Clinical trial NCT05239039
Conditions: Generalized Pustular Psoriasis
Sponsor: Boehringer Ingelheim
Start date: 2022-03-15; Completion date: 2023-07-17
Enrollment: 39 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Expanded Access Program in China 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. This means that no therapy exists and participation in a clinical study is not possible.

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 times. Participants who benefit from the treatment during that time may repeat the treatment in case they experience a new GPP flare-up. The doctors regularly check participants' health and take note of any unwanted effects.

Detailed description:

Arms: arm 1: Patients with Generalized Pustular Psoriasis (GPP) presenting a flare received a single intravenous dose of 900 milligrams of spesolimab. arm 2: Patients with Generalized Pustular Psoriasis (GPP) presenting a flare received a single intravenous dose of 900 milligrams of spesolimab. One week after the initial dose, patients received a second intravenous single dose of 900 mg of spesolimab due to persistence of flare symptoms.
Interventions: intervention 1: spesolimab
Intervention descriptions: intervention 1: spesolimab

Protocol documents:
Prot_000.pdf: 
EXPANDED Access Program (EAP) Protocol
Document Number:
c39436286-01
BI Trial No.
1368-0077
BI Investigational
Medicinal Product(s)
Spesolimab, BI 655130
Title
Multi-centre, open-label, expanded access program of 
 
 spesolimab in patients with generalized pustular 
psoriasis (GPP) presenting with a flare 
Lay Title
An Expanded Access Program in China to provide spesolimab to 
people with a flare-up in Generalized Pustular Psoriasis who have 
no other treatment options
Clinal Trial Leader
TEL:  
Email:
Coordinating 
Investigator
TEL:
Email:
Status
FinalProtocol
Current Version and 
Date
Version:
Date:
V2.0
12 May 2022
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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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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
EXPANDED ACCESS PROGRAM/EXPANDED ACCESS CLINICAL TRIAL 
PROTOCOL SYNOPSIS .....................................................................................2
TABLE OF CONTENTS ........................................................................................................4
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 PROGRAM.................................16
1.4
BENEFIT - RISK ASSESSMENT/ MEDICAL NEEDS STATEMENT.......16
2.
PROGRAM OBJECTIVES AND ENDPOINTS .............................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint................................................................................................22
2.1.3
Secondary endpoints...........................................................................................22
3.
DESCRIPTION OF DESIGN AND PROGRAM POPULATION.................23
3.1
OVERALL PROGRAM DESIGN AND PLAN...............................................23
3.2
SELECTION OF PROGRAM POPULATION...............................................24
3.2.1
Main diagnosis for program entry ....................................................................24
3.2.2
Inclusion criteria .................................................................................................25
3.2.3
Exclusion criteria ................................................................................................25
3.2.4
Discontinuation / withdrawal of patients from program ................................26
3.2.4.1
Discontinuation of trial medication and assessment.............................................26
3.2.4.2
Withdrawal of consent to program participation ..................................................27
3.2.4.3
Discontinuation of the program by the sponsor....................................................27
4.
TREATMENTS...................................................................................................28
4.1
INVESTIGATIONAL TREATMENTS ...........................................................28
4.1.1
Identity of the Investigational Medicinal Product ...........................................28
4.1.2
Packaging, labelling, and re-supply...................................................................28
4.1.3
Storage conditions...............................................................................................28
4.1.4
Drug accountability.............................................................................................29
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................30
4.2.1
Other treatments and emergency procedures..................................................30
4.2.1.1
Emergency procedures..........................................................................................30
4.2.2
Restrictions ..........................................................................................................31




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11.
DESCRIPTION OF PROTOCOL AMENDMENT(S) ...................................53


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ABBREVIATIONS AND DEFINITIONS
AD
Atopic Dermatitis
ADA
Anti-Drug Antibody
ADCC
Antibody-Dependent Cellular Cytotoxicity
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AST
Aspartate Transaminase 
AUC
Area Under the Curve
BI
Boehringer Ingelheim
CA
Competent Authority
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
Cmin
Minimum Plasma Concentration
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as 
“eCRF”)
CRO
Contract Research Organization
CRP
C-Reactive Protein
CTL
Clinical Trial Leader
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
DEDP
Drug exposure during pregnancy 
EACT
Expanded Access Clinical Trial
EAP
Expanded Access Program
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
ERASPEN
European Rare and Severe Psoriasis Expert Network
FACIT-F
Functional Assessment of Chronic Illness Therapy – Fatigue


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FDA
Food and Drug Administration
FIH
First in human
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GPP
GPPGA
Generalized Pustular Psoriasis
Generalized Pustular Psoriasis Physician Global Assessment 
GPPASI
Generalized Pustular Psoriasis Area and Severity Index
GOT
Glutamic-Oxaloacetic Transaminase
GPT
Glutamic-Pyruvic Transaminase
HA
Health Authority
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
IgG
Immunoglobulin G
IL
Interleukin
IMP
Investigational Medicinal Product
INN
International Non-Proprietary Name
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITE
Indirect Target Engagement
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
KO
Knock Out
LPLT
Last Patient Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
MIP
Macrophage Inflammatory Protein


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NOAEL
No-Observed Adverse Effect Level
OPU
Operative Unit
PK
Pharmacokinetics
PSS
Psoriasis Symptom Scale
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
TNF
Tumour necrosis factor
TS
TSAP
Treated Set
Trial Statistical Analysis Plan
UC
Ulcerative Colitis
ULN
Upper Level of Normal
VAS
Visual Analogue Scale
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 aseptic 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 
 or Week 
). Response to flare treatment was not evaluated in these trials 


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and complete pustule and/or skin clearance not demonstrated (R16-1462, R17-3600, R17-
3604, R18-2719, R18-2720, R19-1562, R20-1400, R20-2770).
Management guidelines and recommendations for the treatment of GPP generally 
recommend cyclosporine, retinoids, infliximab or methotrexate as first-line therapies, based 
on case study reports (R19-1562, R17-3600) and practice for the management of plaque 
psoriasis. However, long-term use of these treatments is limited owing to side effects and 
contraindications (retinoids: teratogenicity, severe renal and hepatic dysfunction, ossification 
abnormalities, pseudotumor cerebri, hair loss; cyclosporine: excessive hair growth, renal 
toxicity, lymphoma, severe hepatic dysfunction; methotrexate: liver and bone marrow 
toxicity, lymphoma, hematologic suppression, severe skin reaction, fatal dosing errors). Some 
of these side effects, such as hair loss, excessive hair growth, and teratogenicity, particularly 
limit the use of these treatments in women, who are disproportionately affected by GPP. In 
addition to safety concerns, there is evidence that current treatment options are not optimal. 
An analysis of 60 patients diagnosed with GPP and enrolled in the Corrona Psoriasis Registry 
indicated that 35% of patients previously received 1 biologic medication and 25% received 2 
or more biologics. This suggests that some patients are cycling through medications in order 
to find a treatment that provides acceptable control. For patients currently on biologics, the 
most cited reason for discontinuation of the previous medication was lack of efficacy [data on 
file]. 
GPP is a severe, life-threatning disease. There are limited treatment options, with available 
therapies lacking evidence for effectiveness, and no therapies specifically available for the 
rapid management of flares. As such, there is substantial need for a highly effective treatment 
that rapidly and sustainably clears pustules and skin manifestations as well as associated 
systemic symptoms, with a favourable safety profile, in patients with GPP presenting with a 
flare.
IL-36R signalling in GPP
IL-36 is a member of the IL-1 family of cytokines and includes the isoforms IL-36α, IL-36β 
and IL-36γ and the IL-36 receptor antagonist (IL-36Ra) (R20-2760), which are expressed at 
high levels in epithelial cells (R18-2717, R20-1386, R16-2297). Dysregulated IL-36R 
signalling promotes the infiltration of neutrophilic granulocytes into the epidermis, leading to 
the formation of sterile pustules.
The overexpression of IL-36 or a loss-of-function mutation in the gene encoding IL-36Ra 
(IL36RN) are central to the pathogenesis of GPP (P19-10261, R14-5158). Such loss-of-
function mutations have been identified in patients with GPP, in addition to mutations in 
other genes associated with the IL-36 pathway, including CARD14 (R14-5158, R16-0929, 
R16-0928, R20-2761). Notably, mutations in IL36RN are associated with an earlier age of 
onset of GPP and more severe disease ((R18-2717). Furthermore, biomarker analysis of skin 
biopsies from GPP lesions demonstrates significantly increased levels of all IL-36 isoforms 
versus non-lesional skin ((R18-2717).
In summary, there is strong genetic link between the IL-36 signaling pathway and GPP, with 
experimental data identifying IL-36 as the dominant cytokine driving GPP (R17-3602). 


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Therefore, there is a strong scientific rationale to support that inhibition of IL-36R signaling 
with the humanized anti-IL-36R antibody spesolimab would be beneficial in treatment of 
GPP.
1.2
DRUG PROFILE
1.2.1
Mode of action 
Spesolimab is a humanized monoclonal IgG1 antagonistic antibody that blocks human 
IL-36R signaling. Binding of spesolimab to IL-36R is anticipated to prevent the subsequent 
activation of IL-36R by cognate ligands (IL-36 α, β and γ) and downstream activation of 
proinflammatory and pro-fibrotic pathways. The aim is to reduce epithelial cell / fibroblast / 
immune cell-mediated inflammation and interrupt the inflammatory processes that drive 
pathogenic cytokine production in inflammatory diseases, including GPP.
1.2.2
Nonclinical pharmacology 
Preclinical studies
Spesolimab binds to human IL-36R with a binding avidity of less than 1 pM. Spesolimab 
inhibits IL-36 ligand-stimulated NF-κB activation in transformed epithelial cells as well as 
primary human keratinocytes, dermal fibroblasts and intestinal myofibroblasts, with IC90 
values in a consistent range of 0.7 to 3.7 nM. Spesolimab also inhibits IL-8 release and IFNγ 
secretion in vitro. Mutations of two key residues (L234 and L235) to alanine were made to 
spesolimab to abrogate FcR binding activity and function. Direct assessment of the impact of 
the mutations in the IgG1 FcR binding sites on both antibody-dependent cellular cytotoxicity 
(ADCC) and complement-dependent cytotoxicity (CDC) effector functions revealed that the 
mutations abrogate both ADCC and CDC effector functions and indicate that spesolimab will 
be a non-depleting therapy in vivo. 
Toxicology studies 
Spesolimab does not bind to IL-36R in species commonly studied for toxicological 
evaluation. Therefore, meaningful toxicity studies of spesolimab itself cannot be performed 
in any animal species. However, in i.v. toxicity studies of up to 26 weeks in duration in mice, 


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no adverse effects of IL-36R antagonism were seen, using a surrogate mouse antibody that 
closely resembles the human antibody, at a dose that was 5-fold higher than the dose that was 
protective in an experimental mouse colonic inflammation model. In the 26-week toxicity 
study, male and female mice (20–30/sex/group at 0, 10 and 50 mg/kg/day) were administered 
the surrogate monoclonal antibody twice weekly for 26 weeks by intravenous injection via 
the caudal vein. There were no test article-related changes in clinical observations, body 
weights, food consumption, ophthalmology, clinical pathology parameters (haematology, 
clinical chemistry), organ weights, macroscopic or microscopic examinations. The no-
observed-adverse-effect level (NOAEL) was considered to be 50 mg/kg/day. The in vitro 
cytokine release and tissue cross-reactivity assays demonstrate that the risk of transient 
cytokine release in humans is low and that, as expected, spesolimab stains epithelium in a 
variety of tissues. There were no signs of local irritation after single, 1 mL injections of the 
subcutaneous formulation in rabbits. These preclinical toxicology data support chronic 
spesolimab dosing in humans. In addition, a characterisation of individuals with homozygous 
IL-36R loss-of-function mutations revealed that normal immune function was broadly 
preserved, and that the medical history of these individuals showed no increased risk of 
infections or malignancies. These data suggest that IL-36 signalling pathway inhibition may 
not substantially compromise host defences (R17-3632). 
1.2.3
Clinical experience 
In the first-in-human (FIH) study (1368.1), spesolimab or placebo were administered to 78 
healthy adult volunteers, with 58 subjects assigned to single ascending i.v. doses from 0.001 
mg/kg to 10 mg/kg body weight and 20 subjects assigned to placebo. Safety and tolerability 
of all tested i.v. doses was good. There were no SAEs. AEs categorised as related to 
treatment were observed in 3/20 (15.0%) subjects in the placebo group and in 8/58 (13.8%) 
subjects treated with spesolimab. The most frequent treatment-emergent AEs were 
nasopharyngitis (spesolimab: 20.7%; placebo: 15.0%), headache (spesolimab: 8.6%; placebo: 
15.0%), influenza-like illness (spesolimab: 6.9%; placebo: 10.0%), and diarrhoea 
(spesolimab: 3.4%; placebo: 10.0%). There were two AEs of moderate intensity (injection 
site haematoma, headache), all remaining AEs were of mild intensity. There were no serious 
AEs, no AEs that led to discontinuation of trial drug, no protocol-specified AEs of special 
interest and no other significant AEs according to ICH E3. No relevant changes were 
observed in safety laboratory tests, vital signs, and electrocardiograms (ECGs). Importantly, 
there were no relevant differences in frequencies of subjects with treatment-emergent AEs 
between the treatment groups, and no dose dependency was observed. 


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In a multiple rising dose trial (1368.2), spesolimab or placebo have been administered to 
healthy adult volunteers at multiple ascending i.v. doses of 3, 6,10 and 20 mg/kg given 
weekly for 4 weeks (i.e. 4 administrations) or a single dose of 20mg/kg (eight subjects each, 
3:1 receiving spesolimab or placebo). Overall, multiple i.v. doses of 3 mg/kg, 6 mg/kg, and 
10 mg/kg, as well as single and multiple doses of 20 mg/kg spesolimab were found to be safe 
and well tolerated by the healthy male subjects in this trial. The incidence and intensity of 
drug-related AEs appeared to be higher in the 20 mg/kg multiple dose spesolimab treatment 
group than in the other treatment groups, mainly driven by headache. No dose-dependent 
AEs or other clinically relevant changes in safety laboratory tests, vital signs, or ECG were 
observed (c03320877). 
The open-label, single group phase I study trial (1368.11) was conducted to investigate the 
safety, tolerability, PK and efficacy of a single i.v. dose of spesolimab (10 mg/kg) in seven 
patients with a GPP flare. The proof-of-concept for IL-36R inhibition in GPP was achieved in 
these patients who showed rapid clinical responses to single administrations of spesolimab. 
Five of these seven patients became clear or almost clear of GPP 1 week after the infusion, 
and all of them reached this status 4 weeks after treatment. Within 48 hours of treatment, 
pustules were completely cleared in three patients; pustules were cleared by Week 1 in five 
patients, and by Week 2 in six patients. The early response in the skin was also accompanied 
by an early response in systemic components, with C-reactive protein (CRP) approaching 
normalization within 4 weeks. A major improvement in GPPASI was observed in all patients 
very early with a mean (SD) percent change from baseline of 73.2% (16.2) at Week 2; by 
Week 4, this was further reduced (82.0% from baseline), and was maintained to Week 20 
(83.6%). Additional improvements (mean [SD]) from baseline to Week 2 were observed in 
FACIT-F, 12.3 (10.1); Pain-VAS, –45.9 (32.3); and PSS, –5.14 (3.18), all of which were also 
sustained through Week 4. All patients reported at least one AE, but none was severe, serious, 
led to discontinutation, or considered significant. AEs in four patients were considered drug-
related. The most frequently reported treatment-emergent AE was arthralgia (42.9%). There 
were no clinically relevant laboratory or vital sign abnormalities (c03320877, P19-01888).
The multicenter, randomized, placebo-controlled, double-blind Phase II Effisayil-1 study 
(1368-0013, ClinicalTrials.gov identifier: NCT03782792) was conducted to evaluate the 
efficacy and safety of a single i.v. dose of 900 mg spesolimab compared with placebo in 53 
patients with GPP presenting with a flare. Baseline demographic and disease characteristics 
were generally balanced between arms. At randomization, 18.9% of patients had a GPPGA
total score of 4 (severe), and most patients had a GPPGA pustulation subscore 3 or 4 (high or 
very high-density of pustules), and highly impaired quality of life and clinical burden as 
indicated by DLQI, pain VAS, FACIT-Fatigue and PSS. 
At week 1, 19 patients (54.3%) randomized to spesolimab versus one patient (5.6%) 
randomized to placebo achieved a GPPGA pustulation subscore of 0 (no visible pustules; risk 
difference, 48.7; 95% CI, 21.5–67.2; one-sided P<0.001). A GPPGA total score of 0 or 1 
(clear or almost clear skin) at week 1 was achieved in 15 patients (42.9%) randomized to 
spesolimab versus two patients (11.1%) randomized to placebo (risk difference, 31.7; 95% CI, 


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2.2–52.7; one-sided P=0.012). Clinical responses were observed regardless of IL36RN
mutation status. At week 4, 16 patients (45.7%) receiving a single spesolimab dose at day 1 
achieved a GPPASI 75 versus two patients (11.1%) receiving placebo (risk difference, 34.6; 
95% CI, 5.8–55.4; one-sided P=0.008). Additionally, significantly higher reductions in pain 
VAS (P=0.001) and PSS (P=0.004), and improvement in FACIT-Fatigue scores (P=0.001) at 
week 4 were achieved by patients receiving spesolimab versus those receiving placebo.
At day 8, 12 patients randomized to spesolimab received an open-label (second) dose of 900 
mg spesolimab. Beyond day 8, response rates in patients in the spesolimab arm who received 
one or two doses continued to increase. A total of 23 patients (65.7%) achieved a GPPGA 
pustulation subscore of 0 by week 2, and the same proportion achieved a GPPGA total score 
of 0 or 1 by week 4. These were sustained in at least 60% of patients up to week 12. The 
median percent improvement in the GPPASI score from baseline was 42.8% at week 1 and 
progressively increased up to 81.8% at week 12. A GPPASI 75 was achieved in 13 patients 
(37.1%) at week 2, in 18 patients (51.4%) at week 4, and in 21 patients (60.0%) at week 8, 
and was sustained up to week 12. Rapid reductions in pain VAS score and improvements in 
DLQI scores were achieved through week 4 and sustained through week 12. CRP normalized 
within 4 weeks in patients with elevated baseline CRP (≥ 10mg/L), who received one or two 
doses of spesolimab.
At week 1, 77.1% and 66.7% of patients receiving spesolimab and placebo, respectively, had 
an AE. The most common AE was pustular psoriasis, reported in 37.1% and 38.9% of 
patients randomized to spesolimab or placebo, respectively. Pyrexia was reported in 5.7% 
and 22.2% of the patients receiving spesolimab or placebo, respectively. Infections were 
reported in 17.1% and 5.6% of patients in the spesolimab and placebo groups, respectively. 
SAE were reported in 14.3% and 16.7% of patients in the spesolimab and placebo groups, 
respectively. 
At week 12, 91.4% of patients randomized to spesolimab, including those who received a 
second spesolimab dose at day 8, had an AE, and 25.7% had a SAE. Symptoms observed in 
two patients receiving spesolimab were reported as drug reactions with eosinophilia and 
systemic symptoms (DRESS) with RegiSCAR scores ≤3 (P14-06207) and in close temporal 
relationship to the reported GPP flares, which was two days after treatment in one case. Both 
patients received concomitant paracetamol and antibiotics, cefuroxime and cefepime in one 
patient, and spiramycin in the other. 
Anti-drug antibodies (ADAs) were detected as early as week 2, with cumulative rate of 
46.7% (25 of 45 patients) by week 12. Formation of ADAs did not affect the primary and 
secondary efficacy endpoints at week 1. If ADAs developed, re-treatment of recurring flares 
with spesolimab i.v. was still efficacious even in the presence of high ADA titers. For safety, 
no association between immunogenicity and safety was observed, i.e. there was no indication 
for an association of ADA titers and hypersensitivity events, even against a high ADA titer 
background. Of note, it was shown that additional i.v. administration can be made without 
induction of systemic hypersensitivity reactions while achieving complete pustular clearance.
From Effisayil-1, 39 patients continued treatment with spesolimab as part of the ongoing 
longer-term follow-up study 1368-0025 (ClinicalTrials.gov identifier NCT03886246).


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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. 
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 PROGRAM
The Effisayil-1 trial demonstrated that treatment of GPP flares with spesolimab was 
associated with rapid pustular and skin clearance, as well as improvements in systemic 
symptoms and quality of life, with a favourable benefit–risk profile.
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-
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.


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The risks shown in the table below (Table 1.4: 1) are are derived from general safety 
considerations of immunomodulatory drugs in clinical development and data generated for 
spesolimab to date.
Table 1.4: 1
Risks associated with spesolimab administration 
Risks of clinical 
relevance for this 
program
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 programs.
Patients with hepatic impairment 
will be excluded from the 
program. In case of suspicion of 
hepatic injury during the program 
(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. Hepatic injury 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 program.
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 
program. 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 program 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.
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 
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. 


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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
showed a heterogenous pattern.
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.
Trial treatment discontinuation 
criteria as well as criteria for trial 
treatment restart are implemented 
for relevant cases.
Other risks related to program-specific procedures include blood sampling and 
 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 program 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.
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. 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 


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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 program 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 program. However, the treating physician 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. 
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 program enrolment and during the program by the treating physician 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 treating physicians 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. 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 treating physician and 
sponsor.
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.
PROGRAM OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The aim of this program is to provide early access to the investigational drug spesolimab for 
patients with GPP presenting with a flare. A secondary aim of this program is to collect 
additional data on the safety and tolerability of spesolimab.
2.1.2
Primary endpoint
•
Occurrence of Treatment Emergent Adverse Events (AEs)
2.1.3
Secondary endpoints
•
Occurrence of Treatment Emergent Serious Adverse Events (SAEs)
•
Occurrence of Treatment Emergent Adverse Events of Special Interest (AESIs)






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Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.2.2
Inclusion criteria
1.
Diagnosis of GPP, consistent with ERASPEN criteria, defined as primary, sterile,
macroscopically visible pustules on non-acral skin (excluding cases where pustulation
is restricted to psoriatic plaques). GPP can occur with or without systemic
inflammation, with or without plaque-type psoriasis, and be either relapsing (>1
episode) or persistent (>3 months).
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 treating physician.
3.
Male or female patients, aged 18 to 75 years at time of enrolment. 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 program.
5.
No satisfactory authorized alternative therapy exists, as assessed by the treating
physician.
3.2.3
Exclusion criteria
1.
Women who are pregnant, nursing, or who plan to become pregnant while in the
program.
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 
.
2.
Severe, progressive, or uncontrolled hepatic disease, defined as >3-fold Upper Limit
of Normal (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 treating physician.
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 treating physician.
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.
1A 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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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 treating physician, likely to interfere 
with the safe conduct of the program.
10.
Currently enrolled in another investigational device or drug program, or less than 30 
days since ending another investigational device or drug program(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 treating physician may put the patient at 
risk because of participation in this program or limit the patient’s ability to participate 
in this program.
12.
Presence of acute demyelinating neuropathy. 
3.2.4
Discontinuation / withdrawal of patients from program 
Patients may discontinue program treatment or withdraw consent to program participation for 
any reason. The decision to withdraw consent to program participation and the reason must 
be documented in the patient files and CRF. If the reason for discontinuation is death, this 
should be reported on the SAE form as well, regardless of causal relationship.
3.2.4.1
Discontinuation of trial medication and assessment
An individual patient will discontinue treatment if:
•
The patient wants to discontinue 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 program
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 program 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 hepatic injury 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 


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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 
/treatment for all 
patients or take any other appropriate action to guarantee the safety of the patients
participating in the program. 
If a patient wants to discontinue the participation in the program, 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 
-week assessment in 
patients who have discontinued triam medication or assessment is detailed in section 5.2.4.2.1.
3.2.4.2
Withdrawal of consent to program participation
Patients may withdraw their consent to program participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between treatment discontinuation and withdrawal 
of consent to program participation, as well as explain the options for continued follow-up 
after 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 program by the sponsor
Boehringer Ingelheim reserves the right to discontinue the program 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 program protocol, or the contract impairing the appropriate conduct
of the program.
3. Commercial availability of spesolimab i.v. or 6 months after marketing authorization in 
China, whichever is earlier.
The investigator / the program site will be reimbursed for reasonable expenses incurred in 
case of program 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 program. There is no active comparator or 
placebo.
Table 4.1.1: 1
Spesolimab
Substance:
Spesolimab (BI 655130)
Pharmaceutical formulation:
Solution 
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
Spesolimab
 
Posology:
Method and route of administration:
4.1.2
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). Shipment of material to the local depots and/or sites will be managed via an 
IRT system, which will also monitor expiry dates of available supplies.
An Interactive Response Technology (IRT) system will be used to screen eligible patients, 
assign medication kits, and manage re-supply ordering of medication kits. At program entry, 
as well as subsequent medication administration visits (if applicable), and IRT system will 
assign medication numbers. 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.
For details of packaging and the description of the label, refer to the ISF.
4.1.3
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


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temperature log must be maintained for documentation. Program 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 program medication must be administered in the manner specified in the EAP Protocol 
and instructions for IMP preparation handling and administration of spesolimab.
4.1.4
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
•
Approval of the clinical program protocol by the IRB / ethics committee.
•
Availability of a signed and dated clinical program 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 program protocol.
•
Availability of the proof of a medical licence for the Principal Investigator.
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 program medication must be returned to the sponsor. All used and partially used 
medication must be destroyed locally by the participating site. Receipt, usage and return or 
disposal must be documented on the respective forms. Account must be given for any 
discrepancies.
The investigator or designee must maintain records of the product’s delivery to the 
participating site, the inventory at the site, the use by each patient, and the return to the 
sponsor or warehouse / drug distribution centre or alternative disposal of unused products. If 
applicable, the sponsor or warehouse / drug distribution centre will maintain records of the 
disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and patients
participating in the program. The investigator or designee will maintain records that 
document adequately that the patients were provided the doses specified by the EAP Protocol 
and reconcile all investigational medicinal products received from the sponsor. At the time of 
return to the sponsor or appointed CRO, the investigator or designee must verify that all 
unused drug supplies have been returned by the clinical staff and all used or partially used 
supplies have been destroyed by the participating site, and that no remaining supplies are in 
the investigator’s possession.






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when used consistently and correctly during the study, and for a period of at least 16 weeks
after the last dose of study drug.
Acceptable methods of birth control for this program are:
∀
Combined (estrogen and progestogen containing) hormonal birth control associated 
with inhibition of ovulation
∀
Progestogen-only hormonal birth control associated with inhibition of ovulation
∀
Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS) 
∀
Bilateral tubal occlusion (blocking of the fallopian tubes)
∀
Vasectomy of sexual partner (proven effective by absence of sperm in the ejaculate).
∀
Complete sexual abstinence (not to have male-female vaginal sex)


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.2
ASSESSMENT OF SAFETY
Safety will be assessed descriptively based on the incidence of:
∀
Treatment emergent Adverse events (AEs)
∀
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.
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 treating physician. 
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.
Vital signs will be evaluated at follow-up visits according to standard clinical practice and 
when deemed appropriate by the treating physician.
The results must be included in the source documents available at the site.


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5.2.3
Safety laboratory parameters
Safety laboratory examinations include liver function tests for elibility check: aspartate 
transaminase (AST/GOT), alanine transaminase (ALT/GPT), alkaline phosphatase, and total 
bilirubin. 
Any additional laboratory testing during the program is optional and should be performed at 
the discretion of the treating physician in accordance with the current standard of care, which 
may yield useful information for the management and safety evaluation of the patient.
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 hepatic injury 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). 
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.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀Worsening of the underlying disease or of other pre-existing conditions 
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to program 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 that 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,
-
requires prolongation of existing hospitalisation,


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-
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. 
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 further AEs, which by their nature can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.4.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
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 program, 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 DILI
A potential severe DILI that requires follow-up is defined by the following alterations of 
hepatic laboratory parameters: 

an elevation of AST (aspartate transaminase) and/or ALT (alanine aminotransferase) ≥3 
fold ULN combined with an elevation of total bilirubin ≥2 fold ULN measured in the 
same blood draw sample, or 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 


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(ALT, AST, alkaline phosphatase, total bilirubin) available, the investigator should make sure 
these parameters are analysed. Should the results meet the criteria of hepatic injury alert, the 
procedures described in the DILI checklist should be followed.
Systemic hypersensitivity reactions including
 reactions and anaphylactic reaction
Any suspicion of severe systemic hypersensitivity including 
 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), 
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 1.4 and 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 ICF for details).
5.2.4.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse envent 
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.


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∀
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, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
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.
∀
Disappearance of the event even though the program 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 program
(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 program: the investigator does not need to actively 
monitor the patient for new AEs but should only report any occurrence of cancer and 
program drug-related SAEs and program 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 program, the patient should be re-evaluated to ensure that 
eligibility criteria are still met and the overall program is still running in order to assess 
AEs (serious and non-serious) and AESIs.
Vital Status Data Collection
Patients who withdraw their consent to program participation, who agree to be contacted 
further but do not agree to physical visits, should be followed up as described in section 
3.2.4.2, withdrawal from program treatment. Thus, for patients who withdraw their consent 


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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 program drug-related SAEs and and program 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 
instances, the investigator could inform the sponsor upfront via telephone. This does not 
replace the requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
5.2.4.2.3
Information required
All (S)AEs, including those persisting after individual patient’s end of program, must be 
followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.4.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical program. Once a patient has been enrolled 
in the clinical program and has taken program medication, the investigator must report any 
drug exposure during pregnancy (DEDP) in a program 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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8.
INFORMED CONSENT, PROGRAM RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The program will be carried out in compliance with the protocol, the ethical principles laid 
down in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for 
Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
directive 2001/20/EC / EU regulation  536/2014, the Japanese GCP regulations (Ministry of 
Health and Welfare Ordinance No. 28, March 27, 1997) and other relevant regulations. 
Investigators and site staff must adhere to these principles.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the program 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 program are described in the investigator
contract. As a rule, no program results should be published prior to finalization of the Clinical 
Trial Report of the program.
The certificate of insurance cover is made available to the investigator and the patients and is
stored in the ISF.
8.1
PROGRAM APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT
This program will be initiated only after all required legal documentation has been reviewed 
and approved by the respective Institutional Review Board (IRB / Independent Ethics 
Committee (IEC and competent authority (CA) according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the program, 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 program 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 program patients based on the
patient information form. A language understandable to the patient should be chosen, 
technical terms and expressions avoided, if possible. The patient must be given sufficient 
time to consider participation in the program. The investigator or delegate obtains written 


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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 program collaborator has given a 
supplementary explanation, the program 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 program quality management. It is initiated by the 
assessment of critical data and processes for program 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 program 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 program conduct, 
program design or monitoring approaches. A quality assurance audit/inspection of this 
program 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 program-related files and correspondence, and the informed consent 
documentation of this clinical program.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
section 4.1.4.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and program records that include all observations 
and other data pertinent to the investigation on each program 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 
program and the investigator may need to request previous medical histories and evidence of 
any diagnostic tests. In this case, the investigator must make 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 program (substance, program number, patient number, date 
patient was informed).
•
Dates of patient’s visits, including dispensing of program medication.
•
Medical history (including program 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 program (end date; in case of premature 
discontinuation document the reason for it).
•
Prior to allocation of a patient to a treatment into a clinical program, there must be 
documented evidence in the source data (e.g. medical records) that the program
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 program.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site program-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Program site(s):
The program 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 program (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
Individual patient data obtained as a result of this program is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 
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.
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 program need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.6
PROGRAM MILESTONES
The start of the program is defined as the date when the first patient in the whole program
signs informed consent.
The end of the program is defined as the date when the last patient completes the follow up 
period after the last 
 of spesolimab in the whole program (“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole program 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 program is defined as the premature termination of the program
due to any reason before the end of the program as specified in this protocol.
Temporary halt of the program is defined as any unplanned interruption of the program by 
the sponsor with the intention to resume it.
Suspension of the program is defined as an interruption of the program based on a Health 
Authority request.
8.7
ADMINISTRATIVE STRUCTURE OF THE PROGRAM
The program is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this program. 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.


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BI has appointed a Clinical Trial Leader (CTL), responsible for coordinating all required 
activities, in order to:
-
manage the program in accordance with applicable regulations and internal SOPs,
-
direct the clinical program team in the preparation, conduct, and reporting of the 
program,
-
ensure appropriate training and information of Clinical Trial Managers (CTM), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the program in the participating countries will be performed by the 
respective local or regional BI-organisation (Operating Unit, OPU) in accordance with 
applicable regulations and BI SOPs, or by a Contract Research Organisation (CRO) with 
which the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the clinical program. 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 program.
Tasks and functions assigned in order to organise, manage, and evaluate the program 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 program. 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
P14-06207
Kardaun SH, Sekula P, Valeyrie-Allanore L, Liss Y, Chu CY, Creamer D, et 
al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an 
original multisystem adverse drug reaction. Results from the prospective 
RegiSCAR study. Br J Dermatol. 2013 Nov;169(5):1071–80.
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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R16-2297
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. 
R17-3600
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. 
R17-3602
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 
insurance data]. Gesundheitswesen. 2011 May;73(5):308–13. 
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. 
R20-1386
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: 
https://www.morphosys.com/media-investors/media-center/morphosys-
announces-approval-of-tremfyar-guselkumab-for-the-treatment
R20-1405
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. 
https://www.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). https://www.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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10.
APPENDICES
10.1
APPENDIX 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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SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
 
TRIAL STATISTICAL ANALYSIS PLAN
c40843858-02
BI Trial No.:
1368-0077
Title:
Multi-centre, open-label, expanded access program of 900mg
intravenous (i.v.) spesolimab in patients with generalized pustular
psoriasis (GPP) presenting with a flare
Including Revised Protocol # 2 [c39436286-01] 
Investigational
Product(s):
Spesolimab, BI 655130
Responsible trial 
statistician(s):
Tel.:
Fax: 
Date of statistical 
analysis plan:
17 Aug 2023
Version:
2 Final
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! 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................3
2.
LIST OF ABBREVIATIONS...............................................................................4
3.
INTRODUCTION.................................................................................................5
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................6
5.
ENDPOINTS(S).....................................................................................................6
5.1
PRIMARY ENDPOINT(S)...................................................................................6
5.2
SECONDARY ENDPOINT(S).............................................................................6
5.2.1
Key secondary endpoint(s) ...................................................................................6
5.2.2
Secondary endpoint(s)...........................................................................................6
6.
GENERAL ANALYSIS DEFINITIONS.............................................................7
6.1
TREATMENT(S) ..................................................................................................7
6.2
IMPORTANT PROTOCOL DEVIATIONS......................................................7
6.3
SUBJECT SETS ANALYSED .............................................................................8
6.5
POOLING OF CENTRES....................................................................................8
6.6
HANDLING OF MISSING DATA AND OUTLIERS ......................................8
7.
PLANNED ANALYSIS ......................................................................................11
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........11
7.2
CONCOMITANT DISEASES AND MEDICATION......................................12
7.3
TREATMENT COMPLIANCE ........................................................................12
7.4
PRIMARY ENDPOINT(S).................................................................................12
7.5
SECONDARY ENDPOINT(S)...........................................................................12
7.7
EXTENT OF EXPOSURE .................................................................................12
7.8
SAFETY ANALYSIS..........................................................................................13
7.8.1
Adverse Events ....................................................................................................13
7.8.2
Laboratory data...................................................................................................17
7.8.3
Vital signs.............................................................................................................17
7.8.4
ECG ......................................................................................................................17
7.8.5
Others ...................................................................................................................17
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............18
9. 
REFERENCES ....................................................................................................19
11.
HISTORY TABLE..............................................................................................21


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases of the study for each flare...................................7
Table 6.7: 1
Time windows for assignment of efficacy to visits in each flare treatment 
period................................................................................................................10
Table 7.8.1: 1 Project MedDRA search criteria for User Defined Adverse Event Categories16
Table 11: 1
History table .....................................................................................................21


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
AE 
Adverse event 
AESI 
Adverse event of special interest 
BI 
Boehringer Ingelheim 
BIcMQ 
Boehringer Ingelheim customized MedDRA Query 
BMI 
Body mass index 
CRF 
Case report form 
CTP 
Clinical trial protocol 
CTR 
Clinical trial report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EOS 
End of study 
EOT 
End of treatment 
ES 
Enrolled set 
GPP 
Generalized pustular psoriasis 
GPPGA
Generalized Pustular Psoriasis Physician Global Assessment
i.v. 
intravenous 
ICH 
International council for harmonisation of technical requirements for 
pharmaceuticals for human use 
iPD 
important protocol deviation 
IQR 
Interquartile range 
MedDRA 
Medical dictionary for regulatory activities 
OR 
Original results 
PT 
Preferred Term 
Q1 
1st quartile 
Q3 
3rd quartile 
REP 
Residual effect period 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS
Statistical analysis software 


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Term
Definition / description
 
 dose 
SD 
Standard deviation 
SMQ 
Standardised MedDRA query 
SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
TS
Treated set
TSAP 
Trial statistical analysis plan 
UDAEC 
User-defined adverse event categories 
WHO-DD 
World health organisation – drug dictionary 
3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 
. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
SAS® Version 9.4 or higher will be used for all analyses.
Note that this TSAP applies to trial 1368-0073 (including Revised Protocol # 2 [c36703857-
02]), 1368-0077 (including Revised Protocol # 2 [c39436286-01]), 1368-0109 under the 
Expanded Access Program.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Not applicable.
5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is defined in CTP Section 2.1.2.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)
Secondary endpoints are listed in CTP Section 2.1.3.






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∀
If the day of the start date is missing then the start date is set to first day of the month 
(except for escape medication, where the first dosing day will be used if first dosing 
happened in the same month).
∀
If the day and month of the start date are missing then the start date is set to 1st 
January of the year.
∀
All other cases need to be assessed by the trial team on an individual basis, using the 
above points as guidance.
If a concomitant medication is ticked to be ongoing, it is expected that the end date is missing 
and will not be imputed for display purposes.
Time since first diagnosis
For incomplete information on the date of first diagnosis, time since first diagnosis will be 
calculated as follows:
∀
If the year of first diagnosis is unknown, time since first diagnosis will be set to 
missing.
∀
If day and month of the first diagnosis are unknown, time since first diagnosis will be 
calculated as if diagnosed on the 30th of June of that year.
∀
If only the day of the first diagnosis is unknown, time since first diagnosis will be 
calculated as if diagnosed on the 15th of that month.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is N / Mean / SD / Min / Q1 /  
Median /  Q3 /  Max.
For tables that are provided for endpoints with some extreme data, median,  quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). 
The precision for percentages should be one decimal point, unless the denominator is smaller 
than 100 (in all treatment columns), in which case percentages are given in integer numbers. 
The category “missing” will be displayed only if there are actually missing values.
Disposition of the patient population participating in the trial will be summarised by the 
presentation of the frequency of patients enrolled, enrolled but not treated, enrolled and 
treated, who completed participation in the trial, and who were prematurely discontinued from 
trial, by reason. The iPDs, baseline conditions/medical history, demographic/baseline 
characteristics, concomitant medications, concomitant non-drug therapies, exposure will be 
presented based on TS for the entire trial duration. In addition, the number of flares will also 
be summarized based on TS.
For safety data, per patient analysis based on patient will be used for the analysis, whose 
denominator will be the number of patients or time at risk per patient for all applicable 
periods.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report: 
Sex, ethnicity, race, age, height, weight, BMI, mutation status of the IL36RN, CARD14 and 
AP1S3, disease characteristics for current flare, time since first diagnosis. 
Age [years] will be determined as the difference between year of birth and year of informed 
consent. BMI will be calculated as weight [kg] / height [m]2
Medical History for GPP includes mutation status (IL36RN, CARD14 and AP1S3), as well as 
the details, if any, on the presence of chronic plaque psoriasis or chronic erythrodermic 
psoriasis will be summarized. The method by which diagnosis of GPP was confirmed is also 
collected.
Disease characteristics will include details on current flare.
Time since first diagnosis [years] will be calculated as the difference between date of first 
diagnosis and date of informed consent, divided by 365.25.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant diseases (i.e. baseline conditions) and concomitant non-drug therapies will be 
coded according to the most recent version of MedDRA. Concomitant medications will be 
coded according to the most recent version of the World Health Organisation – Drug 
Dictionary.
A medication/non-drug therapy will be considered concomitant to treatment, if it
∀
is ongoing at the start of that treatment period or
∀
starts within that treatment period (see Section 6.1 for the definition).
A medication/non-drug therapy will be considered as prior medication/non-drug therapy, if 
the end date of the medication/therapy is at any time prior to the start of that treatment period.
Concomitant medication use will be summarized with frequency and percentage of patients 
by Anatomical Therapeutic Chemical 3 (ATC3) class and preferred name. 
Concomitant use of non-drug therapies will be summarised with frequency and percentage. 
Historical medication for GPP will be summarised with frequency and percentage of patients, 
including presentation by type of historical medication (preferred name), and by reason for 
discontinuation.
7.3
TREATMENT COMPLIANCE
Not applicable.
7.4
PRIMARY ENDPOINT(S)
Refer to section 7.8.1 for the description of adverse events including the primary endpoint.
7.5
SECONDARY ENDPOINT(S)
Refer to section 7.8.1 for the description of adverse events including the secondary endpoint.
7.7
EXTENT OF EXPOSURE
Treatment exposure is defined as the total dose of randomized spesolimab [mg] received per 
patient. In general, the total dose of spesolimab [mg] received per 
 is calculated as the 




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The primary endpoint of occurrence of treatment emergent adverse events (TEAE), will be 
analysed as the exposure-adjusted adverse event incidence rates in all flare treatment period 
based on TS by using per patient analysis for TEAE.
Per patient analysis for TEAE
1) The exposure adjusted incidence rate (per 100 patient years) of a selected treatment 
emergent adverse event is defined as the number of patients experiencing the adverse 
event per treatment group during time at risk divided by the total time of patients at 
risk in that treatment group to contribute the event to the analysis multiplied by 100 
(per 100 patient years).
Time at risk [patient years] = (date of onset of AE– first treatment start date within 
that treatment period + 1) / 365.25
For all flare treatment period on a patient level, each flare treatment period is 
combined with the previous flare treatment period as defined in Section 6.1.
2) If, for a patient, the selected treatment emergent adverse event didn’t occur during the 
above defined treatment period (per Section 6.1) then the time at risk will be censored 
at the earliest of date of death, last contact date per EoS page, or the end of the above 
defined treatment period. 
For each selected treatment emergent AE, the exposure adjusted incidence rate will be 
calculated as:
Incidence rate [1/100 Patient years (pt-yrs)] = 100 * number of patients with TEAE / 
Total TEAE-specific time at risk [patient years].
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
exposure adjusted incidence rates (per 100 patient years or per 100 flare treatment period 
years), as well as the number of patients with AEs and the number of flare treatment periods 
with AEs. System organ classes (SOCs) (if applicable) will be sorted according to the 
standard sort order specified by the European Medicines Agency (EMA), preferred terms 
(PTs) (if applicable) will be sorted by total frequency (within SOC).
For further details on summarization of AE data, please refer to "Handling and summarization 
of adverse event data for clinical trial reports and integrated summaries" (3) and "Handling of 
missing and incomplete AE dates" (4).
An overall summary of AEs will be described in all flare treatment period based on TS by per 
patient analysis. The exposure-adjusted incidence rate and frequency will be summarized by 
treatment, primary SOC and PT for the following AEs: drug-related AEs considered by the 
investigator, AEs leading to treatment discontinuation, other significant AEs, SAEs, drug-
related SAEs, AESIs, and user-defined adverse event categories (UDAEC) and serious 
UDAEC (cf. Table 7.8.1: 1). AEs will also be summarized by the maximum intensity.


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According to ICH E3 (5), the sponsor has defined AEs which are to be classified as ‘other 
significant’. For the current trial, these will include those non-serious AEs which were 
reported with ‘action taken = Drug Withdrawn’ or ‘action taken = Dose Reduced’.
The following are considered as AESIs (see Sec 5.2.4.1.4 of CTP):
∀
Potential Severe Drug Induced Liver Injury (DILI )
∀
Systemic hypersensitivity reactions including 
 reactions and anaphylactic 
reaction
∀
Severe infections (according to RCTC grading in the ISF)
∀
Opportunistic and mycobacterium tuberculosis infections
∀
Peripheral neuropathy
The investigator identified AESI will be captured from the eCRF and reported as 
“Investigator reported AESI” table. In addition, user defined adverse event concepts 
(UDAEC) identified through specific search criteria will be reported separately (Table 7.8.1: 
1).
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious
AEs occurring with an incidence of greater than 5% (in preferred terms) will be summarized
by treatment, primary system organ class and preferred term. The frequency of subjects with
SAEs will also be summarized.


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Table 7.8.1: 1 Project MedDRA search criteria for User Defined Adverse Event Categories
User-defined AE category
Label
Description
Infections (serious/severe, 
opportunistic)
Infections ALL
Combined search strategy based on the individual 
UDAECs described below; the UDAEC “severe 
infections (investigator-defined) will be disregarded 
for this search
Opportunistic 
infections
Narrow SMQ “Opportunistic infections”
Tuberculosis 
infections
BIcMQ “Infections”: 
Narrow sub-search 8.2 “Tuberculosis related terms”
Serious infections
all serious events in SOC “Infections and 
infestations”
Severe infections
all events in SOC “Infections and infestations” of at 
least severe RCTC grade, by HLGT
Hypersensitivity
Hypersensitivity ALL
Combined search strategy based on the individual 
UDAECs described below
Anaphylactic reaction
Narrow SMQ “Anaphylactic reaction”
Angioedema
Narrow SMQ “Angioedema”
Hypersensitivity
Narrow SMQ “Hypersensitivity”
DRESS, algorithmic
Based on broad SMQ “Drug reaction with 
eosinophilia and systemic symptoms” (SMQ code 
20000225), defined using algorithm as follows:
A or (B and C and D) or (B and C and E) or (B and 
D and E)
where the categories A, B, C, D and E are defined
categorisations of the PTs of the SMQ. For PTs of 
category A only narrow scope is used, for all other 
categories broad scope is used.
For identification of potential DRESS through the
combination of adverse event occurrences within 
each of the categories B, C, D and E, adverse event 
start and end dates will be used. For the latter, 
potential DRESS is then identified if, within a 7-
day period after occurrence of a relevant 
contributing event (assessed on each day between 
start and end date [inclusive] of the initiating 
event), there is at least one adverse event reported 
(based on start date only) from each of the other 
applicable categories within a specific combination 
of categories as described above (in
parentheses).
If the end date is missing, the event is considered to 
be ongoing, and end date will be the last day of the 
applicable treatment period
DRESS, narrow
Narrow SMQ “Drug reaction with eosinophilia and 
systemic symptoms”, any event within category A 
only


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Malignancies
Malignant tumours
Narrow Sub-SMQ “Malignant tumours”
Narrow Sub-SMQ “Haematological malignant 
tumours”
Narrow Sub-SMQ “Non-Haematological malignant 
tumours”
Malignant skin 
tumours
Broad Sub-SMQ “Skin malignant tumours”
Skin melanomas
HLT Skin melanomas (excl. Ocular)
Non-melanoma skin 
cancer (NMSC)
Broad Sub-SMQ “Skin malignant tumours” 
excluding HLT Skin melanomas (excl. Ocular)
Malignancies 
excluding NMSC
Sub-SMQ “Malignant tumours” excluding
NMSC, whereas NMSC is defined above
3-point MACE
3-point MACE
BIcMQ “Major Adverse Cardiovascular Events” 
with
Narrow sub-search 1.1 “3-Point MACE (part 1/2)”
Narrow sub-search 1.2 “3-Point MACE (part 2/2)”*
Torsades de Pointes
Torsades de Pointes
Broad sub-SMQ “Torsade de pointes/QT 
prolongation”
Peripheral neuropathy
Peripheral neuropathy
Narrow SMQ "Demyelination”
Narrow SMQ "Guillain-Barre syndrome" 
Narrow SMQ "Peripheral neuropathy”
*this is achieved by retrieving all cases found either by running subsearch 1 in narrow scope (BIcMQ 
search ID 32019093 ) or subsearch 2 (BIcMQ serach ID 32019094
7.8.2
Laboratory data
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by investigator, and will be 
analyzed as such.
7.8.3
Vital signs
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analyzed as such.
7.8.4
ECG
Abnormal findings in 12-lead ECG will be reported as baseline conditions (at screening) or as 
AEs (during the trial) if judged clinically relevant by investigator, and will be analyzed as 
such. No separate listing or analysis of ECG data will be prepared.
7.8.5
Others
Local Tolerability will be summarized at Day 1 and Day 8, with the frequency and percentage 
of patients/flare treatment periods who experienced any reaction presented by symptom and 
severity of reaction. 


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database at trial initiation.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: Identify and Manage Important Protocol Deviations (iPD)”, current 
version, Group “Clinical Operations”, IDEA for CON.
3.
KM Asset BI-KMED-BDS-HTG-0041: "Handling and Summarization of Adverse Event 
Data for Clinical Trial Reports and Integrated Summaries", current version, KMED.
4.
KM Asset BI-KMED-BDS-HTG-0035: "Handling of Missing and Incomplete AE 
Dates", current version, KMED.
5.
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports,
current version, EMA webpage.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1 
06-Dec-22
None
This is the final TSAP 
2
17-Aug-23
Section 
3
Added clarifications of this TSAP.
Section 
7
Updated disposition to remove trial 
medication.
Section 
7.8.1
Added AE for disclosure and revised 
AE analyses to focus on per patient 
analysis.