extension trial (1368-
0024). Note: the endpoints of the extension trial refer to different baselines (either baseline 
from parent trial or baseline from extension trial); please see Section 2 for details.
This means most of the procedures performed at the EoT visit of the previous trial should not 
be repeated for V1 of 1368-0024 as the data collected at EoT of the parent trial serve at the 
same time as screening information for V1 of the extension trial. Please see below a 
complete list of V1 assessments and how data are handled.
In exceptional cases visit 1 could be performed up to 28 days after EoT of preceding trial.
Also in this case procedures of V1 will not need to be repeated if investigator considers that 
patient does not have any clinical significant change from EoT visit of parent trial. The time 
between last IMP dose in parent trial (EoT visit) and the first IMP dose in the extension trial 
should not exceed 28 days (±7 days). The time window for Visit 2 may be extended at the 
discretion of the Clinical Trial Leader on a case by case basis.
If the investigator considers the patient to have any clinical significant change, re-testing/re-
evaluation should be done to determine eligibility. Important: results of lab or any other 
assessment that needs to be repeated in the opinion of the investigator must be available prior to V2 
(1st IMP administration in the extension trial).
Re-screening is not allowed. 
Informed Consent
A separate Informed Consent must be obtained for the extension trial before performing any 
other trial procedure.
Review of In/Exclusion criteria 
All in/exclusion criteria must be evaluated/re-considered for the extension trial and 
documented in the corresponding source data; see Section 3.3 for the in/exclusion criteria of 
the extension trial. 


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Baseline Conditions
This refers to chronic diseases, current observable conditions, any new clinically relevant 
findings discovered from the physical examination, ECG, safety labs, and any condition 
requiring therapy (excluding PPP). 
     
-
Baseline conditions from the parent trials need to be re-considered and those 
which are still ongoing after Informed Consent of the extension trial was signed, 
need to be re-recorded with the same information in the eCRF of the extension 
trial.
-
(S)AEs that ended with sequelae in the parent trial need to be included as baseline 
condition in the eCRF of the extension trial
-
Any new baseline condition needs to be recorded in the eCRF of the extension 
trial (for example, a missed baseline condition from the parent trial)
Concomitant Medications and Concomitant Non-Drug Therapies (CT)
-
Ongoing CTs from the parent trial which are still ongoing after the Informed 
Consent of the extension trial was signed, need to be re-recorded with the same 
information in the eCRF of the extension trial.
-
CTs which ended in the parent trial, will not be re-recorded in the eCRF of the 
extension trial.
Demography
Informed consent date, gender, age, race and ethnic origin will be collected/re-recorded in the 
eCRF page of the extension trial. 
Note: information concerning race/ethnicity will be collected, as it has been suggested that 
there may be race/ethnicity variations in the incidence, phenotypic manifestations and 
outcome of PPP. However, in some countries, race may not be collected.
Smoking history
The patient’s smoking history based on the calculation of pack years will be re-assessed for 
the extension trial and newly recorded to the extension trial eCRF. See Appendix 10.4 for 
details.
Medical History:
Past medical history reported in the parent trial eCRF is not re-recorded in the extension trial 
eCRF. 
If some historical information was missed in the parent trial, it should be recorded to the 
parent trial if it is not yet locked. If the parent trial is already locked, the missed information 
can be entered in the extension trial eCRF.
If a new condition developped but recovered during the parent trial this can be recorded in the 
extension trial if considered relevant information by the investigator.
The following assessments will not to be repeated for the extension trial at screening if V1 of 
the extension trial is done at the same time as the EoT visit of the parent trial unless the 
assessment was not done at EoT in parent trial due to any reason. The same is true if the V1 








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6.2.3
Follow-up period and trial completion
For all patients, termination of trial medication and trial completion must be recorded on the
corresponding eCRF.
For patients completing the safety FU period, the EoS visit is scheduled at 16 weeks after the
last dose of study drug. For more details please follow Flow Chart.
6.2.3.1
Early treatment discontinuation
Patient who discontinue treatment prior to the planned EoT visit have to be invited for an
early EoT visit as soon as possible. These patients should be registered as withdrawn from
treatment in IRT and return to the site for the End of Study (EoS) visit 16 weeks after last
study drug intake. For more details please the Flow Chart and Section 3.3.4.
No further follow-up on vital status is performed in the extension trial.
6.2.3.2
Trial completion
Patients who finish the treatment period will return to the site for the EoS visit 16 weeks after 
the EoT visit. Completion is defined as a patient having reached the EoS visit.
6.2.3.3 
Further treatment after the end of the trial
At the end of the trial, patients will be treated for their PPP at the discretion of the 
investigator, according to local PPP guidelines. Ongoing Aes must be followed up 
sufficiently at the discretion of the investigator.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
Given the single arm and open-label nature of this trial, all statistical assessments will be 
performed in a descriptive manner only. No hypothesis testing is intended to be performed.
7.2
PLANNED ANALYSES
7.2.1
General considerations
This trial is designed as a single arm, open-label trial in patients with Palmoplantar Pustulosis 
who have completed the planned treatment period in previous (parent) trials with Spesolimab 
(BI 655130).
The patients eligible for roll over from parent trials receive subcutaneous Spesolimab (BI 
655130) 600 mg q4w as maintenance treatment for up to 5 years.
Thus, there will be only one patient population in this trial for analyses: the treated set for 
maintenance treatment (TS-MT).
There is no confirmatory statistical testing planned during the analysis of this extension trial; 
only descriptive analyses are intended.
Treated Set for Maintenance Treatment (TS-MT)
This patient set includes all patients who were on the maintenance treatment of 600 mg s.c. 
q4w.
Further analysis sets will be defined in the TSAP if necessary.
Important violations of the protocol will include deviations of the key inclusion and exclusion 
criteria, concomitant use of restricted medications, and any other deviations of the protocol 
deemed important by the study team. All decisions concerning important protocol deviations 
will be made prior to final database lock for this extension trial.
Standard statistical parameters (number of non-missing values, mean, standard deviation
(SD), median, quartiles, minimum and maximum) or frequency tables (including patient 
frequencies and percentages) will be calculated where appropriate.
A Clinical Trial Report will be prepared once the final database lock for this extension trial 
has been performed.


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7.2.2
Primary endpoint analyses
Refer to Section 7.2.6 for the description of safety analyses including that for the primary 
endpoint. The primary endpoint will be summarized based on Treated Set for Maintenance 
Treatment (TS-MT).
7.2.3
Secondary endpoint analyses
Secondary endpoint will be assessed descriptively. Further details will be provided in the 
TSAP.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 16 weeks after the 
last dose of study medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’. 
Frequency, severity, and causal relationship of all treatment emergent adverse events will be 
tabulated by system organ class and preferred term after coding according to the current 
version of the Medical Dictionary for Drug Regulatory Activities (MedDRA) at database 
lock. Exposure adjusted incidence rate of all treatment emergent adverse events will also be 
presented.
The exposure adjusted incidence rate (per 100 subject years) of a selected treatment 
emergent adverse event is defined as the number of subjects experiencing the adverse event 
per treatment group during time at risk divided by the total time of subjects at risk in that 
treatment group to contribute the event to the analysis multiplied by 100 (per 100 subject 
year), where:
Time at risk [subject years] = (date of onset of TEAE – study drug start date + 1) / 365.25
If, for a subject, the selected treatment emergent adverse event didn’t occur then the time at 
risk will be censored at min (date of death, last contact date per EoS page, drug stop date + 


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112 days). For each selected treatment emergent AE, the exposure adjusted incidence rate 
will be calculated as:
Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with TEAE / Total 
TEAE-specific time at risk [subject years].
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. 
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Immunogenicity data will be analysed descriptively.
7.2.7
Interim Analyses
In order to ensure the patient’s safety during the trial, an external DMC, independent of the 
trial and project teams, will be set-up to review all available safety data as well as selected 
efficacy data at regular intervals following first-patient-in. A DMC SAP will be produced 
which describes the analyses required for assessment by the DMC. Further details will be 
provided in a DMC charter.


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As the primary aim of this study is to collect long-term safety and efficacy data on the use of 
Spesolimab (BI 655130) in this population, multiple interim analyses may be done over the
5-year conduct phase of this trial to support, for example, regulatory interactions, CTA and 
MAA/BLA submissions, but also to provide important safety and efficacy information to the 
sponsor to guide further development of the compound, and to the investigators via IB 
updates and publications. 
Since patients will be enrolled into this study over a time period of several years and in line 
with the exploratory nature and open label design of the study, such analyses will be 
performed on demand and are not feasible to be pre-defined.
A CTR describing all data collected within this trial will be produced once the last patient in 
the trial has completed the final follow-up visit.
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at all visits. However, missing data will 
still occur and approaches to handle this are proposed below.
For the safety data, including the primary endpoint, no missing data imputations are planned.
For other efficacy endpoints, rules for handling of missing data will be specified in the TSAP 
if necessary.
7.4
RANDOMISATION
Given the single arm nature of this trial, no randomization will be performed.
7.5
DETERMINATION OF SAMPLE SIZE
Given the descriptive nature of this trial, no sample size calculation has been performed. The 
sample size of this open label extension trial is determined based on the sample size of the 
preceding trials.
Approximately 500 patients who meet the entry criteria are expected for inclusion into this 
trial, rolling over from the preceding trials of Spesolimab (BI 655130).


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


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


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


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


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The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A project-independent, fully-external data-monitoring committee (DMC), will be established 
to assess the progress of the clinical trial, including an unblinded safety and efficacy 
assessment at specified intervals, and to recommend to the sponsor whether to continue, 
modify, or stop either a single Spesolimab (BI 655130) dose or the trial due to safety or 
ethical concerns. The tasks and responsibilities of the DMC will be specified in a charter. The 
DMC will maintain written records of all its meetings.
DMC recommendations as well as the final BI decision will be reported to the appropriate 
Regulatory Authorities (Ras)/Health Authorities (Has), IRBs/Ecs, and to investigators as 
requested by local law. The tasks and responsibilities of the DMC are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.


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








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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
10.1.1
Palmoplantar Pustulosis Area and Severity Index (PPP ASI)
Score
0
1
2
3
4
5
6
Erythema (E)
None
Slight
Moderate
Severe
Very 
severe
Pustules (P) 
(total)
None
Slight
Moderate
Severe
Very 
severe
Desquamation 
(D) (scaling)
None
Slight
Moderate
Severe
Very 
severe
Area affected 
(%)*
0
<10
10<30
30<50
50<70
70<90
90 - 100
* where area assessed is glabrous skin on the palms/ soles 
PPP ASI = [(E+P+D) Area x 0.2 (right palm)] + [(E+P+D) Area x 0.2 (left palm)] + [(E+P+D) Area x 0.3 (right 
sole)] + [(E+P+D) Area x 0.3 (left sole)]
10.1.2
Palmoplantar Pustulosis Physician Global Assessment (PPP PGA)
Components 
Erythema* 
0=Clear; 1=Almost Clear; 2=Mild, 3=Moderate, 4=Severe
Pustules 
0=Clear; 1=Almost Clear; 2=Mild, 3=Moderate, 4=Severe
Scaling/Crusting
0=Clear; 1=Almost Clear; 2=Mild, 3=Moderate, 4=Severe
*Do not score eroded area, physiological erythema, frictional hyperkeratosis and calluses
Each of the components (erythema, pustules, scaling/crusting) should be scored and recorded. 
The PPP PGA total score is derived as the mean of all individual components.
PPP PGA Total Score:
0 = If mean=0 for all three components 
1 = If 0 < mean <1.5
2 = If (1.5 <= mean <2.5)
3 = If 2.5 <= mean <3.5
4 = If mean >=3.5


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10.2
DIAGNOSIS OF ANAPHYLAXIS
Clinical Criteria for diagnosing anaphylaxis [R11-4890]
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 
1 year, less than (70 mm Hg +[2 x age] from 1 to 10 years, and less than 90 mm Hg from 11 
to 17 years.


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10.3
SEVERITY OF AE AS DESCRIBED IN THE RHEUMATOLOGY 
COMMON TOXICITY CRITERIA (
Please see ISF for the complete table and [R13-3515]
1 - Mild
2 - Moderate
3 - Severe
4 - Includes Life 
Threatening
Asymptomatic, or 
transient
Short duration (< 
1 week)
No change in life 
style 
No medication or 
OTC 
Symptomatic
Duration (1–2 
weeks) 
Alter lifestyle 
occasionally
Meds relieve. (may 
be prescription),
Study drug 
continued
Prolonged 
symptoms, 
reversible, major 
functional 
impairment
Prescription 
meds/partial relief
May be 
hospitalized<24h
Temporary study 
drug discontinuation, 
or/and dose reduced
At risk of death
Substantial disability, 
especially if 
permanent.
Multiple meds
Hospitalised >24h
Study drug 
discontinued
10.4
SMOKING HISTORY BASED ON CALCULATION OF PACK YEARS 
Calculation of pack years based on number of cigarettes:
Pack years = Number of cigarettes/day   x   years of smoking
20
The following equivalents for the tobacco content should be used for smokers other than 
cigarettes smokers (R08-5197):
One plain or filter cigarette = 1 gram of tobacco
One cigar = 5 grams of tobacco
One cheroot or cigarillo = 3 grams of tobacco
One gram of pipe tobacco = 1 gram of tobacco
Calculation of pack years based on tobacco contents:
Pack years =
Number of grams/day   x   years of smoking
20


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10.5
TRIAL BIOMARKER PLAN


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
17 Aug 2020
EudraCT number
EU number
2020-000189-41
BI Trial number
1368-0024
BI Investigational Medicinal 
Product(s)
Spesolimab, BI 655130
Title of protocol
An open-label, single arm, long term trial of 
Spesolimab treatment in patients with Palmoplantar 
Pustulosis (PPP) who have completed previous BI 
Spesolimab trials
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
1.4.2 Risks
Description of change
Added Benefit/Risk Assessment in the context of 
COVID-19 pandemic
Rationale for change
Benefit/Risk information for investigators 
regarding patients on Spesolimab needed
Section to be changed
1.3.3
Exclusion Criteria
Description of change
Time frame for exclusion criterion #7 was adapted: 
changed from “history of malignancy at screening 
to “history of malignancy within 5 years prior to 
screening in parent trial”.
Rationale for change
Alignment between parent trial 1368-0016 and roll 
over trial to avoid losing patients from parent trial 
with an older history of malignancy
Section to be changed
4.2.1 Restrictions on previous and concomitant 
medications
Description of change
-
Non-steroidal anti-inflammatory drugs 
(NSAIDs) and acetaminophen/paracetamol: 


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changed from “not allowed/restricted use” to 
“allowed but recommended to be maintained at 
stable dose and ot to change medication”
-
Phototherapy: changed from “not allowed” to 
“allowed if palms and soles are exempted”
Rationale for change
Alignment between parent trial 1368-0016 and roll 
over trial to avoid losing patients from parent trial 
due to different medication restrictions.
Section to be changed
5.1.8 Target Plaque Severity Score
Description of change
Clarification added that the same target region 
from parent trial needs to be assessed.
Rationale for change
Target region was not correctly described.
11.2
GLOBAL AMENDMENT 2
Date of amendment
22 Oct 2021
EudraCT number
EU number
2020-000189-41
BI Trial number
1368-0024
BI Investigational Medicinal 
Product(s)
Spesolimab, BI 655130
Title of protocol
An open-label, single arm, long term trial of 
Spesolimab treatment in patients with Palmoplantar 
Pustulosis (PPP) who have completed previous BI 
Spesolimab trials
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Flow Chart incl. foot note 6 and Section 5.2.1
Physical examination
Description of change
Flow Chart: the word “weight” was removed;
Foot note 6 to Flow Chart: “incl. weight” was 
added to “complete physical examination”;
Section 5.2.1: separate sentence on weight 
measurement was removed. “incl. weight” added to 
complete physical examination”, “without weight” 


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added to targeted physical examination.
Rationale for change
Clarification for the time point of the weight 
measurement was needed => weight measurement 
only at the time points of COMPLETE physical 
examination.
Section to be changed
Flow Chart
Description of change
End of Study (EoS): visit window was changed 
from ±7 days to +7 days.
Rationale for change
To cover the whole REP of 16 weeks only the +7 
days visit window is acceptable.  
Section to be changed
Section 3.3.3 Exclusion Criteria 
Description of change
Exclusion criterion nr 14: in addition to the 
conventional units the SI units were newly added. 
Rationale for change
Depending on the country sites are used to work 
with different lab units (conventional vs SI unit). 
To avoid converting of the values by the sites, both 
units are now present.
Section to be changed
4.2.1 Restrictions on previous and concomitant 
medications
Description of change
The following text in brackets was deleted: All 
concomitant or rescue therapies will be recorded 
(including time of intake and dose on study days)
on the appropriate pages of the CRF.
Rationale for change
Time of intake and dose on study days is not 
recorded in the CRF. 
Section to be changed
5.2.2 Vital signs
Description of change
The word “approx.” was added to the time point 
when post-dose vitals signs should be taken.
Rationale for change
Alignment of wording between the following 
sections: footnote nr 7 of Flow Chart, section 5.2.2
“Vital signs” and section 6.2.2. “Treatment 
period”
Section to be changed
5.2.3 Safety laboratory parameters incl. table
Description of change
The words in bold were added: All analyses
(except for the urine pregnancy dipstick tests 
which are done locally at the investigational 
site) will be performed by a central laboratory, the 
respective reference ranges will be provided in the 
ISF.
Table 5.2.3.1: Urine Pregnancy test1 (only for 
female patients of childbearing potential). At the 
drug administration visits, the test will be 
performed and checked at the investigational 
site prior to the administration of study drug.
Urinanalysis: Dipstick (qualitative), test and 
analysis done by central lab…
Rationale for change
Clarification that urine dipstick tests for pregnancy 


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are done at the investigational site but dipstick 
tests for urinalysis (urine macro panel) are done at 
central lab. 
Section to be changed
Table 5.2.3: 1 Safety laboratory tests
Description of change
Urinalysis: Urine RBC/Erythrocytes and 
Urine/WBC Leucocytes has been removed from 
urine dipstick test and were replaced by “Blood”;
Rationale for change
Correction was needed because the dipstick 
urinalysis analyses “blood” only; in case urinalysis 
is positive, microscopic analysis is performed for 
Urine Sediment Erythrocytes and Urine Sediment 
Leucocytes;
Section to be changed
5.2.6.2.1 AE Collection
Description of change
Text was corrected to reflect that after the 1st IMP 
administration in the extension trial, no further AE 
updates should be done in the parent trial.
Rationale for change
Time of 1st IMP administration in the extension 
trial has been defined as EoS for the parent trial. 
After EoS no further updates are to be made for 
the parent trial. 
Section to be changed
6.2.1 Screening period (Medical History)
Description of change
Following information was added: “If a new 
condition developped but recovered during the 
parent trial this can be recorded in the extension 
trial if considered relevant information by the 
investigator.”
Rationale for change
Clarification was needed for conditions that are not 
considered “ongoing” from the parent trial 
(baseline condition) but were not yet medical 
history when the parent trial started as they 
developed during the parent trial, e.g. recovered
AE during parent trial which does not qualify as 
baseline condition (because no longer ongoing after 
IC signature for OLE) but is still considered 
relevant information by the investigator can be 
added as medical history.
Section to be changed
6.2.2 Treatment Period
Description of change
Added: Any observed local tolerability reaction, 
e.g. “swelling”, “induration”, “heat”, “redness”, 
“pain”, and other findings should be reported as an 
adverse event.
Rationale for change
Clarification that the type of the observed local 
tolerability reaction should be specified and 
reported as an Adverse Event


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11.3
GLOBAL AMENDMENT 3
Date of amendment
23 Jun 2022
EudraCT number
EU number
2020-000189-41
BI Trial number
1368-0024
BI Investigational Medicinal 
Product(s)
Spesolimab, BI 655130
Title of protocol
An open-label, single arm, long term trial of 
Spesolimab treatment in patients with Palmoplantar 
Pustulosis (PPP) who have completed previous BI 
Spesolimab trials
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Table 1.4.2: 1 Risks 
Description of change
The risk “Peripheral Neuropathy” was added to the 
table including a summary of data and mitigation 
strategy.
Rationale for change
Added to inform about the newly added potential 
risk “peripheral neuropathy” deriving from the 
three cases reported as Guillain-Barré syndrome by 
the investigator in Spesolimab trials (details in the 
CTP). The cases were considered as peripheral 
neuropathy by the external neurologist expert 
panel’s assessment.
Section to be changed
1.4.2 Risks
Description of change
Differentiation between suspected or diagnosed, 
non-severe/non-serious and severe/serious COVID-
19 infection added.
Rationale for change
Clarification was needed because paragraph 
contained unclear instructions. 
Section to be changed
3.3.3 Exclusion criteria
Description of change
The following Exclusion criterion was added: 
“Presence of acute demyelinating neuropathy.”
Rationale for change
Added as mitigation strategy to account for the 
three cases reported as Guillain-Barré syndrome by 
the investigator in Spesolimab trials. The cases 
were considered as peripheral neuropathy by the 
external neurologist expert panel’s assessment 
(details in the CTP). This way the selection of 
patients with acute demyelinating neuropathy 
would be avoided.


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Section to be changed
3.3.4.2 Implications due to loss of treatment 
response
Description of change
“Patients who need to take rescue medication need 
to be discontinued from the trial. Rescue therapy is 
defined as the use of topical corticosteroids or other 
topical treatment applied on the palms and/or soles, 
systemic immunomodulating treatments or 
biologics and therapy such as tonsillectomy, for the 
treatment of worsening of PPP. For the complete 
list and all details of restricted medication see 
Section 4.2.1 and Table 4.2.1: 1.”
was changed to
“Patients who need to take rescue medication must
be discontinued from the trial. Rescue therapy is 
defined as the use of topical corticosteroids or other 
topical treatment, systemic immunomodulating 
treatments or biologics and therapy such as 
tonsillectomy, for the treatment of worsening of 
PPP. For the complete list and all details of 
restricted medication see Section 4.2.1 and Table 
4.2.1: 1.”
Rationale for change
Clarification was needed that patients must be 
discontinued in case of rescue medication and the 
definition of rescue medication was updated to 
cover also cases where a PPP worsening extends 
beyond palms/soles.
Section to be changed
3.3.4.2 Implications due to loss of treatment 
response
Description of change
“A patient who meets the trial treatment 
discontinuation criteria may be discontinued from 
the trial treatment and administered standard of 
care therapy as judged by the investigator. “ 
was changed to
“A patient who meets the trial treatment 
discontinuation criteria at 2 consecutive visits must
be discontinued from the trial treatment and 
administered standard of care therapy.”
Rationale for change
Update was needed to ensure that patients who 
have no longer a benefit from the IMP discontinue 
the trial and receive treatment acc. to local standard 
of care.
Section to be changed
3.3.4.3 Implications of specific adverse events
Description of change
Following information was added:
“Peripheral Neuropathy
If peripheral neuropathy is suspected, treatment 
with spesolimab should be temporarily 


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discontinued until a full neurological investigation 
has been conducted.
After completion of the neurological investigation, 
treatment can be restarted based on medical 
judgement of the investigator.”
Rationale for change
Added as mitigation strategy to account for the 
three cases reported as Guillain-Barré syndrome in 
Spesolimab trials. The cases were considered as 
peripheral neuropathy by the external neurologist 
expert panel’s assessment (details in the CTP). 
Section to be changed
4.2.1 Restrictions on previous and concomitant 
medications and table 4.2.1: 1
Description of change
1) Other systemic immunomodulating treatment is 
not allowed for the treatment of PPP but no 
longer prohibited for other conditions.
2) Topical treatment for PPP is now prohibited on 
all areas affected by PPP, even if extended 
beyond palms/soles;
3) Topical corticosteroids for other conditions 
than PPP are now prohibited on all regions 
affected by PPP, not only on palms/soles;
4) Topical treatments (other than topical 
corticosteroids) for other conditions than PPP 
are now allowed if they do not affect the PPP 
assessment.
5) Footnote to table 4.2.1: 1 adapted and the word 
“should” was replaced by the word “must”. 
Rationale for change
1) To get in alignment with the parent trial where 
the same approach was followed. 
2) To cover also cases where the topical treatment
for PPP extends beyond palms/soles– this 
change is connected with the change of “3.3.4.2 
Implications due to loss of treatment response”;
3) To cover also cases where topical 
corticosteroids are applied to other regions 
where PPP might extend to.
4) To prohibit topical treatments (other than 
topical corticosteroids) only to regions that may 
affect the PPP assessment.
5) To clarify that patients must be discontinued if 
prohibited medication is taken and to clarify 
that in case of discontinuation “EoT”- and 
“EoS”-visit needs to be done.
Section to be changed
5.2.6.1.4 Adverse events of special interest
Description of change
Added Peripheral Neuropathy as an Adverse events 




 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
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Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
 
TRIAL STATISTICAL ANALYSIS PLAN
c37761029-02
BI Trial No.:
1368-0024
Title:
Trial Statistical Analysis Plan
An open-label, single arm, long term trial of Spesolimab
treatment in patients with Palmoplantar Pustulosis (PPP) who 
have completed previous BI Spesolimab trials [c29867818-02]
Investigational
Product(s):
Spesolimab, BI 655130
Responsible trial 
statistician(s):
Tel.: 
, Fax: 
Tel.: 
, Fax: 
Date of statistical 
analysis plan:
13 SEP 2022 SIGNED
Version:
2.0
Page 1 of 55
Proprietary confidential information
! 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.




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7.7
EXTENT OF EXPOSURE.................................................................................33
7.8
SAFETY ANALYSIS..........................................................................................33
7.8.1
Adverse Events ....................................................................................................33
7.8.2
Laboratory data ..................................................................................................36
7.8.3
Vital signs.............................................................................................................38
7.8.4
ECG......................................................................................................................38
7.8.5
Local tolerability .................................................................................................38
7.8.6
Immunogenicity...................................................................................................38
7.9
ANALYSIS OF COVID-19 IMPACT...............................................................39
7.10
HANDLING OF DMC ANALYSES .................................................................39
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............40
9. 
REFERENCES....................................................................................................41
11.
HISTORY TABLE..............................................................................................55


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases of the study.......................................................15
Table 6.2: 1
Important protocol deviations ..........................................................................16
Table 6.3: 1
Subject sets analysed........................................................................................20
Table 6.7: 1
Time windows for assignment of vital signs to visits for statistical analysis ..25
Table 6.7: 2
Time windows for assignment of efficacy, safety lab, and biomarker 
measurements to visits for statistical analysis..................................................26
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events 
Concepts...........................................................................................................35


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADAs
Anti-drug antibodies
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
BI
Boehringer Ingelheim
BIcMQ
Boehringer Ingelheim customized MedDRA Query
BMI
Body mass index
RPM 
Report planning meeting
CARE
Clinical data analysis and reporting environment
CRF
Case report form
CTA
Clinical trial authorizations
CTP
Clinical trial protocol
CTR
Clinical trial report
DBLM
Database lock meeting
DMC
Data monitor committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eDISH
Evaluation of drug-induced serious hepatotoxicity
EMA
European medicines agency
EOS
End of study
EOT
End of treatment
ES
Enrolled set
EudraCT
European union drug regulating authorities clinical trials
IB
Investigator’s brochure
ICH
International council for harmonisation of technical requirements for 
pharmaceuticals for human use


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Term
Definition / description
iPD
important protocol deviation
ISF
Investigator site file
LD
Day of last treatment received
MAA/BLA
Market Authorization Application/Biologics Licence Application
MACE
Major adverse cardiovascular event
MedDRA
Medical dictionary for regulatory activities
MQRM
Medical quality review meeting
Nab
Neutralizing antibody
NMSC
Non-melanoma skin cancer
NRI
No response imputation
OC
observed cases excluding values after any use of rescue medication or 
6 weeks following last drug administration if patient early 
discontinued treatment
OC-IR
Observed cases including values after rescue therapy or treatment 
discontinuation
OLE
Open label extension
OR
Original results
PD
Protocol deviation
PGA
Physician global assessment
PK
Pharmacokinetic(s)
PRO
Patient-reported outcome
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
RAGe
Report appendix generator
RCTC
Rheumatology common toxicity criteria
REP
Residual effect period
RPM
Report plan meeting
s.c.
subcutaneous
SAE
Serious adverse event


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Term
Definition / description
SAF
Safety analysis set
SAF-MT
Safety analysis set for maintenance treatment
SAP
Statistical analysis plan
SASTM
Statistical analysis software TM
SD
Standard deviation
SDL
Subject data listing
SI
Système international d’unités
SMQ
Standardised MedDRA query
SOC
System organ class
TB
Tuberculosis
TEAE
Treatment emergent adverse event
TS
Treated set
TS-MT
Treated set for maintenance treatment
TSAP
Trial statistical analysis plan
UDAEC
User-defined adverse event categories
ULN
Upper limit of normal range
WHO-DD
World health organisation – drug dictionary
WOCBP
Women of childbearing potential






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5.
ENDPOINTS(S)
For the summary of all efficacy data, only those observations which were collected during the 
on-treatment period will be used.
For estimand and handling of missing data and the occurrence of inter-current events, unless 
otherwise specified, see Section 6.3 and Section 6.6.
Regarding the analyses of the change from baseline by visit or compared to baseline by visit 
for efficacy endpoints, unless otherwise specified, the baseline in parent trial is used, which 
refers to the last measurement collected prior to initiation of treatment in parent trials. 
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is the occurrence of treatment emergent adverse events (TEAEs) up to 
week 260 of maintenance treatment.
Please refer to Section 7.8.1 for the description of the calculation of exposure-adjusted 
adverse event incidence rates.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable. No key secondary endpoints have been specified in the CTP.
5.2.2
Secondary endpoint(s)
Secondary endpoints are defined as described below. Note that for the secondary endpoints, 
any data collected after use of any rescue therapy or after 6 weeks following discontinuation 
of treatment (to allow for incorporation of the continuing maximum treatment effect period) 
in current trial are censored for the purpose of the primary estimand. This approach is in line 
with parent trial 1368.16.
∀
Percent change in PPP ASI from baseline in parent trial at week 48, 96, 144, 192, 240 
and 260
∀
Proportion of patients with PPP ASI50 compared to baseline in parent trial at week 
48, 96, 144, 192, 240 and 260
∀
Proportion of patients with PPP PGA of 0 (clear) or 1 (almost clear) at week 48, 96, 
144, 192, 240 and 260
Derivations of PPP ASI related endpoints and PPP PGA related endpoints are described in 
Section 10.1.1 and Section 10.1.2.


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5.4
OTHER VARIABLE(S)
5.4.1
Safety endpoints
Intensity of adverse events is assessed by Rheumatology Common Toxicity Criteria (RCTC) 
version 2.0.
Safety is assessed based on:
∀
Adverse events
∀
Safety laboratory values
Tests are listed in CTP Table 5.2.3: 1. 
Lab tests are planned to be performed at the central laboratory service provider. 
∀
Physical examination (documentation as baseline condition or AE)
∀
Vital signs, including
o
body temperature
o
pulse rate
o
systolic blood pressure
o
diastolic blood pressure
o
respiratory rate
∀
Relevant findings in 12-lead ECG (documentation as baseline condition or AE)
∀
Local tolerability
Local tolerability will be assessed by the investigator according to ‘swelling’, 
‘induration’, ‘heat’, ‘redness’, ‘pain’, or other findings.
∀
ADA (anti-drug antibody), as detailed in the lab manual
5.4.2
Demographic and other baseline characteristics
Standard demographic data and baseline characteristics are used as recorded in the eCRF. 
These include sex, weight, height, BMI, race, ethnicity, age, site region and smoking history.


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BMI will be calculated as weight [kg] / height [m]2 (based on the last available weight 
measurement prior to the first dose of Spesolimab of extension trial). 
Age [years] will be determined as the difference between year of birth and year of informed 
consent of current study.
Details of smoking history and changes for current extension trial will be summarized in an 
additional output based on treated patients.
Disease characteristics of PPP will describe time since first diagnosis [years] of PPP based on 
treated patients. 
Disease characteristics of plaque psoriasis will describe time since first diagnosis [years]. 
Only treated patients who showed signs of chronic plaque psoriasis at baseline in parent trial 
will be included.
Time since first diagnosis/tonsillectomy [years] will be calculated as the difference between 
date of first diagnosis and date of informed consent of current study, divided by 365.25. For 
calculation in the context of incomplete information on the date of first diagnosis, cf. Section 
6.6.6.
5.4.4
Treatment compliance and treatment exposure
Treatment exposure will be assessed as the total dose of maintenance treatment [mg] 
administered. Per CTP Section 4.1.1, the investigational product is provided in prefilled 
syringes of either 1 mL or 2 mL (PFS-1 or PFS-2) volume, and the unit strength of the 
investigational product is 150 mg in 1 mL solution, the amount of Spesolimab within each 
syringe is 150 mg in 1mL prefilled syringe and 300 mg in 2 mL prefilled syringe. The total 
dose of maintenance treatment [mg] actually received will be calculated as the number of 
PFS-1 syringes actually injected multiplied by 150 mg plus the number of PFS-2 syringes 
actually injected multiplied by the 300 mg, which is:
Actual total dose [mg] =
Actual number of PFS-1  injected × 150 mg + Actual number of PFS-2 injected × 300 mg


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The total duration of exposure will be calculated as the date of last administration of trial 
treatment minus the date of first administration of trial treatment + 1 day.
The treatment compliance per subject (as a % of planned) is defined as the actual total dose 
injected, divided by the total dose that patient should have received, times 100, which is
 !"#$%"&$ '(%)*+#&'" (%) = 0'$1#* $($#* 2(3" [%5]
7*#&&"2 $($#* 2(3" [%5]
= Actual number of PFS-1 injected × 150 mg + Actual number of PFS-2 injected × 300 mg
number of planned visits × 600 mg
× 100.
For the patients who discontinued the study treatment prematurely only the visits on or before 
premature discontinuation will be used for the calculation of overall compliance. 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
The following maintenance treatment is planned in this study:
Spesolimab 600 mg q4w s.c. for up to 5 years for patients who have completed and clinically 
responded to the treatment with study drug (Spesolimab) in previous trials.
The following study phases are defined:
Table 6.1: 1
Flow chart of analysis phases of the study
Study analysis 
phase
Description
Start (included)
End (included)
Screening phase
Screening
Earliest of i) Date of 
informed consent, ii) First 
screening procedure
Date/time of start of injection for 
maintenance study drug minus 1 second
Maintenance 
treatment phase
& Residual 
effect period
Maintenance on-
treatment period
Date/time of start of 
injection of first 
maintenance study drug
(Day 1 for maintenance)
Earliest of: i) Date of injection of last 
maintenance study drug + 112 days at 
23:59, ii) cut-off for interim analysis if 
applicable.
Follow-up1 
phase
Off-treatment 
period
Date of injection of last 
maintenance study drug + 
113 days at 12:00 a m.
Latest of: i) Date of EOS visit (Week 
276 visit); ii) Last contact date on End 
of Study page at 11:59 p m.
Dates are defined individually per patient. If more than one date is associated with a specific visit, measurements 
associated with a specific date are assigned to a study analysis phase according to the rules specified in the table. An 
analysis phase will not extend beyond the start date of the following phase.
1 The follow-up phase only exists if the date of EOS visit or the last contact date is after the date of 
injection/infusion of last study drug + 112 days.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
database (i.e., enrolled patients). Consistency check listings (for identification of violations of 
time windows) and a list of protocol deviations will be provided to be discussed at the 
RPM/DBLM/MQRM. At this meeting, it will be decided whether a discrepant data value can 
be used in analyses or whether it must be queried in the clinical database. Each protocol 
deviation must be assessed to determine whether it is an important Protocol Deviation (iPD). 
For definition of iPDs, and for the process of identification of these, refer to the BI reference 
document "Identify and Manage Important Protocol Deviations (iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM/MQRM minutes via an accompanying Excel spreadsheet (3). The following 
table contains the categories which are considered to be iPDs in this trial. If the data show 
other iPDs, for example, based on monitor visits to the sites, then this table will be 
supplemented accordingly by the time of the RPM/DBLM/MQRM. Not all iPDs will lead to 


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exclusion from analysis sets. IPDs leading to exclusion from analysis sets are indicated as 
such in Table 6.2: 1.
As this is an open label, long term safety trial, all analyses will be performed based on the 
treated population only. Since no confirmatory efficacy testing is planned, no efficacy related 
iPDs leading to exclusion from analysis set are defined.
Table 6.2: 1
Important protocol deviations
Category/
Code
Description
Comments
Excluded 
from
A
Entrance criteria violated
A1
Inclusion criteria not met
A1.01
Have not completed treatment period in the 
parent trial
LABEL: No completion of treatment period in 
parent trial
Inclusion criterion 2
None
A1.02
Have not obtained an individual health benefit, 
per investigator judgement (e.g. PPP PGA of 0 
(clear) or 1 (almost clear) or other clinical 
improvement), from treatment in the parent 
trial
LABEL: No individual health benefit from 
parent trial
Inclusion criterion 3
None
A1.03
Women of childbearing potential (WOCBP) 
who do not use highly effective methods of 
birth control per ICH M3 (R2) that result in a 
low failure rate of less than 1% per year when 
used consistently and correctly
LABEL: Contraception methods not used for 
WOCBP
Inclusion criterion 4
None
A2
Exclusion criteria met
A2.01
Be pregnant, nursing, or plan to become 
pregnant while in the trial
LABEL: Pregnant or nursing
Exclusion criterion 1
None


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Table 6.2: 1 Important protocol deviations (continued)
Category/
Code
Description
Comments
Excluded 
from
A2.02
Have experienced study treatment-limiting 
adverse events during parent trial
LABEL: Treatment-limiting AE during parent 
trial
Exclusion criterion 2
None
A2.03
Congestive heart disease, as assess by the 
investigator
LABEL: Congestive heart disease
Exclusion criterion 4
None
A2.04
Known history of lymphoproliferative disease
LABEL: Lymphoproliferative disease
Exclusion criterion 6
None
A2.05
Any documented active or suspected 
malignancy or history of malignancy within 5 
years prior to screening in parent trial, except 
appropriately treated basal cell carcinoma of 
the skin, squamous cell carcinoma of the skin 
or in situ carcinoma of uterine cervix
LABEL: Malignancy
Exclusion criterion 7
None
A2.06
Have developed active or severe infective 
disease and opportunistic infections/infective 
diseases
LABEL: Infective disease
Exception: Patients with latent TB during 
preceding trial are allowed to be included in the 
extension study, provided they have received 
and/or receive currently appropriate treatment 
according to local guidelines.
Exclusion criterion 8
None
A2.07
Any restricted medication as specified in CTP 
or any drug considered by investigator likely to 
interfere with the safe conduct of the study 
since the last visit of parent trial and during 
screening period for current trial #
LABEL: Restricted medication interfering 
safety
Exclusion criterion 9
None


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Table 6.2: 1 Important protocol deviations (continued)
Category/
Code
Description
Comments
Excluded 
from
A2.08
History of allergy/hypersensitivity to a 
systemically administered trial medication 
agent or its excipients
LABEL: Allergy/hypersensitivity to trial 
medication
Exclusion criterion 11
None
A2.09
Presence of acute demyelinating neuropathy
LABEL: Acute demyelinating neuropathy
Exclusion criterion 18
None
B
Informed consent
B1
Informed consent not available/not done
LABEL: IC not available
Date of informed 
consent missing or no 
signature on patient’s 
“Declaration of 
Informed Consent”
All analyses
B2
Informed consent too late
LABEL: IC too late
Date of informed 
consent not obtained 
prior to any study 
related procedure.
Minimum requirement 
for initial informed 
consent <= date of Visit 
1/date of any study 
procedure; a late 
signature but subject 
was fully informed and 
gave their consent 
verbally before or a 
new informed consent 
version signed late but 
subject’s rights, safety 
or wellbeing were not 
impacted. If this is 
documented later on 
and signed by the 
subject, such cases do 
not qualify as iPD.
None
C
Trial medication
C1
Incorrect treatment medication dose received 
by patients
LABEL: Incorrect medication dose 
administration
Treatment dose > 1200 
mg within 4 weeks.
None


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Table 6.2: 1 Important protocol deviations (continued)
Category/
Code
Description
Comments
Excluded 
from
D
Concomitant medication
D1a
Use of not allowed medication or non-drug 
therapies as per protocol for other reason before 
last drug administration #
LABEL: Restricted medication for other reason
None
D1b
Use of not allowed medication or non-drug 
therapies as per protocol for Covid-19 before 
last drug administration #
LABEL: Restricted medication for Covid-19
None
D1c
Use of rescue medication and not discontinued 
from the trial treatment
LABEL: Rescue medication and not trial 
treatment discontinuation
None
G
Pregnancy test
G1
Pregnancy test not done for woman of 
childbearing potential per CTP flowchart #
LABEL: Pregnancy test not done
Urine pregnancy test 
not done at any visit 
where such is 
scheduled, and serum 
pregnancy test not done 
when urine pregnancy 
test showed positive 
results.
None
# PD will be detected manually;
6.3
SUBJECT SETS ANALYSED
The following analysis sets will be defined for this trial:
Enrolled set (ES)
This patient set includes all patients who signed informed consent. It will be used for display 
of patient disposition.
Safety analysis set for maintenance treatment (SAF-MT)
This patient set includes all patients who received at least one dose of the maintenance 
treatment. This set will be used for presentation of iPDs, patient listings, safety and efficacy 
during the maintenance part of the extension trial.


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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.
Table 6.3: 1
Subject sets analysed
Class of endpoint
Subject set
ES
SAF-MT
Disposition
OR
Compliance and exposure
OR
iPD
OR
Baseline conditions/medical history
OR
Concomitant medications
Concomitant non-drug therapies
OR
Demographics
Baseline characteristics
OR
Primary endpoint
OR
Secondary endpoints
OC: for continuous 
efficacy endpoints
OC-NRI: for binary 
efficacy endpoints
Further endpoints
OC: for continuous 
efficacy endpoints
OC-NRI: for binary 
efficacy endpoints
AE
OR
Lab data, vital signs
OR
OC-IR
NRI = Non Response Imputation, cf. Section 6.6.2.
OC = observed cases excluding values after any use of rescue medication or 6 weeks following last drug administration if 
patient early discontinued treatment, OC-IR = observed cases including also values after any rescue medication or treatment 
discontinuation, OR = original results.


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6.5
POOLING OF CENTRES
All patients from all centres will be pooled for descriptive analyses.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Section 7.3 of the CTP describes the handling of missing data.
The original results (OR) approach implies the presentation of data exactly as observed (not 
using time windows).
OR analysis will be performed on parameters and endpoints that are either not affected by 
patients’ rescue therapy use (e.g. plasma concentration level of Spesolimab, rescue therapy 
use itself), or, if it is not meaningful to apply any imputation rule for the replacement of 
missing values.
6.6.1
Withdrawals
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.
6.6.2
Efficacy data
Based on the different reasons for patients’ data missing for different endpoints, various 
approaches will be used to assess the impact of missing data on the efficacy endpoints of this 


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trial, depending upon the type of the endpoint (cf. Table 6.3: 1). Approaches to be applied are 
described below.
Continuous efficacy endpoints
For efficacy endpoints which are continuous in nature, the following imputation strategy will 
be applied to display the continuous efficacy data. 
∀
Observed cases (OC) approach will include all collected data, with no imputation 
performed on the missing data. Such an OC approach will exclude all values 
measured after intake of a rescue therapy or after 6 weeks following last drug 
administration if a patient discontinued treatment early.
∀
Observed cases including all observed data (OC-IR) will be used as a sensitivity 
method for data display and is an extension of the OC approach which includes 
additionally all values which were measured after rescue therapy or treatment
discontinuation.
Binary efficacy endpoints
For all binary endpoints (i.e. endpoints that are either 1 (patient responded) or 0 (patient did 
not respond)), the following will be performed as the primary imputation approach (analysis 
type: No Response Imputation [NRI]):
∀
If there are data at visits both before and after the visit with a missing outcome, 
then impute as success only if both neighbouring visits also represent a success 
(independent of whether the preceding and following observations were selected 
for analysis based on time windows described in Section 6.7 and no rescue 
treatment has been given during this period);
∀
Otherwise, impute as a failure to achieve a response;
∀
Only patients continuing at this visit per analysis time window will be included in 
the denominator, excluding also ongoing patients before achieving this visit due to
interim cut-off.
6.6.3
Safety data
From CTP Section 7.3: For the safety data, including the primary endpoint, no missing data 
imputations are planned.
For safety data that are not displayed by visit such as AE and possibly clinically significant 
laboratory abnormality, the following describes the approach to be used for the descriptive 
reporting:


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∀
Original results (OR).
For safety data that are displayed by time point (or visit) of measurement, the following
approach is to be used for the descriptive reporting:
∀
Observed cases (OC-IR) approach will be used, with no imputation for any 
missing data, which will include values after any rescue medication or treatment 
discontinuation (see Section 6.3).
The only exceptions where imputation might be necessary for safety evaluation are AE dates 
and start and stop dates for concomitant medications. Missing or incomplete AE dates are 
imputed according to BI standards (4).
Partial start and stop dates for concomitant medications, rescue and historical medication for 
PPP will be imputed to enable subsequent calculation (but not for display) by the following 
“worst case” approach:
∀
If the day of the end date is missing, then the end date is set to last day of the month 
(or to the patient's trial completion date, if it is earlier than the last day of the month).
∀
If the day and month of the end date are missing then the end date is set to 31st of 
December of the year (or to the patient's trial completion date, if it is earlier than the 
31st of December of the year).
∀
If the day of the start date is missing the start date is set to first day of the month 
(except for rescue therapy, where the first dosing day will be used if first dosing 
happened in the same month).
∀
If the day and month of the start date are missing then the start date is set to 1st 
January of the year (except for rescue therapy, where the first dosing day/month of 
study medication will be used if first dosing happened in the same year).
∀
All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance.
If a concomitant medication was ticked to be ongoing, it is expected that the end date is 
missing and will not be imputed for display purposes.


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6.6.6
Time since first diagnosis/tonsillectomy
Time since first diagnosis is derived as specified in Section 5.4.2. The handling of 
missingness will follow the rule implemented in the parent trial described as below.
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows:
∀
If the year of first diagnosis is unknown, time since first diagnosis will be set to 
missing.
∀
If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th June of that year.
∀
If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month.
Time since tonsillectomy will be imputed in the same way.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Measurements reported with date and time and taken prior to start of administration of trial 
treatment will be considered pre-treatment values. Measurements reported with a date only 
(and no time) and taken on the day of first administration of trial treatment will also be 
considered pre-treatment values. These pre-treatment values will be assigned to visits 
according to the nominal visit number as recorded on the eCRF or as provided by the 
laboratory.
Baseline, unless otherwise specified, is defined as the last measurement collected prior to the 
start of administration of the trial treatment.
Baseline for “change from baseline” or “compared to baseline” types of efficacy endpoints , 
unless otherwise specified, is defined as the last measurement collected prior to the start of 
administration of the trial treatment in the parent trial. Baseline for time to event endpoints, is 
defined as the last measurement collected prior to the start of administration of the trial 
treatment in the current extension trial.
Measurements taken after start of administration of trial treatment will be considered either 
on- or off-treatment values based on the definition in Section 6.1, and will be assigned to 
visits for statistical analysis, if applicable, as defined below.
Analysis of AE data, potentially clinically significant abnormal laboratory values, 
concomitant medication, or non-drug therapies, as well as use of rescue therapy will not be 
based on visits. Frequency tables for these data will be using on-treatment data and 
categorized based on their occurring/starting dates. Therefore, no assignment to time 
windows will be necessary for such data.


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The derivation of the last value, minimum value and maximum value of laboratory and vital 
signs data will consider all on-treatment values (whether or not selected in any time window; 
see Table 6.1: 1 for definition of the on-treatment period) within the period of interest; these 
will be derived for analysis of laboratory and vital signs data. For identification of potentially 
clinically significant abnormal laboratory values, all values (whether or not selected in any 
time window) within the on-treatment period will be considered.
All other safety, efficacy 
 measurements will be assigned to visits based on 
extended time windows around the planned visit dates, defined relative to the day of first trial
treatment (which is scheduled for Visit V2). 
The extended time windows for vital signs are defined in Table 6.7: 1 and the extended time 
windows for efficacy, safety lab, 
 measurements are defined in Table 6.7: 2.
Table 6.7: 1
Time windows for assignment of vital signs to visits for statistical analysis
Visit 
number
/name
Planned 
day
Time window (Days)
Visit label
Window
(per CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V1*
Screening
-28 to -1
n/a
V2*
Day 1
Day 1
+/-0
1 A
1 A
≤1 A
1 A
Planned On-Treatment Data
V3
Week 4
Day 29
+/-7 
22
36
2
43
V4
Week 8
Day 57
+/-7
50
64
44
71
V5
Week 12
Day 85
+/-7
78
92
72
99
V6
Week 16
Day 113
+/-7
106
120
100
127
…
…
…
…
Planned 
date-7
Planned 
date+7
End of 
extended 
window of 
last visit+1 
Midpoint 
of planned 
days 
between 
current 
visit and 
next visit
V67/
EOT
Week 260/
EoT
Day 1821
+/-7
1814
1828
End of 
extended 
window of 
last visit+1
LDB +112
Planned Off-Treatment Data
EOS
Week 276/
EoS
Day 1933
+7
1933
1940
LDB +113
Day of last 
f-up value
Days are counted relative to the day of first s.c. treatment in maintenance period, which is defined 
as Day 1 for maintenance.
* For the patients who enter OLE trial, V1 is strongly recommended to be performed during the EOT of 
the preceding parent trial, and the maximum days allowed between EOT of parent trial and V1 is 28 days
(may be extended on a case by case basis); V2 is considered as/identical to the EOS of parent trial.
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made 
after start of infusion of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be
assigned to Day 1. Such data will be listed only.
B LD=Day of last maintenance treatment received.


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Table 6.7: 2
Time windows for assignment of efficacy, safety lab, 
 
measurements to visits for statistical analysis
Visit 
number
/name
Planned 
day
Time window (Days)
Visit label
Window
(per CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V1*
Screening
-28 to -1
n/a
V2*
Day 1
Day 1
+/-0
1 A
1 A
≤1 A
1 A
Planned On-Treatment Data
M1
Week 16
Day 113
+/-7 
106
120
2
169
M2
Week 32
Day 225
+/-7
218
232
170
281
M3
Week 48
Day 337
+/-7
330
344
282
393
M4
Week 64
Day 449
+/-7
442
456
394
505
…
…
…
…
Planned 
date-7
Planned 
date+7
End of 
extended 
window of 
last visit+1 
Midpoint 
of planned 
days 
between 
current 
visit and 
next visit
M16
Week 256
Day 1793
+/-7
1786
1800
1738
1807
M17/
EOT
Week 260/
EoT
Day 1821
+/-7
1814
1828
End of 
extended 
window of 
last visit+1
LDB +112
Planned Off-Treatment Data
EOS
Week 276/
EoS
Day 1933
+7
1933
1940
LDB +113
Day of last 
f-up value
Days are counted relative to the day of first s.c. treatment in maintenance period, which is defined 
as Day 1 for maintenance.
* For the patients who enter OLE trial, V1 is strongly recommended to be performed during the EOT of 
the preceding parent trial, and the maximum days allowed between EOT of parent trial and V1 is 28 days 
(may be extended on a case by case basis); V2 is considered as/identical to the EOS of parent trial.
A Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made 
after start of infusion of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be 
assigned to Day 1. Such data will be listed only.
B LD=Day of last maintenance treatment received.
Repeated and unscheduled efficacy, safety 
 measurements will be handled 
similarly to scheduled measurements and will also be assigned to a time window depending 
upon the date of measurement.
Only one observation per time window will be selected for statistical analysis at a particular 
visit – the value which is closest to the protocol planned visit day will be selected. If there are 
two observations which have the same difference in days to the planned day, the later value
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 the implement of estimand concepts. For example, for the


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OC method, values after rescue therapy intake or 6 weeks following last treatment in case of 
discontinuation should be censored first before assignment of efficacy endpoints.
For visits without an assigned value based on time windows, a value will thereafter be 
imputed (if needed) as defined in Section 6.6. Imputation of efficacy endpoints, when 
applicable, will be performed based on all available observations meeting the imputation 
rules, irrespective of whether the observation was selected in any time window.




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Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treated patient set. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actual missing values. Percentages will be 
based on all patients in the respective patient set whether they have non-missing values or not 
if there is no other particular specification.
Disposition of the patient population participating in the trial will be summarised by 
presentation of the frequency of patients enrolled, treated, enrolled but not treated, who 
completed all doses of trial medication as planned, who completed the trial (EOS), who were 
prematurely discontinued study treatment, by reason and who withdrew from the trial, by 
reason. The frequency of patients with iPDs will be presented; the iPDs will be listed per 
patient.
To better illustrate the long-term disposition of entire maintenance treatment (cf. Section 6.1), 
a summary table regarding patient status over time will be added. The cumulative frequency 
of patients for the following categories will be displayed based on 16-week intervals:
∀
Ongoing on study medication, i.e., without early treatment discontinuation by the time 
point
o
Intake of rescue medication
∀
Pre-maturely stopped study medication, i.e., discontinued study medication by the 
time point
o
Intake of rescue medication
o
Death
o
Any of the above
∀
Ongoing but not achieved the visit
o
Intake of rescue medication
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Descriptive statistics will 
be presented for baseline characteristics for overall population and patients with plaque 
psoriasis ongoing at the baseline of extension trial.
For demographic variables listed in Section 6.4, they will be presented by the number and 
percentage of patients in the categories defined in Section 6.4.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.


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Concomitant diseases (i.e. baseline conditions) and concomitant non-drug therapies will be 
coded according to the most recent version of Medical Dictionary for Drug Regulatory 
Activities (MedDRA). Concomitant medications will be coded according to the most recent 
version of the World Health Organisation – Drug Dictionary (WHO-DD). 
Concomitant diseases which are present at start of the study will be descriptively 
summarized.
A medication/non-drug therapy will be considered concomitant to treatment, if it
∀
is ongoing at the start of current extension trial treatment or
∀
starts within the on-treatment period (see Section 6.1 for the definition).
A medication/non-drug therapy will be considered as prior medication/non-drug therapy, if 
the end date of the medication/therapy is at any time prior to the start of trial treatment.
Concomitant medication use (excluding rescue therapy) taken any time during the on-
treatment period (cf. Section 6.1) will be summarized with frequency and percentage of 
patients by Anatomical Therapeutic Chemical 3 (ATC3) class and preferred name. 
Concomitant use of non-drug therapies (excluding rescue therapy) taken any time during the 
on-treatment period (cf. Section 6.1) will be summarized with frequency and percentage of 
patients. 
Use of rescue therapy will be summarized separately (see Section 7.6.3). 
7.3
TREATMENT COMPLIANCE
Treatment compliance (see Section 5.4.4 for the definition and calculation) will be 
summarized for the SAF-MT using descriptive statistics (N, mean, SD, minimum, median, 
maximum). 
The number and percentage of patients with the following overall compliance categories will 
be presented:
∀
"< 80% of planned",
∀
"80 to 120% of planned" and
∀
"> 120% of planned".
7.4
PRIMARY ENDPOINT(S)
Refer to Section 7.8.1 for the description for adverse events including the primary endpoint.


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
Descriptive summaries and graphical displays (line plots) will be produced using OC method 
for continuous secondary endpoints and OC-NRI method for binary secondary endpoints 
respectively. 


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7.7
EXTENT OF EXPOSURE
An overall table will be summarized for the entire maintenance treatment period. The number 
of subjects who received a dose of trial drug will be tabulated. The amount of treatment 
received [mg] will be summarised by descriptive statistics (N, mean, SD, minimum, median, 
maximum). The total duration of exposure [days] will also be displayed.
7.8
SAFETY ANALYSIS
All safety analyses will be performed for the SAF-MT following BI standards. No hypothesis 
testing is planned.
For the overall maintenance treatment period, the AE data and possibly clinically significant 
laboratory abnormalities will be analysed under OR estimand concept (as defined in Section 
6.6.3); the safety data by visit, i.e., laboratory, vital signs and local tolerability, will be 
analysed under OC-IR estimand concept (as defined in Section 6.6.3).
As the onset time of an AE will not be collected in the trial, any AE which occurs on the 
same day as a treatment dose will be assigned to the “post treatment”. For safety assessments 
by visits, if time is not collected, data on the same day of a treatment dose will be treated to 
be “prior treatment” except for scheduled local tolerability and post-dose vital signs 
assessments.
Off-treatment data will be listed only.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
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 details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event data from Clinical Trials " (6), "Analysis and Presentation of Adverse Event 
data from Clinical Trials – Display Template" (7) and "Handling of missing and incomplete 
AE dates" (4).
The analysis of AEs will be based on the concept of treatment emergent AEs. This means that 
all AEs will be assigned to the screening period, maintenance period (i.e. maintenance 
treatment phase plus REP) or off-treatment period (i.e. follow up) as defined in Section 6.1. 
Since only the start date of an AE is collected (without start time), any AE occurrence on the 
same day as the first Spesolimab administration will be assigned to the on-treatment phase.


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Exposure-adjusted adverse event incidence rates for TEAE will be calculated using the 
following approach:
1)
The exposure adjusted incidence rate (per 100 subject years) of a selected treatment 
emergent adverse event is defined as the number of subjects experiencing the adverse 
event per treatment group during time at risk divided by the total time of subjects at risk 
to contribute the event to the analysis multiplied by 100 (per 100 subject years), where: 
Time at risk [subject years] = (date of onset of AE – first treatment start date+ 1) / 365.25
2)
If, for a subject, the selected treatment emergent adverse event didn’t occur, then the time 
at risk will be censored at min (date of death, last contact date per EoS page, cut-off date 
for the interim analysis, or the end of on-treatment period). For each selected treatment 
emergent AE, the exposure adjusted incidence rate will be calculated as: 
Incidence rate [1/100 Subject years (pt-yrs)] = 100 * number of subjects with TEAE / 
Total TEAE-specific time at risk [subject years].
An overall summary of AEs will be presented. This overall summary will include summary 
statistics for the class of other significant AEs (sponsor definition based on ICH E3) and for 
the class of AESIs.
Based on the specification provided in ICH E3 (8), the sponsor has defined AEs which are to 
be classified as ‘other significant’. For the current trial, these will include those non-serious 
AEs which were reported with ‘action taken = Drug withdrawn’ or ‘action taken = Dose 
reduced’.
The following is considered an AESI in this trial (see Section 5.2.6.1.4 in CTP):
∀
Systemic hypersensitivity reactions including anaphylactic reaction
∀
Severe infections (according to RCTC grading in CTP Appendix 10.3)
∀
Opportunistic and mycobacterium tuberculosis infections
∀
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST (aspartate transaminase) and/or ALT (alanine 
aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 
fold ULN measured in the same blood draw sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
∀
Peripheral Neuropathy
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.


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In addition, user defined adverse event concepts (UDAEC) identified through specific search 
criteria will be reported separately (see Table 7.8.1: 1).
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events Concepts
User-defined AE category
Label 
Description
Infections 
(serious/severe, 
opportunistic)
Infections ALL
Combined search strategy based on the 
individual UDAECs described below; the 
UDAEC “severe infections (investigator-
defined) will be disregarded for this search
Opportunistic 
infections
Narrow SMQ “Opportunistic infections”
Tuberculosis 
infections
BIcMQ “Infections”:
Narrow sub-search 8.2 “Tuberculosis related 
terms”
Serious infections
all serious events in SOC “Infections and
infestations”
Severe infections
all events in SOC “Infections and infestations”
of at least severe RCTC grade, by HLGT
Hypersensitivity
Hypersensitivity ALL
Combined search strategy based on the three 
individual UDAECs described below
Anaphylactic reaction
Narrow SMQ “Anaphylactic reaction”
Angioedema
Narrow SMQ “Angioedema”
Hypersensitivity
Narrow SMQ “Hypersensitivity”
Malignancies
Malignant tumours
Narrow Sub-SMQ “Malignant tumours”
Narrow Sub-SMQ “Haematological malignant 
tumours”
Narrow Sub-SMQ “Non-Haematological 
malignant tumours”
Malignant skin 
tumours
Broad Sub-SMQ “Skin malignant tumours”
Skin melanomas
HLT Skin melanomas (excl. Ocular)
Non-melanoma skin 
cancer (NMSC) 
Broad Sub-SMQ “Skin malignant tumours”
excluding HLT Skin melanomas (excl. 
Ocular)
Malignancies 
excluding NMSC 
Sub-SMQ “Malignant tumours”  excluding 
NMSC, whereas NMSC is defined above
3-point MACE
3-point MACE
BIcMQ “Major Adverse Cardiovascular Events” 
with  
  Narrow sub-search 1.1 “3-Point MACE (part 
1/2)” 
  Narrow sub-search 1.2 “3-Point MACE (part 
2/2)” *


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Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events 
Concepts (continued)
Label 
Description
Torsades de 
Pointes
Torsades de Pointes
Broad sub-SMQ “Torsade de pointes/QT 
prolongation”
DRESS
DRESS (Drug 
reaction with 
eosinophilia and 
systemic symptoms 
syndrome), broad
Algorithmic SMQ on "Drug reaction with 
eosinophilia and systemic symptoms 
syndrome", broad
Algorithm:
A or (B and C and D) or (B and C and E) or 
(B and D and E)
DRESS (Drug 
reaction with 
eosinophilia and 
systemic symptoms 
syndrome), narrow
SMQ “Drug reaction with eosinophilia and 
systemic symptoms syndrome”, narrow
Peripheral 
neuropathy
Peripheral neuropathy
SMQ “Guillain-Barre syndrome”, narrow;
SMQ “Demyelination”, narrow;
SMQ “Peripheral neuropathy”, narrow
* this is achieved by retrieving all cases found either by running subsearch 1 in narrow scope (BIcMQ search ID 32019093 ) or
subsearch 2 (BIcMQ serach ID 32019094
The exposure-adjusted incidence rate and frequency of patients with AEs will be summarized 
by primary system organ class and preferred term. AEs which were considered by the 
investigator to be drug related will be summarised separately. Separate tables will also be 
provided for patients with SAEs, patients with AESIs, patients with AE leading to 
discontinuation of the trial medication, and patients with other significant AEs (as described 
previously) and User-defined Adverse Event Concepts (UDAEC) (See Table 7.8.1: 1). AEs 
will also be summarized by maximum intensity based on the RCTC measure (see Section 
5.4.1).
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by primary system organ class and preferred term. The frequency of patients with SAEs and 
drug related SAEs will also be summarised respectively.
For disclosure of AE data in the EudraCT register, the frequency of non-serious AEs with an 
incidence of greater than 5 % (in preferred terms) and the frequency of SAEs will be 
summarised.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (9). Note that data from the central Laboratory will be used for all displays 
described below, unless otherwise specified.


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For continuous safety laboratory parameters, normalized values will be derived. 
Normalisation means transformation to a standard unit and to a standard reference range. The 
process of normalisation, handling of repeat values at the same visit for by-visit displays, as 
well as standard analyses for safety laboratory data are described in the BI guidance for the 
Display and Analysis of Laboratory Data (9). All analyses considering multiple times of the 
ULN (as described below) will be based on standardized and not normalized values. For 
continuous safety laboratory parameters, differences to baseline will be calculated. For all 
outputs, the last assessment before the first treatment at Day 1 is chosen as the baseline value.
Only patients with at least one available post-baseline value will be included in the analysis 
of an individual laboratory parameter. All individual laboratory data will be listed. Values 
outside the reference range will be flagged.
For derivation of the last value, the minimum value, and the maximum value, all values 
during the on-treatment period will be considered under OR estimand concept. These will be 
derived for analysis of laboratory, vital signs and local tolerability data. For identification of 
potentially clinically significant abnormal laboratory values, all values during on-treatment 
period will also be considered under OR.
Descriptive statistics of laboratory values over time and for the difference from baseline on-
treatment (see Section 6.7) will be based upon normalized values and provided by visit
(including follow up) under OC-IR estimand concept, including summaries of the last value
on treatment, the minimum value on treatment and the maximum value on treatment.
Graphical displays via box plots will be produced for the change from baseline, over tie, for 
each continuous laboratory endpoint.
Laboratory values will be compared to their reference ranges; shift tables will be provided for 
the number of patients with a specific RCTC grade at baseline versus the grade at the last 
measurement on treatment, as well as the worst grade on treatment. These analyses will be 
based on standardized laboratory values.
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on converted lab values, i.e. using SI units. These rules will be listed in the 
SDL appendix of the CTR. Frequency tables will summarize the number of patients with 
potentially clinically significant abnormalities. Patients having an abnormal lab value at 
baseline will be presented separately. A separate listing will present potentially clinically 
significant abnormal lab values; for each functional lab group all patient’s lab values will be 
listed, if there exists at least one lab value with clinically significant abnormality within the 
group.
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥ 10xULN, and 
≥ 20xULN will be displayed based on standardized laboratory values. To support analyses of 
liver related adverse drug effects, the frequency of patients with AST and/or ALT ≥ 3xULN 
combined with a total bilirubin ≥ 2xULN in a 30 day period after AST/ALT elevation will be 
displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a patient can 
potentially be in both alkaline phosphatase strata in case of multiple AST/ALT and bilirubin 


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elevations). The start of the 30 day time span is triggered by each liver enzyme elevation 
above the defined thresholds. This analysis will be based on standardized laboratory values. 
A graphical analysis of the ALT and total bilirubin during the on-treatment period will also 
be performed; the so called eDISH plot. In the graph, for each subject, the peak total bilirubin 
is presented as a fold increase over the ULN against the peak ALT as a fold increase over the 
ULN, on a log10 scale. The measurements displayed or total bilirubin and ALT may, or may 
not, occur on the same date. Two reference lines, 2xULN for total bilirubin and 3xULN for 
ALT, are drawn onto the graph in order to divide the plane into four quadrants. Normal cases 
are in the lower left quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law 
quadrant), while the lower right quadrant is known as the Temple’s corollary range (ALT ≥ 
3xULN and total bilirubin < 2xULN).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate, body temperature, respiratory rate) 
will be descriptive in nature. Descriptive statistics of vital signs over time and for the 
difference from baseline (see Section 6.7) will be provided, including the last value, the 
minimum value and the maximum value during on-treatment period. 
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
Abnormal findings in 12-lead ECG will be reported as baseline conditions (at screening) or as 
AEs (during the trial) if judged clinically relevant by the investigator, and will be analysed as 
such.
No separate listing or analysis of ECG data will be prepared.
7.8.5
Local tolerability
Local tolerability will be summarized by visit under OC-IR estimand concept, with the 
frequency and percentage of patients who experienced any symptoms by severity/intensity.
7.8.6
Immunogenicity
The ADA status and titer as well as frequency of patients with ADA to Spesolimab will be 
presented by visit. Descriptive statistics of ADA titer (for ADA positive patients, when 
available) will be provided by visit. The number of subjects with ADA status 
positive/negative at any time will also be presented. ADA parameters (e.g. treatment-induced 
ADA positive subjects, transient ADA response and persistent ADA response) will also be 


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presented by visit and cumulatively for the overall study duration. Further exploratory 
assessments of the ADA data will be performed once data is available and these will be 
described, if done, in the CTR.
7.9
ANALYSIS OF COVID-19 IMPACT
There is currently an outbreak of respiratory disease, COVID-19 worldwide which has 
impacted the conduct of this trial. This public health emergency has raised more difficulties 
for patients to meet protocol-specified procedures, including administering or using the 
investigational product or adhering to protocol-mandated visits and laboratory/diagnostic 
testing. Site personnel or trial subjects are also under the risk to get infection with COVID-
19.
The start date for the COVID-19 disruption is defined as March 17th, 2020, which is prior to 
trial initiation, and the end date will be updated in future revision. Consequently, there are 
unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 public and 
individual health control measures. To assess the impact on patients’ safety and drug efficacy 
in this trial, the following analyses are planned:
Disposition and iPD:
Frequency of the patients with missed relevant visits or prematurely discontinued from study 
treatment due to COVID-19 and related non-important and important protocol deviations will 
be listed.
AE related to COVID-19:
If there is any case, AE related to COVID-19 infection will be reported separately.
7.10
HANDLING OF DMC ANALYSES
A fully external DMC, independent of the trial and project teams, will be set-up to review all 
available un-blinded safety data as well as selected efficacy data at regular intervals following 
first-patient-in. A separate DMC SAP which describes the analyses required for assessment 
by the DMC will be produced. Further details are provided in a DMC charter.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
Due to the open-label nature of current trial, the treatment information will be loaded into the 
trial database at trial initiation.






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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-
MMM-YY)
Author
Sections 
changed
Brief description of change
1.0
21-DEC-21
None
This is the initial TSAP with necessary 
information for trial conduct.
2.0
13-SEP-22
Section 
5.4.3
The definition of rescue therapy was updated 
based on amended protocol.
“Rescue therapy is defined as both the use of 
medication such as topical corticosteroids or 
other topical treatment applied on the affected 
palms and/or soles, systemic 
immunomodulating treatments or biologics and 
therapy such as tonsillectomy, for the 
treatment of worsening of PPP.” was changed 
to:
“Rescue therapy is defined as the use of topical 
corticosteroids or other topical treatment, 
systemic immunomodulating treatments or 
biologics and therapy such as tonsillectomy, 
for the treatment of worsening of PPP.”
2.0
13-SEP-22
Section 6.2
In table 6.2:1, A2.09 - ‘Presence of acute 
demyelinating neuropathy, LABEL: Acute 
demyelinating neuropathy’ was added as iPD 
based on exclusion 18 in amended protocol.
2.0
13-SEP-22
Section 6.2
In table 6.2:1, D1c – “Use of rescue 
medication and not discontinued from the trial 
treatment, LABEL: Rescue medication and not 
trial treatment discontinuation” was added as 
iPD, based on updates “Patients who need to 
take rescue medication must be discontinued 
from the trial” in amended protocol.
2.0
13-SEP-22
Section 6.7
In table 6.7:1, time window of EOS visit was 
updated based on amended protocol.
2.0
13-SEP-22
Section 6.7
In table 6.7:2, time window of EOS visit was 
updated based on amended protocol.
2.0
13-SEP-22
Section 
7.8.1
Peripheral neuropathy was added as one of 
AESIs based on amended protocol.
2.0
13-SEP-22
Section 
7.8.1
In table 7.8.7:1, peripheral neuropathy was 
added as one of UDAEC in project level.