Clinical trial NCT05200247
Conditions: Generalized Pustular Psoriasis
Sponsor: Boehringer Ingelheim
Start date: 2022-02-17; Completion date: 2023-03-20
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Expanded Access trial in Japan is open to people with a serious skin disease called Generalized Pustular Psoriasis (GPP). This program provides a medicine called spesolimab to people with a GPP flare-up who have no alternative treatment options.

Participants get a single infusion of spesolimab into a vein. They can get another spesolimab infusion one week after the first infusion if the doctors think it is helpful.

Participants are in the program for about 4 months and visit the study site about 5 to 6 times. The doctors regularly check participants' health and take note of any unwanted effects.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: spesolimab
Intervention descriptions: intervention 1: solution for infusion

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Trial Protocol
 
Document Number:
c36703857-02
BI Trial No.
1368-0073
Project No.
1368-P10
BI Investigational
Medicinal Product(s)
Spesolimab, BI 655130
Title
Multi-centre, open-label, expanded access trial of
spesolimab i.v. in patients with generalized pustular 
psoriasis (GPP) presenting with a flare
Lay Title
An Expanded Access trial in Japan to provide spesolimab to 
people with a flare-up in Generalized Pustular Psoriasis 
who have no other treatment options
Clinal Trial Leader
Tokyo 141-6017, Japan
Telephone:
, Fax: 
Coordinating Investigator
Phone:
, Fax:
Current Version and Date
Final Protocol, version 2.0, 06 Jul 2022
Original Protocol Date
24 Sep 2021
Page 1 of 58
Unless otherwise noted, the term "clinical trial" in the study protocol will be changed to "post
marketing clinical trial" upon marketing approval for spesolimab i.v. for GPP indication in Japan
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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Original Protocol date
24 Sep 2021
Revision date
06 Jul 2022
BI trial number
1368-0073
Title of trial
Multi-centre, open-label, expanded access trial of spesolimab i.v. in 
patients with generalized pustular psoriasis (GPP) presenting with a 
flare
Coordinating 
Investigator
Phone:
Fax: 
Trial site(s)
15 ~ 20 sites in Japan
Trial rationale
Current treatment options for controlling flare of GPP, complete 
resolution of symptoms and prevention of reoccurrence of flares are 
limited and often do not provide sustained efficacy. Moreover, as the 
current treatment options have no reports of randomised double-
blind trials, evidence supporting those is limited.
Some of standard of care therapies are not suitable for life-long 
treatment due to their side effect profile and existing 
contraindications.
Spesolimab has the potential to provide rapid and effective treatment 
to patients with GPP presenting with a flare; therefore, this 
expanded-access clinical trial will offer an opportunity for patients 
with no satisfactory therapeutic options early access to the 
investigational drug spesolimab.
Trial objective(s)
The aim of this trial is to provide early access to the investigational 
drug spesolimab for patients with GPP presenting with a flare. A 
secondary aim of this trial is to collect additional data on the safety 
and tolerability of spesolimab.
Trial endpoints
Primary endpoint: 
∀
Occurrence of treatment emergent adverse events (TEAEs)
Secondary endpoint:
Occurrence of:
∀
Treatment emergent serious adverse events (SAEs)
∀
Treatment emergent adverse events of special interest 
(AESIs).
Trial design
Single-arm, open-label, active treatment


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Number of patients 
entered
There is no recruitment goal for this expanded access trial
Diagnosis
Patients with GPP presenting with a flare
Main in- and exclusion 
criteria
Main Inclusion Criteria:
•
Diagnosis of GPP confirmed based on the JDA guidelines for 
the management and treatment of GPP
•
Patient is experiencing a flare, defined as new or worsening of 
widespread eruption of sterile macroscopically visible pustules, 
with or without systemic inflammation, as assessed by the 
investigator Male or female patients, aged 18 to 75 years at time 
of enrollment.Signed and dated written informed consent in 
accordance with ICH-GCP and local legislation prior to 
admission to the trial.
•
No satisfactory authorized alternative therapy exists, as assessed 
by the investigator.
Main Exclusion Criteria:
•
Severe, progressive, or uncontrolled hepatic disease, defined as 
>3-fold Upper Limit of Normal (ULN) elevation in aspartate 
transaminase (AST) or alanine aminotransferase (ALT) or 
alkaline phosphatase, or >2-fold ULN elevation in total 
bilirubin.
•
Active systemic infections (fungal and bacterial disease) during 
the last 2 weeks prior to drug administration, as assessed by the 
investigator.
•
Relevant chronic or acute infections, including active 
tuberculosis (TB), HIV infection or viral hepatitis at the time of 
drug administration.
•
History of allergy / hypersensitivity to systemically 
administered spesolimab or its excipients.
•
Presence of acute demyelinating neuropathy
BI Medicinal product(s) Spesolimab
dose
900 mg
method and route of 
administration
Intravenous (i.v.)
Duration of treatment
Single dose, with the potential for a second dose one week after 
initial infusion, if deemed necessary by the investigator
Statistical methods
Exploratory descriptive statistics of demographic and safety data 
will be presented as appropriate




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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................5
ABBREVIATIONS AND DEFINITIONS.............................................................................7
1.
INTRODUCTION...............................................................................................10
1.1
MEDICAL BACKGROUND.............................................................................10
1.2
DRUG PROFILE................................................................................................12
1.2.1
Mode of action.....................................................................................................12
1.2.2
Nonclinical pharmacology..................................................................................12
1.2.3
Clinical experience..............................................................................................13
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................16
1.4
BENEFIT - RISK ASSESSMENT/ MEDICAL NEEDS STATEMENT.......16
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................24
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........24
2.1.1
Main objectives....................................................................................................24
2.1.2
Primary endpoint................................................................................................24
2.1.3
Secondary endpoint.............................................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................25
3.1
OVERALL TRIAL DESIGN.............................................................................25
3.2
SELECTION OF TRIAL POPULATION .......................................................25
3.2.1
Main diagnosis for trial entry ............................................................................25
3.2.2
Inclusion criteria .................................................................................................26
3.2.3
Exclusion criteria ................................................................................................27
3.2.4
Discontinuation / withdrawal of patients from trial ........................................27
3.2.4.1
Discontinuation of trial medication and assessment.............................................28
3.2.4.2
Withdrawal of consent to trial participation .........................................................28
3.2.4.3
Discontinuation of the trial by the sponsor...........................................................29
4.
TREATMENTS...................................................................................................30
4.1
INVESTIGATIONAL TREATMENTS ...........................................................30
4.1.1
Identity of the Investigational Medicinal Product ...........................................30
4.1.2
Drug assignment and administration of doses for each patient......................30
4.1.3
Packaging, labelling, and re-supply...................................................................31
4.1.4
Storage conditions...............................................................................................31
4.1.5
Drug accountability.............................................................................................31
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................32
4.2.1
Other treatments and emergency procedures..................................................32
4.2.1.1
Emergency procedures..........................................................................................32
4.2.2
Restrictions ..........................................................................................................33


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4.2.2.1
Restrictions regarding concomitant treatment ......................................................33
4.2.2.2
Restrictions on diet and lifestyle...........................................................................34
4.2.2.3
Contraception requirements..................................................................................34
5.
ASSESSMENTS..................................................................................................35
5.1
ASSESSMENT OF EFFICACY........................................................................35
5.2
ASSESSMENT OF SAFETY.............................................................................35
5.2.1
Physical examination ..........................................................................................35
5.2.2
Vital signs.............................................................................................................35
5.2.3
Safety laboratory parameters ............................................................................35
5.2.4
Assessment of adverse events.............................................................................36
5.2.4.1
Definitions of AEs ................................................................................................36
5.2.4.2
Adverse event collection and reporting ................................................................40
6.
INVESTIGATIONAL PLAN.............................................................................42
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................42
6.1.1
Screening period..................................................................................................42
6.1.2
Treatment period(s)............................................................................................42
6.1.3
Follow up period and trial completion..............................................................43
7.
STATISTICAL METHODS ..............................................................................44
7.1
PLANNED ANALYSES.....................................................................................44
7.1.1
Safety analyses.....................................................................................................44
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........45
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................45
8.2
DATA QUALITY ASSURANCE ......................................................................46
8.3
RECORDS...........................................................................................................46
8.3.1
Source documents ...............................................................................................46
8.3.2
Direct access to source data and documents.....................................................47
8.3.3
Storage period of records ...................................................................................47
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................47
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........48
8.6
TRIAL MILESTONES.......................................................................................48
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................48
9.
REFERENCES....................................................................................................50
9.1
PUBLISHED REFERENCES............................................................................50
9.2
UNPUBLISHED REFERENCES......................................................................53
10.
APPENDICES.....................................................................................................54
10.1
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS...................54
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................55
11.1
GLOBAL AMENDMENT 1 ..............................................................................55


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ABBREVIATIONS AND DEFINITIONS
ADA
Anti-Drug Antibody
ADCC
Antibody-Dependent Cellular Cytotoxicity
AE
Adverse Event
AESI
Adverse Event of Special Interest
AGEP
Acute Generalized Exanthematous Pustulosis
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AST
Aspartate Transaminase 
AUC0-tz
Area Under the Curve
BI
Boehringer Ingelheim
CA
Competent Authority
CDC
Complement-dependent cytotoxicity
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
CRA
Clinical Research Associate
CRF
Case Report Form, (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CRP
C-Reactive Protein
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
DEDP
Drug exposure during pregnancy
DILI
Drug Induced Liver Injury
DLQI
Dermatology Quality of Life Index
DRESS
Drug Reaction with Eosinophilia and Systemic Symptoms
EAP
Expanded Access Program
ECG
Electrocardiogram
EOS
End of Study
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
FACIT-F
Functional Assessment of Chronic Illness Therapy – Fatigue
FcR
Fc Receptor


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FDA
Food and Drug Administration
FIH
First in human
GBS
Guillain-Barré syndrome
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GPP
Generalized Pustular Psoriasis
GPPASI
Generalized Pustular Psoriasis Area and Severity Index
GPPGA
Generalized Pustular Psoriasis Pysician Global Assessment
GPSP
Good Psot-Marketing Study Practice
GOT
Glutamic-Oxaloacetic Transaminase
GPT
Glutamic-Pyruvic Transaminase
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
i.v.
intravenous
IB
Investigator’s Brochure
IC
Inhibitory concentration
ICH
International Council on Harmonization
IEC
Independent Ethics Committee
IFN
Interferon
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IL
Interleukin
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITE
Indirect Target Engagement
JDA
Japanese Dermatological Association
KO
Knock Out
LDH
Lactate Dehydrogenase
LPLT
Last Patient Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities


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MIP
Macrophage Inflammatory Protein
NCI
National Cancer Institute
NF-κB 
Nuclear Factor kappa B
NOAEL
No-Observed Adverse Effect Level
OPU
Operative Unit
PK
Pharmacokinetics
PSS
Psoriasis Symptom Scale
RBC
Red Blood Cell
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
SAE
Serious Adverse Event
SD
Standard Deviation
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TMDD
Target-Mediated Drug Disposition
TNF
Tumour necrosis factor
TS
Treated Set
ULN
Upper Level of Normal
VAS
Visual Analogue Scale
WBC
White Blood Cell
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Generalized pustular psoriasis (GPP) is a rare, neutrophilic skin disease characterised by 
episodes of widespread eruption of sterile, macroscopically visible pustules that can occur 
with or without systemic inflammation (R17-3403, R19-1562). The clinical course of GPP is 
heterogeneous and can be characterised as a relapsing disease with recurrent flares, or a 
persistent disease with intermittent flares (R17-3403, R19-1562). It is distinct from plaque 
psoriasis in clinical presentation, pathophysiology, histopathology, response to therapies, 
epidemiology and genetics, although over 65% of patients with GPP may have concurrent 
plaque psoriasis (R16-1463, R16-0933, R18-2717, P19-10261). GPP has varied prevalence 
across geographical regions, with estimates ranging from 1.76 per 1,000,000 persons in 
France to 5 per 10,000 persons in Germany (R16-2698, R18-1635). It is more prevalent in 
females than males (R16-0933).
Untreated GPP is potentially life-threatening. GPP flares, which are often accompanied by 
systemic symptoms (extreme fatigue, high fever, peripheral blood neutrophilia, and acute 
phase response and sepsis), have a risk of rapid deterioration (R16-0933, R16-2698, R20-
2767). If inflammation is not controlled quickly, there is sloughing of the skin leaving the 
body unprotected from external pathogens, resulting in bacteremia and inability to prevent 
the leakage of essential proteins and electrolytes. The consequence is hypoalbuminemia, 
peripheral edema, hypovolemic and/or septic shock, with shut down of hepatic and renal 
function. The morbidity and mortality without supportive care is substantial. Rapid and 
complete resolution of the skin symptoms (i.e. pustules) and systemic inflammation, and thus 
to shorten the duration of the flares, is key in the management of GPP flares to reduce 
negative outcomes. GPP flares are associated with a mean duration of hospitalization of 10 
days (range 3–44 days) (R16-0933). Mortality rates attributed to GPP or its treatment are 
reported to be 2–16% (R16-0933, R16-2698, R20-2767, R17-3605).
Patients with GPP also suffer considerable chronic clinical burden. GPP is a systemic disease 
that can involve extracutaneous manifestations, including osteoarthritis, uveitis, acute 
respiratory distress syndrome and cardiovascular shock (R18-2717), often resulting in high 
concomitant medication usage (R20-3140, R20-2784). As a result of both chronic and acute 
effects, patients with GPP suffer from a substantial impact on quality of life (R20-2784, R20-
1405, R18-1890).
Current treatment options for controlling a GPP flare and maintenance of response are limited 
and do not provide sustained efficacy (R16-0933). There are no treatments approved 
specifically for GPP in the US or centrally approved in the EU. In Japan, biologics, including 
TNF inhibitors (adalimumab, infliximab, and certolizumab pegol), IL-17 inhibitors 
(secukinumab, brodalumab, and ixekizumab), and IL-23 inhibitors (risankizumab and 
guselkumab), are approved for treatment of GPP. Approval of these treatment options for 
GPP in Japan was not based on randomised clinical trials in GPP but on evidence from small 
(<12 patients), open-label, single-arm trials only, which assessed efficacy at late time points 
(mostly at Week 12 or Week 16). Response to flare treatment was not evaluated in these trials 












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From Effisayil-1, 
 continued treatment with spesolimab as part of the ongoing 
longer-term follow-up study 1368-0025 (ClinicalTrials.gov identifier NCT03886246).
Spesolimab has also been assessed in multiple additional phase I and II studies, supporting 
the PK and safety data. Safety, tolerability and pharmacokinetics using single rising 
intravenous dose and single subcutaneous dose of spesolimab was assessed in healthy 
Japanese male volunteers (double-blind, randomised, placebo-controlled design) (1368.9) and 
included 24 patients who received spesolimab; two bioavailability trials (1368.3 and 1368.29) 
enrolled 82 patients to receive spesolimab; and four trials (1368.15, 1368.32, 1368.4 and 
1368.5) enrolled patients with active disease (palmoplantar pustulosis, atopic dermatitis, and 
ulcerative colitis), in which 145 patients (across all four trials) received spesolimab. In all 
trials, spesolimab was generally well tolerated and no safety signals were identified. Most 
reported AEs were of mild or moderate intensity, although there have also been a small 
number of patients experiencing severe or serious AEs in clinical trials. It is unknown 
whether these AEs were caused by spesolimab. Overall AEs observed in subjects who 
received spesolimab were comparable to AEs observed in those who received placebo and no 
dose-limiting adverse effects were observed. 
Chronic administration of spesolimab is being evaluated with a subcutaneous formulation in 
an ongoing 5-year open-label extension and the prevention of flares trial Effisayil 2 
(ClinicalTrials.gov identifiers: NCT03886246 and NCT04399837).
Please refer to the current version of the Investigator’s Brochure (c03320877) for complete 
and updated information on spesolimab in GPP and other diseases under study.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Current treatment options for controlling flare of GPP, complete resolution of symptoms and 
prevention of reoccurrence of flares are limited and often do not provide sustained efficacy. 
Moreover, as the current treatment options have no reports of randomised double-blind trials, 
evidence supporting those is limited.
Some of standard of care therapies are not suitable for life-long treatment due to their side 
effect profile and existing contraindications.
The Effisayil-1 trial demonstrated that treatment of GPP flares with spesolimab was 
associated with unprecedented rapid pustular and skin clearance, as well as improvements in 
systemic symptoms and quality of life, with a favourable benefit–risk profile.
Spesolimab has the potential to provide rapid and effective treatment to patients with GPP 
presenting with a flare; therefore, this EAP will provide access to the investigational product 
spesolimab to patients suffering from this serious and potentially life-threatening condition 
without alternative satisfactory treatment options and not able to be enrolled in a clinical trial.
1.4
BENEFIT - RISK ASSESSMENT/ MEDICAL NEEDS STATEMENT
Spesolimab is an anti-IL-36R antibody with high clinical activity to block IL-36R signaling 
as shown in patients with GPP, a severe inflammatory skin disease driven by uncontrolled IL-


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36 activity. The results from the pivotal phase II Effisayil-1 trial suggest that treatment of 
flare in patients with GPP with spesolimab is associated with rapid and sustained pustular and 
skin clearance. Improvement in systemic markers supports the beneficial effect of spesolimab 
on both skin and systemic components of the disease. The overall treatment effect was 
sustained over time and correlated with improvement in PROs (e.g. pain, fatigue) and quality-
of-life measures. 
No other IL-36 receptor antagonist is currently approved to provide information on identified 
risks in molecules of this class.
The risks shown in the table below (Table 1.4: 1) are derived from general safety 
considerations of immunomodulatory drugs in clinical development and data generated for 
spesolimab to date.


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Table 1.4: 1
Risks associated with spesolimab administration 
Risks of clinical 
relevance for this 
trial
Summary of data, rationale for 
the risk
Mitigation strategy
Drug-induced liver 
injury (DILI)
Although rare, a potential for 
drug-induced liver injury (DILI) 
is under constant surveillance 
by sponsors and regulators. 
Therefore, DILI is considered as 
a standard risk in all BI 
development trials.
Patients with hepatic impairment 
will be excluded from the trial. In 
case of suspicion of DILI during 
the trial (refer to Section 5.2.4.1.4) 
patients need to be followed 
according to a detailed checklist to 
ensure adequate follow-up and 
patient safety. DILI is defined as 
an AESI.
Systemic 
hypersensitivity 
reaction
After administration of any 
biologic agent or protein, there 
is a possibility of occurrence of
immediate (such as 
anaphylaxis) or delayed (such as 
drug reaction with eosinophilia 
and systemic symptoms)
adverse immune reactions.
Patients with a history of 
allergy/hypersensitivity to 
spesolimab or its excipients are 
excluded from the trial.
In case of systemic 
hypersensitivity reactions 
including anaphylactic reaction 
emerging during or after 
administration of spesolimab, the 
investigator should consider, in 
accordance with severity of the 
reaction and local standard of care, 
interruption of therapy and 
treatment of the condition. 
Systemic hypersensitivity reaction 
is defined as an 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 et al. [R11-
4890].


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Table 1.4: 1
Risks associated with spesolimab administration (cont.)
Risks of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Infections
Inhibition of the immune 
response with an immune-
modulating biologic may 
increase the risk of infections.
In clinical trials with 
spesolimab, a higher proportion 
of patients with mild to 
moderate infections was seen in 
the spesolimab treatment group 
than in the placebo treatment 
group.
Nevertheless, there was no 
indication of an increased 
frequency of patients with 
severe, serious, and 
opportunistic infections in 
association with spesolimab 
treatment.
A recent characterisation of 
individuals with homozygous 
IL36R KO mutations revealed 
that normal immune function 
was broadly preserved, 
suggesting that IL36 signalling 
pathway inhibition may not 
substantially compromise host 
defenses [R17-3632].
Patients with any relevant 
chronic or acute infections 
including HIV, viral hepatitis or 
active tuberculosis are excluded 
from the trial. Treatment of 
infections should be initiated 
promptly according to standard 
of care.
Severe infections and 
opportunistic infections are 
considered AESI for this trial. 
These conditions and serious 
infections are subject to close 
monitoring.


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Table 1.4: 1
Risks associated with spesolimab administration (cont.)
Risks of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Malignancies
Inhibition of the immune 
response with an 
immunomodulatory drug may 
potentially impair immune 
defences and thus theoretically 
decrease immune defence 
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 (within 5 
years) history of malignancy will 
be excluded from participation in 
this trial except appropriately 
treated basal or squamous cell 
carcinoma of the skin or in situ 
carcinoma of uterine cervix.
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.
Diagnostics and treatment will be 
initiated according to local 
standard of care.
Malignancies always represent 
SAEs and are subject to close 
monitoring.


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Table 1.4: 1
Risks associated with spesolimab administration (cont.)
Risks of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
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.
Other risks related to trial-specific procedures include blood sampling and i.v. infusion of 
study medication, which can cause local bruising, inflammation, nerve damage and pain.
Based on the findings in nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of Women of Child Bearing Potential 
(WOCBP) in this trial is justified. To minimize the risk of unintentional exposure of an 
embryo or foetus to the investigational drug, WOCBP must agree to the requirements for the 
pregnancy testing and contraceptive methods described in the protocol.


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Benefit–risk assessment in context of COVID-19 pandemic for patients receiving the 
investigational product spesolimab
A thorough assessment based on the data available as of 29 April 2021 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. As reflected in table 1.4:1
above and the patient informed consent form, similar to other immune modulating biological 
treatments, spesolimab may potentially increase the risk of infections. Available non-clinical 
and clinical data (see Spesolimab Investigators Brochure Version 9) have not shown an 
increased frequency of patients with severe, serious and opportunistic infections with 
spesolimab treatment. However, a higher proportion of patients with mild to moderate 
infections was seen in the spesolimab treatment group than in the placebo treatment group.
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 EAP protocol.
As with 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 
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 receiving the 
investigational product spesolimab are not believed to be at higher risk of COVID-19 owing 
to their background or concomitant diseases. Protocol-defined procedures do not impose 
undue risk to trial participants. 
The benefit–risk assessment of spesolimab remains favourable in the context of the COVID-
19 pandemic. Patients receiving the investigational product spesolimab are expected to 
benefit from 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 in this trial. However, the investigator may choose to perform the 
testing as per his or her discretion if useful based on individual medical consideration and in 
the case of suspected COVID-19 infection. 


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To address potential risks associated with operational aspects related to the participation in this 
EAP 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 trial enrolment and during the trial by the investigator with respect to SARS-
CoV-2 infection. As with any other acute infection, a suspected or diagnosed COVID-19 
infection should be treated according to the standard of care and interruption of spesolimab 
should be considered. In case of a confirmed infection, spesolimab should not be administered
and appropriate measures for monitoring, treatment and quarantine will be implemented. 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. Considering all such aspects, the investigator will determine each 
patient’s (continued) participation in the planned trials. BI as the sponsor, where required, will 
support the investigator in their decision making. It is acknowledged that the investigator may 
decide to implement protocol deviations to protect the safety, wellbeing, and/or best interest of 
the patient. The patient may be eligible for spesolimab treatment following recovery from a 
SARS-CoV-2 infection if the patient is expected to derive clinical benefit, as agreed between 
the investigator and sponsor.
BI is supportive of allowing approved COVID-19 virus vaccines in patients/subjects enrolled 
in BI clinical trials, in line with local recommendations/guidance and approved labels. 
Immunocompromised individuals may still receive COVID-19 vaccination if they have no 
contraindications to vaccination. However, they should be counseled (note: by the 
investigators) 
about the unknown vaccine safety profile and effectiveness in 
immunocompromised populations, as well as the potential for reduced immune responses and 
the need to continue to follow all current guidance to protect themselves against COVID-19.
Considering that GPP flares constitute a serious and potentially life-threatening condition, 
and the fact that currently used treatments have limited evidence supporting efficacy and 
safety, the potential benefit of spesolimab for the treatment of flares in adult patients with 
GPP is considered to outweigh the potential risks, therefore justifying providing expanded 
access to patients suffering from this condition.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The aim of this trial is to provide early access to the investigational drug spesolimab for 
patients with GPP presenting with a flare. A secondary aim of this trial is to collect additional 
data on the safety and tolerability of spesolimab.
2.1.2
Primary endpoint
Occurrence of treatment emergent adverse events (TEAEs)
2.1.3
Secondary endpoint
Occurrence of:
•
Treatment emergent serious adverse events (SAEs)
•
Treatment emergent adverse events of special interest (AESIs).


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
This is an open-label, multi-centre, single-arm trial, designed to provide early access to 
spesolimab, for patients with GPP presenting with a flare and for whom no satisfactory 
authorised alternative therapy exists and who are unable to participate in a clinical trial, as 
assessed by the investigator. 
After signing informed consent and if all eligibility criteria are met, patients will receive a 
single dose of 900 mg spesolimab. If deemed necessary by the investigator (i.e. if the flare 
symptoms persist), a second dose of 900 mg spesolimab may be administered one week after 
the initial infusion. 
If only one single dose is administered, then patients will visit the investigator approximately
at week 1, week 4 and week 16. If a second dose may be given, then the dates that patients 
will visit the investigator is changed to approximately at week 1, week 2, week 5 and week17
after initial dose of spesolimab. Please refer to section 6.1 for details on the trial visit 
procedures. Patient’s participation in the trial will end after conclusion of the 16-week 
follow-up period after the last infusion / drug administration.
If a patient experiences a new GPP flare (following the resolution of a previous flare with 
spesolimab treatment) after the 16-week follow-up period the patient may re-enter in the trial 
and be treated again with spesolimab, providing eligibility criteria are still met and the overall 
trial is still running. The same dosing and follow-up requirements apply as for the previous 
flare.  
In the situation that a patient experiences a new GPP flare within the 16-week follow-up 
period and the physician wishes to treat this new flare with spesolimab, eligibility needs to be 
assessed and agreed upon with the BI clinical team.
Sponsor will inform clinial sites of the deadline of patient enrolment for the trial when 
spesolimab receives marketing authorization for GPP treatment. 
3.2
SELECTION OF TRIAL POPULATION
3.2.1
Main diagnosis for trial entry
At screening, the diagnosis of GPP is based on the criteria of the JDA guidelines for the 
management and treatment of GPP. (R19-1562). These diagnosis criteria include:
∀
Systemic symptoms such as fever and fatigue;
∀
Systemic or extensive flush accompanied by multiple sterile pustules that sometimes 
merge to form lakes of pustule;
∀
Neutrophilic subcorneal pustules histopathologically characterized by Kogoj’s 
spongiform pustules;


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∀
The above clinical and histological features recur repeatedly. However, the diseases 
mentioned below can be excluded from initial-onset cases.
Subcorneal pustular dermatosis or pustular drug eruptions (including AGEP)
∀
For a GPP patient with first episode, skin biopsy is to be taken prior to receving IMP 
treatment and histopathological result (findings of Kogoj’s spongiform pustules) will be 
confirmed retrospectively.
Participation in this trial will be available to patients with GPP who meet the eligibility 
requirements specified in section 3.2.2 and section 3.2.3. Owing to the nature and objectives 
of this trial, no recruitment goals or limits apply.
Patients previously enrolled in this trial presenting again with a new episode of a GPP flare
must be re-evaluated and meet eligibility criteria to receive new treatment with spesolimab.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) at the investigational site irrespective of 
whether they have been treated with investigational drug or not.
If retrospectively it is found that a patient has been entered in error (=did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 
contacted immediately. Based on an individual benefit-risk assessment a decision will be 
made whether continued trial participation is possible or not.
3.2.2
Inclusion criteria
1.
Diagnosis of GPP confirmed based on the JDA guidelines for the management and 
treatment of GPP.
2.
Patient is experiencing a flare, defined as new or worsening of widespread eruption of 
sterile macroscopically visible pustules, with or without systemic inflammation, as 
assessed by the investigator.
3.
Male or female patients, aged 18 to 75 years at time of enrollment. Women of 
childbearing potential (WOCBP)1 must be willing and able to use a highly effective 
method of birth control per ICH M3 (R2) that result in a low failure rate of less than 
1% per year when used consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the patient information.
4.
Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
5.
No satisfactory authorised alternative therapy exists, as assessed by the investigator.
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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3.2.3
Exclusion criteria
1.
Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
a)
Women who stop nursing before study drug administration do not need to be 
excluded from participating; they should refrain from breastfeeding for 16 
weeks after the last spesolimab infusion.
2.
Severe, progressive, or uncontrolled hepatic disease, defined as >3-fold ULN 
elevation in AST or ALT or alkaline phosphatase, or >2-fold ULN elevation in total 
bilirubin.
3.
Active systemic infections (fungal and bacterial disease) during the last 2 weeks prior 
to drug administration, as assessed by the investigator.
4.
Increased risk of infectious complications (e.g. recent pyogenic infection, any 
congenital or acquired immunodeficiency (e.g. HIV), past organ or stem cell 
transplantation), as assessed by the investigator.
5.
Relevant chronic or acute infections, including active tuberculosis (TB), HIV 
infection or viral hepatitis at the time of drug administration.
a)
Patients should be evaluated for TB infection prior to initiating treatment with 
spesolimab.
b)
Anti-TB therapy should be considered, in accordance with local guidelines,
prior to initiating spesolimab in patients with latent TB or a history of TB.
6.
History of allergy / hypersensitivity to systemically administered spesolimab or its 
excipients.
7.
Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal or squamous cell 
carcinoma of the skin or in situ carcinoma of uterine cervix.
8.
Immediate life-threatening flare of GPP requiring intensive care treatment according 
to the investigator’s judgement. Life-threatening complications include cardiovascular
/ cytokine driven shock, pulmonary distress syndrome, or renal failure.
9.
Patients who must or wish to continue the intake of restricted medications (other 
IL-36R inhibitors, live vaccinations, or IL-1R/IL-1 inhibitors, see section 4.2.2.1) or 
any drug considered, in the judgement of the investigator, likely to interfere with the 
safe conduct of the study.
10.
Currently enrolled in another investigational device or drug study, or less than 30 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s), or eligible to participate or participating in an ongoing 
actively accruing clinical trial with spesolimab in the treatment of GPP.
11.
A disease or condition that in the opinion of investigator may put the patient at risk 
because of participation in this trial or limit the patient’s ability to participate in this 
trial.
12.
Presence of acute demyelinating neuropathy.
3.2.4
Discontinuation / withdrawal of patients from trial 
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole 
(“withdrawal of consent”) with very different implications; please see Sections 3.2.4.1 and 
3.2.4.2 below.


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The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Section 5.2.4.2).
3.2.4.1
Discontinuation of trial medication and assessment
An individual patient will discontinue treatment if:
∀
The patient wants to discontinue trial treatment. The patient will be asked to explain the 
reasons but has the right to refuse to answer. 
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, the safety of the 
patient cannot be guaranteed as he / she is not willing or able to adhere to the trial
requirements in the future. 
∀
The patient needs to take concomitant medication that interferes with the safety of the 
investigational medicinal product.
∀
The patient can no longer receive treatment for medical reasons such as surgery, adverse 
events, other diseases, or pregnancy.
∀
If a DILI alert (as defined in Section 5.2.4.1.4) is detected without identification of an 
alternative cause in the work-up according to the “DILI checklist”, the patient should not 
receive subsequent doses of investigational medication. (If alternative cause is identified 
and patient has recovered according to investigator assessment, treatment can be restarted 
after consultation with the sponsor.)
∀
If peripheral neuropathy is suspected, treatment with spesolimab should be temporarily 
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.
∀
For individual stopping rules related to specific adverse events, please see Section 4.2.1
“Other treatments and emergency procedures.”
If new efficacy / safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the infusion/treatment for all 
patients or take any other appropriate action to guarantee the safety of the patients
participating in the trial. 
If a patient wants to discontinue the trial participation, the investigator should request that the 
patient consent to be contacted, at least by phone, for a final follow-up assessment at 16 
weeks after last drug intake. Where possible, any new or changes in previously reported AEs 
and concomitant therapies should be recorded at this assessment, as indicated in section 6.1.3. 
Specific information to be collected at the 16-week assessment in patients who have 
discontinued trial medication or assessment is detailed in section 5.2.4.2.1.
3.2.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.


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If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.2.4.1 above. This 
discussion, as well as the patient’s decision, should be well documented in the source.
3.2.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular site 
at any time for the following reasons:
1. New efficacy or safety information invalidating the earlier positive benefit–risk
assessment.
2. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
3. Marketing authorization of spesolimab i.v.
Trial site will be reimbursed for reasonable expenses incurred in case of trial termination 
(except in case of the second reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Product
All patients will be treated with spesolimab in this trial. There is no active comparator or 
placebo.
Table 4.1.1: 1
Spesolimab
Substance:
Spesolimab (BI 655130)
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
Spesolimab 450 mg/vial (60 mg/mL), 7.5 mL fill 
volume
Posology:
900 mg single i.v dose
Method and route of administration:
i.v infusion
4.1.2
Drug assignment and administration of doses for each patient
Trial medication kits will be assigned to patients via Interactive Response Technology (IRT) 
system after verification of all inclusion and exclusion criteria, and patient will receive 
spesolimab 900 mg i.v at Visit 2 (Day 1). If flare symptoms persist after a single infusion of 
study medication, a second infusion (900 mg i.v. spesolimab) is allowed at Visit 3 (Day 8) 
per investigator’s discretion and the medication number of the second dose will be also 
assigned via IRT system.
An Interactive Response Technology (IRT) will be used to screen eligible patients, assign 
medication kits 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.
Site personnel will enter the medication numbers in the eCRF. Note that the patient number is 
different from the medication number (the former is generated during screening via the IRT 
System). Each medication kit (containing 2 vials) will have a unique medication number.
Detailed instructions for administration of spesolimab i.v. are provided in the ISF.


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4.1.3
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). The investigational product consists of a carton holding 2 vials of the trial 
medication. Each carton will have a unique medication number. 
Shipment and re-supply of trial medication to the local depots and/or sites will be managed 
via an IRT system, which will also monitor expiry dates of available supplies.
For details of packaging and the description of the label, refer to the ISF.
4.1.4
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation. Trial medication must be securely 
stored, e.g. in a locked refrigerator or at a pharmacy. If the storage conditions are found to be 
outside the specified range, the Cinical Research Associate (CRA) (as provided in the list of 
contacts) must be contacted immediately. Refer to the ISF for additional information. 
The trial medication must be administered in the manner specified in the trial protocol and 
instructions for IMP preparation handling and administration of spesolimab.
4.1.5
Drug accountability
The primary 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.
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
All unused trial medication must be returned to the sponsor. All used and partially used 
medication must be destroyed locally by the trial site. Receipt, usage and return or disposal 
must be documented on the respective forms. Account must be given for any discrepancies.
The primary 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. 


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These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and patients
participating in the trial. The primary investigator or designee will maintain records that 
document adequately that the patients were provided the doses specified by the trial protocol 
and reconcile all investigational medicinal products received from the sponsor. At the time of 
return to the sponsor or appointed CRO, the primary investigator or designee must verify that 
all unused drug supplies have been returned by the clinical trial staff and all used or partially 
used supplies have been destroyed by the trial site, and that no remaining supplies are in the 
primary investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
All concomitant therapies will be recorded on the appropriate pages of the electronic CRF 
(eCRF).
4.2.1.1
Emergency procedures
Systemic hypersensitivity including infusion reactions and anaphylactic reaction 
In case of systemic hypersensitivity, including infusion reactions and anaphylactic reaction, 
emerging during or after infusion of investigational medication, the investigator should 
consider, in accordance with severity of the reaction and local standard of care, to:
∀
Immediately interrupt the infusion
∀
Treat with systemic antihistamines, i.v. steroids, and in case of a severe allergic 
reaction (e.g., anaphylactic reaction) epinephrine
∀
Refer the patient to an emergency unit
In case of systemic hypersensitivity including infusion reactions, based on the patient’s 
clinical course and the physician’s medical judgment, the infusion may be re-initiated in case 
of mild or moderate systemic hypersensitivity, including infusion reactions (according to NCI
grading, grade 1 or 2), at a slower speed with a gradual increase to complete the infusion as 
detailed in the Instructions for Preparation and Handling of spesolimab in the ISF. In all 
cases, the total duration of infusion should not exceed 180 minutes (3 hours).
In case of anaphylactic reactions based on published criteria (Appendix 10.1; R11-4890), the 
investigator should discontinue treatment with spesolimab.
When a delayed hypersensitivity reaction is suspected, in addition to drawing a blood sample 
for laboratory assessment (complete blood count with differential, comprehensive metabolic 
panel (includes liver enzymes), LDH, immune complexes profile), please evaluate for signs 
of extra-cutaneous organ involvement. The decision to discontinue treatment and/or restart 
treatment after resolution of the reaction should be based on reaction type and severity. 


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In case of potential systemic allergic reaction: where possible, blood samples for 
determination of serum tryptase, as well as histamine, IgE and serum complement component 
assay, should be collected 0.5 h, 2 h, 6 h, 24 h after onset of the event.
Any clinically meaningful changes in laboratory values should be reported as an AE, SAE or 
AESI (as appropriate).
Severe infections (according to RCTC grading the ISF), serious infections, opportunistic or 
mycobacterium tuberculosis infections
Treatment of the infection should be initiated promptly according to local standard of care. 
Active/Latent TB:
A suitable TB test, according to local regulations will be performed at screening. If the result 
is positive, the patient may participate in the trial if further work up (according to local 
practice/guidelines) establishes conclusively that the patient has no evidence of active 
tuberculosis. Active TB patients must be excluded. If the presence of latent tuberculosis is 
established, then treatment should have been initiated and maintained according to local 
country guidelines. If the TB test results are not available at the time of infusion, these 
patients may receive treatment (provided they meet all other inclusion/exclusion criteria) as 
long as the investigator has ruled out active disease based on available documented history 
(i.e. negative for active TB) within 3 months prior to infusion.
Malignancies
In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix, 
treatment discontinuation is to be a consideration if deemed clinically appropriate by the 
investigator. In addition, diagnostics and treatment are to be initiated according to local 
standard of care.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
The medications (or classes of medications) listed in Table 4.2.2.1: 1 must not have been
taken before infusion for the time periods as specified
Table 4.2.2.1: 1
Restricted medications
Medication or class of medications
Restriction duration
IL-36R inhibitors (other than spesolimab 
provided in the trial)
4 weeks prior to any infusion and not until 
after 16 weeks after last infusion of 
spesolimab
Live vaccinations
Anakinra (or other IL-1/IL-1R inhibitors)
Not to be administered concurrently with 
spesolimab


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4.2.2.2
Restrictions on diet and lifestyle
No specific restrictions on diet or lifestyle of the patients are required.
4.2.2.3
Contraception requirements
Women of childbearing potential must use highly effective methods of birth control per ICH 
M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and 
correctly. A list of contraception methods meeting these criteria is provided in the Patient 
Information.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
This is an open-label trial with no active or placebo control. Efficacy will not be evaluated.
5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on the occurrence of:
∀
Treatment emergent adverse events (TEAEs)
∀
Treatment emergent serious adverse events (SAEs)
∀
Treatment emergent adverse events of special interest (AESIs).
No confirmatory safety analysis is planned.
5.2.1
Physical examination
A complete physical examination will be performed before first drug administration at the 
time points specified in the FLOW CHART. Examination includes, at a minimum, general 
appearance, neck, lungs, cardiovascular system, abdomen, extremities, and skin. 
Measurement of height and body weight should also be performed.
Physical examination will be performed at follow-up visits according to standard clinical 
practice and when deemed appropriate by the investigator. 
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated before first drug administration at the time points specified in 
the Flow Chart. This includes measuring temperature, pulse rate and systolic/diastolic blood 
pressure. Pulse rate and blood pressure will be measured after patients have been sitting 
comfortably for at least 5 minutes.
Vital signs will be evaluated at follow-up visits according to standard clinical practice and 
when deemed appropriate by the investigator.
The results must be included in the source documents available at the site.
5.2.3
Safety laboratory parameters
The laboratory tests listed in Table 5.2.3:1 are to be collected at the trial sites and assessed by 
the investigators prior to study drug infusion for eligibility confirmation.
Any additional laboratory testing during the trial is optional and should be performed at the 
discretion of the investigator in accordance with the current standard of care, which may 
yield useful information for the management and safety evaluation of the patient.


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Clinically relevant abnormal findings as judged by the investigator will be reported as 
adverse events (please refer to section 5.2.4).
In case the criteria for DILI are fulfilled, a number of additional measures will be performed 
(please see section 5.2.4.1.4 and the DILI Checklist provided in the ISF). 
Table 5.2.3:1 
Laboratory tests to be assessed at V1 prior to i.v. administration 
(Local Labs)
Category
Test name
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
White blood cell count (WBC)
Platelet count
WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase
Substrates
Total bilirubin 
Infection testing
Hepatitis B Surface Antigen 
Hepatitis B Surface Antibody 
Hepatitis B core Antibody
HBV-DNA (quantitative)1
QuantiFERON® TB or T-Spot® 2
Hepatitis C Antibodies 
HIV-1, and HIV-2 Antibody 
Serum Pregnancy test (only for 
female
patients of childbearing potential)
Human Serum Chorionic Gonadotropin
1 An HBV-DNA test should be conducted if Hepatitis B core Antibody and/or Hepatitis B Surface Antibody is positive and 
Hepatitis B Surface Antigen is negative. If HBV DNA level is undetectable (<2.1 log copies/mL) at screening, the patient 
can participate in this trial.
2 If the 1st QuantiFERON® TB or T-Spot® test result is indeterminate, a retest should be performed.
5.2.4
Assessment of adverse events
5.2.4.1
Definitions of AEs 
5.2.4.1.1
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.


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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 related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀Worsening of the underlying disease or of other pre-existing conditions 
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.4.1.2
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. 
-
An event that possibly leads to disability will be handled as ‘deemed serious for any 
other reason’ and, therefore, reported as an SAE.
5.2.4.1.3
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 5.2.4.2.
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 5.2.4.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.


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5.2.4.1.4
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 5.2.4.2.2.
The following are considered as AESIs:
Potential Severe Drug Induced Liver Injury (DILI)
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined by the 
following alterations of hepatic laboratory parameters: 
∀
An elevation of AST and/or ALT≥3-fold ULN,
combined with an elevation of total bilirubin ≥2-fold ULN measured in the same 
blood sample, or in samples drawn within 30 days of each other, or
∀
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, alkaline phosphatase, 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.
Systemic hypersensitivity reactions including infusion reactions and anaphylactic reaction
Any suspicion of severe systemic hypersensitivity including infusion reactions and any 
anaphylactic reaction should be defined and assessed using the criteria discussed in the 
statement paper from Sampson et al. (Section 4.2.1.1 and Appendix 10.1, R11-4890).
Severe infections (according to RCTC grading in the ISF)
Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, 
posttransplant lymphoproliferative disorder (EBV), progressive multifocal 
leucoencephalopathy, bartonellosis (disseminated only), blastomycosis, toxoplasmosis, 
coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), candidiasis (invasive or 
pharyngeal), cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, 
mucor, lichtheimia), scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, 
salmonellosis (invasive only), HBV reactivation, herpes simplex (invasive only), herpes 
zoster, strongyloides (hyperinfection syndrome and disseminated forms only), 


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paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium species 
(chronic only), microsporidiosis, leishmaniasis (visceral only), trypanosoma cruzi infection 
(Chagas’ disease) (disseminated only), campylobacteriosis (invasive only), shigellosis 
(invasive only), vibriosis (invasive due to vibrio vulnificus), HCV progression (R17-2617).
Peripheral neuropathy
Any event suspected or diagnosed as Peripheral Neuropathy is considered as an AESI.
For the treatment interruption rules, please see section 3.2.4.1
5.2.4.1.5
Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the CRF 
according to the RCTC version 2.0 (refer to ISF for details).
5.2.4.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, considering all relevant factors, including pattern of 
reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases and relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
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, considering 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.
∀
There is an 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.


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∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.4.2
Adverse event collection and reporting
5.2.4.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of study (16 
weeks after last dose of spesolimab, or at the time of withdrawal of participation): 
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of study: the investigator does not need to actively 
monitor the patient for new AEs but should only report any occurrence of cancer and trial
drug-related SAEs and trial drug-related AESIs of which the investigator may become 
aware of by any means of communication, e.g. phone call. Those AEs should however 
not be reported in the CRF.
•
Upon patient re-entry into the trial, the patient should be re-evaluated to ensure that 
eligibility criteria are still met and the overall trial is still running in order to assess AEs 
(serious and non-serious) and AESIs.
Vital Status Data Collection
Patients who discontinue trial medication or participation prematurely, who agree to be 
contacted further but do not agree to physical visits, should be followed up as described in 
section 3.2.4.1, discontinuation of trial medication and assessment. Thus, for patients who 
discontinue trial medication or participation prematurely but agree to be contacted by phone 
for a last follow-up assessment at 16 weeks after last drug intake, the investigator must report
any occurrence of cancer, all deaths / fatal AEs regardless of relationship, and trial drug-
related SAEs and and trial drug-related AESIs the investigator becomes aware of. 
5.2.4.2.2
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 to the sponsor’s unique entry point within 24 
hours of becoming aware of the event. The country-specific process will be specified 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 related to these events, a follow-up SAE form must
be provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.


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5.2.4.2.3
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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (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 Studies 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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6.
INVESTIGATIONAL PLAN
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.1.1
Screening period
After informed consent, patients considered for this trial will undergo an eligibility 
evaluation. Laboratory tests, must be conducted locally to ensure patients meet the inclusion 
and exclusion criteria described in sections 3.2.2 and 3.2.3, which include:
∀
Liver function tests (AST, ALT and alkaline phosphatase)
∀
Complete blood count, with differential
∀
Pregnancy (blood) test in women of childbearing potential
∀
TB test, to rule out active disease
o
In accordance with details in section 4.2.1.1, if TB test results are not 
available at the time of infusion, patients may receive treatment (provided 
they meet all other inclusion/exclusion criteria) as long as the investigator has 
ruled out active disease based on available documented history (i.e. negative 
for active TB) within 3 months prior to infusion.
∀
Possible HIV and viral hepatitis tests, to rule out active disease in presence of clinical 
signs or suspicion
o
If HIV and viral hepatitis test results are not available at the time of infusion, 
patients may receive treatment (provided they meet all other 
inclusion/exclusion criteria) as long as the investigator has ruled out active 
disease based on available documented history (i.e. negative for HIV and viral 
hepatitis) within 3 months prior to infusion.
Once consent is obtained, the patient is considered to have started the screening process and 
is assigned a unique patient number in the IRT system. The patient is to be recorded on the 
enrolment log and registered in the IRT system as a screened patient. All patients who are 
screened must be registered in the IRT system.
Demographics, baseline conditions (including any findings of the physicial examination and
vital signs evaluation) and concomitant therapies will be recorded in the eCRF.
If the patient meets all eligibility criteria, infusion of spesolimab may proceed immediately.
6.1.2
Treatment period(s)
Spesolimab will be administered as a single dose i.v. infusion in the clinic.
If deemed necessary by the investigator (i.e. if the flare symptoms persist), a second dose of 
900 mg spesolimab may be administered one week after the initial infusion. 
IRT transactions are required to obtain all medication kit number assignments. Dates and 
times of infusions will be recorded in the patient’s records and eCRF.


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6.1.3
Follow up period and trial completion
Patients will visit the investigator at approximately week 1, week 4 and week 16 after only 
one single drug administration. If the patient requires a second dose of spesolimab, visits will 
be re-scheduled based on the date of the last infusion, i.e, patients will visit the investigator at 
approximately week 1, week 2, week 5, and week 17 after initial dose of spesolimab.
Additional visits within the 16-week follow-up period can be planned according to standard 
clinical practice. Visits may also be conducted by phone or video if judged appropriate by the 
investigator. At all visits any new or changes in previously reported AEs and concomitant 
therapies will be recorded in the patient’s chart and eCRF. 
Patient’s participation in the trial will end after conclusion of the 16-week follow-up period 
after the last infusion / drug administration. The Trial Completion eCRF page will be 
completed at this time.
A patient will be considered lost to follow-up if the investigator is not able to contact the 
patient despite multiple attempts. Every effort must be made to contact the patient: at least 
two telephone contacts plus one mailing should be documented in the patient’s chart.
If a patient experiences a new GPP flare (following the resolution of a previous flare with 
spesolimab treatment) after the 16-week follow-up period, the patient may re-enter in the trial
with the same patient number and be treated again with spesolimab, providing eligibility 
criteria are still met and the overall trial is still running. The same dosing and follow-up 
requirements apply as for the previous flare.
In the situation that a patient experiences a new GPP flare within the 16-week follow-up 
period and the physician wishes to treat this new flare with spesolimab, eligibility needs to be 
re-assessed and agreed upon with the BI clinical team.
Then, in case of re-entry due to a new GPP flare within the 16-wks follow-up period, the 
patient will end the current follow-up period, and restart the trial from the screening for 
eligibility. If eligibility criteria is met, and permission from BI is granted (see above), the 
patient can be treated again to receive a new dose of spesolimab. After infusion, the patient is 
followed-up for 16-weeks after the latest dose of spesolimab. Also for this scenario, after one 
week, a second dose of spesolimab can be administered, if deemed necessary by the treating 
physician.


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7.
STATISTICAL METHODS
Exploratory descriptive statistics of demographic and safety data will be presented.
7.1
PLANNED ANALYSES
Analyses will be based on the treated set (TS) which includes all patients who have been 
administered spesolimab.
7.1.1
Safety analyses
In general, safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. 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, a period of 16 
weeks after the last dose of trial medication. Adverse events that start before first drug intake 
and deteriorate under treatment will also be considered as ‘treatment-emergent’. 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 trial medication, will be assigned to the on-treatment period for 
evaluation.
All treated patients will be included in the safety analysis. 
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term. after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.


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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 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”.
In addition, the trial also will be carried out in compliance with Good Post-Marketing Study 
Practice (GPSP) upon commencement of the post marketing clinical trial.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the investigator.
The investigator will inform the sponsor or delegate 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 regards to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB and 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 patients in the trial based on the
patient information form. A language understandable to the patient should be chosen, 
technical terms and expressions avoided, if possible. The patient must be given sufficient 


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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 or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, 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. For drug accountability, refer to 
section 4.1.5.
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.


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If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations).
∀
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed).
∀
Dates of patient’s visits, including dispensing of trial medication.
∀
Medical history (including trial indication and concomitant diseases, if applicable).
∀
Medication history.
∀
Adverse events and outcome events (onset date (mandatory), and end date (if available)).
∀
Serious adverse events (onset date (mandatory), and end date (if available)).
∀
Concomitant therapy (start date, changes).
∀
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available).
∀
Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor or deligate will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 


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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 6 and 12 of the WHO GCP 
handbook.
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a patient identification number instead of the patient’s 
name. the code is only available at the site and must not be forwarded to the sponsor. I case 
patient’s records will be forwarded e.g. for SAE processing or adjudication committees, 
personal data that can identify the patient will be redacted by the site prior to forwarding. 
Access to the patient files and clinical data is strictly limited: 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.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate action as well as corrective and preventive 
action will be implemented. Respective regulatory authorities, IRBs / IECs and patients will 
be informed as appropriate.
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 the treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the treatment 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.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).


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A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
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 (CTL), 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 (CTM), 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 CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial. On-site 
monitoring will be performed by BI or a contract research organization appointed by BI.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs or by a
CRO with which the responsibilities and tasks will have been agreed and a written contract 
filed before initiation of the clinical trial.
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.
An IRT vendor will be used in this trial. The physician will receive all necessary instructions 
to access the IRT system from the Sponsor. Detailed IRT functions and procedures will be 
documented in the IRT Manual available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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P19-01888
Bachelez H, Choon S-E, Marrakchi S, Burden AD, Tsai T-F, Morita A, et al. 
Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized 
Pustular Psoriasis. N Engl J Med. 2019 07;380(10):981–3.
P19-10261
Gooderham MJ, Van Voorhees AS, Lebwohl MG. An update on generalized 
pustular psoriasis. Expert Rev Clin Immunol. 2019 Sep;15(9):907–19. 
R11-4890
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, 
Branum A, et al. Second symposium on the definition and management of 
anaphylaxis: Summary report—Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. 
Journal of Allergy and Clinical Immunology. 2006 Feb 1;117(2):391–7. 
R14-5158
Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei X-Y, Fraitag S, et al. 
Interleukin-36-receptor antagonist deficiency and generalized pustular 
psoriasis. N Engl J Med. 2011 Aug 18;365(7):620–8. 
R16-0928
Setta-Kaffetzi N, Simpson MA, Navarini AA, Patel VM, Lu H-C, Allen MH, 
et al. AP1S3 mutations are associated with pustular psoriasis and impaired 
Toll-like receptor 3 trafficking. Am J Hum Genet. 2014 May 1;94(5):790–7.
R16-0929
Berki DM, Liu L, Choon S-E, David Burden A, Griffiths CEM, Navarini AA, 
et al. Activating CARD14 Mutations Are Associated with Generalized 
Pustular Psoriasis but Rarely Account for Familial Recurrence in Psoriasis 
Vulgaris. J Invest Dermatol. 2015 Dec;135(12):2964–70. 
R16-0933
Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. Clinical 
profile, morbidity, and outcome of adult-onset generalized pustular psoriasis: 
analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia. Int J 
Dermatol. 2014 Jun;53(6):676–84. 
R16-1462
Imafuku S, Honma M, Okubo Y, Komine M, Ohtsuki M, Morita A, et al. 
Efficacy and safety of secukinumab in patients with generalized pustular 
psoriasis:  A 52-week analysis from phase III open-label multicenter Japanese 
study. J Dermatol. 2016 Sep;43(9):1011–7. 
R16-1463
Borges-Costa J, Silva R, Gonçalves L, Filipe P, Soares de Almeida L, Marques 
Gomes M. Clinical and laboratory features in acute generalized pustular 
psoriasis: a retrospective study of 34 patients. Am J Clin Dermatol. 2011 Aug 
1;12(4):271–6. 


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Carrier Y, Ma H-L, Ramon HE, Napierata L, Small C, O’Toole M, et al. Inter-
regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo:  
implications in psoriasis pathogenesis. J Invest Dermatol. 2011 
Dec;131(12):2428–37.
R16-2698
Augey F, Renaudier P, Nicolas J-F. Generalized pustular psoriasis 
(Zumbusch): a French epidemiological survey. Eur J Dermatol. 2006 
Dec;16(6):669–73. 
R17-2617
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen P, 
et al. Opportunistic infections and biologic therapies in immune-mediated 
inflammatory diseases: consensus recommendations for infection reporting 
during clinical trials and postmarketing surveillance. Ann Rheum Dis. 2015 
Dec;74(12):2107–16.
R17-3403
Navarini AA, Burden AD, Capon F, Mrowietz U, Puig L, Köks S, et al. 
European consensus statement on phenotypes of pustular psoriasis. J Eur Acad 
Dermatol Venereol. 2017 Nov;31(11):1792–9. 
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Robinson A, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Bebo BF 
Jr, et al. Treatment of pustular psoriasis: From the Medical Board of the 
National Psoriasis Foundation. Journal of the American Academy of 
Dermatology. 2012 Aug 1;67(2):279–88. 
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Johnston A, Xing X, Wolterink L, Barnes DH, Yin ZQ, Reingold L, et al. IL-1 
and IL-36 are dominant cytokines in generalized pustular psoriasis. J Allergy 
Clin Immunol 2017; 140(1); 109-120.
R17-3604
Yamasaki K, Nakagawa H, Kubo Y, Ootaki K. Efficacy and safety of 
brodalumab in patients with generalized pustular psoriasis and psoriatic 
erythroderma: results from a 52-week, open-label study. Br J Dermatol. 2017 
Mar;176(3):741–51.
R17-3605
Zelickson BD, Muller SA. Generalized pustular psoriasis. A review of 63 
cases. Arch Dermatol. 1991 Sep;127(9):1339–45. 
R17-3632
Mahil SK, Catapano M, Di Meglio P, Dand N, Ahlfors H, Carr IM, et al. An 
analysis of IL-36 signature genes and individuals with IL1RL2 knockout 
mutations validates IL-36 as a psoriasis therapeutic target. Sci Transl Med. 
2017 Oct 11;9(411).
R18-1635
Schäfer I, Rustenbach SJ, Radtke M, Augustin J, Glaeske G, Augustin M. 
[Epidemiology of psoriasis in Germany--analysis of secondary health 
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R18-1890
Pfohler C, Muller CSL, Vogt T. Psoriasis vulgaris and psoriasis pustulosa -
epidemiology, quality of life, comorbidities and treatment. Curr Rheumatol 
Rev. 2013;9(1):2–7.
R18-2717
Bachelez H. Pustular psoriasis and related pustular skin diseases. Br J 
Dermatol. 2018 Mar;178(3):614–8. 
R18-2719
Sano S, Kubo H, Morishima H, Goto R, Zheng R, Nakagawa H. Guselkumab, 
a human interleukin-23 monoclonal antibody in Japanese patients with  


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generalized pustular psoriasis and erythrodermic psoriasis: Efficacy and safety  
analyses of a 52-week, phase 3, multicenter, open-label study. J Dermatol. 
2018 May;45(5):529–39. 
R18-2720
Wilsmann-Theis D, Schnell LM, Ralser-Isselstein V, Bieber T, Schön MP, 
Hüffmeier U, et al. Successful treatment with interleukin-17A antagonists of 
generalized pustular psoriasis in patients without IL-36RN mutations. J 
Dermatol. 2018 Jul;45(7):850–4. 
R19-1562
Fujita H, Terui T, Hayama K, Akiyama M, Ikeda S, Mabuchi T, et al. Japanese 
guidelines for the management and treatment of generalized pustular psoriasis: 
The new pathogenesis and treatment of GPP. J Dermatol. 2018 
Nov;45(11):1235–70. 
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Bassoy EY, Towne JE, Gabay C. Regulation and function of interleukin-36 
cytokines. Immunol Rev. 2018 Jan;281(1):169–78.
R20-1400
MorphoSys Announces Approval of Tremfya(R) (Guselkumab) for the 
Treatment of Moderate to Severe Forms of Psoriasis and Psoriatic Arthritis in 
Japan [Internet]. 2018 [cited 2020 Dec 16]. Available from: 
website:morphosys.com/media-investors/media-center/morphosys-announces-
approval-of-tremfyar-guselkumab-for-the-treatment
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Sampogna F, Tabolli S, Söderfeldt B, Axtelius B, Aparo U, Abeni D. 
Measuring quality of life of patients with different clinical types of psoriasis 
using the SF-36. Br J Dermatol. 2006 May;154(5):844–9. 
R20-2256
Updated: COVID-19 recommendations. 
website:psoriasis.org/advance/coronavirus (access date: 15 July 2020); 
National Psoriasis Foundation (NPF); 2020.
R20-2257
COVID-19 rapid guideline: severe asthma (NICE guideline, published: 3 April 
2020). website:nice.org.uk/guidance/ng166 (access date: 15 July 2020); 
National Institute for Health and Care Excellence (NICE); 2020
R20-2258
An update on COVID-19 for the practicing allergist/immunologist (July 9, 
2020). https://education.aaaai.org/resources-for-a-i-clinicians/Update-for-
AI_COVID-19 (access date: 15 July 2020) ; American Academy of Allergy 
Asthma & Immunology (AAAA); 2020.
R20-2760
Dinarello CA. The IL-1 family of cytokines and receptors in rheumatic 
diseases. Nat Rev Rheumatol. 2019 Oct;15(10):612–32.
R20-2761
Mössner R, Wilsmann-Theis D, Oji V, Gkogkolou P, Löhr S, Schulz P, et al. 
The genetic basis for most patients with pustular skin disease remains elusive. 
Br J Dermatol. 2018 Mar;178(3):740–8.
R20-2767
Ryan TJ, Baker H. The prognosis of generalized pustular psoriasis. Br J 
Dermatol. 1971 Nov;85(5):407–11. 
R20-2770
Saeki H, Nakagawa H, Ishii T, Morisaki Y, Aoki T, Berclaz P-Y, et al. 
Efficacy and safety of open-label ixekizumab treatment in Japanese patients 
with moderate-to-severe plaque psoriasis, erythrodermic psoriasis and 


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generalized pustular psoriasis. J Eur Acad Dermatol Venereol. 2015 
Jun;29(6):1148–55.
R20-2784
Kotowsky N, Gao R, Singer D, Garry E, Golembesky AK. PRO29 Healthcare 
Resource Utilization (HCRU) In Patients With Generalized Pustular Psoriasis 
(GPP): A Claims Database Study. Value in Health. 2020 May 1;23:S333–4.
R20-3140
Golembesky AK, Kotowsky N, Gao R, Yamazaki H. PRO16 Healthcare 
Resource Utilization (HCRU) in Patients with Generalized Pustular Psoriasis 
(GPP) in JAPAN: A Claims Database Study. Value in Health Regional Issues. 
2020 Sep 1;22:S98. 
9.2
UNPUBLISHED REFERENCES
c03320877
Investigator´s Brochure BI 655130 for IL36R antibody in Ulcerative Colitis, 
Crohn's Disease, Palmoplantar Pustulosis, Pustular Psoriasis and Atopic 
Dermatitis.
c09985235-01
. Single-blind, partially randomised, 
placebo-controlled Phase I study to investigate safety, tolerability, 
pharmacokinetics and pharmacodynamics of single rising intravenous doses of 
BI 655130 in healthy male volunteers, April 7, 2017


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10.
APPENDICES
10.1
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalised hives, pruritus or flushing, swollen lips
/tongue / uvula)
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (e.g., generalised hives, itch-flush, 
swollen lips / tongue / uvula)
b. Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c.
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline
PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 
1 year, less than (70 mm Hg +[2 x age]) from 1 to 10 years, and less than 90 mm Hg from 11 
to 17 years.
Reference: R11-4890


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
06 Jul 2022
EudraCT number
EU number
NA
BI Trial number
1368-0073
BI Investigational Medicinal 
Product(s)
Spesolimab, BI 655130
Title of protocol
Multi-centre, open-label, expanded access trial of 
spesolimab i.v. in patients with generalized 
pustular psoriasis (GPP) presenting with a flare
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Clinical Trial Protocol Synopsis Table: Main in 
and exclusion criteria
3.2.2 Inclusion Criteria #3
Description of change
Minimum age of inclusion criteria was changed 
from 20 to 18 years.
Rationale for change
The legal age of adulthood was changed per 
revision of local regulation.
Section to be changed
Flow Chart
Description of change
Foot note #8, 9 and 10 in Flow Chart were
corrected to #7, 8 and 9.
Rationale for change
Correction
Section to be changed
Table 1.4: 1, Risk associated with spesolimab 
administration
Description of 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. The cases 
were considered as peripheral neuropathy by the 
external neurologist expert panel’s assessment.
Rationale for change
Added to inform about the newly identified risk 
“peripheral neuropathy”
Section to be changed
Section 3.2.3 Exclusion Criteria #9
Table 4.2.2.1: 1 Restricted Medications
Description of change
Live virus vaccinations was corrected to live 
vaccinations
Rationale for change
Correction


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Section to be changed
Clinical Trial Protocol Synopsis Table: Main in 
and exclusion criteria
Section 3.2.3 Exclusion Criteria #12
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. 
This way the selection of patients with acute 
demyelinating neuropathy would be avoided.
Section to be changed
Section 3.2.4.1 Discontinuation of trial 
medication and assessment.
Description of change
Following information was added.
∀
If peripheral neuropathy is suspected, 
treatment with spesolimab should be 
temporarily 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. 
Section to be changed
Table 5.2.3:1 Laboratory tests to be assessed at 
V1 prior to i.v. administration
Description of change
Category “automatic WBC differential” was 
corrected to “WBC differential”.
Category “manual differential WBC” was 
removed
“Qualitative” was removed from Hepatitis B 
Surface Antigen, Hepatis B Surface Antibody, 
Hepatitis C Antibodies and HIV-1 and HIV-2 
Antibody.
Rationale for change
Correction to remove unnecessary requirement.


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BI Trial No.: 1368-0073
c36703857-02
Clinical Trial Protocol
Page 57 of 58
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (20.0) / Saved on: 22 Apr 2021
Section to be changed
Section 5.2.4.1.4 Adverse events of special 
interest
Description of change
Following information was added.
Peripheral neuropathy
Any event suspected or diagnosed as Peripheral 
Neuropathy is considered as an AESI.
For the treatment interruption rules, please see 
section 3.2.4.1
Rationale for change
To update reporting requirements to ensure all 
cases of suspected peripheral neuropathy 
including the non-serious ones are analyzed 
quickly.
Section to be changed
Section 6.1.3 Follow up period and trial 
completion
Description of change
The information to keep the same patient number 
for the case of re-entry was added.
Rationale for change
Clarification
Section to be changed
Section 6.1.3 Follow up period and trial 
completion
Description of change
The following information was added
Then, in case of re-entry due to a new GPP flare 
within the 16-wks follow-up period, the patient 
will end the current follow-up period, and restart 
the trial from the screening for eligibility. If 
eligibility criteria is met, and permission from BI 
is granted (see above), the patient can be treated 
again to receive a new dose of spesolimab. After 
infusion, the patient is followed-up for 16-weeks 
after the latest dose of spesolimab. Also for this 
scenario, after one week, a second dose of 
spesolimab can be administered, if deemed 
necessary by the treating physician.
Rationale for change
Clarification for the case of re-entry due to a new 
GPP flare within the 16-weeks follow-up period
Section to be changed
Section 8.1 Trial approval, patient information, 
informed consent
Description of change
“trial patients” was corrected to “patients in the 
trial”
Rationale for change
Correction


Boehringer Ingelheim
06 Jul 2022
BI Trial No.: 1368-0073
c36703857-02
Clinical Trial Protocol
Page 58 of 58
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106_RD-03 (20.0) / Saved on: 22 Apr 2021
Section to be changed
9.2 Unpublished references
Description of change
Release date of IB was removed
Rationale for change
To avoid the old release date is kept in the 
protocol


 
 
 
APPROVAL / SIGNATURE PAGE 
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Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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